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WO2024183778A1 - Methionine adenosyltransferase 2a inhibitor and medical use thereof - Google Patents

Methionine adenosyltransferase 2a inhibitor and medical use thereof Download PDF

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Publication number
WO2024183778A1
WO2024183778A1 PCT/CN2024/080417 CN2024080417W WO2024183778A1 WO 2024183778 A1 WO2024183778 A1 WO 2024183778A1 CN 2024080417 W CN2024080417 W CN 2024080417W WO 2024183778 A1 WO2024183778 A1 WO 2024183778A1
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Prior art keywords
alkyl
independently selected
membered
cycloalkyl
haloalkyl
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PCT/CN2024/080417
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French (fr)
Chinese (zh)
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吴景卫
尹磊
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甘李药业股份有限公司
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Publication of WO2024183778A1 publication Critical patent/WO2024183778A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention belongs to the technical field of drug synthesis, and relates to a methionine adenosyltransferase 2A inhibitor, a drug composition containing the inhibitor and pharmaceutical use thereof, in particular to the application of the inhibitor in the preparation of anti-tumor drugs.
  • Methionine adenosyltransferase also known as S-adenosylmethionine synthetase
  • SAM S-adenosylmethionine
  • ATP ATP-adenosylmethionine
  • SAM S-adenosylmethionine
  • ATP ATP-adenosylmethionine
  • SAM is the main methyl donor for the synthesis of polyamines and glutathione. Therefore, regulating the biosynthesis of SAM can affect cell growth, differentiation and function. Studies have shown that the proliferation and metastasis of tumor cells are abnormally dependent on methionine, and inhibiting the methionine cycle can significantly inhibit the proliferation and metastasis of stem cells.
  • MAT1 In mammalian tissues, the MAT gene mainly exists in two different isoenzymes, encoded by MAT1 and MAT2.
  • MAT1 is only expressed in the liver and is used to maintain the differentiation state of hepatocytes and bile duct epithelial cells;
  • MAT2 is commonly expressed in normal cells and cancer cells.
  • MAT2 contains two subunits, MAT2A and MAT2B, which serve as catalytic subunits and regulatory subunits, respectively.
  • MAT2A is a key enzyme in the SAM synthesis pathway. Studies have shown that upregulated expression of MAT2A exists in a variety of cancer cells, and knocking out the MAT2A gene can lead to the death of cancer cells. Therefore, MAT2A is an anti-tumor target.
  • MAT2A is a synthetic lethal target in methylthioadenosine phosphorylase (MTAP)-deficient cancers.
  • MTAP methylthioadenosine phosphorylase
  • MTA methylthioadenosine phosphorylase
  • MTA 5-methylthioadenosine-1-phosphate
  • MTAP deletion is not only present in tissue culture cells, but also in primary leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma and mesothelioma.
  • NSCLC non-small cell lung cancer
  • MTAP is a key enzyme in the methionine recycling pathway and is the only enzyme known to catalyze the degradation of MTA. The loss of MTAP is believed to lead to the accumulation of MTA in cancer cells.
  • MTA inhibits the activity of protein arginine methyltransferase 5 and increases the sensitivity of PRMT5 to further loss of SAM.
  • selective inhibition of MAT2A can reduce the proliferation activity of MTAP-deficient cancer cells.
  • the present invention provides a methionine adenosyltransferase 2A (MAT2A) inhibitor and a pharmaceutically acceptable salt thereof. Also disclosed herein are pharmaceutical compositions comprising such compounds and methods for treating diseases that can be treated by inhibiting MAT2A, such as cancer, including cancers characterized by reduced or inactive methylthioadenosine phosphorylase (MTAP) activity.
  • MAT2A methionine adenosyltransferase 2A
  • MTAP methylthioadenosine phosphorylase
  • a compound is provided, wherein the compound is a compound represented by formula (I-1), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:
  • a 1 and B 1 are independently selected from the group consisting of formula (II), (III), (IV), (V), (VI), (VII) and (VIII):
  • R 1 is absent at each occurrence or is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, -SC 1-6 alkyl, -S(O)-C 1-6 alkyl, -S(O 2 )-C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, C 1-6 deuterated alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and -NR 1a R 1b , wherein R 1a and R 1b are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 1-6 containing 1-3 heteroatoms independently selected from N, O, P and S R 1a and R 1
  • Each occurrence of Z is independently selected from C and N; when Z is selected from N, R 1 is absent;
  • R 2 , R 4 and R 6 are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 haloalkylamino, hydroxy, C 2-6 alkoxy, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
  • G1 and G2 are each independently selected from O, S, and NR2a ;
  • E0 , E1 , E2 , E3, E4 , E5 , E6 , E7 , E8 , E9 , M1 , M2 , M3 , M4 , M5 , M6 and E are each independently selected from N and CR2a , and E7 , E8 , and E9 are not CR2a at the same time;
  • R2a at each occurrence is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, phenylmethylene, -CH2OCH2CH2Si ( CH3 ) 3 , C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-S-, -S(O) -C1-6 alkyl, -SO2 - C1-6 alkyl, -OC1-6 alkyl, -OC1-6 haloalkyl, -NR2bR2c , -C(O)R8c, -C(O)NR8aR8b, -C1-6 alkylene -C3-6 cycloalkyl, C3-6 cycloalkyl-NR2b-, 3-6 membered heterocycloalkyl-NR2b containing 1-3 heteroatoms independently selected from N , O , P and S -, 3-12 membered monocycloalkyl, 5-12 membered
  • R 2b and R 2c are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl , C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl R 2b and R 2c and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl containing 1, 2 , 3 or 4 heteroatoms independently selected from N, O, P and S , wherein the heterocycloalkyl is optionally substituted with 0,
  • R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl , C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl R 8a and R 8b and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted with 0, 1, 2
  • R 8c is independently selected at each occurrence from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl R 5-10 heteroaryl is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloal
  • X2 is selected from C1-6 alkylene and C2-6 alkenylene
  • R 8d is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl
  • J 1 and J 2 are independently selected from a single bond, O, S, C(O), S(O), S(O 2 ), C(R 1c R 1d ), C( ⁇ CR 1e R 1f ) and N(R 3 ), preferably, J 1 and J 2 are not single bonds at the same time;
  • R 1c , R 1d , R 1e and R 1f are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl, and C 5-10 heteroaryl are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic,
  • Linker C is the linker connecting A1 and B1, which is -L a -L b -L c -L d -L e -;
  • L a , L c , and L e at each occurrence are each independently selected from -(L) n -;
  • n is selected from 1, 2, 3, 4, 5 and 6;
  • L is independently selected at each occurrence from a single bond, -O-, -S-, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 haloalkylene, -N(R L6 )C(O)-, -N(R L6 )S(O)-, -N(R L6 )S(O 2 )-, -C(O)-, -OC(O)-, -NR L6 -, -S(O)-, -S(O 2 )-, -S(O 2 )NR L6 -, -CR L1 R L2 -, and C 1-6 alkylenehydroxyl, optionally wherein the C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, and C 1-6 haloalkylene
  • the 1-6 haloalkylene groups are each independently substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from
  • R L6 is independently selected at each occurrence from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl
  • the 5-10 heteroaryl group is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered
  • R L1 and R L2 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, -XL - OR L3 , -XL - NR L4LR L5 , C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, preferably R L1 and R L2 are each independently selected from hydrogen , deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -XL - OR L3 , -XL- NR L4LR L5 and C 3-10 cycloalkyl; or R L1 and R L2 and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered
  • XL at each occurrence is independently selected from C1-6 alkylene and C2 - C6 alkenylene;
  • RL3 is selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl
  • RL4 and RL5 are independently selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl;
  • L b , and L d are each independently selected from a single bond, a cycloalkylene group, a cycloalkenylene group, a heterocycloalkylene group, an arylene group, a heteroarylene group, and a fused heterocycloalkylene group, wherein the cycloalkylene group, the cycloalkenylene group, the heterocycloalkylene group, the arylene group, the heteroarylene group, and the fused heterocycloalkylene group may be optionally substituted with 0, 1, 2, 3, 4, 5 or 6 R 9 ; preferably, L b , L d d is independently selected from a single bond, phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 member
  • R 9 is independently selected from halogen, deuterium, alkyl, haloalkyl, cyano, cycloalkyl, heterocycloalkyl, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; preferably, R 9 is independently selected from halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, C 3 - 7 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; preferably, R 9 is independently selected from F, Cl, Br, I, C 1-6 C 1-3 alkyl, and
  • R 9a , R 9b and R 9c are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl; preferably, R 9a , R 9b and R 9c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene
  • L b and L d are each independently a phenylene group, or a 5-membered heteroarylene group containing 1 or 2 heteroatoms selected from N and S, at least one of La and Le is not a single bond, or when La and Le are both single bonds, L c is selected from -S-, C 2-6 alkylene, C 2-6 alkyleneoxy, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 haloalkylene, -N(R L6 )S(O)-, -N(R L6 )S(O 2 )-, -OC(O)-, -S(O)-, -S(O 2 )-, -S(O 2 )NR L6 -, - and C 1-6 alkylenehydroxyl, optionally, the C 2-6 alkylene, C 2-6 alkyleneoxy, C 2-6 alkenylene, C 2-6 alkynylene, and C 1-6 haloalkylene 1-6 hal
  • Linker C is an aliphatic chain
  • Linker C is optionally substituted -C 8 H 16 -, preferably optionally substituted -(CH 2 ) 8 -, preferably -(CH 2 ) 8 -;
  • L b and L d are not simultaneously single bonds;
  • Linker C is selected from Formula (IX), (X), (XI) and (XII):
  • R 7a and R 7b are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl;
  • X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence;
  • R 7c is selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are connected form a 3-10 membered cycloalkyl;
  • R 7a and R 7b are each independently selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, -XL - OR L3 , -XL - NR L4LR L5 , C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, preferably R L1 and R L2 are each independently selected from hydrogen , deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -XL - OR L3 , -XL- NR L4LR L5 and C 3-10 cycloalkyl; or R 7a and R R 7a and R 7b and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkylene or a
  • XL at each occurrence is independently selected from C1-6 alkylene and C2 - C6 alkenylene;
  • RL3 is selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl
  • RL4 and RL5 are independently selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl;
  • W is selected from the following groups:
  • Q ring and R ring are each independently selected at each occurrence from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene, said phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene optionally substituted with 0-6 R 9 ;
  • R 9a , R 9b and R 9c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene
  • T ring and U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene at each occurrence, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 0, 1, 2 or 3 substituents independently selected from cyano, halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, C 3-6 heterocycloalkyl, and C 3-6 cycloalkyl, preferably, optionally substituted with substituents selected from F, Cl, Br, I, C 1-3 alkyl, and C 1-3 haloalkyl;
  • L1 is selected from the following groups:
  • L2 is selected from the following groups:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are each independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 —, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH ⁇ CH—, —C ⁇ C—, and a single bond;
  • L3 is selected from the following groups:
  • Y 8 , Y 9 , Y 10 , Y 11 and Y 12 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CR Y1 RY2 -, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH ⁇ CH—, —C ⁇ C-, a single bond, phenylene, a 3-6 membered heterocycloalkylene group containing 1-4 heteroatoms independently selected from N, O, P and S, and a 5-6 membered heteroarylene group containing 1-4 heteroatoms independently selected from N, O, P and S;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1-6 alkyl at each occurrence, or R Y1 and R Y2 form a 3-6 membered cycloalkylene or 3-6 membered heterocycloalkylene to the C to which they are attached; and f, g, h, i and j are independently selected from 0, 1, 2 and 3. 3.
  • R 1 is absent at each occurrence or is independently selected from hydrogen, deuterium, F, Cl, Br, I, cyano, hydroxyl, amide, sulfonamide, C 1-3 alkyl, -SC 1-3 alkyl, -S(O)-C 1-3 alkyl, -S(O 2 )-C 1-3 alkyl, -OC 1-3 alkyl, -OC 1-3 haloalkyl, C 1-3 deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and -NR 1a R 1b , wherein R 1a and R 1b are independently selected from hydrogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 deuterated alkyl
  • the present invention relates to a C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C3-6 monocyclic cycloalkyl, C3-6 mono
  • Z is independently selected from C and N at each occurrence; and when Z is N, R 1 is absent; and/or
  • R 2 , R 4 and R 6 are each independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 2-3 alkoxy, C 1-3 haloalkyl, 3-6 membered monocyclic cycloalkyl, 3-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, and 3-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R 2 , R 4 and R 6 are each independently selected from hydrogen, deuterium, chlorine, fluorine, Br, C 1-3 alkyl, 3-6 membered monocyclic cycloalkyl, and 3-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S; and/or
  • R 5 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl and C 1-4 haloalkyl; optionally, the C 1-4 alkyl, C 3-6 cycloalkyl and C 1-4 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, C 1-4 alkyl, amino, hydroxyl and C 1-4 alkoxy; preferably, R 5 is selected from hydrogen, C 1-3 alkyl and C 3-6 cycloalkyl, optionally, the C 1-3 alkyl and C 3-6 cycloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, C 1-6 alkyl, amino and hydroxyl; more preferably, R 5 is selected from H and C 1-3 alkyl; and/or
  • G1 and G2 are each selected from O, S, and NR2a ; and/or
  • R 2a at each occurrence is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, phenylmethylene, -CH 2 OCH 2 CH 2 Si(CH 3 ) 3 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-S-, -S(O)-C 1-3 alkyl, -SO 2 -C 1-3 alkyl, -OC 1-3 alkyl, -OC 1-3 haloalkyl, -NR 2b R 2c , -C 1-3 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl-NR 2b -, 3-6 membered heterocycloalkyl-NR 2b containing 1-3 heteroatoms independently selected from N, O, P and S -, 3-6 membered monocyclic alkyl, 3-6 membered monocyclic heterocyclic alkyl containing 1-3 heteroatoms independently selected
  • R 3 is -X 1 -R 8 , X 1 is selected from a single bond, -O-, -S-, C 1-3 alkyleneoxy, C 2-3 alkenylene and C 1-3 alkylene;
  • R 8 is selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b , C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, and 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S.
  • each occurrence of the Q ring, the R ring, L b and L d is independently selected from the following groups:
  • the compound is selected from the following structures:
  • the compound is selected from the following structures:
  • Linker C is selected from the following structures:
  • a compound, wherein the compound is a compound represented by formula (I), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:
  • ring A and ring B are independently selected from formula (II), (III) and (IV):
  • Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI) and (VII):
  • R 1a , R 1b , R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl and alkoxy; or R 1a and R R 1c and R 1d and the nitrogen atom to which they are commonly attached form a 3-10
  • R2 , R4 and R6 are independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 monoalkylamino, C2-6 dialkylamino, C1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1-6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
  • E, G, J and Z are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -, C 1-6 alkyl-O-, C 1-6 haloalkyl-O-, -NR 2b R 2c , C 3-6 -membered cycloalkylamino, 3-6-membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12-membered monocyclic alkyl, 5-12-membered spirocycloalkyl and 4-12-membered bridged cycloalkyl, 3-12-membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently
  • R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl;
  • X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence;
  • R 7c is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 7d and R 7e are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are connected form a 3-10 membered cycloalkyl;
  • the R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , R 10 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c , -X 5 -NR 10b R 10c , -OR 10a and -X 5 -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 5 is selected from C 5 C 1-6 alkylene and C 2-6 alkeny
  • L1 is selected from the following groups:
  • L2 is selected from the following groups:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 -, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH ⁇ CH—, —C ⁇ C—, and a single bond, wherein the hydrogen atom is optionally substituted with 0-2 substituents independently selected from deuterium, halogen, amino, alkylamino, aminoalkyl, hydroxy, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, and C 3-6 cycloalkyl;
  • R 11 are independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O 2 )R 11a , NR 11b R 11c , -X 6 -NR 11b R 11c , -OR 11a and -X 6 -OR 11a ; R 11a , R 11b and R 11c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 6 is selected from C 1-6 alkylene and C 2-6 alkenylene.
  • R 1a and R 1b are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
  • R2 , R4 and R6 are independently selected from halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 monoalkylamino, C1-3 dialkylamino, C1-3 haloalkylamino, cycloalkyl containing 3-12 membered monocyclic ring, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1 - C6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5
  • R5 is selected from hydrogen, C1-3 alkyl and C1-3 haloalkyl
  • E, G, J and Z are independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-S-, C 1 -C 3 alkyl-SO-, C 1-3 alkyl-SO 2 -, C 1-3 alkyl-O-, C 1-3 haloalkyl-O-, -NR 2b R 2c , C 3-6 membered cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membere
  • R3 is -X1 - R8 , X1 is selected from a chemical bond, C2 - C4 alkenylene and C1 - C4 alkylene;
  • R8 is selected from hydrogen, halogen, C1 - C3 alkyl, C1 - C3 haloalkyl, C6 - C10 aryl, -NR8aR8b , -C(O) R8c , -C(O) NR8aR8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S;
  • R8a and R8b are independently selected from hydrogen, deuterium, C1 - C3 alkyl, C1 - C3 haloalkyl and phenyl at each occurrence , the phenyl being optionally substituted with 0-2 groups selected from C1-4 alkyl, -OR8d and -X2 - R8d ;
  • R8c
  • R 1c and R 1d are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
  • R 7a and R 7b are each independently selected from hydrogen, halogen, C 1-4 alkyl and C 1-4 haloalkyl; or
  • the Q ring is optionally substituted with 1-2 R 9 , each of which is independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms, each of which is independently selected from N, O and S, -S(O 2 )R 9a , NR 9b R 9c and -OR 9a ; each of R 9a , R 9b and R 9c is independently selected from hydrogen, C 1-3 alkyl and C 1-3 haloalkyl at each occurrence; or
  • the R ring is a 5-6 membered heterocycloalkylene or 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , R 10 is independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c and -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl at each occurrence; or
  • the T ring and the U ring are independently selected from phenylene and pyridinylene, respectively, wherein the phenylene and pyridinylene are optionally substituted by 1-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C1-6 alkyl and C3-6 cycloalkyl.
  • R2 is selected from hydrogen, fluorine, chlorine, cyclopropyl, C1-3 alkyl and C1-3 haloalkyl; or
  • R3 is hydrogen
  • R 4 is selected from hydrogen, fluorine, chlorine, bromine and cyclopropyl
  • R6 is selected from hydrogen, fluorine, chlorine and cyclopropyl
  • R5 is selected from hydrogen and methyl
  • R 1c and R 1d are independently selected from hydrogen and C 1 -C 3 alkyl; preferably, R 1c and R 1d are independently selected from hydrogen and methyl; or
  • the Q ring is selected from the following groups:
  • the R ring is selected from the following groups:
  • each R ring group is independently connected to the Q ring in formula (V), and the left connecting site of each R ring group is independently connected to the A ring or the B ring in formula I.
  • the Q ring, R ring, T ring, U ring, W ring, R 1a , R 1b , R 1c , R 1d , R 7a , R 7b , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in claim 1 , 2 or 3.
  • Ring A and Ring B are each independently selected from Formula (II-1), (IV-1) and (III-1):
  • R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 4 , R 5 and R 6 have the same definitions as in claim 1 , 2 or 3.
  • Qa ring is consistent with the definition of Q ring in claim 1, 2 or 3;
  • Ra ring is consistent with the definition of R ring in claim 1, 2 or 3;
  • R1a , R1b , R1c , R1d , R7a , R7b , E, G, J, Z, L2 , R2 and R6 are defined the same as in claim 1, 2 or 3.
  • ring A and ring B are the same or different, and ring A and ring B are independently selected from formula (II), (III) and (IV):
  • Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI), (VI-2) and (VII):
  • R 1a , R 1b , R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyalkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl and alkoxy; or R
  • R 2 , R 4 and R 6 are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 haloalkylamino , 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
  • E, G, J and Z are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, --NHCO-C 1-6 alkyl, -COHN 2 , -C 1-6 alkyl-COHN 2 , sulfonamido, -NHCONH 2 , -NH-CS-NH 2 , amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -, C 1-6 alkyl-O-, C 1-6 haloalkyl-O-, -NR 2b R 2c , C 1-6 alkylamino, C 2-6 dialkylamino, -CONH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 3-6 cycloalkylamin
  • R 3 is -X 1 -R 8 , X 1 is selected from a chemical bond, -O-, -S-, alkoxy, C 2-6 alkenylene and C 1-6 alkylene;
  • R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S;
  • R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, and the phenyl is optionally substituted with 0-2 groups selected from C 1-4 alkyl, halogen, hydroxy, cyano, amino, -OR 8d and -X 2 -R 8d ;
  • R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl;
  • X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence;
  • R 7c is selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are attached form a 3-10 membered cycloalkyl;
  • W is selected from the following groups:
  • the Q ring is selected from 5-6 membered heterocycloalkylene and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and said heteroarylene are optionally substituted by 0-2 R 9 , R 9 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; R 9a , R 9b and R 9c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
  • the R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , R 10 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c , -X 5 -NR 10b R 10c , -OR 10a and -X 5 -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 5 is selected from C 5 C 1-6 alkylene and C 2-6 alkeny
  • the T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 1-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl and C 3-6 cycloalkyl;
  • L1 is selected from the following groups:
  • L2 is selected from the following groups:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 —, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH ⁇ CH—, —C ⁇ C—, and a single bond, wherein the hydrogen atoms in said L 2 are each independently substituted with any substituent selected from deuterium, halogen, amino, alkylamino, aminoalkyl, —CONH 2 , —NHCO—C 1-6 alkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, and C 3-6 cycloalkyl;
  • a is an integer from 0 to 5; b and c are integers from 0 to 3; d and e are integers from 0 to 2; and
  • R11 are independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, cyano, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O2)R11a, NR11bR11c, -X6- NR11bR11c , -OR11a and -X6-OR11a;
  • R11a, R11b and R11c are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, cyano, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O2)R11a, NR11bR11c , -X6 - NR11bR11c , -OR11a and -X6 - OR11a ;
  • R 1a and R 1b are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
  • R2 , R4 and R6 are independently selected from halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, -NHC1-3 alkyl, -N( C1-3 alkyl) C1-3 alkyl, C1-3 haloalkylamino, cycloalkyl containing 3-12 membered monocyclic ring, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1 - C6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered
  • R5 is selected from hydrogen, C1-3 alkyl and C1-3 haloalkyl
  • E, G, J and Z are independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -NHCO-C 1-6 alkyl, -CONH 2 , -C 1-6 alkyl-CONH 2 , sulfonamido, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-S-, C 1 -C 3 alkyl-SO-, C 1-3 alkyl-SO 2 -, C 1-3 alkyl-O-, C 1-3 haloalkyl-O-, -NR 2b R 2c , C 3-6 membered cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated heterocycloalkyl containing 1-3 hetero
  • R3 is -X1 - R8 , X1 is selected from a chemical bond, C2 - C4 alkenylene and C1 - C4 alkylene;
  • R8 is selected from hydrogen, halogen, C1 - C3 alkyl, C1 - C3 haloalkyl, C6 - C10 aryl, -NR8aR8b , -C(O) R8c , -C(O) NR8aR8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S;
  • R8a and R8b are independently selected from hydrogen, deuterium, C1 - C3 alkyl, C1 - C3 haloalkyl and phenyl at each occurrence , the phenyl being optionally substituted with 0-2 groups selected from C1-4 alkyl, -OR8d and -X2 - R8d ;
  • R8c
  • R 1c and R 1d are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
  • R 7a and R 7b are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl and C 1-4 haloalkyl; or
  • the Q ring is optionally substituted with 1-2 R 9 , each of which is independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms, each of which is independently selected from N, O and S, -S(O 2 )R 9a , NR 9b R 9c and -OR 9a ; each of R 9a , R 9b and R 9c is independently selected from hydrogen, deuterium, C 1-3 alkyl and C 1-3 haloalkyl at each occurrence; or
  • the R ring is a 5-6 membered heterocycloalkylene or 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R10 , each occurrence of which is independently selected from halogen, C 1 -C 3 alkyl, hydroxy, amino, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c and -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, deuterium, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl at each occurrence; or
  • the T ring and the U ring are independently selected from a 5-6 membered heterocyclylene group containing 1, 2, or 3 N, O, or S atoms, a phenylene group, and a pyridylene group, wherein the phenylene group and the pyridylene group are optionally substituted by 1 to 3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, cyano, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, and C 3-6 cycloalkyl.
  • R3 is hydrogen
  • R6 is selected from hydrogen, fluorine, chlorine and cyclopropyl
  • R5 is selected from hydrogen and methyl
  • R 1c and R 1d are independently selected from hydrogen and C 1 -C 3 alkyl; preferably, R 1c and R 1d are independently selected from hydrogen and methyl; or
  • the Q ring is selected from the following groups:
  • connection site on the left side of each Q ring group is independently connected to -CR 7a R 7b - in formula (V), and the connection site on the right side of each Q ring group is independently connected to the R ring in formula (V); or
  • the R ring is selected from the following groups:
  • each R ring group is independently connected to the Q ring in formula (V), and the left connecting site of each R ring group is independently connected to the A ring or the B ring in formula I.
  • Q ring, R ring, T ring, U ring, L 1 , L 2 , W, R 1a , R 1b , R 1c , R 1d , R 7a , R 7b , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in claim 2 , 3 or 4.
  • R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 4 , R 5 and R 6 have the same definitions as in claim 1 or 2 or 3 or 4;
  • the A ring and the B ring are identical.
  • Qa ring is consistent with the definition of Q ring in claim 2, 3 or 4;
  • Ra ring is consistent with the definition of R ring in claim 2, 3 or 4;
  • R1a , R1b , R1c , R1d , R7a , R7b , E, G, J, Z, L2 , R2 and R6 are defined the same as in claim 1, 2, 3 or 4.
  • the compound is a compound represented by formula (I), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:
  • ring A and ring B are independently selected from formula (II), (III) and (IV):
  • Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI) and (VII):
  • R 1a , R 1b , R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl and alkoxy; or R 1a and R R 1c and R 1d and the nitrogen atom to which they are commonly attached form a 3-10
  • R2 , R4 and R6 are independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 monoalkylamino, C2-6 dialkylamino, C1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1-6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
  • E, G, J and Z are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -, C 1-6 alkyl-O-, C 1-6 haloalkyl-O-, -NR 2b R 2c , C 3-6 -membered cycloalkylamino, 3-6-membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12-membered monocyclic alkyl, 5-12-membered spirocycloalkyl and 4-12-membered bridged cycloalkyl, 3-12-membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently
  • R 3 is -X 1 -R 8 , X 1 is selected from a chemical bond, C 2-6 alkenylene and C 1-6 alkylene;
  • R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S;
  • R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, the phenyl being optionally substituted with 0-2 groups selected from C 1-4 alkyl, -OR 8d and -X 2 -R 8d ;
  • R 8c is selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 amino
  • R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl;
  • X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence;
  • R 7c is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 7d and R 7e are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are connected form a 3-10 membered cycloalkyl;
  • the W ring is selected from the following groups:
  • the Q ring is selected from 5-6 membered heterocycloalkylene and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and said heteroarylene are optionally substituted by 0-2 R 9 , R 9 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; R 9a , R 9b and R 9c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
  • the R ring is a 5-6 membered heterocycloalkylene or 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , each occurrence of which is independently R 10a , R 10b and R 10c are each independently selected from the group consisting of hydrogen , C 1-6 alkyl and C 1-6 haloalkyl ; X 5 is selected from the group consisting of C 1-6 alkylene and C 2-6 alkenylene ;
  • the T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 1-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl and C 3-6 cycloalkyl;
  • L1 is selected from the following groups:
  • L2 is selected from the following groups:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 -, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH ⁇ CH—, —C ⁇ C—, and a single bond, wherein the hydrogen atom is optionally substituted with 0-2 substituents independently selected from deuterium, halogen, amino, alkylamino, aminoalkyl, hydroxy, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, and C 3-6 cycloalkyl;
  • a is an integer from 0 to 5; b and c are integers from 0 to 3; d and e are integers from 0 to 2; and
  • R 11 are independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O 2 )R 11a , NR 11b R 11c , -X 6 -NR 11b R 11c , -OR 11a and -X 6 -OR 11a ; R 11a , R 11b and R 11c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 6 is selected from C 1-6 alkylene and C 2-6 alkenylene.
  • Ring A and Ring B are independently selected from Formula (II), (III), (IV), (V), (VI), (VII) and (VIII):
  • Linker C is a linker connecting Ring A and Ring B, selected from Formula (IX), (X), (XI) and (XII):
  • R 1 is selected from the group consisting of absence, hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, C 1-6 haloalkyl, -SC 1-6 alkyl, -S(O)-C 1-6 alkyl, -S(O 2 )-C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, C 1-6 deuterated alkyl and -NR 1a R 1b , wherein R 1a and R 1b are independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N,
  • R 1a and R 1b and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, hydroxy, alkylamino, aminoalkyl, and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, hydroxy , alkylamino , aminoalkyl, and alkoxy. Substituted with 1-6 deuterated alkyl, cyano, C 1-6 aminoalkyl and hydroxyl;
  • Z is selected from C and N; when Z is selected from N, R 1 is absent;
  • R2 , R4 and R6 are independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl , C1-6 alkoxy, C1-6 haloalkyl, -NHC1-6 alkyl, -N( C1-6 alkyl) C1-6 alkyl, C1-6 haloalkoxy, C1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, -SC1-6 alkyl
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
  • G1 and G2 are selected from O, S, and NR2a ;
  • M 1-6 and E are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl -S-, -SO-C 1-6 alkyl, -SO 2 -C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, -NR 2b R 2c , -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, -C(O)R 8c , -C(O)NR 8a R 8b , -C 1-6 alkylene-C 1-6 cycloalkyl, C 3-6 -membered cycloalkylamino, 3-6-membered heterocycloalkylamino containing 1-3 heteroatoms
  • J1 and J2 are independently selected from a single bond, O, S, C(O), S(O), S( O2 ), C( R1cR1d ), C( ⁇ CR1eR1f ) and N( R3 ); wherein R1c , R1d , R1e and R1f are independently selected from hydrogen, deuterium, C1-6 alkyl, C1-6 alkoxy, C3-12 monocyclic, spirocyclic or bridged cycloalkyl, C3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C6-10 aryl and C5-10 heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, C3-12 monocyclic, spirocyclic or bridged cycloalkyl, C3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P
  • 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl, and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, C 1-6 alkyl, amino, hydroxy, C 1-6 alkylamino, C 1-6 aminoalkyl, and C 1-6 alkoxy; or R 1c and R 1d and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy; or R 1e and R 1f and the carbon atom to which they are commonly attached form a 3-10 member
  • R 3 is -X 1 -R 8 , X 1 is selected from a chemical bond, -O-, -S-, alkoxy, C 2-6 alkenylene and C 1-6 alkylene;
  • R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S;
  • R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, and the phenyl is optionally substituted with 0-2 groups selected from C 1-4 alkyl, halogen, cyano, amino, -OR 8d and -X 2 -R 8d ;
  • R 8c
  • R 7a and R 7b are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl;
  • X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence;
  • R 7c is selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are attached form a 3-10 membered cycloalkyl;
  • W is selected from the following groups:
  • the Q ring is selected from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring, wherein the phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring are optionally substituted with 0-6 R 9 , and each occurrence of R 9 is independently selected from halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, C 3-7 heterocycloal
  • the R ring is selected from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring, wherein the phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring are optionally substituted with 0-6 R10 , and each occurrence of R10 is independently selected from halogen, deuterium, C1-6 alkyl, hydroxyl, amino, C1-6 haloalkyl, cyano,
  • the T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 0-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl and C 3-6 cycloalkyl;
  • L1 is selected from the following groups:
  • L2 is selected from the following groups:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 —, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH ⁇ CH—, —C ⁇ C—, and a single bond;
  • a is an integer from 0 to 5; b and c are integers from 0 to 3; d and e are integers from 0 to 2; and
  • L 1 and L 2 are optionally substituted by 0-5 R 11 , R 11 are independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O 2 )R 11a , NR 11b R 11c , -X 6 -NR 11b R 11c , -OR 11a and -X 6 -OR 11a ; R 11a , R 11b and R 11c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 6 is selected from C 1-6 alkylene and C 2-6 alkenylene.
  • a pharmaceutical composition characterized in that it comprises a therapeutically effective dose of the compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or excipient.
  • a method for treating a MAT2A-related disease in a patient comprising administering to the patient a therapeutically effective amount of one or more compounds according to any one of claims 1-11 or the pharmaceutical composition according to claim 12; preferably, the MAT2A-related disease is cancer or tumor.
  • MAT2A-related disease preferably, the MAT2A-related disease is cancer or tumor.
  • Alkyl refers to a straight-chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc. Those skilled in the art will recognize that the term “alkyl” may include “alkylene” groups.
  • alkylene refers to a straight-chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated divalent hydrocarbon group having 3 to 6 carbon atoms, such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Alkenyl refers to a straight chain monovalent hydrocarbon radical having 2 to 6 carbon atoms or a 3 to 6 carbon atom A branched monovalent hydrocarbon group, such as propenyl, butenyl, etc.
  • alkynyl group refers to a linear monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched monovalent hydrocarbon group having 3 to 6 carbon atoms containing a triple bond, for example, ethynyl, propynyl, butynyl and the like.
  • Alkoxy refers to a -OR group where R is alkyl as defined above, for example methoxy, ethoxy, propoxy or 2-propoxy, n-, iso- or tert-butoxy and the like.
  • Amino refers to -NH2 .
  • Alkylamino refers to an -NHR group where R is alkyl as defined above, for example, methylamino, ethylamino, propylamino or 2-propylamino, and the like.
  • Aryl refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 3 to 12 ring atoms, for example, phenyl or naphthyl.
  • Alkyl refers to an -(alkylene)-R group where R is aryl as defined above, eg, benzyl, phenethyl, and the like.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Haloalkyl refers to an alkyl group as defined above substituted by 1 to 5 halogen atoms, such as fluorine atoms or chlorine atoms, including groups substituted by different halogens, such as -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc.
  • halogen atoms such as fluorine atoms or chlorine atoms
  • groups substituted by different halogens such as -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc.
  • Hydroalkyl refers to a linear monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical having 3-6 carbon atoms substituted by one or two hydroxyl groups, provided that if two hydroxyl groups are present, they are not simultaneously on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl.
  • salts are meant to include salts of active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (either neat or in a suitable inert solvent).
  • salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include salts derived from the following inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from the following relatively non-toxic organic acids, such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid,
  • inorganic acids such as hydrochlor
  • salts of amino acids such as arginine salts
  • salts of the following organic acids such as glucuronic acid or galacturonic acid, and the like
  • Certain specific compounds of the present invention contain both basic and acidic functional groups, which allows the compounds to be converted into base addition salts or acid addition salts.
  • the neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties (e.g., solubility in polar solvents), but for the purposes of the present invention, these salts are equivalent to the parent form of the compound.
  • the present invention also includes protected derivatives of the compounds disclosed herein.
  • a group such as a hydroxyl group, a carboxyl group, a thiol group or any group containing one or more nitrogen atoms
  • these groups may be protected by suitable protecting groups.
  • suitable protecting groups can be found in TW Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons, Inc (2014), the disclosure of which is incorporated herein by reference in its entirety.
  • Protected derivatives of the compounds of the present disclosure can be prepared by methods well known in the art.
  • the present invention also includes prodrugs of the compounds, or pharmaceutically acceptable salts thereof.
  • Prodrugs of the compounds described herein are those compounds that are susceptible to chemical changes under physiological conditions to provide compounds of the present invention.
  • An example of a prodrug, not limited to, is a compound ("prodrug") administered as an ester, which is then metabolically hydrolyzed to a carboxylic acid, i.e., an active entity.
  • the prodrug can be converted into a compound of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when the prodrug is placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, it can be slowly converted into a compound of the present invention.
  • the compounds disclosed in the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present invention.
  • Certain formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-J), (I-K), (I-L), (I-M), (I-N), (I-O), (I-P), (I-Q), (I-R), (I-S), (I-T), (I-U), (I-V), (I-W), (I-X), (I-Y) and (I-Z) compounds may exist in a variety of crystalline or amorphous forms. Generally, all physical forms such as polymorphs are equivalent for the intended use of the present disclosure and are intended to fall within the scope of the present disclosure.
  • the compounds disclosed in the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., individual enantiomers) are all intended to be included in the isomer range of the compounds of the present invention.
  • stereochemical descriptions refers to compounds in which one isomer is present and substantially free of another isomer.
  • substantially free of another isomer means that the ratio of the two isomers is at least 80/20, more preferably 90/10, or 95/5 or higher.
  • one of the isomers will be present in an amount of at least 99%.
  • the compounds disclosed herein may also contain unnatural amounts of isotopes at one or more atoms constituting such compounds.
  • An unnatural amount of an isotope may be defined as an amount ranging from the amount found in nature to 100% of the atom in question. It differs only when one or more isotopically enriched atoms are present.
  • Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H , 3H , 11C , 13C , 14C , 13N , 15N , 15O , 17O, 18O , 32P , 33P , 35S , 18F , 36Cl , 123I , and 125I , respectively .
  • Isotopically labeled compounds e.g., those labeled with 3H and 14C ) are useful in compound or substrate tissue distribution assays.
  • Tritium (i.e., 3H ) and carbon-14 (i.e., 14C ) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H ) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
  • one or more hydrogen atoms are replaced by 2H or 3 H substitution, or one or more carbon atoms are substituted with 13 C- or 14 C-enriched carbon.
  • Positron emitting isotopes eg, 15 O, 13 N, 11 C, and 15 F
  • PET positron emission tomography
  • Isotopically labeled compounds can generally be prepared by following steps similar to those disclosed in the Examples of the present invention, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • “Pharmaceutically acceptable carrier or excipient” refers to a carrier or excipient that can be used to prepare a pharmaceutical composition, is generally safe, non-toxic and not biologically or otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes one or more such excipients.
  • disease is intended to be generally synonymous with the terms “disorder,””condition,” and “condition” (as in medical condition) and are used interchangeably because they all reflect an abnormal condition of the human or animal body or a part thereof that impairs the normal functioning, usually manifests itself as distinctive signs and symptoms, and results in a shortened life span or reduced quality of life in the human or animal.
  • Patient is often synonymous with the term "subject” and, as used herein, includes all mammals, including humans. Examples of patients include humans, livestock (e.g., cattle, goats, sheep, pigs, and rabbits), and companion animals (e.g., dogs, cats, rabbits, and horses). Preferably, the patient is a human.
  • livestock e.g., cattle, goats, sheep, pigs, and rabbits
  • companion animals e.g., dogs, cats, rabbits, and horses.
  • the patient is a human.
  • in need of treatment refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from treatment. This judgment is based on a variety of factors within the physician's or caregiver's expertise.
  • administering when used for example in patients, cells, tissues, organs or biological fluids, refers to contacting the compounds disclosed herein, pharmaceutical compositions or diagnostic agents containing the same with subjects, cells, tissues, organs or biological fluids.
  • administration includes contact of the agent with the cell (e.g., in vitro or ex vivo), and contact of the agent with the fluid, wherein the fluid is in contact with the cell.
  • therapeutically effective amount refers to, for example, a compound disclosed herein or an embodiment described herein, when administered alone or as part of a pharmaceutical composition and in a single dose or as part of a series of doses to a patient treating a disease, an amount sufficient to affect the treatment of such disease.
  • the "therapeutically effective amount” will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated.
  • the therapeutically effective amount can be determined by measuring the relevant physiological effects, and the therapeutically effective amount can be adjusted in combination with the dosing regimen and diagnostic analysis of the subject's condition, etc. For example, measuring the serum level of a compound disclosed herein (or its metabolite) at a specific time after administration can indicate whether a therapeutically effective amount has been used.
  • Treatment or “treatment” of a disease includes:
  • a disease that is, causing clinical symptoms of a disease to not develop in a mammal that may be exposed to or susceptible to the disease but does not yet experience or show symptoms of the disease;
  • “Inhibition”, “reduction” or any variation of these terms with respect to MAT2A includes any measurable reduction or complete inhibition to achieve the desired result.
  • the reduction in MAT2A activity can be reduced by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any derivable range thereof.
  • the synthesis of compound 1-9 refers to the synthesis of compound 1-5, except that p-vinylaniline in step 1 is replaced by p-bromoaniline.
  • reaction solution is dried over anhydrous sodium sulfate, and the organic phase after drying is evaporated on a rotary evaporator to remove the solvent.
  • the obtained residue is purified by column chromatography to obtain compound 3-4 (1.1g, 36%), which is a white solid.
  • methyl isonicotinate 1.0 g, 7.3 mmol
  • 50 mL of methanol 50 mL
  • 0.2 mL of concentrated sulfuric acid was added, and the temperature was raised to 65°C.
  • ammonium persulfate 15 g, 65.79 mmol
  • 25 mL of water 25 mL
  • TLC monitored the reaction to be complete, concentrated to remove a large amount of methanol, and extracted with 50 mL of water and 150 mL of ethyl acetate, which was repeated three times.
  • 3-iodoaniline (3.0 g, 13.70 mmol) and 1H-imidazole-4-carbonitrile (1.3 g, 13.70 mmol) were dissolved in N, N-dimethylformamide (30 mL) at room temperature, and cuprous iodide (260 mg, 1.37 mmol), trans-N, N-dimethyl-1,2-cyclohexanediamine (200 mg, 1.37 mmol) and cesium carbonate (13.4 g, 41.07 mmol) were added, and the mixture was heated to 100 ° C and stirred for 18 hours under nitrogen protection.
  • Oxalyl chloride (2.0 g, 15.96 mmol) was added dropwise to dichloroethane DCE (10 mL) of compound 32-3 (1.2 g, 7.98 mmol) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After the excess oxalyl chloride was removed by rotary evaporation under reduced pressure, it was diluted with DCE (8 mL) and added dropwise to the DCE/DMF (1.5 mL/0.5 mL) system of compound 2 (500 mg, 2.65 mmol). The reaction was stirred at room temperature for 3 hours. TLC monitored the complete reaction. Acetonitrile was added to the slurry, and the solid after filtration was compound 32-4, 1.35 g, white solid, with a yield of 93%. LC-MS (ESI) m/z: 547 [M+H] + .
  • Phosphorus oxychloride (0.8 mL) was added to a solution of compound 5 (80 mg, 0.16 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 hours, and the excess phosphorus oxychloride was removed by vacuum rotary evaporation. Methylethylamine (47 mg, 0.79 mmol) was dissolved in tetrahydrofuran THF (5 mL) and added dropwise to the reaction system to remove phosphorus oxychloride, and stirred at room temperature for 30 minutes. LC-MS detected complete reaction.
  • compound 34-1 (900 mg, 4 mmol) was dissolved in 5 mL of anhydrous ethanol, p-toluenesulfonyl hydrazide (755 mg, 4 mmol) was added, and the mixture was stirred at room temperature overnight. TLC monitored that compound 34-1 reacted completely and new spots were generated. Then 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)indigo (1.4 g, 4 mmol) and potassium carbonate (1.11 g, 4 mmol) were added, and the temperature was raised to 80 ° C and stirred for 45 minutes.
  • n-Nitrophenyl borate (2.12 g, 12.8 mmol) and 4-bromothiophene-2-carbonitrile (2.0 g, 10.6 mmol) were dissolved in a mixture of dioxane (30 mL) and DMF (4 mL), and an aqueous solution (13 mL) of sodium carbonate (3.38 g, 31.8 mmol) was added.
  • 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex 500 mg, 0.05 mmol was added in a N2 atmosphere, and the mixture was heated to 100°C and reacted overnight.
  • compound 44-1 (1.5 g, 6.944 mmol) was dissolved in ammonia methanol solution (20 mL, 7N), 2 mL of water-sealed Raney nickel was taken, the supernatant was removed after precipitation, methanol was added to wash twice, the supernatant was removed after standing and precipitation, and then the precipitate was diluted with methanol and added to the reaction system, and the hydrogen was replaced three times and kept at room temperature for 4 hours. LC-MS monitored the complete reaction.
  • compound 47-1 (650 mg, 6.944 mmol) was dissolved in ammonia methanol solution (7N, 20 mL), 2 mL of water-sealed Raney nickel was taken, the supernatant was removed after precipitation, methanol was added to wash twice, the supernatant was removed after standing and precipitation, and then the precipitate was diluted with methanol and added to the reaction system, and the hydrogen was replaced three times and kept at room temperature for 4 hours. LC-MS monitored the complete reaction.
  • m-Nitrophenylboronic acid 500 mg, 4.5 mmol
  • compound 50-1 470 mg, 2.5 mmol
  • a mixture of dioxane 5 mL
  • DMF 1 mL
  • an aqueous solution 2 mL
  • sodium carbonate 795 mg, 7.5 mmol
  • 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex 100 mg, 0.125 mmol was added in a N2 atmosphere, and the mixture was heated to 100°C and reacted overnight.
  • m-Nitrophenyl borate (1.86 g, 11.1 mmol) and compound 55-3 (2.79 g, 9.3 mmol) were dissolved in a mixture of dioxane (25 mL) and DMF (4 mL), and an aqueous solution (7 mL) of sodium carbonate (2.96 g, 27.9 mmol) was added.
  • 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (380 mg, 0.46 mmol) was added in a N2 atmosphere, and the mixture was heated to 50°C and reacted overnight.
  • compound 57-1 (2.0 g, 9.90 mmol) was dissolved in ammonia methanol solution (7N, 20 mL), 2 mL of water-sealed Raney nickel was taken, the supernatant was removed after precipitation, methanol was added to wash twice, the supernatant was removed after standing and precipitation, and then the precipitate was diluted with methanol and added to the reaction system, and the hydrogen was replaced three times and kept at room temperature for 4 hours. LC-MS monitored the complete reaction.
  • compound 57-4 (100 mg, 0.18 mmol) was dissolved in 3 mL of anhydrous acetonitrile, cooled to 0 ° C, DIEA (100 mg, 0.78 mmol) and phosphorus oxychloride (130 mg, 0.85 mmol) were added, slowly heated to room temperature and then heated to 80 ° C and stirred for 6 hours.
  • the reaction solution was concentrated to remove a large amount of phosphorus oxychloride, and then a THF solution of dimethylamine (2 mL, 2.5 N) was added and stirred at room temperature for 30 minutes.
  • LC-MS monitored the reaction to be complete.
  • compound 60-2 500 mg, 2.01 mmol was dissolved in tetrahydrofuran (5 mL), cooled to 0 ° C, and a solution of lithium aluminum tetrahydride in tetrahydrofuran (2.5 mL) was added dropwise. Under nitrogen protection, the temperature was raised to 70 ° C and stirred for 2 hours. TLC monitored the complete reaction, and the reaction system was quenched with water (10 mL), extracted with ethyl acetate (50 mL ⁇ 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.
  • Oxalyl chloride (555 mg, 4.37 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (380 mg, 2.18 mmol) in dichloroethane (DCE) (5 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing the excess oxalyl chloride by vacuum rotary evaporation, it was diluted with DCE (2 mL) and then added dropwise to the DCE (3 mL) system of compound 60-3 (146 mg, 0.71 mmol), and the reaction was stirred at room temperature for 3 hours. TLC monitored the complete reaction. Acetonitrile was added to the reaction system for slurrying, and the solid after filtration was compound 60-4, 248 mg, yield 58%, white solid. LC-MS (ESI) m/z: 604 [M + H] + .
  • Phosphorus oxychloride (0.8 mL) was added to a solution of compound 5 (70 mg, 0.12 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 hours, and the excess phosphorus oxychloride was removed by vacuum rotary evaporation. A tetrahydrofuran solution of dimethylamine (4 mL) was added dropwise to the reaction system where phosphorus oxychloride was removed, and stirred at room temperature for 30 minutes. LC-MS detected the complete reaction.
  • 2-amino-6-bromopyridine (1g, 5.8mmol), 1-H-4-cyanoimidazole (540mg, 5.8mmol), cuprous iodide (110mg, 0.6mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (90mg, 0.6mmol) and cesium carbonate (5.6g, 17.2mmol) were dissolved in 20mL anhydrous DMF, nitrogen was replaced three times, and the temperature was raised to 100°C oil bath for 16 hours. LC-MS monitored the reaction to be complete.
  • compound 62-1 500 mg, 2.7 mmol was dissolved in ammonia methanol solution (7N, 10 mL ), take 2mL of water-sealed Raney nickel, remove the supernatant after precipitation, add methanol to wash twice, remove the supernatant after standing precipitation, then dilute the precipitate with methanol and add it to the reaction system, replace hydrogen three times and keep the reaction at room temperature for 4 hours.
  • LC-MS monitors the reaction to be complete. Add 50mL DCM and 10mL methanol to dilute the reaction solution and filter it with diatomaceous earth.
  • Oxalyl chloride (460 mg, 4.06 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (320 mg, 2.03 mmol) in dichloroethane (5 mL) at 0 ° C. Under nitrogen protection, the reaction mixture was stirred at 70 ° C overnight, and the excess oxalyl chloride was removed by vacuum rotary evaporation. After dilution with DCE (2 mL), it was added dropwise to the DCE (3 mL) system of compound 68-5 (140 mg, 0.67 mmol), and the reaction was stirred at room temperature for 3 hours. TLC monitored the complete reaction. Acetonitrile was added to the reaction system for slurrying, and the solid after filtration was compound 68-6, 299 mg, yield 74%, white solid. LC-MS (ESI) m/z: 604 [M + H] + .
  • Phosphorus oxychloride (0.8 mL) was added to a solution of compound 68-7 (60 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 hours, and the excess phosphorus oxychloride was removed by vacuum rotary evaporation. A tetrahydrofuran solution of dimethylamine (4 mL) was added dropwise to the reaction system where phosphorus oxychloride was removed, and stirred at room temperature for 30 minutes. LC-MS detected the complete reaction.
  • Oxalyl chloride (5.9 g, 52.14 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (4.1 g, 26.07 mmol) in dichloroethane (DCE) (50 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride under reduced pressure, it was diluted with DCE (20 mL) and then added dropwise to the DCE (20 mL) system of compound 72-5 (1.8 g, 8.69 mmol), and the reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction.
  • DCE dichloroethane
  • Phosphorus oxychloride (0.8 mL) was added to a solution of compound 72-7 (60 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 h, and the excess phosphorus oxychloride was removed under reduced pressure. A tetrahydrofuran solution of deuterated dimethylamine (4 mL) was added dropwise to the reaction system in which phosphorus oxychloride was removed, and stirred at room temperature for 30 min. LC-MS detected the complete reaction.
  • compound 79-2 (2.0 g, 10.58 mmol) was dissolved in 20 mL of N, N-dimethylformamide, 3-tert-butyloxycarbonylaminopiperidine (2.3 g, 11.64 mmol) and potassium carbonate (4.4 g, 31.74 mmol) were added thereto, and stirred at room temperature for 16 h.
  • TLC monitored the complete reaction, water was added to the reaction system, extracted with ethyl acetate (50 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.
  • Oxalyl chloride (6.1 g, 47.88 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (4.1 g, 23.94 mmol) in dichloroethane (DCE) (50 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride by vacuum rotary evaporation, it was diluted with DCE (20 mL) and then added dropwise to the DCE (30 mL) system of compound 79-5 (1.7 g, 7.98 mmol), and the reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction.
  • DCE dichloroethane
  • Phosphorus oxychloride (0.8 mL) was added to a solution of compound 79-7 (60 mg, 0.10 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 h, and the excess phosphorus oxychloride was removed by vacuum rotary evaporation. After 4 mL of tetrahydrofuran solution of N-ethylmethylamine was dropped into the reaction system, it was stirred at room temperature for 30 min. LC-MS detected the complete reaction.
  • Embodiment 84 is a diagrammatic representation of Embodiment 84.
  • Phosphorus oxychloride (1.0 mL) was added to a solution of compound 72-7 (80 mg, 0.14 mmol) and N,N-diisopropylethylamine (1.0 mL) in acetonitrile CAN (5 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 h, and the excess phosphorus oxychloride was removed by rotary evaporation under reduced pressure. After 4 mL of water was dropped into the reaction system, it was stirred at room temperature for 30 min. LC-MS detected the complete reaction.
  • 2,4,7-Trichloroquinazoline (5.0 g, 21.44 mmol) was dissolved in 50 mL of tetrahydrofuran (THF) at room temperature, 15 mL (31.12 mmol) of a tetrahydrofuran solution of N-ethylmethylamine (2M) was added thereto, and the mixture was stirred at room temperature for 16 h.
  • the reaction was completely monitored by TLC, and the compound 101-1 (3.7 g, white solid) was obtained after vacuum rotary evaporation and concentration, which was directly used in the next step without purification, with a yield of 68%.
  • compound 101-2 (1.0 g, 4.20 mmol) was dissolved in 10 mL of N, N-dimethylformamide, 2-bromo-5-bromomethylthiazole (1.3 g, 5.04 mmol) and potassium carbonate (1.8 g, 12.61 mmol) were added thereto, and stirred at room temperature for 16 h.
  • TLC monitored the complete reaction, water was added to the reaction system, extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.
  • Oxalyl chloride (5.5 g, 43.01 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (3.7 g, 21.51 mmol) in dichloroethane (50 mL) at 0 ° C. Under nitrogen protection, the reaction mixture was stirred at 70 ° C overnight. After removing excess oxalyl chloride under reduced pressure, it was diluted with DCE (20 mL) and then added dropwise to 1-Boc-3-aminopyrrolidine (2.0 g, 10.75 mmol) in DCE (30 mL) system. The reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction.
  • Oxalyl chloride (5.5 g, 43.01 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (3.7 g, 21.51 mmol) in dichloroethane (50 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride under reduced pressure, it was diluted with DCE (20 mL) and then added dropwise to a DCE (30 mL) system of 1-tert-butyloxycarbonyl-3-aminopiperidine (2.0 g, 9.98 mmol), and the reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction.
  • Embodiment 107 is a diagrammatic representation of Embodiment 107.
  • Compound 79 was resolved by SFC to give single-configuration compounds 109 (79-P1) and 110 (79-P2).
  • Compound 80 was resolved by SFC to give single-configuration compounds 111 and 112.
  • Step 3 Synthesis of compounds 113 & 114
  • the synthesis method of compound 116 is similar to that of Example 102, except that dimethylamine in step 3 is replaced by azetidine, and 101-3 in step 5 is replaced by 1-((2-bromothiazol-5-yl)methyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one.

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Abstract

The present invention relates to a compound which is a compound as represented by formula (I), or an isomer, an isotope derivative, a polymorph, a prodrug, and a pharmaceutically acceptable salt or a solvate (I) thereof, wherein the definitions of A, B and C are as defined in the description. Further provided are a pharmaceutical composition and a compound of formula (I), and a method thereof for treating related diseases by means of MAT2A inhibition, wherein the diseases comprise some cancers in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted and/or is not fully functioning.

Description

一种甲硫氨酸腺苷转移酶2A抑制剂及其医药用途A methionine adenosyltransferase 2A inhibitor and its medical use 技术领域Technical Field
本发明属于药物合成技术领域，涉及一种甲硫氨酸腺苷转移酶2A抑制剂、含所述抑制剂的药物组合物及其制药用途，尤其在制备抗肿瘤药物中的应用。The present invention belongs to the technical field of drug synthesis, and relates to a methionine adenosyltransferase 2A inhibitor, a drug composition containing the inhibitor and pharmaceutical use thereof, in particular to the application of the inhibitor in the preparation of anti-tumor drugs.
技术背景Technical Background
甲硫氨酸腺苷转移酶(MAT)又称S-腺苷甲硫氨酸合成酶，是催化甲硫氨酸和ATP合成S-腺苷甲硫氨酸(SAM或AdoMet)的细胞酶，被认为是氨酸循环的限速步骤。在核酸、磷脂、组蛋白、生物胺和蛋白质的甲基化过程中，SAM是合成多胺和谷胱甘肽的主要甲基供体。因此，调控SAM的生物合成可影响细胞的生长、分化和功能。研究表明，肿瘤细胞的增值和转移对甲硫氨酸异常依赖，抑制甲硫氨酸循环能显著抑制干细胞的增值和转移。Methionine adenosyltransferase (MAT), also known as S-adenosylmethionine synthetase, is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP and is considered to be the rate-limiting step in the amino acid cycle. In the methylation process of nucleic acids, phospholipids, histones, biogenic amines and proteins, SAM is the main methyl donor for the synthesis of polyamines and glutathione. Therefore, regulating the biosynthesis of SAM can affect cell growth, differentiation and function. Studies have shown that the proliferation and metastasis of tumor cells are abnormally dependent on methionine, and inhibiting the methionine cycle can significantly inhibit the proliferation and metastasis of stem cells.
在哺乳动物组织中，MAT基因主要存在两种不同的同工酶，分别由MAT1和MAT2编码。MAT1仅在肝脏中表达，用于维持肝细胞和胆管上皮细胞的分化状态；MAT2在正常细胞和癌细胞中普遍表达，MAT2包含两个亚基MAT2A和MAT2B，分别作为催化亚基和调控亚基。MAT2A是SAM合成通路中的关键酶，研究表明MAT2A的表达上调在多种癌细胞中存在，而且敲除MAT2A基因能导致癌细胞的死亡。因此，MAT2A是抗肿瘤的靶点。In mammalian tissues, the MAT gene mainly exists in two different isoenzymes, encoded by MAT1 and MAT2. MAT1 is only expressed in the liver and is used to maintain the differentiation state of hepatocytes and bile duct epithelial cells; MAT2 is commonly expressed in normal cells and cancer cells. MAT2 contains two subunits, MAT2A and MAT2B, which serve as catalytic subunits and regulatory subunits, respectively. MAT2A is a key enzyme in the SAM synthesis pathway. Studies have shown that upregulated expression of MAT2A exists in a variety of cancer cells, and knocking out the MAT2A gene can lead to the death of cancer cells. Therefore, MAT2A is an anti-tumor target.
研究表明，MAT2A为甲基硫腺苷磷酸化酶(MTAP)缺失癌症中的合成致死靶标。MTAP(甲硫腺苷磷酸化酶)是一种在正常组织中广泛表达的酶，它将多胺合成的副产物MTA降解为腺嘌呤和5-甲基硫腺苷-1-磷酸(MTR-1p)。Marjon等人(Cell Reports 15(3)(2016)574-587)报道MTAP缺陷的癌症细胞系对MAT2A的抑制特别敏感。MTAP位于染色体9P21上，与抑癌基因CDKN2A相近，近15％的人类癌症显示MTAP基因缺失，MTAP缺失不仅存在于组织培养细胞中，还存在于原发性白血病、胶质瘤、黑色素瘤、胰腺癌、非小细胞肺癌(NSCLC)、膀胱癌、星形细胞瘤、骨肉瘤、头颈癌、粘液样软骨肉瘤、卵巢癌、子宫内膜癌、乳腺癌、软组织肉瘤、非霍奇金淋巴瘤和间皮瘤。MTAP是甲硫氨酸回收途径中的关键酶，是目前已知的唯一催化MTA降解的酶，MTAP的丢失被认为会导致MTA在癌细胞中积累。MTA的增加抑制了蛋白精氨酸甲基转移酶5(protein arginine methyltransferase 5)的活性，增加了PRMT5对SAM进一步缺失的敏感性。与正常表达MTAP的癌细胞相比，选择性抑制MAT2A能够降低MTAP缺失癌细胞的增殖活性。这些结果表明，MAT2A抑制剂可能为包括MTAP缺失肿瘤患者提供一种新颖的治疗方法。Studies have shown that MAT2A is a synthetic lethal target in methylthioadenosine phosphorylase (MTAP)-deficient cancers. MTAP (methylthioadenosine phosphorylase) is an enzyme that is ubiquitously expressed in normal tissues and degrades MTA, a byproduct of polyamine synthesis, into adenine and 5-methylthioadenosine-1-phosphate (MTR-1p). Marjon et al. (Cell Reports 15(3)(2016)574-587) reported that MTAP-deficient cancer cell lines are particularly sensitive to inhibition of MAT2A. MTAP is located on chromosome 9P21, close to the tumor suppressor gene CDKN2A. Nearly 15% of human cancers show MTAP gene deletion. MTAP deletion is not only present in tissue culture cells, but also in primary leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma and mesothelioma. MTAP is a key enzyme in the methionine recycling pathway and is the only enzyme known to catalyze the degradation of MTA. The loss of MTAP is believed to lead to the accumulation of MTA in cancer cells. The increase in MTA inhibits the activity of protein arginine methyltransferase 5 and increases the sensitivity of PRMT5 to further loss of SAM. Compared with cancer cells that normally express MTAP, selective inhibition of MAT2A can reduce the proliferation activity of MTAP-deficient cancer cells. These results suggest that MAT2A inhibitors may provide a novel therapeutic approach for patients with tumors including those with MTAP deletions.
发明内容Summary of the invention
本发明提供了一种甲硫氨酸腺苷转移酶2A(MAT2A)抑制剂及其药学上可接受的盐。本文还公开了包括此类化合物的药物组合物和治疗可通过抑制MAT2A治疗的疾病的方法，例如癌症，包括特征在于甲硫腺苷磷酸化酶(MTAP)活性降低或无活性的癌症。The present invention provides a methionine adenosyltransferase 2A (MAT2A) inhibitor and a pharmaceutically acceptable salt thereof. Also disclosed herein are pharmaceutical compositions comprising such compounds and methods for treating diseases that can be treated by inhibiting MAT2A, such as cancer, including cancers characterized by reduced or inactive methylthioadenosine phosphorylase (MTAP) activity.
本发明采用如下技术方案：本发明第一方面提供了一种化合物，所述化合物为式(Ⅰ-1)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
The present invention adopts the following technical scheme: In the first aspect of the present invention, a compound is provided, wherein the compound is a compound represented by formula (I-1), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:
其中A1和B1各自独立选自式(Ⅱ)、(Ⅲ)、(Ⅳ)、(Ⅴ)、(Ⅵ)、(Ⅶ) 和(Ⅷ)：
Wherein A 1 and B 1 are independently selected from the group consisting of formula (II), (III), (IV), (V), (VI), (VII) and (VIII):
R1每次出现时不存在或各自独立地选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、C1-6烷基、-S-C1-6烷基、-S(O)-C1-6烷基、-S(O2)-C1-6烷基、-O-C1-6烷基、-O-C1-6卤代烷基、C1-6氘代烷基、3-10元环烷基、3-10元杂环烷基和-NR1aR1b，其中R1a和R1b分别独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个含有1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-10元杂环烷基，其中所述杂环烷基任选地被0、1、2、3或4个独立选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氘代烷基、C1-6烷基、氰基、C1-6氨基烷基、3-10元环烷基、3-10元杂环烷基和羟基的取代基取代；R 1 is absent at each occurrence or is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, -SC 1-6 alkyl, -S(O)-C 1-6 alkyl, -S(O 2 )-C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, C 1-6 deuterated alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and -NR 1a R 1b , wherein R 1a and R 1b are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 1-6 containing 1-3 heteroatoms independently selected from N, O, P and S R 1a and R 1b are substituted with 0, 1 , 2, 3 , 4 , 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl , 3-10 membered heterocycloalkyl and alkoxy; or R 1a and R 1b and the nitrogen atom to which it is commonly attached form a 3-10 membered heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl group is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 deuterated alkyl, C 1-6 alkyl , cyano, C 1-6 aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy;
Z每次出现时各自独立地选自C和N；当Z选自N时，R1不存在；Each occurrence of Z is independently selected from C and N; when Z is selected from N, R 1 is absent;
R2、R4和R6每次出现时分别独立地选自氢、氘、卤素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、-NHC1-6烷基、-N(C1-6烷基)C1-6烷基、C1-6卤代烷氧基、C1-6卤代烷基氨基、羟基、C2-6烷氧基、3-12元单环的环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-12元单杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的5-12元螺杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的4-12元桥杂环烷基、-S-C1-6烷基、-SO-C1-6烷基、-SO2-C1-6烷基、3-6元环烷基-C1-6亚烷基、3-6元环烷基-O-、3-6元杂环烷基-O-、6-10元单环芳基、8-14元并环芳基、含有1-3个分别独立地选自N、O、P和S杂原子的5-12元单环杂芳基和含有1-3个分别独立地选自N、O、P和S杂原子的8-10元并环杂芳基；优选地，R2、R4和R6每次出现时分别独立地选自氢、卤素、C1-3烷基、C2-3烯基、C2-3炔基、C1-3卤代烷基、-NHC1-6烷基、-N(C1-6烷基)C1-6烷基、C1-6卤代烷氧基、C1-6卤代烷基氨基、3-6元单环的环烷基、含有1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-6元单杂环烷基；R 2 , R 4 and R 6 are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 haloalkylamino, hydroxy, C 2-6 alkoxy, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, -SC Preferably, R 2 , R 4 and R 6 are each independently selected from hydrogen, halogen, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl ) C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 alkyl radicals, C 1-6 alkyl radicals , C 2-3 alkynyl radicals, C 1-3 haloalkyl, C 1-3 ... 1-6 haloalkylamino, 3-6 membered monocyclic cycloalkyl, 3-6 membered monoheterocyclic alkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S;
R5选自氢、C1-6烷基、C3-10环烷基、C3-10杂环烷基和C1-6卤代烷基，任选地，所述C1-6烷基、C3-10环烷基、C3-10杂环烷基和C1-6卤代烷基被0-6个独立选自卤素、氘、烷基、氨基、羟基、氨基烷基、烷基氨基、和烷氧基的取代基取代；R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
G1和G2每次出现各自独立地选自O、S、和NR2a； G1 and G2 are each independently selected from O, S, and NR2a ;
E0、E1、E2、E3、E4、E5、E6、E7、E8、E9、M1、M2、M3、M4、M5、M6和E每次出现时分别独立地选自N和CR2a，且E7、E8、和E9不同时为CR2a； E0 , E1 , E2 , E3, E4 , E5 , E6 , E7 , E8 , E9 , M1 , M2 , M3 , M4 , M5 , M6 and E are each independently selected from N and CR2a , and E7 , E8 , and E9 are not CR2a at the same time;
R2a每次出现时各自独立地选自选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、苯基亚甲基、-CH2OCH2CH2Si(CH3)3、C1-6烷基、C1-6卤代烷基、C1-6烷基-S-、-S(O)-C1-6烷基、-SO2-C1-6烷基、-O-C1-6烷基、-O-C1-6卤代烷基、-NR2bR2c、-C(O)R8c、-C(O)NR8aR8b、-C1-6亚烷基-C3-6环烷基、C3-6环烷基-NR2b-、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基-NR2b-、3-12元单环烷基、5-12元螺环烷基、4-12元桥环烷 基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的5-12元螺杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的4-12元桥杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基、3-6元卤代环烷基-O-、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-、6-12元单环芳基、8-12元并环芳基、含有1-3个分别独立地选自N、O、P和S的杂原子的5-12元单环杂芳基、和含有1-3个分别独立地选自N、O、P和S的杂原子的8-10元并环杂芳基；优选地，R2a选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷基-S-、-S(O)-C1-6烷基、-SO2-C1-6烷基、-O-C1-6烷基、-O-C1-6卤代烷基、-NHC1-6烷基、-N(C1-6烷基)C1-6烷基、C3-6环烷基和-C1-6亚烷基-C3-6环烷基；优选地，R2a选自氢、卤素、氰基、羟基、氨基、C1-3烷基、C1-3卤代烷基、-C1-3亚烷基-C3-6环烷基、和C3-6环烷基； R2a at each occurrence is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, phenylmethylene, -CH2OCH2CH2Si ( CH3 ) 3 , C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-S-, -S(O) -C1-6 alkyl, -SO2 - C1-6 alkyl, -OC1-6 alkyl, -OC1-6 haloalkyl, -NR2bR2c , -C(O)R8c, -C(O)NR8aR8b, -C1-6 alkylene -C3-6 cycloalkyl, C3-6 cycloalkyl-NR2b-, 3-6 membered heterocycloalkyl-NR2b containing 1-3 heteroatoms independently selected from N , O , P and S -, 3-12 membered monocycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl alkyl, 3-12 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl alkyl-O-, 3-6 membered halogenated heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 6-12 membered monocyclic aryl, 8-12 membered cycloheteroaryl, 5-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, and 8-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-S-, -S(O)-C 1-6 alkyl, -SO 2 -C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 3-6 cycloalkyl and -C 1-6 alkylene-C 3-6 cycloalkyl; preferably, R 2a is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-3 alkyl, C 1-3 haloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, and C 3-6 cycloalkyl;
R2b和R2c每次出现时各自独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；或R2b和R2c和其共同连接的氮原子组成一个含有1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-10元杂环烷基，其中所述杂环烷基任选地被0、1、2、3或4个独立选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氘代烷基、C1-6烷基、氰基、C1-6氨基烷基、3-10元环烷基、3-10元杂环烷基和羟基的取代基取代；优选R2b和R2c分别独立地选自氢和C1-6烷基；R 2b and R 2c are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl , C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl R 2b and R 2c and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl containing 1, 2 , 3 or 4 heteroatoms independently selected from N, O, P and S , wherein the heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 deuterated alkyl, C 1-6 alkyl, cyano, C 1-6 aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; preferably R 2b and R 2c are independently selected from hydrogen and C 1-6 alkylamino. 1-6 alkyl;
R8a和R8b每次出现时各自独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；或R8a和R8b和其共同连接的氮原子组成一个含有1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-10元杂环烷基，其中所述杂环烷基任选地被0、1、2、3或4个独立选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氘代烷基、C1-6烷基、氰基、C1-6氨基烷基、3-10元环烷基、3-10元杂环烷基和羟基的取代基取代；优选R8a和R8b每次出现时分别独立地选自氢、氘、C1-6烷基、C1-6卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、-OR8d和-X2-R8d基团取代；R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl , C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl R 8a and R 8b and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted with 0, 1, 2 , 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 deuterated alkyl, C 1-6 alkyl, cyano, C 1-6 aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; preferably R 8a and R 8b and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 deuterated alkyl, C 1-6 alkyl, cyano, C 1-6 aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; preferably R 8a and R 8b is independently selected at each occurrence from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, said phenyl being optionally substituted with 0-2 groups selected from C 1-4 alkyl, -OR 8d and -X 2 -R 8d ;
R8c每次出现时各自独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；优选R8c选自氢、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基和C1-6卤代烷基； R 8c is independently selected at each occurrence from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl R 5-10 heteroaryl is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; preferably R 8c is selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 haloalkyl;
X2选自C1-6亚烷基和C2-6亚烯基； X2 is selected from C1-6 alkylene and C2-6 alkenylene;
R8d选自氢、C1-6烷基和C1-6卤代烷基；R 8d is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
J1和J2分别独立地选自单键、O、S、C(O)、S(O)、S(O2)、C(R1cR1d)、C(＝CR1eR1f)和N(R3)，优选地，J1和J2不同时为单键；J 1 and J 2 are independently selected from a single bond, O, S, C(O), S(O), S(O 2 ), C(R 1c R 1d ), C(═CR 1e R 1f ) and N(R 3 ), preferably, J 1 and J 2 are not single bonds at the same time;
其中R1c、R1d、R1e和R1f分别独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6氘代烷基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个个独立地选自卤素、氘、C1-6烷基、氨基、羟基、C1-6烷基氨基、C1-6氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和C1-6烷氧基的取代基取代；或R1c和R1d和其共同连接的碳原子组成一个3-10元亚环烷基或含有1-3个分别独立地选自N、O、P和S的杂原子的3-10元亚杂环烷基，其中所述亚环烷基或亚杂环烷基任选地被0、1、2、3或4个独立地选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氨基烷基和羟基的取代基取代；或R1e和R1f和其共同连接的碳原子组成一个3-10元亚环烷基或含有0、1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-10元亚杂环烷基，其中所述亚环烷基或亚杂环烷基任选地被0、1、2、3或4个独立选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氘代烷基、C1-6烷基、氰基、C1-6氨烷基、3-10元环烷基、3-10元杂环烷基和羟基的取代基取代；R3为-X1-R8，X1选自单键、-O-、-S-、C1-6亚烷氧基、C2-6亚烯基和C1-6亚烷基；R8选自氢、氘、卤素、C1-6烷基、C1-6卤代烷基、C6-10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳基；wherein R 1c , R 1d , R 1e and R 1f are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl, and C 5-10 heteroaryl are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl, and C R 1c and R 1d and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino , C 1-6 aminoalkyl and hydroxy; or R 1e and R 1d and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1 , 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy; wherein 1f and the carbon atom to which it is commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 deuterated alkyl, C 1-6 alkyl, cyano, C 1-6 aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; R 3 is -X 1 -R 8 , X 1 is selected from a single bond, -O-, -S-, C 1-6 alkyleneoxy, C 2-6 alkenylene and C 1-6 alkylene; R 8 is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 -6-10 membered aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, and 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S;
Linker C为连接A1和B1的连接子，为-La-Lb-Lc-Ld-Le-；Linker C is the linker connecting A1 and B1, which is -L a -L b -L c -L d -L e -;
La、Lc、和Le每次出现时各自独立地选自-(L)n-；L a , L c , and L e at each occurrence are each independently selected from -(L) n -;
n选自1、2、3、4、5和6；n is selected from 1, 2, 3, 4, 5 and 6;
L每次出现时独立地选自单键、-O-、-S-、C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、C1-6卤代亚烷基、-N(RL6)C(O)-、-N(RL6)S(O)-、-N(RL6)S(O2)-、-C(O)-、-OC(O)-、-NRL6-、-S(O)-、-S(O2)-、-S(O2)NRL6-、-CRL1RL2-、和C1-6亚烷基羟基，任选地，所述C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、和C1-6卤代亚烷基各自独立地被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；优选地，L每次出现独立地选自单键、-O-、-S-、C1-4亚烷基、C2-4亚烯基、C2-4亚炔基、-CRL1RL2-、-C(O)N(RL6)-、-C(O)-、-OC(O)-、-NRL6-、-S-、-S(O)-、和-S(O2)-，任选地，所述C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、和C1-6卤代亚烷基各自独立地被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；L is independently selected at each occurrence from a single bond, -O-, -S-, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 haloalkylene, -N(R L6 )C(O)-, -N(R L6 )S(O)-, -N(R L6 )S(O 2 )-, -C(O)-, -OC(O)-, -NR L6 -, -S(O)-, -S(O 2 )-, -S(O 2 )NR L6 -, -CR L1 R L2 -, and C 1-6 alkylenehydroxyl, optionally wherein the C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, and C 1-6 haloalkylene The 1-6 haloalkylene groups are each independently substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; preferably, each occurrence of L is independently selected from a single bond, -O-, -S-, C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -CR L1 R L2 -, -C(O)N(R L6 )-, -C(O)-, -OC(O)-, -NR L6 -, -S-, -S(O)-, and -S(O 2 )-, optionally, the C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, and C 2-4 alkynylene are independently selected from the group consisting of: 1-6 haloalkylene groups are each independently substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy;
RL6每次出现时各自独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；优选地，RL6每次出现时各自独立地选自氢、C1-6烷基、C3-10 环烷基和C1-6卤代烷基，任选地，所述C1-6烷基、C3-10环烷基和C1-6卤代烷基被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氨基、羟基、氨基烷基、烷基氨基、和烷氧基的取代基取代；R L6 is independently selected at each occurrence from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl The 5-10 heteroaryl group is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; preferably, each occurrence of R L6 is independently selected from hydrogen, C 1-6 alkyl, C 3-10 Cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
RL1和RL2每次出现时各自独立地选自氢、氘、羟基、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、-XL-ORL3、-XL-NRL4RL5、C1-6氘代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基和C5-10杂芳基，优选地RL1和RL2每次出现时分别独立地选自氢、氘、卤素、C1-6烷基、C1-6卤代烷基、-XL-ORL3、-XL-NRL4RL5和C3-10环烷基；或者RL1和RL2与其共同连接的碳原子形成成一个3-10元亚环烷基或含有1、2或3个分别独立地选自N、O、P和S的杂原子的3-10元亚杂环烷基，其中所述亚环烷基或亚杂环烷基任选地被0、1、2、3或4个独立地选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氨基烷基和羟基的取代基取代；优选地，RL1和RL2和其连接的碳组成3-10元亚环烷基；R L1 and R L2 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, -XL - OR L3 , -XL - NR L4LR L5 , C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, preferably R L1 and R L2 are each independently selected from hydrogen , deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -XL - OR L3 , -XL- NR L4LR L5 and C 3-10 cycloalkyl; or R L1 and R L2 and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1, 2 or 3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy; preferably, RL1 and RL2 and the carbon to which they are attached form a 3-10 membered cycloalkylene;
XL每次出现时各自独立选自C1-6亚烷基和C2-C6亚烯基； XL at each occurrence is independently selected from C1-6 alkylene and C2 - C6 alkenylene;
RL3选自氢、氘、C1-6烷基和C1-6卤代烷基； RL3 is selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl;
RL4和RL5分别独立地选自氢、氘、C1-6烷基和C1-6卤代烷基； RL4 and RL5 are independently selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl;
Lb、和Ld每次出现时各自独立地选自单键、亚环烷基、亚环烯基、亚杂环烷基、亚芳基、亚杂芳基、和亚稠杂环烷基，所述亚环烷基、亚环烯基、亚杂环烷基、亚芳基、亚杂芳基和亚稠杂环烷基可任选地被0、1、2、3、4、5或6个R9取代；优选地，Lb、Ld每次出现各自独立地选自单键、亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1-4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、3-7元亚杂环烯基、5-6元亚杂芳基和4-12元亚稠杂环烷基，所述亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1-4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、5-6元亚杂芳基和4-12元亚稠杂环烷基任选地被0-6个R9取代；优选且La、Lb、Lc、Ld、和Le不同时为单键；L b , and L d are each independently selected from a single bond, a cycloalkylene group, a cycloalkenylene group, a heterocycloalkylene group, an arylene group, a heteroarylene group, and a fused heterocycloalkylene group, wherein the cycloalkylene group, the cycloalkenylene group, the heterocycloalkylene group, the arylene group, the heteroarylene group, and the fused heterocycloalkylene group may be optionally substituted with 0, 1, 2, 3, 4, 5 or 6 R 9 ; preferably, L b , L d d is independently selected from a single bond, phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene at each occurrence, wherein the phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene are optionally substituted with 0-6 R 9 ; preferably, L a , L b , L c , L d , and L e are not single bonds at the same time;
R9每次出现时各自独立选自卤素、氘、烷基、卤代烷基、氰基、环烷基、杂环烷基、-S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a和-X4-OR9a；优选地，R9每次出现时分别独立地选自卤素、氘、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-7杂环烷基、-S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a和-X4-OR9a；优选地，R9每次出现时分别独立地选自F、Cl、Br、I、C1-3烷基、和C1-3卤代烷基；R 9 is independently selected from halogen, deuterium, alkyl, haloalkyl, cyano, cycloalkyl, heterocycloalkyl, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; preferably, R 9 is independently selected from halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, C 3 - 7 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; preferably, R 9 is independently selected from F, Cl, Br, I, C 1-6 C 1-3 alkyl, and C 1-3 haloalkyl;
R9a、R9b和R9c每次出现时各自独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基和C5-10杂芳基；优选地，R9a、R9b和R9c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；R 9a , R 9b and R 9c are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl; preferably, R 9a , R 9b and R 9c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
X4选自C1-6亚烷基和C2-6亚烯基；X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
当Lb和Ld各自独立地为亚苯基、或含有1或2个选自N和S的杂原子的5元亚杂芳基时，La和Le其中至少一个不为单键、或当La和Le同时为单键时，Lc选自-S-、C2-6亚烷基、C2-6亚烷氧基、C2-6亚烯基、C2-6亚炔基、C1-6卤代亚烷基、-N(RL6)S(O)-、-N(RL6)S(O2)-、-OC(O)-、-S(O)-、-S(O2)-、-S(O2)NRL6-、-和C1-6亚烷基羟基，任选地，所述C2-6亚烷基、C2-6亚烷氧基、C2-6亚烯基、C2-6亚炔基、和C1-6卤代亚烷基各自独立地被0、1、2、3、4、5或6个独立地选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；When L b and L d are each independently a phenylene group, or a 5-membered heteroarylene group containing 1 or 2 heteroatoms selected from N and S, at least one of La and Le is not a single bond, or when La and Le are both single bonds, L c is selected from -S-, C 2-6 alkylene, C 2-6 alkyleneoxy, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 haloalkylene, -N(R L6 )S(O)-, -N(R L6 )S(O 2 )-, -OC(O)-, -S(O)-, -S(O 2 )-, -S(O 2 )NR L6 -, - and C 1-6 alkylenehydroxyl, optionally, the C 2-6 alkylene, C 2-6 alkyleneoxy, C 2-6 alkenylene, C 2-6 alkynylene, and C 1-6 haloalkylene 1-6 haloalkylene groups are each independently substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy;
当Linker C为脂肪链时，Linker C为任选被取代的-C8H16-，优选为任选被取代的-(CH2)8-、优选为-(CH2)8-； When Linker C is an aliphatic chain, Linker C is optionally substituted -C 8 H 16 -, preferably optionally substituted -(CH 2 ) 8 -, preferably -(CH 2 ) 8 -;
当Lb、Ld其中一个为亚苯基或含有3个N原子的6元亚杂芳基，另一个为单键时，La、和Le不同时为单键；和When one of L b and L d is a phenylene group or a 6-membered heteroarylene group containing 3 N atoms, and the other is a single bond, L a and L e are not simultaneously single bonds; and
当A1和B1均为式(Ⅴ)，且La、和Le不为单键时，则La、和Le至少一个不为-O-。When A1 and B1 are both of formula (V), and La , and Le are not single bonds, then at least one of La , and Le is not -O-.
在一些实施方案中，其中Linker C选自式(Ⅸ)、(Ⅹ)、(Ⅺ)和(Ⅻ)：
In some embodiments, wherein Linker C is selected from Formula (IX), (X), (XI) and (XII):
R7a和R7b分别独立地选自氢、氘、卤素、C1-6烷基、C1-6卤代烷基、-X3-OR7c、-X3-NR7dR7e和C3-10环烷基；X3每次出现时各自独立选自C1-6亚烷基和C2-C6亚烯基；R7c选自氢、氘、C1-6烷基和C1-6卤代烷基；R7d和R7e分别独立地选自氢、氘、C1-6烷基和C1-6卤代烷基；或者R7a和R7b及其连接的碳组成3-10元环烷基；R 7a and R 7b are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl; X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence; R 7c is selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are connected form a 3-10 membered cycloalkyl;
R7a和R7b每次出现时各自独立地选自氢、氘、羟基、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、-XL-ORL3、-XL-NRL4RL5、C1-6氘代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基和C5-10杂芳基，优选地RL1和RL2每次出现时分别独立地选自氢、氘、卤素、C1-6烷基、C1-6卤代烷基、-XL-ORL3、-XL-NRL4RL5和C3-10环烷基；或者R7a和R7b与其共同连接的碳原子形成成一个3-10元亚环烷基或含有1、2或3个分别独立地选自N、O、P和S的杂原子的3-10元亚杂环烷基，其中所述亚环烷基或亚杂环烷基任选地被0、1、2、3或4个独立地选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氨基烷基和羟基的取代基取代；优选地，R7a和R7b和其连接的碳组成3-10元亚环烷基；R 7a and R 7b are each independently selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, -XL - OR L3 , -XL - NR L4LR L5 , C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, preferably R L1 and R L2 are each independently selected from hydrogen , deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -XL - OR L3 , -XL- NR L4LR L5 and C 3-10 cycloalkyl; or R 7a and R R 7a and R 7b and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1, 2 or 3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy; preferably, R 7a and R 7b and the carbon atom to which they are attached form a 3-10 membered cycloalkylene;
XL每次出现时各自独立选自C1-6亚烷基和C2-C6亚烯基； XL at each occurrence is independently selected from C1-6 alkylene and C2 - C6 alkenylene;
RL3选自氢、氘、C1-6烷基和C1-6卤代烷基； RL3 is selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl;
RL4和RL5分别独立地选自氢、氘、C1-6烷基和C1-6卤代烷基； RL4 and RL5 are independently selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl;
W选自以下基团：
W is selected from the following groups:
Q环和R环每次出现时各自独立地选自亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1、2、3或4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、3-7元亚杂环烯基、5-6元亚杂芳基和4-12元亚稠杂环烷基，所述亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1-4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、5-6元亚杂芳基和4-12元亚稠杂环烷基任选地被0-6个R9取代；Q ring and R ring are each independently selected at each occurrence from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene, said phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene optionally substituted with 0-6 R 9 ;
R9每次出现时各自独立选自卤素、氘、烷基、卤代烷基、氰基、环烷基、杂环烷基、 -S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a和-X4-OR9a；优选地，R9每次出现时分别独立地选自卤素、氘、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-7杂环烷基、-S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a和-X4-OR9a；优选地，R9每次出现时分别独立地选自F、Cl、Br、I、C1-3烷基、和C1-3卤代烷基；； R9, at each occurrence, is independently selected from halogen, deuterium, alkyl, haloalkyl, cyano, cycloalkyl, heterocycloalkyl, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; preferably, R 9 at each occurrence is independently selected from halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, C 3 - 7 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; preferably, R 9 at each occurrence is independently selected from F, Cl, Br, I, C 1-3 alkyl, and C 1-3 haloalkyl;;
R9a、R9b和R9c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；R 9a , R 9b and R 9c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
X4选自C1-6亚烷基和C2-6亚烯基；X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
T环和U环每次出现时分别独立地选自亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基，其中所述亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基任选地被0、1、2或3个独立地选自氰基、卤素、氨基、烷基氨基、氨基烷基、羟基、羟烷基、氨基酰基、氨磺酰基、C1-6烷基、C3-6杂环烷基、和C3-6环烷基的取代基取代，优选地，任选被选自F、Cl、Br、I、C1-3烷基、和C1-3卤代烷基地取代基取代；T ring and U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene at each occurrence, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 0, 1, 2 or 3 substituents independently selected from cyano, halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, C 3-6 heterocycloalkyl, and C 3-6 cycloalkyl, preferably, optionally substituted with substituents selected from F, Cl, Br, I, C 1-3 alkyl, and C 1-3 haloalkyl;
L1选自以下基团：
 L1 is selected from the following groups:
L2选自以下基团： L2 is selected from the following groups:
其中Y1、Y2、Y3、Y4、Y5、Y6、和Y7每次出现时分别独立地选自-O-、-NH-、-NHC(O)-、-NHS(O)-、-NHS(O2)-、-CH2-、-C(O)-、-S(O)-、-S(O2)-、-C(O)NH-、-S(O2)NH-、-CH＝CH-、-C≡C-和单键；wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are each independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 —, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH═CH—, —C≡C—, and a single bond;
a选自0、1、2、3、4和5；b和c分别独立选自0、1、2和3；d和e分别独立选自0、1和2；a is selected from 0, 1, 2, 3, 4 and 5; b and c are independently selected from 0, 1, 2 and 3; d and e are independently selected from 0, 1 and 2;
L3选自以下基团： L3 is selected from the following groups:
Y8、Y9、Y10、Y11和Y12分别独立地选自-O-、-NH-、-NHC(O)-、-NHS(O)-、-NHS(O2)-、-CRY1RY2-、-C(O)-、-S(O)-、-S(O2)-、-C(O)NH-、-S(O2)NH-、-CH＝CH-、-C≡C-、单键、亚苯基、含有1-4个独立地选自N、O、P和S杂原子的3-6元亚杂环烷基和含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂芳基；Y 8 , Y 9 , Y 10 , Y 11 and Y 12 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CR Y1 RY2 -, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH═CH—, —C≡C-, a single bond, phenylene, a 3-6 membered heterocycloalkylene group containing 1-4 heteroatoms independently selected from N, O, P and S, and a 5-6 membered heteroarylene group containing 1-4 heteroatoms independently selected from N, O, P and S;
RY1和RY2每次出现时分别独立地选自氢和C1-6烷基，或RY1和RY2与其连接的C形成3-6元亚环烷基或3-6元亚杂环烷基；和f、g、h、i和j分别独立选自0、1、2和3。3.如权利要求1或2所述的化合物，其中：R Y1 and R Y2 are independently selected from hydrogen and C 1-6 alkyl at each occurrence, or R Y1 and R Y2 form a 3-6 membered cycloalkylene or 3-6 membered heterocycloalkylene to the C to which they are attached; and f, g, h, i and j are independently selected from 0, 1, 2 and 3. 3. A compound as claimed in claim 1 or 2, wherein:
R1每次出现时不存在或各自独立地选自氢、氘、F、Cl、Br、I、氰基、羟基、酰胺基、磺酰胺基、C1-3烷基、-S-C1-3烷基、-S(O)-C1-3烷基、-S(O2)-C1-3烷基、-O-C1-3烷基、-O-C1-3卤代烷基、C1-3氘代烷基、3-6元环烷基、3-6元杂环烷基和-NR1aR1b，其中R1a和R1b分别独立地选自氢、氘、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、C1-3氘代烷 基、C3-6单环环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-6单环杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-3烷基、C1-3烷氧基、C1-3卤代烷基、C3-6单环环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-6单环杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个独立选自F、Cl、Br、I、氘、C1-3烷基、C1-3氘代烷基、氨基、羟基、C1-3烷基氨基、C1-3氨基烷基、氰基、3-6元环烷基、3-6元杂环烷基和C1-3烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个含有1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基，其中所述杂环烷基任选地被0、1、2、3或4个独立选自F、Cl、Br、I、氘、氨基、C1-3烷氧基、C1-3烷基氨基、C1-3氘代烷基、C1-3烷基、氰基、氨基烷基、3-6元环烷基、3-6元杂环烷基和羟基的取代基取代；和/或R 1 is absent at each occurrence or is independently selected from hydrogen, deuterium, F, Cl, Br, I, cyano, hydroxyl, amide, sulfonamide, C 1-3 alkyl, -SC 1-3 alkyl, -S(O)-C 1-3 alkyl, -S(O 2 )-C 1-3 alkyl, -OC 1-3 alkyl, -OC 1-3 haloalkyl, C 1-3 deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and -NR 1a R 1b , wherein R 1a and R 1b are independently selected from hydrogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 deuterated alkyl The present invention relates to a C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C3-6 monocyclic cycloalkyl, C3-6 monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C6-10 aryl and C5-10 heteroaryl, wherein the C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C3-6 monocyclic cycloalkyl, C3-6 monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C6-10 aryl and C5-10 heteroaryl are optionally substituted by 0, 1 , 2, 3, 4, 5 or 6 groups independently selected from F, Cl, Br, I, deuterium, C1-3 alkyl, C1-3 deuterated alkyl, amino, hydroxy, C1-3 alkylamino, C1-3 aminoalkyl, cyano, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and C or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a 3-6 membered heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl group is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, I, deuterium, amino, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 deuterated alkyl, C 1-3 alkyl, cyano, aminoalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and hydroxy; and/or
Z每次出现时各自独立地选自C和N；且当Z为N时，R1不存在；和/或Z is independently selected from C and N at each occurrence; and when Z is N, R 1 is absent; and/or
R2、R4和R6每次出现时分别独立地选自氢、氘、卤素、C1-3烷基、C2-3烷氧基、C1-3卤代烷基、3-6元单环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子3-6元单杂环烷基、3-6元环烷基-O-、3-6元杂环烷基-O-、和含有1-3个分别独立地选自N、O、P和S杂原子的3-12元单环杂芳基；优选地，R2、R4和R6每次出现时分别独立地选自氢、氘、氯、氟、Br、C1-3烷基、3-6元单环的环烷基、和含有1-3个分别独立地选自N、O、P和S的杂原子3-6元单杂环烷基；和/或R 2 , R 4 and R 6 are each independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 2-3 alkoxy, C 1-3 haloalkyl, 3-6 membered monocyclic cycloalkyl, 3-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, and 3-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R 2 , R 4 and R 6 are each independently selected from hydrogen, deuterium, chlorine, fluorine, Br, C 1-3 alkyl, 3-6 membered monocyclic cycloalkyl, and 3-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S; and/or
R5选自氢、C1-4烷基、C3-6环烷基、C3-6杂环烷基和C1-4卤代烷基；任选地，所述C1-4烷基、C3-6环烷基和C1-4卤代烷基被0-6个独立选自卤素、氘、C1-4烷基、氨基、羟基、和C1-4烷氧基的取代基取代；优选地，R5选自氢、C1-3烷基和C3-6环烷基，任选地，所述C1-3烷基、和C3-6环烷基被0-6个独立选自卤素、氘、C1-6烷基、氨基和羟基的取代基取代；更优选地，R5选自H和C1-3烷基；和/或R 5 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl and C 1-4 haloalkyl; optionally, the C 1-4 alkyl, C 3-6 cycloalkyl and C 1-4 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, C 1-4 alkyl, amino, hydroxyl and C 1-4 alkoxy; preferably, R 5 is selected from hydrogen, C 1-3 alkyl and C 3-6 cycloalkyl, optionally, the C 1-3 alkyl and C 3-6 cycloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, C 1-6 alkyl, amino and hydroxyl; more preferably, R 5 is selected from H and C 1-3 alkyl; and/or
G1和G2每次出现选自O、S、和NR2a；和/或 G1 and G2 are each selected from O, S, and NR2a ; and/or
R2a每次出现时各自独立地选自选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、苯基亚甲基、-CH2OCH2CH2Si(CH3)3、C1-3烷基、C1-3卤代烷基、C1-3烷基-S-、-S(O)-C1-3烷基、-SO2-C1-3烷基、-O-C1-3烷基、-O-C1-3卤代烷基、-NR2bR2c、-C1-3亚烷基-C3-6环烷基、C3-6环烷基-NR2b-、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基-NR2b-、3-6元单环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元单环杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基、3-6元卤代环烷基-O-、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-、6-10元单环芳基、含有1-3个分别独立地选自N、O、P和S的杂原子的5-6元单环杂芳基、和含有1-3个分别独立地选自N、O、P和S的杂原子的8-10元并环杂芳基；优选地，R2a选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、氨基、C1-3烷基、C1-3卤代烷基、C1-3烷基-S-、-S(O)-C1-3烷基、-SO2-C1-3烷基、-O-C1-3烷基、-O-C1-3卤代烷基、-NHC1-3烷基、-N(C1-3烷基)C1-3烷基、C3-6环烷基和-C1-3亚烷基-C3-6环烷基；优选地，R2a选自氢、F、Cl、Br、I、氰基、羟基、氨基、C1-3烷基、C1-3卤代烷基、-C1-3亚烷基-C3-6环烷基、和C3-6环烷基；R2b和R2c分别独立地选自氢和C1-6烷基；和/或R 2a at each occurrence is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, phenylmethylene, -CH 2 OCH 2 CH 2 Si(CH 3 ) 3 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-S-, -S(O)-C 1-3 alkyl, -SO 2 -C 1-3 alkyl, -OC 1-3 alkyl, -OC 1-3 haloalkyl, -NR 2b R 2c , -C 1-3 alkylene-C 3-6 cycloalkyl, C 3-6 cycloalkyl-NR 2b -, 3-6 membered heterocycloalkyl-NR 2b containing 1-3 heteroatoms independently selected from N, O, P and S -, 3-6 membered monocyclic alkyl, 3-6 membered monocyclic heterocyclic alkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated heterocyclic alkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocyclic alkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocyclic alkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 6-10 membered monocyclic aryl, 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, and 8-10 membered cyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-S-, -S(O)-C 1-3 alkyl, -SO 2 -C 1-3 alkyl, -OC 1-3 alkyl, -OC 1-3 haloalkyl, -NHC 1-3 alkyl, -N(C 1-3 alkyl)C 1-3 alkyl, C 3-6 cycloalkyl and -C 1-3 alkylene-C 3-6 cycloalkyl; preferably, R 2a is selected from hydrogen, F, Cl, Br, I, cyano, hydroxyl, amino, C 1-3 alkyl, C 1-3 haloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl and C 3-6 cycloalkyl; R 2b and R 2c are each independently selected from hydrogen and C 1-6 alkyl; and/or
J1和J2分别独立地选自单键、-O-、-S-、-C(O)-、-S(O)-、-S(O2)-、-C(R1cR1d)-、-C(＝CR1eR1f)-和-N(R3)-；优选地，J1和J2不同时为单键；其中R1c、R1d、R1e和R1f分别 独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6氘代烷基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个个独立地选自卤素、氘、C1-6烷基、氨基、羟基、C1-6烷基氨基、C1-6氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和C1-6烷氧基的取代基取代；或R1c和R1d和其共同连接的碳原子组成一个3-10元亚环烷基或含有1-3个分别独立地选自N、O、P和S的杂原子的3-10元亚杂环烷基，其中所述亚环烷基或亚杂环烷基任选地被0、1、2、3或4个独立地选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氨基烷基和羟基的取代基取代；或R1e和R1f和其共同连接的碳原子组成一个3-10元亚环烷基或含有0、1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-10元亚杂环烷基，其中所述亚环烷基或亚杂环烷基任选地被0、1、2、3或4个独立选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氘代烷基、C1-6烷基、氰基、C1-6氨烷基、3-10元环烷基、3-10元杂环烷基和羟基的取代基取代；和/或 J1 and J2 are independently selected from a single bond, -O-, -S-, -C(O)-, -S(O)-, -S( O2 ) - , -C( R1cR1d )-, -C(= CR1eR1f )- and -N( R3 )-; preferably, J1 and J2 are not single bonds at the same time; wherein R1c , R1d , R1e and R1f are respectively independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl , C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl are optionally substituted by 0, 1 , 2, 3, 4, 5 or 6 individuals independently selected from halogen, deuterium, C 1-6 alkyl, amino, hydroxyl, C R 1c and R 1d and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy; or R 1e and R 1d and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted with 0, 1 , 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy; 1f and the carbon atom to which it is commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 deuterated alkyl, C 1-6 alkyl, cyano, C 1-6 aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; and/or
R3为-X1-R8，X1选自单键、-O-、-S-、C1-3亚烷氧基、C2-3亚烯基和C1-3亚烷基；R8选自氢、氘、卤素、C1-3烷基、C1-3卤代烷基、C6-10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b、C3-6环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-6杂环烷基、和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳基。R 3 is -X 1 -R 8 , X 1 is selected from a single bond, -O-, -S-, C 1-3 alkyleneoxy, C 2-3 alkenylene and C 1-3 alkylene; R 8 is selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b , C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, and 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S.
在一些实施方案中，所述Q环、R环、Lb和Ld每次出现时各自独立地选自以下基团：
In some embodiments, each occurrence of the Q ring, the R ring, L b and L d is independently selected from the following groups:
在一些实施方案中，所述化合物选自如下结构：
In some embodiments, the compound is selected from the following structures:
在一些实施方案中，所述化合物选自如下结构：
In some embodiments, the compound is selected from the following structures:
其中，A、B、Linker C、式(Ⅱ)～(Ⅻ)定义同权利要求1-8任一项所述。Wherein, A, B, Linker C, and formula (II) to (XII) are defined as described in any one of claims 1-8.
在一些实施方案中，Linker C选自以下结构：


In some embodiments, Linker C is selected from the following structures:


1.化合物，所述化合物为式(Ⅰ)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
1. A compound, wherein the compound is a compound represented by formula (I), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:
其中A环和B环各自独立选自式(Ⅱ)、(Ⅲ)和(Ⅳ)：
Wherein ring A and ring B are independently selected from formula (II), (III) and (IV):
其中Linker C为连接A环和B环的连接子，选自式(Ⅴ)、(Ⅵ)和(Ⅶ)：
Wherein Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI) and (VII):
其中，R1a、R1b、R1c和R1d分别独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0-6个独立选自卤素、氘、烷基、氨基、羟基、烷基氨基、氨烷基、和烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个3-10元杂环烷基，其中所述杂环烷基任选地被0-3个独立选自卤素、氘、氨基、烷氧基、烷基氨基、氨烷基和羟基的取代基取代；或R1c和R1d和其共同连接的氮原子组成一个3-10元杂环烷基，其中所述杂环烷基任选地被0-3个独立选自卤素、氘、氨基、烷氧基、氨烷基和羟基的取代基取代； wherein R 1a , R 1b , R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl and alkoxy; or R 1a and R R 1c and R 1d and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, alkylamino, aminoalkyl and hydroxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, aminoalkyl and hydroxy;
R2、R4和R6分别独立地选自氢、氘、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6单烷基氨基、C2-6双烷基氨基、C1-6卤代烷基氨基、3-12元单环的环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单杂环烷基、5-12元螺杂环烷基和4-12元桥杂环烷基、C1-6烷基-S-、C1-6烷基-SO-、C1-6烷基-SO2-、3-6元环烷基-O-、3-6元杂环烷基-O-、5-10元单环芳基、5-10元并环芳基、和含有1-3个分别独立地选自N、O、P和S杂原子的3-12元单环杂芳基和7-10元并环杂芳基； R2 , R4 and R6 are independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 monoalkylamino, C2-6 dialkylamino, C1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1-6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cycloaryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S;
R5选自氢、C1-6烷基、C3-10环烷基和C1-6卤代烷基，任选地，所述C1-6烷基、C3-10环烷基和C1-6卤代烷基被0-6个独立选自卤素、氘、烷基、氨基、羟基、氨基烷基、烷基氨基、和烷氧基的取代基取代；R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
E、G、J和Z每次出现时分别独立地选自N和CR2a；其中R2a选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、C1-6烷基、C1-6卤代烷基、C1-6烷基-S-、C1-6烷基-SO-、C1-6烷基-SO2-、C1-6烷基-O-、C1-6卤代烷基-O-、-NR2bR2c、C3-6环烷基氨基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基氨基、3-12元单环烷基、5-12元螺环烷基和4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂环烷基、5-12元螺杂环烷基和4-12元桥杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基、3-6元卤代环烷基-O-、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-、5-12元单环芳基、5-12元并环芳基、和含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂芳基和7-10元并环杂芳基；R2b和R2c分别独立地选自氢和C1-6烷基；E, G, J and Z are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -, C 1-6 alkyl-O-, C 1-6 haloalkyl-O-, -NR 2b R 2c , C 3-6 -membered cycloalkylamino, 3-6-membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12-membered monocyclic alkyl, 5-12-membered spirocycloalkyl and 4-12-membered bridged cycloalkyl, 3-12-membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12-membered spirocycloheterocycloalkyl and 4-12-membered bridged heterocycloalkyl, 3-6-membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6-membered R 2b and R 2c are independently selected from hydrogen and C 1-6 alkyl ;
R3为-X1-R8，X1选自化学键、C2-6亚烯基和C1-6亚烷基；R8选自氢、卤素、C1-6烷基、C1-6卤代烷基、C6-10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳环；R8a和R8b每次出现时分别独立地选自氢、氘、C1-6烷基、C1-6卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、-OR8d和-X2-R8d基团取代；R8c选自氢、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基和C1-6卤代烷基；X2选自C1-6亚烷基和C2-6亚烯基；R8d选自氢、C1-6烷基和C1-6卤代烷基；R 3 is -X 1 -R 8 , X 1 is selected from a chemical bond, C 2-6 alkenylene and C 1-6 alkylene; R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, the phenyl being optionally substituted with 0-2 groups selected from C 1-4 alkyl, -OR 8d and -X 2 -R 8d ; R 8c is selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-10 aryl. X2 is selected from C1-6 alkylene and C2-6 alkenylene; R8d is selected from hydrogen, C1-6 alkyl and C1-6 haloalkyl;
R7a和R7b分别独立地选自氢、卤素、C1-6烷基、C1-6卤代烷基、-X3-OR7c、-X3-NR7dR7e和C3-10环烷基；X3每次出现时各自独立选自C1-6亚烷基和C2-C6亚烯基；R7c选自氢、C1-6烷基和C1-6卤代烷基；R7d和R7e分别独立地选自氢、C1-6烷基和C1-6卤代烷基；或者R7a和R7b和其连接的碳组成3-10元环烷基；R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl; X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence; R 7c is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; R 7d and R 7e are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are connected form a 3-10 membered cycloalkyl;
W环选自以下基团：
The W ring is selected from the following groups:
Q环选自含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂环烷基和5-6元亚杂芳基，所述亚杂环烷基和所述亚杂芳基任选地被0-2个R9取代，R9每次出现时分别独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-6杂环烷基、-S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a 和-X4-OR9a；R9a、R9b和R9c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；X4选自C1-6亚烷基和C2-6亚烯基；The Q ring is selected from 5-6 membered heterocycloalkylene and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and said heteroarylene are optionally substituted by 0-2 R 9 , and R 9 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; R 9a , R 9b and R 9c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
R环为含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂环烷基或5-6元亚杂芳基，所述亚杂环烷基和亚杂芳基任选地被0-2个R10取代，R10每次出现时分别独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-6杂环烷基、-S(O2)R10a、-NR10bR10c、-X5-NR10bR10c、-OR10a和-X5-OR10a；R10a、R10b和R10c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；X5选自C1-6亚烷基和C2-6亚烯基；The R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , R 10 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c , -X 5 -NR 10b R 10c , -OR 10a and -X 5 -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 5 is selected from C 5 C 1-6 alkylene and C 2-6 alkenylene;
T环和U环分别独立地选自亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基，其中所述亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基任选地被1-3个独立地选自卤素、氨基、烷基氨基、氨烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的取代基取代；The T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 1-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl and C 3-6 cycloalkyl;
L1选自以下基团：
 L1 is selected from the following groups:
L2选自以下基团： L2 is selected from the following groups:
其中Y1、Y2、Y3、Y4、Y5、Y6、和Y7分别独立地选自-O-、-NH-、-NHC(O)-、-NHS(O)-、-NHS(O2)-、-CH2-、-C(O)-、-S(O)-、-S(O2)-、-C(O)NH-、-S(O2)NH-、-CH＝CH-、-C≡C-和单键，其中所述的氢原子任选地被0-2个独立地选自氘、卤素、氨基、烷基氨基、氨烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的取代基取代；wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 -, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH═CH—, —C≡C—, and a single bond, wherein the hydrogen atom is optionally substituted with 0-2 substituents independently selected from deuterium, halogen, amino, alkylamino, aminoalkyl, hydroxy, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, and C 3-6 cycloalkyl;
a为0-5的整数；b和c分别为0-3的整数；d和e分别为0-2的整数；和a is an integer from 0 to 5; b and c are each an integer from 0 to 3; d and e are each an integer from 0 to 2; and
L1和L2任选地被1-5个R11取代，R11分别独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自氧、硫和氮的杂原子的3-6元杂环烷基、-S(O2)R11a、NR11bR11c、-X6-NR11bR11c、-OR11a和-X6-OR11a；R11a、R11b和R11c每次出现时各自独立地选自氢、C1-6烷基和C1-6卤代烷基；X6选自C1-6亚烷基和C2-6亚烯基。L 1 and L 2 are optionally substituted by 1-5 R 11 , R 11 are independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O 2 )R 11a , NR 11b R 11c , -X 6 -NR 11b R 11c , -OR 11a and -X 6 -OR 11a ; R 11a , R 11b and R 11c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 6 is selected from C 1-6 alkylene and C 2-6 alkenylene.
2.如权利要求1所述的化合物，其中：2. The compound of claim 1, wherein:
R1a和R1b分别独立地选自氢、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、和C1-4烷基，其中C1-4烷基任选地被0-6个独立选自卤素、氘、氨基、羟基、氨烷基和烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个四元、五元或六元杂环烷基，其中所述杂环烷基任选地被0-3个独立地选自卤素、氨基和羟基的取代基取代；或R 1a and R 1b are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
R2、R4和R6分别独立地选自卤素、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、C1-3单烷基氨基、C1-3双烷基氨基、C1-3卤代烷基氨基、含有3-12元单环的环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子3-12元单杂环烷基、5-12元螺杂环烷基和4-12元桥杂环烷基、C1-C6烷基-S-、C1-6烷基-SO-、C1-6烷基-SO2-、3-6元环烷基-O-、3-6元杂环烷基-O-、5-10元单环芳基、5-10元并环芳基、和含有1-3个分别独立地选自N、O、P和S杂原子的3-12元单环杂芳基和7-10元并环杂芳基；或 R2 , R4 and R6 are independently selected from halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 monoalkylamino, C1-3 dialkylamino, C1-3 haloalkylamino, cycloalkyl containing 3-12 membered monocyclic ring, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1 - C6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cycloheteroaryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; or
R5选自氢、C1-3烷基和C1-3卤代烷基；或 R5 is selected from hydrogen, C1-3 alkyl and C1-3 haloalkyl; or
E、G、J和Z分别独立地选自N和CR2a；其中R2a选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、C1-3烷基、C1-3卤代烷基、C1-3烷基-S-、C1-C3烷基-SO-、C1-3烷基-SO2-、C1-3烷基-O-、C1-3卤代烷基-O-、-NR2bR2c、C3-6环烷基氨基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基氨基、3-6元卤代环烷基、含有1-3个独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-；R2b和R2c分别独立地选自氢和C1-C6烷基；或E, G, J and Z are independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-S-, C 1 -C 3 alkyl-SO-, C 1-3 alkyl-SO 2 -, C 1-3 alkyl-O-, C 1-3 haloalkyl-O-, -NR 2b R 2c , C 3-6 membered cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C 1 -C 6 alkyl; or
R3为-X1-R8，X1选自化学键、C2-C4亚烯基和C1-C4亚烷基；R8选自氢、卤素、C1-C3烷基、C1-C3卤代烷基、C6-C10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳环；R8a和R8b每次出现时分别独立地选自氢、氘、C1-C3烷基、C1-C3卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、-OR8d和-X2-R8d基团取代；R8c选自氢、C1-6烷基和C1-6卤代烷基；X2选自C1-6亚烷基和C2-6亚烯基；R8d选自氢、C1-4烷基和C1-4卤代烷基；或 R3 is -X1 - R8 , X1 is selected from a chemical bond, C2 - C4 alkenylene and C1 - C4 alkylene; R8 is selected from hydrogen, halogen, C1 - C3 alkyl, C1 - C3 haloalkyl, C6 - C10 aryl, -NR8aR8b , -C(O) R8c , -C(O) NR8aR8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R8a and R8b are independently selected from hydrogen, deuterium, C1 - C3 alkyl, C1 - C3 haloalkyl and phenyl at each occurrence , the phenyl being optionally substituted with 0-2 groups selected from C1-4 alkyl, -OR8d and -X2 - R8d ; R8c is selected from hydrogen, C1-6 alkyl and C X2 is selected from C1-6 alkylene and C2-6 alkenylene; R8d is selected from hydrogen, C1-4 alkyl and C1-4 haloalkyl; or
R1c和R1d分别独立地选自氢、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、和C1-4烷基，其中C1-4烷基任选地被0-6个独立选自卤素、氘、氨基、羟基、氨烷基和烷氧基的取代基取代；或R1c和R1d和其共同连接的氮原子组成一个四元、五元或六元杂环烷基，其中所述杂环烷基任选地被0-3个独立地选自卤素、氨基和羟基的取代基取代；或R 1c and R 1d are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
R7a和R7b分别独立地选自氢、卤素、C1-4烷基和C1-4卤代烷基；或R 7a and R 7b are each independently selected from hydrogen, halogen, C 1-4 alkyl and C 1-4 haloalkyl; or
Q环任选地被1-2个R9取代，R9每次出现时分别独立地选自卤素、C1-C3烷基、C1-C3卤代烷基、氰基、C3-C6环烷基、含有1-3个杂原子的3-6元杂环烷基，所述杂原子分别独立地选自N、O和S、-S(O2)R9a、NR9bR9c和-OR9a；每个R9a、R9b和R9c每次出现时分别独立地选自氢、C1-3烷基和C1-3卤代烷基；或The Q ring is optionally substituted with 1-2 R 9 , each of which is independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms, each of which is independently selected from N, O and S, -S(O 2 )R 9a , NR 9b R 9c and -OR 9a ; each of R 9a , R 9b and R 9c is independently selected from hydrogen, C 1-3 alkyl and C 1-3 haloalkyl at each occurrence; or
R环为含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂环烷基或5-6元亚杂芳基，所述亚杂环烷基和亚杂芳基任选地被0-2个R10取代，R10每次出现时分别独立地选自卤素、C1-C3烷基、C1-C3卤代烷基、氰基、C3-C6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-6杂环烷基、-S(O2)R10a、-NR10bR10c和-OR10a；R10a、R10b和R10c每次出现时分别独立地选自氢、C1-C3烷基和C1-C3卤代烷基；或The R ring is a 5-6 membered heterocycloalkylene or 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , R 10 is independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c and -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl at each occurrence; or
T环和U环分别独立地选自亚苯基和亚吡啶基，其中所述的亚苯基、亚吡啶基任选地被1-3个独立地选自卤素、氨基、烷基氨基、氨烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的取代基取代。The T ring and the U ring are independently selected from phenylene and pyridinylene, respectively, wherein the phenylene and pyridinylene are optionally substituted by 1-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C1-6 alkyl and C3-6 cycloalkyl.
3.如权利要求1所述的化合物，其中：3. The compound of claim 1, wherein:
R2选自氢、氟、氯、环丙基、C1-3烷基和C1-3卤代烷基；或 R2 is selected from hydrogen, fluorine, chlorine, cyclopropyl, C1-3 alkyl and C1-3 haloalkyl; or
R3为氢；或 R3 is hydrogen; or
R4选自氢、氟、氯、溴和环丙基；或R 4 is selected from hydrogen, fluorine, chlorine, bromine and cyclopropyl; or
R6选自氢、氟、氯和环丙基；或 R6 is selected from hydrogen, fluorine, chlorine and cyclopropyl; or
R5选自氢和甲基；或 R5 is selected from hydrogen and methyl; or
R1c和R1d分别独立地选自氢和C1-C3烷基；优选地，R1c和R1d分别独立地选自氢和甲基；或R 1c and R 1d are independently selected from hydrogen and C 1 -C 3 alkyl; preferably, R 1c and R 1d are independently selected from hydrogen and methyl; or
所述Q环选自以下基团：
The Q ring is selected from the following groups:
其中，所述每个Q环基团左边的连接位点各自独立与式(V)中-CR7aR7b-相连，所述每个Q环基团右边的连接位点各自独立与式(V)中R环相连；或wherein the connection site on the left side of each Q ring group is independently connected to -CR 7a R 7b - in formula (V), and the connection site on the right side of each Q ring group is independently connected to the R ring in formula (V); or
R环选自以下基团：
The R ring is selected from the following groups:
其中，所述每个R环基团的右边的连接位点各自独立与式(Ⅴ)中Q环相连，所述每个R环基团的左边的连接位点各自独立与式Ⅰ中A环或B环相连。The right connecting site of each R ring group is independently connected to the Q ring in formula (V), and the left connecting site of each R ring group is independently connected to the A ring or the B ring in formula I.
4.如权利要求1-3任一项所述的化合物，所述化合物选自式(Ⅰ-A)、(Ⅰ-B)、(Ⅰ-C)、(Ⅰ-D)、(Ⅰ-E)、(Ⅰ-F)和(Ⅰ-G)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
4. The compound according to any one of claims 1 to 3, wherein the compound is selected from the compounds represented by formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) and (I-G), or their isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates:
其中，Q环、R环、T环、U环、W环、R1a、R1b、R1c、R1d、R7a、R7b、R2、R3、R4、R5和R6定义同权利要求1或2或3。Wherein, the Q ring, R ring, T ring, U ring, W ring, R 1a , R 1b , R 1c , R 1d , R 7a , R 7b , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in claim 1 , 2 or 3.
5.如权利要求1-3任一项所述的化合物，其中，A环、B环各自独立地选自式(Ⅱ-1)、(Ⅳ-1)和(Ⅲ-1)：
5. The compound according to any one of claims 1 to 3, wherein Ring A and Ring B are each independently selected from Formula (II-1), (IV-1) and (III-1):
其中，R1a、R1b、R1c、R1d、R2、R3、R4、R5和R6的定义同权利要求1或2或3。wherein R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 4 , R 5 and R 6 have the same definitions as in claim 1 , 2 or 3.
6.如权利要求1-3任一项所述的化合物，其中所述化合物选自式(Ⅰ-A-1)、(Ⅰ-A-2)、(Ⅰ-A-3)、(Ⅰ-A-4)、(Ⅰ-F-1)、(Ⅰ-F-2)、(Ⅰ-F-3)、(Ⅰ-F-4)、(Ⅰ-F-5)、(Ⅰ-F-6)、(Ⅰ-F-7)和(Ⅰ-F-8)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
6. The compound according to any one of claims 1 to 3, wherein the compound is selected from the compounds represented by formula (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-F-3), (I-F-4), (I-F-5), (I-F-6), (I-F-7) and (I-F-8), or their isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates:
其中Qa环的定义与权利要求1或2或3中Q环的定义一致；Ra环的定义与权利要求1或2或3中R环的定义一致；R1a、R1b、R1c、R1d、R7a、R7b、E、G、J、Z、L2、R2和R6的定义同权利要求1或2或3。The definition of Qa ring is consistent with the definition of Q ring in claim 1, 2 or 3; the definition of Ra ring is consistent with the definition of R ring in claim 1, 2 or 3; R1a , R1b , R1c , R1d , R7a , R7b , E, G, J, Z, L2 , R2 and R6 are defined the same as in claim 1, 2 or 3.
2、化合物，所述化合物为式(Ⅰ)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
2. A compound, wherein the compound is a compound represented by formula (I), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:
其中A环和B环相同或不同，A环和B环各自独立选自式(Ⅱ)、(Ⅲ)和(Ⅳ)：
Wherein ring A and ring B are the same or different, and ring A and ring B are independently selected from formula (II), (III) and (IV):
其中Linker C为连接A环和B环的连接子，选自式(Ⅴ)、(Ⅵ)、(Ⅵ-2)和(Ⅶ)：
Wherein Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI), (VI-2) and (VII):
其中，R1a、R1b、R1c和R1d分别独立地选自氢、氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、羟烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0-6个独立选自卤素、氘、烷基、氨基、羟基、烷基氨基、氨烷基、和烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个3-10元杂环烷基，其中所述杂环烷基任选地被0-3个独立选自卤素、氘、氨基、烷氧基、烷基氨基、氨烷基和羟基的取代基取代；或R1c和R1d和其共同连接的氮原子组成一个3-10元杂环烷基，其中所述杂环烷基任选地被0-3个独立选自卤素、氘、氨基、烷氧基、氨烷基和羟基的取代基取代；wherein R 1a , R 1b , R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyalkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl and alkoxy; or R 1a and R R 1c and R 1d and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, alkylamino, aminoalkyl and hydroxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, aminoalkyl and hydroxy;
R2、R4和R6分别独立地选自氢、氘、卤素、C1-6烷基、C1-6烯基、C1-6炔基、C1-6烷氧基、C1-6卤代烷基、-NHC1-6烷基、-N(C1-6烷基)C1-6烷基、C1-6卤代烷氧基、C1-6卤代烷基氨基、3-12元单环的环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单杂环烷基、5-12元螺杂环烷基和4-12元桥杂环烷基、C1-6烷基-S-、C1-6烷基-SO-、C1-6烷基-SO2-、3-6元环烷基-O-、3-6元杂环烷基-O-、5-10元单环芳基、5-10元并环芳基、和含有1-3个分别独立地选自N、O、P和S杂原子的3-12元单环杂芳基和7-10元并环杂芳基；R 2 , R 4 and R 6 are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 haloalkylamino , 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cycloaryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S;
R5选自氢、C1-6烷基、C3-10环烷基和C1-6卤代烷基，任选地，所述C1-6烷基、C3-10环烷基和C1-6卤代烷基被0-6个独立选自卤素、氘、烷基、氨基、羟基、氨基烷基、烷基氨基、和烷氧基的取代基取代；R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
E、G、J和Z每次出现时分别独立地选自N和CR2a；其中R2a选自氢、氘、卤素、氰基、羟基、--NHCO-C1-6烷基、-COHN2、-C1-6烷基-COHN2、磺酰胺基、-NHCONH2、-NH-CS-NH2、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷基-S-、C1-6烷基-SO-、C1-6烷基-SO2-、C1-6烷基-O-、C1-6卤代烷基-O-、-NR2bR2c、C1-6烷基氨基、C2-6二烷基氨基、-CONH2、-NHC1-6烷基、-N(C1-6烷基)C1-6烷基、C3-6环烷基氨基、C3-6环烷基烷氧基、羟烷基、羟烷氧基、羟烷基氨基、烷氧基烷基、烷氧基烷氧基、烷氧基烷基氨基、氨基烷基、氨基烷氧基、氨基烷基氨基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基氨基、3-12元单环烷基、5-12元螺环烷基和4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂环烷基、5-12元螺杂环烷基和4-12元桥杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基、3-6元卤代环烷基-O-、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-、5-12元单环芳基、5-12元并环芳基、和含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂芳基和7-10元并环杂芳基；R2b和R2c分别独立地选自氢和C1-6烷基；E, G, J and Z are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, --NHCO-C 1-6 alkyl, -COHN 2 , -C 1-6 alkyl-COHN 2 , sulfonamido, -NHCONH 2 , -NH-CS-NH 2 , amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -, C 1-6 alkyl-O-, C 1-6 haloalkyl-O-, -NR 2b R 2c , C 1-6 alkylamino, C 2-6 dialkylamino, -CONH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 3-6 cycloalkylamino, C 1-6 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12 membered monocyclic alkyl, 5-12 membered spirocyclic alkyl and 4-12 membered bridged cycloalkyl, 3-12 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spirocyclic heterocycloalkyl and 4-12 membered bridged heterocycloalkyl, 1-3 heteroatoms independently selected from N, O, P and S ... 3-6 membered halogenated heterocycloalkyl containing heteroatoms selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered monocyclic aryl, 5-12 membered paracyclic aryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered paracyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C 1-6 alkyl;
R3为-X1-R8，X1选自化学键、-O-、-S-、烷氧基、C2-6亚烯基和C1-6亚烷基；R8选自氢、卤素、C1-6烷基、C1-6卤代烷基、C6-10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳环；R8a和R8b每次出现时分别独立地选自氢、氘、C1-6烷基、C1-6卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、卤素、羟基、氰基、氨基、-OR8d和-X2-R8d基团取代；R8c选自氢、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基和C1-6卤代烷基；X2选自C1-6亚烷基和C2-6亚烯基；R8d选自氢、C1-6烷基和C1-6卤代烷基； R 3 is -X 1 -R 8 , X 1 is selected from a chemical bond, -O-, -S-, alkoxy, C 2-6 alkenylene and C 1-6 alkylene; R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, and the phenyl is optionally substituted with 0-2 groups selected from C 1-4 alkyl, halogen, hydroxy, cyano, amino, -OR 8d and -X 2 -R 8d ; R 8c is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 haloalkyl; X 2 is selected from C 1-6 alkylene and C 2-6 alkenylene; R 8d is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
R7a和R7b分别独立地选自氢、卤素、C1-6烷基、C1-6卤代烷基、-X3-OR7c、-X3-NR7dR7e和C3-10环烷基；X3每次出现时各自独立选自C1-6亚烷基和C2-C6亚烯基；R7c选自氢、氘、C1-6烷基和C1-6卤代烷基；R7d和R7e分别独立地选自氢、氘、C1-6烷基和C1-6卤代烷基；或者R7a和R7b和其连接的碳组成3-10元环烷基；R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl; X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence; R 7c is selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are attached form a 3-10 membered cycloalkyl;
W选自以下基团：
W is selected from the following groups:
Q环选自含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂环烷基和5-6元亚杂芳基，所述亚杂环烷基和所述亚杂芳基任选地被0-2个R9取代，R9每次出现时分别独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-6杂环烷基、-S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a和-X4-OR9a；R9a、R9b和R9c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；X4选自C1-6亚烷基和C2-6亚烯基；The Q ring is selected from 5-6 membered heterocycloalkylene and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and said heteroarylene are optionally substituted by 0-2 R 9 , R 9 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; R 9a , R 9b and R 9c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
R环为含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂环烷基或5-6元亚杂芳基，所述亚杂环烷基和亚杂芳基任选地被0-2个R10取代，R10每次出现时分别独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-6杂环烷基、-S(O2)R10a、-NR10bR10c、-X5-NR10bR10c、-OR10a和-X5-OR10a；R10a、R10b和R10c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；X5选自C1-6亚烷基和C2-6亚烯基；The R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , R 10 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c , -X 5 -NR 10b R 10c , -OR 10a and -X 5 -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 5 is selected from C 5 C 1-6 alkylene and C 2-6 alkenylene;
T环和U环分别独立地选自亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基，其中所述亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基任选地被1-3个独立地选自卤素、氨基、烷基氨基、氨烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的取代基取代；The T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 1-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl and C 3-6 cycloalkyl;
L1选自以下基团：
 L1 is selected from the following groups:
L2选自以下基团： L2 is selected from the following groups:
其中Y1、Y2、Y3、Y4、Y5、Y6、和Y7分别独立地选自-O-、-NH-、-NHC(O)-、-NHS(O)-、-NHS(O2)-、-CH2-、-C(O)-、-S(O)-、-S(O2)-、-C(O)NH-、-S(O2)NH-、-CH＝CH-、-C≡C-和单键，其中所述L2中的氢原子各自独立地被选自氘、卤素、氨基、烷基氨基、氨烷基、-CONH2、-NHCO-C1-6烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的任一取代基取代；wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 —, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH═CH—, —C≡C—, and a single bond, wherein the hydrogen atoms in said L 2 are each independently substituted with any substituent selected from deuterium, halogen, amino, alkylamino, aminoalkyl, —CONH 2 , —NHCO—C 1-6 alkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, and C 3-6 cycloalkyl;
a为0-5的整数；b和c分别为0-3的整数；d和e分别为0-2的整数；和a is an integer from 0 to 5; b and c are integers from 0 to 3; d and e are integers from 0 to 2; and
L1和L2任选地被1-5个R11取代，R11分别独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自氧、硫和氮的杂原子的3-6元杂环烷基、-S(O2)R11a、NR11bR11c、-X6-NR11bR11c、-OR11a和-X6-OR11a；R11a、R11b和R11c每次出现时各自 独立地选自氢、C1-6烷基和C1-6卤代烷基；X6选自C1-6亚烷基和C2-6亚烯基。 L1 and L2 are optionally substituted by 1-5 R11 , R11 are independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, cyano, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O2)R11a, NR11bR11c, -X6- NR11bR11c , -OR11a and -X6-OR11a; R11a, R11b and R11c are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, cyano, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O2)R11a, NR11bR11c , -X6 - NR11bR11c , -OR11a and -X6 - OR11a ; R11a , R11b and R11c are each independently selected from independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 6 is selected from C 1-6 alkylene and C 2-6 alkenylene.
3.如权利要求2所述的化合物，其中：3. The compound of claim 2, wherein:
R1a和R1b分别独立地选自氢、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、和C1-4烷基，其中C1-4烷基任选地被0-6个独立选自卤素、氘、氨基、羟基、氨烷基和烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个四元、五元或六元杂环烷基，其中所述杂环烷基任选地被0-3个独立地选自卤素、氨基和羟基的取代基取代；或R 1a and R 1b are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
R2、R4和R6分别独立地选自卤素、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、-NHC1-3烷基、-N(C1-3烷基)C1-3烷基、C1-3卤代烷基氨基、含有3-12元单环的环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子3-12元单杂环烷基、5-12元螺杂环烷基和4-12元桥杂环烷基、C1-C6烷基-S-、C1-6烷基-SO-、C1-6烷基-SO2-、3-6元环烷基-O-、3-6元杂环烷基-O-、5-10元单环芳基、5-10元并环芳基、和含有1-3个分别独立地选自N、O、P和S杂原子的3-12元单环杂芳基和7-10元并环杂芳基；或 R2 , R4 and R6 are independently selected from halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, -NHC1-3 alkyl, -N( C1-3 alkyl) C1-3 alkyl, C1-3 haloalkylamino, cycloalkyl containing 3-12 membered monocyclic ring, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1 - C6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cycloheteroaryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; or
R5选自氢、C1-3烷基和C1-3卤代烷基；或 R5 is selected from hydrogen, C1-3 alkyl and C1-3 haloalkyl; or
E、G、J和Z分别独立地选自N和CR2a；其中R2a选自氢、氘、卤素、氰基、羟基、-NHCO-C1-6烷基、-CONH2、-C1-6烷基-CONH2、磺酰胺基、C1-3烷基、C1-3卤代烷基、C1-3烷基-S-、C1-C3烷基-SO-、C1-3烷基-SO2-、C1-3烷基-O-、C1-3卤代烷基-O-、-NR2bR2c、C3-6环烷基氨基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基氨基、3-6元卤代环烷基、含有1-3个独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-；R2b和R2c分别独立地选自氢和C1-C6烷基；或E, G, J and Z are independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -NHCO-C 1-6 alkyl, -CONH 2 , -C 1-6 alkyl-CONH 2 , sulfonamido, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-S-, C 1 -C 3 alkyl-SO-, C 1-3 alkyl-SO 2 -, C 1-3 alkyl-O-, C 1-3 haloalkyl-O-, -NR 2b R 2c , C 3-6 membered cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C 1 -C 6 alkyl; or
R3为-X1-R8，X1选自化学键、C2-C4亚烯基和C1-C4亚烷基；R8选自氢、卤素、C1-C3烷基、C1-C3卤代烷基、C6-C10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳环；R8a和R8b每次出现时分别独立地选自氢、氘、C1-C3烷基、C1-C3卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、-OR8d和-X2-R8d基团取代；R8c选自氢、C1-6烷基和C1-6卤代烷基；X2选自C1-6亚烷基和C2-6亚烯基；R8d选自氢、C1-4烷基和C1-4卤代烷基；或 R3 is -X1 - R8 , X1 is selected from a chemical bond, C2 - C4 alkenylene and C1 - C4 alkylene; R8 is selected from hydrogen, halogen, C1 - C3 alkyl, C1 - C3 haloalkyl, C6 - C10 aryl, -NR8aR8b , -C(O) R8c , -C(O) NR8aR8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R8a and R8b are independently selected from hydrogen, deuterium, C1 - C3 alkyl, C1 - C3 haloalkyl and phenyl at each occurrence , the phenyl being optionally substituted with 0-2 groups selected from C1-4 alkyl, -OR8d and -X2 - R8d ; R8c is selected from hydrogen, C1-6 alkyl and C X2 is selected from C1-6 alkylene and C2-6 alkenylene; R8d is selected from hydrogen, C1-4 alkyl and C1-4 haloalkyl; or
R1c和R1d分别独立地选自氢、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、和C1-4烷基，其中C1-4烷基任选地被0-6个独立选自卤素、氘、氨基、羟基、氨烷基和烷氧基的取代基取代；或R1c和R1d和其共同连接的氮原子组成一个四元、五元或六元杂环烷基，其中所述杂环烷基任选地被0-3个独立地选自卤素、氨基和羟基的取代基取代；或R 1c and R 1d are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
R7a和R7b分别独立地选自氢、氘、卤素、C1-4烷基和C1-4卤代烷基；或R 7a and R 7b are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl and C 1-4 haloalkyl; or
Q环任选地被1-2个R9取代，R9每次出现时分别独立地选自卤素、C1-C3烷基、C1-C3卤代烷基、氰基、C3-C6环烷基、含有1-3个杂原子的3-6元杂环烷基，所述杂原子分别独立地选自N、O和S、-S(O2)R9a、NR9bR9c和-OR9a；每个R9a、R9b和R9c每次出现时分别独立地选自氢、氘、C1-3烷基和C1-3卤代烷基；或The Q ring is optionally substituted with 1-2 R 9 , each of which is independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms, each of which is independently selected from N, O and S, -S(O 2 )R 9a , NR 9b R 9c and -OR 9a ; each of R 9a , R 9b and R 9c is independently selected from hydrogen, deuterium, C 1-3 alkyl and C 1-3 haloalkyl at each occurrence; or
R环为含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂环烷基或5-6元亚杂芳基，所述亚杂环烷基和亚杂芳基任选地被0-2个R10取代，R10每次出现时分别独立地选 自卤素、C1-C3烷基、羟基、氨基、C1-C3卤代烷基、氰基、C3-C6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-6杂环烷基、-S(O2)R10a、-NR10bR10c和-OR10a；R10a、R10b和R10c每次出现时分别独立地选自氢、氘、C1-C3烷基和C1-C3卤代烷基；或The R ring is a 5-6 membered heterocycloalkylene or 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R10 , each occurrence of which is independently selected from halogen, C 1 -C 3 alkyl, hydroxy, amino, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c and -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, deuterium, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl at each occurrence; or
T环和U环分别独立地选自含有1、2、3个N、O、S原子的5-6元亚杂环基、亚苯基和亚吡啶基，其中所述的亚苯基、亚吡啶基任选地被1-3个独立地选自卤素、氨基、烷基氨基、氨烷基、氰基、烷氧基、卤代烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的取代基取代。The T ring and the U ring are independently selected from a 5-6 membered heterocyclylene group containing 1, 2, or 3 N, O, or S atoms, a phenylene group, and a pyridylene group, wherein the phenylene group and the pyridylene group are optionally substituted by 1 to 3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, cyano, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, and C 3-6 cycloalkyl.
4.如权利要求3所述的化合物，其中：4. The compound of claim 3, wherein:
R2选自氢、氟、氯、环丙基、C1-3烷基和C1-3卤代烷基；或 R2 is selected from hydrogen, fluorine, chlorine, cyclopropyl, C1-3 alkyl and C1-3 haloalkyl; or
R3为氢；或 R3 is hydrogen; or
R4选自氢、氟、氯、溴和环丙基；或R 4 is selected from hydrogen, fluorine, chlorine, bromine and cyclopropyl; or
R6选自氢、氟、氯和环丙基；或 R6 is selected from hydrogen, fluorine, chlorine and cyclopropyl; or
R5选自氢和甲基；或 R5 is selected from hydrogen and methyl; or
R1c和R1d分别独立地选自氢和C1-C3烷基；优选地，R1c和R1d分别独立地选自氢和甲基；或R 1c and R 1d are independently selected from hydrogen and C 1 -C 3 alkyl; preferably, R 1c and R 1d are independently selected from hydrogen and methyl; or
所述Q环选自以下基团：
The Q ring is selected from the following groups:
其中，所述每个Q环基团左边的连接位点各自独立与式(V)中-CR7aR7b-相连，所述每个Q环基团右边的连接位点各自独立与式(V)中R环相连；或wherein the connection site on the left side of each Q ring group is independently connected to -CR 7a R 7b - in formula (V), and the connection site on the right side of each Q ring group is independently connected to the R ring in formula (V); or
R环选自以下基团：
The R ring is selected from the following groups:
其中，所述每个R环基团的右边的连接位点各自独立与式(Ⅴ)中Q环相连，所述每个R环基团的左边的连接位点各自独立与式Ⅰ中A环或B环相连。The right connecting site of each R ring group is independently connected to the Q ring in formula (V), and the left connecting site of each R ring group is independently connected to the A ring or the B ring in formula I.
5.如权利要求1-4任一项所述的化合物，所述化合物选自式(Ⅰ-A)、(Ⅰ-B)、(Ⅰ-C)、(Ⅰ-D)、(Ⅰ-E)、(Ⅰ-F)和(Ⅰ-G)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
5. The compound according to any one of claims 1 to 4, wherein the compound is selected from the compounds represented by formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) and (I-G), or their isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates:
其中，Q环、R环、T环、U环、L1、L2、W、R1a、R1b、R1c、R1d、R7a、R7b、R2、R3、R4、R5和R6定义同权利要求2、3或4。Wherein, Q ring, R ring, T ring, U ring, L 1 , L 2 , W, R 1a , R 1b , R 1c , R 1d , R 7a , R 7b , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in claim 2 , 3 or 4.
6.如权利要求1-4任一项所述的化合物，其中，A环、B环相同或不同，所述A环和B环各自独立地选自式(Ⅱ-1)、(Ⅳ-1)和(Ⅲ-1)：
6. The compound according to any one of claims 1 to 4, wherein the A ring and the B ring are the same or different, and the A ring and the B ring are each independently selected from the formula (II-1), (IV-1) and (III-1):
其中，R1a、R1b、R1c、R1d、R2、R3、R4、R5和R6的定义同权利要求1或2或3或4；wherein R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 4 , R 5 and R 6 have the same definitions as in claim 1 or 2 or 3 or 4;
优选地，所述A环和B环相同。Preferably, the A ring and the B ring are identical.
7.如权利要求1-4任一项所述的化合物，其中所述化合物选自式(Ⅰ-A-1)、(Ⅰ-A-2)、(Ⅰ-A-3)、(Ⅰ-A-4)、(Ⅰ-F-1)、(Ⅰ-F-2)、(Ⅰ-F-3)、(Ⅰ-F-4)、(Ⅰ-F-5)、(Ⅰ-F-6)、(Ⅰ-F-7)和(Ⅰ-F-8)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
7. A compound according to any one of claims 1 to 4, wherein the compound is selected from the group consisting of compounds represented by formula (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-F-3), (I-F-4), (I-F-5), (I-F-6), (I-F-7) and (I-F-8), or isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates thereof:
其中Qa环的定义与权利要求2或3或4中Q环的定义一致；Ra环的定义与权利要求2或3或4中R环的定义一致；R1a、R1b、R1c、R1d、R7a、R7b、E、G、J、Z、L2、R2和R6的定义同权利要求1或2或3或4。The definition of Qa ring is consistent with the definition of Q ring in claim 2, 3 or 4; the definition of Ra ring is consistent with the definition of R ring in claim 2, 3 or 4; R1a , R1b , R1c , R1d , R7a , R7b , E, G, J, Z, L2 , R2 and R6 are defined the same as in claim 1, 2, 3 or 4.
在一些实施方案中，所述化合物为式(Ⅰ)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
In some embodiments, the compound is a compound represented by formula (I), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:
其中A环和B环各自独立选自式(Ⅱ)、(Ⅲ)和(Ⅳ)：
Wherein ring A and ring B are independently selected from formula (II), (III) and (IV):
其中Linker C为连接A环和B环的连接子，选自式(Ⅴ)、(Ⅵ)和(Ⅶ)：
Wherein Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI) and (VII):
其中，R1a、R1b、R1c和R1d分别独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0-6个独立选自卤素、氘、烷基、氨基、羟基、烷基氨基、氨烷基、和烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个3-10元杂环烷基，其中所述杂环烷基任选地被0-3个独立选自卤素、氘、氨基、烷氧基、烷基氨基、氨烷基和羟基的取代基取代；或R1c和R1d和其共同连接的氮原子组成一个3-10元杂环烷基，其中所述杂环烷基任选地被0-3个独立选自卤素、氘、氨基、烷氧基、氨烷基和羟基的取代基取代；wherein R 1a , R 1b , R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl and alkoxy; or R 1a and R R 1c and R 1d and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, alkylamino, aminoalkyl and hydroxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, aminoalkyl and hydroxy;
R2、R4和R6分别独立地选自氢、氘、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6单烷基氨基、C2-6双烷基氨基、C1-6卤代烷基氨基、3-12元单环的环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单杂环烷基、5-12元螺杂环烷基和4-12元桥杂环烷基、C1-6烷基-S-、C1-6烷基-SO-、C1-6烷基-SO2-、3-6元环烷基-O-、3-6元杂环烷基-O-、5-10元单环芳基、5-10元并环芳基、和含有1-3个分别独立地选自N、O、P和S杂原子的3-12元单环杂芳基和7-10元并环杂芳基； R2 , R4 and R6 are independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 monoalkylamino, C2-6 dialkylamino, C1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1-6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cycloaryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S;
R5选自氢、C1-6烷基、C3-10环烷基和C1-6卤代烷基，任选地，所述C1-6烷基、C3-10环烷基和C1-6卤代烷基被0-6个独立选自卤素、氘、烷基、氨基、羟基、氨基烷基、烷基氨基、和烷氧基的取代基取代；R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
E、G、J和Z每次出现时分别独立地选自N和CR2a；其中R2a选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、C1-6烷基、C1-6卤代烷基、C1-6烷基-S-、C1-6烷基-SO-、C1-6烷基-SO2-、C1-6烷基-O-、C1-6卤代烷基-O-、-NR2bR2c、C3-6环烷基氨基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基氨基、3-12元单环烷基、5-12元螺环烷基和4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂环烷基、5-12元螺杂环烷基和4-12元桥杂环烷基、含有1-3个分别 独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基、3-6元卤代环烷基-O-、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-、5-12元单环芳基、5-12元并环芳基、和含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂芳基和7-10元并环杂芳基；R2b和R2c分别独立地选自氢和C1-6烷基；E, G, J and Z are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -, C 1-6 alkyl-O-, C 1-6 haloalkyl-O-, -NR 2b R 2c , C 3-6 -membered cycloalkylamino, 3-6-membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12-membered monocyclic alkyl, 5-12-membered spirocycloalkyl and 4-12-membered bridged cycloalkyl, 3-12-membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12-membered spirocycloalkyl and 4-12-membered bridged heterocycloalkyl, 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated heterocycloalkyl, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered monocyclic aryl, 5-12 membered paracyclic aryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered paracyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C 1-6 alkyl;
R3为-X1-R8，X1选自化学键、C2-6亚烯基和C1-6亚烷基；R8选自氢、卤素、C1-6烷基、C1-6卤代烷基、C6-10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳环；R8a和R8b每次出现时分别独立地选自氢、氘、C1-6烷基、C1-6卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、-OR8d和-X2-R8d基团取代；R8c选自氢、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基和C1-6卤代烷基；X2选自C1-6亚烷基和C2-6亚烯基；R8d选自氢、C1-6烷基和C1-6卤代烷基；R 3 is -X 1 -R 8 , X 1 is selected from a chemical bond, C 2-6 alkenylene and C 1-6 alkylene; R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, the phenyl being optionally substituted with 0-2 groups selected from C 1-4 alkyl, -OR 8d and -X 2 -R 8d ; R 8c is selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-10 aryl. X2 is selected from C1-6 alkylene and C2-6 alkenylene; R8d is selected from hydrogen, C1-6 alkyl and C1-6 haloalkyl;
R7a和R7b分别独立地选自氢、卤素、C1-6烷基、C1-6卤代烷基、-X3-OR7c、-X3-NR7dR7e和C3-10环烷基；X3每次出现时各自独立选自C1-6亚烷基和C2-C6亚烯基；R7c选自氢、C1-6烷基和C1-6卤代烷基；R7d和R7e分别独立地选自氢、C1-6烷基和C1-6卤代烷基；或者R7a和R7b和其连接的碳组成3-10元环烷基；R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl; X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence; R 7c is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; R 7d and R 7e are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are connected form a 3-10 membered cycloalkyl;
W环选自以下基团：
The W ring is selected from the following groups:
Q环选自含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂环烷基和5-6元亚杂芳基，所述亚杂环烷基和所述亚杂芳基任选地被0-2个R9取代，R9每次出现时分别独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-6杂环烷基、-S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a和-X4-OR9a；R9a、R9b和R9c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；X4选自C1-6亚烷基和C2-6亚烯基；The Q ring is selected from 5-6 membered heterocycloalkylene and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and said heteroarylene are optionally substituted by 0-2 R 9 , R 9 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; R 9a , R 9b and R 9c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
R环为含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂环烷基或5-6元亚杂芳基，所述亚杂环烷基和亚杂芳基任选地被0-2个R10取代，R10每次出现时分别独立 地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-6杂环烷基、-S(O2)R10a、-NR10bR10c、-X5-NR10bR10c、-OR10a和-X5-OR10a；R10a、R10b和R10c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；X5选自C1-6亚烷基和C2-6亚烯基；The R ring is a 5-6 membered heterocycloalkylene or 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , each occurrence of which is independently R 10a , R 10b and R 10c are each independently selected from the group consisting of hydrogen , C 1-6 alkyl and C 1-6 haloalkyl ; X 5 is selected from the group consisting of C 1-6 alkylene and C 2-6 alkenylene ;
T环和U环分别独立地选自亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基，其中所述亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基任选地被1-3个独立地选自卤素、氨基、烷基氨基、氨烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的取代基取代；The T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 1-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl and C 3-6 cycloalkyl;
L1选自以下基团：
 L1 is selected from the following groups:
L2选自以下基团： L2 is selected from the following groups:
其中Y1、Y2、Y3、Y4、Y5、Y6、和Y7分别独立地选自-O-、-NH-、-NHC(O)-、-NHS(O)-、-NHS(O2)-、-CH2-、-C(O)-、-S(O)-、-S(O2)-、-C(O)NH-、-S(O2)NH-、-CH＝CH-、-C≡C-和单键，其中所述的氢原子任选地被0-2个独立地选自氘、卤素、氨基、烷基氨基、氨烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的取代基取代；wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 -, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH═CH—, —C≡C—, and a single bond, wherein the hydrogen atom is optionally substituted with 0-2 substituents independently selected from deuterium, halogen, amino, alkylamino, aminoalkyl, hydroxy, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, and C 3-6 cycloalkyl;
a为0-5的整数；b和c分别为0-3的整数；d和e分别为0-2的整数；和a is an integer from 0 to 5; b and c are integers from 0 to 3; d and e are integers from 0 to 2; and
L1和L2任选地被1-5个R11取代，R11分别独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自氧、硫和氮的杂原子的3-6元杂环烷基、-S(O2)R11a、NR11bR11c、-X6-NR11bR11c、-OR11a和-X6-OR11a；R11a、R11b和R11c每次出现时各自独立地选自氢、C1-6烷基和C1-6卤代烷基；X6选自C1-6亚烷基和C2-6亚烯基。
L 1 and L 2 are optionally substituted by 1-5 R 11 , R 11 are independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O 2 )R 11a , NR 11b R 11c , -X 6 -NR 11b R 11c , -OR 11a and -X 6 -OR 11a ; R 11a , R 11b and R 11c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 6 is selected from C 1-6 alkylene and C 2-6 alkenylene.
其中A环和B环各自独立选自式(Ⅱ)、(Ⅲ)、(Ⅳ)、(Ⅴ)、(Ⅵ)、(Ⅶ)和(Ⅷ)：
Wherein Ring A and Ring B are independently selected from Formula (II), (III), (IV), (V), (VI), (VII) and (VIII):
其中Linker C为连接A环和B环的连接子，选自式(Ⅸ)、(Ⅹ)、(Ⅺ)和(Ⅻ)：
Wherein Linker C is a linker connecting Ring A and Ring B, selected from Formula (IX), (X), (XI) and (XII):
其中，R1选自不存在、氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、C1-6烷基、C1-6卤代烷基、-S-C1-6烷基、-S(O)-C1-6烷基、-S(O2)-C1-6烷基、-O-C1-6烷基、-O-C1-6卤代烷基、C1-6氘代烷基和-NR1aR1b，其中R1a和R1b分别独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0-6个独立选自卤素、氘、烷基、氨基、羟基、烷基氨基、氨烷基、和烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个含有1-3个分别独立地选自N、O、P和S的杂原子的3-10元杂环烷基，其中所述杂环烷基任选地被0-3个独立选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6烷基、C1-6氘代烷基、氰基、C1-6氨烷基和羟基的取代基取代；wherein R 1 is selected from the group consisting of absence, hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, C 1-6 haloalkyl, -SC 1-6 alkyl, -S(O)-C 1-6 alkyl, -S(O 2 )-C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, C 1-6 deuterated alkyl and -NR 1a R 1b , wherein R 1a and R 1b are independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 1-12 aryl. R 1a and R 1b and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, hydroxy, alkylamino, aminoalkyl, and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, hydroxy , alkylamino , aminoalkyl, and alkoxy. Substituted with 1-6 deuterated alkyl, cyano, C 1-6 aminoalkyl and hydroxyl;
Z选自C和N；当Z选自N时，R1不存在； Z is selected from C and N; when Z is selected from N, R 1 is absent;
R2、R4和R6分别独立地选自氢、氘、卤素、C1-6烷基、C1-6烯基、C1-6炔基、C1-6烷氧基、C1-6卤代烷基、-NHC1-6烷基、-N(C1-6烷基)C1-6烷基、C1-6卤代烷氧基、C1-6卤代烷基氨基、3-12元单环的环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的5-12元螺杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的4-12元桥杂环烷基、-S-C1-6烷基、-SO-C1-6烷基、-SO2-C1-6烷基、3-6元环烷基-O-、3-6元杂环烷基-O-、5-10元单环芳基、5-10元并环芳基、含有1-3个分别独立地选自N、O、P和S杂原子的3-12元单环杂芳基和含有1-3个分别独立地选自N、O、P和S杂原子的7-10元并环杂芳基； R2 , R4 and R6 are independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl , C1-6 alkoxy, C1-6 haloalkyl, -NHC1-6 alkyl, -N( C1-6 alkyl) C1-6 alkyl, C1-6 haloalkoxy, C1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, -SC1-6 alkyl, -SO-C1-6 alkyl, -S ... 1-6 alkyl, -SO 2 -C 1-6 alkyl, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered paracyclic aryl, 3-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, and 7-10 membered paracyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S;
R5选自氢、C1-6烷基、C3-10环烷基和C1-6卤代烷基，任选地，所述C1-6烷基、C3-10环烷基和C1-6卤代烷基被0-6个独立选自卤素、氘、烷基、氨基、羟基、氨基烷基、烷基氨基、和烷氧基的取代基取代；R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
G1和G2选自O、S、和NR2a； G1 and G2 are selected from O, S, and NR2a ;
E0-9、M1-6和E每次出现时分别独立地选自N和CR2a；其中R2a选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷基-S-、-SO-C1-6烷基、-SO2-C1-6烷基、-O-C1-6烷基、-O-C1-6卤代烷基、-NR2bR2c、-NHC1-6烷基、-N(C1-6烷基)C1-6烷基、-C(O)R8c、-C(O)NR8aR8b、-C1-6亚烷基-C1-6环烷基、C3-6环烷基氨基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基氨基、3-12元单环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的5-12元螺杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的4-12元桥杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基、3-6元卤代环烷基-O-、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-、5-12元单环芳基、5-12元并环芳基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂芳基、含有1-3个分别独立地选自N、O、P和S的杂原子的7-10元并环杂芳基；R2b和R2c分别独立地选自氢和C1-6烷基；R8a和R8b每次出现时分别独立地选自氢、氘、C1-6烷基、C1-6卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、-OR8d和-X2-R8d基团取代；R8c选自氢、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基和C1-6卤代烷基；X2选自C1-6亚烷基和C2-6亚烯基；R8d选自氢、C1-6烷基和C1-6卤代烷基；E 0-9 , M 1-6 and E are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl -S-, -SO-C 1-6 alkyl, -SO 2 -C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, -NR 2b R 2c , -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, -C(O)R 8c , -C(O)NR 8a R 8b , -C 1-6 alkylene-C 1-6 cycloalkyl, C 3-6 -membered cycloalkylamino, 3-6-membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12-membered monocycloalkyl, 5-12-membered spirocycloalkyl, 4-12-membered bridged cycloalkyl, 3-12-membered monocycloheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12-membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12-membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12-membered monocycloheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, -6-membered halogenated heterocycloalkyl, 3-6-membered cycloalkyl-O-, 3-6-membered halogenated cycloalkyl, 3-6-membered halogenated cycloalkyl-O-, 3-6-membered halogenated heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6-membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12-membered monocyclic aryl, 5-12-membered cycloheteroaryl, 3-12-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, 7-10-membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; R R 2b and R 2c are each independently selected from hydrogen and C 1-6 alkyl; R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, said phenyl being optionally substituted with 0-2 groups selected from C 1-4 alkyl, -OR 8d and -X 2 -R 8d ; R 8c is selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 haloalkyl; X 2 is selected from C 1-6 alkylene and C 2-6 alkenylene; R 8d is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
J1和J2分别独立地选自单键、O、S、C(O)、S(O)、S(O2)、C(R1cR1d)、C(＝CR1eR1f)和N(R3)；其中R1c、R1d、R1e和R1f分别独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0-6个独立地选自卤素、氘、C1-6烷基、氨基、羟基、C1-6烷基氨基、C1-6氨烷基、和C1-6烷氧基的取代基取代；或R1c和R1d和其共同连接的碳原子组成一个3-10元环烷基或含有1-3个分别独立地选自N、O、P和S的杂原子的3-10元杂环烷基，其中所述环烷基或杂环烷基任选地被0-3个独立地选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氨烷基和羟基的取代基取代；或R1e和R1f和其共同连接的碳原子组成一个3-10元环烷基 或含有1-3个分别独立地选自N、O、P和S的杂原子的3-10元杂环烷基，其中所述环烷基或杂环烷基任选地被0-3个独立选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氨烷基和羟基的取代基取代； J1 and J2 are independently selected from a single bond, O, S, C(O), S(O), S( O2 ), C( R1cR1d ), C( ═CR1eR1f ) and N( R3 ); wherein R1c , R1d , R1e and R1f are independently selected from hydrogen, deuterium, C1-6 alkyl, C1-6 alkoxy, C3-12 monocyclic, spirocyclic or bridged cycloalkyl, C3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C6-10 aryl and C5-10 heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, C3-12 monocyclic, spirocyclic or bridged cycloalkyl, C3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C6-10 aryl and C5-10 heteroaryl. 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl, and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, C 1-6 alkyl, amino, hydroxy, C 1-6 alkylamino, C 1-6 aminoalkyl, and C 1-6 alkoxy; or R 1c and R 1d and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy; or R 1e and R 1f and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkyl group or heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy;
R3为-X1-R8，X1选自化学键、-O-、-S-、烷氧基、C2-6亚烯基和C1-6亚烷基；R8选自氢、卤素、C1-6烷基、C1-6卤代烷基、C6-10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳环；R8a和R8b每次出现时分别独立地选自氢、氘、C1-6烷基、C1-6卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、卤素、氰基、氨基、-OR8d和-X2-R8d基团取代；R8c选自氢、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基和C1-6卤代烷基；X2选自C1-6亚烷基和C2-6亚烯基；R8d选自氢、C1-6烷基和C1-6卤代烷基；R 3 is -X 1 -R 8 , X 1 is selected from a chemical bond, -O-, -S-, alkoxy, C 2-6 alkenylene and C 1-6 alkylene; R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, and the phenyl is optionally substituted with 0-2 groups selected from C 1-4 alkyl, halogen, cyano, amino, -OR 8d and -X 2 -R 8d ; R 8c is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 haloalkyl; X 2 is selected from C 1-6 alkylene and C 2-6 alkenylene; R 8d is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
R7a和R7b分别独立地选自氢、氘、卤素、C1-6烷基、C1-6卤代烷基、-X3-OR7c、-X3-NR7dR7e和C3-10环烷基；X3每次出现时各自独立选自C1-6亚烷基和C2-C6亚烯基；R7c选自氢、氘、C1-6烷基和C1-6卤代烷基；R7d和R7e分别独立地选自氢、氘、C1-6烷基和C1-6卤代烷基；或者R7a和R7b和其连接的碳组成3-10元环烷基；R 7a and R 7b are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl; X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence; R 7c is selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are attached form a 3-10 membered cycloalkyl;
W选自以下基团：
W is selected from the following groups:
Q环选自亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1-4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、3-7元亚杂环烯基、5-6元亚杂芳基和4-12元稠杂环，所述亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1-4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、5-6元亚杂芳基和4-12元亚稠杂环任选地被0-6个R9取代，R9每次出现时分别独立地选自卤素、氘、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-7杂环烷基、-S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a和-X4-OR9a；R9a、R9b和R9c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；X4选自C1-6亚烷基和C2-6亚烯基；The Q ring is selected from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring, wherein the phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring are optionally substituted with 0-6 R 9 , and each occurrence of R 9 is independently selected from halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, C 3-7 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; R 9a , R 9b and R 9c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
R环选自亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1-4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、3-7元亚杂环烯基、5-6元亚杂芳基和4-12元稠杂环，所述亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1-4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、3-7元亚杂环烯基、5-6元亚杂芳基和4-12元稠杂环任选地被0-6个R10取代，R10每次出现时分别独立地选自卤素、氘、C1-6烷基、羟基、氨基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-7杂环烷基、-S(O2)R10a、-NR10bR10c、-X5-NR10bR10c、-OR10a和-X5-OR10a；R10a、R10b和R10c每次出现时分别独立地选自氢、氘、C1-6烷基和C1-6卤代烷基；X5选自C1-6亚烷基和C2-6亚烯基；The R ring is selected from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring, wherein the phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring are optionally substituted with 0-6 R10 , and each occurrence of R10 is independently selected from halogen, deuterium, C1-6 alkyl, hydroxyl, amino, C1-6 haloalkyl, cyano, C3-6 cycloalkyl, C3-7 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 ) R 10a , -NR 10b R 10c , -X 5 -NR 10b R 10c , -OR 10a and -X 5 -OR 10a ; R 10a , R 10b and R 10c are each independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; X 5 is selected from C 1-6 alkylene and C 2-6 alkenylene;
T环和U环分别独立地选自亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基，其中所述亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基任选地被0-3个独立地选自卤素、氨基、烷基氨基、氨烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的取代基取代；The T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 0-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl and C 3-6 cycloalkyl;
L1选自以下基团：
 L1 is selected from the following groups:
L2选自以下基团： L2 is selected from the following groups:
其中Y1、Y2、Y3、Y4、Y5、Y6、和Y7分别独立地选自-O-、-NH-、-NHC(O)-、-NHS(O)-、-NHS(O2)-、-CH2-、-C(O)-、-S(O)-、-S(O2)-、-C(O)NH-、-S(O2)NH-、-CH＝CH-、-C≡C-和单键；wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 —, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH═CH—, —C≡C—, and a single bond;
a为0-5的整数；b和c分别为0-3的整数；d和e分别为0-2的整数；和a is an integer from 0 to 5; b and c are integers from 0 to 3; d and e are integers from 0 to 2; and
L1和L2任选地被0-5个R11取代，R11分别独立地选自氘、卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自氧、硫和氮的杂原子的3-6元杂环烷基、-S(O2)R11a、NR11bR11c、-X6-NR11bR11c、-OR11a和-X6-OR11a；R11a、R11b和R11c每次出现时各自独立地选自氢、C1-6烷基和C1-6卤代烷基；X6选自C1-6亚烷基和C2-6亚烯基。L 1 and L 2 are optionally substituted by 0-5 R 11 , R 11 are independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O 2 )R 11a , NR 11b R 11c , -X 6 -NR 11b R 11c , -OR 11a and -X 6 -OR 11a ; R 11a , R 11b and R 11c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 6 is selected from C 1-6 alkylene and C 2-6 alkenylene.
11.如权利要求1-10任一项所述的化合物，其中所述化合物选自以下结构：

11. The compound according to any one of claims 1 to 10, wherein the compound is selected from the following structures:

12.一种药物组合物，其特征在于所述药物组合物中包含治疗有效剂量的权利要求1-11中任一项所述的化合物及药学上可接受的载体或赋形剂。12. A pharmaceutical composition, characterized in that it comprises a therapeutically effective dose of the compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or excipient.
13.权利要求1-11中任一项所述的化合物或权利要求12所述的药物组合物用于制备治疗MAT2A相关疾病的药物中的用途；优选地，所述MAT2A相关疾病为癌症或肿瘤。13. Use of the compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12 for preparing a medicament for treating a MAT2A-related disease; preferably, the MAT2A-related disease is cancer or tumor.
14.一种治疗患者的MAT2A相关的疾病的方法，该方法包括向所述患者施用治疗有效量的一种或多种权利要求1-11中任一项所述的化合物或权利要求12所述的药物组合物；优选地，所述MAT2A相关疾病为癌症或肿瘤。14. A method for treating a MAT2A-related disease in a patient, the method comprising administering to the patient a therapeutically effective amount of one or more compounds according to any one of claims 1-11 or the pharmaceutical composition according to claim 12; preferably, the MAT2A-related disease is cancer or tumor.
15.权利要求1-11中任一项所述的化合物或权利要求12所述的药物组合物，其用于治疗MAT2A相关疾病；优选地，所述MAT2A相关疾病为癌症或肿瘤。15. The compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12, for use in treating a MAT2A-related disease; preferably, the MAT2A-related disease is cancer or tumor.
具体实施方式：Specific implementation method:
下面结合实施例对本发明做进一步的说明，实施例仅为解释性的，决不意味着它以任何方式限制本发明的范围。本领域技术人员根据本发明的教导做出的各种变化均应在本申请权利要求所要求的保护范围之内。The present invention is further described below in conjunction with examples, which are only illustrative and do not limit the scope of the present invention in any way. Various changes made by those skilled in the art based on the teachings of the present invention should be within the scope of protection required by the claims of this application.
定义：definition:
除非另外说明，否则在说明书和权利要求书中使用的下列术语出于本申请的目的而定义，且具有以下含义：Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meanings:
“烷基”是指具有1至6个碳原子的直链饱和一价烃基或3至6个碳原子的支链饱和一价烃基，例如甲基、乙基、丙基、2-丙基、丁基、戊基等。本领域技术人员应认识到术语“烷基”可包括“亚烷基”基团。"Alkyl" refers to a straight-chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc. Those skilled in the art will recognize that the term "alkyl" may include "alkylene" groups.
除非另外说明，“亚烷基”是指具有1至6个碳原子的直链饱和二价烃基或3至6个碳原子的支链饱和二价烃基，例如亚甲基、亚乙基、亚丙基、1-甲基亚丙基、2-甲基亚丙基、亚丁基、亚戊基等。Unless otherwise specified, "alkylene" refers to a straight-chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated divalent hydrocarbon group having 3 to 6 carbon atoms, such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
“烯基”是指包含双键的具有2至6个碳原子的直链一价烃基或3至6个碳原子 的支链一价烃基，例如丙烯基、丁烯基等。"Alkenyl" refers to a straight chain monovalent hydrocarbon radical having 2 to 6 carbon atoms or a 3 to 6 carbon atom A branched monovalent hydrocarbon group, such as propenyl, butenyl, etc.
“炔基”是指包含三键的具有2至6个碳原子的直链一价烃基或3至6个碳原子的支链一价烃基，例如乙炔基、丙炔基、丁炔基等。The "alkynyl group" refers to a linear monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched monovalent hydrocarbon group having 3 to 6 carbon atoms containing a triple bond, for example, ethynyl, propynyl, butynyl and the like.
“烷氧基”是指-OR基团，其中R是如上定义的烷基，例如甲氧基、乙氧基、丙氧基或2-丙氧基、正、异或叔丁氧基等。"Alkoxy" refers to a -OR group where R is alkyl as defined above, for example methoxy, ethoxy, propoxy or 2-propoxy, n-, iso- or tert-butoxy and the like.
“氨基”是指‐NH2。"Amino" refers to -NH2 .
“烷基氨基”是指‐NHR基团，其中R是如上定义的烷基，例如，甲基氨基、乙基氨基、丙基氨基或2‐丙基氨基等。"Alkylamino" refers to an -NHR group where R is alkyl as defined above, for example, methylamino, ethylamino, propylamino or 2-propylamino, and the like.
“芳基”是指具有3至12个环原子的单价单环或双环的芳香烃基，例如苯基或萘基。"Aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 3 to 12 ring atoms, for example, phenyl or naphthyl.
“芳烷基”是指‐(亚烷基)‐R基团，其中R是如上定义的芳基，例如苄基、苯乙基等。"Aralkyl" refers to an -(alkylene)-R group where R is aryl as defined above, eg, benzyl, phenethyl, and the like.
“卤素”是指氟、氯、溴或碘。"Halogen" refers to fluorine, chlorine, bromine or iodine.
“卤代烷基”是指被1至5个卤素原子取代的如上定义的烷基，例如氟原子或氯原子，包括被不同卤素取代的基团，例如-CH2Cl、-CF3、-CHF2、-CH2CF3、-CF2CF3、-CF(CH3)2等。当烷基仅被氟取代时，在本申请中可以称为氟烷基。"Haloalkyl" refers to an alkyl group as defined above substituted by 1 to 5 halogen atoms, such as fluorine atoms or chlorine atoms, including groups substituted by different halogens, such as -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When the alkyl group is substituted only by fluorine, it may be referred to as a fluoroalkyl group in the present application.
“羟烷基”是指被一个或两个羟基取代的具有1至6个碳原子的直链一价烃基或3-6个碳的支链一价烃基，前提是如果存在两个羟基，则它们不同时在相同的碳原子上。代表性实例包括但不限于羟甲基、2-羟乙基、2-羟丙基、3-羟丙基、1-(羟甲基)-2-甲基丙基、2-羟丁基、3-羟丁基、4-羟丁基、2,3-二羟丙基、1-(羟甲基)-2-羟乙基、2,3-二羟丁基、3,4-二羟丁基和2-(羟甲基)-3-羟丙基。"Hydroxyalkyl" refers to a linear monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical having 3-6 carbon atoms substituted by one or two hydroxyl groups, provided that if two hydroxyl groups are present, they are not simultaneously on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl.
如本发明单独或组合所用，“氧代”是指＝(O)。As used herein, "oxo," alone or in combination, refers to =(O).
如本发明所用，“药学上可接受的盐”是指包括用相对无毒的酸或碱制备的活性化合物的盐，这取决于本文所述化合物上发现的特定取代基。当本文公开的化合物包含相对酸性的官能团时，可以通过使这种化合物的中性形式与足够量的所需碱(纯净物或在合适的惰性溶剂中)接触来获得碱加成盐。衍生自药学上可接受的无机碱的盐的实例包括铝、铵、钙、铜、铁、亚铁、锂、镁、三价锰、二价锰、钾、钠、锌等。衍生自药学上可接受的有机碱的盐包括伯、仲和叔胺的盐，包括取代胺、环胺、天然存在的胺等，例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、氨基葡萄糖、组氨酸、海巴明(hydrabamine)、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。当本发明的化合物包含相对碱性的官能团时，可以通过使这种化合物的中性形式与足够量的所需酸(纯净物或在合适的惰性溶剂中)接触来获得酸加成盐。药学上可接受的酸加成盐的实例包括衍生自以下无机酸的盐，例如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢碘酸或亚磷酸等，以及衍生自以下相对无毒的有机酸的盐，例如乙酸、丙酸、异丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等。还包括氨基酸的盐，例如精氨酸盐等，以及以下有机酸的盐，例如葡糖醛酸或半乳糖醛酸等(参见，例如，Berge，S.M.等，“药用盐”，药学科学杂志，1977年，66，1-19页)。本发明的某些特定化合物同时包含碱性和酸性官能团，这使得该化合物可以转化为碱加成盐或酸加成盐。As used herein, "pharmaceutically acceptable salts" are meant to include salts of active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds disclosed herein contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (either neat or in a suitable inert solvent). Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from the following inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from the following relatively non-toxic organic acids, such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids, such as arginine salts, and salts of the following organic acids, such as glucuronic acid or galacturonic acid, and the like (see, for example, Berge, S.M. et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66, pp. 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups, which allows the compounds to be converted into base addition salts or acid addition salts.
化合物的中性形式可以通过使盐与碱或酸接触并以常规方式分离母体化合物来再生。化合物的母体形式在某些物理性质(例如在极性溶剂中的溶解度)方面与各种盐形式不同，但是出于本发明的目的，这些盐与化合物的母体形式等效。The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (e.g., solubility in polar solvents), but for the purposes of the present invention, these salts are equivalent to the parent form of the compound.
本发明还包括本公开的化合物的被保护的衍生物。例如，当本公开的化合物包含诸 如羟基、羧基、硫醇的基团或任何包含一个或多个氮原子的基团时，这些基团可以被合适的保护基保护。合适的保护基团的完整列表可在T.W.Greene，有机合成中的保护基，第5版，约翰威利父子股份有限公司(John Wiley&Sons，Inc)(2014年)找到，其公开内容通过引用整体并入本文。本公开的化合物的被保护的衍生物可以通过本领域众所周知的方法来制备。The present invention also includes protected derivatives of the compounds disclosed herein. When a group such as a hydroxyl group, a carboxyl group, a thiol group or any group containing one or more nitrogen atoms, these groups may be protected by suitable protecting groups. A complete list of suitable protecting groups can be found in TW Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons, Inc (2014), the disclosure of which is incorporated herein by reference in its entirety. Protected derivatives of the compounds of the present disclosure can be prepared by methods well known in the art.
本发明还包括所述化合物的前药，或其药学上可接受的盐。本文描述的化合物的前药是在生理条件下容易发生化学变化以提供本发明的化合物的那些化合物。前药的一个实例，非限制，是作为酯施用的化合物(“前药”)，然后被代谢水解为羧酸，即活性实体。另外，前药可以在离体环境中通过化学或生化方法转化为本发明的化合物。例如，当将前药置于具有合适的酶或化学试剂的透皮贴剂储库中时，其可以缓慢地转化为本发明的化合物。The present invention also includes prodrugs of the compounds, or pharmaceutically acceptable salts thereof. Prodrugs of the compounds described herein are those compounds that are susceptible to chemical changes under physiological conditions to provide compounds of the present invention. An example of a prodrug, not limited to, is a compound ("prodrug") administered as an ester, which is then metabolically hydrolyzed to a carboxylic acid, i.e., an active entity. In addition, the prodrug can be converted into a compound of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when the prodrug is placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, it can be slowly converted into a compound of the present invention.
本发明公开的化合物可以以非溶剂化形式以及溶剂化形式存在，包括水合形式。通常，溶剂化形式等效于非溶剂化形式，并且旨在包括在本发明的范围内。某些式(Ⅰ-A)、(Ⅰ-B)、(Ⅰ-C)、(Ⅰ-D)、(Ⅰ-E)、(Ⅰ-F)、(Ⅰ-G)、(Ⅰ-H)、(Ⅰ-J)、(Ⅰ-K)、(Ⅰ-L)、(Ⅰ-M)、(Ⅰ-N)、(Ⅰ-O)、(Ⅰ-P)、(Ⅰ-Q)、(Ⅰ-R)、(Ⅰ-S)、(Ⅰ-T)、(Ⅰ-U)、(Ⅰ-V)、(Ⅰ-W)、(Ⅰ-X)、(Ⅰ-Y)和(Ⅰ-Z)化合物可以多种结晶或无定形形式存在。通常，所有物理形式如多晶型物对于本公开所预期的用途是等同的，并且旨在落入本公开的范围内。The compounds disclosed in the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present invention. Certain formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-J), (I-K), (I-L), (I-M), (I-N), (I-O), (I-P), (I-Q), (I-R), (I-S), (I-T), (I-U), (I-V), (I-W), (I-X), (I-Y) and (I-Z) compounds may exist in a variety of crystalline or amorphous forms. Generally, all physical forms such as polymorphs are equivalent for the intended use of the present disclosure and are intended to fall within the scope of the present disclosure.
本发明公开的化合物具有不对称碳原子(光学中心)或双键；外消旋体、非对映异构体、几何异构体、区域异构体和单独的异构体(例如，单独的对映异构体)均旨在包括在本发明化合物的异构体范围内。当显示立体化学描述时，是指其中存在一种异构体且基本不含另一种异构体的化合物。“基本上不含”的另一种异构体表示两种异构体的比率至少为80/20，更优选为90/10，或95/5或更高。The compounds disclosed in the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., individual enantiomers) are all intended to be included in the isomer range of the compounds of the present invention. When stereochemical descriptions are shown, it refers to compounds in which one isomer is present and substantially free of another isomer. "Substantially free" of another isomer means that the ratio of the two isomers is at least 80/20, more preferably 90/10, or 95/5 or higher.
在一些实施方式中，其中一个异构体将以至少99％的量存在本发明公开的化合物还可在构成这种化合物的一个或多个原子上包含非自然量的同位素。非自然量的同位素可以定义为所讨论原子的自然界中发现的量到100％的量。仅在存在一个或多个富集同位素的原子时才不同。可被掺入本发明化合物(的示例性同位素，包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素，例如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、32P、33P、35S、18F、36Cl、123I和125I。同位素标记的化合物(例如，用3H和14C标记的化合物)可用于化合物或底物组织分布测定。氚(即3H)和碳‐14(即14C)同位素因其易于制备和可检测性而有用。此外，用较重的同位素例如氘(即2H)取代可以提供由于更好的代谢稳定性而产生的某些治疗优势(例如，体内半衰期增加或剂量要求减少)。在一些实施方式中，在本文公开的化合物中，一个或多个氢原子被2H或3H取代，或一个或多个碳原子被13C‐或14C‐富集的碳取代。正电子发射同位素(例如15O、13N、11C和15F)可用于正电子发射断层扫描(PET)研究以检查底物受体的占有率。In some embodiments, one of the isomers will be present in an amount of at least 99%. The compounds disclosed herein may also contain unnatural amounts of isotopes at one or more atoms constituting such compounds. An unnatural amount of an isotope may be defined as an amount ranging from the amount found in nature to 100% of the atom in question. It differs only when one or more isotopically enriched atoms are present. Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H , 3H , 11C , 13C , 14C , 13N , 15N , 15O , 17O, 18O , 32P , 33P , 35S , 18F , 36Cl , 123I , and 125I , respectively . Isotopically labeled compounds (e.g., those labeled with 3H and 14C ) are useful in compound or substrate tissue distribution assays. Tritium (i.e., 3H ) and carbon-14 (i.e., 14C ) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H ) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in the compounds disclosed herein, one or more hydrogen atoms are replaced by 2H or 3 H substitution, or one or more carbon atoms are substituted with 13 C- or 14 C-enriched carbon. Positron emitting isotopes (eg, 15 O, 13 N, 11 C, and 15 F) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.
同位素标记的化合物通常可以按照与本发明实施例中公开的相似的以下步骤，用同位素标记的试剂替换非同位素标记的试剂来制备。Isotopically labeled compounds can generally be prepared by following steps similar to those disclosed in the Examples of the present invention, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
“药学上可接受的载体或赋形剂”是指可用于制备药物组合物的载体或赋形剂，通常安全、无毒且不是生物学或其他方面不期望的，并且包括兽医用途以及人类药物用途均可接受的载体或赋形剂。在说明书和权利要求书中使用的“药学上可接受的载体/赋形剂”包括一种或多种这样的赋形剂。"Pharmaceutically acceptable carrier or excipient" refers to a carrier or excipient that can be used to prepare a pharmaceutical composition, is generally safe, non-toxic and not biologically or otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable carrier/excipient" as used in the specification and claims includes one or more such excipients.
如本文所用，“疾病”旨在与术语“紊乱”、“病症”和“病状”(如在医学病状中)通常同义，可互换使用，因为它们均反映出人体或动物体或其一部分的损害正常功能的异常病状，通常表现为区别的体征和症状，并导致人体或动物的寿命缩短或生活质量降低。 As used herein, "disease" is intended to be generally synonymous with the terms "disorder,""condition," and "condition" (as in medical condition) and are used interchangeably because they all reflect an abnormal condition of the human or animal body or a part thereof that impairs the normal functioning, usually manifests itself as distinctive signs and symptoms, and results in a shortened life span or reduced quality of life in the human or animal.
“患者”通常与术语“受试者”同义，并且如本文所用，包括所有哺乳动物(包括人类在内)。患者的例子包括人、牲畜(例如牛、山羊、绵羊、猪和兔子)，以及陪伴动物(例如狗、猫、兔和马)。优选地，患者是人类。"Patient" is often synonymous with the term "subject" and, as used herein, includes all mammals, including humans. Examples of patients include humans, livestock (e.g., cattle, goats, sheep, pigs, and rabbits), and companion animals (e.g., dogs, cats, rabbits, and horses). Preferably, the patient is a human.
如本文所用，“需要治疗”是指由医师或其他护理者做出的受试者需要或将从治疗中受益的判断。该判断是基于医师或护理人员专业知识范围内的多种因素做出的。As used herein, "in need of treatment" refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from treatment. This judgment is based on a variety of factors within the physician's or caregiver's expertise.
“施用”、“给药”等，在用于例如患者，细胞，组织，器官或生物流体时，是指将本发明公开的化合物、包含其的药物组合物或诊断剂与受试者，细胞，组织，器官或生物流体接触。在细胞的情况下，施用包括试剂与细胞的接触(例如体外或离体)，以及试剂与流体的接触，其中流体与细胞接触。"Administering", "dosing", etc., when used for example in patients, cells, tissues, organs or biological fluids, refers to contacting the compounds disclosed herein, pharmaceutical compositions or diagnostic agents containing the same with subjects, cells, tissues, organs or biological fluids. In the case of cells, administration includes contact of the agent with the cell (e.g., in vitro or ex vivo), and contact of the agent with the fluid, wherein the fluid is in contact with the cell.
如本文所用，“治疗有效量”是指例如本发明公开的化合物或本文所述的实施方式，当将其单独或作为药物组合物的一部分并以单次剂量或作为一系列剂量的一部分施用于治疗疾病的患者时，足以影响这种疾病的治疗的量。“治疗有效量”将根据化合物、疾病及其严重程度以及待治疗的哺乳动物的年龄、体重等而变化。治疗有效量可以通过测量相关的生理效应来确定，并且可以结合给药方案和对受试者状况的诊断分析等来调整治疗有效量。举例来说，在给药后的特定时间测量本发明公开的化合物(或其代谢物)的血清水平可以指示是否已使用了治疗有效量。As used herein, "therapeutically effective amount" refers to, for example, a compound disclosed herein or an embodiment described herein, when administered alone or as part of a pharmaceutical composition and in a single dose or as part of a series of doses to a patient treating a disease, an amount sufficient to affect the treatment of such disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated. The therapeutically effective amount can be determined by measuring the relevant physiological effects, and the therapeutically effective amount can be adjusted in combination with the dosing regimen and diagnostic analysis of the subject's condition, etc. For example, measuring the serum level of a compound disclosed herein (or its metabolite) at a specific time after administration can indicate whether a therapeutically effective amount has been used.
“治疗”或疾病的“治疗”包括："Treatment" or "treatment" of a disease includes:
(1)预防疾病，即在可能暴露于或易患该疾病但尚未经历或未显示出疾病症状的哺乳动物中使得疾病的临床症状不发展；(1) preventing a disease, that is, causing clinical symptoms of a disease to not develop in a mammal that may be exposed to or susceptible to the disease but does not yet experience or show symptoms of the disease;
(2)抑制疾病，即阻止或减轻疾病或其临床症状的发展；或者(2) inhibit the disease, i.e., prevent or alleviate the development of the disease or its clinical symptoms; or
(3)缓解疾病，即引起疾病或其临床症状消退。(3) Relieve the disease, that is, cause the disease or its clinical symptoms to disappear.
关于MAT2A的“抑制”、“降低”或这些术语的任何变形包括任何可测量的降低或完全抑制以达到期望的结果。例如，与其正常活性相比，MAT2A活性的降低可以减少约、至多约或至少约5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％、95％、99％或更高，或其任何可推导的范围。"Inhibition", "reduction" or any variation of these terms with respect to MAT2A includes any measurable reduction or complete inhibition to achieve the desired result. For example, compared to its normal activity, the reduction in MAT2A activity can be reduced by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any derivable range thereof.
本发明中所使用的物质的缩写及其对应的全称
DIEA N,N-二异丙基乙胺
DCE 二氯乙烷
DMF N,N-二甲基甲酰胺
TBTU O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯
THF 四氢呋喃
NaHMDS 二(三甲基硅基)氨基钠
PE 石油醚
EA 乙酸乙酯
DEAD 偶氮二甲酸二乙酯
SEMCl 2-(三甲基硅烷基)乙氧甲基氯
NBS N-溴代丁二酰亚胺
TFA 三氟乙酸
Boc 叔丁氧羰基
SFC 超临界流体色谱
DMAP 4-二甲氨基吡啶
DTT 二硫苏糖醇
L23 聚氧乙烯月桂醚
BGG 牛血清γ球蛋白
HATU 2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
EDCI 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺
HOBT 1-羟基苯并三唑
DCC N,N'-二环己基碳二亚胺
NMP N-甲基吡咯烷酮
PyBOP 1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐
DABCO 三乙烯二胺SEM:(三甲基硅)乙氧基甲基Abbreviations of substances used in the present invention and their corresponding full names
DIEA N,N-Diisopropylethylamine
DCE Dichloroethane
DMF N,N-Dimethylformamide
TBTU O-Benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate
THF Tetrahydrofuran
NaHMDS Sodium bis(trimethylsilyl)amide
PE Petroleum Ether
EA Ethyl acetate
DEAD Diethyl azodicarboxylate
SEMCl 2-(Trimethylsilyl)ethoxymethyl chloride
NBS N-Bromosuccinimide
TFA Trifluoroacetic acid
Boc tert-Butyloxycarbonyl
SFC Supercritical Fluid Chromatography
DMAP 4-dimethylaminopyridine
DTT Dithiothreitol
L23 Polyoxyethylene lauryl ether
BGG bovine serum gamma globulin
HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
HOBT 1-Hydroxybenzotriazole
DCC N,N'-Dicyclohexylcarbodiimide
NMP N-Methylpyrrolidone
PyBOP 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate
DABCO Triethylenediamine SEM: (Trimethylsilyl)ethoxymethyl
实施例1
Example 1
合成路线
Synthetic route
步骤一：化合物1-2的合成 Step 1: Synthesis of compound 1-2
取化合物2-氟-4-氯苯甲酰胺(1.7g,10mmol)溶于二氯乙烷(30mL)中，在氮气保护下在0℃下缓慢滴加草酰氯(1.9g,15mmol)。滴加完毕后，在60℃下加热搅拌，直到TLC检测显示反应完全。反应混合物冷却至室温后，在旋转蒸发仪上蒸除溶剂和过量的草酰氯，得到的固体混合物待用。Take the compound 2-fluoro-4-chlorobenzamide (1.7 g, 10 mmol) and dissolve it in dichloroethane (30 mL). Slowly add oxalyl chloride (1.9 g, 15 mmol) at 0°C under nitrogen protection. After the addition is complete, heat and stir at 60°C until TLC detection shows that the reaction is complete. After the reaction mixture is cooled to room temperature, the solvent and excess oxalyl chloride are evaporated on a rotary evaporator to obtain a solid mixture for standby use.
将上一步得到的固体混合物溶于二氯乙烷(10mL)中，在氮气保护下在0℃下将该溶液缓慢滴加到对乙烯苯胺(1.3g,11mmol)的二氯乙烷溶液(10mL)中，滴加完毕后，室温下反应1小时，直至大量白色固体析出，过滤，滤饼用二氯甲烷洗涤，烘干得到化合物1-2，3.0g，产率94％。LC-MS(ESI)m/z:319[M+H]+.The solid mixture obtained in the previous step was dissolved in dichloroethane (10 mL), and the solution was slowly added dropwise to a dichloroethane solution (10 mL) of p-vinylaniline (1.3 g, 11 mmol) at 0°C under nitrogen protection. After the addition was completed, the mixture was reacted at room temperature for 1 hour until a large amount of white solid precipitated, filtered, and the filter cake was washed with dichloromethane and dried to obtain compound 1-2, 3.0 g, with a yield of 94%. LC-MS (ESI) m/z: 319 [M+H] + .
步骤二：化合物1-3的合成Step 2: Synthesis of compound 1-3
取化合物1-2(2.6g,8mmol)溶于DMF(50mL)中，在氮气保护下在0℃下缓慢滴加NaHMDS(8mL,2M in THF)。滴加完毕后，在100℃下加热搅拌，直到TLC显示反应完全。Compound 1-2 (2.6 g, 8 mmol) was dissolved in DMF (50 mL), and NaHMDS (8 mL, 2 M in THF) was slowly added dropwise at 0°C under nitrogen protection. After the addition was complete, the mixture was heated and stirred at 100°C until TLC showed that the reaction was complete.
反应混合物冷却至室温后，倒入冰水(20mL)中，搅拌，用二氯甲烷(20mL×3)萃取。合并萃取有机相，用水(50mL×3)洗涤，无水硫酸钠干燥。干燥后的有机相在旋转蒸发仪上蒸除溶剂，得到的残余物经过柱层析纯化，得到产物1-3，1.9g，产率78％。LC-MS(ESI)m/z:299[M+H]+ . After the reaction mixture was cooled to room temperature, it was poured into ice water (20 mL), stirred, and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with water (50 mL × 3), and dried over anhydrous sodium sulfate. The organic phase after drying was evaporated on a rotary evaporator to remove the solvent, and the obtained residue was purified by column chromatography to obtain product 1-3, 1.9 g, with a yield of 78%. LC-MS (ESI) m/z: 299 [M + H] + .
步骤三：化合物1-4的合成Step 3: Synthesis of compound 1-4
取化合物1-3(0.3g,1mmol)和N,N-二异丙基乙胺(0.3g,2mmol)溶于无水乙腈中(10mL)中，在氮气保护下在0℃下缓慢滴加三氯氧磷(0.3g,2mmol)。滴加完毕后，在80℃下加热搅拌，直到TLC显示反应完全。反应混合物冷却至室温后，在旋转蒸发仪上蒸除溶剂，得到的固体混合物待用。Take compound 1-3 (0.3 g, 1 mmol) and N, N-diisopropylethylamine (0.3 g, 2 mmol) and dissolve them in anhydrous acetonitrile (10 mL). Add phosphorus oxychloride (0.3 g, 2 mmol) slowly at 0 ° C under nitrogen protection. After the addition is complete, heat and stir at 80 ° C until TLC shows that the reaction is complete. After the reaction mixture is cooled to room temperature, the solvent is evaporated on a rotary evaporator to obtain a solid mixture for standby use.
步骤四：化合物1-5的合成Step 4: Synthesis of Compound 1-5
在0℃下将二甲胺(1mL,2M in THF)溶液滴加到化合物1-4的无水四氢呋喃溶液中，室温下搅拌，直到TLC显示反应完全。Add dimethylamine (1 mL, 2 M in THF) solution dropwise to the anhydrous tetrahydrofuran solution of compound 1-4 at 0°C and stir at room temperature until TLC shows the reaction is complete.
反应混合物倒入冰水(20mL)中，搅拌，用二氯甲烷(20mL×3)萃取。合并萃取有机相，用水(50mL×3)洗涤，无水硫酸钠干燥。干燥后的有机相在旋转蒸发仪上蒸除溶剂，得到的残余物经过柱层析纯化，得到产物1-5，0.26g，产率80％。LC-MS(ESI)m/z:326[M+H]+ . The reaction mixture was poured into ice water (20 mL), stirred, and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with water (50 mL × 3), and dried over anhydrous sodium sulfate. The organic phase after drying was evaporated on a rotary evaporator to remove the solvent, and the obtained residue was purified by column chromatography to obtain product 1-5, 0.26 g, with a yield of 80%. LC-MS (ESI) m/z: 326 [M + H] + .
步骤五：化合物1-9的合成Step 5: Synthesis of Compound 1-9
化合物1-9的合成参照化合物1-5的合成，区别在于把步骤一中的对乙烯苯胺替换为对溴苯胺。The synthesis of compound 1-9 refers to the synthesis of compound 1-5, except that p-vinylaniline in step 1 is replaced by p-bromoaniline.
步骤六：化合物1的合成Step 6: Synthesis of compound 1
取化合物1-5(0.16g,0.5mmol)、化合物1-9(0.19g,0.5mmol)、吡啶(0.16g,2mmol)、锌粉(0.03g,0.5mmol)和(Ph3P)2Pd(II)Cl2(0.04g,0.05mmol)溶于乙腈(10mL)中，在氮气保护下在80℃下加热搅拌，直到TLC显示反应完成。Compound 1-5 (0.16 g, 0.5 mmol), compound 1-9 (0.19 g, 0.5 mmol), pyridine (0.16 g, 2 mmol), zinc powder (0.03 g, 0.5 mmol) and (Ph 3 P) 2 Pd(II)Cl 2 (0.04 g, 0.05 mmol) were dissolved in acetonitrile (10 mL) and heated with stirring at 80° C. under nitrogen protection until TLC showed the reaction was completed.
反应混合物倒入冰水(20mL)中，搅拌，用二氯甲烷(20mL×3)萃取。合并萃取有机相，用水(50mL×3)洗涤，无水硫酸钠干燥。干燥后的有机相在旋转蒸发仪上蒸除溶剂，得到的残余物经过柱层析纯化得到粗产品，经HPLC制备纯化后得到化合物1，71mg,产率23％。LC-MS(ESI)m/z:312.1[M/2+H]+.The reaction mixture was poured into ice water (20 mL), stirred, and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with water (50 mL × 3), and dried over anhydrous sodium sulfate. The organic phase after drying was evaporated on a rotary evaporator to remove the solvent, and the obtained residue was purified by column chromatography to obtain a crude product, which was purified by HPLC to obtain compound 1, 71 mg, with a yield of 23%. LC-MS (ESI) m/z: 312.1 [M/2+H] + .
实施例2
Example 2
合成路线
Synthetic route
步骤一：化合物2的合成Step 1: Synthesis of compound 2
取化合物1(62mg,0.1mmol)溶于甲醇(10mL)中，氮气置换三次后搅拌10分钟，加入10％钯碳(10mg),再用氢气置换三次，在氢气环境下继续搅拌反应，直到TLC显示反应完全。Compound 1 (62 mg, 0.1 mmol) was dissolved in methanol (10 mL), and the atmosphere was replaced with nitrogen three times, followed by stirring for 10 minutes. 10% palladium carbon (10 mg) was added, and the atmosphere was replaced with hydrogen three times. The reaction was continued by stirring under a hydrogen atmosphere until TLC showed that the reaction was complete.
反应混合物经硅藻土过滤后倒入冰水(20mL)中，搅拌，用二氯甲烷(20mL×3)萃取。合并萃取有机相，用水(50mL×3)洗涤，无水硫酸钠干燥。干燥后的有机相在旋转蒸发仪上蒸除溶剂，得到的残余物经过柱层析纯化得到粗产品，经HPLC制备纯化后得到化合物2，53mg,产率95％。LC-MS(ESI)m/z:279.1[M/2+H]+.1H NMR(600MHz,DMSO)δ8.01(d,J＝8.2Hz,2H),7.51(d,J＝8.1Hz,4H),7.46(t,J＝7.9Hz,2H),7.22(d,J＝8.1Hz,4H),7.15(t,J＝7.7Hz,2H),6.45(d,J＝8.5Hz,2H),3.31(s,12H),3.07(s,4H).The reaction mixture was filtered through diatomaceous earth and poured into ice water (20 mL), stirred, and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with water (50 mL × 3), and dried over anhydrous sodium sulfate. The organic phase after drying was evaporated on a rotary evaporator to remove the solvent, and the obtained residue was purified by column chromatography to obtain a crude product, which was purified by HPLC to obtain compound 2, 53 mg, with a yield of 95%. LC-MS(ESI)m/z:279.1[M/2+H] + . 1 H NMR(600MHz, DMSO)δ8.01(d,J＝8.2Hz,2H),7.51(d,J＝8.1Hz,4H),7.46(t,J＝7.9Hz,2H),7.22(d,J＝8.1Hz,4H),7.15(t, J＝7.7Hz,2H),6.45(d,J＝8.5Hz,2H),3.31(s,12H),3.07(s,4H).
实施例3
Example 3
合成路线
Synthetic route
步骤一：化合物3-1的合成Step 1: Synthesis of compound 3-1
取间碘苯胺(5.0g,22.8mmol)溶于二氯甲烷(15mL)中，室温下加入二碳酸二叔丁酯(15.72mL,68.5mmol)，搅拌过夜，直到TLC显示反应完全。Take m-iodoaniline (5.0 g, 22.8 mmol) and dissolve it in dichloromethane (15 mL). Add di-tert-butyl dicarbonate (15.72 mL, 68.5 mmol) at room temperature and stir overnight until TLC shows that the reaction is complete.
反应混合物倒入冰水(40mL)中，搅拌，用二氯甲烷(40mL×3)萃取。合并萃取有机相，用水(100mL×3)洗涤，无水硫酸钠干燥。干燥后的有机相在旋转蒸发仪上蒸除溶剂，得到的残余物经过柱层析纯化，得到产物3-1，7.0g，产率96％。LC-MS(ESI)m/z:220[M+H-100]+。The reaction mixture was poured into ice water (40 mL), stirred, and extracted with dichloromethane (40 mL × 3). The organic phases were combined, washed with water (100 mL × 3), and dried over anhydrous sodium sulfate. The organic phase after drying was evaporated on a rotary evaporator to remove the solvent, and the obtained residue was purified by column chromatography to obtain product 3-1, 7.0 g, yield 96%. LC-MS (ESI) m/z: 220 [M + H-100] + .
步骤二：化合物3-2的合成Step 2: Synthesis of compound 3-2
化合物3-1(4.0g，12.5mmol)和1H-氰基咪唑(1.4g,15.0mmol)于N，N-二甲基甲酰胺(17mL)中依次加入碳酸铯(8.16g,25mmol)、(1R，2R)-N1，N2-二甲基环己烷-1，2-二胺(0.45mL,10％w.t.)和碘化亚铜(0.40g,10％w.t.)。在N2氛围下加热到100℃反应过夜。反应混合物用乙酸乙酯和水萃取，有机相合并，无水硫酸钠干燥。干燥后的有机相在旋转蒸发仪上蒸除溶剂，得到的残余物经过柱层析纯化，得到化合物3-2，1.97g，产率55％。LC-MS(ESI)m/z:285[M+H]+.Compound 3-1 (4.0 g, 12.5 mmol) and 1H-cyanoimidazole (1.4 g, 15.0 mmol) were added to N, N-dimethylformamide (17 mL) in turn with cesium carbonate (8.16 g, 25 mmol), (1R, 2R)-N1, N2-dimethylcyclohexane-1, 2-diamine (0.45 mL, 10% wt) and cuprous iodide (0.40 g, 10% wt). The mixture was heated to 100 ° C under N 2 atmosphere and reacted overnight. The reaction mixture was extracted with ethyl acetate and water, and the organic phases were combined and dried over anhydrous sodium sulfate. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the obtained residue was purified by column chromatography to obtain compound 3-2, 1.97 g, with a yield of 55%. LC-MS (ESI) m/z: 285 [M + H] + .
步骤三：化合物3-3的合成Step 3: Synthesis of compound 3-3
取化合物3-2(1.5g,2.79mmol)溶于四氢呋喃(50mL)中，在0℃下缓慢滴加2.5M LiAlH4/THF(4.2mL),逐渐加热到75℃，反应20min。通过硅藻土过滤，用四氢呋喃洗涤，滤液浓缩干燥，得到粗品化合物3-3，其为黄色油状，直接用于下一步。LC-MS(ESI)m/z:189[M+H]+.Compound 3-2 (1.5 g, 2.79 mmol) was dissolved in tetrahydrofuran (50 mL), and 2.5 M LiAlH 4 /THF (4.2 mL) was slowly added dropwise at 0°C, and gradually heated to 75°C for 20 min. The mixture was filtered through diatomaceous earth, washed with tetrahydrofuran, and the filtrate was concentrated and dried to obtain a crude compound 3-3 in the form of a yellow oil, which was used directly in the next step. LC-MS (ESI) m/z: 189 [M+H] + .
步骤四：化合物3-4的合成Step 4: Synthesis of compound 3-4
取4-氯-2-氟苯甲酰胺(2.76g,16.0mmol)溶于1，2-二氯乙烷(30mL)中，在0℃下缓慢滴加草酰氯(2.0mL，23.9mmol),加热到55℃，反应一小时，然后升温到80℃，过夜反应。TLC监测原料基本消失，直接将反应液旋干，得到相应的异氰酸酯中间体。将其尽快溶于二氯乙烷(DCE)(2mL)中，在冰水浴下滴加到分散有化合物3-3的DCE(5mL)混合液中，逐渐升温到室温。反应液用无水硫酸钠干燥，干燥后的有机相在旋转蒸发仪上蒸除溶剂，得到的残余物经过柱层析纯化，得到化合物3-4(1.1g,36％)，其为白色固体。LC-MS(ESI)m/z:587[M+H]+。Take 4-chloro-2-fluorobenzamide (2.76g, 16.0mmol) and dissolve it in 1,2-dichloroethane (30mL). Slowly add oxalyl chloride (2.0mL, 23.9mmol) at 0℃, heat to 55℃, react for one hour, then heat to 80℃ and react overnight. TLC monitoring shows that the raw material basically disappears, and the reaction solution is directly spin-dried to obtain the corresponding isocyanate intermediate. Dissolve it in dichloroethane (DCE) (2mL) as soon as possible, add it dropwise to the DCE (5mL) mixed solution dispersed with compound 3-3 under an ice-water bath, and gradually warm it to room temperature. The reaction solution is dried over anhydrous sodium sulfate, and the organic phase after drying is evaporated on a rotary evaporator to remove the solvent. The obtained residue is purified by column chromatography to obtain compound 3-4 (1.1g, 36%), which is a white solid. LC-MS (ESI) m/z: 587[M+H] + .
步骤五：化合物3-5的合成 Step 5: Synthesis of compound 3-5
在0℃下缓慢向含有化合物3-4(500mg,0.85mmol)的四氢呋喃(15mL)和N，N-二甲基甲酰胺(0.5mL)混合液中滴加2MNaHMDS/THF(2.5mL)，加热到75℃，反应1.5天，TLC监测原料基本消失。反应液用无水硫酸钠干燥，干燥后的有机相在旋转蒸发仪上蒸除溶剂，得到的残余物经过柱层析纯化，得到化合物3-5(100mg,21％)，其为白色固体。LC-MS(ESI)m/z:547[M+H]+。2M NaHMDS/THF (2.5 mL) was slowly added dropwise to a mixture of tetrahydrofuran (15 mL) and N, N-dimethylformamide (0.5 mL) containing compound 3-4 (500 mg, 0.85 mmol) at 0°C, heated to 75°C, and reacted for 1.5 days. TLC monitoring showed that the raw material basically disappeared. The reaction solution was dried over anhydrous sodium sulfate, and the organic phase after drying was evaporated on a rotary evaporator to remove the solvent. The obtained residue was purified by column chromatography to obtain compound 3-5 (100 mg, 21%) as a white solid. LC-MS (ESI) m/z: 547 [M+H] + .
步骤六：化合物3的合成Step 6: Synthesis of compound 3
在将化合物3-5(100mg,0.18mmol)分散到乙腈(10mL)中，在0℃下分别加入DIEA(0.3mL，1.8mmol)和POCl3(0.85mL，0.92mmol)，升温到80℃回流过夜。TLC监测原料基本消失，将反应液旋干，并迅速加入二甲胺的四氢呋喃溶液(3mL)，室温搅拌。TLC监测原料基本消失，反应液用无水硫酸钠干燥，干燥后的有机相在旋转蒸发仪上蒸除溶剂，得到的残余物经过柱层析纯化，得到粗品，再通过高效液相色谱法HPLC纯化，得到化合物3，57mg，产率53％。LC-MS(ESI)m/z:301.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.05(d,J＝8.8Hz,1H),7.96(d,J＝8.8Hz,1H),7.81(d,J＝8.2Hz,1H),7.68(dd,J＝10.5,5.2Hz,3H),7.27(d,J＝7.8Hz,1H),7.19(ddd,J＝15.2,8.8,2.0Hz,2H),6.43(d,J＝2.0Hz,1H),5.20(s,2H),3.31(s,6H),3.24(s,6H)。Compound 3-5 (100 mg, 0.18 mmol) was dispersed in acetonitrile (10 mL), DIEA (0.3 mL, 1.8 mmol) and POCl 3 (0.85 mL, 0.92 mmol) were added at 0°C, and the mixture was heated to 80°C and refluxed overnight. The raw material was basically disappeared by TLC monitoring, the reaction solution was spin-dried, and a tetrahydrofuran solution of dimethylamine (3 mL) was quickly added and stirred at room temperature. The raw material was basically disappeared by TLC monitoring, the reaction solution was dried over anhydrous sodium sulfate, and the organic phase after drying was evaporated on a rotary evaporator to remove the solvent. The residue was purified by column chromatography to obtain a crude product, which was then purified by high performance liquid chromatography HPLC to obtain compound 3, 57 mg, with a yield of 53%. LC-MS (ESI) m/z: 301.1[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.32 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.96 ( d, J = 8.8 Hz, 1H), 7.81 ( d, J = 8.2 Hz, 1H), 7.68 ( dd, J = 10. 5,5.2Hz,3H),7.27(d,J＝7.8Hz,1H),7.19(ddd,J＝15.2,8.8,2.0Hz,2H),6.43(d,J＝2.0Hz,1H),5.20(s,2H),3.31(s,6H),3.24(s,6H).
实施例4
Example 4
合成路线
Synthetic route
步骤一：化合物4的合成Step 1: Synthesis of compound 4
在将化合物3-5(100mg,0.18mmol)分散到乙腈(10mL)中，在0℃下分别加入DIEA(0.3mL，1.8mmol)和POCl3(0.85mL，0.92mmol)，升温到80℃回流过夜。TLC监测原料基本消失，将反应液旋干，并迅速加入甲胺的四氢呋喃溶液(3mL)，室温搅拌。TLC监测原料基本消失，反应液用无水硫酸钠干燥，干燥后的有机相在旋转蒸发仪上蒸除溶剂，得到的残余物经过柱层析纯化，得到粗品，再通过高效液相色谱法HPLC纯化，得到化合物4，0.53g，产率49％。LC-MS(ESI)m/z:287.1[M/2+H]+.Compound 3-5 (100 mg, 0.18 mmol) was dispersed in acetonitrile (10 mL), DIEA (0.3 mL, 1.8 mmol) and POCl 3 (0.85 mL, 0.92 mmol) were added at 0°C, and the temperature was raised to 80°C and refluxed overnight. TLC monitoring showed that the raw material basically disappeared, the reaction solution was spin-dried, and a tetrahydrofuran solution of methylamine (3 mL) was quickly added and stirred at room temperature. TLC monitoring showed that the raw material basically disappeared, the reaction solution was dried over anhydrous sodium sulfate, and the organic phase after drying was evaporated on a rotary evaporator to remove the solvent. The obtained residue was purified by column chromatography to obtain a crude product, which was then purified by high performance liquid chromatography HPLC to obtain compound 4, 0.53 g, with a yield of 49%. LC-MS (ESI) m/z: 287.1 [M/2+H] + .
实施例5
Example 5
合成路线
Synthetic route
步骤一：化合物5的合成Step 1: Synthesis of compound 5
取化合物3(30mg,0.05mmol)溶于甲醇(10mL)中，氮气置换三次后搅拌10分钟，加入10％钯碳(10mg),再用氢气置换三次，在氢气环境下继续搅拌反应，直到TLC显示反应完全。Compound 3 (30 mg, 0.05 mmol) was dissolved in methanol (10 mL), and the atmosphere was replaced with nitrogen three times, followed by stirring for 10 minutes. 10% palladium carbon (10 mg) was added, and the atmosphere was replaced with hydrogen three times. The reaction was continued under stirring in a hydrogen environment until TLC showed that the reaction was complete.
反应混合物经硅藻土过滤后倒入冰水(20mL)中，搅拌，用二氯甲烷(20mL×3)萃取。合并萃取有机相，用水(50mL×3)洗涤，无水硫酸钠干燥。干燥后的有机相在旋转蒸发仪上蒸除溶剂，得到的残余物经过柱层析纯化得到粗产品，经HPLC制备纯化后得到化合物5，23mg,产率88％。LC-MS(ESI)m/z:267.1[M/2+H]+.The reaction mixture was filtered through diatomaceous earth and poured into ice water (20 mL), stirred, and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with water (50 mL × 3), and dried over anhydrous sodium sulfate. The organic phase after drying was evaporated on a rotary evaporator to remove the solvent, and the obtained residue was purified by column chromatography to obtain a crude product, which was purified by HPLC to obtain compound 5, 23 mg, with a yield of 88%. LC-MS (ESI) m/z: 267.1 [M/2+H] + .
实施例6
Example 6
合成路线
Synthetic route
步骤一：化合物6的合成Step 1: Synthesis of compound 6
取化合物4(60mg,0.1mmol)溶于甲醇(10mL)中，氮气置换三次后搅拌10分钟，加入10％钯碳(20mg),再用氢气置换三次，在氢气环境下继续搅拌反应，直到TLC显示反应完全。Compound 4 (60 mg, 0.1 mmol) was dissolved in methanol (10 mL), and the atmosphere was replaced with nitrogen three times, followed by stirring for 10 minutes. 10% palladium carbon (20 mg) was added, and the atmosphere was replaced with hydrogen three times. The reaction was continued by stirring under a hydrogen atmosphere until TLC showed that the reaction was complete.
反应混合物经硅藻土过滤后倒入冰水(20mL)中，搅拌，用二氯甲烷(20mL×3)萃取。合并萃取有机相，用水(50mL×3)洗涤，无水硫酸钠干燥。干燥后的有机相在旋转蒸发仪上蒸除溶剂，得到的残余物经过柱层析纯化得到粗产品，经HPLC制备纯化 后得到化合物6，38mg,产率73％。LC-MS(ESI)m/z:253.1[M/2+H]+.The reaction mixture was filtered through diatomaceous earth and poured into ice water (20 mL), stirred, and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with water (50 mL × 3), and dried over anhydrous sodium sulfate. The organic phase after drying was evaporated on a rotary evaporator to remove the solvent, and the residue was purified by column chromatography to obtain a crude product, which was purified by HPLC preparation Compound 6 was obtained, 38 mg, with a yield of 73%. LC-MS (ESI) m/z: 253.1 [M/2+H] + .
实施例7
Example 7
合成路线
Synthetic route
步骤一：化合物7-1的合成Step 1: Synthesis of compound 7-1
室温下将间羟基苯甲酸甲酯(1g，6.58mmol)溶于20mL无水乙腈中，加入3-溴甲基苯甲酸甲酯(1.5g，6.59mmol)和碳酸铯(4.3g，13.11mmol)，升温至80℃搅拌3小时。TLC监测反应完全，加50mL水和150mL乙酸乙酯萃取，反复三次，无水硫酸钠干燥有机相后浓缩得到化合物7-1，1.97g，产率99％。LC-MS(ESI)m/z:301[M+H]+.Methyl m-hydroxybenzoate (1 g, 6.58 mmol) was dissolved in 20 mL of anhydrous acetonitrile at room temperature, methyl 3-bromomethylbenzoate (1.5 g, 6.59 mmol) and cesium carbonate (4.3 g, 13.11 mmol) were added, and the temperature was raised to 80 ° C and stirred for 3 hours. TLC monitored the reaction to be complete, and 50 mL of water and 150 mL of ethyl acetate were added for extraction, and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 7-1, 1.97 g, with a yield of 99%. LC-MS (ESI) m/z: 301 [M + H] + .
步骤二：化合物7-2的合成Step 2: Synthesis of compound 7-2
室温下，将化合物7-1(600mg，2mmol)溶于10mL DMF中，将体系降温至0℃后，缓慢滴加2.5N氢化铝锂的THF溶液(2.4mL，6mmol)，之后缓慢升至室温搅拌30分钟。TLC和LCMS监测反应完全。加水淬灭反应，用EA萃取水相三次，浓缩后经快速色谱柱分离纯化(PE:EA＝2:1)得到化合物7-2，0.42g，产率86％。LC-MS(ESI)m/z:245[M+H]+.At room temperature, compound 7-1 (600 mg, 2 mmol) was dissolved in 10 mL DMF, the system was cooled to 0 ° C, and 2.5 N lithium aluminum hydride THF solution (2.4 mL, 6 mmol) was slowly added dropwise, and then slowly heated to room temperature and stirred for 30 minutes. TLC and LCMS monitored the reaction to be complete. Water was added to quench the reaction, and the aqueous phase was extracted with EA three times. After concentration, the compound 7-2 was separated and purified by flash chromatography (PE: EA = 2: 1), 0.42 g, and the yield was 86%. LC-MS (ESI) m/z: 245 [M + H] + .
步骤三：化合物7-3的合成Step 3: Synthesis of compound 7-3
室温下，将化合物7-2(420mg，1.71mmol)溶于10mL DCM中，分批次缓慢加入戴斯马丁氧化剂(1.76g，4.15mmol)，保持室温搅拌16小时。反应结束后为灰色悬浊液。TLC和LCMS监测反应完全。加碳酸氢钠溶液淬灭反应，用DCM萃取有机相三次，合并有机相浓缩后经快速色谱柱层析(PE:EA,0-70％,10分钟)分离得到化合物7-3，0.40g，产率97％。LC-MS(ESI)m/z:241[M+H]+.At room temperature, compound 7-2 (420 mg, 1.71 mmol) was dissolved in 10 mL DCM, and Dess-Martin oxidant (1.76 g, 4.15 mmol) was slowly added in batches, and stirred at room temperature for 16 hours. After the reaction was completed, a gray suspension was obtained. TLC and LCMS monitored the reaction to be complete. Sodium bicarbonate solution was added to quench the reaction, and the organic phase was extracted three times with DCM. The organic phases were combined and concentrated, and then separated by flash chromatography (PE: EA, 0-70%, 10 minutes) to obtain compound 7-3, 0.40 g, with a yield of 97%. LC-MS (ESI) m/z: 241 [M+H] + .
步骤四：化合物7的合成Step 4: Synthesis of compound 7
室温下，将化合物7-3(90mg，0.373mmol)溶于5mL无水乙醇，加入对甲苯磺酰肼(140mg，0.753mmol)，保持室温搅拌1小时。TLC监测化合物3小时且有新点生成。之后加入5-溴靛红(170mg，0.756mmol)和碳酸钾(310mg，2.246mmol)，升温至80℃搅拌过夜。LCMS监测反应完全，加30mL DCM和10mLMeOH稀释反应 液后过滤，滤液用EtOH打浆后经HPLC纯化后得到化合物7，52mg，产率20％。LC-MS(ESI)m/z:659.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ12.38(s,2H),9.57(s,2H),7.58(d,J＝4.7Hz,2H),7.51–7.44(m,4H),7.34–7.27(m,3H),7.15(dd,J＝8.3,2.6Hz,1H),7.10(dd,J＝4.4,2.2Hz,2H),7.03–7.00(m,1H),6.91(dt,J＝7.5,1.2Hz,1H),5.22(s,2H).At room temperature, compound 7-3 (90 mg, 0.373 mmol) was dissolved in 5 mL of anhydrous ethanol, p-toluenesulfonyl hydrazide (140 mg, 0.753 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The compound was monitored by TLC for 3 hours and new spots were generated. Then 5-bromoindigo red (170 mg, 0.756 mmol) and potassium carbonate (310 mg, 2.246 mmol) were added, and the temperature was raised to 80 ° C and stirred overnight. LCMS monitored the reaction to be complete, and 30 mL of DCM and 10 mL of MeOH were added to dilute the reaction. The filtrate was filtered, and the filtrate was slurried with EtOH and purified by HPLC to obtain compound 7, 52 mg, with a yield of 20%. LC-MS (ESI) m/z: 659.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.38 (s, 2H), 9.57 (s, 2H), 7.58 (d, J = 4.7 Hz, 2H), 7.51–7.44 (m, 4H), 7.34–7.27 (m, 3H), 7.15 (dd, J = 8.3, 2.6 Hz, 1H), 7.10 (dd, J = 4.4, 2.2 Hz, 2H), 7.03–7.00 (m, 1H), 6.91 (dt, J = 7.5, 1.2 Hz, 1H), 5.22 (s, 2H).
实施例8
Example 8
合成路线
Synthetic route
步骤一：化合物8的合成Step 1: Synthesis of compound 8
化合物8的合成方法参照实施例7中的步骤四，区别在于把5-溴靛红替换为5-溴-7-氮杂靛红。LC-MS(ESI)m/z:661.0[M+H]+.The synthesis method of compound 8 is similar to step 4 in Example 7, except that 5-bromo-7-aza-insatin is replaced by 5-bromo-7-aza-insatin. LC-MS (ESI) m/z: 661.0 [M+H] + .
实施例9
Embodiment 9
合成路线
Synthetic route
步骤一：化合物9-1的合成 Step 1: Synthesis of compound 9-1
室温下将异烟酸甲酯(1.0g，7.3mmol)溶于50mL甲醇中，加入0.2mL浓硫酸，升温至65℃。之后将过硫酸铵(15g，65.79mmol)溶于25mL水中，滴加进反应体系中，70℃回流搅拌3小时。TLC监测反应完全，浓缩除去大量甲醇，加50mL水和150mL乙酸乙酯萃取，反复三次，无水硫酸钠干燥有机相后浓缩得红色固体化合物9-1，0.6g，产率52％。LC-MS(ESI)m/z:168[M+H]+ .步骤二：化合物9-2的合成At room temperature, methyl isonicotinate (1.0 g, 7.3 mmol) was dissolved in 50 mL of methanol, 0.2 mL of concentrated sulfuric acid was added, and the temperature was raised to 65°C. Then, ammonium persulfate (15 g, 65.79 mmol) was dissolved in 25 mL of water, added dropwise to the reaction system, and refluxed at 70°C with stirring for 3 hours. TLC monitored the reaction to be complete, concentrated to remove a large amount of methanol, and extracted with 50 mL of water and 150 mL of ethyl acetate, which was repeated three times. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a red solid compound 9-1, 0.6 g, with a yield of 52%. LC-MS (ESI) m/z: 168 [M+H] + . Step 2: Synthesis of compound 9-2
室温下将化合物9-1(600mg，3.593mmol)溶于20mL THF中，加入间羟基苯甲酸甲酯(550mg，3.618mmol)和三苯基膦(1.2g，4.563mmol)，降温至0℃，缓慢滴加DEAD(750mg，4.310mmol)，之后升至室温搅拌20分钟。TLC监测反应完全，加碳酸氢钠溶液和EA萃取三次，浓缩后经快速色谱柱层析分离纯化(PE:EA,0-50％,15min)得白色固体化合物9-2，1.0g，产率93％。LC-MS(ESI)m/z:302[M+H]+.Compound 9-1 (600 mg, 3.593 mmol) was dissolved in 20 mL THF at room temperature, methyl m-hydroxybenzoate (550 mg, 3.618 mmol) and triphenylphosphine (1.2 g, 4.563 mmol) were added, the temperature was lowered to 0°C, DEAD (750 mg, 4.310 mmol) was slowly added dropwise, and then the temperature was raised to room temperature and stirred for 20 minutes. TLC monitored the reaction to be complete, sodium bicarbonate solution and EA were added for extraction three times, and after concentration, the mixture was separated and purified by flash chromatography (PE:EA, 0-50%, 15 min) to obtain a white solid compound 9-2, 1.0 g, with a yield of 93%. LC-MS (ESI) m/z: 302 [M + H] + .
步骤三：化合物9-3的合成Step 3: Synthesis of compound 9-3
室温下，将化合物9-2(1g，3.32mmol)溶于20mL DMF中，将体系降温至0℃后，缓慢滴加2.5N氢化铝锂的THF溶液(2.6mL，6.5mmol)，之后缓慢升至室温搅拌30分钟。TLC和LCMS监测反应完全。加水淬灭反应，用EA萃取水相三次，浓缩后经快速色谱柱分离纯化(PE:EA＝2:1)得黄色油状化合物9-3，550mg，产率68％。LC-MS(ESI)m/z:246[M+H]+.At room temperature, compound 9-2 (1 g, 3.32 mmol) was dissolved in 20 mL DMF. After the system was cooled to 0 °C, 2.5 N lithium aluminum hydride THF solution (2.6 mL, 6.5 mmol) was slowly added dropwise, and then slowly heated to room temperature and stirred for 30 minutes. TLC and LCMS monitored the reaction to be complete. Water was added to quench the reaction, and the aqueous phase was extracted with EA three times. After concentration, it was separated and purified by flash chromatography (PE: EA = 2: 1) to obtain a yellow oily compound 9-3, 550 mg, with a yield of 68%. LC-MS (ESI) m/z: 246 [M + H] + .
步骤四：化合物9-4的合成Step 4: Synthesis of compound 9-4
室温下，将化合物9-3(550mg，2.236mmol)溶于20mL DCM中，分批次缓慢加入戴斯马丁氧化剂(2.27g，5.354mmol)，保持室温搅拌16小时。反应结束后为墨绿色悬浊液。TLC和LCMS监测反应完全。加碳酸氢钠溶液淬灭反应，用DCM萃取有机相三次，合并有机相浓缩后经快速色谱柱层析(PE:EA,0-70％,10分钟)分离得白色固体化合物9-4，260mg，产率48％。LC-MS(ESI)m/z:242[M+H]+.At room temperature, compound 9-3 (550 mg, 2.236 mmol) was dissolved in 20 mL DCM, and Dess-Martin periodinane (2.27 g, 5.354 mmol) was slowly added in batches, and stirred at room temperature for 16 hours. After the reaction was completed, a dark green suspension was obtained. TLC and LCMS monitored the reaction to be complete. Sodium bicarbonate solution was added to quench the reaction, and the organic phase was extracted three times with DCM. The organic phases were combined and concentrated, and then separated by flash column chromatography (PE: EA, 0-70%, 10 minutes) to obtain a white solid compound 9-4, 260 mg, with a yield of 48%. LC-MS (ESI) m/z: 242 [M+H] + .
步骤五：化合物9的合成Step 5: Synthesis of compound 9
室温下，将化合物9-4(100mg，0.413mmol)溶于5mL无水乙醇，加入对甲苯磺酰肼(160mg，0.860mmol)，保持室温搅拌1小时。TLC监测化合物3小时且有新点生成。之后加入5-溴靛红(280mg，1.244mmol)和碳酸钾(340mg，2.464mmol)，升温至80℃搅拌过夜。LCMS监测反应完全，加30mL DCM和10mLMeOH稀释反应液后过滤，滤液用EtOH打浆后经HPLC纯化后得白色固体化合物9，36mg，产率13％。LC-MS(ESI)m/z:660.0[M+H]+.At room temperature, compound 9-4 (100 mg, 0.413 mmol) was dissolved in 5 mL of anhydrous ethanol, p-toluenesulfonyl hydrazide (160 mg, 0.860 mmol) was added, and the mixture was stirred at room temperature for 1 hour. TLC monitored the compound for 3 hours and new spots were generated. Then 5-bromoindigo red (280 mg, 1.244 mmol) and potassium carbonate (340 mg, 2.464 mmol) were added, and the temperature was raised to 80 ° C and stirred overnight. LCMS monitored the reaction to be complete, and the reaction solution was diluted with 30 mL of DCM and 10 mL of MeOH and then filtered. The filtrate was slurried with EtOH and purified by HPLC to obtain a white solid compound 9, 36 mg, with a yield of 13%. LC-MS (ESI) m/z: 660.0 [M + H] + .
实施例10
Example 10
合成路线
Synthetic route
步骤一：化合物10的合成Step 1: Synthesis of compound 10
化合物10的合成方法参照实施例9中的步骤五，区别在于把5-溴靛红替换为5-溴-7-氮杂靛红。LC-MS(ESI)m/z:662.0[M+H]+.The synthesis method of compound 10 is similar to step 5 in Example 9, except that 5-bromo-7-aza-insatin is replaced by 5-bromo-7-aza-insatin. LC-MS (ESI) m/z: 662.0 [M+H] + .
实施例11
Embodiment 11
合成方法Synthesis method
化合物11的合成方法参照实施例3，区别在于把步骤四中的2-氟-4-氯苯甲酰胺替换为2-氟-4-三氟甲基苯甲酰胺。LC-MS(ESI)m/z:335.1[M/2+H]+.The synthesis method of compound 11 is similar to that of Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced by 2-fluoro-4-trifluoromethylbenzamide. LC-MS (ESI) m/z: 335.1 [M/2+H] + .
实施例12
Example 12
合成路线
Synthetic route
步骤一：化合物12-1的合成 Step 1: Synthesis of compound 12-1
5-溴靛红(3.0g,13.3mmol)溶于DMF(22mL)中，加入碳酸钾(3.7g,26.6mmol)和SEMCl(3.3g,20.0mmol)，室温搅拌过夜。TLC监测原料基本消失，将反应液旋干，残余物通过硅胶柱色谱法纯化(EA：PE＝1：19)，得到化合物12-1，3.4g,产率72％，为红色固体。LC-MS(ESI)m/z:356[M+H]+.5-Bromoindigo red (3.0 g, 13.3 mmol) was dissolved in DMF (22 mL), potassium carbonate (3.7 g, 26.6 mmol) and SEMCl (3.3 g, 20.0 mmol) were added, and stirred at room temperature overnight. TLC monitoring showed that the raw material basically disappeared, the reaction solution was spin-dried, and the residue was purified by silica gel column chromatography (EA: PE = 1: 19) to obtain compound 12-1, 3.4 g, yield 72%, as a red solid. LC-MS (ESI) m/z: 356 [M + H] + .
步骤二：化合物12-2的合成Step 2: Synthesis of compound 12-2
间碘苯甲醛(2.22g，9.6mmol)和对甲基苯磺酰肼(1.78g,9.6mmol)于EtOH(15mL)中室温搅拌1小时，TLC检测原料基本消失，依次加入碳酸钾(2.64g,1.84mmol)和化合物12-1(2.64g,9.6mmol)。在N2氛围下加热到80℃反应过夜。TLC监测原料基本消失，将反应液旋干，残余物通过硅胶柱色谱法纯化(EA：PE＝1：24)，得到化合物12-2，3.03g，产率56％，其为红色油状。LC-MS(ESI)m/z:572[M+H]+.Meta-iodobenzaldehyde (2.22 g, 9.6 mmol) and p-methylbenzenesulfonyl hydrazide (1.78 g, 9.6 mmol) were stirred at room temperature in EtOH (15 mL) for 1 hour. The raw material was basically disappeared by TLC detection. Potassium carbonate (2.64 g, 1.84 mmol) and compound 12-1 (2.64 g, 9.6 mmol) were added in sequence. The reaction was heated to 80 ° C under N 2 atmosphere overnight. The raw material was basically disappeared by TLC monitoring. The reaction solution was spin-dried and the residue was purified by silica gel column chromatography (EA: PE = 1: 24) to obtain compound 12-2, 3.03 g, with a yield of 56%, which was a red oil. LC-MS (ESI) m/z: 572 [M + H] + .
步骤三：化合物12-3的合成Step 3: Synthesis of compound 12-3
化合物12-2(3.03g,5.3mmol)溶于四氢呋喃(25mL)中，依次加入碳酸钾(732mg，5.3mmol)和硫酸二甲酯(0.61mL，6.4mmol)，室温搅拌过夜。EA/H2O萃取，有机相旋干，得到化合物12-3，3.40g，产率95％，其为红色固体。LC-MS(ESI)m/z:586[M+H]+.Compound 12-2 (3.03 g, 5.3 mmol) was dissolved in tetrahydrofuran (25 mL), potassium carbonate (732 mg, 5.3 mmol) and dimethyl sulfate (0.61 mL, 6.4 mmol) were added in sequence, and stirred at room temperature overnight. EA/H 2 O was extracted, and the organic phase was dried to obtain compound 12-3, 3.40 g, with a yield of 95%, as a red solid. LC-MS (ESI) m/z: 586 [M+H] + .
步骤四：化合物12-4的合成Step 4: Synthesis of compound 12-4
化合物12-3(1.5g，2.6mmol)和1H-氰基咪唑(286mg,3.1mmol)于N，N-二甲基甲酰胺(20mL)中依次加入碳酸铯(1.67g,5.1mmol)、(1R，2R)-N1，N2-二甲基环己烷-1，2-二胺(0.17mL,10％w.t.)和碘化亚铜(150mg,10％w.t.)。在N2氛围下加热到100℃反应过夜。反应混合物用乙酸乙酯和水萃取，有机相合并，浓缩，并通过硅胶柱色谱法纯化(EA：PE＝1：2)，得到化合物12-4，460mg，产率33％。LC-MS(ESI)m/z:551[M+H]+.Compound 12-3 (1.5 g, 2.6 mmol) and 1H-cyanoimidazole (286 mg, 3.1 mmol) were added to N, N-dimethylformamide (20 mL) in turn with cesium carbonate (1.67 g, 5.1 mmol), (1R, 2R)-N1, N2-dimethylcyclohexane-1, 2-diamine (0.17 mL, 10% wt) and cuprous iodide (150 mg, 10% wt). The mixture was heated to 100 ° C under N 2 atmosphere and reacted overnight. The reaction mixture was extracted with ethyl acetate and water, the organic phases were combined, concentrated, and purified by silica gel column chromatography (EA: PE = 1: 2) to obtain compound 12-4, 460 mg, with a yield of 33%. LC-MS (ESI) m/z: 551 [M + H] + .
步骤五：化合物12-5的合成Step 5: Synthesis of compound 12-5
将化合物12-4(198mg，0.36mmol)分散到7N NH3/MeOH(30mL)中，加入雷尼镍(200mg)，在H2氛围下室温搅拌2小时。TLC检测几乎无原料，将反应液通过C-18反向柱层析纯化，得到化合物12-5，180mg,产率91％，其为白色固体。LC-MS(ESI)m/z:555[M+H]+.Compound 12-4 (198 mg, 0.36 mmol) was dispersed in 7N NH 3 /MeOH (30 mL), and Raney nickel (200 mg) was added, and stirred at room temperature for 2 hours under H 2 atmosphere. TLC detection showed that there was almost no raw material, and the reaction solution was purified by C-18 reverse column chromatography to obtain compound 12-5, 180 mg, with a yield of 91%, which was a white solid. LC-MS (ESI) m/z: 555 [M+H] + .
步骤六：化合物12-6的合成Step 6: Synthesis of compound 12-6
4-氯-2-氟苯甲酰胺(100mg,0.58mmol)溶于1，2-二氯乙烷(3mL)中，在0℃下缓慢滴加草酰氯(0.07mL，0.87mmol),加热到55℃，反应1小时，然后升温到80℃，过夜反应。TLC监测原料基本消失，直接将反应液旋干，得到相应的异氰酸酯中间体。将其尽快溶于DCE(1mL)，在冰水浴下滴加到分散有化合物12-5(180mg，0.32mmol)的DCE(1mL)混合液中，逐渐升温到室温。反应液过滤得到化合物12-6，40mg,产率25％，其为白色固体。LC-MS(ESI)m/z:754[M+H]+.4-Chloro-2-fluorobenzamide (100 mg, 0.58 mmol) was dissolved in 1,2-dichloroethane (3 mL), and oxalyl chloride (0.07 mL, 0.87 mmol) was slowly added dropwise at 0 ° C, heated to 55 ° C, reacted for 1 hour, and then heated to 80 ° C and reacted overnight. TLC monitoring showed that the raw material basically disappeared, and the reaction solution was directly spin-dried to obtain the corresponding isocyanate intermediate. It was dissolved in DCE (1 mL) as soon as possible, and added dropwise to a DCE (1 mL) mixed solution dispersed with compound 12-5 (180 mg, 0.32 mmol) under an ice-water bath, and gradually heated to room temperature. The reaction solution was filtered to obtain compound 12-6, 40 mg, with a yield of 25%, which was a white solid. LC-MS (ESI) m/z: 754 [M + H] + .
步骤七：化合物12-7的合成Step 7: Synthesis of compound 12-7
在0℃下缓慢向含有化合物12-6(50mg,66.4μmol)的四氢呋喃(2mL)混合液中滴加2M NaHMDS/THF(120μL)，加热到80℃，反应4小时。将反应液旋干通过高效液相色谱法HPLC纯化，得到化合物12-7，12mg,产率22％，其为白色固体。重复以上实验，得到化合物12-7(30mg)。LC-MS(ESI)m/z:734[M+H]+.2M NaHMDS/THF (120 μL) was slowly added to a mixture of tetrahydrofuran (2 mL) containing compound 12-6 (50 mg, 66.4 μmol) at 0°C, heated to 80°C, and reacted for 4 hours. The reaction solution was spin-dried and purified by HPLC to obtain compound 12-7, 12 mg, with a yield of 22%, as a white solid. The above experiment was repeated to obtain compound 12-7 (30 mg). LC-MS (ESI) m/z: 734 [M + H] + .
步骤八：化合物12-8的合成Step 8: Synthesis of compound 12-8
将化合物12-7(15mg,20.5μmol)分散到乙腈(3mL)中，在0℃下分别加入DIEA(0.3mL)和POCl3(0.1mL)，升温到80℃回流过夜。TLC监测原料基本消失，将反应液旋干，并迅速加入二甲胺的四氢呋喃溶液(3mL)，室温搅拌。通过pre-TLC纯化(MeOH:DCM＝1:10)，得到化合物12-8，14mg，产率90％,为黄色固体。LC-MS(ESI) m/z:761[M+H]+.Compound 12-7 (15 mg, 20.5 μmol) was dispersed in acetonitrile (3 mL), DIEA (0.3 mL) and POCl 3 (0.1 mL) were added at 0°C, and the mixture was heated to 80°C and refluxed overnight. The raw material was basically disappeared by TLC monitoring, the reaction solution was spin-dried, and a tetrahydrofuran solution of dimethylamine (3 mL) was quickly added and stirred at room temperature. Compound 12-8 was obtained by pre-TLC purification (MeOH:DCM=1:10), 14 mg, 90% yield, as a yellow solid. LC-MS (ESI) m/z:761[M+H] + .
步骤九：化合物12的合成Step 9: Synthesis of compound 12
将化合物12-8(14mg)溶于DCM(3mL)中,在0℃下逐滴滴加BBr3，搅拌10分钟，然后室温下搅拌3小时。反应液旋干后通过高效液相色谱法HPLC纯化，得到化合物9，5mg，产率44％。LC-MS(ESI)m/z:309.0[M/2+H]+.Compound 12-8 (14 mg) was dissolved in DCM (3 mL), and BBr 3 was added dropwise at 0°C, stirred for 10 minutes, and then stirred at room temperature for 3 hours. The reaction solution was spin-dried and purified by HPLC to obtain compound 9, 5 mg, with a yield of 44%. LC-MS (ESI) m/z: 309.0 [M/2+H] + .
实施例13
Example 13
合成路线
Synthetic route
合成方法Synthesis method
化合物13的合成方法中的步骤一、二和三分别参照实施例12中的步骤七、八和九。LC-MS(ESI)m/z:270.1[M/2+H]+.实施例14
Steps 1, 2 and 3 in the synthesis of compound 13 refer to steps 7, 8 and 9 in Example 12, respectively. LC-MS (ESI) m/z: 270.1 [M/2+H] + . Example 14
合成方法Synthesis method
化合物14的合成方法参照实施例3，区别在于把步骤四中的2-氟-4-氯苯甲酰胺替换为2-氟-4-三氟甲基苯甲酰胺，把最后一步的二甲胺替换为氮杂环丁烷。LC-MS(ESI)m/z:347.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.40-8.33(m,1H),8.05(d,J＝8.4Hz, 1H),7.96(d,J＝8.2Hz,1H),7.93(s,1H),7.83(dd,J＝8.2,2.4Hz,1H),7.73-7.71(m,1H),7.71-7.68(m,2H),7.48(dd,1H),7.44(d,J＝8.5Hz,1H),7.30(dd,J＝7.7,1.8Hz,1H),6.63(d,J＝1.6Hz,1H),5.28(s,2H),5.02-4.54(m,4H),4.47-4.13(m,4H),2.46-2.38(m,4H).The synthesis method of compound 14 is similar to that of Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced by 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced by azetidine. LC-MS (ESI) m/z: 347.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.40-8.33 (m, 1H), 8.05 (d, J = 8.4 Hz, 1H),7.96(d,J＝8.2Hz,1H),7.93(s,1H),7.83(dd,J＝8.2,2.4Hz,1H),7.73-7.71(m,1H),7.71-7.68(m,2H),7.48(dd,1H),7.44(d,J＝8.5Hz,1H),7.30( dd,J＝7.7,1.8Hz,1H),6.63(d,J＝1.6Hz,1H),5.28(s,2H),5.02-4.54(m,4H),4.47-4.13(m,4H),2.46-2.38(m,4H).
实施例15
Embodiment 15
合成方法Synthesis method
化合物15的合成方法参照实施例实施例3，区别在于把步骤四中的2-氟-4-氯苯甲酰胺替换为2-氟-4-三氟甲基苯甲酰胺，把最后一步的二甲胺替换为3-羟基氮杂环丁烷盐酸盐。LC-MS(ESI)m/z:363.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),8.06(d,J＝8.4Hz,1H),7.97(d,J＝8.4Hz,1H),7.93(s,1H),7.85-7.79(m,1H),7.74-7.65(m,3H),7.46(d,J＝8.7Hz,1H),7.42(d,J＝8.4Hz,1H),7.28(d,1H),6.62(s,1H),5.98(d,J＝5.9Hz,1H),5.90(d,J＝5.9Hz,1H),5.27(s,2H),5.09-4.75(m,2H),4.69-4.63(m,1H),4.62-4.58(m,1H),4.55-4.24(m,4H),4.26-3.73(m,2H).The synthesis method of compound 15 refers to Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced by 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced by 3-hydroxyazetidine hydrochloride. LC-MS (ESI) m/z: 363.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.31 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.85-7.79 (m, 1H), 7.74-7.65 (m, 3H), 7.46 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.28 (d, 1H ),6.62(s,1H),5.98(d,J＝5.9Hz,1H),5.90(d,J＝5.9Hz,1H),5.27(s,2H),5.09-4.75(m,2H),4.69-4.63(m,1H),4.62-4.58(m,1H),4.55-4.24(m,4H) ,4.26-3.73(m,2H).
实施例16
Example 16
合成方法Synthesis method
化合物16的合成方法参照实施例3，区别在于把步骤四中的2-氟-4-氯苯甲酰胺替换为2-氟-4-三氟甲基苯甲酰胺，把最后一步的二甲胺替换为吡咯烷。LC-MS(ESI)m/z:361.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝8.5Hz,1H),8.33(s,1H),8.27(d,J＝8.6Hz,1H),7.94(s,1H),7.82(d,J＝8.3Hz,1H),7.74(s,1H),7.72-7.67(m,2H),7.48(d,J＝8.6Hz,1H),7.43(d,J＝8.5Hz,1H),7.29(d,J＝7.8Hz,1H),6.63(s,1H),5.27(s,2H),3.96-3.74(m,8H),2.03-1.88(m,8H).The synthesis method of compound 16 refers to Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced by 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced by pyrrolidine. LC-MS(ESI)m/z:361.1[M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 )δ8.37(d,J＝8.5Hz,1H),8.33(s,1H),8.27(d,J＝8.6Hz,1H),7.94(s,1H),7.82(d,J＝8.3Hz,1H),7 .74(s,1H),7.72-7.67(m,2H),7.48(d,J＝8.6Hz,1H),7.43(d,J＝8.5Hz,1H) ,7.29(d,J＝7.8Hz,1H),6.63(s,1H),5.27(s,2H),3.96-3.74(m,8H),2.03- 1.88(m,8H).
实施例17
Embodiment 17
合成方法 Synthesis method
化合物17的合成方法参照实施例3，区别在于把步骤四中的2-氟-4-氯苯甲酰胺替换为2-氟-4-三氟甲基苯甲酰胺，把最后一步的二甲胺替换为环丁基胺。LC-MS(ESI)m/z:361.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.82(d,J＝6.8Hz,1H),8.61(d,J＝6.9Hz,1H),8.49(d,J＝8.4Hz,1H),8.39(d,J＝8.4Hz,1H),8.31(s,1H),7.88(s,1H),7.82(dd,J＝8.3,2.3Hz,1H),7.74(d,J＝2.3Hz,1H),7.71-7.66(m,2H),7.59(dd,J＝8.5,1.7Hz,1H),7.52(d,J＝8.4Hz,1H),7.30(dd,J＝7.9,1.8Hz,1H),6.60(s,1H),5.26(s,2H),4.67(dd,J＝23.8,8.0Hz,2H),2.36-2.26(m,4H),2.24-2.10(m,4H),1.81-1.68(m,4H).The synthesis method of compound 17 refers to Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced by 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced by cyclobutylamine. LC-MS (ESI) m/z: 361.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.82 (d, J = 6.8 Hz, 1H), 8.61 (d, J = 6.9 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.88 (s, 1H), 7.82 (dd, J = 8.3, 2.3 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.71-7.66 (m, 2H), 7. .59(dd,J＝8.5,1.7Hz,1H),7.52(d,J＝8.4Hz,1H),7.30(dd,J＝7.9,1.8Hz,1H),6.60(s,1H),5.26(s,2H),4.67(dd,J＝23.8,8.0Hz,2H),2.36-2.26(m,4H) ,2.24-2.10(m,4H),1.81-1.68(m,4H).
实施例18
Embodiment 18
合成方法Synthesis method
化合物18的合成方法参照实施例3，区别在于把步骤四中的2-氟-4-氯苯甲酰胺替换为2-氟-4-三氟甲基苯甲酰胺，把最后一步的二甲胺替换为(S)-吡咯烷-3-醇。LC-MS(ESI)m/z:377.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.38(s,1H),8.32(d,J＝1.4Hz,1H),8.28(d,J＝8.6Hz,1H),7.95(s,1H),7.83(ddd,J＝8.2,2.4,0.9Hz,1H),7.75(s,1H),7.73-7.68(m,2H),7.48(dd,J＝8.7,1.8Hz,1H),7.43(dd,J＝8.6,1.7Hz,1H),7.31(d,J＝7.8Hz,1H),6.65-6.62(m,1H),5.19(s,2H),5.16(d,1H),5.09(d,J＝3.3Hz,1H),4.47-4.41(m,1H),4.41-4.36(m,1H),4.12-3.58(m,8H),2.05-1.89(m,4H).The synthesis method of compound 18 refers to Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced by 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced by (S)-pyrrolidin-3-ol. LC-MS (ESI) m/z: 377.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.38 (s, 1H), 8.32 (d, J = 1.4 Hz, 1H), 8.28 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 7.83 (ddd, J = 8.2, 2.4, 0.9 Hz, 1H), 7.75 (s, 1H), 7.73-7.68 (m, 2H), 7.48 (dd, J = 8.7, 1.8 Hz, 1H), 7.43 (dd, J = 8. .6,1.7Hz,1H),7.31(d,J＝7.8Hz,1H),6.65-6.62(m,1H),5.19(s,2H),5.16(d,1H),5.09(d,J＝3.3Hz,1H),4.47-4.41(m,1H),4.41-4.36(m,1H),4.1 2-3.58(m,8H),2.05-1.89(m,4H).
实施例19
Embodiment 19
合成方法Synthesis method
化合物19的合成方法参照实施例3，区别在于把步骤四中的2-氟-4-氯苯甲酰胺替换为2-氟-4-三氟甲基苯甲酰胺，把最后一步的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:349.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.33(d,J＝1.5Hz,1H),8.19(d,J＝8.6Hz,1H),8.08(d,J＝8.5Hz,1H),7.97(s,1H),7.83(ddd,J＝8.3,2.4,1.0Hz,1H),7.75(t,J＝2.1Hz,1H),7.73-7.67(m,2H),7.49(dd,J＝8.6,1.8Hz,1H),7.44(dd,J＝8.5,1.7Hz,1H),7.34-7.30(m,1H),6.64(d,J＝1.8Hz,1H),5.26(s,2H),3.74(q,J＝6.8Hz,2H),3.66(q,J＝7.0Hz,2H),3.34(s,3H),3.24(s,3H),1.33(t,J＝7.6,6.0Hz,3H),1.28(t,J＝7.0,1.5Hz,3H).The synthesis method of compound 19 is similar to that of Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced by 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced by methylethylamine. LC-MS (ESI) m/z: 349.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.33(d,J＝1.5Hz,1H),8.19(d,J＝8.6Hz,1H),8.08(d,J＝8.5Hz,1H),7.97(s,1H),7.83(ddd,J＝8.3,2.4,1.0Hz,1H),7.75(t,J＝2.1Hz,1H),7.73-7.67( m,2H),7.49(dd,J＝8.6,1.8Hz,1H),7.44(dd,J ＝8.5,1.7Hz,1H),7.34-7.30(m,1H),6.64(d,J＝1.8Hz,1H),5.26(s,2H),3.74(q,J＝6.8Hz,2H),3.66(q,J＝7.0Hz,2H),3.34(s,3H),3.24(s,3H),1.33 (t,J＝7.6,6.0Hz,3H),1.28(t,J＝7.0,1.5Hz,3H).
实施例20
Embodiment 20
合成方法Synthesis method
化合物20的合成方法参照实施例实施例3，区别在于把步骤四中的2-氟-4-氯苯甲酰胺替换为2-氟-4-三氟甲基苯甲酰胺，把最后一步的二甲胺替换为四氢呋喃-3-胺。LC-MS(ESI)m/z:377.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.69(d,J＝6.3Hz,1H),8.56(d,J＝8.5Hz,1H),8.51-8.43(m,2H),8.33(s,1H),7.92(s,1H),7.83(dd,J＝7.8,2.2Hz,1H),7.75(s,1H),7.73-7.66(m,2H),7.60(d,J＝8.6Hz,1H),7.53(d,J＝8.4Hz,1H),7.32(d,J＝7.9Hz,1H),6.61(s,1H),5.27(s,2H),4.82-4.67(m,2H),3.98-3.87(m,4H),3.79-3.71(m,3H),2.32-2.19(m,2H),2.04-1.95(m,3H).The synthesis method of compound 20 refers to Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced by 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced by tetrahydrofuran-3-amine. LC-MS (ESI) m/z: 377.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.69 (d, J = 6.3 Hz, 1H), 8.56 (d, J = 8.5 Hz, 1H), 8.51-8.43 (m, 2H), 8.33 (s, 1H), 7.92 (s, 1H), 7.83 (dd, J = 7.8, 2.2 Hz, 1H), 7.75 (s, 1H), 7.73-7.66 (m, 2H), 7.60 (d, J = 8.6 Hz, 1H),7.53(d,J＝8.4Hz,1H),7.32(d,J＝7.9Hz,1H),6.61(s,1H),5.27(s,2H),4.82-4.67(m,2H),3.98-3.87(m,4H),3.79-3.71(m,3H),2.32-2.19(m ,2H),2.04-1.95(m,3H).
实施例21
Embodiment 21
合成方法Synthesis method
化合物21的合成方法参照实施例实施例3，区别在于把步骤四中的2-氟-4-氯苯甲酰胺替换为2-氟-4-三氟甲基苯甲酰胺，把最后一步的二甲胺替换为(R)-吡咯烷-3-醇。LC-MS(ESI)m/z:377.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.38(s,1H),8.32(d,J＝1.4Hz,1H),8.28(d,J＝8.6Hz,1H),7.95(s,1H),7.83(ddd,J＝8.2,2.4,0.9Hz,1H),7.75(s,1H),7.73-7.68(m,2H),7.48(dd,J＝8.7,1.8Hz,1H),7.43(dd,J＝8.6,1.7Hz,1H),7.31(d,J＝7.8Hz,1H),6.65-6.62(m,1H),5.19(s,2H),5.16(d,1H),5.09(d,J＝3.3Hz,1H),4.47-4.41(m,1H),4.41-4.36(m,1H),4.12-3.58(m,8H),2.05-1.89(m,4H).The synthesis method of compound 21 is similar to that of Example 3, except that 2-fluoro-4-chlorobenzamide in step 4 is replaced by 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced by (R)-pyrrolidin-3-ol. LC-MS (ESI) m/z: 377.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.38(s,1H),8.32(d,J＝1.4Hz,1H),8.28(d,J＝8.6Hz,1H),7.95(s,1H),7.83(ddd,J＝8.2,2.4,0.9Hz,1H),7.75(s,1H),7.73-7.68(m,2H),7.48(dd,J ＝8.7,1.8Hz,1H),7.43(dd,J＝8 .6,1.7Hz,1H),7.31(d,J＝7.8Hz,1H),6.65-6.62(m,1H),5.19(s,2H),5.16(d,1H),5.09(d,J＝3.3Hz,1H),4.47-4.41(m,1H),4.41-4.36(m,1H),4.1 2-3.58(m,8H),2.05-1.89(m,4H).
实施例22
Example 22
合成方法Synthesis method
化合物22的合成方法参照实施例实施例3，区别在于把最后一步的二甲胺替换为甲基乙基胺。LC-MS(ESI)m/z:315.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.33(d,J＝1.3Hz,1H),7.98(d,J＝8.8Hz,1H),7.88(d,J＝8.8Hz,1H),7.82(dd,J＝8.2,1.6Hz,1H),7.74-7.65(m,4H),7.28(d,J＝8.6Hz,1H),7.20(ddd,J＝14.5,8.8,2.0Hz,2H),6.42 (d,J＝2.1Hz,1H),5.19(s,2H),3.70(q,J＝7.1Hz,2H),3.63(q,J＝7.1Hz,2H),3.30(s,3H),3.21(s,3H),1.32-1.26(m,6H).The synthesis method of compound 22 refers to Example 3, except that the dimethylamine in the last step is replaced by methylethylamine. LC-MS (ESI) m/z: 315.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.33 (d, J = 1.3 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.82 (dd, J = 8.2, 1.6 Hz, 1H), 7.74-7.65 (m, 4H), 7.28 (d, J = 8.6 Hz, 1H), 7.20 (ddd, J = 14.5, 8.8, 2.0 Hz, 2H), 6.42 (d,J＝2.1Hz,1H),5.19(s,2H),3.70(q,J＝7.1Hz,2H),3.63(q,J＝7.1Hz,2H),3.30(s,3H),3.21(s,3H),1.32-1.26(m,6H).
实施例23
Embodiment 23
合成路线
Synthetic route
步骤一：化合物23-1的合成Step 1: Synthesis of compound 23-1
室温下将2-氯3-氰基吡啶(1.0g，7mmol)、环丙基甲酸(3.1g，36mmol)和硝酸银(0.4g,2mmol)溶解于10％的稀硫酸(10mL)中，室温下搅拌30分钟，缓慢滴加过硫酸铵水溶液(3.3g，14mmol),室温下过夜，TLC监测反应完全。用氨水调节pH至8-9，抽滤，滤液用乙酸乙酯萃取三次，有机相用饱和氯化钠水溶液洗涤一次，减压蒸除溶剂得化合物23-1，1.1g，产率85％。LC-MS(ESI)m/z:179[M+H]+。2-Chloro-3-cyanopyridine (1.0 g, 7 mmol), cyclopropylcarboxylic acid (3.1 g, 36 mmol) and silver nitrate (0.4 g, 2 mmol) were dissolved in 10% dilute sulfuric acid (10 mL) at room temperature, stirred at room temperature for 30 minutes, and slowly added with aqueous ammonium persulfate solution (3.3 g, 14 mmol), and left overnight at room temperature. TLC monitored the reaction to be complete. The pH was adjusted to 8-9 with aqueous ammonia, filtered, and the filtrate was extracted three times with ethyl acetate. The organic phase was washed once with saturated aqueous sodium chloride solution, and the solvent was evaporated under reduced pressure to obtain compound 23-1, 1.1 g, with a yield of 85%. LC-MS (ESI) m/z: 179 [M+H] + .
步骤二：化合物23-2的合成Step 2: Synthesis of compound 23-2
取化合物23-1(1.1g，6mmol)溶于乙醇(10mL)中，室温下滴加80％水合肼(5mL),在封管条件下加热到80℃，过夜反应，TLC监测反应完全。残余物通过硅胶柱色谱法纯化，得到化合物23-2，0.8g，产率80％。LC-MS(ESI)m/z:175[M+H]+。Compound 23-1 (1.1 g, 6 mmol) was dissolved in ethanol (10 mL), and 80% hydrazine hydrate (5 mL) was added dropwise at room temperature. The mixture was heated to 80°C under sealed conditions and reacted overnight. The reaction was monitored by TLC to determine the completion of the reaction. The residue was purified by silica gel column chromatography to obtain compound 23-2, 0.8 g, with a yield of 80%. LC-MS (ESI) m/z: 175 [M+H] + .
步骤三：化合物23-3的合成Step 3: Synthesis of compound 23-3
将3-羟基苯甲酸甲酯(100mg,0.66mmol)加入到3-(溴甲基)苯甲酸甲酯(196mg，0.66mmol)与碳酸钾(272mg，19.8mmol)的DMF(10mL)混合液中，氮气条件下室温反应4小时，TLC显示原料反应完全。将反应液倒入水中，加乙酸乙酯萃取，合 并有机相，水洗，饱和食盐水洗，硅胶柱层析纯化浓缩得到化合物23-3，130mg，产率66％。LC-MS(ESI)m/z:301[M+H]+.Add methyl 3-hydroxybenzoate (100 mg, 0.66 mmol) to a mixture of methyl 3-(bromomethyl)benzoate (196 mg, 0.66 mmol) and potassium carbonate (272 mg, 19.8 mmol) in DMF (10 mL), and react at room temperature for 4 hours under nitrogen. TLC shows that the raw materials react completely. Pour the reaction solution into water, extract with ethyl acetate, and combine The organic phase was washed with water and saturated brine, purified and concentrated by silica gel column chromatography to obtain compound 23-3, 130 mg, with a yield of 66%. LC-MS (ESI) m/z: 301 [M+H] + .
步骤四：化合物23-4的合成Step 4: Synthesis of compound 23-4
将化合物23-3(130mg，0.43mmol)在甲醇(2.5mL)中溶解后，在0℃下滴加氢氧化钠水溶液(3mL，4M)，50℃过夜反应，TLC显示原料反应完全。将反应液冷却后在0℃用稀盐酸调pH至3-4。倒入冰水中，加乙酸乙酯萃取，浓缩有机相得到化合物23-4，78mg粗品，收率67％。LC-MS(ESI)m/z:273[M+H]+.After dissolving compound 23-3 (130 mg, 0.43 mmol) in methanol (2.5 mL), sodium hydroxide aqueous solution (3 mL, 4 M) was added dropwise at 0°C and reacted at 50°C overnight. TLC showed that the raw material was completely reacted. After cooling the reaction solution, the pH was adjusted to 3-4 with dilute hydrochloric acid at 0°C. Pour into ice water, extract with ethyl acetate, and concentrate the organic phase to obtain compound 23-4, 78 mg crude product, yield 67%. LC-MS (ESI) m/z: 273 [M + H] + .
步骤五：化合物23的合成Step 5: Synthesis of compound 23
将化合物23-4(78mg，0.29mmol)的DMF(0.5mL)溶液滴加到TBTU(138mg，0.43mmol)和三乙胺(73mg，0.72mmol)的DMF(0.5mL)溶液中，最后滴加化合物23-2(100mg，0.57mmol)的DMF(0.5mL)溶液，50℃过夜反应，TLC显示原料反应完全。待反应液冷却后加50mL水和150mL乙酸乙酯萃取，反复三次，合并有机相浓缩后经HPLC纯化得化合物23，25mg，收率12％。LC-MS(ESI)m/z:585.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.11(dd,J＝8.1,3.3Hz,2H),7.78(s,1H),7.68(t,J＝6.7Hz,2H),7.52(t,J＝7.7Hz,1H),7.41(t,J＝7.9Hz,1H),7.36(s,1H),7.32-7.21(m,4H),6.50(s,4H),5.24(s,2H),2.14-2.08(m,2H),0.93-0.83(m,4H),0.77-0.67(m,4H).Compound 23-4 (78 mg, 0.29 mmol) in DMF (0.5 mL) was added dropwise to a solution of TBTU (138 mg, 0.43 mmol) and triethylamine (73 mg, 0.72 mmol) in DMF (0.5 mL), and finally compound 23-2 (100 mg, 0.57 mmol) in DMF (0.5 mL) was added dropwise. The mixture was reacted at 50°C overnight. TLC showed that the reaction of the raw materials was complete. After the reaction solution was cooled, 50 mL of water and 150 mL of ethyl acetate were added for extraction, and the mixture was repeated three times. The organic phases were combined, concentrated, and purified by HPLC to obtain compound 23, 25 mg, with a yield of 12%. LC-MS (ESI) m/z: 585.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.11 (dd, J = 8.1, 3.3Hz, 2H), 7.78 (s, 1H), 7.68 (t, J = 6.7Hz, 2H), 7.52 (t, J = 7.7Hz, 1H), 7.41 (t, J = 7 .9Hz,1H),7.36(s,1H),7.32-7.21(m,4H),6.50(s,4H),5.24(s,2H),2.14-2.08(m,2H),0.93-0.83(m,4H),0.77-0.67(m,4H).
实施例24
Embodiment 24
合成方法Synthesis method
化合物24的合成方法参照实施例3，区别在于把最后一步的二甲胺替换为N-甲基-2-羟基乙胺。LC-MS(ESI)m/z:331.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.33(d,J＝1.3Hz,1H),8.20(d,J＝8.8Hz,1H),8.11(d,J＝8.8Hz,1H),7.82(d,J＝9.8Hz,1H),7.72-7.70(m,1H),7.70-7.67(m,2H),7.30-7.26(m,1H),7.22(dd,J＝8.8,2.0Hz,2H),7.18(dd,J＝8.8,2.0Hz,1H),6.43(d,J＝2.1Hz,1H),5.20(s,2H),5.05(t,1H),4.99(t,J＝5.2Hz,1H),3.76-3.69(m,4H),3.33(s,3H),3.26(s,3H),1.50-1.42(m,4H).The synthesis method of compound 24 is similar to that of Example 3, except that the dimethylamine in the last step is replaced by N-methyl-2-hydroxyethylamine. LC-MS (ESI) m/z: 331.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.33 (d, J = 1.3 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 9.8 Hz, 1H), 7.72-7.70 (m, 1H), 7.70-7.67 (m, 2H), 7.30-7.26 (m, 1H), 7.22 (dd, J = 8.8, 2.0H z,2H),7.18(dd,J＝8.8,2.0Hz,1H),6.43(d,J＝2.1Hz,1H),5.20(s,2H),5.05(t,1H),4.99(t,J＝5.2Hz,1H),3.76-3.69(m,4H),3.33(s,3H),3.26(s,3H ),1.50-1.42(m,4H).
实施例25
Embodiment 25
合成方法Synthesis method
化合物25的合成方法参照实施例实施例3，区别在于把最后一步的二甲胺替换为环丙基胺。LC-MS(ESI)m/z:313.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝4.0Hz,1H),8.34-8.28(m,2H),8.17(d,J＝8.7Hz,1H),8.09(d,J＝8.8Hz,1H),7.82(d,J＝8.3Hz,1H),7.74-7.61(m,3H),7.27(dd,1H),7.23(dd,J＝8.6,1.7Hz,1H),6.39(d,J＝1.9Hz,1H),5.21(s,2H),3.11-2.98(m,2H),2.00(dd,J＝14.3,6.8Hz,2H),0.83-0.63(m,6H). The synthesis method of compound 25 is similar to that of Example 3, except that the dimethylamine in the last step is replaced by cyclopropylamine. LC-MS (ESI) m/z: 313.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.51(d,J＝4.0Hz,1H),8.34-8.28(m,2H),8.17(d,J＝8.7Hz,1H),8.09(d,J＝8.8Hz,1H),7.82(d,J＝8.3Hz,1H),7.74-7.61(m,3H),7.27(dd,1H),7.23 (dd,J＝8.6,1.7Hz,1H),6.39(d,J＝1.9Hz,1H),5.21(s,2H),3.11-2.98(m,2H),2.00(dd,J＝14.3,6.8Hz,2H),0.83-0.63(m,6H).
实施例26
Embodiment 26
合成方法Synthesis method
化合物26的合成方法参照实施例3，区别在于把最后一步的二甲胺替换为氨的甲醇溶液。LC-MS(ESI)m/z:273.0[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝1.2Hz,1H),8.16(d,J＝8.7Hz,1H),8.08(d,J＝8.6Hz,1H),7.81(d,J＝9.7Hz,1H),7.72(s,1H),7.69-7.61(m,4H),7.26-7.25(m,2H),6.39(d,J＝1.9Hz,1H),5.77(s,4H),5.20(s,2H).The synthesis method of compound 26 is similar to that of Example 3, except that the dimethylamine in the last step is replaced by ammonia methanol solution. LC-MS (ESI) m/z: 273.0 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.32 (d, J = 1.2 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 9.7 Hz, 1H), 7.72 (s, 1H), 7.69-7.61 (m, 4H), 7.26-7.25 (m, 2H), 6.39 (d, J = 1.9 Hz, 1H), 5.77 (s, 4H), 5.20 (s, 2H).
实施例27
Embodiment 27
合成方法Synthesis method
化合物27的合成方法参照实施例3，区别在于把步骤的2-氟-4-氯苯甲酰胺替换为2-氟-4-三氟甲基苯甲酰胺，把最后一步的二甲胺替换为氨的甲醇溶液。LC-MS(ESI)m/z:307.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.36(d,J＝8.4Hz,1H),8.32(s,1H),8.27(d,J＝8.4Hz,1H),7.91(s,1H),7.82(dd,J＝8.5,2.3Hz,1H),7.75(t,J＝2.1Hz,1H),7.69(t,2H),7.56(d,J＝8.6,1.7Hz,1H),7.50(d,J＝8.5,1.6Hz,1H),7.30(d,J＝7.8,1.9Hz,1H),6.90(s,4H),6.61(s,1H),5.26(s,2H).The synthesis method of compound 27 refers to Example 3, except that 2-fluoro-4-chlorobenzamide in the first step is replaced by 2-fluoro-4-trifluoromethylbenzamide, and dimethylamine in the last step is replaced by ammonia methanol solution. LC-MS(ESI)m/z:307.1[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.36(d,J＝8.4Hz,1H),8.32(s,1H),8.27(d,J＝8.4Hz,1H),7.91(s,1H),7.82(dd,J＝8.5,2.3Hz,1 H),7.75(t,J＝2.1Hz,1H),7.69(t,2H),7.56(d,J＝8.6,1.7Hz,1H),7.50(d,J＝8.5,1.6Hz,1H),7.30(d,J＝7.8,1.9Hz,1H),6.90(s,4H),6.61(s,1H),5.26 (s,2H).
实施例28
Embodiment 28
合成方法Synthesis method
化合物28的合成方法参照实施例实施例3，区别在于把最后一步的二甲胺替换为2,2,2-三氟乙胺。LC-MS(ESI)m/z:355.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ9.09(t,J＝6.0Hz,1H),8.89(t,J＝6.1Hz,1H),8.32(d,J＝1.1Hz,1H),8.26(d,J＝8.7Hz,1H),8.18(d,J＝8.7Hz,1H),7.83(dd,1H),7.76(s,1H),7.72(d,J＝1.8Hz,1H),7.71-7.67(m,2H),7.36(dd,J＝8.7,1.9Hz,1H),7.33-7.30(m,2H),6.45(d,J＝1.9Hz,1H),5.23(s,2H),4.50-4.32(m,4H).The synthesis method of compound 28 is similar to that of Example 3, except that the dimethylamine in the last step is replaced by 2,2,2-trifluoroethylamine. LC-MS (ESI) m/z: 355.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ9.09(t,J＝6.0Hz,1H),8.89(t,J＝6.1Hz,1H),8.32(d,J＝1.1Hz,1H),8.26(d,J＝8.7Hz,1H),8.18(d,J＝8.7Hz,1H),7.83(dd,1H),7.76(s,1H),7.72(d,J ＝1.8Hz,1H),7.71-7.67(m,2H),7.36(dd,J＝8.7,1.9Hz,1H),7.33-7.30(m,2H),6.45(d,J＝1.9Hz,1H),5.23(s,2H),4.50-4.32(m,4H).
实施例29
Embodiment 29
合成方法Synthesis method
化合物29的合成方法参照实施例3，区别在于把最后一步的二甲胺替换为杂氮环丁烷。LC-MS(ESI)m/z:313.1[M/2+H]+.The synthesis method of compound 29 is similar to that of Example 3, except that the dimethylamine in the last step is replaced by azetidine. LC-MS (ESI) m/z: 313.1 [M/2+H] + .
实施例30
Embodiment 30
合成路线
Synthetic route
步骤一：化合物30-1的合成Step 1: Synthesis of compound 30-1
间碘苯胺(500mg，2.3mmol)和5-氰基噻吩-2-硼酸(524mg，3.4mmol)溶于THF(7.5mL)中，加入碳酸钠(725mg，6.8mmol)的水溶液(1.5mL)，在N2氛围中加入1，1'-双(二苯基膦)二茂铁-二氯化钯(II)二氯甲烷络合物(185mg，0.2mmol)，加热到65℃，过夜反应。用EA/H2O萃取，合并有机相，浓缩，通过硅胶柱色谱法纯化(EA:PE＝1:9)。重复实验，得到化合物30-1，785mg，产率57％，为黄色固体。LC-MS(ESI)m/z:201[M+H]+.m-Iodoaniline (500 mg, 2.3 mmol) and 5-cyanothiophene-2-boronic acid (524 mg, 3.4 mmol) were dissolved in THF (7.5 mL), and an aqueous solution (1.5 mL) of sodium carbonate (725 mg, 6.8 mmol) was added. 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (185 mg, 0.2 mmol) was added in a N2 atmosphere, and the mixture was heated to 65°C and reacted overnight. The mixture was extracted with EA/ H2O , the organic phases were combined, concentrated, and purified by silica gel column chromatography (EA:PE=1:9). The experiment was repeated to obtain compound 30-1, 785 mg, with a yield of 57%, as a yellow solid. LC-MS (ESI) m/z: 201 [M+H] + .
步骤二：化合物30-2的合成Step 2: Synthesis of compound 30-2
将化合物30-1(100mg，0.5mmol)溶于THF(2mL)中，在0℃下缓慢滴加2.5M LiAlH4/THF(0.4mL)，室温搅拌。TLC监测反应完全，加入水淬灭，用EA萃取，合并有机相，浓缩、干燥，得到化合物30-2，86mg，产率85％，其为淡黄色固体。LC-MS(ESI)m/z:205[M+H]+. Compound 30-1 (100 mg, 0.5 mmol) was dissolved in THF (2 mL), and 2.5 M LiAlH 4 /THF (0.4 mL) was slowly added dropwise at 0°C and stirred at room temperature. TLC monitored the reaction completion, and water was added to quench the reaction. The mixture was extracted with EA, and the organic phases were combined, concentrated, and dried to obtain compound 30-2, 86 mg, with a yield of 85%, as a light yellow solid. LC-MS (ESI) m/z: 205 [M+H] + .
步骤三：化合物30-3的合成Step 3: Synthesis of compound 30-3
4-氯-2-氟苯甲酰胺(100mg,0.58mmol)溶于1，2-二氯乙烷(3mL)中，在0℃下缓慢滴加草酰氯(0.07mL，0.87mmol),加热到55℃，反应1小时，然后升温到80℃，过夜反应。TLC监测原料基本消失，直接将反应液旋干，得到相应的异氰酸酯中间体。将其尽快溶于DCE(1mL)，在冰水浴下滴加到分散有化合物30-2(86mg，0.42mmol)的DCE(1mL)混合液中，逐渐升温到室温。反应液过滤得到化合物30-3，210mg，产率83％，其为淡黄色固体。LC-MS(ESI)m/z:603[M+H]+.4-Chloro-2-fluorobenzamide (100 mg, 0.58 mmol) was dissolved in 1,2-dichloroethane (3 mL), and oxalyl chloride (0.07 mL, 0.87 mmol) was slowly added dropwise at 0 ° C, heated to 55 ° C, reacted for 1 hour, and then heated to 80 ° C and reacted overnight. TLC monitoring showed that the raw material basically disappeared, and the reaction solution was directly spin-dried to obtain the corresponding isocyanate intermediate. It was dissolved in DCE (1 mL) as soon as possible, and added dropwise to a DCE (1 mL) mixed solution dispersed with compound 30-2 (86 mg, 0.42 mmol) under an ice-water bath, and gradually heated to room temperature. The reaction solution was filtered to obtain compound 30-3, 210 mg, with a yield of 83%, which was a light yellow solid. LC-MS (ESI) m/z: 603 [M + H] + .
步骤四：化合物30-4的合成Step 4: Synthesis of compound 30-4
在0℃下缓慢向含有化合物30-3(150mg,0.25mmol)的DMF(5mL)溶液中滴加2M NaHMDS/THF(0.75mL)，加热到70℃，反应4小时。加过量的水淬灭反应，加入ACN，大量白色固体析出，过滤得到固体，干燥。得到化合物30-4，重复实验，得到化合物30-4，174mg，产率89％，为白色固体。LC-MS(ESI)m/z:563[M+H]+.2M NaHMDS/THF (0.75 mL) was slowly added dropwise to a DMF (5 mL) solution containing compound 30-3 (150 mg, 0.25 mmol) at 0°C, heated to 70°C, and reacted for 4 hours. Excess water was added to quench the reaction, and ACN was added. A large amount of white solid precipitated, which was filtered to obtain a solid and dried. Compound 30-4 was obtained. The experiment was repeated to obtain compound 30-4, 174 mg, with a yield of 89%, as a white solid. LC-MS (ESI) m/z: 563 [M + H] + .
步骤五：化合物30的合成Step 5: Synthesis of compound 30
在将化合物30-4(111mg,0.2mmol)分散到乙腈(5mL)中，在0℃下分别加入DIEA(0.34mL)和POCl3(0.1mL)，升温到70℃回流过夜。TLC监测原料基本消失，将反应液旋干，并迅速加入二甲胺的四氢呋喃溶液(10mL)，室温搅拌。反应液旋干，用甲醇打浆后，通过高效液相色谱法HPLC纯化，得到化合物30，44mg，产率36％。LC-MS(ESI)m/z:309.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.04(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,1H),7.72(d,J＝8.0Hz,1H),7.67(d,J＝1.9Hz,1H),7.57(dd,J＝15.3,7.5Hz,2H),7.45(d,J＝3.7Hz,1H),7.27(d,J＝3.7Hz,1H),7.24-7.16(m,3H),6.37(d,J＝2.0Hz,1H),5.48(s,2H),3.30(s,6H),3.25(s,6H).Compound 30-4 (111 mg, 0.2 mmol) was dispersed in acetonitrile (5 mL), DIEA (0.34 mL) and POCl 3 (0.1 mL) were added at 0°C, and the mixture was heated to 70°C and refluxed overnight. TLC monitoring showed that the raw material was basically gone, the reaction solution was spin-dried, and a tetrahydrofuran solution of dimethylamine (10 mL) was quickly added and stirred at room temperature. The reaction solution was spin-dried, slurried with methanol, and purified by HPLC to obtain compound 30, 44 mg, with a yield of 36%. LC-MS (ESI) m/z: 309.1[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.04 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.57 ( dd,J＝15.3,7.5Hz,2H),7.45(d,J＝3.7Hz,1H),7.27(d,J＝3.7Hz,1H),7.24-7.16(m,3H),6.37(d,J＝2.0Hz,1H),5.48(s,2H),3.30(s,6H),3.25(s,6H).
实施例31
Embodiment 31
合成方法Synthesis method
化合物31的合成方法参照实施例30，区别在于把步骤五中的二甲胺替换为甲基乙基胺。LC-MS(ESI)m/z:323.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.71(dt,J＝7.8,1.4Hz,1H),7.66(d,J＝2.0Hz,1H),7.58(t,J＝7.9Hz,1H),7.56(t,J＝1.9Hz,1H),7.45(d,J＝3.7Hz,1H),7.27(d,J＝3.7Hz,1H),7.23-7.19(m,3H),6.37(d,J＝2.1Hz,1H),5.48(s,2H),3.70(q,J＝7.0Hz,2H),3.65(q,J＝7.0Hz,2H),3.30(s,3H),3.23(s,3H),1.32-1.27(m,6H).The synthesis method of compound 31 refers to Example 30, except that dimethylamine in step 5 is replaced by methylethylamine. LC-MS (ESI) m/z: 323.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ7.97 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.71 (dt, J=7.8, 1.4 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.56 (t, J=1.9 Hz, 1H), 7.45 (d, J=3.7 Hz, 1H), 7.27(d,J＝3.7Hz,1H),7.23-7.19(m,3H),6.37(d,J＝2.1Hz,1H),5.48(s,2H),3.70(q,J＝7.0Hz,2H),3.65(q,J＝7.0Hz,2H),3.30(s,3H),3.23(s,3H), 1.32-1.27(m,6H).
实施例32
Embodiment 32
合成路线
Synthetic route
步骤一：化合物32-1的合成Step 1: Synthesis of compound 32-1
室温下将过氧化氢(10mL)加入到2-氟-4-甲基苯腈(2.0g，14.81mmol)、水(15mL)、氢氧化钠溶液(30％，5mL)组成的混合溶液中。35℃搅拌过夜，TLC监测完全反应。加水(50mL)稀释，有大量固体析出，过滤固体即为化合物32-1，1.4g，白色固体，产率61％。LC-MS(ESI)m/z:154[M+H]+.Hydrogen peroxide (10 mL) was added to a mixed solution of 2-fluoro-4-methylbenzonitrile (2.0 g, 14.81 mmol), water (15 mL), and sodium hydroxide solution (30%, 5 mL) at room temperature. Stirred at 35°C overnight, and the reaction was complete after TLC monitoring. Water (50 mL) was added to dilute the mixture, and a large amount of solid precipitated. The solid was filtered to obtain compound 32-1, 1.4 g, white solid, with a yield of 61%. LC-MS (ESI) m/z: 154 [M+H] + .
步骤二：化合物32-2的合成Step 2: Synthesis of compound 32-2
室温下将3-碘苯胺(3.0g，13.70mmol)和1H-咪唑-4-甲腈(1.3g，13.70mmol)溶解在N,N-二甲基甲酰胺(30mL)中，加入碘化亚铜(260mg，1.37mmol)、反式-N,N-二甲基-1,2-环己二胺(200mg，1.37mmol)和碳酸铯(13.4g，41.07mmol)，氮气保护下升温至100℃搅拌18小时。TLC监测完全反应，加水80mL，用乙酸乙酯(100mL x 3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品使用无水乙醇(100mL)打浆，过滤后固体即为化合物32-2，1.93g，粉红色固体，产率76％。LC-MS(ESI)m/z:185[M+H]+.3-iodoaniline (3.0 g, 13.70 mmol) and 1H-imidazole-4-carbonitrile (1.3 g, 13.70 mmol) were dissolved in N, N-dimethylformamide (30 mL) at room temperature, and cuprous iodide (260 mg, 1.37 mmol), trans-N, N-dimethyl-1,2-cyclohexanediamine (200 mg, 1.37 mmol) and cesium carbonate (13.4 g, 41.07 mmol) were added, and the mixture was heated to 100 ° C and stirred for 18 hours under nitrogen protection. TLC monitored the complete reaction, 80 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was slurried with anhydrous ethanol (100 mL), and the solid after filtration was compound 32-2, 1.93 g, pink solid, with a yield of 76%. LC-MS (ESI) m/z: 185 [M+H] + .
步骤三：化合物32-3的合成Step 3: Synthesis of compound 32-3
室温条件下，雷尼镍(1.8g，30.98mmol)滴入到化合物32-2(1.9g，10.33mmol)的氨-甲醇(20mL)溶液中，氢气气氛中搅拌过夜。TLC监测完全反应，过滤除去雷尼镍，滤液经C18柱层析(水:乙腈，5-95％，20min)纯化得到化合物32-3，1.35g，粉红色固体，产率69％。LC-MS(ESI)m/z:189[M+H]+.At room temperature, Raney nickel (1.8 g, 30.98 mmol) was added dropwise to a solution of compound 32-2 (1.9 g, 10.33 mmol) in ammonia-methanol (20 mL), and stirred overnight in a hydrogen atmosphere. TLC monitored the complete reaction, filtered to remove the Raney nickel, and the filtrate was purified by C18 column chromatography (water: acetonitrile, 5-95%, 20 min) to obtain compound 32-3, 1.35 g, pink solid, with a yield of 69%. LC-MS (ESI) m/z: 189 [M + H] + .
步骤四：化合物32-4的合成Step 4: Synthesis of compound 32-4
0℃下将草酰氯(2.0g，15.96mmol)滴加到化合物32-3(1.2g，7.98mmol)的二氯乙烷DCE(10mL)中。氮气保护下，反应混合液在70℃搅拌过夜，减压旋蒸除去多余的草酰氯后，用DCE(8mL)稀释滴入化合物2(500mg，2.65mmol)的DCE/DMF(1.5mL/0.5mL)体系中，反应在室温下搅拌3小时。TLC监测完全反应。加入乙腈打浆，过滤后固体即为化合物32-4，1.35g，白色固体，产率93％。LC-MS(ESI)m/z:547[M+H]+.Oxalyl chloride (2.0 g, 15.96 mmol) was added dropwise to dichloroethane DCE (10 mL) of compound 32-3 (1.2 g, 7.98 mmol) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After the excess oxalyl chloride was removed by rotary evaporation under reduced pressure, it was diluted with DCE (8 mL) and added dropwise to the DCE/DMF (1.5 mL/0.5 mL) system of compound 2 (500 mg, 2.65 mmol). The reaction was stirred at room temperature for 3 hours. TLC monitored the complete reaction. Acetonitrile was added to the slurry, and the solid after filtration was compound 32-4, 1.35 g, white solid, with a yield of 93%. LC-MS (ESI) m/z: 547 [M+H] + .
步骤五：化合物32-5的合成Step 5: Synthesis of compound 32-5
0℃下将氢化钠(183mg，4.27mmol)加入到化合物32-4(500mg，0.85mmol)的N,N-二甲基甲酰胺DMF(10mL)中，氮气保护下，升温至90℃搅拌3小时。LC-MS 检测原料基本消失。用水淬灭，滴加稀盐酸(0.5mol/L)至pH为中性，过滤后固体用乙腈打浆，再次过滤后固体即为化合物32-5，396mg，白色固体，产率92％。LC-MS(ESI)m/z:507[M+H]+.Sodium hydride (183 mg, 4.27 mmol) was added to compound 32-4 (500 mg, 0.85 mmol) in DMF (10 mL) at 0°C, and the mixture was heated to 90°C and stirred for 3 hours under nitrogen protection. LC-MS The raw material was basically gone. Quenched with water, diluted hydrochloric acid (0.5 mol/L) was added dropwise until the pH was neutral, the solid was slurried with acetonitrile after filtration, and the solid was filtered again to obtain compound 32-5, 396 mg, white solid, with a yield of 92%. LC-MS (ESI) m/z: 507 [M+H] + .
步骤六：化合物32的合成Step 6: Synthesis of compound 32
0℃下将三氯氧磷(0.8mL)加入到化合物5(80mg，0.16mmol)和N,N-二异丙基乙胺(0.8mL)的乙腈ACN(4mL)溶液中。在氮气保护下，反应混合液在90℃下反应4小时，减压旋蒸去除多余的三氯氧磷。将甲乙胺(47mg，0.79mmol)溶于四氢呋喃THF(5mL)中滴入除去三氯氧磷的反应体系中，室温下搅拌30分钟。LC-MS检测完全反应。二氯甲烷/甲醇溶解后经硅胶柱层析(二氯甲烷:甲醇，0-10％，15min)纯化得到粗产品，经HPLC纯化后得到化合物32，4.25mg，黄色固体，产率5％。LC-MS(ESI)m/z:295.2[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.46(s,1H),8.32(d,1H),7.84(d,J＝8.4Hz,1H),7.79(dd,J＝9.7Hz,1H),7.76(d,J＝8.3Hz,1H),7.69–7.62(m,2H),7.38(s,1H),7.22(d,J＝7.4Hz,1H),6.99(dd,J＝14.6,8.4Hz,2H),6.29(s,1H),5.20(s,2H),3.69(q,J＝6.8Hz,2H),3.62(q,J＝14.1,7.0Hz,2H),3.28(s,3H),3.18(s,3H),2.38(s,3H),2.21(s,3H),1.17(t,6H).Phosphorus oxychloride (0.8 mL) was added to a solution of compound 5 (80 mg, 0.16 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 hours, and the excess phosphorus oxychloride was removed by vacuum rotary evaporation. Methylethylamine (47 mg, 0.79 mmol) was dissolved in tetrahydrofuran THF (5 mL) and added dropwise to the reaction system to remove phosphorus oxychloride, and stirred at room temperature for 30 minutes. LC-MS detected complete reaction. After dissolution in dichloromethane/methanol, the crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 32 was obtained after purification by HPLC, 4.25 mg, yellow solid, and a yield of 5%. LC-MS (ESI) m/z: 295.2 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.46(s,1H),8.32(d,1H),7.84(d,J＝8.4Hz,1H),7.79(dd,J＝9.7Hz,1H),7.76(d,J＝8.3Hz,1H),7.69–7.62(m,2H),7.38(s,1H),7.22(d,J＝7.4Hz,1H) ,6.99(dd, J＝14.6,8.4Hz,2H),6.29(s,1H),5.20(s,2H),3.69(q,J＝6.8Hz,2H),3.62(q,J＝14.1,7.0Hz,2H),3.28(s,3H),3.18(s,3H),2.38(s,3H),2.21(s,3H) ,1.17(t,6H).
实施例33
Embodiment 33
合成方法Synthesis method
化合物33的合成方法参照实施例32，区别在于把步骤六中的甲乙胺替换为二乙胺。LC-MS(ESI)m/z:309.2[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.76(s,1H),8.39(d,1H),7.84(d,J＝8.4Hz,1H),7.79(dd,J＝9.7Hz,1H),7.76(d,J＝8.3Hz,1H),7.69–7.62(m,2H),7.38(s,1H),7.28(d,J＝7.4Hz,1H),6.53(dd,2H),6.41(s,1H),5.20(s,2H),3.71(q,4H),3.56(q,4H),3.25(s,3H),3.16(s,3H),1.38(t,6H),1.24(t,6H).The synthesis method of compound 33 is similar to that of Example 32, except that methylethylamine in step 6 is replaced by diethylamine. LC-MS (ESI) m/z: 309.2 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.76(s,1H),8.39(d,1H),7.84(d,J＝8.4Hz,1H),7.79(dd,J＝9.7Hz,1H),7.76(d,J＝8.3Hz,1H),7.69–7.62(m,2H),7.38(s,1H),7.28(d,J＝7.4Hz,1H) ,6.53(dd,2H),6.41(s,1H),5.20(s,2H),3.71(q,4H),3.56(q,4H),3.25(s,3H),3.16(s,3H),1.38(t,6H),1.24(t,6H).
实施例34
Embodiment 34
合成路线
Synthetic route
步骤一：化合物34-1的合成Step 1: Synthesis of compound 34-1
将4-溴丁酸甲酯(1.8g，9.8mmol)的DMF(3mL)溶液滴加到间羟基苯甲醛(1.0g，8.2mmol)与碳酸钾(2.3g，16.4mmol)的DMF(10mL)混合液中，氮气条件下50℃过夜反应，TLC监测反应完全。待反应液冷却后加50mL水和150mL乙酸乙酯萃取，反复三次，合并有机相，C-18反相柱层析纯化(ACN:H2O＝39％)浓缩得到化合物34-1，900mg，产率50％。LC-MS(ESI)m/z:223[M+H]+.A solution of methyl 4-bromobutyrate (1.8 g, 9.8 mmol) in DMF (3 mL) was added dropwise to a mixture of m-hydroxybenzaldehyde (1.0 g, 8.2 mmol) and potassium carbonate (2.3 g, 16.4 mmol) in DMF (10 mL). The mixture was reacted at 50 °C overnight under nitrogen. The reaction was complete when monitored by TLC. After the reaction solution was cooled, 50 mL of water and 150 mL of ethyl acetate were added for extraction. The extraction was repeated three times. The organic phases were combined and purified by C-18 reverse phase column chromatography (ACN:H 2 O=39%). The mixture was concentrated to obtain compound 34-1, 900 mg, with a yield of 50%. LC-MS (ESI) m/z: 223 [M+H] + .
步骤二：化合物34-2的合成Step 2: Synthesis of compound 34-2
室温下，将化合物34-1(900mg，4mmol)溶于5mL无水乙醇，加入对甲苯磺酰肼(755mg，4mmol)，保持室温搅拌过夜。TLC监测化合物34-1反应完全且有新点生成。之后加入5-溴-1-((2-(三甲基硅基)乙氧基)甲基)靛红(1.4g，4mmol)和碳酸钾(1.11g，4mmol)，升温至80℃搅拌45分钟。LCMS监测反应完全，待反应液冷却后加50mL水和150mL乙酸乙酯萃取，反复三次，合并有机相，硅胶柱层析纯化浓缩后用甲醇打浆得到化合物34-2，630mg，产率28％。LC-MS(ESI)m/z:562[M+H]+.At room temperature, compound 34-1 (900 mg, 4 mmol) was dissolved in 5 mL of anhydrous ethanol, p-toluenesulfonyl hydrazide (755 mg, 4 mmol) was added, and the mixture was stirred at room temperature overnight. TLC monitored that compound 34-1 reacted completely and new spots were generated. Then 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)indigo (1.4 g, 4 mmol) and potassium carbonate (1.11 g, 4 mmol) were added, and the temperature was raised to 80 ° C and stirred for 45 minutes. LCMS monitored that the reaction was complete, and after the reaction solution was cooled, 50 mL of water and 150 mL of ethyl acetate were added for extraction, which was repeated three times. The organic phases were combined, purified and concentrated by silica gel column chromatography, and then slurried with methanol to obtain compound 34-2, 630 mg, with a yield of 28%. LC-MS (ESI) m/z: 562 [M + H] + .
步骤三：化合物34-3的合成Step 3: Synthesis of compound 34-3
将化合物34-2(630mg,1.12mmol)溶于6mL甲醇中，加入氢氧化钠(90mg，2.25mmol)和1mL水，升温至50℃搅拌过夜反应,。待反应液冷却后在0℃用稀盐酸调pH至中性。加30mLDCM和10mLMeOH稀释反应液后过滤，滤液用甲醇打浆得到化合物34-3，188mg，产率30％。LC-MS(ESI)m/z:548[M+H]+.Compound 34-2 (630 mg, 1.12 mmol) was dissolved in 6 mL of methanol, sodium hydroxide (90 mg, 2.25 mmol) and 1 mL of water were added, and the temperature was raised to 50 °C and stirred overnight for reaction. After the reaction solution was cooled, the pH was adjusted to neutral with dilute hydrochloric acid at 0 °C. The reaction solution was diluted with 30 mL of DCM and 10 mL of MeOH and filtered. The filtrate was slurried with methanol to obtain compound 34-3, 188 mg, with a yield of 30%. LC-MS (ESI) m/z: 548 [M + H] + .
步骤四：化合物34-4的合成Step 4: Synthesis of compound 34-4
将化合物34-3(188mg，0.34mmol)的DMF(0.3mL)溶液滴加到TBTU(166mg，0.52mmol)和三乙胺(87mg，0.82mmol)的DMF(0.3mL)溶液中，最后滴加化合物23-2的DMF(0.3mL)溶液，50℃过夜反应，TLC显示原料反应完全。待反应液冷却后加50mL水和150mL乙酸乙酯萃取，反复三次，合并有机相浓缩后经HPLC纯化得化合物34-4，70mg，产率29％。LC-MS(ESI)m/z:704[M+H]+。A solution of compound 34-3 (188 mg, 0.34 mmol) in DMF (0.3 mL) was added dropwise to a solution of TBTU (166 mg, 0.52 mmol) and triethylamine (87 mg, 0.82 mmol) in DMF (0.3 mL), and finally a solution of compound 23-2 in DMF (0.3 mL) was added dropwise. The mixture was reacted at 50°C overnight. TLC showed that the reaction of the raw materials was complete. After the reaction solution was cooled, 50 mL of water and 150 mL of ethyl acetate were added for extraction, and the extraction was repeated three times. The organic phases were combined and concentrated, and then purified by HPLC to obtain compound 34-4, 70 mg, with a yield of 29%. LC-MS (ESI) m/z: 704 [M+H] + .
步骤五：化合物34的合成Step 5: Synthesis of compound 34
将化合物34-4(70mg，0.1mmol)溶于三氟乙酸：二氯甲烷(6mL，v:v＝1:5)的混合溶液中，室温搅拌反应4小时。TLC显示反应完全，反应液浓缩，硅胶柱层析纯化后经HPLC纯化得化合物34，3.5mg，产率6％。LC-MS(ESI)m/z:574.1[M+H]+.Compound 34-4 (70 mg, 0.1 mmol) was dissolved in a mixture of trifluoroacetic acid and dichloromethane (6 mL, v:v = 1:5) and stirred at room temperature for 4 hours. TLC showed that the reaction was complete, and the reaction solution was concentrated, purified by silica gel column chromatography and then purified by HPLC to obtain compound 34, 3.5 mg, with a yield of 6%. LC-MS (ESI) m/z: 574.1 [M + H] + .
实施例35
Embodiment 35
合成方法Synthesis method
化合物35的合成方法参照实施例32，区别在于把步骤六中的甲乙胺替换为二甲胺。LC-MS(ESI)m/z:281.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),7.91(d,J＝8.3Hz,1H),7.83(d,J＝8.4Hz,1H),7.79(dd,J＝7.9Hz,1H),7.68-7.61(m,2H),7.36(s,1H),7.21(d,J＝6.2Hz,2H),6.98(t,2H),6.28(s,1H),5.20(s,2H),3.29(s,6H),3.22(s,6H),2.37(s,3H),2.21(s,3H).The synthesis method of compound 35 refers to Example 32, except that methylethylamine in step six is replaced by dimethylamine. LC-MS(ESI)m/z:281.1[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.32(s,1H),7.91(d,J＝8.3Hz,1H),7.83(d,J＝8.4Hz,1H),7.79(dd,J＝7.9Hz,1H),7.68-7.61(m, 2H),7.36(s,1H),7.21(d,J＝6.2Hz,2H),6.98(t,2H),6.28(s,1H),5.20(s,2H),3.29(s,6H),3.22(s,6H),2.37(s,3H),2.21(s,3H).
实施例36
Embodiment 36
合成方法Synthesis method
化合物36的合成方法参照实施例32，区别在于把步骤六中的甲乙胺替换为叔丁胺。LC-MS(ESI)m/z:309.2[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.45(s,1H),8.32(s,1H),8.16(d,J＝8.4Hz,1H),8.08(d,J＝8.1Hz,1H),7.79(d,J＝8.2Hz,1H),7.72(s,1H),7.65(t,J＝8.0Hz,2H),7.34(d,J＝14.6Hz,2H),6.97(t,J＝9.3Hz,2H),6.21(s,1H),5.18(s,2H),2.36(s,3H),2.19(s,3H),1.53(s,9H),1.50(s,9H).The synthesis method of compound 36 is similar to that of Example 32, except that methylethylamine in step 6 is replaced by tert-butylamine. LC-MS (ESI) m/z: 309.2 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.71(s,1H),8.45(s,1H),8.32(s,1H),8.16(d,J＝8.4Hz,1H),8.08(d,J＝8.1Hz,1H),7.79(d,J＝8.2Hz,1H),7.72(s,1H),7.65(t,J＝8.0Hz,2H),7.34 (d,J＝14.6Hz,2H),6.97(t,J＝9.3Hz,2H),6.21(s,1H),5.18(s,2H),2.36(s,3H),2.19(s,3H),1.53(s,9H),1.50(s,9H).
实施例37
Embodiment 37
合成方法Synthesis method
化合物37的合成方法参照实施例32，区别在于把步骤四中的2-氟-4-甲基苯甲酰胺替换为2，4-二氟苯甲酰胺。LC-MS(ESI)m/z:299.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.30(d,J＝1.5Hz,1H),8.05(q,J＝9.1,6.0Hz,1H),7.95(q,J＝9.1,6.2Hz,1H),7.80(dd,J＝7.9,2.3Hz,1H),7.72-7.63(m,3H),7.42(dd,J＝11.6,2.6Hz,1H),7.26(d,J＝7.5,1.8Hz,1H),7.06-6.96(m,2H),6.20(dd,J＝10.7,2.6Hz,1H),5.18(s,2H),3.70(q,J＝7.0Hz,2H),3.63(q,J＝7.0Hz,2H),3.30(s,3H),3.21(s,3H),1.34-1.29(m,6H).The synthesis method of compound 37 refers to Example 32, except that 2-fluoro-4-methylbenzamide in step 4 is replaced by 2,4-difluorobenzamide. LC-MS (ESI) m/z: 299.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.30 (d, J = 1.5 Hz, 1H), 8.05 (q, J = 9.1, 6.0 Hz, 1H), 7.95 (q, J = 9.1, 6.2 Hz, 1H), 7.80 (dd, J = 7.9, 2.3 Hz, 1H), 7.72-7.63 (m, 3H), 7.42 (dd, J = 11.6, 2.6 Hz, 1H), 7.26 (d, J = 7.5,1.8Hz,1H),7.06-6.96(m,2H),6.20(dd,J＝10.7,2.6Hz,1H),5.18(s,2H),3.70(q,J＝7.0Hz,2H),3.63(q,J＝7.0Hz,2H),3.30(s,3H),3.21(s,3H), 1.34-1.29(m,6H).
实施例38
Embodiment 38
合成方法Synthesis method
化合物38的合成方法参照实施例32，区别在于把步骤四中的2-氟-4-甲基苯甲酰胺替换为2，4-二氟苯甲酰胺，把步骤六中的甲乙胺替换为二甲胺。LC-MS(ESI)m/z:285.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.30(d,J＝1.4Hz,1H),8.11(dd,J＝9.1,6.0Hz,1H),8.02(dd,J＝9.1,6.2Hz,1H),7.81(dd,1H),7.71-7.64(m,3H),7.41(dd,J＝11.7,2.6Hz,1H),7.26(d,J＝8.0,1.4Hz,1H),7.06-6.96(m,2H),6.20(dd,J＝10.8,2.6Hz,1H),5.19(s,2H),3.30(s,6H),3.23(s,6H).The synthesis method of compound 38 refers to Example 32, except that 2-fluoro-4-methylbenzamide in step 4 is replaced by 2,4-difluorobenzamide, and methylethylamine in step 6 is replaced by dimethylamine. LC-MS(ESI)m/z:285.1[M/2+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ8.30(d,J＝1.4Hz,1H),8.11(dd,J＝9.1,6.0Hz,1H),8.02(dd,J＝9.1,6.2Hz,1H),7.81(dd,1H),7.71 -7.64(m,3H),7.41(dd,J＝11.7,2.6Hz,1H),7.26(d,J＝8.0,1.4Hz,1H),7.06-6.96(m,2H),6.20(dd,J＝10.8,2.6Hz,1H),5.19(s,2H),3.30(s,6H),3.23( s,6H).
实施例39
Embodiment 39
合成方法Synthesis method
化合物39的合成方法参照实施例32，区别在于把步骤四中的2-氟-4-甲基苯甲酰胺替换为2氟-4-环丙基苯甲酰胺。LC-MS(ESI)m/z:321.2[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.80(t,J＝8.6Hz,2H),7.75-7.63(m,4H),7.27(s,1H),7.22(d,J＝7.7Hz,1H),6.83(d,J＝8.5Hz,1H),6.75(d,J＝8.6Hz,1H),6.24(d,J＝1.7Hz,1H),5.20(s,2H),3.67(q,J＝7.0Hz,2H),3.61(q,J＝7.0Hz,2H),3.26(s,3H),3.18(s,3H),2.57(d,J＝9.7Hz,3H),2.54(d,J＝5.7Hz,3H),1.81(tt,J＝8.4,4.9Hz,1H),1.49-1.42(m,1H),1.10-0.98(m,8H).The synthesis method of compound 39 refers to Example 32, except that 2-fluoro-4-methylbenzamide in step 4 is replaced by 2-fluoro-4-cyclopropylbenzamide. LC-MS (ESI) m/z: 321.2 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.33 (s, 1H), 7.80 (t, J = 8.6 Hz, 2H), 7.75-7.63 (m, 4H), 7.27 (s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 6.24 (d, J = 1.7 Hz, 1H), 5.20 (s, 2H), 3.67 (q,J＝7.0Hz,2H),3.61(q,J＝7.0Hz,2H),3.26(s,3H),3.18(s,3H),2.57(d,J＝9.7Hz,3H),2.54(d,J＝5.7Hz,3H),1.81(tt,J＝8.4,4.9Hz,1H),1.49-1.42 (m,1H),1.10-0.98(m,8H).
实施例40
Embodiment 40
合成方法Synthesis method
化合物40的合成方法参照实施例32，区别在于把步骤四中的2-氟-4-甲基苯甲酰胺替换为2氟-4-环丙基苯甲酰胺，把步骤六中的甲乙胺替换为二甲胺。LC-MS(ESI)m/z:307.1[M/2+H]+.The synthesis method of compound 40 is similar to that of Example 32, except that 2-fluoro-4-methylbenzamide in step 4 is replaced by 2-fluoro-4-cyclopropylbenzamide, and methylethylamine in step 6 is replaced by dimethylamine. LC-MS (ESI) m/z: 307.1 [M/2+H] + .
实施例41
Embodiment 41
合成路线
Synthetic route
步骤一：化合物41-1的合成Step 1: Synthesis of compound 41-1
间硝基苯硼酸酯(2.12g，12.8mmol)和4-溴噻吩-2-甲腈(2.0g，10.6mmol)溶于二氧六环(30mL)和DMF(4mL)的混合液中，加入碳酸钠(3.38g，31.8mmol)的水溶液(13mL)，在N2氛围中加入1，1'-双(二苯基膦)二茂铁-二氯化钯(II)二氯甲烷络合物(500mg，0.05mmol)，加热到100℃，过夜反应。TLC显示反应完全，反应液用EA/H2O萃取，有机相合并浓缩，通过硅胶柱色谱法纯化，得到化合物41-1，3.4g，产率81％，为白色固体。LC-MS(ESI)m/z:231[M+H]+.m-Nitrophenyl borate (2.12 g, 12.8 mmol) and 4-bromothiophene-2-carbonitrile (2.0 g, 10.6 mmol) were dissolved in a mixture of dioxane (30 mL) and DMF (4 mL), and an aqueous solution (13 mL) of sodium carbonate (3.38 g, 31.8 mmol) was added. 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (500 mg, 0.05 mmol) was added in a N2 atmosphere, and the mixture was heated to 100°C and reacted overnight. TLC showed that the reaction was complete, and the reaction solution was extracted with EA/ H2O , and the organic phases were combined and concentrated, and purified by silica gel column chromatography to obtain compound 41-1, 3.4 g, with a yield of 81%, as a white solid. LC-MS (ESI) m/z: 231 [M+H] + .
步骤二：化合物41-2的合成Step 2: Synthesis of compound 41-2
将化合物41-1(500mg，2.2mmol)分散到THF(5mL)中，加入雷尼镍(200mg)，在H2氛围下室温搅拌过夜。TLC和LC-MS检测几乎无原料，将反应液通过硅藻土过滤，THF洗涤，通过C-18反向柱层析纯化，得到化合物41-2，200mg，产率45％，其为白色固体。LC-MS(ESI)m/z:205[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.44(d,J＝1.5Hz,1H),7.21(d,J＝1.6Hz,1H),7.03(t,J＝7.8Hz,1H),6.83(t,J＝2.0Hz,1H),6.78(dt,J＝7.7,1.3Hz,1H),6.50-6.46(m,1H),5.08(s,2H),3.90(d,J＝1.1Hz,2H),2.03(s,2H).Compound 41-1 (500 mg, 2.2 mmol) was dispersed in THF (5 mL), Raney nickel (200 mg) was added, and the mixture was stirred at room temperature overnight under H 2 atmosphere. TLC and LC-MS detected that there was almost no starting material, and the reaction solution was filtered through diatomaceous earth, washed with THF, and purified by C-18 reverse column chromatography to obtain compound 41-2, 200 mg, with a yield of 45%, as a white solid. LC-MS(ESI)m/z:205[M+H] + .1H NMR(400MHz,DMSO-d6)δ7.44(d,J＝1.5Hz,1H),7.21(d,J＝1.6Hz,1H),7.03(t,J＝7.8Hz,1H),6.83(t,J＝2.0Hz,1H),6.78(dt,J ＝7.7,1.3Hz,1H),6.50-6.46(m,1H),5.08(s,2H),3.90(d,J＝1.1Hz,2H),2.03(s,2H).
步骤三：化合物41-3的合成Step 3: Synthesis of compound 41-3
4-氯-2-氟苯甲酰胺(200mg,1.16mmol)溶于1，2-二氯乙烷(3mL)中，在0℃下缓慢滴加草酰氯(0.3mL，1.74mmol),加热到55℃，反应1小时，然后升温到80℃，过夜反应。TLC监测原料基本消失，直接将反应液旋干，得到相应的异氰酸酯中间体。将其尽快溶于DCE(1mL)，在冰水浴下滴加到分散有化合物41-2(100mg，0.05mmol)的DCE(1mL)混合液中，逐渐升温到室温。反应液过滤得到化合物41-3，244mg，产率83％，其为白色固体。LC-MS(ESI)m/z:603[M+H]+.4-Chloro-2-fluorobenzamide (200 mg, 1.16 mmol) was dissolved in 1,2-dichloroethane (3 mL), and oxalyl chloride (0.3 mL, 1.74 mmol) was slowly added dropwise at 0 ° C, heated to 55 ° C, reacted for 1 hour, and then heated to 80 ° C and reacted overnight. TLC monitoring showed that the raw material basically disappeared, and the reaction solution was directly spin-dried to obtain the corresponding isocyanate intermediate. It was dissolved in DCE (1 mL) as soon as possible, and added dropwise to a mixed solution of DCE (1 mL) dispersed with compound 41-2 (100 mg, 0.05 mmol) under an ice-water bath, and gradually heated to room temperature. The reaction solution was filtered to obtain compound 41-3, 244 mg, with a yield of 83%, which was a white solid. LC-MS (ESI) m/z: 603 [M + H] + .
步骤四：化合物41-4的合成Step 4: Synthesis of compound 41-4
在0℃下缓慢向含有化合物41-3(224mg,0.37mmol)的DMF(7mL)溶液中滴加2M NaHMDS/THF(1.1mL)，加热到75℃，反应4小时。加过量的水淬灭反应，然后加入ACN，大量白色固体析出，过滤、干燥。重复实验，得到化合物41-4，200mg， 产率88％)，为白色固体。LC-MS(ESI)m/z:563[M+H]+.2M NaHMDS/THF (1.1 mL) was slowly added dropwise to a DMF (7 mL) solution containing compound 41-3 (224 mg, 0.37 mmol) at 0°C, heated to 75°C, and reacted for 4 hours. Excess water was added to quench the reaction, and then ACN was added. A large amount of white solid precipitated, which was filtered and dried. Repeat the experiment to obtain compound 41-4, 200 mg, Yield 88%), white solid. LC-MS (ESI) m/z: 563 [M+H] + .
步骤五：化合物41的合成Step 5: Synthesis of compound 41
将化合物41-4(100mg,0.18mmol)分散到乙腈(5mL)中，在0℃下分别加入DIEA(0.3mL)和POCl3(0.1mL)，升温到80℃回流过夜。TLC监测原料基本消失，将反应液旋干，并迅速加入二甲胺的四氢呋喃溶液(3mL)，室温搅拌。反应液旋干，通过高效液相色谱法HPLC纯化，得到化合物41，12.34mg，11％，为淡黄色固体。LC-MS(ESI)m/z:309.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.06(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,1H),7.87-7.78(m,2H),7.74(s,1H),7.69-7.58(m,3H),7.26-7.16(m,3H),6.40(d,J＝2.1Hz,1H),5.47(s,2H),3.31(s,6H),3.25(s,6H).Compound 41-4 (100 mg, 0.18 mmol) was dispersed in acetonitrile (5 mL), DIEA (0.3 mL) and POCl 3 (0.1 mL) were added at 0°C, and the mixture was heated to 80°C and refluxed overnight. TLC monitoring showed that the raw material was almost gone, the reaction solution was spin-dried, and a tetrahydrofuran solution of dimethylamine (3 mL) was quickly added and stirred at room temperature. The reaction solution was spin-dried and purified by HPLC to obtain compound 41, 12.34 mg, 11%, as a light yellow solid. 1 3H ) ,7.26-7.16(m,3H),6.40(d,J=2.1Hz,1H),5.47(s,2H) , 3.31(s,6H),3.25(s,6H).
实施例42
Embodiment 42
合成方法Synthesis method
化合物42的合成方法参照实施例41，区别在于把步骤五中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:323.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.99(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.85(d,J＝1.5Hz,1H),7.82(d,J＝7.9Hz,1H),7.75(s,1H),7.66(d,J＝2.0Hz,1H),7.63(t,2H),7.25-7.19(m,3H),6.40(d,J＝2.1Hz,1H),5.46(s,2H),3.71(q,J＝7.0Hz,2H),3.65(q,J＝7.0Hz,2H),3.31(s,3H),3.23(s,3H),1.32(t,J＝7.0Hz,3H),1.27(t,J＝7.0Hz,3H).The synthesis method of compound 42 is similar to that of Example 41, except that dimethylamine in step 5 is replaced by methylethylamine. LC-MS (ESI) m/z: 323.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.99(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.85(d,J＝1.5Hz,1H),7.82(d,J＝7.9Hz,1H),7.75(s,1H),7.66(d,J＝2.0Hz,1H),7.63(t,2H),7.25-7.1 9(m,3H),6.40(d,J＝2.1Hz,1H),5.46(s,2H),3.71(q,J＝7.0Hz,2H),3.65(q,J＝7.0Hz,2H),3.31(s,3H),3.23(s,3H),1.32(t,J＝7.0Hz,3H),1.27(t,J =7.0Hz,3H).
实施例43
Embodiment 43
合成方法Synthesis method
化合物43的合成方法参照实施例41，区别在于把步骤五中的二甲胺替换为甲胺。LC-MS(ESI)m/z:295.0[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.67(q,J＝4.5Hz,1H),8.56(q,J＝4.5Hz,1H),8.12(d,J＝8.7Hz,1H),8.07(d,J＝8.7Hz,1H),7.84(d,J＝1.5Hz,1H),7.82-7.80(m,1H),7.72(s,1H),7.64-7.61(m,2H),7.28(td,J＝8.3,2.0Hz,2H),7.22(dd,J＝7.7,2.1Hz,1H),6.37(d,J＝2.1Hz,1H),5.48(s,2H),2.98(d,J＝4.5Hz,3H),2.94(d,J＝4.5Hz,3H),2.03-1.96(m,1H),0.86(t,J＝6.9Hz,1H).The synthesis method of compound 43 refers to Example 41, except that dimethylamine in step 5 is replaced by methylamine. LC-MS (ESI) m/z: 295.0 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.67 (q, J = 4.5 Hz, 1H), 8.56 (q, J = 4.5 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 1.5 Hz, 1H), 7.82-7.80 (m, 1H), 7.72 (s, 1H), 7.64-7.61 (m, 2H), 7.28 ( td,J＝8.3,2.0Hz,2H),7.22(dd,J＝7.7,2.1Hz,1H),6.37(d,J＝2.1Hz,1H),5.48(s,2H),2.98(d,J＝4.5Hz,3H),2.94(d,J＝4.5Hz,3H),2.03-1.96(m,1H), 0.86(t,J＝6.9Hz,1H).
实施例44
Embodiment 44
合成路线
Synthetic route
步骤一：化合物44-1的合成Step 1: Synthesis of compound 44-1
室温下，将5-溴-3-氨基-2-甲基吡啶(2g，10.70mmol)、联硼酸频那醇酯(10.8g，42.52mmol)、Pd(dppf)Cl2(860mg，1.176mmol)、醋酸钾(3g，32.26mmol)溶于60mL二氧六环中，氮气置换三次后升温至100℃油浴5小时，LCMS监测反应完全，降温之后加入5-溴噻吩-2-甲腈(2g，10.64mmol)、碳酸钠(3.4g，32.08mmol)、四三苯基膦钯(1.22g，1.055mmol)和12mL水，之后升温至80℃搅拌16小时。LC-MS显示反应完全。加水和EA萃取三次，合并有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,20min)得化合物44-1，1.5g，产率65％，绿色固体。LC-MS(ESI)m/z:216[M+H]+.At room temperature, 5-bromo-3-amino-2-methylpyridine (2 g, 10.70 mmol), biboronic acid pinacol ester (10.8 g, 42.52 mmol), Pd(dppf)Cl 2 (860 mg, 1.176 mmol), potassium acetate (3 g, 32.26 mmol) were dissolved in 60 mL of dioxane, and the mixture was replaced with nitrogen three times and heated to 100° C. in an oil bath for 5 hours. The reaction was complete after LCMS monitoring. After cooling, 5-bromothiophene-2-carbonitrile (2 g, 10.64 mmol), sodium carbonate (3.4 g, 32.08 mmol), tetrakistriphenylphosphine palladium (1.22 g, 1.055 mmol) and 12 mL of water were added, and then the mixture was heated to 80° C. and stirred for 16 hours. LC-MS showed that the reaction was complete. Water and EA were added for extraction three times, and the organic phases were combined and concentrated and separated by flash chromatography (DCM: MeOH, 0-10%, 20 min) to obtain compound 44-1, 1.5 g, yield 65%, green solid. LC-MS (ESI) m/z: 216 [M+H] + .
步骤二：化合物44-2的合成Step 2: Synthesis of compound 44-2
室温下，将化合物44-1(1.5g，6.944mmol)溶于氨的甲醇溶液(20mL，7N)，取2mL水封的雷尼镍，沉淀后移走上清液，加甲醇洗涤两次，静置沉淀后移走上清液，之后将沉淀物用甲醇稀释后加入反应体系，置换氢气三次后保持室温反应4小时。LC-MS监测反应完全。加50mL DCM和10mL甲醇稀释反应液后垫硅藻土过滤，滤液浓缩后经快速色谱柱分离纯化(DCM:MeOH,0-10％,20min)后得化合物44-2，160mg，产率10％，黄色半油状。LC-MS(ESI)m/z:220[M+H]+.At room temperature, compound 44-1 (1.5 g, 6.944 mmol) was dissolved in ammonia methanol solution (20 mL, 7N), 2 mL of water-sealed Raney nickel was taken, the supernatant was removed after precipitation, methanol was added to wash twice, the supernatant was removed after standing and precipitation, and then the precipitate was diluted with methanol and added to the reaction system, and the hydrogen was replaced three times and kept at room temperature for 4 hours. LC-MS monitored the complete reaction. After adding 50 mL DCM and 10 mL methanol to dilute the reaction solution, diatomaceous earth was padded and filtered, the filtrate was concentrated and purified by flash chromatography column (DCM: MeOH, 0-10%, 20 min) to obtain compound 44-2, 160 mg, yield 10%, yellow semi-oil. LC-MS (ESI) m/z: 220 [M + H] + .
步骤三：化合物44-3的合成Step 3: Synthesis of compound 44-3
室温下，将2-氟-4-氯苯甲酰胺(250mg，1.445mmol)溶于5mL DCE中，降温至0℃后缓慢滴加草酰氯(280mg，2.204mmol)，缓慢升至室温后再升温至70℃搅拌16小时。之后浓缩除去过量草酰氯，溶解于1mL DCE后滴加至化合物44-2(160mg，0.727mmol)的DCE(5mL)溶液中，保持室温反应3小时。有大量白色固体析出。过滤即得化合物44-3，230mg，产率51％，黄褐色固体。LC-MS(ESI)m/z:618[M+H]+.At room temperature, 2-fluoro-4-chlorobenzamide (250 mg, 1.445 mmol) was dissolved in 5 mL DCE, cooled to 0 °C, and then slowly added with oxalyl chloride (280 mg, 2.204 mmol), slowly heated to room temperature, and then heated to 70 °C and stirred for 16 hours. After that, the excess oxalyl chloride was removed by concentration, dissolved in 1 mL DCE, and then added dropwise to a DCE (5 mL) solution of compound 44-2 (160 mg, 0.727 mmol), and kept at room temperature for 3 hours. A large amount of white solid precipitated. Compound 44-3 was obtained by filtration, 230 mg, yield 51%, yellow-brown solid. LC-MS (ESI) m/z: 618 [M+H] + .
步骤四：化合物44-4的合成Step 4: Synthesis of compound 44-4
室温下，将化合物44-3(230mg，0.372mmol)溶于4mL DMF中，降温至0℃，分批加入氢化钠(60mg，1.5mmol)，室温搅拌10分钟后升温至90℃搅拌16小时。LC-MS监测反应完全，加水淬灭反应。之后用1M的盐酸调节pH到6左右，有大量固体析出，过滤，滤饼用DCM/MeOH再次打浆得到化合物44-4，150mg，产率70％，白色固体。LC-MS(ESI)m/z:578[M+H]+.At room temperature, compound 44-3 (230 mg, 0.372 mmol) was dissolved in 4 mL DMF, cooled to 0 ° C, sodium hydride (60 mg, 1.5 mmol) was added in batches, stirred at room temperature for 10 minutes, and then heated to 90 ° C and stirred for 16 hours. LC-MS monitored the reaction to be complete, and water was added to quench the reaction. After that, 1 M hydrochloric acid was used to adjust the pH to about 6, and a large amount of solid precipitated. The filter cake was slurried again with DCM/MeOH to obtain compound 44-4, 150 mg, yield 70%, white solid. LC-MS (ESI) m/z: 578 [M + H] + .
步骤五：化合物44的合成 Step 5: Synthesis of compound 44
室温下，将化合物44-4(50mg，0.0865mmol)溶于3mL无水乙腈中，降温至0℃，加入DIEA(100mg，0.775mmol)和三氯氧磷(130mg，0.850mmol)，缓慢升至室温后升温至80℃搅拌6小时。反应液浓缩除去大量三氯氧磷，之后加入二甲胺的THF溶液(2mL，2.5N)，室温搅拌30分钟。LC-MS监测反应完全。浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,20min)得到粗品化合物，之后经HPLC制备纯化后得化合物44，11.2mg，产率20％，淡黄色固体。LC-MS(ESI)m/z:316.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.82(d,J＝2.3Hz,1H),8.09(d,J＝8.8Hz,1H),8.00-7.95(m,2H),7.67(d,J＝2.0Hz,1H),7.52(d,J＝3.7Hz,1H),7.32(d,J＝3.7Hz,1H),7.24(dd,J＝8.8,2.1Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),6.38(d,J＝2.1Hz,1H),5.49(s,2H),3.33(s,6H),3.25(s,6H),2.14(s,3H).At room temperature, compound 44-4 (50 mg, 0.0865 mmol) was dissolved in 3 mL of anhydrous acetonitrile, cooled to 0 ° C, DIEA (100 mg, 0.775 mmol) and phosphorus oxychloride (130 mg, 0.850 mmol) were added, slowly heated to room temperature and then heated to 80 ° C and stirred for 6 hours. The reaction solution was concentrated to remove a large amount of phosphorus oxychloride, and then a THF solution of dimethylamine (2 mL, 2.5 N) was added and stirred at room temperature for 30 minutes. LC-MS monitored the reaction to be complete. After concentration, the crude compound was separated by flash chromatography (DCM: MeOH, 0-10%, 20 min), and then prepared and purified by HPLC to obtain compound 44, 11.2 mg, 20% yield, light yellow solid. LC-MS (ESI) m/z: 316.6 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.82 (d, J = 2.3Hz, 1H), 8.09 (d, J = 8.8Hz, 1H), 8.00-7.95 (m, 2H), 7.67 (d, J = 2.0Hz, 1H), 7.52 (d, J＝3.7Hz,1H),7.32(d,J＝3.7Hz,1H),7.24(dd,J＝8.8,2.1Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),6.38(d,J＝2.1Hz,1H),5.49(s,2H),3.33(s,6H),3.25(s,6H) ,2.14(s,3H).
实施例45
Embodiment 45
合成方法Synthesis method
化合物45的合成方法参照实施例44，区别在于把步骤五中的二甲胺替换为甲胺。LC-MS(ESI)m/z:302.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.81(d,J＝2.2Hz,1H),8.14(d,J＝8.7Hz,1H),8.06(d,J＝8.7Hz,1H),7.97(d,J＝2.2Hz,1H),7.65(d,J＝1.9Hz,1H),7.51(d,J＝3.7Hz,1H),7.32(dd,J＝8.5,2.0Hz,1H),7.28(dd,J＝8.8,2.4Hz,1H),7.23(s,1H),6.69(s,2H),6.35(d,J＝2.0Hz,1H),5.50(s,2H),2.99(d,J＝4.4Hz,3H),2.93(d,J＝4.3Hz,3H),2.14(s,3H).The synthesis method of compound 45 is similar to that of Example 44, except that dimethylamine in step 5 is replaced by methylamine. LC-MS (ESI) m/z: 302.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.81(d,J＝2.2Hz,1H),8.14(d,J＝8.7Hz,1H),8.06(d,J＝8.7Hz,1H),7.97(d,J＝2.2Hz,1H),7.65(d,J＝1.9Hz,1H),7.51(d,J＝3.7Hz,1H),7.32(dd,J＝8.5, 2.0Hz,1H),7.28(dd,J＝8.8,2.4Hz,1H),7.23(s,1H),6.69(s,2H),6.35(d,J＝2.0Hz,1H),5.50(s,2H),2.99(d,J＝4.4Hz,3H),2.93(d,J＝4.3Hz,3H),2.1 4(s,3H).
实施例46
Embodiment 46
合成路线
Synthetic route
步骤一：化合物46-1的合成Step 1: Synthesis of compound 46-1
室温下，将4-溴丁酸甲酯(1.3g，7.5mmol)的DMF(3mL)溶液滴加到间硝基苯酚(1.0g，7.1mmol)与碳酸钾(2.0g，14.2mmol)的DMF:H2O(14mL:2.3mL)混合液中，氮气条件下50℃过夜反应。待反应液冷却后加50mL水和150mL乙酸乙酯萃取，反复三次，合并有机相，C-18反相柱层析纯化(ACN:H2O＝45％)浓缩得到化合物46-1，1.0g，产率60％。LC-MS(ESI)m/z:240[M+H]+.At room temperature, a solution of methyl 4-bromobutyrate (1.3 g, 7.5 mmol) in DMF (3 mL) was added dropwise to a mixture of m-nitrophenol (1.0 g, 7.1 mmol) and potassium carbonate (2.0 g, 14.2 mmol) in DMF:H 2 O (14 mL:2.3 mL), and the mixture was reacted at 50°C overnight under nitrogen. After the reaction solution was cooled, 50 mL of water and 150 mL of ethyl acetate were added for extraction, and the extraction was repeated three times. The organic phases were combined, purified by C-18 reverse phase column chromatography (ACN:H 2 O=45%), and concentrated to obtain compound 46-1, 1.0 g, with a yield of 60%. LC-MS (ESI) m/z: 240 [M+H] + .
步骤二：化合物46-2的合成Step 2: Synthesis of compound 46-2
将铁粉(1.2g，21mmol)与氯化铵(2.2g，42mmol)溶于水中，氮气条件下100℃加热搅拌半小时后加入化合物46-1(1.0g，4.2mmol)，100℃加热搅拌过夜反应，TLC监测反应完全。待反应液冷却后过滤，滤液加50mL水和150mL二氯甲烷萃取，反复三次，合并有机相，硅胶柱层析纯化得到化合物46-2，470mg，产率53％。LC-MS(ESI)m/z:210[M+H]+.Iron powder (1.2 g, 21 mmol) and ammonium chloride (2.2 g, 42 mmol) were dissolved in water. After heating and stirring at 100°C for half an hour under nitrogen, compound 46-1 (1.0 g, 4.2 mmol) was added. The mixture was heated and stirred at 100°C overnight to react. TLC monitored the reaction to be complete. After the reaction solution was cooled, it was filtered. The filtrate was extracted with 50 mL of water and 150 mL of dichloromethane. The extraction was repeated three times. The organic phases were combined and purified by silica gel column chromatography to obtain compound 46-2, 470 mg, with a yield of 53%. LC-MS (ESI) m/z: 210 [M+H] + .
步骤三：化合物46-3的合成Step 3: Synthesis of compound 46-3
室温下，将2-氟-4-氯苯甲酰胺(434mg，2.5mmol)溶于10mLDCE中，降温至0℃后缓慢滴加草酰氯(470mg，3.7mmol)，缓慢升至室温后再升温至70℃搅拌16小时。浓缩除去过量草酰氯，溶解于2mLDCE后滴加至化合物46-2(470mg，2.24mmol)的DCE溶液中，保持室温反应3小时。有大量白色固体析出。过滤即得化合物46-3，800mg，产率78％，白色固体。LC-MS(ESI)m/z:409[M+H]+.At room temperature, 2-fluoro-4-chlorobenzamide (434 mg, 2.5 mmol) was dissolved in 10 mL DCE, cooled to 0 °C, and then oxalyl chloride (470 mg, 3.7 mmol) was slowly added dropwise, slowly heated to room temperature, and then heated to 70 °C and stirred for 16 hours. Excess oxalyl chloride was removed by concentration, dissolved in 2 mL DCE, and then added dropwise to a DCE solution of compound 46-2 (470 mg, 2.24 mmol), and the reaction was maintained at room temperature for 3 hours. A large amount of white solid precipitated. Compound 46-3 was obtained by filtration, 800 mg, yield 78%, white solid. LC-MS (ESI) m/z: 409 [M + H] + .
步骤四：化合物46-4的合成Step 4: Synthesis of compound 46-4
室温下，将化合物46-3(800mg，2.0mmol)溶于DMF(8mL)中，降温至0℃，滴加NaHMDS(2mol/L，2.2mL)，室温搅拌10分钟后升温至65℃搅拌2小时。LC-MS监测反应完全，加水淬灭反应。反应液加50mL水和150mL二氯甲烷萃取，反复三次，合并有机相，得到化合物46-4，500mg，产率65％。LC-MS(ESI)m/z:389[M+H]+.At room temperature, compound 46-3 (800 mg, 2.0 mmol) was dissolved in DMF (8 mL), cooled to 0 ° C, and NaHMDS (2 mol/L, 2.2 mL) was added dropwise. After stirring at room temperature for 10 minutes, the temperature was raised to 65 ° C and stirred for 2 hours. LC-MS monitored the reaction to be complete, and water was added to quench the reaction. The reaction solution was extracted with 50 mL of water and 150 mL of dichloromethane, and the extraction was repeated three times. The organic phases were combined to obtain compound 46-4, 500 mg, with a yield of 65%. LC-MS (ESI) m/z: 389 [M + H] + .
步骤五：化合物46-5的合成Step 5: Synthesis of compound 46-5
室温下，将化合物46-4(500mg，1.29mmol)溶于无水乙腈(8mL)中，降温至0℃，加入DIEA(666mg，0.9mL)和三氯氧磷(493mg，0.3mL)，缓慢升至室温后升温至80℃搅拌6小时。反应液浓缩除去大量三氯氧磷，之后加入甲乙胺的THF溶液(10mL，2.5N)，室温搅拌30分钟。LC-MS监测反应完全。浓缩后经色谱柱层析分离(DCM:MeOH,0-10％,20min)得到化合物46-5，350mg，产率63％。LC-MS(ESI)m/z: 430[M+H]+.At room temperature, compound 46-4 (500 mg, 1.29 mmol) was dissolved in anhydrous acetonitrile (8 mL), cooled to 0 ° C, DIEA (666 mg, 0.9 mL) and phosphorus oxychloride (493 mg, 0.3 mL) were added, slowly heated to room temperature and then heated to 80 ° C and stirred for 6 hours. The reaction solution was concentrated to remove a large amount of phosphorus oxychloride, and then a THF solution of methylethylamine (10 mL, 2.5 N) was added and stirred at room temperature for 30 minutes. LC-MS monitored the reaction to be complete. After concentration, the compound 46-5 was separated by chromatographic column chromatography (DCM: MeOH, 0-10%, 20 min) to obtain 350 mg of compound 46-5 with a yield of 63%. LC-MS (ESI) m/z: 430[M+H] + .
步骤六：化合物46-6的合成Step 6: Synthesis of compound 46-6
将化合物46-5(350mg，0.81mmol)溶于甲醇(5mL)中，加入氢氧化钠(65mg,1.6mmol)和水(1mL)，搅拌过夜反应。LC-MS监测反应完全，在0℃用稀盐酸调pH至中性。加30mLDCM和10mLMeOH稀释反应液后过滤，滤液用甲醇打浆得到化合物46-6，50mg，产率15％。LC-MS(ESI)m/z:416[M+H]+.Compound 46-5 (350 mg, 0.81 mmol) was dissolved in methanol (5 mL), sodium hydroxide (65 mg, 1.6 mmol) and water (1 mL) were added, and the mixture was stirred overnight. The reaction was complete when monitored by LC-MS, and the pH was adjusted to neutral with dilute hydrochloric acid at 0°C. The reaction solution was diluted with 30 mL DCM and 10 mL MeOH and filtered, and the filtrate was slurried with methanol to obtain compound 46-6, 50 mg, with a yield of 15%. LC-MS (ESI) m/z: 416 [M + H] + .
步骤七：化合物46的合成Step 7: Synthesis of compound 46
将化合物46-6(50mg，0.12mmol)的DMF(0.3mL)溶液滴加到TBTU(48mg，0.15mmol)和三乙胺(30mg，0.3mmol)的DMF(0.3mL)溶液中，最后滴加化合物23-2(21mg，0.12mmol)的DMF(0.3mL)溶液，50℃过夜反应，TLC显示原料反应完全。待反应液冷却后加10mL水和20mL乙酸乙酯萃取，反复三次，合并有机相浓缩后经HPLC纯化得化合物46，20mg，产率29％。LC-MS(ESI)m/z:572.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.09(d,J＝8.1Hz,1H),7.96(d,J＝8.8Hz,1H),7.48(t,J＝8.1Hz,1H),7.25(d,J＝8.1Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),7.09(dd,J＝8.4,1.9Hz,1H),6.90(s,1H),6.86(d,J＝7.7Hz,1H),6.40(s,2H),6.38(d,J＝2.0Hz,1H),4.15-4.07(m,2H),3.70(q,J＝7.0Hz,2H),3.29(s,3H),2.26-2.14(m,2H),2.13-2.06(m,2H),2.04-1.94(m,1H),1.36-1.26(m,3H),1.06-0.94(m,4H).A solution of compound 46-6 (50 mg, 0.12 mmol) in DMF (0.3 mL) was added dropwise to a solution of TBTU (48 mg, 0.15 mmol) and triethylamine (30 mg, 0.3 mmol) in DMF (0.3 mL), and finally a solution of compound 23-2 (21 mg, 0.12 mmol) in DMF (0.3 mL) was added dropwise. The mixture was reacted at 50°C overnight. TLC showed that the reaction of the raw materials was complete. After the reaction solution was cooled, 10 mL of water and 20 mL of ethyl acetate were added for extraction, and the mixture was repeated three times. The organic phases were combined, concentrated, and purified by HPLC to obtain compound 46, 20 mg, with a yield of 29%. LC-MS (ESI) m/z: 572.2 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.09(d,J＝8.1Hz,1H),7.96(d,J＝8.8Hz,1H),7.48(t,J＝8.1Hz,1H),7.25(d,J＝8.1Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),7.09(dd,J＝8.4,1.9Hz,1H),6.90 (s,1H),6.86(d,J＝7.7Hz,1H), 6.40(s,2H),6.38(d,J＝2.0Hz,1H),4.15-4.07(m,2H),3.70(q,J＝7.0Hz,2H),3.29(s,3H),2.26-2.14(m,2H),2.13-2.06(m,2H),2.04-1.94(m,1H) ,1.36-1.26(m,3H),1.06-0.94(m,4H).
实施例47
Embodiment 47
合成路线
Synthetic route
步骤一：化合物47-1的合成Step 1: Synthesis of compound 47-1
室温下，将5-溴-3-氨基吡啶(2.0g，11.56mmol)、联硼酸频那醇酯(10.8g，42.52mmol)、Pd(dppf)Cl2(860mg，1.176mmol)、醋酸钾(3g，32.26mmol)溶于60mL二氧六环中，氮气置换三次后升温至100℃油浴5小时，LC-MS监测反应完全,浓缩除去二氧六环，加PE分散反应液后过滤，滤饼用DCM/MeOH混合溶液分散后，再次过滤，所得滤液浓缩后，加入5-溴噻吩-2-甲腈(1.0g，5.32mmol)、碳酸钠(3.4g，32.08 mmol)、四三苯基膦钯(1.22g，1.055mmol)、30mL THF和6mL水，之后升温至60℃搅拌5小时。LC-MS监测5-溴噻吩-2-甲腈消失。加水和EA萃取三次，合并有机相，浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,20min)得化合物47-1，650mg，产率60％，灰绿色固体。LC-MS(ESI)m/z:202[M+H]+.At room temperature, 5-bromo-3-aminopyridine (2.0 g, 11.56 mmol), bipyraclostrobin (10.8 g, 42.52 mmol), Pd(dppf)Cl 2 (860 mg, 1.176 mmol), and potassium acetate (3 g, 32.26 mmol) were dissolved in 60 mL of dioxane. After nitrogen replacement three times, the temperature was raised to 100° C. in an oil bath for 5 hours. The reaction was complete after LC-MS monitoring. The dioxane was concentrated to remove the dioxane, and the reaction solution was filtered after adding PE to disperse the reaction solution. The filter cake was dispersed with a DCM/MeOH mixed solution and filtered again. After the filtrate was concentrated, 5-bromothiophene-2-carbonitrile (1.0 g, 5.32 mmol) and sodium carbonate (3.4 g, 32.08 mmol), tetrakistriphenylphosphine palladium (1.22g, 1.055mmol), 30mL THF and 6mL water, then heated to 60℃ and stirred for 5 hours. LC-MS monitored the disappearance of 5-bromothiophene-2-carbonitrile. Water and EA were added for extraction three times, the organic phases were combined, concentrated and separated by flash chromatography (DCM: MeOH, 0-10%, 20min) to obtain compound 47-1, 650mg, yield 60%, gray-green solid. LC-MS (ESI) m/z: 202[M+H] + .
步骤二：化合物47-2的合成Step 2: Synthesis of compound 47-2
室温下，将化合物47-1(650mg，6.944mmol)溶于氨的甲醇溶液(7N，20mL)，取2mL水封的雷尼镍，沉淀后移走上清液，加甲醇洗涤两次，静置沉淀后移走上清液，之后将沉淀物用甲醇稀释后加入反应体系，置换氢气三次后保持室温反应4小时。LC-MS监测反应完全。加50mL DCM和10mL甲醇稀释反应液后垫硅藻土过滤，滤液浓缩后经快速色谱柱分离纯化(DCM:MeOH,0-10％,20min)后得化合物47-2，240mg，产率36％，灰黄色固体。LC-MS(ESI)m/z:206[M+H]+.At room temperature, compound 47-1 (650 mg, 6.944 mmol) was dissolved in ammonia methanol solution (7N, 20 mL), 2 mL of water-sealed Raney nickel was taken, the supernatant was removed after precipitation, methanol was added to wash twice, the supernatant was removed after standing and precipitation, and then the precipitate was diluted with methanol and added to the reaction system, and the hydrogen was replaced three times and kept at room temperature for 4 hours. LC-MS monitored the complete reaction. After adding 50 mL DCM and 10 mL methanol to dilute the reaction solution, diatomaceous earth was used for filtration, and the filtrate was concentrated and purified by flash chromatography (DCM: MeOH, 0-10%, 20 min) to obtain compound 47-2, 240 mg, 36% yield, gray-yellow solid. LC-MS (ESI) m/z: 206 [M + H] + .
步骤三：化合物47-3的合成Step 3: Synthesis of compound 47-3
室温下，将2-氟-4-氯苯甲酰胺(400mg，2.312mmol)溶于5mL DCE中，降温至0℃后缓慢滴加草酰氯(450mg，3.543mmol)，缓慢升至室温后再升温至70℃搅拌16小时。之后浓缩除去过量草酰氯，溶解于1mL DCE后滴加至化合物47-2(240mg，1.165mmol)的DCE(5mL)溶液中，保持室温反应3小时。有大量白色固体析出。过滤即得化合物47-3，430mg，产率61％，黄褐色固体。LC-MS(ESI)m/z:604[M+H]+.At room temperature, 2-fluoro-4-chlorobenzamide (400 mg, 2.312 mmol) was dissolved in 5 mL DCE, cooled to 0 °C, and then slowly added with oxalyl chloride (450 mg, 3.543 mmol), slowly heated to room temperature, and then heated to 70 °C and stirred for 16 hours. After that, the excess oxalyl chloride was removed by concentration, dissolved in 1 mL DCE, and then added dropwise to a DCE (5 mL) solution of compound 47-2 (240 mg, 1.165 mmol), and kept at room temperature for 3 hours. A large amount of white solid precipitated. Compound 47-3 was obtained by filtration, 430 mg, yield 61%, yellow-brown solid. LC-MS (ESI) m/z: 604 [M + H] + .
步骤四：化合物47-4的合成Step 4: Synthesis of compound 47-4
室温下，将化合物47-3(430mg，0.712mmol)溶于7mL DMF中，降温至0℃，分批加入氢化钠(120mg，3.0mmol)，室温搅拌10分钟后升温至90℃搅拌16小时。LC-MS监测反应完全，加水淬灭反应。之后用1M的盐酸调节pH到6左右，有大量固体析出，过滤，滤饼用DCM/MeOH再次打浆得到化合物47-4，360mg，产率90％，黄色固体。LC-MS(ESI)m/z:564[M+H]+.At room temperature, compound 47-3 (430 mg, 0.712 mmol) was dissolved in 7 mL DMF, cooled to 0 ° C, sodium hydride (120 mg, 3.0 mmol) was added in batches, stirred at room temperature for 10 minutes, and then heated to 90 ° C and stirred for 16 hours. LC-MS monitored the reaction to be complete, and water was added to quench the reaction. After that, 1 M hydrochloric acid was used to adjust the pH to about 6, and a large amount of solid precipitated. The filter cake was slurried again with DCM/MeOH to obtain compound 47-4, 360 mg, yield 90%, yellow solid. LC-MS (ESI) m/z: 564 [M + H] + .
步骤五：化合物47的合成Step 5: Synthesis of compound 47
室温下，将化合物47-4(100mg，0.177mmol)溶于3mL无水乙腈中，降温至0℃，加入DIEA(100mg，0.775mmol)和三氯氧磷(130mg，0.850mmol)，缓慢升至室温后升温至80℃搅拌6小时。反应液浓缩除去大量三氯氧磷，之后加入二甲胺的THF溶液(2mL，2.5N)，室温搅拌30分钟。LC-MS监测反应完全。浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,20min)得到130mg粗品化合物，之后经HPLC制备纯化后得化合物47，9mg，产率16％，淡黄色固体。LC-MS(ESI)m/z:309.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.94(d,J＝2.2Hz,1H),8.42(d,J＝2.2Hz,1H),8.09-8.03(m,2H),7.98(d,J＝8.8Hz,1H),7.67(d,J＝2.0Hz,1H),7.59(d,J＝3.7Hz,1H),7.34(d,J＝3.8Hz,1H),7.21(ddd,J＝10.2,8.7,2.0Hz,2H),6.47(d,J＝2.1Hz,1H),5.51(s,2H),3.31(s,6H),3.25(s,6H).At room temperature, compound 47-4 (100 mg, 0.177 mmol) was dissolved in 3 mL of anhydrous acetonitrile, cooled to 0 ° C, DIEA (100 mg, 0.775 mmol) and phosphorus oxychloride (130 mg, 0.850 mmol) were added, slowly heated to room temperature and then heated to 80 ° C and stirred for 6 hours. The reaction solution was concentrated to remove a large amount of phosphorus oxychloride, and then a THF solution of dimethylamine (2 mL, 2.5 N) was added and stirred at room temperature for 30 minutes. LC-MS monitored the reaction to be complete. After concentration, the crude compound was separated by flash chromatography (DCM: MeOH, 0-10%, 20 min) to obtain 130 mg of crude compound, which was then purified by HPLC to obtain compound 47, 9 mg, with a yield of 16%, and a light yellow solid. 1 J＝2.0Hz,1H), 7.59 (d,J＝3.7Hz,1H),7.34(d,J＝3.8Hz,1H),7.21(ddd,J＝10.2,8.7,2.0Hz,2H) , 6.47(d,J＝2.1Hz,1H),5.51(s,2H),3.31(s,6H),3.25(s,6 H).
实施例48
Embodiment 48
合成方法 Synthesis method
化合物48的合成方法参照实施例47，区别在于把步骤五中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:323.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.94(d,J＝2.2Hz,1H),8.42(d,J＝2.2Hz,1H),8.07(t,J＝2.2Hz,1H),7.99(d,J＝8.8Hz,1H),7.91(d,J＝8.7Hz,1H),7.67(d,J＝2.0Hz,1H),7.59(d,J＝3.7Hz,1H),7.34(d,J＝3.7Hz,1H),7.26-7.18(m,2H),6.47(d,J＝2.1Hz,1H),5.50(s,2H),3.72(q,J＝7.0Hz,2H),3.65(q,J＝7.0Hz,2H),3.31(s,3H),3.23(s,3H),1.31(t,J＝7.0Hz,3H),1.27(t,J＝7.0Hz,3H).The synthesis method of compound 48 refers to Example 47, except that dimethylamine in step 5 is replaced by methylethylamine. LC-MS (ESI) m/z: 323.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.94 (d, J = 2.2 Hz, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.07 (t, J = 2.2 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 3.7 Hz, 1H), 7.34 (d, J = 3.7 Hz ,1H),7.26-7.18(m,2H),6.47(d,J＝2.1Hz,1H),5.50(s,2H),3.72(q,J＝7.0Hz,2H),3.65(q,J＝7.0Hz,2H),3.31(s,3H),3.23(s,3H),1.31(t,J＝7.0Hz, 3H),1.27(t,J=7.0Hz,3H).
实施例49
Embodiment 49
合成方法Synthesis method
化合物49的合成方法参照实施例47，区别在于把步骤五中的二甲胺替换为甲胺。LC-MS(ESI)m/z:295.5[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.93(d,J＝2.1Hz,1H),8.71(q,J＝4.8Hz,1H),8.56(q,J＝4.7Hz,1H),8.41(d,J＝2.2Hz,1H),8.12(d,J＝8.7Hz,1H),8.09-8.04(m,2H),7.65(d,J＝1.9Hz,1H),7.58(d,J＝3.7Hz,1H),7.35-7.26(m,3H),6.45(d,J＝1.9Hz,1H),5.52(s,2H),2.98(d,J＝4.5Hz,3H),2.94(d,J＝4.4Hz,3H).The synthesis method of compound 49 is similar to that of Example 47, except that dimethylamine in step 5 is replaced by methylamine. LC-MS (ESI) m/z: 295.5 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.93(d,J＝2.1Hz,1H),8.71(q,J＝4.8Hz,1H),8.56(q,J＝4.7Hz,1H),8.41(d,J＝2.2Hz,1H),8.12(d,J＝8.7Hz,1H),8.09-8.04(m,2H),7.65(d,J＝1.9Hz,1 H),7.58(d,J＝3.7Hz,1H),7.35-7.26(m,3H),6.45(d,J＝1.9Hz,1H),5.52(s,2H),2.98(d,J＝4.5Hz,3H),2.94(d,J＝4.4Hz,3H).
实施例50
Embodiment 50
合成路线
Synthetic route
步骤一：化合物50-1的合成Step 1: Synthesis of compound 50-1
3-噻吩甲腈(1.0g，9.2mmol)溶在乙酸：氯仿(15mL，1v/2v)中，分批加入NBS(2.52g，13.8mmol)，70℃过夜反应。TLC显示反应完全，反应液用水淬灭，DCM萃取三次，有机相合并浓缩，通过硅胶柱色谱法纯化(EA：PE＝1：19)，得到化合物 50-1，520mg，产率30％，棕色油状。LC-MS(ESI)m/z:188[M+H]+.3-Thiophenecarbonitrile (1.0 g, 9.2 mmol) was dissolved in acetic acid:chloroform (15 mL, 1 v/2 v), and NBS (2.52 g, 13.8 mmol) was added in batches, and the mixture was reacted at 70°C overnight. TLC showed that the reaction was complete, and the reaction solution was quenched with water, extracted with DCM three times, and the organic phases were combined and concentrated, and purified by silica gel column chromatography (EA:PE=1:19) to obtain the compound 50-1, 520 mg, yield 30%, brown oil. LC-MS (ESI) m/z: 188 [M+H] + .
步骤二：化合物50-2的合成Step 2: Synthesis of compound 50-2
间硝基苯硼酸(500mg，4.5mmol)和化合物50-1(470mg，2.5mmol)溶于二氧六环(5mL)和DMF(1mL)的混合液中，加入碳酸钠(795mg，7.5mmol)的水溶液(2mL)，在N2氛围中加入1，1'-双(二苯基膦)二茂铁-二氯化钯(II)二氯甲烷络合物(100mg，0.125mmol)，加热到100℃，过夜反应。TLC显示反应完全，反应液通过硅胶柱色谱法纯化(EA：PE＝2：25)，得到粗品化合物50-2，565mg，产率93％，为淡黄色色固体，直接用于下一步。LC-MS(ESI)m/z:231[M+H]+.m-Nitrophenylboronic acid (500 mg, 4.5 mmol) and compound 50-1 (470 mg, 2.5 mmol) were dissolved in a mixture of dioxane (5 mL) and DMF (1 mL), and an aqueous solution (2 mL) of sodium carbonate (795 mg, 7.5 mmol) was added. 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (100 mg, 0.125 mmol) was added in a N2 atmosphere, and the mixture was heated to 100°C and reacted overnight. TLC showed that the reaction was complete, and the reaction solution was purified by silica gel column chromatography (EA:PE=2:25) to obtain a crude compound 50-2, 565 mg, with a yield of 93%, as a light yellow solid, which was directly used in the next step. LC-MS (ESI) m/z: 231 [M+H] + .
步骤三：化合物50-3的合成Step 3: Synthesis of compound 50-3
将化合物50-2(295mg，1.3mmol)分散到THF(5mL)中，加入雷尼镍(200mg)，在H2氛围下室温搅拌5小时。LC-MS和TLC检测几乎无原料剩余，将反应液通过硅藻土过滤，THF洗涤，C-18反相柱层析纯化，得到化合物50-3，100mg，产率39％，为黄色固体。LC-MS(ESI)m/z:205[M+H]+.Compound 50-2 (295 mg, 1.3 mmol) was dispersed in THF (5 mL), and Raney nickel (200 mg) was added, and stirred at room temperature for 5 hours under H 2 atmosphere. LC-MS and TLC detected that there was almost no raw material remaining. The reaction solution was filtered through diatomaceous earth, washed with THF, and purified by C-18 reverse phase column chromatography to obtain compound 50-3, 100 mg, with a yield of 39%, as a yellow solid. LC-MS (ESI) m/z: 205 [M + H] + .
步骤四：化合物50-4的合成Step 4: Synthesis of compound 50-4
4-氯-2-氟苯甲酰胺(200mg,1.2mmol)溶于1，2-二氯乙烷(5mL)中，在0℃下缓慢滴加草酰氯(0.15mL，1.7mmol),加热到55℃，反应1小时，然后升温到80℃，过夜反应。TLC监测原料基本消失，直接将反应液旋干，得到相应的异氰酸酯中间体。将其尽快溶于DCE(1mL)，在冰水浴下滴加到含化合物50-3(100mg，0.5mmol)的DCE(1.5mL)和DMF(1mL)的混合液中，逐渐升温到室温。反应液过滤，干燥，得到化合物50-4，140mg，47％，其为白色固体。LC-MS(ESI)m/z:603[M+H]+.4-Chloro-2-fluorobenzamide (200 mg, 1.2 mmol) was dissolved in 1,2-dichloroethane (5 mL), and oxalyl chloride (0.15 mL, 1.7 mmol) was slowly added dropwise at 0 ° C, heated to 55 ° C, reacted for 1 hour, and then heated to 80 ° C and reacted overnight. TLC monitoring showed that the raw material basically disappeared, and the reaction solution was directly spin-dried to obtain the corresponding isocyanate intermediate. It was dissolved in DCE (1 mL) as soon as possible, and added dropwise to a mixed solution of DCE (1.5 mL) and DMF (1 mL) containing compound 50-3 (100 mg, 0.5 mmol) under an ice-water bath, and gradually heated to room temperature. The reaction solution was filtered and dried to obtain compound 50-4, 140 mg, 47%, which was a white solid. LC-MS (ESI) m/z: 603 [M + H] + .
步骤五：化合物50-5的合成Step 5: Synthesis of compound 50-5
在0℃下缓慢向含有化合物50-4(120mg,0.2mmol)的DMF(2mL)溶液中加入NaH(50mg，60％)，加热到80℃，反应2小时。TLC监测原料基本消失，加过量的水淬灭反应，用稀盐酸调节反应液的pH值至中性，大量白色固体析出，过滤得到固体，干燥。得到粗品化合物50-5，125mg，产率99％，为白色固体，直接用于下一步。LC-MS(ESI)m/z:563[M+H]+.Slowly add NaH (50 mg, 60%) to a DMF (2 mL) solution containing compound 50-4 (120 mg, 0.2 mmol) at 0°C, heat to 80°C, and react for 2 hours. TLC monitoring shows that the raw material has basically disappeared, add excess water to quench the reaction, adjust the pH value of the reaction solution to neutral with dilute hydrochloric acid, and a large amount of white solid precipitates. The solid is filtered and dried. The crude compound 50-5 is obtained, 125 mg, with a yield of 99%, as a white solid, which is directly used in the next step. LC-MS (ESI) m/z: 563 [M + H] + .
步骤六：化合物50的合成Step 6: Synthesis of compound 50
化合物50-5(50mg,0.09mmol)分散到乙腈(4mL)中，在0℃下分别加入DIEA(0.15mL)和POCl3(0.05mL)，升温到80℃回流4小时。TLC监测原料基本消失，将反应液旋干，并迅速加入二甲胺的四氢呋喃溶液(2mL)，室温搅拌。反应液旋干，通过pre-TLC纯化(MeOH:DCM＝1:9)，然后高效液相色谱法HPLC纯化，得到化合物50,12mg,，产率25％，为白色固体。LC-MS(ESI)m/z:309.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.05(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,1H),7.73(dt,J＝8.0,1.3Hz,1H),7.61(t,J＝7.8Hz,1H),7.57(t,J＝1.9Hz,1H),7.48(dd,J＝12.9,1.7Hz,2H),7.40(d,J＝1.3Hz,1H),7.26-7.23(m,1H),7.22-7.16(m,2H),6.40(d,J＝2.1Hz,1H),5.28(s,2H),3.31(s,6H),3.25(s,6H).Compound 50-5 (50 mg, 0.09 mmol) was dispersed in acetonitrile (4 mL), DIEA (0.15 mL) and POCl 3 (0.05 mL) were added at 0°C, and the temperature was raised to 80°C and refluxed for 4 hours. TLC monitoring showed that the raw material was basically gone, the reaction solution was spin-dried, and a tetrahydrofuran solution of dimethylamine (2 mL) was quickly added and stirred at room temperature. The reaction solution was spin-dried, purified by pre-TLC (MeOH:DCM=1:9), and then purified by HPLC to obtain compound 50, 12 mg, with a yield of 25%, as a white solid. LC-MS (ESI) m/z: 309.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.05(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,1H),7.73(dt,J＝8.0,1.3Hz,1H),7.61(t,J＝7.8Hz,1H),7.57(t,J＝1.9Hz,1H),7.48(dd,J＝12.9,1.7Hz,2H),7. 40(d,J＝1.3Hz,1H),7.26-7.23(m,1H),7.22-7.16(m,2H),6.40(d,J＝2.1Hz,1H),5.28(s,2H),3.31(s,6H),3.25(s,6H).
实施例51
Embodiment 51
合成方法Synthesis method
化合物51的合成方法参照实施例50，区别在于把步骤五中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:323.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.98(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.74-7.71(m,1H),7.61(t,J＝7.8Hz,1H),7.58(d,J＝2.0Hz,1H),7.50(d,J＝1.4Hz,1H),7.46(d,J＝2.0Hz,1H),7.39(s,1H),7.26-7.23(m,1H),7.23-7.17(m,2H),6.40(d,J＝2.1Hz,1H),5.27(s,2H),3.71(q,J＝7.0Hz,2H),3.65(q,J＝7.0Hz,2H),3.30(s,3H),3.23(s,3H),1.32(t,J＝7.0Hz,3H),1.28(t,J＝7.0Hz,3H).The synthesis method of compound 51 refers to Example 50, except that dimethylamine in step 5 is replaced by methylethylamine. LC-MS (ESI) m/z: 323.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ7.98 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.74-7.71 (m, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.50 (d, J=1.4 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.39 (s, 1H), 7.26-7.2 3(m,1H),7.23-7.17(m,2H),6.40(d,J＝2.1Hz,1H),5.27(s,2H),3.71(q,J＝7.0Hz,2H),3.65(q,J＝7.0Hz,2H),3.30(s,3H),3.23(s,3H),1.32(t,J＝7 .0Hz,3H),1.28(t,J＝7.0Hz,3H).
实施例52
Embodiment 52
合成方法Synthesis method
化合物52的合成方法参照实施例44，区别在于把步骤二中的5-溴噻吩-2-甲腈替换为4-溴噻吩-2-甲腈。LC-MS(ESI)m/z:316.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.95(d,J＝2.1Hz,1H),8.11(d,J＝8.8Hz,1H),8.03(d,J＝2.2Hz,1H),7.98(d,J＝8.8Hz,1H),7.79(d,J＝1.6Hz,1H),7.64(d,J＝2.0Hz,1H),7.25(dd,J＝8.8,2.1Hz,1H),7.19(dd,J＝8.8,2.0Hz,1H),6.41(d,J＝2.1Hz,1H),5.47(s,2H),3.34(s,6H),3.25(s,6H),2.16(s,3H).The synthesis method of compound 52 is similar to that of Example 44, except that 5-bromothiophene-2-carbonitrile in step 2 is replaced by 4-bromothiophene-2-carbonitrile. LC-MS (ESI) m/z: 316.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.95(d,J＝2.1Hz,1H),8.11(d,J＝8.8Hz,1H),8.03(d,J＝2.2Hz,1H),7.98(d,J＝8.8Hz,1H),7.79(d,J＝1.6Hz,1H),7.64(d,J＝2.0Hz,1H),7.25(dd,J＝8.8, 2.1Hz,1H),7.19(dd,J＝8.8,2.0Hz,1H),6.41(d,J＝2.1Hz,1H),5.47(s,2H),3.34(s,6H),3.25(s,6H),2.16(s,3H).
实施例53
Embodiment 53
合成方法Synthesis method
化合物53的合成方法参照实施例44，区别在于把步骤二中的5-溴噻吩-2-甲腈替换为4-溴噻吩-2-甲腈，把步骤五中的二甲胺的四氢呋喃溶液替换为氨的甲醇溶液。LC-MS(ESI)m/z:288.5[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.94(d,J＝2.2Hz,1H),8.30(s,1H),8.20(d,J＝8.7Hz,2H),8.10(d,J＝8.5Hz,2H),8.05(d,J＝2.1Hz,1H),8.02-7.98(m,1H),7.93(s,1H),7.78(s,1H),7.61(d,J＝1.9Hz,1H),7.31(dd,J＝8.6,2.0Hz,1H),7.26(dd,J＝8.6,1.8Hz,1H),6.38(d,J＝2.0Hz,1H),5.47(s,2H),2.16(s,3H).The synthesis method of compound 53 is similar to that of Example 44, except that 5-bromothiophene-2-carbonitrile in step 2 is replaced by 4-bromothiophene-2-carbonitrile, and the tetrahydrofuran solution of dimethylamine in step 5 is replaced by a methanol solution of ammonia. LC-MS (ESI) m/z: 288.5 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.94(d,J＝2.2Hz,1H),8.30(s,1H),8.20(d,J＝8.7Hz,2H),8.10(d,J＝8.5Hz,2H),8.05(d,J＝2.1Hz,1H),8.02-7.98(m,1H),7.93(s,1H),7.78(s,1H) ,7.61(d,J＝1.9Hz,1H),7.31(dd,J＝8.6,2.0Hz,1H),7.26(dd,J＝8.6,1.8Hz,1H),6.38(d,J＝2.0Hz,1H),5.47(s,2H),2.16(s,3H).
实施例54
Embodiment 54
合成方法 Synthesis method
化合物54的合成方法参照实施例30，区别在于把步骤三中的2-氟-4-氯苯甲酰胺替换为2-氟-4-三氟甲基苯甲酰胺。LC-MS(ESI)m/z:343.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝8.5Hz,1H),8.17(d,J＝8.4Hz,1H),7.87(s,1H),7.72(dt,J＝8.0,1.3Hz,1H),7.60-7.56(m,2H),7.47-7.45(m,1H),7.45(d,J＝3.5Hz,2H),7.26(dd,J＝4.7,2.9Hz,2H),6.62(d,J＝1.8Hz,1H),5.57(s,2H),3.33(s,6H),3.28(s,6H).The synthesis method of compound 54 is similar to that of Example 30, except that 2-fluoro-4-chlorobenzamide in step 3 is replaced by 2-fluoro-4-trifluoromethylbenzamide. LC-MS(ESI)m/z:343.1[M/2+H] + .1H NMR(400MHz, DMSO-d 6 )δ8.24(d,J＝8.5Hz,1H),8.17(d,J＝8.4Hz,1H),7.87(s,1H),7.72(dt,J＝8.0,1.3Hz,1H),7.60-7.5 6(m,2H),7.47-7.45(m,1H),7.45(d,J＝3.5Hz,2H),7.26(dd,J＝4.7,2.9Hz,2H),6.62(d,J＝1.8Hz,1H),5.57(s,2H),3.33(s,6H),3.28(s,6H).
实施例55
Embodiment 55
合成路线
Synthetic route
步骤一：化合物55-1的合成Step 1: Synthesis of compound 55-1
吡咯-3-甲醛(2.0g，21.0mmol)溶于THF(20mL)中，-2℃下分批加入NBS(3.94g，22.0mmol)，搅拌2小时。TLC检测反应，补加0.1eq NBS，继续反应1小时。向反应液中加入硫代硫酸钠溶液淬灭反应，用EA萃取三次，有机相合并浓缩，通过硅胶柱色谱法纯化(EA：PE＝13：50)，得到粗品化合物。固体通过乙酸乙酯打浆，得到化合物55-2，2.4g，65％，其为粉红色固体。LC-MS(ESI)m/z:174[M+H]+.Pyrrole-3-carboxaldehyde (2.0 g, 21.0 mmol) was dissolved in THF (20 mL), and NBS (3.94 g, 22.0 mmol) was added in batches at -2°C and stirred for 2 hours. The reaction was detected by TLC, and 0.1 eq of NBS was added, and the reaction was continued for 1 hour. Sodium thiosulfate solution was added to the reaction solution to quench the reaction, and EA was extracted three times. The organic phases were combined and concentrated, and purified by silica gel column chromatography (EA: PE = 13: 50) to obtain a crude compound. The solid was slurried by ethyl acetate to obtain compound 55-2, 2.4 g, 65%, which was a pink solid. LC-MS (ESI) m/z: 174 [M + H] + .
步骤二：化合物55-2的合成Step 2: Synthesis of compound 55-2
0℃下，将(氨基氧基)磺酸(6.2g，54.8mmol)溶于水(20mL)中，分批加入化合物55-1(2.4g，13.7mmol)，室温搅拌。TLC检测无原料后，用碳酸氢钠水溶液调节pH至7～8。向反应液中加入二氯甲烷萃取，有机相合并浓缩，通过硅胶柱色谱法纯化(EA：PE＝9：50)，得到化合物55-2，1.3g，57％，其为白色固体。LC-MS(ESI)m/z:171[M+H]+.At 0°C, (aminooxy)sulfonic acid (6.2 g, 54.8 mmol) was dissolved in water (20 mL), and compound 55-1 (2.4 g, 13.7 mmol) was added in batches and stirred at room temperature. After TLC detection showed that there was no raw material, the pH was adjusted to 7-8 with sodium bicarbonate aqueous solution. Dichloromethane was added to the reaction solution for extraction, and the organic phases were combined and concentrated, and purified by silica gel column chromatography (EA: PE = 9: 50) to obtain compound 55-2, 1.3 g, 57%, which was a white solid. LC-MS (ESI) m/z: 171 [M + H] + .
步骤三：化合物55-3的合成Step 3: Synthesis of compound 55-3
化合物55-2(1.3g,7.7mmol)溶于DMF(10mL)中，加入碳酸钾(2.13g，15.4mmol)、SEMCl(2.1mL，2.8mmol)，室温搅拌过夜。反应液通过硅胶柱色谱法纯化(EA： PE＝1：19)，得到化合物55-3，2.79g，91％，为粉红色固体。LC-MS(ESI)m/z:301[M+H]+.Compound 55-2 (1.3 g, 7.7 mmol) was dissolved in DMF (10 mL), potassium carbonate (2.13 g, 15.4 mmol) and SEMCl (2.1 mL, 2.8 mmol) were added, and stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography (EA: PE＝1:19), to obtain compound 55-3, 2.79 g, 91%, as a pink solid. LC-MS (ESI) m/z: 301 [M+H] + .
步骤四：化合物55-4的合成Step 4: Synthesis of compound 55-4
间硝基苯硼酸酯(1.86g，11.1mmol)和化合物55-3(2.79g，9.3mmol)溶于二氧六环(25mL)和DMF(4mL)的混合液中，加入碳酸钠(2.96g，27.9mmol)的水溶液(7mL)，在N2氛围中加入1，1'-双(二苯基膦)二茂铁-二氯化钯(II)二氯甲烷络合物(380mg，0.46mmol)，加热到50℃，过夜反应。反应液通过硅胶柱色谱法纯化(EA：PE＝1：9)，得到化合物55-4，2.4g，74％，为淡黄色固体。LC-MS(ESI)m/z:344[M+H]+.m-Nitrophenyl borate (1.86 g, 11.1 mmol) and compound 55-3 (2.79 g, 9.3 mmol) were dissolved in a mixture of dioxane (25 mL) and DMF (4 mL), and an aqueous solution (7 mL) of sodium carbonate (2.96 g, 27.9 mmol) was added. 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (380 mg, 0.46 mmol) was added in a N2 atmosphere, and the mixture was heated to 50°C and reacted overnight. The reaction solution was purified by silica gel column chromatography (EA:PE=1:9) to obtain compound 55-4, 2.4 g, 74%, as a light yellow solid. LC-MS (ESI) m/z: 344 [M+H] + .
步骤五：化合物55-5的合成Step 5: Synthesis of compound 55-5
将化合物55-4(1.7g，4.9mmol)分散到NH3/MeOH(70mL)中，加入雷尼镍(2.0g)，在H2氛围下室温搅拌5小时。LC-MS和TLC检测几乎无原料，将反应液通过硅藻土过滤，THF洗涤，然后通过C-18反相柱层析纯化，得到化合物55-5，1.0g，64％，其为淡黄色固体。LC-MS(ESI)m/z:318[M+H]+.Compound 55-4 (1.7 g, 4.9 mmol) was dispersed in NH 3 /MeOH (70 mL), and Raney nickel (2.0 g) was added, and stirred at room temperature for 5 hours under H 2 atmosphere. LC-MS and TLC detected that there was almost no starting material, and the reaction solution was filtered through diatomaceous earth, washed with THF, and then purified by C-18 reverse phase column chromatography to obtain compound 55-5, 1.0 g, 64%, which was a light yellow solid. LC-MS (ESI) m/z: 318 [M+H] + .
步骤六：化合物55-6的合成Step 6: Synthesis of compound 55-6
4-氯-2-氟苯甲酰胺(300mg,1.7mmol)溶于1，2-二氯乙烷(5mL)中，在0℃下缓慢滴加草酰氯(0.22mL，2.6mmol),加热到55℃，反应1小时，然后升温到80℃，过夜反应。TLC监测原料基本消失，直接将反应液旋干，得到相应的异氰酸酯中间体。将其尽快溶于DCE(1mL)，在冰水浴下滴加到分散有化合物55-5(200mg，0.6mmol)的DCE(1mL)混合液中，逐渐升温到室温。反应液过滤得到化合物55-6，380mg，84％，其为白色固体。LC-MS(ESI)m/z:716[M+H]+.4-Chloro-2-fluorobenzamide (300mg, 1.7mmol) was dissolved in 1,2-dichloroethane (5mL), oxalyl chloride (0.22mL, 2.6mmol) was slowly added dropwise at 0°C, heated to 55°C, reacted for 1 hour, then heated to 80°C, and reacted overnight. TLC monitoring showed that the raw material basically disappeared, and the reaction solution was directly spin-dried to obtain the corresponding isocyanate intermediate. It was dissolved in DCE (1mL) as soon as possible, and added dropwise to a mixed solution of DCE (1mL) dispersed with compound 55-5 (200mg, 0.6mmol) under an ice-water bath, and gradually heated to room temperature. The reaction solution was filtered to obtain compound 55-6, 380mg, 84%, which was a white solid. LC-MS (ESI) m/z: 716 [M + H] + .
步骤七：化合物55-7的合成Step 7: Synthesis of compound 55-7
在0℃下缓慢向含有化合物55-6(360mg,0.5mmol)的DMF(3mL)溶液中滴加2M NaHMDS/THF(1.5mL)，加热到90℃，反应2小时。加过量的水淬灭反应，用稀盐酸调节反应液的pH值至中性，大量白色固体析出，过滤得到固体，干燥，得到化合物55-7，270mg，79％，为白色固体。LC-MS(ESI)m/z:676[M+H]+.2M NaHMDS/THF (1.5 mL) was slowly added dropwise to a DMF (3 mL) solution containing compound 55-6 (360 mg, 0.5 mmol) at 0°C, heated to 90°C, and reacted for 2 hours. Excessive water was added to quench the reaction, and the pH value of the reaction solution was adjusted to neutral with dilute hydrochloric acid. A large amount of white solid precipitated, and the solid was filtered and dried to obtain compound 55-7, 270 mg, 79%, as a white solid. LC-MS (ESI) m/z: 676 [M+H] + .
步骤八：化合物55-8的合成Step 8: Synthesis of compound 55-8
将化合物55-7(100mg,0.15mmol)分散到乙腈(4mL)中，在0℃下分别加入DIEA(0.26mL)和POCl3(0.1mL)，升温到80℃回流4小时。TLC监测原料基本消失，将反应液旋干，并迅速加入二甲胺的四氢呋喃溶液(4mL)，室温搅拌。通过将反应液通过pre-TLC纯化(MeOH:DCM＝1:15)，然后C-18反向柱层析纯化，得到化合物55-8，50mg，46％，为白色固体。LC-MS(ESI)m/z:365[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.95(d,J＝8.9Hz,1H),7.60(d,J＝6.4Hz,2H),7.56(d,J＝2.1Hz,1H),7.43(d,J＝2.3Hz,1H),7.21(d,J＝2.1Hz,1H),7.19-7.13(m,2H),7.07(d,J＝1.9Hz,1H),6.42(d,J＝2.1Hz,1H),6.35(d,J＝1.9Hz,1H),5.19(s,2H),5.14(s,2H),3.42(s,3H),3.30(s,6H),3.23(s,6H),0.70(t,J＝7.8Hz,2H),0.23(s,9H).Compound 55-7 (100 mg, 0.15 mmol) was dispersed in acetonitrile (4 mL), DIEA (0.26 mL) and POCl 3 (0.1 mL) were added at 0°C, and the mixture was heated to 80°C and refluxed for 4 hours. The raw material was basically disappeared by TLC monitoring, the reaction solution was spin-dried, and a tetrahydrofuran solution of dimethylamine (4 mL) was quickly added and stirred at room temperature. The reaction solution was purified by pre-TLC (MeOH:DCM=1:15) and then purified by C-18 reverse column chromatography to obtain compound 55-8, 50 mg, 46%, as a white solid. LC-MS (ESI) m/z: 365 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.03(d,J＝8.8Hz,1H),7.95(d,J＝8.9Hz,1H),7.60(d,J＝6.4Hz,2H),7.56(d,J＝2.1Hz,1H),7.43(d,J＝2.3Hz,1H),7.21(d,J＝2.1Hz,1H),7.19-7.13(m, 2H),7.07( d,J＝1.9Hz,1H),6.42(d,J＝2.1Hz,1H),6.35(d,J＝1.9Hz,1H),5.19(s,2H),5.14(s,2H),3.42(s,3H),3.30(s,6H),3.23(s,6H),0.70(t,J＝7.8Hz,2H) ,0.23(s,9H).
步骤九：化合物55的合成Step 9: Synthesis of compound 55
化合物55-8(15mg，0.02mmol)溶于DCM(7mL),加入TFA(0.5mL)，室温搅拌过夜。通过将反应液旋干，通过高效液相色谱法HPLC纯化，得到化合物55，2.5mg，产率21％，为粉色固体。LC-MS(ESI)m/z:300.6[M/2+H]+.Compound 55-8 (15 mg, 0.02 mmol) was dissolved in DCM (7 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was spin-dried and purified by HPLC to obtain compound 55, 2.5 mg, with a yield of 21%, as a pink solid. LC-MS (ESI) m/z: 300.6 [M/2+H] + .
实施例56
Embodiment 56
合成方法Synthesis method
化合物56的合成方法参照实施例44，区别在于把步骤一中的5-溴噻吩-2-甲腈替换为4-溴噻吩-2-甲腈，把步骤五中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:330.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.94(d,J＝2.2Hz,1H),8.07-7.99(m,2H),7.97-7.87(m,2H),7.80(d,J＝1.6Hz,1H),7.64(d,J＝2.1Hz,1H),7.26(dd,J＝8.8,2.1Hz,1H),7.20(dd,J＝8.7,2.0Hz,1H),6.40(d,J＝2.2Hz,1H),5.46(s,2H),3.82-3.62(m,4H),3.33(s,3H),3.23(s,3H),2.15(s,3H),1.32-1.23(m,6H).The synthesis method of compound 56 is similar to that of Example 44, except that 5-bromothiophene-2-carbonitrile in step 1 is replaced by 4-bromothiophene-2-carbonitrile, and dimethylamine in step 5 is replaced by methylethylamine. LC-MS (ESI) m/z: 330.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.94(d,J＝2.2Hz,1H),8.07-7.99(m,2H),7.97-7.87(m,2H),7.80(d,J＝1.6Hz,1H),7.64(d,J＝2.1Hz,1H),7.26(dd,J＝8.8,2.1Hz,1H),7.20(dd,J＝8.7 ,2.0Hz,1H),6.40(d,J＝2.2Hz,1H),5.46(s,2H),3.82-3.62(m,4H),3.33(s,3H),3.23(s,3H),2.15(s,3H),1.32-1.23(m,6H).
实施例57
Embodiment 57
合成路线
Synthetic route
步骤一：化合物57-1的合成Step 1: Synthesis of compound 57-1
室温下，将5-溴-3-氨基吡啶(2.0g，11.56mmol)、联硼酸频那醇酯(10.8g，42.52mmol)、Pd(dppf)Cl2(860mg，1.176mmol)、醋酸钾(3.0g，32.26mmol)溶于60mL二氧六环中，氮气置换三次后升温至100℃油浴5小时，LC-MS监测反应完全，浓缩除去二氧六环，加PE分散反应液后过滤，滤饼用DCM/MeOH混合溶液分散后，再次过滤，所得滤液浓缩后，加入4-溴噻吩-2-甲腈(2.0g，10.64mmol)、碳酸钠(3.4g，32.08mmol)、四三苯基膦钯(1.22g，1.055mmol)、30mL THF和6mL水，之后升温至60℃搅拌5小时。LC-MS监测4-溴噻吩-2-甲腈消失。加水和EA萃取三次，合并有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,20min)得化合物57-1，2.0 g，产率86％，绿色固体。LC-MS(ESI)m/z:202[M+H]+.At room temperature, 5-bromo-3-aminopyridine (2.0 g, 11.56 mmol), bipyraclostrobin (10.8 g, 42.52 mmol), Pd(dppf)Cl 2 (860 mg, 1.176 mmol), potassium acetate (3.0 g, 32.26 mmol) were dissolved in 60 mL of dioxane. After nitrogen replacement three times, the temperature was raised to 100° C. in an oil bath for 5 hours. The reaction was completed after LC-MS monitoring. The dioxane was concentrated to remove the dioxane. The reaction solution was dispersed with PE and then filtered. The filter cake was dispersed with a DCM/MeOH mixed solution and filtered again. After the filtrate was concentrated, 4-bromothiophene-2-carbonitrile (2.0 g, 10.64 mmol), sodium carbonate (3.4 g, 32.08 mmol), tetrakistriphenylphosphine palladium (1.22 g, 1.055 mmol), 30 mL of THF and 6 mL of water were added, and then the temperature was raised to 60° C. and stirred for 5 hours. LC-MS monitoring of 4-bromothiophene-2-carbonitrile disappeared. Water and EA were added for extraction three times, and the organic phases were combined, concentrated, and separated by flash chromatography (DCM: MeOH, 0-10%, 20min) to obtain compound 57-1, 2.0 g, yield 86%, green solid. LC-MS (ESI) m/z: 202 [M+H] + .
步骤二：化合物57-2的合成Step 2: Synthesis of compound 57-2
室温下，将化合物57-1(2.0g，9.90mmol)溶于氨的甲醇溶液(7N，20mL)，取2mL水封的雷尼镍，沉淀后移走上清液，加甲醇洗涤两次，静置沉淀后移走上清液，之后将沉淀物用甲醇稀释后加入反应体系，置换氢气三次后保持室温反应4小时。LC-MS监测反应完全。加50mL DCM和10mL甲醇稀释反应液后垫硅藻土过滤，滤液浓缩后经快速色谱柱分离纯化(DCM:MeOH,0-10％,20min)后得化合物57-2，700mg，产率34％，黄色固体。LC-MS(ESI)m/z:206[M+H]+.At room temperature, compound 57-1 (2.0 g, 9.90 mmol) was dissolved in ammonia methanol solution (7N, 20 mL), 2 mL of water-sealed Raney nickel was taken, the supernatant was removed after precipitation, methanol was added to wash twice, the supernatant was removed after standing and precipitation, and then the precipitate was diluted with methanol and added to the reaction system, and the hydrogen was replaced three times and kept at room temperature for 4 hours. LC-MS monitored the complete reaction. After adding 50 mL DCM and 10 mL methanol to dilute the reaction solution, diatomaceous earth was padded and filtered, the filtrate was concentrated and separated and purified by flash chromatography column (DCM: MeOH, 0-10%, 20 min) to obtain compound 57-2, 700 mg, yield 34%, yellow solid. LC-MS (ESI) m/z: 206 [M + H] + .
步骤三：化合物57-3的合成Step 3: Synthesis of compound 57-3
室温下，将2-氟-4-氯苯甲酰胺(1.2g，6.936mmol)溶于20mL DCE中，降温至0℃后缓慢滴加草酰氯(1.3g，10.24mmol)，缓慢升至室温后再升温至70℃搅拌16小时。之后浓缩除去过量草酰氯，溶解于3mL DCE后滴加至化合物57-2(700mg，3.4mmol)的DCE/DMF(20mL，5:1)溶液中，保持室温反应30分钟。有大量固体析出。过滤即得化合物57-3，1.5g，产率73％，淡黄色固体。LC-MS(ESI)m/z:604[M+H]+.At room temperature, 2-fluoro-4-chlorobenzamide (1.2 g, 6.936 mmol) was dissolved in 20 mL DCE, cooled to 0 °C, and then oxalyl chloride (1.3 g, 10.24 mmol) was slowly added dropwise, slowly heated to room temperature, and then heated to 70 °C and stirred for 16 hours. After that, the excess oxalyl chloride was removed by concentration, dissolved in 3 mL DCE, and then added dropwise to a DCE/DMF (20 mL, 5:1) solution of compound 57-2 (700 mg, 3.4 mmol), and kept at room temperature for 30 minutes. A large amount of solid precipitated. Compound 57-3 was obtained by filtration, 1.5 g, yield 73%, light yellow solid. LC-MS (ESI) m/z: 604 [M + H] + .
步骤四：化合物57-4的合成Step 4: Synthesis of compound 57-4
室温下，将化合物57-3(1.5g，2.5mmol)溶于30mL DMF中，降温至0℃，分批加入氢化钠(400mg，10mmol)，室温搅拌10分钟后升温至90℃搅拌16小时。LC-MS监测反应完全，加水淬灭反应。之后用1M的盐酸调节pH到6左右，有大量固体析出，过滤，滤饼用DCM/MeOH再次打浆得到化合物57-4，1.0g，产率71％，红色固体。LC-MS(ESI)m/z:564[M+H]+.At room temperature, compound 57-3 (1.5 g, 2.5 mmol) was dissolved in 30 mL DMF, cooled to 0 ° C, sodium hydride (400 mg, 10 mmol) was added in batches, stirred at room temperature for 10 minutes, and then heated to 90 ° C and stirred for 16 hours. LC-MS monitored the reaction to be complete, and water was added to quench the reaction. After that, 1 M hydrochloric acid was used to adjust the pH to about 6, and a large amount of solid precipitated. The filter cake was slurried again with DCM/MeOH to obtain compound 57-4, 1.0 g, yield 71%, red solid. LC-MS (ESI) m/z: 564 [M + H] + .
步骤五：化合物57的合成Step 5: Synthesis of compound 57
室温下，将化合物57-4(100mg，0.18mmol)溶于3mL无水乙腈中，降温至0℃，加入DIEA(100mg，0.78mmol)和三氯氧磷(130mg，0.85mmol)，缓慢升至室温后升温至80℃搅拌6小时。反应液浓缩除去大量三氯氧磷，之后加入二甲胺的THF溶液(2mL，2.5N)，室温搅拌30分钟。LC-MS监测反应完全。浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,20min)得到粗品化合物，之后经HPLC制备纯化后得化合物57，19mg，产率35％，白色固体。LC-MS(ESI)m/z:309.6[M/2+H]+.At room temperature, compound 57-4 (100 mg, 0.18 mmol) was dissolved in 3 mL of anhydrous acetonitrile, cooled to 0 ° C, DIEA (100 mg, 0.78 mmol) and phosphorus oxychloride (130 mg, 0.85 mmol) were added, slowly heated to room temperature and then heated to 80 ° C and stirred for 6 hours. The reaction solution was concentrated to remove a large amount of phosphorus oxychloride, and then a THF solution of dimethylamine (2 mL, 2.5 N) was added and stirred at room temperature for 30 minutes. LC-MS monitored the reaction to be complete. After concentration, the crude compound was separated by flash chromatography (DCM: MeOH, 0-10%, 20 min), and then prepared and purified by HPLC to obtain compound 57, 19 mg, yield 35%, white solid. LC-MS (ESI) m/z: 309.6 [M/2+H] + .
1H NMR(400MHz,DMSO-d6)δ9.06(d,J＝2.1Hz,1H),8.44(d,J＝2.2Hz,1H),8.14(t,J＝2.2Hz,1H),8.07(d,J＝8.8Hz,1H),8.03-7.95(m,2H),7.82(d,J＝1.6Hz,1H),7.64(d,J＝2.1Hz,1H),7.22(ddd,J＝17.5,8.8,2.0Hz,2H),6.50(d,J＝2.1Hz,1H),5.48(s,2H),3.33(s,6H),3.25(s,6H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.06 (d, J = 2.1 Hz, 1H), 8.44 (d, J = 2.2 Hz, 1H), 8.14 (t, J = 2.2 Hz, 1H), 8.07 (d,J＝8.8Hz,1H),8.03-7.95(m,2H),7.82(d,J＝1.6Hz,1H),7.64(d,J＝2.1Hz,1H),7.22(ddd,J＝ 17.5,8.8,2.0Hz,2H),6.50(d,J＝2.1Hz,1H),5.48(s,2H),3.33(s,6H),3.25(s,6H).
实施例58
Embodiment 58
合成方法Synthesis method
化合物58的合成方法参照实施例57，区别在于把步骤五中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:323.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ9.06(d,J＝2.1Hz,1H),8.45(d,J＝2.2Hz,1H),8.15(t,J＝2.2Hz,1H),8.05-7.98(m,2H),7.91(d,J＝8.8Hz,1H),7.83(d,J＝1.6Hz,1H),7.64(d,J＝2.0Hz,1H),7.22(ddd,J＝17.6,8.8,2.0Hz,2H), 6.49(d,J＝2.1Hz,1H),5.47(s,2H),3.72(q,J＝7.0Hz,2H),3.65(q,J＝7.1Hz,2H),3.32(s,3H),3.23(s,3H),1.34-1.24(m,6H).The synthesis method of compound 58 refers to Example 57, except that dimethylamine in step 5 is replaced by methylethylamine. LC-MS (ESI) m/z: 323.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ9.06 (d, J=2.1 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.15 (t, J=2.2 Hz, 1H), 8.05-7.98 (m, 2H), 7.91 (d, J=8.8 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.22 (ddd, J=17.6, 8.8, 2.0 Hz, 2H), 6.49(d,J＝2.1Hz,1H),5.47(s,2H),3.72(q,J＝7.0Hz,2H),3.65(q,J＝7.1Hz,2H),3.32(s,3H),3.23(s,3H),1.34-1.24(m,6H).
实施例59
Embodiment 59
合成方法Synthesis methods
化合物59的合成方法参照实施例57，区别在于把步骤五中的二甲胺替换为二甲基-D6-胺盐酸盐。LC-MS(ESI)m/z:315.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ9.07(d,J＝2.0Hz,1H),8.45(d,J＝2.2Hz,1H),8.17(d,J＝2.3Hz,1H),8.07(d,J＝8.7Hz,1H),8.02(d,J＝1.5Hz,1H),7.99(d,J＝8.8Hz,1H),7.82(d,J＝1.5Hz,1H),7.64(d,J＝2.0Hz,1H),7.22(ddd,J＝16.2,8.7,2.0Hz,2H),6.51(d,J＝2.1Hz,1H),5.48(s,2H).The synthesis method of compound 59 refers to Example 57, except that the dimethylamine in step 5 is replaced by dimethyl-D6-amine hydrochloride. LC-MS (ESI) m/z: 315.6 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.07 (d, J = 2.0Hz, 1H), 8.45 (d, J = 2.2Hz, 1H), 8.17 (d, J = 2.3Hz, 1H), 8.07 (d, J = 8.7Hz, 1H), 8.02 ( d,J＝1.5Hz,1H),7.99(d,J＝8.8Hz,1H),7.82(d,J＝1.5Hz,1H),7.64(d,J＝2.0H z,1H),7.22(ddd,J＝16.2,8.7,2.0Hz,2H),6.51(d,J＝2.1Hz,1H),5.48(s,2H) .
实施例60
Embodiment 60
合成路线
Synthetic route
步骤一：化合物60-1的合成Step 1: Synthesis of compound 60-1
室温下将2-溴噻吩-5-羧酸乙酯(1.5g，6.38mmol)、3-硝基苯硼酸(1.3g，7.66mmol)和碳酸钠(2.0g，19.15mmol)溶解在四氢呋喃(12mL)中，加入四三苯基膦钯(750mg，0.64mmol)和水(3mL)，氮气保护下升温至70℃搅拌18小时。TLC监测完全反应，加水30mL，用乙酸乙酯(50mL×3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯， 0-50％，15min)，浓缩后即为化合物60-1，1.1g，产率62％，淡黄色固体。LC-MS(ESI)m/z:279[M+H]+.At room temperature, ethyl 2-bromothiophene-5-carboxylate (1.5 g, 6.38 mmol), 3-nitrobenzeneboronic acid (1.3 g, 7.66 mmol) and sodium carbonate (2.0 g, 19.15 mmol) were dissolved in tetrahydrofuran (12 mL), tetrakistriphenylphosphine palladium (750 mg, 0.64 mmol) and water (3 mL) were added, and the temperature was raised to 70 ° C and stirred for 18 hours under nitrogen protection. TLC monitored the complete reaction, 30 mL of water was added, and the organic phase was extracted with ethyl acetate (50 mL×3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 0-50%, 15min), after concentration, compound 60-1 was obtained, 1.1 g, yield 62%, light yellow solid. LC-MS (ESI) m/z: 279 [M+H] + .
步骤二：化合物60-2的合成Step 2: Synthesis of compound 60-2
室温下将化合物60-1(1.1g，3.96mmol)溶解在胺-甲醇(75mL)溶液中，室温下搅拌4小时。TLC监测完全反应，减压旋蒸浓缩后固体即为化合物60-2，984mg，产率99％，淡黄色固体，化合物60-2无需纯化直接用于下一步反应。LC-MS(ESI)m/z:250[M+H]+.Compound 60-1 (1.1 g, 3.96 mmol) was dissolved in amine-methanol (75 mL) solution at room temperature and stirred at room temperature for 4 hours. TLC monitored the complete reaction. After vacuum rotary evaporation and concentration, the solid was compound 60-2, 984 mg, yield 99%, light yellow solid. Compound 60-2 was directly used in the next step without purification. LC-MS (ESI) m/z: 250 [M + H] + .
步骤三：化合物60-3的合成Step 3: Synthesis of compound 60-3
室温下，将化合物60-2(500mg，2.01mmol)溶解在四氢呋喃(5mL)中，降温至0℃，逐滴加入四氢铝锂的四氢呋喃(2.5mL)溶液，氮气保护下，升温至70℃搅拌2小时。TLC监测完全反应，反应体系中加水(10mL)淬灭，用乙酸乙酯(50mL×3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)，浓缩后即为化合物60-3，146mg，产率35％，淡黄色固体。LC-MS(ESI)m/z:206[M+H]+.At room temperature, compound 60-2 (500 mg, 2.01 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0 ° C, and a solution of lithium aluminum tetrahydride in tetrahydrofuran (2.5 mL) was added dropwise. Under nitrogen protection, the temperature was raised to 70 ° C and stirred for 2 hours. TLC monitored the complete reaction, and the reaction system was quenched with water (10 mL), extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and after concentration, it was compound 60-3, 146 mg, yield 35%, light yellow solid. LC-MS (ESI) m/z: 206 [M + H] + .
步骤四：化合物60-4的合成Step 4: Synthesis of compound 60-4
0℃下将草酰氯(555mg，4.37mmol)滴加到4-氯-2-氟苯甲酰胺(380mg，2.18mmol)的二氯乙烷DCE(5mL)中。氮气保护下，反应混合液在70℃搅拌过夜，减压旋蒸除去多余的草酰氯后，用DCE(2mL)稀释后滴入化合物60-3(146mg，0.71mmol)的DCE(3mL)体系中，反应在室温下搅拌3小时。TLC监测完全反应。反应体系加入乙腈打浆，过滤后固体即为化合物60-4，248mg，产率58％，白色固体。LC-MS(ESI)m/z:604[M+H]+.Oxalyl chloride (555 mg, 4.37 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (380 mg, 2.18 mmol) in dichloroethane (DCE) (5 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing the excess oxalyl chloride by vacuum rotary evaporation, it was diluted with DCE (2 mL) and then added dropwise to the DCE (3 mL) system of compound 60-3 (146 mg, 0.71 mmol), and the reaction was stirred at room temperature for 3 hours. TLC monitored the complete reaction. Acetonitrile was added to the reaction system for slurrying, and the solid after filtration was compound 60-4, 248 mg, yield 58%, white solid. LC-MS (ESI) m/z: 604 [M + H] + .
步骤五：化合物60-5的合成Step 5: Synthesis of compound 60-5
0℃下将氢化钠(87mg，2.05mmol)加入到化合物60-4(248mg，0.41mmol)的N,N-二甲基甲酰胺DMF(5mL)中，氮气保护下，升温至90℃搅拌3小时。LC-MS检测原料基本消失。反应体系加水淬灭，滴加稀盐酸(0.5mol/L)至pH为中性，过滤后固体用乙腈打浆，再次过滤后固体即为化合物60-5，70mg，产率30％，白色固体。LC-MS(ESI)m/z:564[M+H]+.Sodium hydride (87 mg, 2.05 mmol) was added to compound 60-4 (248 mg, 0.41 mmol) in DMF (5 mL) at 0°C, and the mixture was heated to 90°C and stirred for 3 hours under nitrogen protection. LC-MS detected that the raw material was basically gone. The reaction system was quenched with water, and dilute hydrochloric acid (0.5 mol/L) was added dropwise until the pH was neutral. After filtration, the solid was slurried with acetonitrile, and the solid was filtered again to obtain compound 60-5, 70 mg, with a yield of 30%, as a white solid. LC-MS (ESI) m/z: 564 [M+H] + .
步骤六：化合物60的合成Step 6: Synthesis of compound 60
0℃下将三氯氧磷(0.8mL)加入到化合物5(70mg，0.12mmol)和N,N-二异丙基乙胺(0.8mL)的乙腈ACN(4mL)溶液中。在氮气保护下，反应混合液在90℃下反应4小时，减压旋蒸去除多余的三氯氧磷。将二甲胺的四氢呋喃溶液(4mL)中滴入除去三氯氧磷的反应体系中，室温下搅拌30分钟。LC-MS检测完全反应。二氯甲烷/甲醇溶解后经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，经HPLC制备纯化后得到化合物60，21.03mg，产率28.40％，淡黄色固体。LC-MS(ESI)m/z:309.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),8.06-7.95(m,3H),7.82(t,J＝1.9Hz,1H),7.78(d,J＝2.1Hz,1H),7.68(t,J＝7.9Hz,1H),7.41(dd,J＝7.8,2.1,1.1Hz,1H),7.20(ddd,J＝8.8,3.6,2.0Hz,2H),6.37(d,J＝2.1Hz,1H),5.53(s,2H),3.31(s,6H),3.24(s,6H).Phosphorus oxychloride (0.8 mL) was added to a solution of compound 5 (70 mg, 0.12 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 hours, and the excess phosphorus oxychloride was removed by vacuum rotary evaporation. A tetrahydrofuran solution of dimethylamine (4 mL) was added dropwise to the reaction system where phosphorus oxychloride was removed, and stirred at room temperature for 30 minutes. LC-MS detected the complete reaction. After dissolving in dichloromethane/methanol, the crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 60 was obtained after purification by HPLC preparation, 21.03 mg, yield 28.40%, light yellow solid. LC-MS (ESI) m/z: 309.6 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.13 (s, 1H), 8.06-7.95 (m, 3H), 7.82 (t, J = 1.9Hz, 1H), 7.78 (d, J = 2.1Hz, 1H), 7.68 (t, J = 7.9Hz, 1H),7.41(dd,J＝7.8,2.1,1.1Hz,1H),7.20(ddd,J＝8.8,3.6,2.0Hz,2H),6.37(d,J＝2.1Hz,1H),5.53(s,2H),3.31(s,6H),3.24(s,6H).
实施例61
Embodiment 61
合成方法Synthesis method
化合物61的合成方法参照实施例57，区别在于把步骤五中的二甲胺替换为甲胺。LC-MS(ESI)m/z:295.5[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ9.06(d,J＝2.1Hz,1H),8.83-8.77(m,1H),8.73-8.62(m,1H),8.44(d,J＝2.2Hz,1H),8.18-8.13(m,2H),8.09(d,J＝8.7Hz,1H),8.01(d,J＝1.6Hz,1H),7.80(s,1H),7.62(d,J＝2.0Hz,1H),7.31(ddd,J＝19.5,8.6,1.9Hz,2H),6.48(d,J＝2.0Hz,1H),5.55-5.42(m,2H),3.00(d,J＝4.4Hz,3H),2.95(d,J＝4.3Hz,3H).The synthesis method of compound 61 is similar to that of Example 57, except that dimethylamine in step 5 is replaced by methylamine. LC-MS (ESI) m/z: 295.5 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ9.06(d,J＝2.1Hz,1H),8.83-8.77(m,1H),8.73-8.62(m,1H),8.44(d,J＝2.2Hz,1H),8.18-8.13(m,2H),8.09(d,J＝8.7Hz,1H),8.01(d,J＝1.6Hz,1H), 7.80(s,1H),7.62(d,J＝2.0Hz,1H),7.31(ddd,J＝19.5,8.6,1.9Hz,2H),6.48(d,J＝2.0Hz,1H),5.55-5.42(m,2H),3.00(d,J＝4.4Hz,3H),2.95(d,J＝4.3 Hz,3H).
实施例62
Embodiment 62
合成路线
Synthetic route
步骤一：化合物62-1的合成Step 1: Synthesis of compound 62-1
室温下，将2-氨基-6-溴吡啶(1g，5.8mmol)、1-H-4-氰基咪唑(540mg，5.8mmol)、碘化亚铜(110mg，0.6mmol)、反-N,N'-二甲基环己烷-1,2-二胺(90mg，0.6mmol)和碳酸铯(5.6g，17.2mmol)溶于20mL无水DMF，置换氮气三次，升温至100℃油浴反应16小时。LC-MS监测反应完全。加水和EA萃取三次，合并有机相用饱和食盐水洗涤两次，浓缩后经乙醇打浆得化合物62-1，500mg，产率47％，黄色固体。LC-MS(ESI)m/z:186[M+H]+.At room temperature, 2-amino-6-bromopyridine (1g, 5.8mmol), 1-H-4-cyanoimidazole (540mg, 5.8mmol), cuprous iodide (110mg, 0.6mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (90mg, 0.6mmol) and cesium carbonate (5.6g, 17.2mmol) were dissolved in 20mL anhydrous DMF, nitrogen was replaced three times, and the temperature was raised to 100℃ oil bath for 16 hours. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the organic phases were combined and washed twice with saturated brine, concentrated and slurried with ethanol to obtain compound 62-1, 500mg, yield 47%, yellow solid. LC-MS (ESI) m/z: 186 [M + H] + .
步骤二：化合物62-2的合成Step 2: Synthesis of compound 62-2
室温下，将化合物62-1(500mg，2.7mmol)溶于氨的甲醇溶液(7N，10mL )，取2mL水封的雷尼镍，沉淀后移走上清液，加甲醇洗涤两次，静置沉淀后移走上清液，之后将沉淀物用甲醇稀释后加入反应体系，置换氢气三次后保持室温反应4小时。LC-MS监测反应完全。加50mL DCM和10mL甲醇稀释反应液后垫硅藻土过滤，滤液浓缩后经反向色谱柱分离纯化(水/乙腈，40％)后得化合物62-2，500mg，产率97％。LC-MS(ESI)m/z:190[M+H]+.At room temperature, compound 62-1 (500 mg, 2.7 mmol) was dissolved in ammonia methanol solution (7N, 10 mL ), take 2mL of water-sealed Raney nickel, remove the supernatant after precipitation, add methanol to wash twice, remove the supernatant after standing precipitation, then dilute the precipitate with methanol and add it to the reaction system, replace hydrogen three times and keep the reaction at room temperature for 4 hours. LC-MS monitors the reaction to be complete. Add 50mL DCM and 10mL methanol to dilute the reaction solution and filter it with diatomaceous earth. After the filtrate is concentrated, it is separated and purified by reverse chromatographic column (water/acetonitrile, 40%) to obtain compound 62-2, 500mg, with a yield of 97%. LC-MS (ESI) m/z: 190[M+H] + .
步骤三：化合物62-3的合成Step 3: Synthesis of compound 62-3
室温下，将2-氟-4-三氟甲基苯甲酰胺(920mg，5.3mmol)溶于10mL DCE中，降温至0℃后缓慢滴加草酰氯(1g，7.9mmol)，缓慢升至室温后再升温至70℃搅拌16小时。之后浓缩除去过量草酰氯，溶解于2mL DCE后滴加至化合物62-2(500mg，2.6mmol)的DCE/DMF(20mL，5:1)溶液中，保持室温反应1小时。有大量白色固体析出。过滤即得化合物62-3，957mg，产率62％，白色固体。LC-MS(ESI)m/z:588[M+H]+.At room temperature, 2-fluoro-4-trifluoromethylbenzamide (920 mg, 5.3 mmol) was dissolved in 10 mL DCE, cooled to 0 °C, and then oxalyl chloride (1 g, 7.9 mmol) was slowly added dropwise, slowly heated to room temperature, and then heated to 70 °C and stirred for 16 hours. After that, the excess oxalyl chloride was removed by concentration, dissolved in 2 mL DCE, and then added dropwise to a DCE/DMF (20 mL, 5:1) solution of compound 62-2 (500 mg, 2.6 mmol), and kept at room temperature for 1 hour. A large amount of white solid precipitated. Compound 62-3 was obtained by filtration, 957 mg, yield 62%, white solid. LC-MS (ESI) m/z: 588 [M + H] + .
步骤四：化合物62-4的合成Step 4: Synthesis of compound 62-4
室温下，将化合物62-3(957mg，1.6mmol)溶于10mL DMF中，降温至0℃，分批加入氢化钠(260mg，6.5mmol)，室温搅拌10分钟后升温至90℃搅拌16小时。LC-MS监测反应完全，加水淬灭反应。之后用1M的盐酸调节pH到6左右，有大量固体析出，过滤，滤饼用DCM/MeOH再次打浆得到化合物62-4，700mg，产率79％，黄色固体。LC-MS(ESI)m/z:548[M+H]+.At room temperature, compound 62-3 (957 mg, 1.6 mmol) was dissolved in 10 mL DMF, cooled to 0 ° C, sodium hydride (260 mg, 6.5 mmol) was added in batches, stirred at room temperature for 10 minutes, and then heated to 90 ° C and stirred for 16 hours. LC-MS monitored the reaction to be complete, and water was added to quench the reaction. After that, 1 M hydrochloric acid was used to adjust the pH to about 6, and a large amount of solid precipitated. The filter cake was slurried again with DCM/MeOH to obtain compound 62-4, 700 mg, yield 79%, yellow solid. LC-MS (ESI) m/z: 548 [M + H] + .
步骤五：化合物62的合成Step 5: Synthesis of compound 62
室温下，将化合物62-4(100mg，0.18mmol)溶于5mL无水乙腈中，降温至0℃，加入DIEA(0.5mL)和三氯氧磷(0.5mL)，缓慢升至室温后升温至80℃搅拌6小时。反应液浓缩除去大量三氯氧磷，之后加入二甲胺的THF溶液(3mL，2.5N)，室温搅拌30分钟。LCMS监测反应完全。浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,20min)得到粗品化合物，之后经HPLC制备纯化后得化合物62，19mg，产率17％，白色固体。LC-MS(ESI)m/z:301.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.55(s,1H),8.24(t,J＝7.9Hz,1H),8.06(d,J＝8.8Hz,1H),7.96(dd,J＝14.2,8.5Hz,2H),7.77(s,1H),7.67(d,J＝2.0Hz,1H),7.46(d,J＝7.6Hz,1H),7.23(dd,J＝8.8,2.1Hz,1H),7.17(dd,J＝8.7,2.0Hz,1H),6.55(d,J＝2.1Hz,1H),5.21(s,2H),3.33(s,6H),3.23(s,6H).At room temperature, compound 62-4 (100 mg, 0.18 mmol) was dissolved in 5 mL of anhydrous acetonitrile, cooled to 0 ° C, DIEA (0.5 mL) and phosphorus oxychloride (0.5 mL) were added, slowly heated to room temperature, and then heated to 80 ° C and stirred for 6 hours. The reaction solution was concentrated to remove a large amount of phosphorus oxychloride, and then a THF solution of dimethylamine (3 mL, 2.5 N) was added and stirred at room temperature for 30 minutes. LCMS monitored the reaction to be complete. After concentration, the crude compound was separated by flash chromatography (DCM: MeOH, 0-10%, 20 min), and then purified by HPLC to obtain compound 62, 19 mg, yield 17%, white solid. LC-MS(ESI)m/z:301.6[M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 )δ8.55(s,1H),8.24(t,J＝7.9Hz,1H),8.06(d,J＝8.8Hz,1H),7.96(dd,J＝14.2,8.5Hz,2H),7.77(s, 1H),7.67(d,J＝2.0Hz,1H),7.46(d,J＝7.6Hz,1H),7.23(dd,J＝8.8,2.1Hz,1H),7.17(dd,J＝8.7,2.0Hz,1H),6.55(d,J＝2.1Hz,1H),5.21(s,2H),3.33(s,6H) ,3.23(s,6H).
实施例63
Embodiment 63
合成方法Synthesis method
化合物63的合成方法参照实施例62，区别在于把步骤五中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:315.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝1.4Hz,1H),8.23(t,J＝7.9Hz,1H),7.98(dd,J＝11.0,8.5Hz,2H),7.87(d,J＝8.8Hz,1H),7.75(d,J＝1.4Hz,1H),7.67(d,J＝2.1Hz,1H),7.45(d,J＝7.6Hz,1H),7.24(dd,J＝8.8,2.1Hz,1H),7.17(dd,J＝8.7,2.0Hz,1H),6.54(d,J＝2.1Hz,1H),5.19(s,2H),3.72(q,J＝7.0Hz,2H),3.63(q,J＝7.0Hz,2H),3.32(s,3H),3.21(s,3H),1.31(t,J＝7.0Hz,3H),1.27(t,J＝7.0Hz,3H). The synthesis method of compound 63 refers to Example 62, except that dimethylamine in step 5 is replaced by methylethylamine. LC-MS (ESI) m/z: 315.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ8.51 (d, J=1.4 Hz, 1H), 8.23 (t, J=7.9 Hz, 1H), 7.98 (dd, J=11.0, 8.5 Hz, 2H), 7.87 (d, J=8.8 Hz, 1H), 7.75 (d, J=1.4 Hz, 1H), 7.67 (d, J=2.1 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.24 (dd, J=8.8, 2.1 Hz,1H),7.17(dd,J＝8.7,2.0Hz,1H),6.54(d,J＝2.1Hz,1H),5.19(s,2H),3.72(q,J＝7.0Hz,2H),3.63(q,J＝7.0Hz,2H),3.32(s,3H),3.21(s,3H),1.31(t ,J＝7.0Hz,3H),1.27(t,J＝7.0Hz,3H).
实施例64
Embodiment 64
合成方法Synthesis method
化合物64的合成方法参照实施例46，区别在于把步骤五中的甲乙胺替换为甲胺。LC-MS(ESI)m/z:272.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.62(d,J＝4.5Hz,1H),8.12-8.05(m,2H),7.48(t,J＝8.1Hz,1H),7.30-7.23(m,2H),7.09(dd,J＝8.3,2.0Hz,1H),6.90(s,1H),6.85(d,J＝7.7Hz,1H),6.42(s,2H),6.35(d,J＝1.9Hz,1H),4.10(t,J＝6.2Hz,2H),2.97(d,J＝4.4Hz,3H),2.26-2.15(m,2H),2.14-2.05(m,2H),1.23(s,1H),1.05-0.97(m,4H).The synthesis method of compound 64 is similar to that of Example 46, except that methylethylamine in step 5 is replaced by methylamine. LC-MS (ESI) m/z: 272.6 [M/2+H] + .1H NMR (400 MHz, DMSO-d 6 )δ8.62(d,J＝4.5Hz,1H),8.12-8.05(m,2H),7.48(t,J＝8.1Hz,1H),7.30-7.23(m,2H),7.09(dd,J＝8.3,2.0Hz,1H),6.90(s,1H),6.85(d,J＝7.7Hz,1H),6.42(s,2H),6.35(d,J＝1.9Hz,1H),4.10(t,J＝6.2Hz,2H),2.97(d,J＝4.4Hz,3H),2.26-2.15(m,2H),2.14-2.05(m,2H),1.23(s,1H),1.05-0.97(m,4H).
实施例65
Embodiment 65
合成方法Synthesis method
化合物65的合成方法参照实施例62，区别在于把步骤五中的二甲胺替换为甲胺。LC-MS(ESI)m/z:287.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.96-8.89(m,1H),8.61-8.56(m,1H),8.48(s,1H),8.20(dt,J＝15.4,8.3Hz,2H),8.06(d,J＝8.7Hz,1H),7.96(d,J＝8.2Hz,1H),7.73(s,1H),7.61(d,J＝1.9Hz,1H),7.43(d,J＝7.6Hz,1H),7.31(dd,J＝8.6,2.0Hz,1H),7.23(dd,J＝8.6,1.9Hz,1H),6.51(d,J＝1.9Hz,1H),5.20(s,2H),2.98(d,J＝4.3Hz,3H),2.92(d,J＝4.4Hz,3H).The synthesis method of compound 65 refers to Example 62, except that dimethylamine in step 5 is replaced by methylamine. LC-MS (ESI) m/z: 287.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.96-8.89 (m, 1H), 8.61-8.56 (m, 1H), 8.48 (s, 1H), 8.20 (dt, J = 15.4, 8.3 Hz, 2H), 8.06 (d, J = 8.7 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.73 (s, 1H), 7.61 (d, J = 1.9 Hz, 1H ),7.43(d,J＝7.6Hz,1H),7.31(dd,J＝8.6,2.0Hz,1H),7.23(dd,J＝8.6,1.9Hz,1H),6.51(d,J＝1.9Hz,1H),5.20(s,2H),2.98(d,J＝4.3Hz,3H),2.92(d,J＝4. 4Hz,3H).
实施例66
Embodiment 66
合成路线
Synthetic route
步骤一：化合物66-1的合成Step 1: Synthesis of compound 66-1
向含5-溴-4-甲基-2-噻吩甲酸甲酯(1.0g，4.3mmol)和(5-氨基吡啶-3-基)硼酸(0.75g，5.1mmol)的二氧六环(10mL)和N，N-二甲基甲酰胺(2mL)的混合液中加入含碳酸钠(1.35g，12.9mmol)的水溶液(2mL)，置换氮气后，加入1，1'-双(二苯基膦)二茂铁-二氯化钯(II)二氯甲烷络合物(0.30g，0.43mmol)，在氮气氛围下，升温到70℃，反应5个小时。TLC检测反应结束后，用硅藻土过滤，乙酸乙酯洗涤，滤液浓缩后，用乙酸乙酯和水萃取三次，合并有机相。用无水硫酸钠干燥，浓缩后，通过柱层析纯化(EA：PE＝22：25)得到化合物66-1，0.66g，为黄色油状，收率95％。LC-MS(ESI)m/z:249[M+H]+.To a mixture of dioxane (10 mL) and N,N-dimethylformamide (2 mL) containing 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (1.0 g, 4.3 mmol) and (5-aminopyridin-3-yl)boric acid (0.75 g, 5.1 mmol), an aqueous solution (2 mL) containing sodium carbonate (1.35 g, 12.9 mmol) was added, and after nitrogen was replaced, 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (0.30 g, 0.43 mmol) was added, and the temperature was raised to 70° C. under a nitrogen atmosphere, and the reaction was performed for 5 hours. After the reaction was completed by TLC detection, the mixture was filtered with diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated, extracted three times with ethyl acetate and water, and the organic phases were combined. After drying with anhydrous sodium sulfate and concentration, the product was purified by column chromatography (EA:PE=22:25) to obtain compound 66-1, 0.66 g, as a yellow oil, with a yield of 95%. LC-MS (ESI) m/z: 249 [M+H] + .
步骤二：化合物66-2的合成Step 2: Synthesis of compound 66-2
向化合物66-1(0.44g，1.8mmol)中加入氨水(20mL)，室温搅拌24小时，LC-MS检测反应结束后，过滤、干燥，得到化合物66-2，0.27mg，为白色固体，收率65％。LC-MS(ESI)m/z:234[M+H]+.Ammonia water (20 mL) was added to compound 66-1 (0.44 g, 1.8 mmol), and the mixture was stirred at room temperature for 24 hours. After the reaction was completed by LC-MS, the mixture was filtered and dried to obtain compound 66-2, 0.27 mg, as a white solid, with a yield of 65%. LC-MS (ESI) m/z: 234 [M+H] + .
步骤三：化合物66-3的合成Step 3: Synthesis of compound 66-3
在0℃下向含有化合物66-2(0.25g,1.1mmol)的四氢呋喃(3mL)中逐滴滴加LiAlH4(1.7mL，2.5M in THF)，升温至80℃搅拌过夜。LC-MS检测反应结束后，向反应液中加入冰水淬灭，通过硅藻土过滤，用甲醇/二氯甲烷的混合溶液(MeOH:DCM＝1:10)洗涤滤饼，得到的滤液浓缩后，通过反向柱层析纯化，得到化合物66-3，0.10g，为淡黄色固体，收率44％。LC-MS(ESI)m/z:220[M+H]+.LiAlH 4 (1.7 mL, 2.5 M in THF) was added dropwise to tetrahydrofuran (3 mL) containing compound 66-2 (0.25 g, 1.1 mmol) at 0°C, and the temperature was raised to 80°C and stirred overnight. After the reaction was completed by LC-MS detection, ice water was added to the reaction solution to quench, filtered through diatomaceous earth, and the filter cake was washed with a mixed solution of methanol/dichloromethane (MeOH:DCM=1:10). After the filtrate was concentrated, it was purified by reverse column chromatography to obtain compound 66-3, 0.10 g, as a light yellow solid, with a yield of 44%. LC-MS (ESI) m/z: 220 [M+H] + .
步骤四：化合物66-4的合成Step 4: Synthesis of compound 66-4
取化合物2-氟-4-氯苯甲酰胺(180mg,1.0mmol)溶于1，2-二氯乙烷(5mL)中，在氮气保护下在0℃下缓慢滴加草酰氯(0.2mL，1.6mmol),滴加完毕后，加热到55℃，搅拌1小时，然后升温到80℃，搅拌过夜，TLC显示反应完全。反应混合物冷却至室温后，在旋转蒸发仪上蒸除溶剂和过量草酰氯，得到白色固体混合物。将得到的固体混合物溶于二氯乙烷(1mL)，在氮气保护下在0℃下将该溶液缓慢滴加到化合物3的二氯乙烷(1mL)中，滴加完毕后，室温反应2小时，直至大量白色固体析出，过滤、干燥，得到化合物66-4，0.11g，收率36％，其为白色固体。LC-MS(ESI)m/z:618[M+H]+.Compound 2-fluoro-4-chlorobenzamide (180 mg, 1.0 mmol) was dissolved in 1,2-dichloroethane (5 mL), and oxalyl chloride (0.2 mL, 1.6 mmol) was slowly added dropwise at 0 ° C under nitrogen protection. After the addition was completed, it was heated to 55 ° C and stirred for 1 hour, then heated to 80 ° C and stirred overnight. TLC showed that the reaction was complete. After the reaction mixture was cooled to room temperature, the solvent and excess oxalyl chloride were evaporated on a rotary evaporator to obtain a white solid mixture. The obtained solid mixture was dissolved in dichloroethane (1 mL), and the solution was slowly added dropwise to the dichloroethane (1 mL) of compound 3 at 0 ° C under nitrogen protection. After the addition was completed, the reaction was reacted at room temperature for 2 hours until a large amount of white solid precipitated, filtered and dried to obtain compound 66-4, 0.11 g, with a yield of 36%, which was a white solid. LC-MS (ESI) m/z: 618 [M + H] + .
步骤五：化合物66-5的合成 Step 5: Synthesis of compound 66-5
含有取化合物66-4(70mg，0.11mmol)溶于DMF(2.5mL)溶液中，在氮气保护下在0℃下加入NaH(27mg，60％石蜡)，加热到70℃，反应3小时。反应结束后，冷却至室温，向反应液中加过量的水淬灭反应，用稀盐酸调节反应液的pH值至中性，大量白色固体析出，过滤得到固体，干燥，得到化合物66-5，50mg，收率77％，为白色固体。LC-MS(ESI)m/z:578[M+H]+.Compound 66-4 (70 mg, 0.11 mmol) was dissolved in DMF (2.5 mL) solution, and NaH (27 mg, 60% paraffin) was added at 0°C under nitrogen protection, and heated to 70°C for 3 hours. After the reaction was completed, it was cooled to room temperature, and an excess of water was added to the reaction solution to quench the reaction. The pH value of the reaction solution was adjusted to neutral with dilute hydrochloric acid, and a large amount of white solid precipitated. The solid was filtered and dried to obtain compound 66-5, 50 mg, with a yield of 77%, as a white solid. LC-MS (ESI) m/z: 578 [M + H] + .
步骤六：化合物66的合成Step 6: Synthesis of compound 66
将化合物66-5(30mg，0.052mmol)分散到乙腈(2mL)中，在氮气氛围在0℃下分别滴加DIEA(0.1mL)和POCl3(0.05mL)，升温到80℃回流4小时。待TLC显示反应完全后，将反应液降温至室温，在旋转蒸发仪上蒸除溶剂，得到固体混合物。在室温下向该固体混合物中迅速加入二甲胺的四氢呋喃溶液(2.5mL，2M in THF)，室温搅拌。反应结束后，在旋转蒸发仪上蒸除溶剂，得到油状物。将该油状物溶解在甲醇和二氯甲烷的混合液中，通过pre-TLC纯化(MeOH:DCM＝1:10)，再通过高效液相色谱纯化，得到化合物66，4.1mg,收率13％，为白色固体。LC-MS(ESI)m/z:316.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.74(d,J＝2.1Hz,1H),8.48(d,J＝2.3Hz,1H),8.05(d,J＝8.8Hz,1H),7.99(d,J＝8.8Hz,1H),7.90(t,J＝2.2Hz,1H),7.67(d,J＝2.0Hz,1H),7.25-7.19(m,2H),7.15(s,1H),6.51(d,J＝2.1Hz,1H),5.46(s,2H),3.31(s,6H),3.25(s,6H),2.27(s,3H).Compound 66-5 (30 mg, 0.052 mmol) was dispersed in acetonitrile (2 mL), and DIEA (0.1 mL) and POCl 3 (0.05 mL) were added dropwise at 0°C under a nitrogen atmosphere, and the mixture was heated to 80°C and refluxed for 4 hours. After TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, and the solvent was evaporated on a rotary evaporator to obtain a solid mixture. A tetrahydrofuran solution of dimethylamine (2.5 mL, 2M in THF) was quickly added to the solid mixture at room temperature and stirred at room temperature. After the reaction was completed, the solvent was evaporated on a rotary evaporator to obtain an oily substance. The oily substance was dissolved in a mixture of methanol and dichloromethane, purified by pre-TLC (MeOH:DCM=1:10), and then purified by HPLC to obtain compound 66, 4.1 mg, yield 13%, as a white solid. LC-MS (ESI) m/z: 316.6 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.74 (d, J = 2.1Hz, 1H), 8.48 (d, J = 2.3Hz, 1H), 8.05 (d, J = 8.8Hz, 1H), 7.99 (d, J = 8.8Hz, 1H), 7.90 ( t,J＝2.2Hz,1H),7.67(d,J＝2.0Hz,1H),7.25-7.19(m,2H),7.15(s,1H),6.51(d,J＝2.1Hz,1H),5.46(s,2H),3.31(s,6H),3.25(s,6H),2.27(s,3H).
实施例67
Embodiment 67
合成方法Synthesis method
化合物67的合成方法参照实施例62，区别在于把步骤一中的2-氨基-6-溴吡啶替换为2-溴-4-氨基吡啶。LC-MS(ESI)m/z:301.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.67(d,J＝5.3Hz,1H),8.53(s,1H),8.06(d,J＝8.7Hz,1H),7.97(d,J＝8.7Hz,1H),7.93(s,1H),7.81(s,1H),7.63(d,J＝2.1Hz,1H),7.38(d,J＝5.3Hz,1H),7.25(dd,J＝8.8,2.1Hz,1H),7.18(dd,J＝8.7,2.0Hz,1H),6.66(d,J＝2.1Hz,1H),5.22(s,2H),3.32(s,6H),3.24(s,6H).The synthesis method of compound 67 is similar to that of Example 62, except that 2-amino-6-bromopyridine in step 1 is replaced by 2-bromo-4-aminopyridine. LC-MS (ESI) m/z: 301.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.67(d,J＝5.3Hz,1H),8.53(s,1H),8.06(d,J＝8.7Hz,1H),7.97(d,J＝8.7Hz,1H),7.93(s,1H),7.81(s,1H),7.63(d,J＝2.1Hz,1H),7.38(d,J＝5.3Hz,1H ),7.25(dd,J＝8.8,2.1Hz,1H),7.18(dd,J＝8.7,2.0Hz,1H),6.66(d,J＝2.1Hz,1H),5.22(s,2H),3.32(s,6H),3.24(s,6H).
实施例68
Embodiment 68
合成路线
Synthetic route
步骤一：化合物68-1的合成Step 1: Synthesis of compound 68-1
室温下将5-溴-3-氨基吡啶(5.0g，28.90mmol)、双联频哪醇硼酸酯(29.4g，115.61mmol)和醋酸钾(8.1g，86.71mmol)溶解在50mL 1,4-二氧六环中，加入[1,1’-双(二苯基磷)二茂铁]二氯化钯二氯甲烷络合物(1.2g，1.45mmol)，氮气保护下升温至100℃搅拌过夜。TLC监测完全反应，加石油醚(80mL×3)后过滤除去剩余的双联频哪醇硼酸酯，滤渣用二氯甲烷/甲醇＝10:1的溶液100mL溶解过滤除去剩余的醋酸钾。滤液浓缩后用乙酸乙酯100mL打浆。过滤后即为化合物68-1，4.6g，灰色固体，不经纯化处理直接用于后续反应。LC-MS(ESI)m/z:139[M+H]+.5-Bromo-3-aminopyridine (5.0 g, 28.90 mmol), bis-pinacol borate (29.4 g, 115.61 mmol) and potassium acetate (8.1 g, 86.71 mmol) were dissolved in 50 mL of 1,4-dioxane at room temperature, and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (1.2 g, 1.45 mmol) was added. The mixture was heated to 100 °C and stirred overnight under nitrogen protection. TLC monitored the complete reaction, and petroleum ether (80 mL × 3) was added and the remaining bis-pinacol borate was removed by filtration. The residue was dissolved in 100 mL of a solution of dichloromethane/methanol = 10:1 and the remaining potassium acetate was removed by filtration. The filtrate was concentrated and slurried with 100 mL of ethyl acetate. After filtration, compound 68-1, 4.6 g, was obtained as a gray solid, which was directly used in subsequent reactions without purification. LC-MS (ESI) m/z: 139 [M+H] + .
步骤二：化合物68-2的合成Step 2: Synthesis of compound 68-2
室温下将2-溴噻唑-4-羧酸甲酯(4.0g，18.02mmol)溶解在50mL胺-甲醇溶液中，室温下搅拌4小时。TLC监测完全反应，减压旋蒸浓缩后所得固体即为化合物68-2，3.6g，产率97％，黄色固体，化合物68-2无需纯化直接用于下一步反应。LC-MS(ESI)m/z:207[M+H]+.Methyl 2-bromothiazole-4-carboxylate (4.0 g, 18.02 mmol) was dissolved in 50 mL of amine-methanol solution at room temperature and stirred at room temperature for 4 hours. TLC monitored the complete reaction. The solid obtained after vacuum rotary evaporation was compound 68-2, 3.6 g, yield 97%, yellow solid. Compound 68-2 was used directly in the next step without purification. LC-MS (ESI) m/z: 207 [M+H] + .
步骤三：化合物68-3的合成Step 3: Synthesis of compound 68-3
室温下，将化合物68-2(1.0mg，4.86mmol)溶解在10mL二氯甲烷中，向其中加入三乙胺(1.8mL)后降温至0℃，逐滴加入三氟乙酸酐(0.8mL)，室温下搅拌2小时。TLC监测完全反应，反应体系中加饱和碳酸氢钠溶液(4mL)淬灭，用二氯甲烷(20mL×3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-50％，15min)，浓缩后即为化合物68-3，846mg，产率92％，淡黄色固体。LC-MS(ESI)m/z:189[M+H]+.At room temperature, compound 68-2 (1.0 mg, 4.86 mmol) was dissolved in 10 mL of dichloromethane, triethylamine (1.8 mL) was added thereto, the temperature was lowered to 0°C, trifluoroacetic anhydride (0.8 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. TLC monitored the complete reaction, saturated sodium bicarbonate solution (4 mL) was added to the reaction system to quench, and the mixture was extracted with dichloromethane (20 mL × 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 0-50%, 15 min), and after concentration, it was compound 68-3, 846 mg, 92% yield, and a light yellow solid. LC-MS (ESI) m/z: 189 [M + H] + .
步骤四：化合物68-4的合成Step 4: Synthesis of compound 68-4
室温下化合物68-3(500mg，2.66mmol)、化合物68-1(1.1g，7.98mmol)、碳酸钠(845mg，7.98mmol)溶解在5mL四氢呋喃中，向其中加入水(1.25mL)和四三苯基膦钯(307mg，0.27mmol)，氮气保护下升温至70℃搅拌过夜。TLC监测完全反应，加入水(10mL)后用乙酸乙酯(20mL×3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)，浓缩后即为化合物68-4，487mg，产率91％，淡黄色固体。LC-MS(ESI)m/z:203[M+H]+. Compound 68-3 (500 mg, 2.66 mmol), compound 68-1 (1.1 g, 7.98 mmol), and sodium carbonate (845 mg, 7.98 mmol) were dissolved in 5 mL of tetrahydrofuran at room temperature, and water (1.25 mL) and tetrakistriphenylphosphine palladium (307 mg, 0.27 mmol) were added thereto. The temperature was raised to 70 ° C and stirred overnight under nitrogen protection. TLC monitored the complete reaction, and after adding water (10 mL), it was extracted with ethyl acetate (20 mL×3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and after concentration, it was compound 68-4, 487 mg, with a yield of 91%, and a light yellow solid. LC-MS (ESI) m/z: 203 [M+H] + .
步骤五：化合物68-5的合成Step 5: Synthesis of compound 68-5
室温下将化合物68-4(487mg，2.41mmol)溶解在10mL胺-甲醇溶液中，向其中加入雷尼镍，氢气气氛中室温搅拌4小时。TLC监测完全反应，过滤除去雷尼镍，粗产品经过C18柱层析(乙腈：水，5-95％，15min)，减压旋蒸浓缩后所得固体即为化合物68-5，140mg，产率28％，淡黄色油状。LC-MS(ESI)m/z:207[M+H]+.Compound 68-4 (487 mg, 2.41 mmol) was dissolved in 10 mL of amine-methanol solution at room temperature, and Raney nickel was added thereto. The mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. The reaction was completely monitored by TLC, and the Raney nickel was removed by filtration. The crude product was chromatographed on a C18 column (acetonitrile: water, 5-95%, 15 min), and the solid obtained after vacuum rotary evaporation concentration was compound 68-5, 140 mg, yield 28%, light yellow oil. LC-MS (ESI) m/z: 207 [M+H] + .
步骤六：化合物68-6的合成Step 6: Synthesis of compound 68-6
0℃下将草酰氯(460mg，4.06mmol)滴加到4-氯-2-氟苯甲酰胺(320mg，2.03mmol)的二氯乙烷DCE(5mL)中。氮气保护下，反应混合液在70℃搅拌过夜，减压旋蒸除去多余的草酰氯后，用DCE(2mL)稀释后滴入化合物68-5(140mg，0.67mmol)的DCE(3mL)体系中，反应在室温下搅拌3小时。TLC监测完全反应。反应体系加入乙腈打浆，过滤后固体即为化合物68-6，299mg，产率74％，白色固体。LC-MS(ESI)m/z:604[M+H]+.Oxalyl chloride (460 mg, 4.06 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (320 mg, 2.03 mmol) in dichloroethane (5 mL) at 0 ° C. Under nitrogen protection, the reaction mixture was stirred at 70 ° C overnight, and the excess oxalyl chloride was removed by vacuum rotary evaporation. After dilution with DCE (2 mL), it was added dropwise to the DCE (3 mL) system of compound 68-5 (140 mg, 0.67 mmol), and the reaction was stirred at room temperature for 3 hours. TLC monitored the complete reaction. Acetonitrile was added to the reaction system for slurrying, and the solid after filtration was compound 68-6, 299 mg, yield 74%, white solid. LC-MS (ESI) m/z: 604 [M + H] + .
步骤七：化合物68-7的合成Step 7: Synthesis of compound 68-7
0℃下将氢化钠(102mg，2.48mmol)加入到化合物68-6(299mg，0.50mmol)的N,N-二甲基甲酰胺DMF(5mL)中，氮气保护下，升温至90℃搅拌3小时。LC-MS检测原料基本消失。反应体系加水淬灭，滴加稀盐酸(0.5mol/L)至pH为中性，过滤后固体用乙腈打浆，再次过滤后固体即为化合物68-7，246mg，产率87％，白色固体。LC-MS(ESI)m/z:564[M+H]+.Sodium hydride (102 mg, 2.48 mmol) was added to compound 68-6 (299 mg, 0.50 mmol) in DMF (5 mL) at 0 °C, and the mixture was heated to 90 °C and stirred for 3 hours under nitrogen protection. LC-MS detected that the raw material was basically gone. The reaction system was quenched with water, and dilute hydrochloric acid (0.5 mol/L) was added dropwise until the pH was neutral. After filtering, the solid was slurried with acetonitrile, and the solid was filtered again to obtain compound 68-7, 246 mg, with a yield of 87%, as a white solid. LC-MS (ESI) m/z: 564 [M+H] + .
步骤八：化合物68的合成Step 8: Synthesis of compound 68
0℃下将三氯氧磷(0.8mL)加入到化合物68-7(60mg，0.11mmol)和N,N-二异丙基乙胺(0.8mL)的乙腈ACN(4mL)溶液中。在氮气保护下，反应混合液在90℃下反应4小时，减压旋蒸去除多余的三氯氧磷。将二甲胺的四氢呋喃溶液(4mL)中滴入除去三氯氧磷的反应体系中，室温下搅拌30分钟。LC-MS检测完全反应。二氯甲烷/甲醇溶解后经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，经HPLC纯化后得到化合物68，20.57mg，产率30％，淡黄色固体。LC-MS(ESI)m/z:310.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ9.21(d,J＝2.0Hz,1H),8.64(d,J＝2.2Hz,1H),8.32(t,J＝2.2Hz,1H),8.08(d,J＝8.8Hz,1H),7.98(d,J＝8.9Hz,1H),7.68(d,J＝2.0Hz,1H),7.59(s,1H),7.25(dd,J＝8.8,2.1Hz,1H),7.18(dd,J＝8.8,2.0Hz,1H),6.59(d,J＝2.1Hz,1H),5.45(s,2H),3.37(s,6H),3.26(s,6H).Phosphorus oxychloride (0.8 mL) was added to a solution of compound 68-7 (60 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 hours, and the excess phosphorus oxychloride was removed by vacuum rotary evaporation. A tetrahydrofuran solution of dimethylamine (4 mL) was added dropwise to the reaction system where phosphorus oxychloride was removed, and stirred at room temperature for 30 minutes. LC-MS detected the complete reaction. After dissolving in dichloromethane/methanol, the crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 68 was obtained after HPLC purification, 20.57 mg, 30% yield, and a light yellow solid. LC-MS (ESI) m/z: 310.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ9.21(d,J＝2.0Hz,1H),8.64(d,J＝2.2Hz,1H),8.32(t,J＝2.2Hz,1H),8.08(d,J＝8.8Hz,1H),7.98(d,J＝8.9Hz,1H),7.68(d,J＝2.0Hz,1H),7.59(s,1H),7. 25(dd,J＝8.8,2.1Hz,1H),7.18(dd,J＝8.8,2.0Hz,1H),6.59(d,J＝2.1Hz,1H),5.45(s,2H),3.37(s,6H),3.26(s,6H).
实施例69
Embodiment 69
合成方法Synthesis methods
化合物69的合成方法参照实施例68，区别在于把步骤八中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:324.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ9.21(d,J＝2.0Hz,1H),8.65(d,J＝2.3Hz,1H),8.32(t,J＝2.2Hz,1H),8.01(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.69(d,J＝2.0Hz,1H),7.58(s,1H),7.26(dd,J＝8.8,2.1Hz,1H),7.18(dd,J＝8.8,2.0Hz,1H),6.59(d,J＝2.1Hz,1H),5.44(s,2H),3.74(q,J＝7.0Hz,2H),3.65(q,J＝7.0Hz,2H),3.37(s,3H),3.24(s,3H),1.33(t,J＝7.0Hz,3H),1.27(t,J＝7.0Hz,3H). The synthesis method of compound 69 refers to Example 68, except that dimethylamine in step eight is replaced by methylethylamine. LC-MS (ESI) m/z: 324.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ9.21 (d, J=2.0 Hz, 1H), 8.65 (d, J=2.3 Hz, 1H), 8.32 (t, J=2.2 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.58 (s, 1H), 7.26 (dd, J=8.8, 2.1 Hz, 1H), 7.18(dd,J＝8.8,2.0Hz,1H),6.59(d,J＝2.1Hz,1H),5.44(s,2H),3.74(q,J＝7.0Hz,2H),3.65(q,J＝7.0Hz,2H),3.37(s,3H),3.24(s,3H),1.33(t,J＝7.0 Hz,3H),1.27(t,J=7.0Hz,3H).
实施例70
Embodiment 70
合成方法Synthesis methods
化合物70的合成方法参照实施例68，区别在于把步骤八中的二甲胺替换为甲胺。LC-MS(ESI)m/z:296.0[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ9.21(d,J＝2.0Hz,1H),8.77(q,J＝4.8Hz,1H),8.63(d,J＝2.2Hz,1H),8.56(q,J＝4.6Hz,1H),8.32(t,J＝2.1Hz,1H),8.15(d,J＝8.7Hz,1H),8.08(d,J＝8.7Hz,1H),7.62(d,J＝1.9Hz,1H),7.54(s,1H),7.33(dd,J＝8.7,1.9Hz,1H),7.26(dd,J＝8.6,1.8Hz,1H),6.57(d,J＝1.9Hz,1H),5.47(s,2H),3.00(d,J＝4.4Hz,3H),2.95(d,J＝4.4Hz,3H).The synthesis method of compound 70 refers to Example 68, except that dimethylamine in step eight is replaced by methylamine. LC-MS (ESI) m/z: 296.0 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ9.21 (d, J=2.0 Hz, 1H), 8.77 (q, J=4.8 Hz, 1H), 8.63 (d, J=2.2 Hz, 1H), 8.56 (q, J=4.6 Hz, 1H), 8.32 (t, J=2.1 Hz, 1H), 8.15 (d, J=8.7 Hz, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.62 ( d,J＝1.9Hz,1H),7.54(s,1H),7.33(dd,J＝8.7,1.9Hz,1H),7.26(dd,J＝8.6,1.8Hz,1H),6.57(d,J＝1.9Hz,1H),5.47(s,2H),3.00(d,J＝4.4Hz,3H),2.95(d, J＝4.4Hz,3H).
实施例71
Embodiment 71
合成方法Synthesis methods
化合物71的合成方法参照实施例46，区别在于把步骤五中的甲乙胺替换为二甲胺。LC-MS(ESI)m/z:279.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.10(d,J＝8.1Hz,1H),8.03(d,J＝8.8Hz,1H),7.53-7.47(m,1H),7.26(d,J＝8.1Hz,1H),7.19(dd,J＝8.8,2.0Hz,1H),7.11-7.07(m,1H),6.90(t,J＝1.9Hz,1H),6.86(d,J＝7.7Hz,1H),6.42(s,2H),6.38(dd,J＝8.3,1.9Hz,1H),4.11(t,J＝6.2Hz,2H),3.30(s,6H),2.21(qd,J＝7.9,4.0Hz,1H),2.16-2.10(m,2H),2.08(s,2H),1.06-0.96(m,4H).The synthesis method of compound 71 refers to Example 46, except that methylethylamine in step 5 is replaced by dimethylamine. LC-MS (ESI) m/z: 279.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.10 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.53-7.47 (m, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.19 (dd, J = 8.8, 2.0 Hz, 1H), 7.11-7.07 (m, 1H), 6.90 (t, J = 1.9 Hz, 1H), 6.86 (d, J = 2. ＝7.7Hz,1H),6.42(s,2H),6.38(dd,J＝8.3,1.9Hz,1H),4.11(t,J＝6.2Hz,2H),3.30(s,6H),2.21(qd,J＝7.9,4.0Hz,1H),2.16-2.10(m,2H),2.08(s,2H) ,1.06-0.96(m,4H).
实施例72
Embodiment 72
合成路线
Synthetic route
步骤一：化合物72-1的合成Step 1: Synthesis of compound 72-1
室温下将5-溴-3-氨基吡啶(5.0g，28.90mmol)、双联频哪醇硼酸酯(29.4g，115.61mmol)和醋酸钾(8.1g，86.71mmol)溶解在50mL 1,4-二氧六环中，加入[1,1’-双(二苯基磷)二茂铁]二氯化钯二氯甲烷络合物(1.2g，1.45mmol)，氮气保护下升温至100℃搅拌过夜。TLC监测完全反应，加石油醚(80mL×3)后过滤除去剩余的双联频哪醇硼酸酯，滤渣用二氯甲烷/甲醇＝10:1的溶液100mL溶解过滤除去剩余的醋酸钾。滤液浓缩后用乙酸乙酯100mL打浆。过滤后即为化合物72-1，4.6g，灰色固体，不经纯化处理直接用于后续反应。LC-MS(ESI)m/z:139[M+H]+.5-Bromo-3-aminopyridine (5.0 g, 28.90 mmol), bis-pinacol borate (29.4 g, 115.61 mmol) and potassium acetate (8.1 g, 86.71 mmol) were dissolved in 50 mL of 1,4-dioxane at room temperature, and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (1.2 g, 1.45 mmol) was added. The mixture was heated to 100 °C and stirred overnight under nitrogen protection. TLC monitored the complete reaction, and petroleum ether (80 mL × 3) was added and the remaining bis-pinacol borate was filtered out. The residue was dissolved in 100 mL of a solution of dichloromethane/methanol = 10:1 and the remaining potassium acetate was removed by filtration. The filtrate was concentrated and slurried with 100 mL of ethyl acetate. After filtration, compound 72-1, 4.6 g, was obtained as a gray solid, which was directly used in subsequent reactions without purification. LC-MS (ESI) m/z: 139 [M+H] + .
步骤二：化合物72-2的合成Step 2: Synthesis of compound 72-2
室温下将2-溴噻唑-5-羧酸乙酯(5.0g，21.18mmol)溶解在50mL胺-甲醇溶液中，室温下搅拌4h。TLC监测完全反应，减压浓缩后得到化合物72-2(4.5g，黄色固体)，无需纯化直接用于下一步反应，产率100％。LC-MS(ESI)m/z:207[M+H]+。Ethyl 2-bromothiazole-5-carboxylate (5.0 g, 21.18 mmol) was dissolved in 50 mL of amine-methanol solution at room temperature and stirred at room temperature for 4 h. The reaction was completed by TLC monitoring. After concentration under reduced pressure, compound 72-2 (4.5 g, yellow solid) was obtained, which was directly used in the next step without purification, with a yield of 100%. LC-MS (ESI) m/z: 207 [M+H] + .
步骤三：化合物72-3的合成Step 3: Synthesis of compound 72-3
室温下，将化合物72-2(4.5g，21.74mmol)溶解在50mL二氯甲烷中，向其中加入三乙胺11.3mL后降温至0℃，逐滴加入三氟乙酸酐5.0mL，室温下搅拌2h。TLC监测完全反应，反应体系中加饱和碳酸氢钠溶液40mL淬灭，用二氯甲烷(80mL x3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-50％，15min)得到化合物3(4.1g，淡黄色固体)，产率99％。LC-MS(ESI)m/z:189[M+H]+.At room temperature, compound 72-2 (4.5 g, 21.74 mmol) was dissolved in 50 mL of dichloromethane, 11.3 mL of triethylamine was added thereto, and the temperature was lowered to 0 ° C. 5.0 mL of trifluoroacetic anhydride was added dropwise, and the mixture was stirred at room temperature for 2 h. TLC monitored the complete reaction, 40 mL of saturated sodium bicarbonate solution was added to the reaction system to quench, and the mixture was extracted with dichloromethane (80 mL x3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate, 0-50%, 15 min) to obtain compound 3 (4.1 g, light yellow solid) with a yield of 99%. LC-MS (ESI) m/z: 189 [M + H] + .
步骤四：化合物72-4的合成Step 4: Synthesis of compound 72-4
室温下化合物72-3(4.1g，21.69mmol)、化合物72-1(3.3g，23.86mmol)、碳酸钠(6.9g，65.07mmol)溶解在50mL四氢呋喃中，向其中加入水(12.5mL)和四三苯基膦钯(1.2g，1.08mmol)，氮气保护下升温至70℃搅拌过夜。TLC监测完全反应，加入水60mL后用乙酸乙酯(100mLx3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)得到化合物72-4(2.1g，红色固体)，产率48％。LC-MS(ESI)m/z:203[M+H]+.Compound 72-3 (4.1 g, 21.69 mmol), compound 72-1 (3.3 g, 23.86 mmol), and sodium carbonate (6.9 g, 65.07 mmol) were dissolved in 50 mL of tetrahydrofuran at room temperature, water (12.5 mL) and tetrakistriphenylphosphine palladium (1.2 g, 1.08 mmol) were added thereto, and the mixture was heated to 70 ° C and stirred overnight under nitrogen protection. TLC monitored the complete reaction, and after adding 60 mL of water, it was extracted with ethyl acetate (100 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min) to obtain compound 72-4 (2.1 g, red solid) with a yield of 48%. LC-MS (ESI) m/z: 203 [M + H] + .
步骤五：化合物72-5的合成 Step 5: Synthesis of compound 72-5
室温下将化合物72-4(2.1g，10.34mmol)溶解在20mL胺-甲醇溶液中，向其中加入雷尼镍，氢气气氛下室温搅拌4h。TLC监测完全反应，过滤除去雷尼镍，粗产品经过C18柱层析(乙腈：水，5-95％，15min)得到化合物72-5(1.8g，淡黄色油状)，产率84％。LC-MS(ESI)m/z:207[M+H]+.Compound 72-4 (2.1 g, 10.34 mmol) was dissolved in 20 mL of amine-methanol solution at room temperature, and Raney nickel was added thereto, and stirred at room temperature for 4 h under hydrogen atmosphere. TLC monitored the complete reaction, filtered to remove Raney nickel, and the crude product was chromatographed on a C18 column (acetonitrile: water, 5-95%, 15 min) to obtain compound 72-5 (1.8 g, light yellow oil), with a yield of 84%. LC-MS (ESI) m/z: 207 [M+H] + .
步骤六：化合物72-6的合成Step 6: Synthesis of compound 72-6
0℃下将草酰氯(5.9g，52.14mmol)滴加到4-氯-2-氟苯甲酰胺(4.1g，26.07mmol)的二氯乙烷DCE(50mL)中。氮气保护下，反应混合液在70℃搅拌过夜，减压除去多余的草酰氯后，用DCE(20mL)稀释后滴入化合物72-5(1.8g，8.69mmol)的DCE(20mL)体系中，反应在室温下搅拌3h。TLC监测完全反应。反应体系加入乙腈打浆，过滤后得到化合物72-6(2.7g，红色固体)，产率51％。LC-MS(ESI)m/z:605[M+H]+.Oxalyl chloride (5.9 g, 52.14 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (4.1 g, 26.07 mmol) in dichloroethane (DCE) (50 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride under reduced pressure, it was diluted with DCE (20 mL) and then added dropwise to the DCE (20 mL) system of compound 72-5 (1.8 g, 8.69 mmol), and the reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction. Acetonitrile was added to the reaction system for slurrying, and compound 72-6 (2.7 g, red solid) was obtained after filtration with a yield of 51%. LC-MS (ESI) m/z: 605 [M+H] + .
步骤七：化合物72-7的合成Step 7: Synthesis of compound 72-7
0℃下将氢化钠(0.9g，22.30mmol)加入到化合物72-6(2.7g，4.46mmol)的N,N-二甲基甲酰胺DMF(30mL)中，氮气保护下，升温至90℃搅拌3h。LC-MS检测原料基本消失。反应体系加水淬灭，滴加稀盐酸(0.5mol/L)至pH为中性，过滤后固体用乙腈打浆，再次过滤后得到化合物72-7(2.1g，淡红色固体)，产率83％。LC-MS(ESI)m/z:565[M+H]+.Sodium hydride (0.9 g, 22.30 mmol) was added to compound 72-6 (2.7 g, 4.46 mmol) in DMF (30 mL) at 0 °C, and the mixture was heated to 90 °C and stirred for 3 h under nitrogen protection. LC-MS detected that the raw material was basically gone. The reaction system was quenched with water, and dilute hydrochloric acid (0.5 mol/L) was added dropwise until the pH was neutral. After filtration, the solid was slurried with acetonitrile and filtered again to obtain compound 72-7 (2.1 g, light red solid) with a yield of 83%. LC-MS (ESI) m/z: 565 [M+H] + .
步骤八：化合物72的合成Step 8: Synthesis of Compound 72
0℃下将三氯氧磷(0.8mL)加入到化合物72-7(60mg，0.11mmol)和N,N-二异丙基乙胺(0.8mL)的乙腈ACN(4mL)溶液中。在氮气保护下，反应混合液在90℃下反应4h，减压去除多余的三氯氧磷。将氘代二甲胺的四氢呋喃溶液(4mL)中滴入除去三氯氧磷的反应体系中，室温下搅拌30min。LC-MS检测完全反应。二氯甲烷/甲醇溶解后经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，经HPLC纯化后得到化合物72(3.61mg，白色固体)，产率10.42％。LC-MS(ESI)m/z:316.1[M/2+H]+。1H NMR(600MHz,DMSO-d6)δ9.17(d,J＝2.0Hz,1H),8.61(dd,J＝9.7,2.2Hz,1H),8.32(dd,J＝11.9,2.1Hz,1H),8.21(t,J＝9.0,7.2Hz,2H),8.00(d,J＝8.4Hz,1H),7.98(d,J＝8.7,1.8Hz,1H),7.79(d,J＝2.1Hz,1H),7.36–7.31(m,1H),6.53(t,J＝2.5Hz,1H),5.56(s,2H).Phosphorus oxychloride (0.8 mL) was added to a solution of compound 72-7 (60 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 h, and the excess phosphorus oxychloride was removed under reduced pressure. A tetrahydrofuran solution of deuterated dimethylamine (4 mL) was added dropwise to the reaction system in which phosphorus oxychloride was removed, and stirred at room temperature for 30 min. LC-MS detected the complete reaction. After dissolving in dichloromethane/methanol, the crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 72 (3.61 mg, white solid) was obtained after purification by HPLC with a yield of 10.42%. LC-MS (ESI) m/z: 316.1 [M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ9.17(d,J＝2.0Hz,1H),8.61(dd,J＝9.7,2.2Hz,1H),8.32(dd,J＝11.9,2.1Hz,1H),8.21(t,J＝9.0,7.2Hz,2H),8.00(d,J＝8.4Hz,1H), 7.98(d,J＝8.7,1.8Hz,1H),7.79(d,J＝2.1Hz,1H),7.36–7.31(m,1H),6.53(t,J＝2.5Hz,1H),5.56(s,2H).
实施例73
Embodiment 73
合成方法Synthesis methods
化合物73的合成方法参照实施例62，区别在于把步骤一中的2-氨基-6-溴吡啶替换为4-氨基-6-溴嘧啶。LC-MS(ESI)m/z:302.1[M/2+H]+。1H NMR(600MHz,DMSO-d6)δ9.18(d,J＝1.1Hz,1H),8.71(d,J＝1.4Hz,1H),8.15(d,J＝1.1Hz,1H),8.07(d,J＝8.8Hz,1H),7.97(d,J＝8.8Hz,1H),7.89(d,J＝1.3Hz,1H),7.57(d,J＝2.1Hz,1H),7.27(dd,J＝8.8,2.0Hz,1H),7.19(dd,J＝8.8,2.0Hz,1H),6.96(d,J＝2.0Hz,1H),5.25(s,2H),3.32(s,6H),3.25(s,6H).The synthesis method of compound 73 is similar to that of Example 62, except that 2-amino-6-bromopyridine in step 1 is replaced by 4-amino-6-bromopyrimidine. LC-MS (ESI) m/z: 302.1 [M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ9.18 (d, J = 1.1Hz, 1H), 8.71 (d, J = 1.4Hz, 1H), 8.15 (d, J = 1.1Hz, 1H), 8.07 (d, J = 8.8Hz, 1H), 7.97 (d, J = 8.8Hz, 1H), 7.89 (d, J = 1.3Hz, 1H),7.57(d,J＝2.1Hz,1H),7.27(dd,J＝8.8,2.0Hz,1H),7.19(dd,J＝8.8,2.0Hz,1H),6.96(d,J＝2.0Hz,1H),5.25(s,2H),3.32(s,6H),3.25(s,6H).
实施例74
Embodiment 74
合成方法Synthesis methods
化合物74的合成方法参照实施例47，区别在于把步骤五中的二甲胺替换为氮杂环丁烷。LC-MS(ESI)m/z:321.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.93(d,J＝2.2Hz,1H),8.39(d,J＝2.2Hz,1H),8.04(t,J＝2.2Hz,1H),7.84(d,J＝8.7Hz,1H),7.77(d,J＝8.8Hz,1H),7.66(d,J＝2.0Hz,1H),7.58(d,J＝3.7Hz,1H),7.31(d,J＝3.7Hz,1H),7.24-7.18(m,3H),5.52(s,2H),5.37-5.29(m,2H),4.95-4.01(m,8H),3.26-3.20(m,2H).The synthesis method of compound 74 is similar to that of Example 47, except that dimethylamine in step 5 is replaced by azetidine. LC-MS (ESI) m/z: 321.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.93(d,J＝2.2Hz,1H),8.39(d,J＝2.2Hz,1H),8.04(t,J＝2.2Hz,1H),7.84(d,J＝8.7Hz,1H),7.77(d,J＝8.8Hz,1H),7.66(d,J＝2.0Hz,1H),7.58(d,J＝3.7Hz ,1H),7.31(d,J＝3.7Hz,1H),7.24-7.18(m,3H),5.52(s,2H),5.37-5.29(m,2H),4.95-4.01(m,8H),3.26-3.20(m,2H).
实施例75
Embodiment 75
合成方法
Synthesis method
将NaH(5.5mg，0.23mmol)在0℃下分批缓慢加入到化合物71(30mg，0.05mmol)的DMF(0.5mL)溶液中，氮气条件下室温搅拌半小时后，将碘甲烷(23mg，0.16mmol)滴加进反应液中，继续室温搅拌一小时后TCL检测反应完全。后处理：反应液滴加入冰水中淬灭，用乙酸乙酯50mL萃取三次，有机相用饱和食盐水洗一次，无水硫酸钠干燥有机相后浓缩经HPLC纯化得化合物75，(8mg，收率27％)，LC-MS(ESI)m/z:293.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,2H),7.48-7.40(m,1H),7.20(dd,J＝8.8,2.1Hz,1H),7.15(d,J＝6.5Hz,1H),6.94(s,1H),6.83(d,J＝7.4Hz,1H),6.75(s,1H),6.40-6.35(m,1H),3.92(s,2H),3.34(s,6H),3.30(s,6H),2.23(dd,J＝12.4,6.2Hz,2H),1.91(s,1H),1.24(s,2H),1.04(d,J＝6.4Hz,4H).NaH (5.5 mg, 0.23 mmol) was slowly added to a DMF (0.5 mL) solution of compound 71 (30 mg, 0.05 mmol) in batches at 0°C. After stirring at room temperature for half an hour under nitrogen, iodomethane (23 mg, 0.16 mmol) was added dropwise to the reaction solution. Stirring at room temperature for one hour was continued. The reaction was complete as detected by TCL. Post-treatment: The reaction solution was added dropwise to ice water for quenching, extracted three times with 50 mL of ethyl acetate, the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by HPLC to obtain compound 75 (8 mg, yield 27%), LC-MS (ESI) m/z: 293.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.03(d,J＝8.8Hz,2H),7.48-7.40(m,1H),7.20(dd,J＝8.8,2.1Hz,1H),7.15(d,J＝6.5Hz,1H),6.94(s,1H),6.83(d,J＝7.4Hz,1H),6.75(s,1H),6.40-6. 35(m,1H),3.92(s,2H),3.34(s,6H),3.30(s,6H),2.23(dd,J＝12.4,6.2Hz,2H),1.91(s,1H),1.24(s,2H),1.04(d,J＝6.4Hz,4H).
实施例76
Embodiment 76
合成方法Synthesis methods
化合物76的合成方法参照实施例47，区别在于把步骤五中的二甲胺替换为氘代二甲胺。LC-MS(ESI)m/z:315.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.94(d,J＝2.2Hz,1H),8.42(d,J＝2.2Hz,1H),8.07-8.02(m,2H),7.97(d,J＝8.7Hz,1H),7.67(d,J＝2.0Hz,1H),7.58(d,J＝3.7Hz,1H),7.33(d,J＝3.7Hz,1H),7.21(ddd,J＝10.2,8.7,2.0Hz,2H),6.47(d,J＝2.1Hz,1H),5.51(s,2H).The synthesis method of compound 76 refers to Example 47, except that the dimethylamine in step 5 is replaced by deuterated dimethylamine. LC-MS (ESI) m/z: 315.6 [M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ8.94 (d, J = 2.2Hz, 1H), 8.42 (d, J = 2.2Hz, 1H), 8.07-8.02 (m, 2H), 7.97 (d, J = 8.7Hz, 1H), 7.67 (d, J＝2.0Hz,1H),7.58(d,J＝3.7Hz,1H),7.33(d,J＝3.7Hz,1H),7.21(ddd,J＝10.2,8.7,2.0Hz,2H),6.47(d,J＝2.1Hz,1H),5.51(s,2H).
实施例77
Embodiment 77
合成方法Synthesis methods
化合物77的合成方法参照实施例47，区别在于把步骤五中的二甲胺替换为吡咯烷。LC-MS(ESI)m/z:335.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.93(d,J＝2.2Hz,1H),8.40(d,J＝2.2Hz,1H),8.17(d,J＝8.8Hz,1H),8.11(d,J＝8.8Hz,1H),8.05(t,J＝2.3Hz,1H),7.65(d,J＝2.1Hz,1H),7.59(d,J＝3.7Hz,1H),7.32(d,J＝3.7Hz,1H),7.21(td,J＝8.7,2.1Hz,2H),6.46(d,J＝2.1Hz,1H),5.52(s,2H),3.90-3.72(m,7H),2.03-1.86(m,9H).The synthesis method of compound 77 is similar to that of Example 47, except that dimethylamine in step 5 is replaced by pyrrolidine. LC-MS (ESI) m/z: 335.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.93(d,J＝2.2Hz,1H),8.40(d,J＝2.2Hz,1H),8.17(d,J＝8.8Hz,1H),8.11(d,J＝8.8Hz,1H),8.05(t,J＝2.3Hz,1H),7.65(d,J＝2.1Hz,1H),7.59(d,J＝3.7Hz ,1H),7.32(d,J＝3.7Hz,1H),7.21(td,J＝8.7,2.1Hz,2H),6.46(d,J＝2.1Hz,1H),5.52(s,2H),3.90-3.72(m,7H),2.03-1.86(m,9H).
实施例78
Embodiment 78
合成方法Synthesis methods
化合物78的合成方法参照实施例72，区别在于把步骤八中的氘代二甲胺替换为甲乙胺。LC-MS(ESI)m/z:324.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ9.17(d,J＝2.1Hz,1H),8.60(d,J＝2.2Hz,1H),8.31(t,J＝2.2Hz,1H),8.22(s,1H),7.99(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.78(d,J＝2.0Hz,1H),7.25-7.20(m,2H),6.52(d,J＝2.1Hz,1H),5.55(s,2H),3.72(q,J＝7.0Hz,2H),3.65(q,J＝7.0Hz,2H),3.32(s,3H),3.23(s,3H),1.35-1.27(m,6H).The synthesis method of compound 78 is similar to that of Example 72, except that deuterated dimethylamine in step 8 is replaced by methylethylamine. LC-MS (ESI) m/z: 324.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.17(d,J＝2.1Hz,1H),8.60(d,J＝2.2Hz,1H),8.31(t,J＝2.2Hz,1H),8.22(s,1H),7.99(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.78(d,J＝2.0Hz,1H),7. 25-7.20(m,2H),6.52(d,J＝2.1Hz,1H),5.55(s,2H),3.72(q,J＝7.0Hz,2H),3.65(q,J＝7.0Hz,2H),3.32(s,3H),3.23(s,3H),1.35-1.27(m,6H).
实施例79
Embodiment 79
合成路线
Synthetic route
步骤一：化合物79-1的合成Step 1: Synthesis of compound 79-1
室温下将2-溴噻唑-5-羧酸甲酯(5.0g，21.18mmol)溶解在50mL胺-甲醇溶液中，室温下搅拌4h。TLC监测完全反应，减压浓缩后得到化合物79-1(4.5g，黄色固体)，无需纯化直接用于下一步反应，产率100％。LC-MS(ESI)m/z:207[M+H]+.Methyl 2-bromothiazole-5-carboxylate (5.0 g, 21.18 mmol) was dissolved in 50 mL of amine-methanol solution at room temperature and stirred at room temperature for 4 h. The reaction was completely monitored by TLC. After concentration under reduced pressure, compound 79-1 (4.5 g, yellow solid) was obtained, which was directly used for the next step without purification, with a yield of 100%. LC-MS (ESI) m/z: 207 [M+H] + .
步骤二：化合物79-2的合成Step 2: Synthesis of compound 79-2
室温下，将化合物79-1(4.5g，21.74mmol)溶解在50mL二氯甲烷中，向其中加入三乙胺11.3mL后降温至0℃，逐滴加入三氟乙酸酐5.0mL，室温下搅拌2h。TLC监测完全反应，反应体系中加饱和碳酸氢钠溶液40mL淬灭，用二氯甲烷(80mL x3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-50％，15min)得到化合物79-2(4.1g，淡黄色固体)，产率99％。LC-MS(ESI)m/z:189[M+H]+.At room temperature, compound 79-1 (4.5 g, 21.74 mmol) was dissolved in 50 mL of dichloromethane, 11.3 mL of triethylamine was added thereto, and the temperature was lowered to 0 ° C. 5.0 mL of trifluoroacetic anhydride was added dropwise, and stirred at room temperature for 2 h. TLC monitored the complete reaction, 40 mL of saturated sodium bicarbonate solution was added to the reaction system to quench, and the reaction system was extracted with dichloromethane (80 mL x3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate, 0-50%, 15 min) to obtain compound 79-2 (4.1 g, light yellow solid), with a yield of 99%. LC-MS (ESI) m/z: 189 [M + H] + .
步骤三：化合物79-3的合成Step 3: Synthesis of compound 79-3
室温下，将化合物79-2(2.0g，10.58mmol)溶解在20mL N,N-二甲基甲酰胺中，向其中加入3-叔丁氧羰基氨基哌啶(2.3g，11.64mmol)和碳酸钾(4.4g，31.74mmol)，室温下搅拌16h。TLC监测完全反应，反应体系中加水，用乙酸乙酯(50mL x 3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)得到化合物79-3(2.9g，白色固体)，产率89％。LC-MS(ESI)m/z:309[M+H]+.At room temperature, compound 79-2 (2.0 g, 10.58 mmol) was dissolved in 20 mL of N, N-dimethylformamide, 3-tert-butyloxycarbonylaminopiperidine (2.3 g, 11.64 mmol) and potassium carbonate (4.4 g, 31.74 mmol) were added thereto, and stirred at room temperature for 16 h. TLC monitored the complete reaction, water was added to the reaction system, extracted with ethyl acetate (50 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was subjected to silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min) to obtain compound 79-3 (2.9 g, white solid) with a yield of 89%. LC-MS (ESI) m/z: 309 [M + H] + .
步骤四：化合物79-4的合成Step 4: Synthesis of compound 79-4
室温下将化合物79-3(2.9g，9.42mmol)溶解在20mL 1,4-二氧六环中，向其中加入盐酸-二氧六环溶液20mL，室温下搅拌30min。TLC监测完全反应，浓缩后得到化合物79-4的盐酸盐(2.2g，白色固体)，产率96％。LC-MS(ESI)m/z:209[M+H]+.步骤五：化合物79-5的合成Compound 79-3 (2.9 g, 9.42 mmol) was dissolved in 20 mL 1,4-dioxane at room temperature, 20 mL hydrochloric acid-dioxane solution was added thereto, and stirred at room temperature for 30 min. TLC monitored the complete reaction, and after concentration, the hydrochloride of compound 79-4 (2.2 g, white solid) was obtained with a yield of 96%. LC-MS (ESI) m/z: 209 [M+H] + . Step 5: Synthesis of compound 79-5
室温下将化合物79-4的盐酸盐(2.2g，9.02mmol)溶解在25mL胺-甲醇溶液中，向其中加入雷尼镍，氢气保护下室温搅拌4h。TLC监测完全反应，过滤除去雷尼镍， 粗产品经过C18柱层析(乙腈：水，5-95％，15min)得到化合物79-5(1.7g，白色固体)，产率88％。LC-MS(ESI)m/z:213[M+H]+ The hydrochloride of compound 79-4 (2.2 g, 9.02 mmol) was dissolved in 25 mL of amine-methanol solution at room temperature, and Raney nickel was added thereto. The mixture was stirred at room temperature for 4 h under hydrogen protection. The reaction was complete after TLC monitoring, and the Raney nickel was removed by filtration. The crude product was purified by C18 column chromatography (acetonitrile: water, 5-95%, 15 min) to give compound 79-5 (1.7 g, white solid) with a yield of 88%. LC-MS (ESI) m/z: 213 [M+H] +
步骤六：化合物79-6的合成Step 6: Synthesis of compound 79-6
0℃下将草酰氯(6.1g，47.88mmol)滴加到4-氯-2-氟苯甲酰胺(4.1g，23.94mmol)的二氯乙烷DCE(50mL)中。氮气保护下，反应混合液在70℃搅拌过夜，减压旋蒸除去多余的草酰氯后，用DCE(20mL)稀释后滴入化合物79-5(1.7g，7.98mmol)的DCE(30mL)体系中，反应在室温下搅拌3h。TLC监测完全反应。反应体系加入乙腈打浆过滤后得到化合物6(2.5g，白色固体)，产率51％。LC-MS(ESI)m/z:611[M+H]+.Oxalyl chloride (6.1 g, 47.88 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (4.1 g, 23.94 mmol) in dichloroethane (DCE) (50 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride by vacuum rotary evaporation, it was diluted with DCE (20 mL) and then added dropwise to the DCE (30 mL) system of compound 79-5 (1.7 g, 7.98 mmol), and the reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction. Acetonitrile was added to the reaction system and the mixture was pulped and filtered to obtain compound 6 (2.5 g, white solid) with a yield of 51%. LC-MS (ESI) m/z: 611 [M+H] + .
步骤七：化合物79-7的合成Step 7: Synthesis of compound 79-7
0℃下将氢化钠(0.8g，20.46mmol)加入到化合物79-6(2.5g，4.09mmol)的N,N-二甲基甲酰胺DMF(25mL)中，氮气保护下，升温至90℃搅拌3h。LC-MS检测原料基本消失。反应体系加水淬灭，滴加稀盐酸(0.5mol/L)至pH为中性，过滤后固体用乙腈打浆，再次过滤后得到化合物79-7(1.7g，白色固体)，产率70％。LC-MS(ESI)m/z:591[M+H]+.Sodium hydride (0.8 g, 20.46 mmol) was added to compound 79-6 (2.5 g, 4.09 mmol) in DMF (25 mL) at 0 °C, and the mixture was heated to 90 °C and stirred for 3 h under nitrogen protection. LC-MS detected that the raw material was basically gone. The reaction system was quenched with water, and dilute hydrochloric acid (0.5 mol/L) was added dropwise until the pH was neutral. After filtration, the solid was slurried with acetonitrile and filtered again to obtain compound 79-7 (1.7 g, white solid) with a yield of 70%. LC-MS (ESI) m/z: 591 [M+H] + .
步骤八：化合物79的合成Step 8: Synthesis of Compound 79
0℃下将三氯氧磷(0.8mL)加入到化合物79-7(60mg，0.10mmol)和N,N-二异丙基乙胺(0.8mL)的乙腈ACN(4mL)溶液中。在氮气保护下，反应混合液在90℃下反应4h，减压旋蒸去除多余的三氯氧磷。将N-乙基甲基胺的四氢呋喃溶液4mL中滴入反应体系后，室温下搅拌30min。LC-MS检测完全反应。二氯甲烷/甲醇溶解后经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，经HPLC制备纯化后得到化合物79(2.76mg，白色固体)，产率8.5％。LC-MS(ESI)m/z:327[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ7.90(d,J＝8.8Hz,1H),7.82(dd,J＝5.4,3.4Hz,2H),7.78(d,J＝2.0Hz,1H),7.42(s,1H),7.22-7.18(m,2H),5.29(s,2H),3.95-3.84(m,1H),3.61(q,J＝23.2,7.0Hz,4H),3.39(s,3H),3.32(s,3H),3.22(s,3H),3.19(s,3H),2.03-1.95(m,4H),1.77-1.71(m,2H),1.50-1.41(m,2H).Phosphorus oxychloride (0.8 mL) was added to a solution of compound 79-7 (60 mg, 0.10 mmol) and N,N-diisopropylethylamine (0.8 mL) in acetonitrile ACN (4 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 h, and the excess phosphorus oxychloride was removed by vacuum rotary evaporation. After 4 mL of tetrahydrofuran solution of N-ethylmethylamine was dropped into the reaction system, it was stirred at room temperature for 30 min. LC-MS detected the complete reaction. After dissolving in dichloromethane/methanol, it was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min) to obtain a crude product, which was purified by HPLC preparation to obtain compound 79 (2.76 mg, white solid) with a yield of 8.5%. LC-MS (ESI) m/z: 327 [M/2+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ7.90(d,J＝8.8Hz,1H),7.82(dd,J＝5.4,3.4Hz,2H),7.78(d,J＝2.0Hz,1H),7.42(s,1H),7.22-7.18(m,2H),5.29(s,2H),3.95-3.84(m,1H),3.61(q,J＝23.2,7.0Hz,4H),3.39(s,3H),3.32(s,3H),3.22(s,3H),3.19(s,3H),2.03-1.95(m,4H),1.77-1.71(m,2H),1.50-1.41(m,2H).
实施例80
Embodiment 80
合成方法Synthesis method
化合物80的合成方法参照实施例79，区别在于把步骤八中的甲乙胺替换为二甲胺。LC-MS(ESI)m/z:313.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.98(d,J＝8.8Hz,1H),7.89(d,J＝8.7Hz,1H),7.81(d,J＝2.0Hz,1H),7.77(d,J＝2.0Hz,1H),7.42(s,1H),7.20(ddd,J＝8.6,6.5,1.9Hz,2H),5.33-5.25(m,2H),4.16(t,1H),3.96(dd,J＝12.3,4.0Hz,1H),3.93-3.86(m,1H),3.72(d,J＝12.9Hz,1H),3.24(s,6H),3.21(s,6H),3.15-3.07(m,1H),2.80-2.71(m,1H),1.81-1.70(m,3H).The synthesis method of compound 80 refers to Example 79, except that methylethylamine in step eight is replaced by dimethylamine. LC-MS (ESI) m/z: 313.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ7.98 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.42 (s, 1H), 7.20 (ddd, J=8.6, 6.5, 1.9 Hz, 2H), 5.33-5.25 (m, 2H), 4.16 (t,1H),3.96(dd,J＝12.3,4.0Hz,1H),3.93-3.86(m,1H),3.72(d,J＝12.9Hz,1H),3.24(s,6H),3.21(s,6H),3.15-3.07(m,1H),2.80-2.71(m,1H),1.8 1-1.70(m,3H).
实施例81
Embodiment 81
合成路线
Synthetic route
步骤一：化合物81-1的合成Step 1: Synthesis of compound 81-1
将氢氧化钾(1.1g，19.6mmol)加入到3-硝基溴苄(4g，18.5mmol)的1，3-丙二醇(40mL)溶液中，氮气条件下80℃反应三小时。待反应液冷却后加300mL水和500mL二氯甲烷萃取，反复三次，无水硫酸钠干燥有机相后浓缩，硅胶柱层析纯化(EA：PE＝20％)浓缩得到化合物81-1(2.4g，LC-MS(ESI)m/z:212[M+H]+，收率62％)。步骤二：化合物81-2的合成Potassium hydroxide (1.1 g, 19.6 mmol) was added to a solution of 3-nitrobenzyl bromide (4 g, 18.5 mmol) in 1,3-propylene glycol (40 mL), and the mixture was reacted at 80°C for three hours under nitrogen. After the reaction solution was cooled, 300 mL of water and 500 mL of dichloromethane were added for extraction, and the extraction was repeated three times. The organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by silica gel column chromatography (EA: PE = 20%) to obtain compound 81-1 (2.4 g, LC-MS (ESI) m/z: 212 [M+H] + , yield 62%). Step 2: Synthesis of compound 81-2
将化合物81-1(2.4g，11.3mmol)，三异丙基氯硅烷(4.4g，22.8mmol)和咪唑(2.3g，33.8mmol)溶于二氯甲烷(30ml)中，氮气条件下室温搅拌过夜反应，TLC监测反应完全。反应液加200mL水和250mL二氯甲烷萃取，反复三次，合并有机相，硅胶柱层析纯化浓缩得到化合物82-2(4g，LC-MS(ESI)m/z:368[M+H]+，收率96％)。步骤三：化合物81-3的合成Compound 81-1 (2.4 g, 11.3 mmol), triisopropylsilyl chloride (4.4 g, 22.8 mmol) and imidazole (2.3 g, 33.8 mmol) were dissolved in dichloromethane (30 ml), stirred at room temperature overnight under nitrogen, and the reaction was complete after TLC monitoring. The reaction solution was extracted with 200 mL of water and 250 mL of dichloromethane, and the extraction was repeated three times. The organic phases were combined, purified and concentrated by silica gel column chromatography to obtain compound 82-2 (4 g, LC-MS (ESI) m/z: 368 [M+H] + , yield 96%). Step 3: Synthesis of compound 81-3
将铁粉与氯化铵溶于水中氮气条件下100℃加热搅拌半小时后加入化合物81-2(1 g，2.72mmol)100℃加热搅拌过夜反应，TLC监测反应完全。待反应液冷却后过滤，滤液加100mL水和200mL二氯甲烷萃取，反复三次，合并有机相，浓缩得到化合物82-3(700mg，LC-MS(ESI)m/z:338[M+H]+，收率76％)。Iron powder and ammonium chloride were dissolved in water under nitrogen atmosphere at 100°C, heated and stirred for half an hour, and compound 81-2 (1 g, 2.72 mmol) was heated and stirred at 100°C overnight to react, and the reaction was complete after TLC monitoring. After the reaction solution was cooled, it was filtered, and the filtrate was extracted with 100 mL of water and 200 mL of dichloromethane, and the extraction was repeated three times. The organic phases were combined and concentrated to obtain compound 82-3 (700 mg, LC-MS (ESI) m/z: 338 [M+H] + , yield 76%).
步骤四：化合物81-4的合成Step 4: Synthesis of compound 81-4
室温下，将2-氟-4-氯苯甲酰胺(434mg，2.5mmol)溶于10mL DCE中，降温至0℃后缓慢滴加草酰氯(470mg，3.7mmol)，缓慢升至室温后再升温至70℃搅拌16小时。浓缩除去过量草酰氯，溶解于2mL DCE后滴加至化合物81-3(700mg，2.07mmol)的DCE溶液中，保持室温反应3小时。有大量白色固体析出。过滤即得白色固体标题化合物81-4(650mg，LC-MS(ESI)m/z:537[M+H]+，收率60％)。At room temperature, 2-fluoro-4-chlorobenzamide (434 mg, 2.5 mmol) was dissolved in 10 mL DCE, cooled to 0 °C, and oxalyl chloride (470 mg, 3.7 mmol) was slowly added dropwise, slowly heated to room temperature, and then heated to 70 °C and stirred for 16 hours. Excess oxalyl chloride was removed by concentration, dissolved in 2 mL DCE, and then added dropwise to a DCE solution of compound 81-3 (700 mg, 2.07 mmol), and kept at room temperature for 3 hours. A large amount of white solid precipitated. Filtration gave the title compound 81-4 as a white solid (650 mg, LC-MS (ESI) m/z: 537 [M+H] + , yield 60%).
步骤五：化合物81-5的合成Step 5: Synthesis of compound 81-5
室温下，将化合物81-4(650mg，1.2mmol)溶于8mL DMF中，降温至0℃，滴加NaHMDS(2mol/L，0.6mL)，室温搅拌10分钟后升温至65℃搅拌2小时。LC-MS监测反应完全，加水淬灭反应。反应液加50mL水和150mL二氯甲烷萃取，反复三次，合并有机相，硅胶柱层析纯化浓缩得到化合物81-5(570mg，LC-MS(ESI)m/z:517[M+H]+，收率92％)。At room temperature, compound 81-4 (650 mg, 1.2 mmol) was dissolved in 8 mL of DMF, cooled to 0 °C, and NaHMDS (2 mol/L, 0.6 mL) was added dropwise. After stirring at room temperature for 10 minutes, the temperature was raised to 65 °C and stirred for 2 hours. LC-MS monitored the reaction to be complete, and water was added to quench the reaction. The reaction solution was extracted with 50 mL of water and 150 mL of dichloromethane, and the extraction was repeated three times. The organic phases were combined, purified and concentrated by silica gel column chromatography to obtain compound 81-5 (570 mg, LC-MS (ESI) m/z: 517 [M+H] + , yield 92%).
步骤六：化合物81-6的合成Step 6: Synthesis of compound 81-6
室温下，将化合物81-5(570mg，1.1mmol)溶于10mL无水乙腈中，降温至0℃，加入DIEA(712mg，0.96mL)和三氯氧磷(493mg，0.3mL)，缓慢升至室温后升温至80℃搅拌6小时。反应液浓缩除去大量三氯氧磷，之后加入二甲胺的四氢呋喃溶液(5mL，2M in THF)，室温搅拌30分钟。LC-MS监测反应完全。浓缩后经色谱柱层析分离(EA,100％，6min)得到化合物81-6(488mg，LC-MS(ESI)m/z:544[M+H]+，收率81％)。At room temperature, compound 81-5 (570 mg, 1.1 mmol) was dissolved in 10 mL of anhydrous acetonitrile, cooled to 0 ° C, DIEA (712 mg, 0.96 mL) and phosphorus oxychloride (493 mg, 0.3 mL) were added, slowly heated to room temperature and then heated to 80 ° C and stirred for 6 hours. The reaction solution was concentrated to remove a large amount of phosphorus oxychloride, and then a tetrahydrofuran solution of dimethylamine (5 mL, 2M in THF) was added and stirred at room temperature for 30 minutes. LC-MS monitored the reaction to be complete. After concentration, the compound 81-6 (488 mg, LC-MS (ESI) m/z: 544 [M + H] + , yield 81%) was obtained by column chromatography (EA, 100%, 6 min).
步骤七：化合物81-7的合成Step 7: Synthesis of compound 81-7
将化合物81-6(488mg，0.89mmol)溶于10mL甲醇中，在0℃向反应液中滴加四丁基氟化铵(1.7ml，1.78mmol)，室温搅拌反应半小时。LC-MS监测反应完全。加80mL食盐水和100mL二氯甲烷萃取，反复三次，将有机相浓缩后得到化合物81-7(207mg，LC-MS(ESI)m/z:388[M+H]+，收率61％)。Compound 81-6 (488 mg, 0.89 mmol) was dissolved in 10 mL of methanol, and tetrabutylammonium fluoride (1.7 ml, 1.78 mmol) was added dropwise to the reaction solution at 0°C, and the mixture was stirred at room temperature for half an hour. The reaction was complete when monitored by LC-MS. 80 mL of saline and 100 mL of dichloromethane were added for extraction, and the extraction was repeated three times. The organic phase was concentrated to obtain compound 81-7 (207 mg, LC-MS (ESI) m/z: 388 [M+H] + , yield 61%).
步骤八：化合物81-8的合成Step 8: Synthesis of compound 81-8
将化合物81-7(200mg，0.51mmol)溶于10mL丙酮与1ml乙酸的混合溶液中，在0℃向反应液中滴加琼斯试剂(0.4ml，1.02mmol)，室温搅拌反应八个小时，LC-MS监测反应完全。加40mL水和50mL乙酸乙酯萃取，反复三次，将有机相浓缩后经HPLC纯化得30mg化合物81-8(66mg，LC-MS(ESI)m/z:402[M+H]+，收率32％)。Compound 81-7 (200 mg, 0.51 mmol) was dissolved in a mixed solution of 10 mL acetone and 1 ml acetic acid, Jones reagent (0.4 ml, 1.02 mmol) was added dropwise to the reaction solution at 0°C, and the mixture was stirred at room temperature for eight hours. The reaction was complete after monitoring by LC-MS. 40 mL water and 50 mL ethyl acetate were added for extraction, and the extraction was repeated three times. The organic phase was concentrated and purified by HPLC to obtain 30 mg of compound 81-8 (66 mg, LC-MS (ESI) m/z: 402 [M+H] + , yield 32%).
步骤九：化合物81的合成Step 9: Synthesis of compound 81
将化合物81-8(20mg，0.05mmol)的DMF(0.3mL)溶液滴加到TBTU(48mg，0.15mmol)和三乙胺(20mg，0.19mmol)的DMF(0.3mL)溶液中，最后滴加化合物23-2(9.5mg，0.05mmol)的DMF(0.3mL)溶液，50℃反应半小时，TLC显示原料反应完全。待反应液冷却后加10mL水和20mL乙酸乙酯萃取，反复三次，有机食盐水洗一次，无水硫酸钠干燥有机相后浓缩经HPLC纯化,化合物811.5mg(LC-MS(ESI)m/z:279.6[M/2+H]+，收率5.4％)。A solution of compound 81-8 (20 mg, 0.05 mmol) in DMF (0.3 mL) was added dropwise to a solution of TBTU (48 mg, 0.15 mmol) and triethylamine (20 mg, 0.19 mmol) in DMF (0.3 mL), and finally a solution of compound 23-2 (9.5 mg, 0.05 mmol) in DMF (0.3 mL) was added dropwise. The mixture was reacted at 50°C for half an hour. TLC showed that the reaction of the raw materials was complete. After the reaction solution was cooled, 10 mL of water and 20 mL of ethyl acetate were added for extraction, and the reaction was repeated three times. The organic phase was washed once with saline solution. The organic phase was dried over anhydrous sodium sulfate and concentrated and purified by HPLC. Compound 811.5 mg (LC-MS (ESI) m/z: 279.6 [M/2+H] + , yield 5.4%).
实施例82
Embodiment 82
合成方法Synthesis methods
化合物82的合成方法参照实施例72，区别在于把步骤八中的氘代二甲胺替换为二甲胺。LC-MS(ESI)m/z:310.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ9.17(d,J＝2.1Hz,1H),8.60(d,J＝2.3Hz,1H),8.31(t,J＝2.2Hz,1H),8.21(s,1H),8.05(d,J＝8.8Hz,1H),7.98(d,J＝8.7Hz,1H),7.79(d,J＝2.0Hz,1H),7.24-7.19(m,2H),6.53(d,J＝2.1Hz,1H),5.56(s,2H),3.32(s,6H),3.25(s,6H).The synthesis method of compound 82 refers to Example 72, except that deuterated dimethylamine in step eight is replaced by dimethylamine. LC-MS (ESI) m/z: 310.1[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.17 (d, J = 2.1Hz, 1H), 8.60 (d, J = 2.3Hz, 1H), 8.31 (t, J = 2.2Hz, 1H), 8.21 (s, 1H), 8.05 (d, J = 8.8 Hz,1H),7.98(d,J＝8.7Hz,1H),7.79(d,J＝2.0Hz,1H),7.24-7.19(m,2H),6.53(d,J＝2.1Hz,1H),5.56(s,2H),3.32(s,6H),3.25(s,6H).
实施例83
Embodiment 83
合成方法Synthesis methods
化合物83的合成方法参照实施例72，区别在于把步骤八中的氘代二甲胺替换为氮杂环丁烷。LC-MS(ESI)m/z:322.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ9.16(d,J＝2.1Hz,1H),8.57(d,J＝2.3Hz,1H),8.29(t,J＝2.2Hz,1H),8.18(s,1H),7.84(d,J＝8.7Hz,1H),7.77(dd,J＝5.3,3.4Hz,2H),7.22(dt,J＝8.7,2.3Hz,2H),6.51(d,J＝2.0Hz,1H),5.56(s,2H),3.53(t,8H),2.45-2.36(m,4H).The synthesis method of compound 83 refers to Example 72, except that deuterated dimethylamine in step eight is replaced by azetidine. LC-MS (ESI) m/z: 322.1[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.16 (d, J = 2.1Hz, 1H), 8.57 (d, J = 2.3Hz, 1H), 8.29 (t, J = 2.2Hz, 1H), 8.18 (s, 1H), 7.84 (d, J = 8.7 Hz,1H),7.77(dd,J＝5.3,3.4Hz,2H),7.22(dt,J＝8.7,2.3Hz,2H),6.51(d,J＝2.0Hz,1H),5.56(s,2H),3.53(t,8H),2.45-2.36(m,4H).
实施例84
Embodiment 84
合成方法Synthesis methods
化合物84的合成方法参照实施例47，区别在于把步骤二中的氢气替换为氘气。LC-MS(ESI)m/z:310.4[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.94(d,J＝2.2Hz,1H),8.42(d,J＝2.2Hz,1H),8.08-8.03(m,2H),7.98(d,J＝8.8Hz,1H),7.67(s,1H),7.58(d,J＝3.7Hz,1H),7.33(d,J＝3.8Hz,1H),7.21(ddd,J＝10.2,8.9,2.1Hz,2H),6.48(d,J＝2.1Hz,1H),3.32(s,6H),3.25(s,6H).The synthesis method of compound 84 is similar to that of Example 47, except that the hydrogen gas in step 2 is replaced by deuterium gas. LC-MS (ESI) m/z: 310.4[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.94 (d, J = 2.2Hz, 1H), 8.42 (d, J = 2.2Hz, 1H), 8.08-8.03 (m, 2H), 7.98 (d, J = 8.8Hz, 1H), 7.67 (s, 1H),7.58(d,J＝3.7Hz,1H),7.33(d,J＝3.8Hz,1H),7.21(ddd,J＝10.2,8.9,2.1Hz,2H),6.48(d,J＝2.1Hz,1H),3.32(s,6H),3.25(s,6H).
实施例85
Embodiment 85
合成路线
Synthetic route
步骤一：化合物85的合成Step 1: Synthesis of compound 85
0℃下将三氯氧磷(1.0mL)加入到化合物72-7(80mg，0.14mmol)和N,N-二异丙基乙胺(1.0mL)的乙腈CAN(5mL)溶液中。在氮气保护下，反应混合液在90℃下反应4h，减压旋蒸去除多余的三氯氧磷。将4mL水滴入反应体系后，室温下搅拌30min。LC-MS检测完全反应。用二氯甲烷/甲醇溶解后经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，经HPLC纯化后得到化合物85(3.05mg，白色固体)，产率3.86％。LC-MS(ESI)m/z:565.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ11.91(s,2H),9.25(d,J＝2.1Hz,1H),8.74(d,J＝2.3Hz,1H),8.49(t,J＝2.2Hz,1H),8.21(s,1H),8.02(dd,J＝18.2,8.4Hz,2H),7.83(d,J＝1.8Hz,1H),7.34(dq,J＝8.5,3.4,1.8Hz,2H),6.57(d,J＝1.9Hz,1H),5.59(s,2H).Phosphorus oxychloride (1.0 mL) was added to a solution of compound 72-7 (80 mg, 0.14 mmol) and N,N-diisopropylethylamine (1.0 mL) in acetonitrile CAN (5 mL) at 0°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 4 h, and the excess phosphorus oxychloride was removed by rotary evaporation under reduced pressure. After 4 mL of water was dropped into the reaction system, it was stirred at room temperature for 30 min. LC-MS detected the complete reaction. After dissolving in dichloromethane/methanol, the crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 85 (3.05 mg, white solid) was obtained after purification by HPLC with a yield of 3.86%. LC-MS (ESI) m/z: 565.0[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 11.91 (s, 2H), 9.25 (d, J = 2.1Hz, 1H), 8.74 (d, J = 2.3Hz, 1H), 8.49 (t, J = 2.2Hz, 1H), 8.21 (s, 1H), 8. 02(dd,J＝18.2,8.4Hz,2H),7.83(d,J＝1.8Hz,1H),7.34(dq,J＝8.5,3.4,1.8Hz,2H),6.57(d,J＝1.9Hz,1H),5.59(s,2H).
实施例86
Embodiment 86
合成方法Synthesis method
化合物86的合成方法参照实施例47，区别在于把步骤二中的氢气替换为氘气，步骤五中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:324.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.94(d,J＝2.1Hz,1H),8.42(d,J＝2.2Hz,1H),8.07(d,J＝2.0Hz,1H),7.99(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.67(s,1H),7.59(d,J＝3.7Hz,1H),7.34(d,J＝4.4Hz,1H),7.22(td,J＝9.9,9.4,2.1Hz,2H),6.47(d,J＝2.1Hz,1H),3.68(dq,J＝25.6,7.0Hz,4H),3.31(s,3H),3.23(s,3H),1.30(dd,J＝15.1,8.0Hz,6H).The synthesis method of compound 86 is similar to that of Example 47, except that the hydrogen in step 2 is replaced by deuterium, and the dimethylamine in step 5 is replaced by methylethylamine. LC-MS (ESI) m/z: 324.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.94(d,J＝2.1Hz,1H),8.42(d,J＝2.2Hz,1H),8.07(d,J＝2.0Hz,1H),7.99(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.67(s,1H),7.59(d,J＝3.7Hz,1H),7. 34(d,J＝4.4Hz,1H),7.22(td,J＝9.9,9.4,2.1Hz,2H),6.47(d,J＝2.1Hz,1H),3.68(dq,J＝25.6,7.0Hz,4H),3.31(s,3H),3.23(s,3H),1.30(dd,J＝15.1, 8.0Hz,6H).
实施例87
Embodiment 87
合成方法Synthesis method
化合物87的合成方法参照实施例47，区别在于把步骤二中的氢气替换为氘气，步骤五中的二甲胺替换为甲基异丙基胺。LC-MS(ESI)m/z:338.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.94(d,J＝2.1Hz,1H),8.43(d,J＝2.2Hz,1H),8.07(d,J＝2.2Hz,1H),7.97(d,J＝8.8Hz,1H),7.90(d,J＝8.7Hz,1H),7.67(t,J＝1.7Hz,1H),7.59(d,J＝3.7Hz,1H),7.36-7.31(m,1H),7.21(ddd,J＝10.9,8.7,2.1Hz,2H),6.47(d,J＝2.1Hz,1H),4.77(dp,J＝28.9,6.6Hz,2H),3.15(s,3H),3.07(s,3H),1.29(d,J＝6.6Hz,6H),1.24(d,J＝6.6Hz,6H).The synthesis method of compound 87 is similar to that of Example 47, except that hydrogen in step 2 is replaced by deuterium, and dimethylamine in step 5 is replaced by methylisopropylamine. LC-MS (ESI) m/z: 338.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.94 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.67 (t, J = 1.7 Hz, 1H), 7.59 (d, J = 3.7 Hz, 1H), 7.36-7. 31(m,1H),7.21(ddd,J＝10.9,8.7,2.1Hz,2H),6.47(d,J＝2.1Hz,1H),4.77(dp,J＝28.9,6.6Hz,2H),3.15(s,3H),3.07(s,3H),1.29(d,J＝6.6Hz,6H),1. 24(d,J＝6.6Hz,6H).
实施例88
Embodiment 88
合成方法Synthesis method
化合物88的合成方法参照实施例47，区别在于把步骤二中的氢气替换为氘气，步骤五中的二甲胺替换为乙胺。LC-MS(ESI)m/z:310.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.93(d,J＝2.2Hz,1H),8.66(t,J＝5.5Hz,1H),8.48(t,J＝5.4Hz,1H),8.42(d,J＝2.2Hz,1H),8.18(d,J＝8.7Hz,1H),8.12(d,J＝8.7Hz,1H),8.07(d,J＝2.0Hz,1H),7.64(s,1H),7.58(d,J＝3.7Hz,1H),7.30(dd,J＝8.4,2.4Hz,2H),6.44(d,J＝2.0Hz,1H),3.58-3.45(m,4H),1.24(d,J＝4.1Hz,3H),1.21(d,J＝7.1Hz,3H).The synthesis method of compound 88 is similar to that of Example 47, except that the hydrogen in step 2 is replaced by deuterium, and the dimethylamine in step 5 is replaced by ethylamine. LC-MS (ESI) m/z: 310.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.93(d,J＝2.2Hz,1H),8.66(t,J＝5.5Hz,1H),8.48(t,J＝5.4Hz,1H),8.42(d,J＝2.2Hz,1H),8.18(d,J＝8.7Hz,1H),8.12(d,J＝8.7Hz,1H),8.07(d,J＝2.0 Hz,1H),7.64(s,1H),7.58(d,J＝3.7Hz,1H),7.30(dd,J＝8.4,2.4Hz,2H),6.44(d,J＝2.0Hz,1H),3.58-3.45(m,4H),1.24(d,J＝4.1Hz,3H),1.21(d,J＝7.1Hz ,3H).
实施例89
Embodiment 89
合成路线
Synthetic route
步骤一：化合物89的合成Step 1: Synthesis of compound 89
室温下，将化合物76(5mg，0.00794mmol)溶于0.4mL二氯甲烷和0.1mL甲醇的混合溶液中，加入30μL盐酸二氧六环溶液(4N)，保持室温搅拌20分钟。之后减压浓缩后冻干得4mg化合物89，白色固体。LC-MS(ESI)m/z:315.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ9.02(d,J＝2.2Hz,1H),8.53(d,J＝2.2Hz,1H),8.20(d,J＝2.2Hz,1H),8.08(dd,J＝12.8,8.8Hz,2H),7.75(d,J＝2.0Hz,1H),7.64(d,J＝3.7Hz,1H),7.37(d,J＝3.7Hz,1H),7.27(dt,J＝9.0,2.4Hz,2H),6.59(d,J＝2.0Hz,1H),5.55(s,2H).At room temperature, compound 76 (5 mg, 0.00794 mmol) was dissolved in a mixed solution of 0.4 mL of dichloromethane and 0.1 mL of methanol, 30 μL of dioxane hydrochloride solution (4N) was added, and stirred at room temperature for 20 minutes, then concentrated under reduced pressure and lyophilized to obtain 4 mg of compound 89 as a white solid. LC-MS(ESI)m/z:315.6[M/2+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ9.02(d,J＝2.2Hz,1H),8.53(d,J＝2.2Hz,1H),8.20(d,J＝2.2Hz,1H),8.08(dd,J＝12.8,8.8Hz,2H), 7.75(d,J＝2.0Hz,1H),7.64(d,J＝3.7Hz,1H),7.37(d,J＝3.7Hz,1H),7.27(dt,J＝9.0,2.4Hz,2H),6.59(d,J＝2.0Hz,1H),5.55(s,2H).
实施例90
Embodiment 90
合成方法Synthesis method
化合物90的合成方法参照实施例47，区别在于把步骤五中的二甲胺替换为氨的甲醇溶液。LC-MS(ESI)m/z:281.5[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.93(d,J＝2.2Hz,1H),8.46-8.39(m,2H),8.16(d,J＝8.7Hz,2H),8.1-8.07(m,3H),7.64(d,J＝1.9Hz,1H),7.58(d,J＝3.7Hz,1H),7.32-7.24(m,4H),6.45(d,J＝1.9Hz,1H),5.51(s,2H).The synthesis method of compound 90 is similar to that of Example 47, except that the dimethylamine in step 5 is replaced by ammonia methanol solution. LC-MS (ESI) m/z: 281.5 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.93 (d, J = 2.2 Hz, 1H), 8.46-8.39 (m, 2H), 8.16 (d, J = 8.7 Hz, 2H), 8.1-8.07 (m, 3H), 7.64 (d, J = 1.9 Hz, 1H), 7.58 (d, J = 3.7 Hz, 1H), 7.32-7.24 (m, 4H), 6.45 (d, J = 1.9 Hz, 1H), 5.51 (s, 2H).
实施例91
Embodiment 91
合成方法Synthesis method
化合物91的合成方法参照实施例47，区别在于把步骤五中的二甲胺替换为N,O-二甲基羟胺。LC-MS(ESI)m/z:325.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.97(d,J＝2.1Hz,1H),8.51(d,J＝9.0Hz,1H),8.47-8.44(m,2H),8.09(t,J＝2.2Hz,1H),7.73(d,J＝2.0Hz,1H),7.60(d,J＝3.8Hz,1H),7.35(d,J＝3.8Hz,1H),7.32-7.25(m,2H),6.51(d,J＝2.1Hz,1H),5.59-5.54(m,2H),3.84(s,3H),3.78(s,3H),3.50(s,3H),3.44(s,3H).The synthesis method of compound 91 is similar to that of Example 47, except that the dimethylamine in step 5 is replaced by N,O-dimethylhydroxylamine. LC-MS (ESI) m/z: 325.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.97(d,J＝2.1Hz,1H),8.51(d,J＝9.0Hz,1H),8.47-8.44(m,2H),8.09(t,J＝2.2Hz,1H),7.73(d,J＝2.0Hz,1H),7.60(d,J＝3.8Hz,1H),7.35(d,J＝3.8Hz, 1H),7.32-7.25(m,2H),6.51(d,J＝2.1Hz,1H),5.59-5.54(m,2H),3.84(s,3H),3.78(s,3H),3.50(s,3H),3.44(s,3H).
实施例92
Embodiment 92
合成方法Synthesis method
化合物92的合成方法参照实施例79，区别在于把步骤八中的甲乙胺替换为氮杂环丁烷。LC-MS(ESI)m/z:325.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.80-7.70(m,4H),7.38(s,1H),7.19(dt,J＝8.7,6.8,1.9Hz,2H),5.31(s,2H),4.45(d,J＝270.0Hz,8H),3.99-3.82(m,2H),3.71(d,J＝13.3Hz,1H),3.09(td,J＝13.0,12.4,4.3Hz,1H),2.77(dd,J＝11.6,4.7Hz,1H),2.43-2.33(m,4H),2.17(m,1H),2.05-1.96(m,1H),1.76(q,J＝10.7,7.7Hz,2H).The synthesis method of compound 92 is similar to that of Example 79, except that methylethylamine in step eight is replaced by azetidine. LC-MS (ESI) m/z: 325.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.80-7.70(m,4H),7.38(s,1H),7.19(dt,J＝8.7,6.8,1.9Hz,2H),5.31(s,2H),4.45(d,J＝270.0Hz,8H),3.99-3.82(m,2H),3.71(d,J＝13.3Hz,1H),3 .09(td,J＝13.0,12.4,4.3Hz,1H),2.77(dd,J＝11.6,4.7Hz,1H),2.43-2.33(m,4H),2.17(m,1H),2.05-1.96(m,1H),1.76(q,J＝10.7,7.7Hz,2H).
实施例93
Embodiment 93
合成方法Synthesis method
化合物93的合成方法参照实施例47，区别在于把步骤五中的二甲胺替换为氮杂环丁烷-3-甲腈盐酸盐。LC-MS(ESI)m/z:346.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.95(d,J＝2.1Hz,1H),8.40(d,J＝2.2Hz,1H),8.04(t,J＝2.2Hz,1H),7.80(d,J＝8.7Hz,1H),7.76-7.69(m,2H),7.58(d,J＝3.7Hz,1H),7.32(d,J＝3.8Hz,1H),7.23(td,J＝12.0,8.7,2.0Hz,2H),6.51(d,J＝2.0Hz,1H),5.54(s,2H),4.73(m,8H),4.07-3.92(m,2H).The synthesis method of compound 93 refers to Example 47, except that the dimethylamine in step 5 is replaced by azetidine-3-carbonitrile hydrochloride. LC-MS(ESI)m/z:346.6[M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 )δ8.95(d,J＝2.1Hz,1H),8.40(d,J＝2.2Hz,1H),8.04(t,J＝2.2Hz,1H),7.80(d,J＝8.7Hz,1H),7.76- 7.69(m,2H),7.58(d,J＝3.7Hz,1H),7.32(d,J＝3.8Hz,1H),7.23(td,J＝12.0,8.7,2.0Hz,2H),6.51(d,J＝2.0Hz,1H),5.54(s,2H),4.73(m,8H),4.07-3.9 2(m,2H).
实施例94
Embodiment 94
合成方法Synthesis method
化合物94的合成方法参照实施例47，区别在于把步骤二中的氢气替换为氘气，步骤五中的二甲胺替换为氮杂环丁烷。LC-MS(ESI)m/z:322.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.93(d,J＝2.1Hz,1H),8.39(d,J＝2.2Hz,1H),8.04(t,J＝1.7Hz,1H),7.84(d,J＝8.7Hz,1H),7.77(d,J＝8.7Hz,1H),7.66(q,J＝1.6Hz,1H),7.58(d,J＝3.7Hz,1H),7.31(dd,J＝3.8,1.6Hz,1H),7.21(ddd,J＝12.1,8.7,2.0Hz,2H),6.46(d,J＝2.1Hz,1H),4.53(d,J＝311.1Hz,8H),2.46-2.43(m,2H),2.40(m,2H). The synthesis method of compound 94 is similar to that of Example 47, except that the hydrogen in step 2 is replaced by deuterium, and the dimethylamine in step 5 is replaced by azetidine. LC-MS (ESI) m/z: 322.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.93(d,J＝2.1Hz,1H),8.39(d,J＝2.2Hz,1H),8.04(t,J＝1.7Hz,1H),7.84(d,J＝8.7Hz,1H),7.77(d,J＝8.7Hz,1H),7.66(q,J＝1.6Hz,1H),7.58(d,J＝3.7Hz,1H),7.31(dd,J＝3.8,1.6Hz,1H),7.21(ddd,J＝12.1,8.7,2.0Hz,2H),6.46(d,J＝2.1Hz,1H),4.53(d,J＝311.1Hz,8H),2.46-2.43(m,2H),2.40(m,2H).
实施例95
Embodiment 95
合成方法Synthesis method
化合物95的合成方法参照实施例47，区别在于把步骤五中的二甲胺替换为3-甲基-3-氮杂环丁烷醇盐酸盐。LC-MS(ESI)m/z:351.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.94(d,J＝2.2Hz,1H),8.39(d,J＝2.2Hz,1H),8.04(t,J＝2.2Hz,1H),7.85(d,J＝8.8Hz,1H),7.79(d,J＝8.7Hz,1H),7.67(d,J＝2.0Hz,1H),7.58(d,J＝3.7Hz,1H),7.31(d,J＝3.7Hz,1H),7.20(td,J＝10.1,8.7,2.0Hz,2H),6.47(d,J＝2.1Hz,1H),5.87(s,1H),5.81(s,1H),5.52(s,2H),4.36(m,J＝255.2Hz,8H),1.48(s,3H),1.44(s,3H).The synthesis method of compound 95 refers to Example 47, except that the dimethylamine in step 5 is replaced by 3-methyl-3-azetidinol hydrochloride. LC-MS (ESI) m/z: 351.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.94 (d, J = 2.2 Hz, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.04 (t, J = 2.2 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 3.7 Hz, 1H), 7.31 (d,J＝3.7Hz,1H),7.20(td,J＝10.1,8.7,2.0Hz,2H),6.47(d,J＝2.1Hz,1H),5.87(s,1H),5.81(s,1H),5.52(s,2H),4.36(m,J＝255.2Hz,8H),1.48(s,3H ),1.44(s,3H).
实施例96
Embodiment 96
合成方法Synthesis method
化合物96的合成方法参照实施例79，区别在于把步骤八中的甲乙胺替换为水。LC-MS(ESI)m/z:571.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ11.82(s,1H),11.58(s,1H),7.99(t,J＝8.4Hz,2H),7.82(d,2H),7.41(s,1H),7.32(ddd,J＝12.5,8.4,1.7Hz,2H),5.33(s,2H),3.98(d,J＝12.4Hz,1H),3.86(t,J＝11.7Hz,1H),3.81(d,J＝13.1Hz,1H),3.05(t,J＝12.6Hz,1H),2.04-1.99(m,2H),1.85-1.81(m,1H),1.77(q,1H),1.48-1.44(m,1H).The synthesis method of compound 96 is similar to that of Example 79, except that methylethylamine in step eight is replaced by water. LC-MS (ESI) m/z: 571.1 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ11.82(s,1H),11.58(s,1H),7.99(t,J＝8.4Hz,2H),7.82(d,2H),7.41(s,1H),7.32(ddd,J＝12.5,8.4,1.7Hz,2H),5.33(s,2H),3.98(d,J＝12.4Hz,1H ),3.86(t,J＝11.7Hz,1H),3.81(d,J＝13.1Hz,1H),3.05(t,J＝12.6Hz,1H),2.04-1.99(m,2H),1.85-1.81(m,1H),1.77(q,1H),1.48-1.44(m,1H).
实施例97
Embodiment 97
合成方法Synthesis method
化合物97的合成方法参照实施例68，区别在于把步骤八中的二甲胺替换为甲乙异丙基胺。LC-MS(ESI)m/z:338.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ9.19(d,J＝4.4Hz,1H),8.65(d,J＝2.1Hz,1H),8.31(t,J＝2.0Hz,1H),7.99(d,J＝8.8Hz,1H),7.89(d,J＝8.8Hz,1H),7.69(d,1H),7.57(s,1H),7.25(dd,J＝8.8,1.9Hz,1H),7.17(dd,J＝8.7Hz,1H),6.58(d,J＝1.9Hz,1H),5.43(s,2H),4.87-4.78(m,1H),4.77-4.67(m,1H),3.17(s,3H),3.07(s,3H),1.30(d,J＝6.6Hz,6H),1.23(d,J＝6.6Hz,6H). The synthesis method of compound 97 refers to Example 68, except that dimethylamine in step eight is replaced by methylethylisopropylamine. LC-MS (ESI) m/z: 338.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.19 (d, J = 4.4 Hz, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.31 (t, J = 2.0 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.69 (d, 1H), 7.57 (s, 1H), 7.25 (dd, J = 8.8, 1.9 Hz, 1H) ,7.17(dd,J＝8.7Hz,1H),6.58(d,J＝1.9Hz,1H),5.43(s,2H),4.87-4.78(m,1H),4.77-4.67(m,1H),3.17(s,3H),3.07(s,3H),1.30(d,J＝6.6Hz,6H),1. 23(d,J＝6.6Hz,6H).
实施例98
Embodiment 98
合成方法Synthesis method
化合物98的合成方法参照实施例47，区别在于把步骤五中的二甲胺替换为3-甲基-氮杂环丁烷盐酸盐。LC-MS(ESI)m/z:335.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)8.93(d,J＝2.2Hz,1H),8.39(d,J＝2.2Hz,1H),8.04(t,J＝2.2Hz,1H),7.84(d,J＝8.8Hz,1H),7.77(d,J＝8.7Hz,1H),7.65(d,J＝2.0Hz,1H),7.58(d,J＝3.7Hz,1H),7.30(d,J＝3.6Hz,1H),7.20(td,J＝8.3,2.0Hz,2H),6.46(d,J＝2.0Hz,1H),5.51(s,2H),4.35(m,J＝208.4Hz,8H),2.95-2.80(m,2H),1.30(d,J＝6.9Hz,3H),1.26(d,J＝6.9Hz,3H).The synthesis method of compound 98 refers to Example 47, except that the dimethylamine in step 5 is replaced by 3-methyl-azetidine hydrochloride. LC-MS (ESI) m/z: 335.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) 8.93 (d, J = 2.2 Hz, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.04 (t, J = 2.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 3.7 Hz, 1H), 7.30 (d, J＝3.6Hz,1H),7.20(td,J＝8.3,2.0Hz,2H),6.46(d,J＝2.0Hz,1H),5.51(s,2H),4.35(m,J＝208.4Hz,8H),2.95-2.80(m,2H),1.30(d,J＝6.9Hz,3H),1.26(d ,J＝6.9Hz,3H).
实施例99
Embodiment 99
合成方法Synthesis method
化合物99的合成方法参照实施例47，区别在于把步骤五中的二甲胺替换为3,3-二氟氮杂环丁烷盐酸盐。LC-MS(ESI)m/z:357.5[M/2+H]+.1H NMR(400MHz,DMSO-d6)8.96(d,J＝2.1Hz,1H),8.41(d,J＝2.2Hz,1H),8.06(t,J＝2.2Hz,1H),7.83(d,J＝8.7Hz,1H),7.77(d,J＝8.5Hz,2H),7.59(d,J＝3.7Hz,1H),7.33(d,J＝3.7Hz,1H),7.25(td,J＝8.5,2.0Hz,2H),6.53(d,J＝2.0Hz,1H),5.56(s,2H),5.11-4.76(m,8H).The synthesis method of compound 99 refers to Example 47, except that the dimethylamine in step 5 is replaced by 3,3-difluoroazetidine hydrochloride. LC-MS(ESI)m/z:357.5[M/2+H] + . 1 H NMR(400MHz, DMSO-d 6 )8.96(d,J＝2.1Hz,1H),8.41(d,J＝2.2Hz,1H),8.06(t,J＝2.2Hz,1H),7.83(d,J＝8.7Hz,1H),7.77(d ,J＝8.5Hz,2H),7.59(d,J＝3.7Hz,1H),7.33(d,J＝3.7Hz,1H),7.25(td,J＝8.5,2.0Hz,2H),6.53(d,J＝2.0Hz,1H),5.56(s,2H),5.11-4.76(m,8H).
实施例100
Embodiment 100
合成方法Synthesis method
化合物100的合成方法参照实施例68，区别在于把步骤八中的二甲胺替换为氮杂环丁烷。LC-MS(ESI)m/z:322.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ9.20(d,J＝1.9Hz,1H),8.61(d,J＝2.2Hz,1H),8.28(t,J＝2.0Hz,1H),7.86(d,J＝8.8Hz,1H),7.78(d,J＝8.7Hz,1H),7.65(d,J＝1.7Hz,1H),7.56(s,1H),7.25(dd,J＝8.7,1.9Hz,1H),7.18(dd,J＝8.7,1.8Hz,1H),6.58(d,J＝1.9Hz,1H),5.46(s,2H),2.50-2.37(m,8H),1.24(s, 2H),0.89-0.77(m,2H).The synthesis method of compound 100 is similar to that of Example 68, except that dimethylamine in step eight is replaced by azetidine. LC-MS (ESI) m/z: 322.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ9.20(d,J＝1.9Hz,1H),8.61(d,J＝2.2Hz,1H),8.28(t,J＝2.0Hz,1H),7.86(d,J＝8.8Hz,1H),7.78(d,J＝8.7Hz,1H),7.65(d,J＝1.7Hz,1H),7.56(s,1H),7. 25(dd,J＝8.7,1.9Hz,1H),7.18(dd,J＝8.7,1.8Hz,1H),6.58(d,J＝1.9Hz,1H),5.46(s,2H),2.50-2.37(m,8H),1.24(s, 2H), 0.89-0.77 (m, 2H).
实施例101
Embodiment 101
合成路线
Synthetic route
步骤一：化合物101-1的合成Step 1: Synthesis of compound 101-1
室温下将2,4,7-三氯喹唑啉(5.0g，21.44mmol)溶解在50mL四氢呋喃(THF)中，向其中加入N-乙基甲基胺的四氢呋喃溶液(2M)15mL(31.12mmol)，室温下搅拌16h。TLC监测完全反应，减压旋蒸浓缩后得到化合物101-1(3.7g，白色固体)，无需纯化直接用于下一步反应，产率68％。LC-MS(ESI)m/z:256[M+H]+.2,4,7-Trichloroquinazoline (5.0 g, 21.44 mmol) was dissolved in 50 mL of tetrahydrofuran (THF) at room temperature, 15 mL (31.12 mmol) of a tetrahydrofuran solution of N-ethylmethylamine (2M) was added thereto, and the mixture was stirred at room temperature for 16 h. The reaction was completely monitored by TLC, and the compound 101-1 (3.7 g, white solid) was obtained after vacuum rotary evaporation and concentration, which was directly used in the next step without purification, with a yield of 68%. LC-MS (ESI) m/z: 256 [M + H] + .
步骤二：化合物101-2的合成Step 2: Synthesis of compound 101-2
室温下，将化合物101-1(3.7g，14.45mmol)溶解在50mL冰醋酸中，升温至100℃搅拌16h。TLC监测完全反应，反应体系中加饱和碳酸氢钠溶液淬灭，用乙酸乙酯(80mL x3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(二氯甲烷：甲醇，0-20％，15min)得到化合物101-2(3.1g，淡黄色固体)，产率90％。LC-MS(ESI)m/z:238.0[M+H]+. At room temperature, compound 101-1 (3.7 g, 14.45 mmol) was dissolved in 50 mL of glacial acetic acid, heated to 100 ° C and stirred for 16 h. TLC monitored the complete reaction, quenched the reaction system with saturated sodium bicarbonate solution, extracted with ethyl acetate (80 mL x3), and washed the organic phase with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-20%, 15 min) to obtain compound 101-2 (3.1 g, light yellow solid) with a yield of 90%. LC-MS (ESI) m/z: 238.0 [M + H] + .
步骤三：化合物101-3的合成Step 3: Synthesis of compound 101-3
室温下，将化合物101-2(1.0g，4.20mmol)溶解在10mLN,N-二甲基甲酰胺中，向其中加入2-溴-5-溴甲基噻唑(1.3g，5.04mmol)和碳酸钾(1.8g，12.61mmol)，室温下搅拌16h。TLC监测完全反应，反应体系中加水，用乙酸乙酯(30mLx3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物101-3(970mg，白色固体)，产率56％。LC-MS(ESI)m/z:413[M+H]+.At room temperature, compound 101-2 (1.0 g, 4.20 mmol) was dissolved in 10 mL of N, N-dimethylformamide, 2-bromo-5-bromomethylthiazole (1.3 g, 5.04 mmol) and potassium carbonate (1.8 g, 12.61 mmol) were added thereto, and stirred at room temperature for 16 h. TLC monitored the complete reaction, water was added to the reaction system, extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 101-3 (970 mg, white solid) with a yield of 56%. LC-MS (ESI) m/z: 413 [M + H] + .
步骤四：化合物101-4的合成Step 4: Synthesis of compound 101-4
0℃下将草酰氯(5.5g，43.01mmol)滴加到4-氯-2-氟苯甲酰胺(3.7g，21.51mmol)的二氯乙烷DCE(50mL)中。氮气保护下，反应混合液在70℃搅拌过夜，减压除去多余的草酰氯后，用DCE(20mL)稀释后滴入1-Boc-3-氨基吡咯烷(2.0g，10.75mmol)的DCE(30mL)体系中，反应在室温下搅拌3h。TLC监测完全反应。反应体系加入乙腈打浆过滤后得到化合物101-4(3.7g，白色固体)，产率89％。LC-MS(ESI)m/z:386[M+H]+.Oxalyl chloride (5.5 g, 43.01 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (3.7 g, 21.51 mmol) in dichloroethane (50 mL) at 0 ° C. Under nitrogen protection, the reaction mixture was stirred at 70 ° C overnight. After removing excess oxalyl chloride under reduced pressure, it was diluted with DCE (20 mL) and then added dropwise to 1-Boc-3-aminopyrrolidine (2.0 g, 10.75 mmol) in DCE (30 mL) system. The reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction. Acetonitrile was added to the reaction system and the mixture was pulped and filtered to obtain compound 101-4 (3.7 g, white solid) with a yield of 89%. LC-MS (ESI) m/z: 386 [M + H] + .
步骤五：化合物101-5的合成Step 5: Synthesis of compound 101-5
0℃下将氢化钠(960mg，24.03mmol)加入到化合物4(3.7g，9.61mmol)的N,N-二甲基甲酰胺DMF(40mL)中，氮气保护下，升温至90℃搅拌3h。LC-MS检测原料基本消失。反应体系加水淬灭，滴加稀盐酸(0.5mol/L)至pH为中性，过滤后固体用乙腈打浆，再次过滤后得到化合物101-5(2.7g，白色固体)，产率77％。LC-MS(ESI)m/z:366[M+H]+.Sodium hydride (960 mg, 24.03 mmol) was added to compound 4 (3.7 g, 9.61 mmol) in DMF (40 mL) at 0 °C, and the mixture was heated to 90 °C and stirred for 3 h under nitrogen protection. LC-MS detected that the raw material was basically gone. The reaction system was quenched with water, and dilute hydrochloric acid (0.5 mol/L) was added dropwise until the pH was neutral. After filtration, the solid was slurried with acetonitrile and filtered again to obtain compound 101-5 (2.7 g, white solid) with a yield of 77%. LC-MS (ESI) m/z: 366 [M+H] + .
步骤六：化合物101-6的合成Step 6: Synthesis of compound 101-6
室温下将化合物101-5(2.7g，7.40mmol)溶解在30mL乙腈中，向其中加入1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(5.8g，11.10mmol)和二甲胺的四氢呋喃溶液(9mL，18.49mmol)，而后逐滴加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)(3.9g，25.89mmol)。反应混合液在室温下搅拌30min，TLC监测完全反应。粗产品通过硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)得到化合物101-6(2.1g，白色固体)，产率72％。LC-MS(ESI)m/z:393[M+H]+.Compound 101-5 (2.7 g, 7.40 mmol) was dissolved in 30 mL of acetonitrile at room temperature, 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate (5.8 g, 11.10 mmol) and a tetrahydrofuran solution of dimethylamine (9 mL, 18.49 mmol) were added thereto, and then 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.9 g, 25.89 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 min, and the complete reaction was monitored by TLC. The crude product was subjected to silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min) to obtain compound 101-6 (2.1 g, white solid) with a yield of 72%. LC-MS (ESI) m/z: 393 [M+H] + .
步骤七：化合物101-7的合成Step 7: Synthesis of Compound 101-7
室温下将化合物101-6(2.1g，5.36mmol)溶解在20mL1,4-二氧六环中，向其中加入盐酸-二氧六环溶液20mL，室温下搅拌30min。TLC监测完全反应，浓缩后得到化合物101-7的盐酸盐(1.7g，白色固体)，产率97％。LC-MS(ESI)m/z:292[M+H]+.步骤八：化合物101的合成Compound 101-6 (2.1 g, 5.36 mmol) was dissolved in 20 mL of 1,4-dioxane at room temperature, and 20 mL of hydrochloric acid-dioxane solution was added thereto, and stirred at room temperature for 30 min. TLC monitored the complete reaction, and after concentration, the hydrochloride of compound 101-7 (1.7 g, white solid) was obtained with a yield of 97%. LC-MS (ESI) m/z: 292 [M+H] + . Step 8: Synthesis of compound 101
室温下将化合物101-7(50mg，0.15mmol)溶解在1mL N,N-二甲基甲酰胺中，向其中加入化合物101-3(62mg，0.15mmol)和碳酸铯(148mg，0.45mmol)。反应混合液在120℃下搅拌16h。LC-MS检测完全反应。经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，HPLC制备纯化后得到化合物101(1.27mg，白色固体)，产率1.36％。LC-MS(ESI)m/z:313.1[M/2+H]+.1HNMR(400MHz,DMSO-d6)δ7.90(dd,J＝8.8,4.8Hz,2H),7.72(dd,J＝12.4,2.0Hz,2H),7.38(s,1H),7.20(d,2H),5.29(s,2H),3.75-3.69(m,1H),3.66(q,2H),3.64-3.61(m,1H),3.41(q,1H),3.22(s,9H),2.71-2.55(m,2H),2.30-2.21(m,1H),1.51-1.39(m,1H),1.29(t,J＝7.3Hz,3H).Compound 101-7 (50 mg, 0.15 mmol) was dissolved in 1 mL of N,N-dimethylformamide at room temperature, and compound 101-3 (62 mg, 0.15 mmol) and cesium carbonate (148 mg, 0.45 mmol) were added thereto. The reaction mixture was stirred at 120 ° C for 16 h. LC-MS detected the complete reaction. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 101 (1.27 mg, white solid) was obtained after HPLC preparation and purification, with a yield of 1.36%. LC-MS(ESI)m/z:313.1[M/2+H] + . 1 HNMR(400MHz,DMSO-d 6 )δ7.90(dd,J＝8.8,4.8Hz,2H),7.72(dd,J＝12.4,2.0Hz,2H),7.38(s,1H),7.20(d,2H),5.29(s,2H),3.75-3.69(m,1H),3.66(q,2H),3.64-3.61(m,1H),3.41(q,1H),3.22(s,9H),2.71-2.55(m,2H),2.30-2.21(m,1H),1.51-1.39(m,1H),1.29(t,J＝7.3Hz,3H).
实施例102
Embodiment 102
合成路线
Synthetic route
步骤一：化合物102-1的合成Step 1: Synthesis of compound 102-1
0℃下将草酰氯(5.5g，43.01mmol)滴加到4-氯-2-氟苯甲酰胺(3.7g，21.51mmol)的二氯乙烷DCE(50mL)中。氮气保护下，反应混合液在70℃搅拌过夜，减压除去多余的草酰氯后，用DCE(20mL)稀释后滴入1-叔丁氧羰基-3-氨基哌啶(2.0g，9.98mmol)的DCE(30mL)体系中，反应在室温下搅拌3h。TLC监测完全反应。反应体系加入乙腈打浆过滤后得到化合物102-1(3.9g，白色固体)，产率98％。LC-MS(ESI)m/z:400[M+H]+.Oxalyl chloride (5.5 g, 43.01 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (3.7 g, 21.51 mmol) in dichloroethane (50 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride under reduced pressure, it was diluted with DCE (20 mL) and then added dropwise to a DCE (30 mL) system of 1-tert-butyloxycarbonyl-3-aminopiperidine (2.0 g, 9.98 mmol), and the reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction. Acetonitrile was added to the reaction system and the mixture was pulped and filtered to obtain compound 102-1 (3.9 g, white solid) with a yield of 98%. LC-MS (ESI) m/z: 400[M+H] + .
步骤二：化合物102-2的合成Step 2: Synthesis of compound 102-2
0℃下将氢化钠(980mg，24.43mmol)加入到化合物102-1(3.9g，9.77mmol)的N,N-二甲基甲酰胺DMF(40mL)中，氮气保护下，升温至90℃搅拌3h。LC-MS检测原料基本消失。反应体系加水淬灭，滴加稀盐酸(0.5mol/L)至pH为中性，过滤后固体用乙腈打浆，再次过滤后得到化合物102-2(2.2g，白色固体)，产率59％。LC-MS(ESI)m/z:380[M+H]+.Sodium hydride (980 mg, 24.43 mmol) was added to compound 102-1 (3.9 g, 9.77 mmol) in DMF (40 mL) at 0°C, and the mixture was heated to 90°C and stirred for 3 h under nitrogen protection. LC-MS detected that the raw material was basically gone. The reaction system was quenched with water, and dilute hydrochloric acid (0.5 mol/L) was added dropwise until the pH was neutral. After filtration, the solid was slurried with acetonitrile and filtered again to obtain compound 102-2 (2.2 g, white solid) with a yield of 59%. LC-MS (ESI) m/z: 380 [M+H] + .
步骤三：化合物102-3的合成Step 3: Synthesis of compound 102-3
室温下将化合物102-2(2.2g，5.80mmol)溶解在30mL乙腈中，向其中加入1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(4.5g，8.71mmol)和二甲胺的四氢呋喃溶液(8mL，14.51mmol)，而后逐滴加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)(3.1g，20.31mmol)。反应混合液在室温下搅拌30min，TLC监测完全反应。粗产品通过硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)得到化合物102-3(2.0g，白色固体)，产率85％。LC-MS(ESI)m/z:407[M+H]+.Compound 102-2 (2.2 g, 5.80 mmol) was dissolved in 30 mL of acetonitrile at room temperature, 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate (4.5 g, 8.71 mmol) and a tetrahydrofuran solution of dimethylamine (8 mL, 14.51 mmol) were added thereto, and then 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.1 g, 20.31 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 min, and the complete reaction was monitored by TLC. The crude product was subjected to silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min) to obtain compound 102-3 (2.0 g, white solid) with a yield of 85%. LC-MS (ESI) m/z: 407 [M+H] + .
步骤四：化合物102-4的合成 Step 4: Synthesis of compound 102-4
室温下将化合物102-3(2.0g，4.92mmol)溶解在20mL1,4-二氧六环中，向其中加入盐酸-二氧六环溶液20mL，室温下搅拌30min。TLC监测完全反应，浓缩得到化合物102-4的盐酸盐(1.5g，白色固体)，产率89％。LC-MS(ESI)m/z:307[M+H]+.步骤五：化合物102的合成Compound 102-3 (2.0 g, 4.92 mmol) was dissolved in 20 mL of 1,4-dioxane at room temperature, and 20 mL of hydrochloric acid-dioxane solution was added thereto, and stirred at room temperature for 30 min. TLC monitored the complete reaction, and the hydrochloride of compound 102-4 (1.5 g, white solid) was obtained by concentration, with a yield of 89%. LC-MS (ESI) m/z: 307 [M+H] + . Step 5: Synthesis of compound 102
室温下将化合物102-4(15mg，0.05mmol)溶解在1mL N,N-二甲基甲酰胺中，向其中加入化合物101-3(20mg，0.05mmol)和碳酸铯(50mg，0.15mmol)。反应混合液在120℃下搅拌16h。LC-MS检测完全反应。经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，HPLC制备纯化后得到化合物102(1.22mg，白色固体)，产率3.8％。LC-MS(ESI)m/z:319.1[M/2+H]+.1HNMR(400MHz,DMSO-d6)δ7.90(dd,J＝8.8,4.4Hz,2H),7.79(dd,J＝17.2,2.0Hz,2H),7.41(s,1H),7.20(td,J＝8.9,7.1,1.9Hz,2H),5.29(d,J＝3.8Hz,2H),4.22-4.13(m,1H),4.00-3.93(m,2H),3.89(t,1H),3.72(d,J＝13.3Hz,1H),3.64(q,J＝7.0Hz,2H),3.34(t,3H),3.22(s,3H),3.21(s,6H),3.16-3.05(m,1H),2.81-2.70(m,1H),2.04-1.99(m,2H).Compound 102-4 (15 mg, 0.05 mmol) was dissolved in 1 mL of N,N-dimethylformamide at room temperature, and compound 101-3 (20 mg, 0.05 mmol) and cesium carbonate (50 mg, 0.15 mmol) were added thereto. The reaction mixture was stirred at 120°C for 16 h. LC-MS detected the complete reaction. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 102 (1.22 mg, white solid) was obtained after HPLC preparation and purification, with a yield of 3.8%. LC-MS (ESI) m/z: 319.1 [M/2+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ7.90(dd,J＝8.8,4.4Hz,2H),7.79(dd,J＝17.2,2.0Hz,2H),7.41(s,1H),7.20(td,J＝8.9,7.1,1.9Hz,2H),5.29(d,J＝3.8Hz,2H),4.22-4.13(m,1H),4.0 0-3.93(m ,2H),3.89(t,1H),3.72(d,J＝13.3Hz,1H),3.64(q,J＝7.0Hz,2H),3.34(t,3H),3.22(s,3H),3.21(s,6H),3.16-3.05(m,1H),2.81-2.70(m,1H),2.0 4-1.99(m,2H).
实施例103
Embodiment 103
合成方法Synthesis method
化合物103的合成方法参照实施例68，区别在于把步骤八中的二甲胺替换为3-甲基氮杂环丁烷盐酸盐。LC-MS(ESI)m/z:336.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ9.19(d,J＝2.0Hz,1H),8.61(d,J＝2.3Hz,1H),8.28(d,J＝2.4Hz,1H),7.86(d,J＝8.8Hz,1H),7.78(d,J＝8.7Hz,1H),7.65(d,J＝2.0Hz,1H),7.56(s,1H),7.24(dd,J＝8.7,2.0Hz,1H),7.18(dd,J＝8.7,1.9Hz,1H),6.57(d,J＝2.0Hz,1H),5.46(s,2H),5.10-3.75(m,8H),1.31(d,J＝6.9Hz,3H),1.27(d,J＝6.9Hz,3H).The synthesis method of compound 103 is similar to that of Example 68, except that the dimethylamine in step eight is replaced by 3-methylazetidine hydrochloride. LC-MS (ESI) m/z: 336.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.19(d,J＝2.0Hz,1H),8.61(d,J＝2.3Hz,1H),8.28(d,J＝2.4Hz,1H),7.86(d,J＝8.8Hz,1H),7.78(d,J＝8.7Hz,1H),7.65(d,J＝2.0Hz,1H),7.56(s,1H),7 .24(dd,J＝8.7,2.0Hz,1H),7.18(dd,J＝8.7,1.9Hz,1H),6.57(d,J＝2.0Hz,1H),5.46(s,2H),5.10-3.75(m,8H),1.31(d,J＝6.9Hz,3H),1.27(d,J＝6.9Hz,3 H).
实施例104
Embodiment 104
合成方法Synthesis method
化合物104的合成方法参照实施例68，区别在于把步骤八中的二甲胺替换为3,3-二氟氮杂环丁烷盐酸盐。LC-MS(ESI)m/z:358.0[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ9.22(d,J＝2.0Hz,1H),8.63(d,J＝2.3Hz,1H),8.31(t,J＝2.3Hz,1H),7.85(d,J＝8.8Hz,1H),7.80-7.72(m,2H),7.62(s,1H),7.28(dd,J＝8.7,2.0Hz,1H),7.22(dd,J＝8.6,1.9Hz,1H),6.66(s,1H),5.51(s,2H),5.18-4.78(m,8H).The synthesis method of compound 104 was similar to that of Example 68, except that dimethylamine in step eight was replaced by 3,3-difluoroazetidine hydrochloride. LC-MS(ESI)m/z:358.0[M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 )δ9.22(d,J＝2.0Hz,1H),8.63(d,J＝2.3Hz,1H),8.31(t,J＝2.3Hz,1H),7.85(d,J＝8.8Hz,1H),7.80- 7.72(m,2H),7.62(s,1H),7.28(dd,J＝8.7,2.0Hz,1H),7.22(dd,J＝8.6,1.9Hz,1H),6.66(s,1H),5.51(s,2H),5.18-4.78(m,8H).
实施例105
Embodiment 105
合成方法Synthesis method
化合物105的合成方法参照实施例68，区别在于把步骤八中的二甲胺替换为氮杂环丁烷-3-甲腈盐酸盐。LC-MS(ESI)m/z:347.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ9.20(d,J＝2.0Hz,1H),8.62(d,J＝2.3Hz,1H),8.29(t,J＝2.3Hz,1H),7.82(d,J＝8.8Hz,1H),7.75-7.69(m,2H),7.59(s,1H),7.26(dd,J＝8.7,2.0Hz,1H),7.20(dd,J＝8.7,2.0Hz,1H),6.62(d,J＝2.0Hz,1H),5.48(s,2H),5.12-4.32(m,8H),4.04(tt,J＝8.9,6.1Hz,1H),3.98(tt,J＝9.1,6.1Hz,1H).The synthesis method of compound 105 is similar to that of Example 68, except that the dimethylamine in step eight is replaced by azetidine-3-carbonitrile hydrochloride. LC-MS (ESI) m/z: 347.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ9.20(d,J＝2.0Hz,1H),8.62(d,J＝2.3Hz,1H),8.29(t,J＝2.3Hz,1H),7.82(d,J＝8.8Hz,1H),7.75-7.69(m,2H),7.59(s,1H),7.26(dd,J＝8.7,2.0Hz,1H) ,7.20(dd,J＝8.7,2.0Hz,1H),6.62(d,J＝2.0Hz,1H),5.48(s,2H),5.12-4.32(m,8H),4.04(tt,J＝8.9,6.1Hz,1H),3.98(tt,J＝9.1,6.1Hz,1H).
实施例106
Embodiment 106
合成方法Synthesis method
化合物106的合成方法参照实施例101，区别在于把步骤一中的甲乙胺替换为二甲胺。LC-MS(ESI)m/z:306.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝9.0Hz,1H),7.91(d,1H),7.72(dd,J＝13.6,2.0Hz,2H),7.38(s,1H),7.20(d,J＝8.6Hz,2H),5.30(s,2H),4.07-3.96(m,1H),3.75-3.69(m,1H),3.68-3.63(m,1H),3.24(s,6H),3.22(s,6H),2.64-2.57(m,1H),2.27(q,J＝8.1,4.1Hz,1H),2.04-1.99(m,2H).The synthesis method of compound 106 is similar to that of Example 101, except that methylethylamine in step 1 is replaced by dimethylamine. LC-MS (ESI) m/z: 306.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.97(d,J＝9.0Hz,1H),7.91(d,1H),7.72(dd,J＝13.6,2.0Hz,2H),7.38(s,1H),7.20(d,J＝8.6Hz,2H),5.30(s,2H),4.07-3.96(m,1H),3.75-3.69(m,1 H),3.68-3.63(m,1H),3.24(s,6H),3.22(s,6H),2.64-2.57(m,1H),2.27(q,J＝8.1,4.1Hz,1H),2.04-1.99(m,2H).
实施例107
Embodiment 107
合成方法Synthesis method
化合物107的合成方法参照实施例68，区别在于把步骤八中的二甲胺替换为N,O-二甲基羟胺。LC-MS(ESI)m/z:326.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ9.23(d,J＝2.1Hz,1H),8.66(d,J＝2.2Hz,1H),8.54(d,J＝9.0Hz,1H),8.46(d,J＝9.0Hz,1H),8.36(d,J＝2.3Hz,1H),7.72(d,J＝2.1Hz,1H),7.61(s,1H),7.31(dd,J＝9.0,2.2Hz,1H),7.26(dd,J＝9.0,2.0Hz,1H),6.63(d,J＝2.3Hz,1H),5.51(s,2H),3.86(s,3H),3.79(s,3H).3.52(s,6H).The synthesis method of compound 107 is similar to that of Example 68, except that the dimethylamine in step eight is replaced by N,O-dimethylhydroxylamine. LC-MS (ESI) m/z: 326.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ9.23(d,J＝2.1Hz,1H),8.66(d,J＝2.2Hz,1H),8.54(d,J＝9.0Hz,1H),8.46(d,J＝9.0Hz,1H),8.36(d,J＝2.3Hz,1H),7.72(d,J＝2.1Hz,1H),7.61(s,1H),7 .31(dd,J＝9.0,2.2Hz,1H),7.26(dd,J＝9.0,2.0Hz,1H),6.63(d,J＝2.3Hz,1H),5.51(s,2H),3.86(s,3H),3.79(s,3H).3.52(s,6H).
实施例108
Embodiment 108
合成方法Synthesis method
化合物108的合成方法参照实施例68，区别在于把步骤八中的二甲胺替换为3-甲基-3-氮杂环丁烷醇盐酸盐。LC-MS(ESI)m/z:352.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ9.20(d,J＝2.0Hz,1H),8.62(d,J＝2.3Hz,1H),8.29(d,J＝2.4Hz,1H),7.87(d,J＝8.8Hz,1H),7.79(d,J＝8.7Hz,1H),7.66(d,J＝2.0Hz,1H),7.57(s,1H),7.23(dd,J＝8.6,2.0Hz,1H),7.17(dd,J＝8.8,1.9Hz,1H),6.58(d,J＝2.0Hz,1H),5.88(s,1H),5.81(s,1H),5.46(s,2H),4.88-3.95(m,8H),1.49(s,3H),1.45(s,3H).The synthesis method of compound 108 is similar to that of Example 68, except that the dimethylamine in step eight is replaced by 3-methyl-3-azetidinol hydrochloride. LC-MS (ESI) m/z: 352.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ9.20(d,J＝2.0Hz,1H),8.62(d,J＝2.3Hz,1H),8.29(d,J＝2.4Hz,1H),7.87(d,J＝8.8Hz,1H),7.79(d,J＝8.7Hz,1H),7.66(d,J＝2.0Hz,1H),7.57(s,1H),7. 23(dd,J＝8.6,2.0Hz,1H),7.17(dd,J＝8.8,1.9Hz,1H),6.58(d,J＝2.0Hz,1H),5.88(s,1H),5.81(s,1H),5.46(s,2H),4.88-3.95(m,8H),1.49(s,3H),1. 45(s,3H).
实施例109&110
Embodiment 109 & 110
将化合物79通过SFC拆分得到单一构型化合物109(79-P1)和110(79-P2)。Compound 79 was resolved by SFC to give single-configuration compounds 109 (79-P1) and 110 (79-P2).
实施例111&112
Embodiment 111 & 112
将化合物80通过SFC拆分得到单一构型化合物111和112。Compound 80 was resolved by SFC to give single-configuration compounds 111 and 112.
实施例113&114
Embodiment 113 & 114
合成路线
Synthetic route
步骤一：化合物113-1的合成Step 1: Synthesis of compound 113-1
室温下，将哌嗪(930mg,10.8mmol)溶于20mL无水乙腈中，加入1-溴-2-丁醇(5g，32.7mmol)和碳酸钾(6.4g，46.4mmol)，之后升温至80℃反应过夜。TLC点板后用碘显色剂显色监测反应完全，温度降至室温后过滤除去碳酸钾，滤液浓缩后通过柱层析纯化得到1.4g化合物113-1，白色固体，收率64％。LC-MS(ESI)m/z:231[M+H]+.At room temperature, piperazine (930 mg, 10.8 mmol) was dissolved in 20 mL of anhydrous acetonitrile, 1-bromo-2-butanol (5 g, 32.7 mmol) and potassium carbonate (6.4 g, 46.4 mmol) were added, and then the temperature was raised to 80°C for overnight reaction. After TLC plate spotting, iodine colorimetric agent was used to monitor the reaction completion. After the temperature was lowered to room temperature, potassium carbonate was filtered out, and the filtrate was concentrated and purified by column chromatography to obtain 1.4 g of compound 113-1 as a white solid with a yield of 64%. LC-MS (ESI) m/z: 231 [M+H] + .
步骤二：化合物113-2的合成Step 2: Synthesis of compound 113-2
室温下，将化合物113-1(1.4g,6.93mmol)溶于20mL干燥的二氯甲烷中，降温至0℃，分批次加入四溴化碳(6.4g，19.3mmol)，之后分批加入三苯基膦(3.4g，13.0mmol)，缓慢升至室温后搅拌2小时。TLC点板后用碘显色剂显色监测反应完全，体系经快速色谱柱层析分离(PE:EA,0-100％,15min)得到700mg化合物113-2，黄色油状，收率31％。LC-MS(ESI)m/z:355[M+H]+.At room temperature, compound 113-1 (1.4 g, 6.93 mmol) was dissolved in 20 mL of dry dichloromethane, cooled to 0°C, carbon tetrabromide (6.4 g, 19.3 mmol) was added in batches, and then triphenylphosphine (3.4 g, 13.0 mmol) was added in batches, and the mixture was slowly heated to room temperature and stirred for 2 hours. After TLC plate spotting, the reaction was monitored by iodine colorimetric agent. The system was separated by flash chromatography column (PE: EA, 0-100%, 15 min) to obtain 700 mg of compound 113-2, yellow oil, with a yield of 31%. LC-MS (ESI) m/z: 355 [M+H] + .
步骤三：化合物113&114的合成Step 3: Synthesis of compounds 113 & 114
室温下，将7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(100mg,0.446mmol)溶于2mL干燥的DMF中，加入碳酸钾(250mg，1.812mmol)，升温至100℃搅拌20分钟，之后加入化合物113-2(150mg，0.459mmol)，保持100℃搅拌20分钟。LC-MS监测反应完全，体系经快速色谱柱层析分离(EA:MeOH,0-30％,15min)得到50mg粗品混合物。之后经HPLC制备纯化后得化合物113及114。At room temperature, 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (100 mg, 0.446 mmol) was dissolved in 2 mL of dry DMF, potassium carbonate (250 mg, 1.812 mmol) was added, the temperature was raised to 100°C and stirred for 20 minutes, then compound 113-2 (150 mg, 0.459 mmol) was added, and the temperature was kept at 100°C and stirred for 20 minutes. LC-MS monitored the reaction to be complete, and the system was separated by flash chromatography (EA: MeOH, 0-30%, 15 min) to obtain 50 mg of a crude mixture. Compounds 113 and 114 were then prepared and purified by HPLC.
化合物113：12mg，白色固体，收率8％，LC-MS(ESI)m/z:214.4[M/3+H]+.1H NMR(600MHz,DMSO-d6)δ8.15-8.10(m,1H),7.93-7.86(m,1H),7.59-7.47(m,2H),7.29-7.17(m,2H),4.12-3.97(m,2H),3.20(s,3H),3.30-3.24(m,9H),3.23-3.20(m,2H),3.19-3.17(m,2H),3.00-2.94(m,1H),2.93-2.88(m,1H),2.62-2.60(m,2H),2.42-2.36(m,4H),0.93-0.88(m,6H)Compound 113: 12 mg, white solid, yield 8%, LC-MS (ESI) m/z: 214.4 [M/3+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.15-8.10(m,1H),7.93-7.86(m,1H),7.59-7.47(m,2H),7.29-7.17(m,2H),4.12-3.97(m,2H),3.20(s,3H),3.30-3.24(m,9H),3.23-3.20(m,2 H),3.19-3.17(m,2H),3.00-2.94(m,1H),2.93-2.88(m,1H),2.62-2.60(m,2H),2.42-2.36(m,4H),0.93-0.88(m,6H)
化合物114：9mg，白色固体，收率6％，LC-MS(ESI)m/z:214.4[M/3+H]+.1H NMR(600MHz,DMSO-d6)7.94(dd,J＝8.7,3.5Hz,2H),7.55(d,J＝10.6Hz,2H),7.17(d,J＝8.9Hz,2H),4.12-3.94(m,5H),3.49(q,2H),3.30(q,2H),3.22(d,J＝3.2Hz,12H),2.62-2.60(m,2H),2.43-2.41(m,1H),2.39-2.38(m,1H),2.34-2.32(m,2H),2.30-2.28(m,2H),0.88-0.86(m,6H).Compound 114: 9 mg, white solid, yield 6%, LC-MS (ESI) m/z: 214.4 [M/3+H] + . 1 H NMR (600 MHz, DMSO-d 6 )7.94(dd,J＝8.7,3.5Hz,2H),7.55(d,J＝10.6Hz,2H),7.17(d,J＝8.9Hz,2H),4.12-3.94(m,5H),3.49(q,2H),3.30(q,2H),3.22(d,J＝3.2Hz,12H),2.62-2 .60(m,2H),2.43-2.41(m,1H),2.39-2.38(m,1H),2.34-2.32(m,2H),2.30-2.28(m,2H),0.88-0.86(m,6H).
实施例115
Embodiment 115
合成方法Synthesis method
化合物115的合成方法参照实施例68，区别在于把步骤八中的二甲胺替换为4-甲 基哌嗪。LC-MS(ESI)m/z:365.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ9.24(d,J＝2.1Hz,1H),8.66(d,J＝2.3Hz,1H),8.37–8.31(m,1H),7.96(d,J＝8.7Hz,1H),7.88(d,J＝8.7Hz,1H),7.80(d,J＝1.9Hz,1H),7.63(s,1H),7.31(dd,J＝8.7,2.0Hz,1H),7.26(dd,J＝8.7,1.9Hz,1H),6.71(d,J＝2.0Hz,1H),5.50(s,2H),4.55-4.18(m,5H),3.58(s,3H),3.56(s,3H),2.89-2.76(m,11H).The synthesis method of compound 115 is similar to that of Example 68, except that dimethylamine in step eight is replaced by 4-methyl 1H NMR (600MHz, DMSO - d 6 )δ9.24(d,J＝2.1Hz,1H),8.66(d,J＝2.3Hz,1H),8.37–8.31(m,1H),7.96(d,J＝8.7Hz,1H),7.88(d,J＝8.7Hz,1H),7.80(d,J＝1.9Hz,1H),7.63(s,1H),7.3 1(dd,J＝8.7,2.0Hz,1H),7.26(dd,J＝8.7,1.9Hz,1H),6.71(d,J＝2.0Hz,1H),5.50(s,2H),4.55-4.18(m,5H),3.58(s,3H),3.56(s,3H),2.89-2.76(m,11 H).
实施例116
Embodiment 116
合成方法Synthesis method
化合物116的合成方法参照实施例102，区别在于把步骤三中的二甲胺替换为氮杂环丁烷，步骤五中的101-3替换为1-((2-溴噻唑-5-基)甲基)-7-氯-4-(二甲胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:319.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(d,J＝8.8Hz,1H),7.77(dd,J＝5.7,2.0Hz,2H),7.73(d,J＝8.6Hz,1H),7.41(s,1H),7.19(td,2H),5.29(d,J＝6.4Hz,2H),4.71-4.08(m,4H),3.95-3.87(m,2H),3.72(d,J＝13.3Hz,1H),3.24(s,6H),3.09(td,J＝13.0,4.3Hz,1H),2.77(q,J＝15.6Hz,1H),2.37(q,2H),2.04-1.95(m,1H),1.80-1.72(m,2H),1.70(d,J＝12.0Hz,1H).The synthesis method of compound 116 is similar to that of Example 102, except that dimethylamine in step 3 is replaced by azetidine, and 101-3 in step 5 is replaced by 1-((2-bromothiazol-5-yl)methyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 319.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.97(d,J＝8.8Hz,1H),7.77(dd,J＝5.7,2.0Hz,2H),7.73(d,J＝8.6Hz,1H),7.41(s,1H),7.19(td,2H),5.29(d,J＝6.4Hz,2H),4.71-4.08(m,4H),3.95- 3.87(m,2H), 3.72(d,J＝13.3Hz,1H),3.24(s,6H),3.09(td,J＝13.0,4.3Hz,1H),2.77(q,J＝15.6Hz,1H),2.37(q,2H),2.04-1.95(m,1H),1.80-1.72(m,2H),1.70( d,J＝12.0Hz,1H).
实施例117
Embodiment 117
合成方法Synthesis method
化合物117的合成方法参照实施例102，区别在于把步骤三中的二甲胺替换为氮杂环丁烷。LC-MS(ESI)m/z:326.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.84(d,J＝8.8Hz,1H),7.72(dd,J＝5.7,2.0Hz,2H),7.65(d,J＝8.6Hz,1H),7.41(s,1H),7.16(td,2H),5.27(d,J＝6.4Hz,2H),4.74-4.18(m,4H),3.99-3.79(m,2H),3.72(q,2H),3.62(m,1H),3.29(s,3H),3.13(t,3H),3.09(td,J＝13.0,4.3Hz,1H),2.77(q,J＝15.6Hz,1H),2.27(q,2H),2.19-1.95(m,1H),1.82-1.74(m,2H),1.66(d,J＝12.0Hz,1H).The synthesis method of compound 117 refers to Example 102, except that the dimethylamine in step 3 is replaced by azetidine. LC-MS (ESI) m/z: 326.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ7.84 (d, J=8.8 Hz, 1H), 7.72 (dd, J=5.7, 2.0 Hz, 2H), 7.65 (d, J=8.6 Hz, 1H), 7.41 (s, 1H), 7.16 (td, 2H), 5.27 (d, J=6.4 Hz, 2H), 4.74-4.18 (m, 4H), 3.99-3.79 (m, 2H), 3.72 (q, 2H),3.62(m,1H),3.29(s,3H),3.13(t,3H),3.09(td,J＝13.0,4.3Hz,1H),2.77(q,J＝15.6Hz,1H),2.27(q,2H),2.19-1.95(m,1H),1.82-1.74(m,2H ),1.66(d,J=12.0Hz,1H).
实施例118
Embodiment 118
合成方法Synthesis method
化合物118的合成方法参照实施例101，区别在于把步骤一中的甲乙胺替换为二甲 胺，步骤六中的二甲胺替换为氮杂环丁烷。LC-MS(ESI)m/z:312.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝8.8Hz,1H),7.79-7.70(m,3H),7.38(s,1H),7.20(dd,J＝8.7,1.9Hz,2H),5.30(s,2H),4.49(s,2H),3.72(dd,J＝9.6,7.0Hz,2H),3.69-3.66(m,1H),3.68-3.64(m,1H),3.61(t,J＝9.5Hz,2H),3.24(s,6H),2.54(m,1H),2.44(m,1H),2.38(q,J＝7.5Hz,2H),2.24(td,J＝8.1,3.8Hz,1H).The synthesis method of compound 118 is similar to that of Example 101, except that methylethylamine in step 1 is replaced by dimethyl Amine, dimethylamine in step 6 was replaced by azetidine. LC-MS (ESI) m/z: 312.1 [M/2 + H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.97(d,J＝8.8Hz,1H),7.79-7.70(m,3H),7.38(s,1H),7.20(dd,J＝8.7,1.9Hz,2H),5.30(s,2H),4.49(s,2H),3.72(dd,J＝9.6,7.0Hz,2H),3.69-3.66( m,1H),3.68-3.64(m,1H),3.61(t,J＝9.5Hz,2H),3.24(s,6H),2.54(m,1H),2.44(m,1H),2.38(q,J＝7.5Hz,2H),2.24(td,J＝8.1,3.8Hz,1H).
实施例119
Embodiment 119
合成路线
Synthetic route
步骤一：化合物119-1的合成Step 1: Synthesis of compound 119-1
室温下，将2-溴噻唑-4-甲醛(1g,5.21mmol)溶于10mL THF中，降温至0℃，在氮气保护下缓慢滴加甲基溴化镁(3N)，之后升至室温反应1小时。LCMS监测反应完全，冰浴下滴加饱和氯化铵溶液淬灭反应，加EA萃取三次，合并有机相浓缩后,经快速色谱柱层析分离(PE:EA,0-50％,10min)得到737mg化合物119-1，收率68％。LC-MS(ESI)m/z:208[M+H]+.At room temperature, 2-bromothiazole-4-carboxaldehyde (1g, 5.21mmol) was dissolved in 10mL THF, cooled to 0°C, and methylmagnesium bromide (3N) was slowly added dropwise under nitrogen protection, and then the temperature was raised to room temperature for 1 hour. LCMS monitored the reaction to be complete, and saturated ammonium chloride solution was added dropwise under ice bath to quench the reaction, and EA was added for extraction three times. After the organic phases were combined and concentrated, they were separated by flash chromatography (PE:EA, 0-50%, 10min) to obtain 737mg of compound 119-1, with a yield of 68%. LC-MS (ESI) m/z: 208 [M+H] + .
步骤二：化合物119-2的合成Step 2: Synthesis of compound 119-2
室温下，将化合物119-1(737mg，3.54mmol)溶于10mL干燥的DCM中，降温至0℃，在氮气保护下缓慢滴加三溴化磷(1.5g，5.54mmol)，之后升至室温反应1小时。LC-MS监测反应完全。冰浴下将体系滴加到碳酸氢钠溶液中淬灭反应，加DCM萃取三次，合并有机相浓缩后,经快速色谱柱层析分离(PE:EA,0-50％,10min)得到780mg化合物119-2，收率82％。LC-MS(ESI)m/z:270[M+H]+.At room temperature, compound 119-1 (737 mg, 3.54 mmol) was dissolved in 10 mL of dry DCM, cooled to 0°C, and phosphorus tribromide (1.5 g, 5.54 mmol) was slowly added dropwise under nitrogen protection, and then the temperature was raised to room temperature for 1 hour. LC-MS monitored the reaction to be complete. The system was added dropwise to a sodium bicarbonate solution under an ice bath to quench the reaction, and DCM was added for extraction three times. After the organic phases were combined and concentrated, they were separated by flash chromatography (PE:EA, 0-50%, 10 min) to obtain 780 mg of compound 119-2, with a yield of 82%. LC-MS (ESI) m/z: 270 [M + H] + .
步骤三：化合物119-3的合成Step 3: Synthesis of compound 119-3
室温下，将化合物119-2(300mg，1.102mmol)和7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(250mg，1.12mmol)溶于5mL干燥的DMF中，加入碳酸钾(460mg，3.33mmol)，升温至100℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到35mg化合物119-3，收率8％。LC-MS(ESI)m/z:413[M+H]+.At room temperature, compound 119-2 (300 mg, 1.102 mmol) and 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (250 mg, 1.12 mmol) were dissolved in 5 mL of dry DMF, potassium carbonate (460 mg, 3.33 mmol) was added, and the temperature was raised to 100°C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine and concentrated and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 35 mg of compound 119-3, with a yield of 8%. LC-MS (ESI) m/z: 413 [M+H] + .
步骤四：化合物119的合成Step 4: Synthesis of compound 119
室温下，将化合物119-3(35mg，0.0847mmol)和7-氯-4-(二甲基氨基)-1-(吡咯烷-3-基)喹唑啉-2(1H)-酮(101-7，30mg，0.103mmol)溶于2mL干燥的DMF中，加入碳酸铯(83mg，0.255mmol)，升温至120℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相浓缩后经快速色谱柱层析分离 (DCM:MeOH,0-10％,10min)得到30mg淡黄色粗品，之后经HPLC制备纯化后得3.9mg化合物119，收率6％。LC-MS(ESI)m/z:313.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.91(dd,J＝8.7,4.9Hz,2H),7.74(dd,J＝7.2,2.0Hz,1H),7.67(dd,J＝10.6,2.0Hz,1H),7.21(dt,J＝9.0,2.4Hz,1H),7.13(ddd,J＝8.7,5.2,2.0Hz,1H),6.64(d,J＝1.8Hz,1H),6.17-6.09(m,1H),5.34-5.29(m,1H),3.77-3.60(m,4H),3.23-3.21(m,12H),2.70-2.63(m,2H),1.73(d,J＝7.2Hz,3H).At room temperature, compound 119-3 (35 mg, 0.0847 mmol) and 7-chloro-4-(dimethylamino)-1-(pyrrolidin-3-yl)quinazolin-2(1H)-one (101-7, 30 mg, 0.103 mmol) were dissolved in 2 mL of dry DMF, cesium carbonate (83 mg, 0.255 mmol) was added, and the temperature was raised to 120°C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine and concentrated and separated by flash chromatography. (DCM: MeOH, 0-10%, 10 min) to obtain 30 mg of pale yellow crude product, which was then purified by HPLC to obtain 3.9 mg of compound 119, with a yield of 6%. LC-MS (ESI) m/z: 313.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.91(dd,J＝8.7,4.9Hz,2H),7.74(dd,J＝7.2,2.0Hz,1H),7.67(dd,J＝10.6,2.0Hz,1H),7.21(dt,J＝9.0,2.4Hz,1H),7.13(ddd,J＝8.7,5.2,2.0Hz,1H),6.6 4(d,J＝1.8Hz,1H),6.17-6.09(m,1H),5.34-5.29(m,1H),3.77-3.60(m,4H),3.23-3.21(m,12H),2.70-2.63(m,2H),1.73(d,J＝7.2Hz,3H).
实施例120
Embodiment 120
合成方法Synthesis method
化合物120的合成方法参照实施例119，区别在于把步骤四中的101-7替换为7-氯-4-氨基-1-(吡咯烷-3-基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:299.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.99(d,J＝8.4Hz,1H),7.91(d,J＝8.7Hz,1H),7.78(d,J＝3.9Hz,1H),7.63(s,1H),7.30(d,J＝8.4Hz,1H),7.13(dt,J＝8.9,2.7Hz,1H),6.65(d,J＝6.1Hz,1H),6.18-6.07(m,1H),5.60-5.48(m,1H),3.80-3.63(m,4H),3.22(s,6H),2.68-2.56(m,2H),1.72(d,J＝7.1Hz,3H).The synthesis method of compound 120 is similar to that of Example 119, except that 101-7 in step 4 is replaced by 7-chloro-4-amino-1-(pyrrolidin-3-yl)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 299.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.99(d,J＝8.4Hz,1H),7.91(d,J＝8.7Hz,1H),7.78(d,J＝3.9Hz,1H),7.63(s,1H),7.30(d,J＝8.4Hz,1H),7.13(dt,J＝8.9,2.7Hz,1H),6.65(d,J＝6.1Hz, 1H),6.18-6.07(m,1H),5.60-5.48(m,1H),3.80-3.63(m,4H),3.22(s,6H),2.68-2.56(m,2H),1.72(d,J＝7.1Hz,3H).
实施例121&122
Embodiment 121 & 122
合成方法Synthesis method
化合物121和122的合成方法参照实施例113和114，区别在于把步骤一中的1-溴-2-丁醇替换为2-碘乙醇，。The synthesis method of compounds 121 and 122 refers to Examples 113 and 114, except that 1-bromo-2-butanol in step 1 is replaced by 2-iodoethanol.
化合物121：LC-MS(ESI)m/z:195.7[M/3+H]+.1H NMR(600MHz,DMSO-d6)δ8.12(d,J＝9.0Hz,1H),7.94(d,J＝8.8Hz,1H),7.52(d,J＝2.0Hz,1H),7.50(s,1H),7.26(dd,J＝9.0,2.0Hz,1H),7.18(d,J＝8.7Hz,1H),4.37(dd,J＝24.0,18.4Hz,2H),4.11(dd,J＝25.5,19.1Hz,2H),3.41-3.47(m,4H),3.31(s,6H),3.22(s,6H),2.69(dd,J＝17.6,12.0Hz,2H),2.34-2.42(m,6H).Compound 121: LC-MS (ESI) m/z: 195.7 [M/3+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.12(d,J＝9.0Hz,1H),7.94(d,J＝8.8Hz,1H),7.52(d,J＝2.0Hz,1H),7.50(s,1H),7.26(dd,J＝9.0,2.0Hz,1H),7.18(d,J＝8.7Hz,1H),4.37(dd,J＝24.0,1 8.4Hz,2H),4.11(dd,J＝25.5,19.1Hz,2H),3.41-3.47(m,4H),3.31(s,6H),3.22(s,6H),2.69(dd,J＝17.6,12.0Hz,2H),2.34-2.42(m,6H).
化合物122：LC-MS(ESI)m/z:195.7[M/3+H]+.1H NMR(600MHz,DMSO-d6)δ7.95(t,J＝6.7Hz,2H),7.51(d,J＝1.7Hz,2H),7.19(dd,J＝8.8,1.7Hz,2H),4.14(t,J＝6.6Hz,4H),3.22(s,12H),2.51-2.47(m,4H).Compound 122: LC-MS (ESI) m/z: 195.7[M/3+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ7.95 (t, J = 6.7Hz, 2H), 7.51 ( d,J＝1.7Hz,2H),7.19(dd,J＝8.8,1.7Hz,2H),4.14(t,J＝6.6Hz,4H),3.22(s,12H),2.51-2.47(m,4H ).
实施例123
Embodiment 123
合成路线
Synthetic route
步骤一：化合物123-1的合成Step 1: Synthesis of compound 123-1
室温下将2,4,7-三氯喹唑啉(5.0g，21.44mmol)溶解在50mL四氢呋喃(THF)中，向其中加入二甲胺的四氢呋喃溶液(2M，17mL，31.12mmol)，室温下搅拌16h。TLC监测完全反应，减压旋蒸浓缩后得到化合物123-1(3.8g，白色固体)，无需纯化直接用于下一步反应，产率74％。LC-MS(ESI)m/z:242[M+H]+.2,4,7-Trichloroquinazoline (5.0 g, 21.44 mmol) was dissolved in 50 mL of tetrahydrofuran (THF) at room temperature, and a tetrahydrofuran solution of dimethylamine (2 M, 17 mL, 31.12 mmol) was added thereto, and stirred at room temperature for 16 h. The reaction was completely monitored by TLC, and the compound 123-1 (3.8 g, white solid) was obtained after vacuum rotary evaporation and concentration, which was directly used in the next step without purification, with a yield of 74%. LC-MS (ESI) m/z: 242 [M + H] + .
步骤二：化合物123-2的合成Step 2: Synthesis of compound 123-2
室温下，将化合物123-1(3.8g，15.77mmol)溶解在50mL冰醋酸中，升温至100℃搅拌16h。TLC监测完全反应，反应体系中加饱和碳酸氢钠溶液淬灭，用乙酸乙酯(80mL x3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(二氯甲烷：甲醇，0-20％，15min)得到化合物123-2,(3.3g，淡黄色固体)，产率93％。LC-MS(ESI)m/z:224[M+H]+.At room temperature, compound 123-1 (3.8 g, 15.77 mmol) was dissolved in 50 mL of glacial acetic acid, heated to 100 ° C and stirred for 16 h. TLC monitored the complete reaction, quenched the reaction system with saturated sodium bicarbonate solution, extracted with ethyl acetate (80 mL x3), and washed the organic phase with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-20%, 15 min) to obtain compound 123-2 (3.3 g, light yellow solid), with a yield of 93%. LC-MS (ESI) m/z: 224 [M + H] + .
步骤三：化合物123-3的合成Step 3: Synthesis of compound 123-3
室温下，将化合物123-2(1.0g，4.48mmol)溶解在10mL N,N-二甲基甲酰胺中，向其中加入1-Boc-3-溴甲基吡咯烷(1.4g，5.38mmol)和碳酸钾(1.9g，13.44mmol)，室温下搅拌16h。TLC监测完全反应，反应体系中加水，用乙酸乙酯(30mLx3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物123-3，(340mg，白色固体)，产率19％。LC-MS(ESI)m/z:407[M+H]+.At room temperature, compound 123-2 (1.0 g, 4.48 mmol) was dissolved in 10 mL of N, N-dimethylformamide, 1-Boc-3-bromomethylpyrrolidine (1.4 g, 5.38 mmol) and potassium carbonate (1.9 g, 13.44 mmol) were added thereto, and stirred at room temperature for 16 h. TLC monitored the complete reaction, water was added to the reaction system, extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 123-3 (340 mg, white solid), with a yield of 19%. LC-MS (ESI) m/z: 407 [M + H] + .
步骤四：化合物123-4的合成Step 4: Synthesis of compound 123-4
室温下将化合物123-3(340mg，0.84mmol)溶解在4mL 1,4-二氧六环中，向其中加入盐酸-二氧六环溶液4mL，室温下搅拌30min。TLC监测完全反应，浓缩后得到 化合物123-4的盐酸盐(251mg，白色固体)，产率98％。LC-MS(ESI)m/z:307[M+H]+.步骤五：化合物123-5的合成Compound 123-3 (340 mg, 0.84 mmol) was dissolved in 4 mL of 1,4-dioxane at room temperature, 4 mL of hydrochloric acid-dioxane solution was added thereto, and stirred at room temperature for 30 min. The reaction was completed after TLC monitoring, and the product was concentrated to obtain Hydrochloride of compound 123-4 (251 mg, white solid), yield 98%. LC-MS (ESI) m/z: 307 [M+H] + . Step 5: Synthesis of compound 123-5
0℃下将草酰氯(14.7g，115.61mmol)滴加到4-氯-2-氟苯甲酰胺(10.0g，57.80mmol)的二氯乙烷DCE(100mL)中。氮气保护下，反应混合液在70℃搅拌过夜，减压除去多余的草酰氯后，用DCE(50mL)稀释后滴入2-氨基-6-溴吡啶(5.0g，28.90mmol)的DCE(50mL)体系中，反应在室温下搅拌3h。TLC监测完全反应。反应体系加入乙腈打浆过滤后得到化合物123-5(10.3g，白色固体)，产率93％。LC-MS(ESI)m/z:370[M+H]+.Oxalyl chloride (14.7 g, 115.61 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (10.0 g, 57.80 mmol) in dichloroethane (DCE) (100 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After removing excess oxalyl chloride under reduced pressure, it was diluted with DCE (50 mL) and then added dropwise to a DCE (50 mL) system of 2-amino-6-bromopyridine (5.0 g, 28.90 mmol), and the reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction. Acetonitrile was added to the reaction system and the mixture was pulped and filtered to obtain compound 123-5 (10.3 g, white solid) with a yield of 93%. LC-MS (ESI) m/z: 370 [M+H] + .
步骤六：化合物123-6的合成Step 6: Synthesis of compound 123-6
0℃下将双(三甲基硅基)氨基钠的四氢呋喃溶液(36.5mL，69.41mmol)加入到化合物123-5(10.3g，27.76mmol)的四氢呋喃溶液(100mL)中，氮气保护下，升温至70℃搅拌3h。LC-MS检测反应完全。体系加水淬灭，滴加稀盐酸(0.5mol/L)至pH为中性，过滤后固体用乙腈打浆，再次过滤后得到化合物123-6(9.2g，白色固体)，产率95％。LC-MS(ESI)m/z:352[M+H]+.At 0°C, a tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (36.5 mL, 69.41 mmol) was added to a tetrahydrofuran solution (100 mL) of compound 123-5 (10.3 g, 27.76 mmol), and the mixture was heated to 70°C and stirred for 3 h under nitrogen protection. LC-MS detected that the reaction was complete. The system was quenched with water, and dilute hydrochloric acid (0.5 mol/L) was added dropwise until the pH was neutral. After filtration, the solid was slurried with acetonitrile and filtered again to obtain compound 123-6 (9.2 g, white solid) with a yield of 95%. LC-MS (ESI) m/z: 352 [M+H] + .
步骤七：化合物123-7的合成Step 7: Synthesis of compound 123-7
室温下将化合物123-6(200mg，0.57mmol)溶解在5mL乙腈中，向其中加入1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(444mg，0.85mmol)和二甲胺的四氢呋喃溶液(0.7mg，1.42mmol)，而后逐滴加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)(303mg，1.99mmol)。反应混合液在室温下搅拌30min，TLC监测完全反应。粗产品通过硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)得到化合物123-7(127mg，白色固体)，产率92％。LC-MS(ESI)m/z:379[M+H]+.Compound 123-6 (200 mg, 0.57 mmol) was dissolved in 5 mL of acetonitrile at room temperature, 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate (444 mg, 0.85 mmol) and a tetrahydrofuran solution of dimethylamine (0.7 mg, 1.42 mmol) were added thereto, and then 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (303 mg, 1.99 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 min, and the complete reaction was monitored by TLC. The crude product was subjected to silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min) to obtain compound 123-7 (127 mg, white solid) with a yield of 92%. LC-MS (ESI) m/z: 379 [M+H] + .
步骤八：化合物123的合成Step 8: Synthesis of compound 123
室温下将化合物123-7(50mg，0.13mmol)溶解在1mL N,N-二甲基甲酰胺中，向其中加入化合物123-4(45mg，0.13mmol)和碳酸铯(128mg，0.39mmol)。反应混合液在120℃下搅拌16h。LC-MS检测完全反应。经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，HPLC制备纯化后得到化合物123(9.86mg，白色固体)，产率9.6％。LC-MS(ESI)m/z:303.1[M/2+H]+.1HN MR(400MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.97(d,J＝8.7Hz,1H),7.72(t,J＝7.8Hz,1H),7.60(d,J＝2.0Hz,1H),7.20(dt,2H),6.54(dd,J＝7.9,3.5Hz,2H),6.45(d,J＝2.1Hz,1H),5.41(d,2H),4.22(dq,J＝41.1,14.4,7.4Hz,1H),3.69(m,1H),3.51(d,J＝3.8Hz,2H),3.30(s,6H),3.23(s,6H),2.04-1.96(m,1H),1.86-1.79(m,1H).Compound 123-7 (50 mg, 0.13 mmol) was dissolved in 1 mL of N,N-dimethylformamide at room temperature, and compound 123-4 (45 mg, 0.13 mmol) and cesium carbonate (128 mg, 0.39 mmol) were added thereto. The reaction mixture was stirred at 120°C for 16 h. LC-MS detected the complete reaction. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 123 (9.86 mg, white solid) was obtained after HPLC preparation and purification, with a yield of 9.6%. LC-MS (ESI) m/z: 303.1 [M/2+H] + . 1 HN MR (400 MHz, DMSO-d 6 )δ8.03(d,J＝8.8Hz,1H),7.97(d,J＝8.7Hz,1H),7.72(t,J＝7.8Hz,1H),7.60(d,J＝2.0Hz,1H),7.20(dt,2H),6.54(dd,J＝7.9,3.5Hz,2H),6.45(d,J＝2.1Hz, 1H),5.41(d,2H),4.22(dq,J＝41.1,14.4,7.4Hz,1H),3.69(m,1H),3.51(d,J＝3.8Hz,2H),3.30(s,6H),3.23(s,6H),2.04-1.96(m,1H),1.86-1.79( m,1H).
实施例124
Embodiment 124
合成路线
Synthetic route
步骤一：化合物124-1的合成Step 1: Synthesis of compound 124-1
室温下，将化合物123-2(1.0g，4.48mmol)溶解在10mLN,N-二甲基甲酰胺中，向其中加入1-Boc-3-溴甲基吡咯烷(1.4g，5.38mmol)和碳酸钾(1.9g，13.44mmol)，室温下搅拌16h。TLC监测完全反应，反应体系中加水，用乙酸乙酯(30mLx3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物124-1(631mg，白色固体)，产率35％。LC-MS(ESI)m/z:407[M+H]+.At room temperature, compound 123-2 (1.0 g, 4.48 mmol) was dissolved in 10 mL of N, N-dimethylformamide, 1-Boc-3-bromomethylpyrrolidine (1.4 g, 5.38 mmol) and potassium carbonate (1.9 g, 13.44 mmol) were added thereto, and stirred at room temperature for 16 h. TLC monitored the complete reaction, water was added to the reaction system, extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 124-1 (631 mg, white solid) with a yield of 35%. LC-MS (ESI) m/z: 407 [M + H] + .
步骤二：化合物124-2的合成Step 2: Synthesis of compound 124-2
室温下将化合物124-1(631mg，1.56mmol)溶解在7mL 1,4-二氧六环中，向其中加入盐酸-二氧六环溶液7mL，室温下搅拌30min。TLC监测完全反应，浓缩后得到化合物124-2的盐酸盐(526mg，白色固体)，产率97％。LC-MS(ESI)m/z:307[M+H]+.步骤三：化合物124的合成Compound 124-1 (631 mg, 1.56 mmol) was dissolved in 7 mL of 1,4-dioxane at room temperature, and 7 mL of hydrochloric acid-dioxane solution was added thereto, and stirred at room temperature for 30 min. TLC monitored the complete reaction, and after concentration, the hydrochloride of compound 124-2 (526 mg, white solid) was obtained with a yield of 97%. LC-MS (ESI) m/z: 307 [M+H] + . Step 3: Synthesis of compound 124
室温下将化合物124-2(50mg，0.13mmol)溶解在1mL N,N-二甲基甲酰胺中，向其中加入化合物123-7(45mg，0.13mmol)和碳酸铯(128mg，0.39mmol)。反应混合液在120℃下搅拌16h。LC-MS检测完全反应。经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，HPLC制备纯化后得到化合物124(4.09mg，白色固体)，产率5.2％。LC-MS(ESI)m/z:303.1[M/2+H]+.1HN MR(400MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.97(d,J＝8.7Hz,1H),7.72(t,J＝7.8Hz,1H),7.60(d,J＝2.0Hz,1H),7.20(dt,2H),6.54(dd,J＝7.9,3.5Hz,2H),6.45(d,J＝2.1Hz,1H),5.41(d,2H),4.22(dq,J＝41.1,14.4,7.4Hz,1H),3.69(m,1H),3.51(d,J＝3.8Hz,2H),3.30(s,6H),3.23(s,6H),2.04-1.96(m,1H),1.86-1.79(m,1H).Compound 124-2 (50 mg, 0.13 mmol) was dissolved in 1 mL of N,N-dimethylformamide at room temperature, and compound 123-7 (45 mg, 0.13 mmol) and cesium carbonate (128 mg, 0.39 mmol) were added thereto. The reaction mixture was stirred at 120°C for 16 h. LC-MS detected the complete reaction. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 124 (4.09 mg, white solid) was obtained after HPLC preparation and purification, with a yield of 5.2%. LC-MS (ESI) m/z: 303.1 [M/2+H] + . 1 HN MR (400 MHz, DMSO-d 6 )δ8.03(d,J＝8.8Hz,1H),7.97(d,J＝8.7Hz,1H),7.72(t,J＝7.8Hz,1H),7.60(d,J＝2.0Hz,1H),7.20(dt,2H),6.54(dd,J＝7.9,3.5Hz,2H),6.45(d,J＝2.1Hz, 1H),5.41(d,2H),4.22(dq,J＝41.1,14.4,7.4Hz,1H),3.69(m,1H),3.51(d,J＝3.8Hz,2H),3.30(s,6H),3.23(s,6H),2.04-1.96(m,1H),1.86-1.79( m,1H).
实施例125&126
Example 125 & 126
合成方法Synthesis method
化合物125和126的合成方法参照实施例113和114，区别在于把步骤一中的1-溴-2-丁醇替换为2-溴-1-丙醇，步骤三中的7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(123-2)替换为101-2。LC-MS(ESI)m/z:214.4[M/3+H]+.The synthesis method of compounds 125 and 126 refers to Examples 113 and 114, except that 1-bromo-2-butanol in step 1 is replaced by 2-bromo-1-propanol, and 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2) in step 3 is replaced by 101-2. LC-MS (ESI) m/z: 214.4 [M/3+H] + .
实施例127&128
Example 127 & 128
合成方法Synthesis method
化合物127和128的合成方法参照实施例113和114，区别在于把步骤一中的1-溴-2-丁醇替换为2-碘乙醇，步骤三中的7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(123-2)替换为7-氯-4-氨基喹唑啉-2(1H)-酮。The synthesis method of compounds 127 and 128 refers to Examples 113 and 114, except that 1-bromo-2-butanol in step 1 is replaced by 2-iodoethanol, and 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2) in step 3 is replaced by 7-chloro-4-aminoquinazolin-2(1H)-one.
化合物127：LC-MS(ESI)m/z:177.1[M/3+H]+.1H NMR(400MHz,DMSO-d6)δ8.15(d,J＝8.7Hz,1H),8.06(d,J＝8.6Hz,1H),8.01-7.81(m,4H),7.51-.45(m,2H),7.32(dd,J＝8.7,2.2Hz,1H),7.23(dd,J＝8.6,1.9Hz,1H),4.37(t,J＝5.8Hz,2H),4.14(t,J＝6.7Hz,2H),2.68-2.61(m,4H),2.35-2.31(m,4H),2.09-1.92(m,4H).Compound 127: LC-MS (ESI) m/z: 177.1 [M/3+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.15 (d, J = 8.7Hz, 1H), 8.06 ( d,J＝8.6Hz,1H),8.01-7.81(m,4H),7.51-.45(m,2H),7.32(dd,J＝8.7,2.2Hz,1H),7.23(dd,J＝8.6 ,1.9Hz,1H),4.37(t,J＝5.8Hz,2H),4.14(t,J＝6.7Hz,2H),2.68-2.61(m,4H),2.35-2.31(m,4H),2.09 -1.92(m,4H).
化合物128：LC-MS(ESI)m/z:177.1[M/3+H]+.1H NMR(400MHz,DMSO-d6)δ8.06(d,J＝8.6Hz,2H),7.99-7.91(m,2H),7.89-7.82(m,2H),7.48-7.46(m,2H),7.24(dd,J＝8.6,1.9Hz,2H),4.16-4.10(m,4H),2.71-2.63(m,4H),2.47-2.46(m,4H),2.05-1.94(m,4H).Compound 128: LC-MS (ESI) m/z: 177.1 [M/3+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.06 (d, J = 8.6Hz, 2H), 7.99- 7.91(m,2H),7.89-7.82(m,2H),7.48-7.46(m,2H),7.24(dd,J＝8.6,1.9Hz,2H),4.16-4.10(m,4H),2.71- 2.63(m,4H),2.47-2.46(m,4H),2.05-1.94(m,4H).
实施例129
Embodiment 129
合成方法Synthesis method
化合物129的合成方法参照实施例113，区别在于把步骤一中的1-溴-2-丁醇替换为2-碘乙醇，步骤三中的7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(123-2)替换为7-氯-4-(甲氨基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:186.4[M/3+H]+.1H NMR(600MHz,DMSO-d6)δ8.44(s,2H),8.21(d,J＝8.9Hz,1H),7.97(d,J＝8.8Hz,1H),7.55(s,1H),7.37(s,1H),7.26(dd,J＝9.0,2.3Hz,1H),7.14(dd,J＝8.9,2.0Hz,1H),5.41(d,J＝16.2Hz,4H),5.17(d,J＝11.0Hz,4H),3.74–3.59(m,8H),3.32,(s,3H),3.26(s,3H).The synthesis method of compound 129 refers to Example 113, except that 1-bromo-2-butanol in step 1 is replaced by 2-iodoethanol, and 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2) in step 3 is replaced by 7-chloro-4-(methylamino)quinazolin-2(1H)-one. LC-MS(ESI)m/z:186.4[M/3+H] + . 1 H NMR(600MHz, DMSO-d 6 )δ8.44(s,2H),8.21(d,J＝8.9Hz,1H),7.97(d,J＝8.8Hz,1H),7.55(s,1H),7.37(s,1H),7.26(dd,J =9.0,2.3Hz,1H),7.14(dd,J＝8.9,2.0Hz,1H),5.41(d,J＝16.2Hz,4H),5.17(d,J＝11.0Hz,4H),3.74–3.59(m,8H),3.32,(s,3H),3.26(s,3H).
实施例130&131
Embodiment 130 & 131
合成方法Synthesis method
化合物130和131的合成方法参照实施例113和114。 The synthesis methods of compounds 130 and 131 refer to Examples 113 and 114.
化合物130：LC-MS(ESI)m/z:205.1[M/3+H]+.1H NMR(600MHz,DMSO-d6)δ8.16(d,J＝8.9Hz,1H),7.98(d,J＝8.8Hz,1H),7.53(s,1H),7.37(s,1H),7.29(dd,J＝9.0,2.3Hz,1H),7.20(dd,J＝8.9,2.0Hz,1H),5.11(d,J＝16.2Hz,2H),5.03(d,J＝11.0Hz,2H),3.74-3.59(m,8H),3.32,(s,6H),3.26(s,6H).Compound 130: LC-MS (ESI) m/z: 205.1[M/3+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ8.16 (d, J = 8.9Hz, 1H), 7.98 ( d,J＝8.8Hz,1H),7.53(s,1H),7.37(s,1H),7.29(dd,J＝9.0,2.3Hz,1H),7.20(dd,J＝8.9,2.0Hz,1H ),5.11(d,J＝16.2Hz,2H),5.03(d,J＝11.0Hz,2H),3.74-3.59(m,8H),3.32,(s,6H),3.26(s,6H).
化合物131：LC-MS(ESI)m/z:205.1[M/3+H]+.1H NMR(600MHz,DMSO-d6)δ7.99(d,J＝8.8Hz,2H),7.39(d,J＝2.0Hz,2H),7.20(dd,J＝8.7,2.0Hz,2H),5.04(d,J＝21.0Hz,4H),3.78(s,2H),3.64(d,4H),3.49(s,2H),3.26(s,12H).Compound 131: LC-MS (ESI) m/z: 205.1[M/3+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ7.99 (d, J = 8.8Hz, 2H), 7.39 ( d,J＝2.0Hz,2H),7.20(dd,J＝8.7,2.0Hz,2H),5.04(d,J＝21.0Hz,4H),3.78(s,2H),3.64(d,4H), 3.49(s,2H),3.26(s,12H).
实施例132&133
Example 132 & 133
合成方法Synthesis method
化合物132和133的合成方法参照实施例113和114。区别在于把步骤一中的1-溴-2-丁醇替换为2-甲基-2-溴乙醇。The synthesis method of compounds 132 and 133 refers to Examples 113 and 114, except that 1-bromo-2-butanol in step 1 is replaced by 2-methyl-2-bromoethanol.
化合物132：LC-MS(ESI)m/z:200.4[M/3+H]+.1H NMR(600MHz,DMSO-d6)δδ8.12(t,J＝8.9Hz,1H),7.92(dd,J＝8.8,3.2Hz,1H),7.58-7.47(m,2H),7.26(t,J＝9.4,7.2Hz,1H),7.14(t,J＝8.4Hz,1H),4.44-4.35(m,1H),4.15-4.09(m,1H),4.08-3.95(m,2H),3.23-3.22(m,1H),3.21(s,6H),3.19-3.17(m,1H),2.98-2.87(m,4H),2.39-2.29(m,4H),1.27(d,J＝6.4Hz,3H),0.92(d,3H).Compound 132: LC-MS (ESI) m/z: 200.4 [M/3+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δδ8.12(t,J＝8.9Hz,1H),7.92(dd,J＝8.8,3.2Hz,1H),7.58-7.47(m,2H),7.26(t,J＝9.4,7.2Hz,1H),7.14(t,J＝8.4Hz,1H),4.44-4.35(m,1H),4.15-4. 09(m,1H),4.08-3.95(m,2H),3.23-3.22(m,1H),3.21(s,6H),3.19-3.17(m,1H),2.98-2.87(m,4H),2.39-2.29(m,4H),1.27(d,J＝6.4Hz,3H),0.92 (d,3H).
化合物133：LC-MS(ESI)m/z:200.4[M/3+H]+.1H NMR(600MHz,DMSO-d6)δ7.94(d,2H),7.55(d,J＝8.0Hz,2H),7.17(d,2H),4.14-3.94(m,4H),3.22(s,12H),3.20(d,J＝4.8Hz,2H),2.96-2.81(m,4H),2.31-2.24(m,4H),0.90(d,J＝6.8Hz,6H).Compound 133: LC-MS (ESI) m/z: 200.4 [M/3+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ7.94 (d, 2H), 7.55 (d, J = 8.0 Hz,2H),7.17(d,2H),4.14-3.94(m,4H),3.22(s,12H),3.20(d,J＝4.8Hz,2H),2.96-2.81(m,4H),2.31 -2.24(m,4H),0.90(d,J＝6.8Hz,6H).
实施例134&135
Example 134 & 135
合成方法Synthesis method
化合物134和135的合成方法参照实施例113和114，区别在于把步骤一中的1-溴-2-丁醇替换为2-碘乙醇，步骤三中的7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(123-2)替换为4-(吖啶-1-基)-7-氯喹唑啉-2(1H)-酮。The synthesis method of compounds 134 and 135 refers to Examples 113 and 114, except that 1-bromo-2-butanol in step 1 is replaced by 2-iodoethanol, and 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2) in step 3 is replaced by 4-(acridin-1-yl)-7-chloroquinazolin-2(1H)-one.
化合物134：LC-MS(ESI)m/z:203.7[M/3+H]+.1H NMR(600MHz,DMSO-d6)δ7.88(d,J＝8.8Hz,1H),7.77(d,J＝8.7Hz,1H),7.64-7.47(m,2H),7.29(d,J＝8.8Hz,1H),7.21(d,J＝8.6Hz,1H),4.85-4.04(m,12H),3.29-2.52(m,10H),2.50-2.27(m,6H).Compound 134: LC-MS (ESI) m/z: 203.7 [M/3+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ7.88 (d, J = 8.8Hz, 1H), 7.77 ( d,J＝8.7Hz,1H),7.64-7.47(m,2H),7.29(d,J＝8.8Hz,1H),7.21(d,J＝8.6Hz,1H),4.85-4.04(m,12H ),3.29-2.52(m,10H),2.50-2.27(m,6H).
化合物135：LC-MS(ESI)m/z:203.7[M/3+H]+.1H NMR(600MHz,DMSO-d6)δ7.75(d,J＝8.7Hz,2H),7.50(d,2H),7.19(d,J＝8.7Hz,2H),4.68-4.32(m,8H),4.19-4.09(m, 4H),2.47-2.42(m,10H),2.40-2.36(m,6H).Compound 135: LC-MS (ESI) m/z: 203.7[M/3+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ7.75 (d, J = 8.7Hz, 2H), 7.50 ( d,2H),7.19(d,J＝8.7Hz,2H),4.68-4.32(m,8H),4.19-4.09(m, 4H),2.47-2.42(m,10H),2.40-2.36(m,6H).
实施例136
Embodiment 136
合成方法Synthesis method
化合物136的合成方法参照实施例102。LC-MS(ESI)m/z:320.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.90(dd,J＝8.8,4.4Hz,2H),7.79(dd,J＝17.2,2.0Hz,2H),7.41(s,1H),7.20(td,J＝8.9,7.1,1.9Hz,2H),5.29(d,J＝3.8Hz,2H),4.22-4.13(m,1H),4.00-3.93(m,2H),3.89(t,1H),3.72(d,J＝13.3Hz,1H),3.64(q,J＝7.0Hz,2H),3.34(t,3H),3.22(s,3H),3.21(s,6H),3.16-3.05(m,1H),2.81-2.70(m,1H),2.04-1.99(m,2H).The synthesis method of compound 136 refers to Example 102. LC-MS (ESI) m/z: 320.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ7.90 (dd, J=8.8, 4.4 Hz, 2H), 7.79 (dd, J=17.2, 2.0 Hz, 2H), 7.41 (s, 1H), 7.20 (td, J=8.9, 7.1, 1.9 Hz, 2H), 5.29 (d, J=3.8 Hz, 2H), 4.22-4.13 (m, 1H), 4.00-3.93 (m ,2H),3.89(t,1H),3.72(d,J＝13.3Hz,1H),3.64(q,J＝7.0Hz,2H),3.34(t,3H),3.22(s,3H),3.21(s,6H),3.16-3.05(m,1H),2.81-2.70(m,1H),2.0 4-1.99(m,2H).
实施例137&138
Example 137 & 138
将化合物136通过SFC拆分得到单一构型化合物137(136-P1)和138(136-P1)Compound 136 was separated by SFC to obtain single-configuration compounds 137 (136-P1) and 138 (136-P1).
实施例139
Embodiment 139
合成方法Synthesis method
化合物139的合成方法参照实施例123，区别在于把步骤五中2-氨基-6-溴吡啶替换为5-溴-3-氨基吡啶。LC-MS(ESI)m/z:303.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.07-7.94(m,3H),7.72(d,J＝1.9Hz,1H),7.59(d,J＝2.0Hz,1H),7.21(dq,J＝8.8,4.5,2.0Hz,2H),6.84(s,1H),6.46(d,J＝2.1Hz,1H),4.21(dq,J＝44.5,14.3,7.5Hz,2H),3.49(q,J＝7.0Hz,1H),3.31(s,6H),3.24(s,6H),3.21-3.14(m,1H),2.80(q,J＝7.0Hz,1H),2.13-2.03(m,1H),2.00(dt,J＝12.4,6.7Hz,2H),1.90-1.81(m,1H).The synthesis method of compound 139 refers to Example 123, except that 2-amino-6-bromopyridine in step 5 is replaced by 5-bromo-3-aminopyridine. LC-MS (ESI) m/z: 303.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.07-7.94 (m, 3H), 7.72 (d, J = 1.9 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.21 (dq, J = 8.8, 4.5, 2.0 Hz, 2H), 6.84 (s, 1H), 6.46 (d, J = 2.1 Hz, 1H), 4.21 (dq, J = 44.5, 14.3, 7.5H z,2H),3.49(q,J＝7.0Hz,1H),3.31(s,6H),3.24(s,6H),3.21-3.14(m,1H),2.80(q,J＝7.0Hz,1H),2.13-2.03(m,1H),2.00(dt,J＝12.4,6.7Hz,2H),1. 90-1.81(m,1H).
实施例140
Embodiment 140
合成方法 Synthesis method
化合物140的合成方法参照实施例124，区别在于把步骤三中的123-7替换为1-(5-溴吡啶-3-基)-7-氯-4-(二甲胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:303.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.13(d,J＝9.1Hz,1H),8.07(d,J＝2.7Hz,1H),8.04(d,J＝8.8Hz,1H),7.73(d,J＝1.9Hz,1H),7.54(d,J＝2.3Hz,1H),7.31-7.18(m,2H),6.93(t,J＝2.3Hz,1H),6.45(d,J＝2.1Hz,1H),4.42-4.29(m,2H),3.57-3.49(m,1H),3.50-3.41(m,1H),3.32(s,6H),3.31(s,6H),3.25-3.17(m,1H),2.91-2.80(m,1H),2.26-2.15(m,1H),2.05-1.86(m,2H).The synthesis method of compound 140 refers to Example 124, except that 123-7 in step 3 is replaced by 1-(5-bromopyridin-3-yl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 303.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (d, J = 9.1 Hz, 1H), 8.07 (d, J = 2.7 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 2.3 Hz, 1H), 7.31-7.18 (m, 2H), 6.93 (t, J = 2.3 Hz, 1H), 6.45 (d, J = 2 .1Hz,1H),4.42-4.29(m,2H),3.57-3.49(m,1H),3.50-3.41(m,1H),3.32(s,6H),3.31(s,6H),3.25-3.17(m,1H),2.91-2.80(m,1H),2.26-2.15(m ,1H),2.05-1.86(m,2H).
实施例141&142
Example 141 & 142
合成方法Synthesis method
化合物141和142的合成方法参照实施例113和114，区别在于把步骤一中的1-溴-2-丁醇替换为2-碘乙醇，步骤三中的7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(123-2)替换为101-2。The synthesis method of compounds 141 and 142 refers to Examples 113 and 114, except that 1-bromo-2-butanol in step 1 is replaced by 2-iodoethanol, and 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2) in step 3 is replaced by 101-2.
化合物141：LC-MS(ESI)m/z:205.1[M/3+H]+.1H NMR(600MHz,DMSO-d6)δ7.88(dd,J＝8.8,2.7Hz,2H),7.61(d,J＝1.9Hz,2H),7.19(dd,J＝8.7,1.9Hz,2H),4.84(t,J＝5.8Hz,2H),4.44(s,2H),4.10(t,J＝6.2Hz,3H),3.65-3.58(m,8H),3.49(dd,J＝10.2,5.1Hz,2H),3.41(dd,J＝10.0,5.0Hz,2H),3.39(s,4H),3.20(s,3H),1.29-1.24(m,6H).Compound 141: LC-MS (ESI) m/z: 205.1 [M/3+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.88(dd,J＝8.8,2.7Hz,2H),7.61(d,J＝1.9Hz,2H),7.19(dd,J＝8.7,1.9Hz,2H),4.84(t,J＝5.8Hz,2H),4.44(s,2H),4.10(t,J＝6.2Hz,3H),3.65-3.58(m ,8H),3.49(dd,J＝10.2,5.1Hz,2H),3.41(dd,J＝10.0,5.0Hz,2H),3.39(s,4H),3.20(s,3H),1.29-1.24(m,6H).
化合物142：LC-MS(ESI)m/z:205.1[M/3+H]+.1H NMR(600MHz,DMSO-d6)δ8.07(d,J＝9.0Hz,2H),7.53(t,J＝4.3Hz,2H),7.28(dd,J＝9.0,2.2Hz,2H),4.87(s,2H),4.49(s,6H),4.32(dd,J＝9.6,4.6Hz,3H),3.76-3.69(m,8H),3.32(s,6H),1.29(t,J＝7.0Hz,6H).Compound 142: LC-MS (ESI) m/z: 205.1 [M/3+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ 8.07 (d, J = 9.0 Hz, 2H), 7.53 ( t,J＝4.3Hz,2H),7.28(dd,J＝9.0,2.2Hz,2H),4.87(s,2H),4.49(s,6H),4.32(dd,J＝9.6,4.6Hz,3H ),3.76-3.69(m,8H),3.32(s,6H),1.29(t,J=7.0Hz,6H).
实施例143
Embodiment 143
合成方法Synthesis method
化合物143的合成方法参照实施例123，区别在于把步骤一中的123-2替换为101-2，步骤五中2-氨基-6-溴吡啶替换为5-溴-3-氨基吡啶。LC-MS(ESI)m/z:310.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.04(d,J＝8.8Hz,1H),8.00(s,1H),7.90(d,J＝8.8Hz,1H),7.72(d,J＝2.0Hz,1H),7.59(d,J＝2.0Hz,1H),7.21(dt,J＝8.8,1.8Hz,2H),6.84(s,1H),6.46(d,J＝2.1Hz,1H),4.21(dq,J＝51.9,14.3,7.5Hz,2H),3.70-3.57(m,2H),3.53-3.46(m,1H),3.40(t,3H),3.31(s,6H),3.21(s,3H),3.19-3.15(m,1H),2.81(q,1H),2.10-2.03(m,1H),1.92-1.81(m,1H),1.51-1.40(m,2H).The synthesis method of compound 143 refers to Example 123, except that 123-2 in step 1 is replaced by 101-2, and 2-amino-6-bromopyridine in step 5 is replaced by 5-bromo-3-aminopyridine. LC-MS (ESI) m/z: 310.1 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.04 (d, J = 8.8 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.21 (dt, J = 8.8, 1.8 Hz, 2H), 6.84 (s, 1H), 6.46 (d, J = 2.1 Hz, 1H), 4.21 (dq, J = 51. 9,14.3,7.5Hz,2H),3.70-3.57(m,2H),3.53-3.46(m,1H),3.40(t,3H),3.31(s,6H),3.21(s,3H),3.19-3.15(m,1H),2.81(q,1H),2.10-2.03(m,1 H),1.92-1.81(m,1H),1.51-1.40(m,2H).
实施例144
Embodiment 144
合成方法Synthesis method
化合物144的合成方法参照实施例124，区别在于把步骤一中的123-2替换为101-2。LC-MS(ESI)m/z:310.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.08-8.03(m,3H),7.73(d,J＝2.0Hz,1H),7.54(d,J＝2.3Hz,1H),7.28(dd,J＝8.9,2.3Hz,1H),7.21(dd,J＝8.8,2.1Hz,1H),6.93(t,J＝2.4Hz,1H),6.45(d,J＝2.1Hz,1H),4.36(qd,J＝10.7,7.0Hz,2H),3.71(q,J＝7.0Hz,2H),3.58-3.49(m,1H),3.49-3.42(m,1H),3.37,(s,3H),3.34,(t,3H),3.31(s,6H),3.21(dd,J＝9.9,6.5Hz,1H),2.85(p,J＝7.1Hz,1H),2.21(dt,J＝12.0,6.0Hz,1H),2.04-1.99(m,1H),1.94-1.86(m,1H).The synthesis method of compound 144 refers to Example 124, except that 123-2 in step 1 is replaced by 101-2. LC-MS (ESI) m/z: 310.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08-8.03 (m, 3H), 7.73 (d, J=2.0 Hz, 1H), 7.54 (d, J=2.3 Hz, 1H), 7.28 (dd, J=8.9, 2.3 Hz, 1H), 7.21 (dd, J=8.8, 2.1 Hz, 1H), 6.93 (t, J=2.4 Hz, 1H), 6.45 (d, J=2.1 Hz, 1H), 4.36 (qd, J=10.7, 7.0 Hz, 2H), 3.71 (q, J= 7.0Hz,2H),3.58-3.49(m,1H),3.49-3.42(m,1H),3.37,(s,3H),3.34,(t,3H),3.31(s,6H),3.21(dd,J＝9.9,6.5Hz,1H),2.85(p,J＝7.1Hz,1H),2.21( dt,J＝12.0,6.0Hz,1H),2.04-1.99(m,1H),1.94-1.86(m,1H).
实施例145
Embodiment 145
合成方法Synthesis method
化合物145的合成方法参照实施例102。区别在于把步骤五中的101-3替换为1-((2-溴噻唑-5-基)甲基)-7-氯-4-(甲氨基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:306.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.51(q,J＝4.7Hz,1H),8.05(d,J＝8.7Hz,1H),7.89(d,J＝8.7Hz,1H),7.81(d,J＝1.9Hz,1H),7.75(d,J＝1.9Hz,1H),7.40(s,1H),7.28(dd,J＝8.6,1.9Hz,1H),7.19(dd,J＝8.7,1.9Hz,1H),5.32(t,J＝4.6Hz,2H),4.18(t,J＝11.9Hz,1H),3.99-3.87(m,2H),3.71(d,J＝13.2Hz,2H),3.63-3.59(m,2H),3.21(s,6H),3.16-3.07(m,1H),2.92(d,J＝4.4Hz,3H),2.75(d,J＝10.5Hz,1H).The synthesis method of compound 145 is similar to that of Example 102. The difference is that 101-3 in step 5 is replaced by 1-((2-bromothiazol-5-yl)methyl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 306.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.51(q,J＝4.7Hz,1H),8.05(d,J＝8.7Hz,1H),7.89(d,J＝8.7Hz,1H),7.81(d,J＝1.9Hz,1H),7.75(d,J＝1.9Hz,1H),7.40(s,1H),7.28(dd,J＝8.6,1.9Hz,1 H),7.19(dd,J＝8.7,1.9Hz,1H), 5.32(t,J＝4.6Hz,2H),4.18(t,J＝11.9Hz,1H),3.99-3.87(m,2H),3.71(d,J＝13.2Hz,2H),3.63-3.59(m,2H),3.21(s,6H),3.16-3.07(m,1H),2.92(d ,J＝4.4Hz,3H),2.75(d,J＝10.5Hz,1H).
实施例146&147
Example 146 & 147
合成路线
Synthetic route
步骤一：化合物146和147的合成Step 1: Synthesis of compounds 146 and 147
取化合物123-2(0.2g，0.089mmol)和碳酸钾(0.5g，0.36mmol)分散到N,N-二甲基甲酰胺(2mL)溶液中，加热到120℃，迅速向反应液中加入N,N'-(乙烷-1,2-二基)双(2-溴乙酰胺)(0.27g，0.089mmol)，反应30分钟。反应液经硅胶层析色谱柱(洗脱剂：甲醇/乙酸乙酯＝1/5～1/1)纯化，分别得到化合物146和147的粗品，再经制备高效液相色谱纯化，制备液冷冻干燥，分别得到4.33mg化合物146，和5.31mg化合物147，为白色固体。Compound 123-2 (0.2 g, 0.089 mmol) and potassium carbonate (0.5 g, 0.36 mmol) were dispersed in N, N-dimethylformamide (2 mL) solution, heated to 120 ° C, and N, N'-(ethane-1,2-diyl)bis(2-bromoacetamide) (0.27 g, 0.089 mmol) was quickly added to the reaction solution, and the reaction was continued for 30 minutes. The reaction solution was purified by silica gel chromatography column (eluent: methanol/ethyl acetate = 1/5 to 1/1) to obtain crude products of compounds 146 and 147, respectively, and then purified by preparative high performance liquid chromatography, and the preparative solution was freeze-dried to obtain 4.33 mg of compound 146 and 5.31 mg of compound 147, respectively, as white solids.
化合物146：LC-MS(ESI)m/z:294.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.17-8.15(m,2H),8.05(t,J＝5.4Hz,1H),7.96(d,J＝8.7Hz,1H),7.52(d,J＝2.3Hz,1H),7.28(dd,J＝9.0,2.3Hz,1H),7.25(d,J＝2.0Hz,1H),7.18(dd,J＝8.7,2.0Hz,1H),4.71(s,2H),4.66(s,2H),3.33(s,6H),3.25(s,6H),3.16(t,J＝4.2Hz,4H).Compound 146: LC-MS (ESI) m/z: 294.1 [M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ8.17-8.15 (m, 2H), 8.05 (t, J ＝5.4Hz,1H),7.96(d,J＝8.7Hz,1H),7.52(d,J＝2.3Hz,1H),7.28(dd,J＝9.0,2.3Hz,1H),7.25(d,J ＝2.0Hz,1H),7.18(dd,J＝8.7,2.0Hz,1H),4.71(s,2H),4.66(s,2H),3.33(s,6H),3.25(s,6H),3.16 (t,J＝4.2Hz,4H).
化合物147：LC-MS(ESI)m/z:294.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.18(t,2H),7.96(d,J＝8.8Hz,2H),7.30(d,J＝2.0Hz,2H),7.17(dd,J＝8.8,2.0Hz,2H),4.68(s,4H),3.25(s,12H),3.16-3.12(m,4H).Compound 147: LC-MS (ESI) m/z: 294.1 [M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ8.18 (t, 2H), 7.96 (d, J = 8.8 Hz,2H),7.30(d,J＝2.0Hz,2H),7.17(dd,J＝8.8,2.0Hz,2H),4.68(s,4H),3.25(s,12H),3.16-3.12(m ,4H).
实施例148
Embodiment 148
合成路线
Synthetic route
步骤一：化合物148-1的合成Step 1: Synthesis of compound 148-1
室温下，将化合物23-2(0.95g，5.5mmol)溶于二氯甲烷(15mL)中，加入三乙胺(1.8g，18.0mmol)和DMAP(0.067g，0.55mmol)，将反应液降温至0℃，向反应液中缓慢滴加三氟乙酸酐(5.7g，27.5mmol)，室温搅拌0.5小时。反应液减压浓缩，残余物经硅胶层析色谱柱(洗脱剂：石油醚/乙酸乙酯＝13/3)纯化，得到化合物148-1，0.62g，为淡黄色固体，收率42％。LC-MS(ESI)m/z:271[M+H]+.At room temperature, compound 23-2 (0.95 g, 5.5 mmol) was dissolved in dichloromethane (15 mL), triethylamine (1.8 g, 18.0 mmol) and DMAP (0.067 g, 0.55 mmol) were added, the reaction solution was cooled to 0 ° C, trifluoroacetic anhydride (5.7 g, 27.5 mmol) was slowly added dropwise to the reaction solution, and stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography column (eluent: petroleum ether/ethyl acetate = 13/3) to obtain compound 148-1, 0.62 g, as a light yellow solid, with a yield of 42%. LC-MS (ESI) m/z: 271 [M + H] + .
步骤二：化合物148-2的合成Step 2: Synthesis of compound 148-2
室温下，将化合物148-1(0.50g，2.0mmol)、叔丁基-4-(2-羟乙基)哌嗪-1-羧酸酯(0.90g，4.0mmol)和碳酸铯(1.3g，4.0mmol)分散到1,4-二氧六环(5mL)溶液中，加热到120℃，搅拌过夜。反应结束后，冷却至室温，将反应液用乙酸乙酯(20mL×3)和水(20mL)萃取，合并浓缩有机相，残余物经硅胶层析色谱柱(洗脱剂：石油醚/ 乙酸乙酯＝1/1)纯化，得到化合物148-2，0.86g，为淡黄色油状，收率98％。LC-MS(ESI)m/z:450[M+H]+.At room temperature, compound 148-1 (0.50 g, 2.0 mmol), tert-butyl-4-(2-hydroxyethyl)piperazine-1-carboxylate (0.90 g, 4.0 mmol) and cesium carbonate (1.3 g, 4.0 mmol) were dispersed in a 1,4-dioxane (5 mL) solution, heated to 120°C, and stirred overnight. After the reaction was completed, it was cooled to room temperature, and the reaction solution was extracted with ethyl acetate (20 mL×3) and water (20 mL). The organic phases were combined and concentrated, and the residue was purified by silica gel chromatography column (eluent: petroleum ether/ Ethyl acetate = 1/1) to obtain compound 148-2, 0.86 g, as a light yellow oil, with a yield of 98%. LC-MS (ESI) m/z: 450 [M+H] + .
步骤三：化合物148-3的合成Step 3: Synthesis of compound 148-3
室温下，将化合物148-2(0.50g，0.66mmol)溶到二氯甲烷(10mL)中，向反应液中滴加三氟乙酸(1.0mL)，室温搅拌2小时。反应液减压浓缩，得到化合物148-3，0.30g，为黄色油状，收率77％。LC-MS(ESI)m/z:350[M+H]+.At room temperature, compound 148-2 (0.50 g, 0.66 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1.0 mL) was added dropwise to the reaction solution, and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 148-3, 0.30 g, as a yellow oil, with a yield of 77%. LC-MS (ESI) m/z: 350 [M+H] + .
步骤四：化合物148-4的合成Step 4: Synthesis of compound 148-4
室温下，将化合物148-3(0.30g，0.86mmol)、三乙胺(0.26g，2.6mmol)溶到二氯甲烷(3.0mL)中，降温至0℃，向反应液中缓慢滴加氯乙酰氯(0.12g，1.0mmol)，室温反应1小时。反应液减压浓缩，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝1/5)纯化，得到化合物148-4，0.1g，收率28％。LC-MS(ESI)m/z:426[M+H]+.步骤五：化合物148-5的合成At room temperature, compound 148-3 (0.30 g, 0.86 mmol) and triethylamine (0.26 g, 2.6 mmol) were dissolved in dichloromethane (3.0 mL), cooled to 0°C, and chloroacetyl chloride (0.12 g, 1.0 mmol) was slowly added dropwise to the reaction solution, and the reaction was allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: methanol/dichloromethane = 1/5) to obtain compound 148-4, 0.1 g, with a yield of 28%. LC-MS (ESI) m/z: 426 [M+H] + . Step 5: Synthesis of compound 148-5
将化合物148-4，(50mg，0.12mmol)、化合物148-1(33mg，0.12mmol)和碳酸钾(50mg，0.35mmol)溶到N,N-二甲基甲酰胺(1.0mL)中，加热到90℃，搅拌2小时。待反应液冷却至室温后，用乙酸乙酯(5mL×3)和饱和食盐水(5mL)萃取，合并浓缩有机相，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝1/10)纯化，得到化合物148-5，20mg，收率26％。LC-MS(ESI)m/z:330.6[M/2+H]+.Compound 148-4 (50 mg, 0.12 mmol), compound 148-1 (33 mg, 0.12 mmol) and potassium carbonate (50 mg, 0.35 mmol) were dissolved in N,N-dimethylformamide (1.0 mL), heated to 90 ° C, and stirred for 2 hours. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate (5 mL × 3) and saturated brine (5 mL), and the organic phase was combined and concentrated. The residue was purified by silica gel chromatography column (eluent: methanol/dichloromethane = 1/10) to obtain compound 148-5, 20 mg, yield 26%. LC-MS (ESI) m/z: 330.6 [M/2 + H] + .
步骤六：化合物148的合成Step 6: Synthesis of compound 148
将化合物148-5(10mg，0.015mmol)溶到甲醇(1.0mL)中，向反应液中滴加氨的甲醇溶液(0.60mL，7M)，加热到50℃，反应2小时。反应液经制备高效液相色谱纯化，制备液冷冻干燥，得到化合物148。LC-MS(ESI)m/z:282.6[M/2+H]+.Compound 148-5 (10 mg, 0.015 mmol) was dissolved in methanol (1.0 mL), and ammonia methanol solution (0.60 mL, 7 M) was added dropwise to the reaction solution, heated to 50°C, and reacted for 2 hours. The reaction solution was purified by preparative high performance liquid chromatography, and the preparative solution was freeze-dried to obtain compound 148. LC-MS (ESI) m/z: 282.6 [M/2+H] + .
实施例149
Embodiment 149
合成方法Synthesis method
化合物149的合成方法参照实施例102。区别在于把步骤五中的101-3替换为1-((2-溴噻唑-5-基)甲基)-7-氟-4-(二甲氨基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:305.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.05(dd,J＝9.1,6.2Hz,1H),7.89(d,J＝8.7Hz,1H),7.80(s,1H),7.56(dd,J＝11.6,2.5Hz,1H),7.44(s,1H),7.19(dd,J＝8.8,1.8Hz,1H),7.02(td,J＝8.5,2.4Hz,1H),5.27(q,J＝15.8Hz,2H),4.17(t,1H),3.97–3.86(m,2H),3.72(d,J＝13.0Hz,1H),3.24(s,6H),3.21(s,6H),3.14-3.07(m,1H),3.04-3.00(m,1H),2.80-2.71(m,1H),2.04-1.96(m,2H).The synthesis method of compound 149 refers to Example 102. The difference is that 101-3 in step 5 is replaced by 1-((2-bromothiazol-5-yl)methyl)-7-fluoro-4-(dimethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 305.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.05 (dd, J = 9.1, 6.2 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.80 (s, 1H), 7.56 (dd, J = 11.6, 2.5 Hz, 1H), 7.44 (s, 1H), 7.19 (dd, J = 8.8, 1.8 Hz, 1H), 7.02 (td, J = 8.5, 2.4 Hz, 1H), 5.27 (q ,J＝15.8Hz,2H),4.17(t,1H),3.97–3.86(m,2H),3.72(d,J＝13.0Hz,1H),3.24(s,6H),3.21(s,6H),3.14-3.07(m,1H),3.04-3.00(m,1H),2.80-2.7 1(m,1H),2.04-1.96(m,2H).
实施例150
Embodiment 150
合成路线
Synthetic route
步骤一：化合物150-1的合成Step 1: Synthesis of compound 150-1
室温下，将化合物123-2(500mg，2.23mmol)和(2-溴乙基)氨基甲酸叔丁酯(1.5g，6.70mmol)溶于10mL干燥的DMF中，加入碳酸钾(920mg，6.67mmol)，升温至100℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到230mg化合物150-1，收率28％。LC-MS(ESI)m/z:367[M+H]+.At room temperature, compound 123-2 (500 mg, 2.23 mmol) and (2-bromoethyl)carbamic acid tert-butyl ester (1.5 g, 6.70 mmol) were dissolved in 10 mL of dry DMF, potassium carbonate (920 mg, 6.67 mmol) was added, and the temperature was raised to 100 ° C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine and concentrated and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 230 mg of compound 150-1, with a yield of 28%. LC-MS (ESI) m/z: 367 [M + H] + .
步骤二：化合物150-2的合成Step 2: Synthesis of compound 150-2
室温下，将化合物150-1(230mg，0.628mmol)溶于3mL 1,4-二氧六环中，搅拌中加入3mL盐酸二氧六环溶液(4N)，保持室温反应1小时。LC-MS监测反应完全。过滤反应液得到150mg化合物150-2，收率90％。LC-MS(ESI)m/z:267[M+H]+.At room temperature, compound 150-1 (230 mg, 0.628 mmol) was dissolved in 3 mL of 1,4-dioxane, and 3 mL of dioxane hydrochloride solution (4N) was added during stirring. The reaction was kept at room temperature for 1 hour. LC-MS monitored the reaction to be complete. The reaction solution was filtered to obtain 150 mg of compound 150-2, with a yield of 90%. LC-MS (ESI) m/z: 267 [M+H] + .
步骤三：化合物150-3的合成Step 3: Synthesis of compound 150-3
室温下，将7-氯-4-(二甲基氨基)-1-(哌啶-3-基)喹唑啉-2(1H)-酮(102-4，300mg，1mmol)溶于5mL干燥的THF中，加入三乙胺(327mg，3.24mmol)，降温至0℃后，缓慢滴加氯乙酰氯(168mg，1.5mmol)至反应体系中，之后升至室温反应1小时。LCMS监测反应完全。加水和EA萃取三次，合并有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到320mg化合物105-3，收率84％。LC-MS(ESI)m/z:383[M+H]+.At room temperature, 7-chloro-4-(dimethylamino)-1-(piperidin-3-yl)quinazolin-2(1H)-one (102-4, 300 mg, 1 mmol) was dissolved in 5 mL of dry THF, triethylamine (327 mg, 3.24 mmol) was added, and the temperature was lowered to 0°C, and chloroacetyl chloride (168 mg, 1.5 mmol) was slowly added dropwise to the reaction system, and then the temperature was raised to room temperature for 1 hour. LCMS monitored the reaction to be complete. Water and EA were added for extraction three times, and the organic phases were combined and concentrated and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 320 mg of compound 105-3, with a yield of 84%. LC-MS (ESI) m/z: 383 [M + H] + .
步骤四：化合物150的合成Step 4: Synthesis of compound 150
室温下，将化合物150-2(40mg，0.150mmol)和化合物150-3(60mg，0.157mmol)溶于2mL干燥的DMF中，加入碳酸钾(60mg，0.435mmol)，升温至100℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到20mg粗品，之后经HPLC制备纯化后得9mg化合物150，收率9％。LC-MS(ESI)m/z:307.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.92-8.83(m,1H),8.02(t,J＝8.3Hz,1H),7.92(dd,J＝8.7,6.9Hz,1H),7.63-7.60(m,1H),7.28-7.19(m,2H),4.46-4.34(m,3H),4.21-4.09(m,2H),4.07-3.94(m,1H),3.72-3.60(m,4H),3.26(d,J＝4.4Hz,6H),3.22(d,J＝3.8Hz,6H),3.18-3.10(m,2H),2.68-2.61(m,2H),1.85-1.79(m,2H).At room temperature, compound 150-2 (40 mg, 0.150 mmol) and compound 150-3 (60 mg, 0.157 mmol) were dissolved in 2 mL of dry DMF, potassium carbonate (60 mg, 0.435 mmol) was added, and the temperature was raised to 100°C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine and concentrated, and then separated by flash chromatography column chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 20 mg of crude product, which was then purified by HPLC to obtain 9 mg of compound 150, with a yield of 9%. LC-MS (ESI) m/z: 307.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.92-8.83(m,1H),8.02(t,J＝8.3Hz,1H),7.92(dd,J＝8.7,6.9Hz,1H),7.63-7.60(m,1H),7.28-7.19(m,2H),4.46-4.34(m,3H),4.21-4.09(m,2H), 4.07-3.94(m,1H),3.72-3.60(m,4H),3.26(d,J＝4.4Hz,6H),3.22(d,J＝3.8Hz,6H),3.18-3.10(m,2H),2.68-2.61(m,2H),1.85-1.79(m,2H).
实施例151&152
Embodiment 151 & 152
合成路线
Synthetic route
步骤一：化合物151-1的合成Step 1: Synthesis of compound 151-1
室温下，将化合物102-4(200mg，0.651mmol)溶于5mL干燥的DMF中，加入氯乙酸乙酯(120mg，0.980mmol)和碳酸钾(270mg，1.96mmol)，升至100℃反应4小时。LC-MS监测反应完全。加水和EA萃取三次，合并有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到140mg化合物151-1，收率55％。LC-MS(ESI)m/z:393[M+H]+.At room temperature, compound 102-4 (200 mg, 0.651 mmol) was dissolved in 5 mL of dry DMF, ethyl chloroacetate (120 mg, 0.980 mmol) and potassium carbonate (270 mg, 1.96 mmol) were added, and the temperature was raised to 100 ° C for 4 hours. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the organic phases were combined and concentrated and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 140 mg of compound 151-1, with a yield of 55%. LC-MS (ESI) m/z: 393 [M + H] + .
步骤二：化合物151-2的合成Step 2: Synthesis of compound 151-2
室温下，将化合物151-1(140mg，0.356mmol)溶于3mL甲醇和3mL水中，加入氢氧化锂(42mg，1.75mmol)，室温反应2小时。LC-MS监测反应完全。浓缩除去甲醇，加1N的盐酸调节pH至2-3，加DCM萃取后，水相浓缩后过反向柱(流动相为水和乙腈，梯度5-95％，20分钟)得到90mg化合物151-2，收率69％。LC-MS(ESI)m/z:365[M+H]+.At room temperature, compound 151-1 (140 mg, 0.356 mmol) was dissolved in 3 mL of methanol and 3 mL of water, and lithium hydroxide (42 mg, 1.75 mmol) was added. The reaction was allowed to react at room temperature for 2 hours. LC-MS monitored the reaction to be complete. The methanol was removed by concentration, and 1 N hydrochloric acid was added to adjust the pH to 2-3. After extraction with DCM, the aqueous phase was concentrated and passed through a reverse column (the mobile phase was water and acetonitrile, gradient 5-95%, 20 minutes) to obtain 90 mg of compound 151-2, with a yield of 69%. LC-MS (ESI) m/z: 365 [M+H] + .
步骤三：化合物151和152的合成Step 3: Synthesis of compounds 151 and 152
室温下，将化合物151-2(20mg，0.0549mmol)溶于2mL干燥的DMF中，加入DIEA(21mg，0.163mmol)和HATU(42mg，0.111mmol)，室温搅拌20分钟后，加入1-(2-氨基乙基)-7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(150-2，15mg，0.0561mmol)，保持室温反应1小时。LC-MS监测反应完全。反应液直接经HPLC制备纯化得化合物151和152。At room temperature, compound 151-2 (20 mg, 0.0549 mmol) was dissolved in 2 mL of dry DMF, DIEA (21 mg, 0.163 mmol) and HATU (42 mg, 0.111 mmol) were added, and after stirring at room temperature for 20 minutes, 1-(2-aminoethyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (150-2, 15 mg, 0.0561 mmol) was added, and the reaction was kept at room temperature for 1 hour. LC-MS monitored the reaction to be complete. The reaction solution was directly purified by HPLC to obtain compounds 151 and 152.
化合物151：LC-MS(ESI)m/z:307.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.41(t,J＝5.8Hz,1H),7.90(dd,J＝8.8,3.7Hz,2H),7.78(d,J＝2.0Hz,1H),7.62(d,J＝1.9Hz,1H),7.16(ddd,J＝13.3,8.8,1.9Hz,2H),4.43-4.31(m,1H),4.16-4.06(m,2H),3.28-3.24(m,2H),3.21(s,12H),3.09-2.99(m,2H),2.73-2.63(m,4H),2.05-1.95(m,2H),1.74-1.62(m,2H).Compound 151: LC-MS (ESI) m/z: 307.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.41(t,J＝5.8Hz,1H),7.90(dd,J＝8.8,3.7Hz,2H),7.78(d,J＝2.0Hz,1H),7.62(d,J＝1.9Hz,1H),7.16(ddd,J＝13.3,8.8,1.9Hz,2H),4.43-4.31(m,1H), 4.16-4.06(m,2H),3.28-3.24(m,2H),3.21(s,12H),3.09-2.99(m,2H),2.73-2.63(m,4H),2.05-1.95(m,2H),1.74-1.62(m,2H).
化合物152：LC-MS(ESI)m/z:293.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.99(d,J＝8.4Hz,1H),7.83(d,J＝8.7Hz,1H),7.72(d,J＝2.3Hz,2H),7.30(dd,J＝8.3,1.6Hz,1H),7.11(dd,J＝8.8,1.9Hz,1H),4.58-4.40(m,1H),4.16-4.02(m,2H),3.23-3.20(m,3H),3.19(s,6H),3.05-2.95(m,2H),2.70-2.63(m,2H),2.15-2.05(m,1H),2.05-1.94(m,2H),1.82-1.63(m,4H).Compound 152: LC-MS (ESI) m/z: 293.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.40(s,1H),7.99(d,J＝8.4Hz,1H),7.83(d,J＝8.7Hz,1H),7.72(d,J＝2.3Hz,2H),7.30(dd,J＝8.3,1.6Hz,1H),7.11(dd,J＝8.8,1.9Hz,1H),4.58-4.40(m, 1H),4.16-4.02(m,2H),3.23-3.20(m,3H),3.19(s,6H),3.05-2.95(m,2H ),2.70-2.63(m,2H),2.15-2.05(m,1H),2.05-1.94(m,2H),1.82-1.63(m, 4H).
实施例153
Embodiment 153
合成路线
Synthetic route
步骤一：化合物153-1的合成Step 1: Synthesis of compound 153-1
0℃下将草酰氯(470mg，3.68mmol)滴加到4-氯-2-氟苯甲酰胺(320mg，1.84mmol)的二氯乙烷DCE(5mL)中。氮气保护下，反应混合液在70℃搅拌过夜，减压旋蒸除去多余的草酰氯后，用DCE(2mL)稀释后滴入1-叔丁氧羰基-3-氨基-4-氟哌啶(200mg，0.92mmol)的DCE(3mL)体系中，反应在室温下搅拌3h。TLC监测完全反应。反应体系加入乙腈打浆过滤后得到化合物153-1(392mg，白色固体)，产率99％。LC-MS(ESI)m/z:418[M+H]+.Oxalyl chloride (470 mg, 3.68 mmol) was added dropwise to 4-chloro-2-fluorobenzamide (320 mg, 1.84 mmol) in dichloroethane (5 mL) at 0°C. Under nitrogen protection, the reaction mixture was stirred at 70°C overnight. After the excess oxalyl chloride was removed by vacuum rotary evaporation, it was diluted with DCE (2 mL) and then added dropwise to a DCE (3 mL) system of 1-tert-butyloxycarbonyl-3-amino-4-fluoropiperidine (200 mg, 0.92 mmol). The reaction was stirred at room temperature for 3 h. TLC monitored the complete reaction. Acetonitrile was added to the reaction system and the mixture was pulped and filtered to obtain compound 153-1 (392 mg, white solid) with a yield of 99%. LC-MS (ESI) m/z: 418 [M+H] + .
步骤二：化合物153-2的合成Step 2: Synthesis of compound 153-2
0℃下将氢化钠(94mg，2.34mmol)加入到化合物153-1(392mg，0.94mmol)的N,N-二甲基甲酰胺DMF(4mL)中，氮气保护下，升温至90℃搅拌3h。LC-MS检测原料基本消失。反应体系加水淬灭，滴加稀盐酸(0.5mol/L)至pH为中性，过滤后固体用乙腈打浆，再次过滤后得到化合物153-2(69mg，白色固体)，产率19％。LC-MS(ESI)m/z:378[M+H]+.Sodium hydride (94 mg, 2.34 mmol) was added to compound 153-1 (392 mg, 0.94 mmol) in DMF (4 mL) at 0°C, and the mixture was heated to 90°C and stirred for 3 h under nitrogen protection. LC-MS detected that the raw material was basically gone. The reaction system was quenched with water, and dilute hydrochloric acid (0.5 mol/L) was added dropwise until the pH was neutral. After filtration, the solid was slurried with acetonitrile and filtered again to obtain compound 153-2 (69 mg, white solid) with a yield of 19%. LC-MS (ESI) m/z: 378 [M+H] + .
步骤三：化合物153-3的合成Step 3: Synthesis of compound 153-3
室温下将化合物153-2(69mg，0.18mmol)溶解在1mL乙腈中，向其中加入1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(140mg，0.27mmol)和二甲胺的四氢呋喃溶液(200μL，0.45mmol)，而后逐滴加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)(100mg，0.63mmol)。反应混合液在室温下搅拌30min，TLC监测完全反应。粗产品通过硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)得到化合物153-3(60mg，白色固体)，产率83％。LC-MS(ESI)m/z:404[M+H]+.Compound 153-2 (69 mg, 0.18 mmol) was dissolved in 1 mL of acetonitrile at room temperature, 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate (140 mg, 0.27 mmol) and a tetrahydrofuran solution of dimethylamine (200 μL, 0.45 mmol) were added thereto, and then 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (100 mg, 0.63 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 min, and the complete reaction was monitored by TLC. The crude product was subjected to silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min) to obtain compound 153-3 (60 mg, white solid) with a yield of 83%. LC-MS (ESI) m/z: 404 [M+H] + .
步骤四：化合物153-4的合成Step 4: Synthesis of compound 153-4
室温下将化合物153-3(60mg，0.15mmol)溶解在1mL 1,4-二氧六环中，向其中加入盐酸-二氧六环溶液1mL，室温下搅拌30min。TLC监测完全反应，浓缩后得到化合物153-4的盐酸盐(54mg，白色固体)，产率99％。LC-MS(ESI)m/z:304[M+H]+.步骤五：化合物153的合成Compound 153-3 (60 mg, 0.15 mmol) was dissolved in 1 mL of 1,4-dioxane at room temperature, 1 mL of hydrochloric acid-dioxane solution was added thereto, and stirred at room temperature for 30 min. TLC monitored the complete reaction, and after concentration, the hydrochloride of compound 153-4 (54 mg, white solid) was obtained with a yield of 99%. LC-MS (ESI) m/z: 304 [M+H] + . Step 5: Synthesis of compound 153
室温下将化合物153-4(54mg，0.17mmol)溶解在1mL N,N-二甲基甲酰胺中，向其中加入1-((2-溴噻唑-5-基)甲基)-7-氯-4-(二甲胺基)喹唑啉-2(1H)-酮(50mg，0.13 mmol)和碳酸铯(123mg，0.39mmol)。反应混合液在120℃下搅拌16h。LC-MS检测完全反应。经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，HPLC制备后得到化合物153(4.6mg，白色固体)，产率5.8％。LC-MS(ESI)m/z:312.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.05(dd,J＝9.1,6.2Hz,1H),7.89(d,J＝8.7Hz,1H),7.80(s,1H),7.56(dd,J＝11.6,2.5Hz,1H),7.44(s,1H),7.19(dd,J＝8.8,1.8Hz,1H),7.02(td,J＝8.5,2.4Hz,1H),6.83(dd,1H),5.27(q,J＝15.8Hz,2H),4.17(t,1H),3.97-3.86(m,2H),3.72(d,J＝13.0Hz,1H),3.24(s,6H),3.21(s,6H),3.14-3.07(m,1H),3.04-3.00(m,1H),2.04-1.96(m,2H).Compound 153-4 (54 mg, 0.17 mmol) was dissolved in 1 mL of N,N-dimethylformamide at room temperature, and 1-((2-bromothiazol-5-yl)methyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (50 mg, 0.13 mmol) and cesium carbonate (123 mg, 0.39 mmol). The reaction mixture was stirred at 120 ° C for 16 h. LC-MS detected the complete reaction. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min). Compound 153 (4.6 mg, white solid) was obtained after HPLC preparation with a yield of 5.8%. LC-MS (ESI) m/z: 312.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.05(dd,J＝9.1,6.2Hz,1H),7.89(d,J＝8.7Hz,1H),7.80(s,1H),7.56(dd,J＝11.6,2.5Hz,1H),7.44(s,1H),7.19(dd,J＝8.8,1.8Hz,1H),7.02(td,J＝8.5 ,2.4Hz,1H),6.83 (dd,1H),5.27(q,J＝15.8Hz,2H),4.17(t,1H),3.97-3.86(m,2H),3.72(d,J＝13.0Hz,1H),3.24(s,6H),3.21(s,6H),3.14-3.07(m,1H),3.04-3.00(m,1 H),2.04-1.96(m,2H).
实施例154
Embodiment 154
合成路线Synthetic route
化合物154的合成方法参照实施例146。区别在于把步骤一中的123-2替换为101-2。LC-MS(ESI)m/z:308.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.19(t,2H),7.90(d,J＝8.7Hz,2H),7.30(d,J＝2.0Hz,2H),7.18(dd,J＝8.8,2.0Hz,2H),4.68(s,4H),3.65(q,J＝7.0Hz,4H),3.23(s,6H),3.16-3.12(m,4H),1.27(t,J＝7.0Hz,6H).The synthesis method of compound 154 refers to Example 146. The difference is that 123-2 in step 1 is replaced by 101-2. LC-MS (ESI) m/z: 308.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (t, 2H), 7.90 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 2.0 Hz, 2H), 7.18 (dd, J = 8.8, 2.0 Hz, 2H), 4.68 (s, 4H), 3.65 (q, J = 7.0 Hz, 4H), 3.23 (s, 6H), 3.16-3.12 (m, 4H), 1.27 (t, J = 7.0 Hz, 6H).
实施例155
Embodiment 155
合成路线
Synthetic route
步骤一：化合物155-1的合成Step 1: Synthesis of compound 155-1
室温下，将7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(123-2，300mg，1.34mmol)和氯乙酸乙酯(250mg，2.04mmol)溶于5mL干燥的DMF中，加入碳酸钾(550mg，3.99mmol)，升温至100℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次， 饱和食盐水洗涤合并的有机相浓缩后，经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到120mg化合物155-1，收率29％。LC-MS(ESI)m/z:310[M+H]+.At room temperature, 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2, 300 mg, 1.34 mmol) and ethyl chloroacetate (250 mg, 2.04 mmol) were dissolved in 5 mL of dry DMF, potassium carbonate (550 mg, 3.99 mmol) was added, and the temperature was raised to 100°C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times. The combined organic phase was washed with saturated brine and concentrated, and then separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 120 mg of compound 155-1, with a yield of 29%. LC-MS (ESI) m/z: 310 [M+H] + .
步骤二：化合物155-2的合成Step 2: Synthesis of compound 155-2
室温下，将化合物155-1(120mg，0.387mmol)溶于3mL甲醇和3mL水中，加入氢氧化锂(40mg，1.67mmol)，室温反应2小时。LC-MS监测反应完全。浓缩除去甲醇，加1N的盐酸调节pH至2-3，加DCM萃取后，水相浓缩后过反向柱(流动相为水和乙腈，梯度5-95％，20分钟)得到40mg化合物155-2，收率37％。LC-MS(ESI)m/z:282[M+H]+.At room temperature, compound 155-1 (120 mg, 0.387 mmol) was dissolved in 3 mL of methanol and 3 mL of water, and lithium hydroxide (40 mg, 1.67 mmol) was added. The reaction was allowed to react at room temperature for 2 hours. LC-MS monitored the reaction to be complete. The methanol was removed by concentration, and 1 N hydrochloric acid was added to adjust the pH to 2-3. After extraction with DCM, the aqueous phase was concentrated and passed through a reverse column (the mobile phase was water and acetonitrile, gradient 5-95%, 20 minutes) to obtain 40 mg of compound 155-2, with a yield of 37%. LC-MS (ESI) m/z: 282 [M+H] + .
步骤三：化合物155-3的合成Step 3: Synthesis of compound 155-3
室温下，将7-氯-4-(二甲基氨基)-1-(哌啶-3-基)喹唑啉-2(1H)-酮(102-4，200mg，0.651mmol)溶于5mL干燥的DMF中，加入N-Boc-溴乙胺(220mg，0.982mmol)和碳酸钾(270mg，1.96mmol)，升至100℃反应过夜。LC-MS监测反应完全。加水和EA萃取三次，合并有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到100mg化合物155-3，收率34％。LC-MS(ESI)m/z:450[M+H]+.At room temperature, 7-chloro-4-(dimethylamino)-1-(piperidin-3-yl)quinazolin-2(1H)-one (102-4, 200 mg, 0.651 mmol) was dissolved in 5 mL of dry DMF, N-Boc-bromoethylamine (220 mg, 0.982 mmol) and potassium carbonate (270 mg, 1.96 mmol) were added, and the temperature was raised to 100 ° C for overnight reaction. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the organic phases were combined and concentrated and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 100 mg of compound 155-3, with a yield of 34%. LC-MS (ESI) m/z: 450 [M+H] + .
步骤四：化合物155-4的合成Step 4: Synthesis of compound 155-4
室温下，将化合物155-3(100mg，0.222mmol)溶于2mL二氧六环中，缓慢滴加盐酸二氧六环溶液(2mL，4N)，之后保持室温反应2小时。LC-MS监测反应完全。浓缩后冻干得到56mg化合物155-4，收率72％。LC-MS(ESI)m/z:350[M+H]+.At room temperature, compound 155-3 (100 mg, 0.222 mmol) was dissolved in 2 mL of dioxane, and dioxane hydrochloride solution (2 mL, 4 N) was slowly added dropwise, and then kept at room temperature for 2 hours. LC-MS monitored the reaction to be complete. After concentration and freeze-drying, 56 mg of compound 155-4 was obtained, with a yield of 72%. LC-MS (ESI) m/z: 350 [M+H] + .
步骤五：化合物155的合成Step 5: Synthesis of compound 155
室温下，将化合物155-2(40mg，0.142mmol)溶于2mL干燥的DMF中，加入DIEA(40mg，0.310mmol)和HATU(58mg，0.153mmol)，室温搅拌20分钟后，加入化合物155-4(36mg，0.103mmol)，保持室温反应30分钟。LC-MS监测反应完全。反应液直接经HPLC制备纯化得6mg化合物155,收率10％。LC-MS(ESI)m/z:314.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.08(t,J＝5.6Hz,1H),7.89(dd,J＝8.7,5.2Hz,2H),7.52(d,J＝2.0Hz,1H),7.22-7.14(m,3H),4.70(d,J＝8.3Hz,2H),4.21(s,1H),3.65(q,4H),3.23(s,3H),3.20(s,6H),3.00-2.92(m,2H),2.88-2.77(m,3H),2.06-1.94(m,3H),1.76-1.62(m,3H),1.28(s,3H).At room temperature, compound 155-2 (40 mg, 0.142 mmol) was dissolved in 2 mL of dry DMF, DIEA (40 mg, 0.310 mmol) and HATU (58 mg, 0.153 mmol) were added, and after stirring at room temperature for 20 minutes, compound 155-4 (36 mg, 0.103 mmol) was added, and the reaction was maintained at room temperature for 30 minutes. LC-MS monitored the reaction to be complete. The reaction solution was directly purified by HPLC to obtain 6 mg of compound 155, with a yield of 10%. LC-MS(ESI)m/z:314.1[M/2+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ8.08(t,J＝5.6Hz,1H),7.89(dd,J＝8.7,5.2Hz,2H),7.52(d,J＝2.0Hz,1H),7.22-7.14(m,3H),4.7 0(d,J＝8.3Hz,2H),4.21(s,1H),3.65(q,4H),3.23(s,3H),3.20(s,6H),3. 00-2.92(m,2H),2.88-2.77(m,3H),2.06-1.94(m,3H),1.76-1.62(m,3H), 1.28(s,3H).
实施例156
Embodiment 156
合成路线
Synthetic route
步骤一：化合物156-1的合成Step 1: Synthesis of compound 156-1
室温下，将化合物101-2(0.5g，2.1mmol)、氯乙酸乙酯(0.39g，3.2mmol)和碳酸钾(0.87g，6.3mmol)分散到N,N-二甲基甲酰胺(5mL)溶液中，加热到100℃，搅拌过夜。待反应液冷却至室温，用乙酸乙酯(20mL×3)和水(20mL)萃取，合并浓缩有机相，残余物经快速硅胶层柱(洗脱剂：石油醚/乙酸乙酯＝1/10)纯化，得到化合物156-1，0.3g，为白色固体，收率44％。LC-MS(ESI)m/z:324[M+H]+.At room temperature, compound 101-2 (0.5 g, 2.1 mmol), ethyl chloroacetate (0.39 g, 3.2 mmol) and potassium carbonate (0.87 g, 6.3 mmol) were dispersed in N,N-dimethylformamide (5 mL) solution, heated to 100 ° C, and stirred overnight. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate (20 mL × 3) and water (20 mL), the organic phase was combined and concentrated, and the residue was purified by rapid silica gel column (eluent: petroleum ether/ethyl acetate = 1/10) to obtain compound 156-1, 0.3 g, as a white solid, with a yield of 44%. LC-MS (ESI) m/z: 324 [M + H] + .
步骤二：化合物156-2的合成Step 2: Synthesis of compound 156-2
将化合物156-1(0.30g，0.93mmol)溶到甲醇(1mL)中，向反应液中加入氢氧化锂一水合物(0.20g，4.6mmol)的水溶液(0.5mL)，室温搅拌两小时。反应液减压浓缩，向残余物中加入少量水，在搅拌状态下，然后逐滴加入2N盐酸，调节反应液pH为4，伴随大量白色固体析出。抽滤、干燥，得到化合物156-2，0.20g，收率74％。LC-MS(ESI)m/z:296[M+H]+.Compound 156-1 (0.30 g, 0.93 mmol) was dissolved in methanol (1 mL), and an aqueous solution (0.5 mL) of lithium hydroxide monohydrate (0.20 g, 4.6 mmol) was added to the reaction solution, and stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure, and a small amount of water was added to the residue. Under stirring, 2N hydrochloric acid was then added dropwise to adjust the pH of the reaction solution to 4, accompanied by the precipitation of a large amount of white solid. Filtered and dried to obtain compound 156-2, 0.20 g, yield 74%. LC-MS (ESI) m/z: 296 [M + H] + .
步骤三：化合物156的合成Step 3: Synthesis of compound 156
在氮气保护下，将化合物156-2(50mg，0.17mmol)溶于N,N-二甲基甲酰胺(0.3mL)中，加入DIEA(44mg，0.34mmol)，室温搅拌30分钟，然后依次向反应液中滴加HATU(100mg，0.26mmol)的N,N-二甲基甲酰胺(0.2mL)溶液和化合物148-3(70mg，0.19mmol)的N,N-二甲基甲酰胺(0.1mL)溶液。室温搅拌30分钟。反应液经乙酸乙酯(5mL×3)和水(5mL)萃取，合并浓缩有机相，残余物经快速硅胶层柱(洗脱剂：甲醇/二氯甲烷＝1/15)纯化，得到标题化合物的粗品，再经制备高效液相色谱纯化，制备液冷冻干燥，得到化合物156，3.62mg,收率12％，为白色固体。LC-MS(ESI)m/z:314.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.18(d,1H),7.93(d,J＝8.8Hz,1H),7.60(d,J＝2.3Hz,1H),7.41(d,J＝9.3Hz,1H),7.36(d,J＝2.0Hz,1H),7.21(dd,J＝8.8,2.0Hz,1H),5.05(s,2H),4.76(t,2H),4.03-3.78(m,5H),3.69-3.63(m,5H),3.28(s,3H),3.25(s,3H),2.58-2.52(m,4H),1.33(t,J＝7.0Hz,3H),1.28(t,J＝7.0Hz,3H).Under nitrogen protection, compound 156-2 (50 mg, 0.17 mmol) was dissolved in N, N-dimethylformamide (0.3 mL), DIEA (44 mg, 0.34 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, HATU (100 mg, 0.26 mmol) in N, N-dimethylformamide (0.2 mL) and compound 148-3 (70 mg, 0.19 mmol) in N, N-dimethylformamide (0.1 mL) were added dropwise to the reaction solution. Stir at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate (5 mL × 3) and water (5 mL), the organic phases were combined and concentrated, and the residue was purified by a rapid silica gel column (eluent: methanol/dichloromethane = 1/15) to obtain a crude product of the title compound, which was then purified by preparative high performance liquid chromatography, and the preparative solution was freeze-dried to obtain compound 156, 3.62 mg, with a yield of 12%, as a white solid. LC-MS(ESI)m/z:314.1[M/2+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ8.18(d,1H),7.93(d,J＝8.8Hz,1H),7.60(d,J＝2.3Hz,1H),7.41(d,J＝9.3Hz,1H),7.36(d,J＝2.0Hz,1H),7.21(dd,J＝8.8,2.0Hz,1H),5.05(s,2H),4.76( t,2H),4.03-3.78(m,5H),3.69-3.63(m,5H),3.28(s,3H),3.25(s,3H),2.58-2.52(m,4H),1.33(t,J＝7.0Hz,3H),1.28(t,J＝7.0Hz,3H).
实施例157
Embodiment 157
合成路线
Synthetic route
步骤一：化合物157的合成Step 1: Synthesis of compound 157
室温下，将7-氯-1-(1-(2-氯乙酰基)哌啶-3-基)-4-(二甲基氨基)喹唑啉-2(1H)-酮(150-3,30mg，0.0785mmol)溶于2mL干燥的DMF中，降温至0℃后，缓慢加入氢化钠(7mg，0.175mmol)至反应体系中，升至室温反应1小时，之后加入7-氯-4-(二甲基氨基)-1-(2-羟乙基)喹唑啉-2(1H)-酮(20mg，0.0746mmol)，保持室温反应2小时。LC-MS监测反应完全。饱和氯化铵溶液淬灭反应，加水和EA萃取三次，合并有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到20mg粗品，之后经制备纯化得4mg化合物157，收率8％。LC-MS(ESI)m/z:307.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.08(t,J＝5.6Hz,1H),7.89(dd,J＝8.7,5.2Hz,2H),7.52(d,J＝2.0Hz,1H),7.22-7.14(m,3H),4.70(d,J＝8.3Hz,2H),4.21(s,1H),3.65(q,4H),3.23(s,3H),3.20(s,6H),3.00-2.92(m,2H),2.88-2.77(m,3H),2.06-1.94(m,3H),1.76-1.62(m,3H),1.28(s,3H).At room temperature, 7-chloro-1-(1-(2-chloroacetyl)piperidin-3-yl)-4-(dimethylamino)quinazolin-2(1H)-one (150-3, 30 mg, 0.0785 mmol) was dissolved in 2 mL of dry DMF, cooled to 0°C, and sodium hydride (7 mg, 0.175 mmol) was slowly added to the reaction system, and the temperature was raised to room temperature for 1 hour, followed by the addition of 7-chloro-4-(dimethylamino)-1-(2-hydroxyethyl)quinazolin-2(1H)-one (20 mg, 0.0746 mmol), and the reaction was maintained at room temperature for 2 hours. LC-MS monitored the reaction to be complete. The reaction was quenched with saturated ammonium chloride solution, and water and EA were added for extraction three times. The organic phases were combined and concentrated, and then separated by flash chromatography (DCM:MeOH, 0-10%, 10 min) to obtain 20 mg of crude product, which was then purified by preparative purification to obtain 4 mg of compound 157, with a yield of 8%. LC-MS(ESI)m/z:307.6[M/2+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ8.08(t,J＝5.6Hz,1H),7.89(dd,J＝8.7,5.2Hz,2H),7.52(d,J＝2.0Hz,1H),7.22-7.14(m,3H),4.7 0(d,J＝8.3Hz,2H),4.21(s,1H),3.65(q,4H),3.23(s,3H),3.20(s,6H),3. 00-2.92(m,2H),2.88-2.77(m,3H),2.06-1.94(m,3H),1.76-1.62(m,3H), 1.28(s,3H).
实施例158
Embodiment 158
合成方法Synthesis method
化合物158的合成方法参照实施例102。区别在于把步骤五中的101-3替换为4-(吖啶-1-基)-1-((2-溴噻唑-5-基)甲基)-7-氯喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:319.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.89(d,J＝8.7Hz,1H),7.82(d,J＝2.0Hz,1H),7.78-7.74(m,2H),7.39(s,1H),7.20(ddd,J＝8.7,3.0,1.9Hz,2H),5.31(d,J＝4.0Hz,2H),4.91-4.26(m,3H),4.23-4.12(m,2H),4.00-3.85(m,2H),3.71(d,J＝13.4Hz,1H),3.21(s,6H),3.16-3.06(m,1H),2.83-2.70(m,1H),2.39(p,2H),1.78-1.74(m,2H).The synthesis method of compound 158 is similar to that of Example 102. The difference is that 101-3 in step 5 is replaced by 4-(acridin-1-yl)-1-((2-bromothiazol-5-yl)methyl)-7-chloroquinazolin-2(1H)-one. LC-MS (ESI) m/z: 319.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.89(d,J＝8.7Hz,1H),7.82(d,J＝2.0Hz,1H),7.78-7.74(m,2H),7.39(s,1H),7.20(ddd,J＝8.7,3.0,1.9Hz,2H),5.31(d,J＝4.0Hz,2H),4.91-4.26(m, 3H),4.23-4.12(m,2H),4.00-3.85(m,2H),3.71(d,J＝13.4Hz,1H),3.21(s,6H),3.16-3.06(m,1H),2.83-2.70(m,1H),2.39(p,2H),1.78-1.74(m,2H ).
实施例159
Embodiment 159
合成方法Synthesis method
化合物159的合成方法参照实施例102。区别在于把步骤五中的101-3替换为1-((2-溴噻唑-5-基)甲基)-4-(甲乙胺基)-7-氟喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:312.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.98(dd,J＝9.1,6.2Hz,1H),7.89(d,J＝8.7Hz,1H),7.81(d,J＝2.0Hz,1H),7.56(dd,J＝11.7,2.5Hz,1H),7.44(s,1H),7.19(dd,J＝ 8.7,1.8Hz,1H),7.03(td,J＝9.1,8.1,2.5Hz,1H),5.26(q,J＝5.2Hz,2H),4.17(t,1H),3.99-3.84(m,2H),3.72(d,J＝13.2Hz,1H),3.64(q,J＝7.0Hz,2H),3.41,(t,3H),3.22(s,3H),3.21(s,6H),3.15-3.02(m,1H),2.76(q,1H),2.04-1.99(m,1H),2.00-1.95(m,1H),1.51-1.42(m,1H).The synthesis method of compound 159 refers to Example 102. The difference is that 101-3 in step 5 is replaced by 1-((2-bromothiazol-5-yl)methyl)-4-(methylethylamino)-7-fluoroquinazolin-2(1H)-one. LC-MS (ESI) m/z: 312.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.98 (dd, J = 9.1, 6.2 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 11.7, 2.5 Hz, 1H), 7.44 (s, 1H), 7.19 (dd, J = 8.7,1.8Hz,1H),7.03(td,J＝9.1,8.1,2.5Hz,1H),5.26(q,J＝5.2Hz,2H),4.17(t,1H),3.99-3.84(m,2H),3.72(d,J＝13.2Hz,1H),3.64(q,J＝7.0Hz,2H) ,3.41,(t,3H),3.22(s,3H),3.21(s,6H),3.15-3.02(m,1H),2.76(q,1H),2.04-1.99(m,1H),2.00-1.95(m,1H),1.51-1.42(m,1H).
实施例160
Embodiment 160
合成方法Synthesis method
化合物160的合成方法参照实施例102。区别在于把步骤五中的101-3替换为1-((2-溴噻唑-5-基)甲基)-4-(二甲胺基)-7-三氟甲基喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:330.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.05(dd,J＝9.1,6.2Hz,1H),7.89(d,J＝8.7Hz,1H),7.80(s,1H),7.56(dd,J＝11.6,2.5Hz,1H),7.44(s,1H),7.19(dd,J＝8.8,1.8Hz,1H),7.02(td,J＝8.5,2.4Hz,1H),5.27(q,J＝15.8Hz,2H),4.17(t,1H),3.97-3.86(m,2H),3.72(d,J＝13.0Hz,1H),3.24(s,6H),3.21(s,6H),3.14-3.07(m,1H),3.04-3.00(m,1H),2.80-2.71(m,1H),2.04-1.96(m,2H).The synthesis method of compound 160 is similar to that of Example 102. The difference is that 101-3 in step 5 is replaced by 1-((2-bromothiazol-5-yl)methyl)-4-(dimethylamino)-7-trifluoromethylquinazolin-2(1H)-one. LC-MS (ESI) m/z: 330.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.05(dd,J＝9.1,6.2Hz,1H),7.89(d,J＝8.7Hz,1H),7.80(s,1H),7.56(dd,J＝11.6,2.5Hz,1H),7.44(s,1H),7.19(dd,J＝8.8,1.8Hz,1H),7.02(td,J＝8.5 ,2.4Hz,1H),5.27(q ,J＝15.8Hz,2H),4.17(t,1H),3.97-3.86(m,2H),3.72(d,J＝13.0Hz,1H),3.24(s,6H),3.21(s,6H),3.14-3.07(m,1H),3.04-3.00(m,1H),2.80-2.7 1(m,1H),2.04-1.96(m,2H).
实施例161
Embodiment 161
合成方法Synthesis method
化合物161的合成方法参照实施例102。区别在于把步骤一中的1-叔丁氧羰基-3-氨基哌啶替换为1-叔丁氧羰基-3-氨基-5,5-二氟哌啶。LC-MS(ESI)m/z:330.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.92(td,J＝10.9,8.7Hz,2H),7.78(t,J＝2.2Hz,2H),7.47(s,1H),7.24(dd,J＝8.7,1.8Hz,1H),7.21(dd,J＝8.8,2.0Hz,1H),5.32(d,J＝4.7Hz,2H),4.32(t,1H),4.13(t,J＝12.6Hz,1H),4.05(d,J＝12.4Hz,1H),4.00-3.91(m,1H),3.75(d,1H),3.64(q,J＝7.2Hz,2H),3.41(t,3H),3.23(s,6H),3.22(s,3H),2.45-2.36(m,1H),1.52-1.42(m,1H).The synthesis method of compound 161 refers to Example 102. The difference is that 1-tert-butyloxycarbonyl-3-aminopiperidine in step 1 is replaced by 1-tert-butyloxycarbonyl-3-amino-5,5-difluoropiperidine. LC-MS (ESI) m/z: 330.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ7.92 (td, J=10.9, 8.7 Hz, 2H), 7.78 (t, J=2.2 Hz, 2H), 7.47 (s, 1H), 7.24 (dd, J=8.7, 1.8 Hz, 1H), 7.21 (dd, J=8.8, 2.0 Hz, 1H), 5.32 (d, J=4.7 Hz, 2H), 4.32 (t, 1H), 4.13 (t, J=2. ＝12.6Hz,1H),4.05(d,J＝12.4Hz,1H),4.00-3.91(m,1H),3.75(d,1H),3.64(q,J＝7.2Hz,2H),3.41(t,3H),3.23(s,6H),3.22(s,3H),2.45-2.36(m,1 H),1.52-1.42(m,1H).
实施例162
Embodiment 162
合成路线
Synthetic route
步骤一：化合物162-1的合成Step 1: Synthesis of compound 162-1
室温下，将化合物123-2(1.0g，4.48mmol)溶解在10mL N,N-二甲基甲酰胺中，向其中加入1-Boc-3-溴甲基氮杂环丁烷(1.3g，5.38mmol)和碳酸钾(1.9g，13.44mmol)，室温下搅拌16h。TLC监测完全反应，反应体系中加水，用乙酸乙酯(30mL x 3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物162-1(650mg，白色固体)，产率37％。LC-MS(ESI)m/z:393[M+H]+.At room temperature, compound 123-2 (1.0 g, 4.48 mmol) was dissolved in 10 mL of N, N-dimethylformamide, 1-Boc-3-bromomethylazetidine (1.3 g, 5.38 mmol) and potassium carbonate (1.9 g, 13.44 mmol) were added thereto, and stirred at room temperature for 16 h. TLC monitored the complete reaction, water was added to the reaction system, extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 162-1 (650 mg, white solid) with a yield of 37%. LC-MS (ESI) m/z: 393 [M + H] + .
步骤二：化合物162-2的合成Step 2: Synthesis of compound 162-2
室温下将化合物162-1(650mg，1.66mmol)溶解在7mL 1,4-二氧六环中，向其中加入盐酸-二氧六环溶液7mL，室温下搅拌30min。TLC监测完全反应，浓缩后得到化合物162-2的盐酸盐(513mg，白色固体)，产率99％。LC-MS(ESI)m/z:293[M+H]+.步骤三：化合物162的合成Compound 162-1 (650 mg, 1.66 mmol) was dissolved in 7 mL of 1,4-dioxane at room temperature, and 7 mL of hydrochloric acid-dioxane solution was added thereto, and stirred at room temperature for 30 min. TLC monitored the complete reaction, and after concentration, the hydrochloride of compound 162-2 (513 mg, white solid) was obtained with a yield of 99%. LC-MS (ESI) m/z: 293 [M+H] + . Step 3: Synthesis of compound 162
室温下将化合物123-7(100mg，0.34mmol)溶解在1mL N,N-二甲基甲酰胺中，向其中加入化合物162-2(130mg，0.34mmol)和碳酸铯(335mg，1.02mmol)。反应混合液在120℃下搅拌16h。LC-MS检测完全反应。经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，HPLC制备纯化后得到化合物162(33.85mg，白色固体)，产率16.9％。LC-MS(ESI)m/z:296.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.04(d,J＝8.8Hz,1H),7.97(d,J＝8.8Hz,1H),7.75(t,1H),7.68(d,J＝2.0Hz,1H),7.21(dd,J＝8.8,2.1Hz,2H),6.64(d,J＝7.3Hz,1H),6.50(d,J＝8.3Hz,1H),6.43(d,J＝2.1Hz,1H),4.44(d,J＝7.5Hz,2H),3.96(t,J＝8.1Hz,2H),3.80(dd,J＝8.2,5.4Hz,2H),3.31(s,6H),3.24(s,6H),3.17-3.07(m,1H).Compound 123-7 (100 mg, 0.34 mmol) was dissolved in 1 mL of N,N-dimethylformamide at room temperature, and compound 162-2 (130 mg, 0.34 mmol) and cesium carbonate (335 mg, 1.02 mmol) were added thereto. The reaction mixture was stirred at 120°C for 16 h. LC-MS detected the complete reaction. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 162 (33.85 mg, white solid) was obtained after HPLC preparation and purification, with a yield of 16.9%. LC-MS (ESI) m/z: 296.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.04(d,J＝8.8Hz,1H),7.97(d,J＝8.8Hz,1H),7.75(t,1H),7.68(d,J＝2.0Hz,1H),7.21(dd,J＝8.8,2.1Hz,2H),6.64(d,J＝7.3Hz,1H),6.50(d,J＝8.3Hz,1 H), 6.43 (d, J = 2.1Hz, 1H), 4.44 (d, J = 7.5Hz, 2H), 3.96 (t, J = 8.1Hz, 2H), 3.80 (dd, J = 8.2, 5.4Hz, 2H), 3.31 (s, 6H), 3.24 (s, 6H), 3.17-3.07 (m, 1H).
实施例163
Embodiment 163
合成方法Synthesis method
化合物160的合成方法参照实施例123。区别在于把步骤一中的2,4,7-三氯喹唑啉替换为2,4-二氯喹唑啉。LC-MS(ESI)m/z:286.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.96(d,J＝8.2,1.4Hz,1H),7.72(t,J＝7.8Hz,1H),7.65(t,J＝8.6,7.1,1.5Hz,1H),7.52(d,J＝8.6Hz,1H),7.22-7.15(m,2H),6.54(d,J＝7.8Hz,2H), 6.44(d,J＝2.1Hz,1H),4.30-4.15(m,2H),3.57-3.47(m,2H),3.30(s,6H),3.23(s,6H),2.80-2.69(m,1H),2.11-1.99(m,1H),1.91-1.77(m,1H).The synthesis method of compound 160 refers to Example 123. The difference is that 2,4,7-trichloroquinazoline in step 1 is replaced by 2,4-dichloroquinazoline. LC-MS (ESI) m/z: 286.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.03 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.2, 1.4 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.65 (t, J = 8.6, 7.1, 1.5 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.22-7.15 (m, 2H), 6.54 (d, J = 7.8 Hz, 2H), 6.44(d,J＝2.1Hz,1H),4.30-4.15(m,2H),3.57-3.47(m,2H),3.30(s,6H),3.23(s,6H),2.80-2.69(m,1H),2.11-1.99(m,1H),1.91-1.77(m,1H).
实施例164
Embodiment 164
合成方法Synthesis method
化合物164的合成方法参照实施例123。区别在于把步骤一中的2,4,7-三氯喹唑啉替换为2,4-二氯喹唑啉，把步骤五中的4-氯-2-氟苯甲酰胺替换为2-氟苯甲酰胺。LC-MS(ESI)m/z:269.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.98(dd,J＝14.1,8.2,1.4Hz,2H),7.75-7.61(m,2H),7.55-7.46(m,2H),7.21-7.12(m,2H),6.57-6.48(m,3H),4.21(h,J＝6.8Hz,2H),3.58-3.43(m,2H),3.31(s,6H),3.23(s,6H),2.79-2.68(m,1H),2.10-1.98(m,1H),1.89-1.78(m,1H).The synthesis method of compound 164 refers to Example 123, except that 2,4,7-trichloroquinazoline in step 1 is replaced by 2,4-dichloroquinazoline, and 4-chloro-2-fluorobenzamide in step 5 is replaced by 2-fluorobenzamide. LC-MS (ESI) m/z: 269.1[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ7.98 (dd, J = 14.1, 8.2, 1.4Hz, 2H), 7.75-7.61 (m, 2H), 7.55-7.46 (m, 2H), 7.21-7.12 (m, 2H), 6. 57-6.48(m,3H),4.21(h,J=6.8Hz,2H),3.58-3.43(m,2H),3.31(s,6H),3.23(s,6H),2.79-2.68(m,1H),2.10-1.98(m,1H),1.89-1.78(m,1H).
实施例165
Embodiment 165
合成方法Synthesis method
化合物165的合成方法参照实施例102。区别在于把步骤一中的4-氯-2-氟苯甲酰胺替换为4-三氟甲基-2-氟苯甲酰胺。LC-MS(ESI)m/z:337.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.09(d,J＝9.2Hz,2H),7.90(d,J＝8.8Hz,1H),7.78(d,J＝2.1Hz,1H),7.45(d,J＝8.4Hz,1H),7.39(s,1H),7.21(dd,J＝8.8,2.0Hz,1H),5.34-5.28(m,2H),4.32–4.20(m,1H),4.06(d,J＝11.7Hz,1H),3.86(t,J＝11.8Hz,1H),3.71-3.59(m,4H),3.24(s,6H),3.22(s,3H),3.20-3.11(m,1H),2.89-2.77(m,1H),1.81-1.69(m,3H),1.27(t,J＝7.0Hz,3H).The synthesis method of compound 165 refers to Example 102. The difference is that 4-chloro-2-fluorobenzamide in step 1 is replaced by 4-trifluoromethyl-2-fluorobenzamide. LC-MS (ESI) m/z: 337.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.09 (d, J = 9.2 Hz, 2H), 7.90 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 2.1 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H), 7.21 (dd, J = 8.8, 2.0 Hz, 1H), 5.34-5.28 (m, 2H), 4.32–4.20 (m, 1H), 4.06(d,J＝11.7Hz,1H),3.86(t,J＝11.8Hz,1H),3.71-3.59(m,4H),3.24(s,6H),3.22(s,3H),3.20-3.11(m,1H),2.89-2.77(m,1H),1.81-1.69(m,3 H),1.27(t,J＝7.0Hz,3H).
实施例166
Embodiment 166
合成方法Synthesis method
化合物166的合成方法参照实施例72。区别在于把步骤六中的4-氯-2-氟苯甲酰胺替换为2-氟苯甲酰胺。LC-MS(ESI)m/z:276.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ9.15(d,J＝2.0Hz,1H),8.59(d,J＝2.2Hz,1H),8.27(t,J＝2.2Hz,1H),8.20(s,1H),8.04(dd,J＝8.3,1.4Hz,1H),7.98(d,1H),7.71-7.66(m,2H),7.46(td,J＝8.6,7.2,1.4Hz,1H),7.23-7.16(m,2H),6.54(dd,J＝8.5,1.1Hz,1H),5.54(s,2H),3.32(s,6H),3.26(s,6H). The synthesis method of compound 166 refers to Example 72, except that 4-chloro-2-fluorobenzamide in step 6 is replaced by 2-fluorobenzamide. LC-MS(ESI)m/z:276.1[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.15(d,J＝2.0Hz,1H),8.59(d,J＝2.2Hz,1H),8.27(t,J＝2.2Hz,1H),8.20(s,1H),8.04(dd,J＝8.3 ,1.4Hz,1H),7.98(d,1H),7.71-7.66(m,2H),7.46(td,J＝8.6,7.2,1.4Hz,1H),7.23-7.16(m,2H),6.54(dd,J＝8.5,1.1Hz,1H),5.54(s,2H),3.32(s,6H) ,3.26(s,6H).
实施例167
Embodiment 167
合成方法Synthesis method
化合物167的合成方法参照实施例72。区别在于把步骤六中的4-氯-2-氟苯甲酰胺替换为2-氟苯甲酰胺，步骤八中的氘代二甲胺替换为甲乙胺。LC-MS(ESI)m/z:290.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ9.15(d,J＝2.0Hz,1H),8.59(d,J＝2.3Hz,1H),8.28(t,J＝2.2Hz,1H),8.20(s,1H),7.97(dd,J＝8.2,1.4Hz,1H),7.91(d,J＝8.1Hz,1H),7.69-7.65(m,2H),7.46(td,J＝8.6,7.1,1.4Hz,1H),7.22-7.16(m,2H),6.54(dd,J＝8.6,1.1Hz,1H),5.53(s,2H),3.73(q,J＝7.0Hz,2H),3.66(q,J＝7.0Hz,2H),3.37(t,3H),3.31(t,3H),3.24(s,3H),3.19(s,3H).The synthesis method of compound 167 refers to Example 72. The difference is that 4-chloro-2-fluorobenzamide in step 6 is replaced by 2-fluorobenzamide, and deuterated dimethylamine in step 8 is replaced by methylethylamine. LC-MS (ESI) m/z: 290.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.15 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 2.3 Hz, 1H), 8.28 (t, J = 2.2 Hz, 1H), 8.20 (s, 1H), 7.97 (dd, J = 8.2, 1.4 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.69-7.65 (m, 2H), 7.46 (td, J = 8.6, 7. 1,1.4Hz,1H),7.22-7.16(m,2H),6.54(dd,J＝8.6,1.1Hz,1H),5.53(s,2H),3.73(q,J＝7.0Hz,2H),3.66(q,J＝7.0Hz,2H),3.37(t,3H),3.31(t,3H),3.2 4(s,3H),3.19(s,3H).
实施例168
Embodiment 168
合成路线
Synthetic route
步骤一：化合物168-1的合成Step 1: Synthesis of compound 168-1
室温下，将2,4-二氯吡啶并[2,3-d]嘧啶(1g，5.02mmol)溶于15mL干燥的THF中，加入二甲胺的THF溶液(2N)，室温搅拌2小时。LC-MS监测反应完全。减压浓缩后，加入30mL冰乙酸，升温至100℃搅拌过夜。LC-MS监测反应完全。降至室温后加入大量DCM/MeOH混合溶液分散均匀，之后过滤除掉固体杂质，滤液浓缩后经快速色谱柱层析分离(DCM:MeOH,0-15％,10min)得到900mg化合物168-1，收率94％。LC-MS(ESI)m/z:191[M+H]+.At room temperature, 2,4-dichloropyrido[2,3-d]pyrimidine (1 g, 5.02 mmol) was dissolved in 15 mL of dry THF, and a THF solution of dimethylamine (2N) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was complete as monitored by LC-MS. After concentration under reduced pressure, 30 mL of glacial acetic acid was added, and the mixture was heated to 100 °C and stirred overnight. The reaction was complete as monitored by LC-MS. After cooling to room temperature, a large amount of DCM/MeOH mixed solution was added and dispersed evenly, and then solid impurities were removed by filtration. After the filtrate was concentrated, it was separated by flash chromatography (DCM:MeOH, 0-15%, 10 min) to obtain 900 mg of compound 168-1, with a yield of 94%. LC-MS (ESI) m/z: 191 [M+H] + .
步骤二：化合物168-2的合成Step 2: Synthesis of compound 168-2
室温下，将化合物168-1(300mg，1.57mmol)和2-溴-5-(溴甲基)噻唑(450mg，1.75mmol)溶于5mL干燥的DMF中，加入碳酸钾(650mg，4.71mmol)，室温搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到180mg化合物168-2，收率31％。LC-MS(ESI)m/z:366[M+H]+. At room temperature, compound 168-1 (300 mg, 1.57 mmol) and 2-bromo-5-(bromomethyl)thiazole (450 mg, 1.75 mmol) were dissolved in 5 mL of dry DMF, potassium carbonate (650 mg, 4.71 mmol) was added, and stirred at room temperature overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine and concentrated and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 180 mg of compound 168-2, with a yield of 31%. LC-MS (ESI) m/z: 366 [M + H] + .
步骤三：化合物168的合成Step 3: Synthesis of compound 168
室温下，将化合物168-2(50mg，0.137mmol)和7-氯-4-(二甲基氨基)-1-(哌啶-3-基)喹唑啉-2(1H)-酮(102-4，63mg，0.205mmol)溶于2mL干燥的DMF中，加入碳酸铯(135mg，0.412mmol)，升温至120℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到30mg淡黄色粗品化合物，之后经HPLC制备纯化后得5mg化合物168，收率6％。LC-MS(ESI)m/z:296.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.69(dd,J＝4.7,1.7Hz,1H),8.44(dd,J＝8.1,1.7Hz,1H),7.90(d,J＝8.7Hz,1H),7.82(d,J＝2.0Hz,1H),7.27-7.17(m,3H),5.38(s,2H),4.25-4.15(m,1H),3.98-3.91(m,2H),3.75-3.65(m,2H),3.29(s,6H),3.22(s,6H),3.17-3.07(m,2H),1.78-1.72(m,2H).At room temperature, compound 168-2 (50 mg, 0.137 mmol) and 7-chloro-4-(dimethylamino)-1-(piperidin-3-yl)quinazolin-2(1H)-one (102-4, 63 mg, 0.205 mmol) were dissolved in 2 mL of dry DMF, cesium carbonate (135 mg, 0.412 mmol) was added, and the temperature was raised to 120°C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine and concentrated and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 30 mg of pale yellow crude compound, which was then purified by HPLC to obtain 5 mg of compound 168, with a yield of 6%. LC-MS (ESI) m/z: 296.6 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.69 (dd, J = 4.7, 1.7Hz, 1H), 8.44 (dd, J = 8.1, 1.7Hz, 1H), 7.90 (d, J = 8.7Hz, 1H), 7.82 (d, J = 2.0Hz, 1 H),7.27-7.17(m,3H),5.38(s,2H),4.25-4.15(m,1H),3.98-3.91(m,2H), 3.75-3.65(m,2H),3.29(s,6H),3.22(s,6H),3.17-3.07(m,2H),1.78-1.7 2(m,2H).
实施例169
Embodiment 169
合成方法Synthesis method
化合物169的合成方法参照实施例102。区别在于把步骤五中的101-3替换为1-((2-溴噻唑-5-基)甲基)-4-(二甲胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:296.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.97(d,1H),7.89(d,J＝8.7Hz,1H),7.80(d,J＝2.0Hz,1H),7.67(dd,J＝5.6,1.6Hz,2H),7.40(s,1H),7.21-7.17(m,2H),5.32-5.25(m,2H),4.23-4.11(m,1H),3.94-3.88(m,2H),3.72(d,J＝13.3Hz,1H),3.24(s,6H),3.21(s,6H),3.14-3.04(m,1H),2.82-2.69(m,1H),1.78-1.70(m,3H).The synthesis method of compound 169 refers to Example 102. The difference is that 101-3 in step 5 is replaced by 1-((2-bromothiazol-5-yl)methyl)-4-(dimethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 296.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.97(d,1H),7.89(d,J＝8.7Hz,1H),7.80(d,J＝2.0Hz,1H),7.67(dd,J＝5.6,1.6Hz,2H),7.40(s,1H),7.21-7.17(m,2H),5.32-5.25(m,2H),4.23-4.1 1(m,1H),3.94-3.88(m,2H),3.72(d,J＝13.3Hz,1H),3.24(s,6H),3.21(s,6H),3.14-3.04(m,1H),2.82-2.69(m,1H),1.78-1.70(m,3H).
实施例170
Embodiment 170
合成方法Synthesis method
化合物170的合成方法参照实施例123。区别在于把步骤五中的2-氨基-6-溴吡啶替换为2-溴-4-氨基吡啶。LC-MS(ESI)m/z:303.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝5.3Hz,1H),8.04(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,1H),7.61(d,J＝2.1Hz,1H),7.21(ddd,J＝8.8,4.9,2.0Hz,2H),6.54(d,J＝2.1Hz,1H),6.47(dd,J＝5.3,1.7Hz,1H),6.37(s,1H),4.30–4.16(m,2H),3.30(s,6H),3.24(d,J＝2.0Hz,6H),2.81-2.74(m,2H),2.08(p,J＝6.2Hz,1H),2.04-1.98(m,2H),1.83(dq,J＝14.9,7.6Hz,1H),1.46(t,J＝7.2Hz,1H).The synthesis method of compound 170 refers to Example 123. The difference is that 2-amino-6-bromopyridine in step 5 is replaced by 2-bromo-4-aminopyridine. LC-MS (ESI) m/z: 303.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.24 (d, J = 5.3 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.21 (ddd, J = 8.8, 4.9, 2.0 Hz, 2H), 6.54 (d, J = 2.1 Hz, 1H), 6.47 (dd, J = 5.3, 1.7 Hz, 1H), 6 .37(s,1H),4.30–4.16(m,2H),3.30(s,6H),3.24(d,J＝2.0Hz,6H),2.81-2.74(m,2H),2.08(p,J＝6.2Hz,1H),2.04-1.98(m,2H),1.83(dq,J＝14.9,7 .6Hz,1H),1.46(t,J＝7.2Hz,1H).
实施例171&172
Example 171 & 172
合成路线
Synthetic route
步骤一：化合物171和172的合成Step 1: Synthesis of compounds 171 and 172
室温下，将7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(123-2，100mg，0.446mmol)溶于5mL干燥的DMF中，加入碳酸钾(250mg，1.812mmol)，升温至100℃搅拌30分钟，保持高温加入1,2-双(2-氯乙氧基)乙烷(84mg，0.449mmol)，继续搅拌1小时。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到70mg粗品，经制备纯化后得到化合物171及172。At room temperature, 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2, 100 mg, 0.446 mmol) was dissolved in 5 mL of dry DMF, potassium carbonate (250 mg, 1.812 mmol) was added, the temperature was raised to 100°C and stirred for 30 minutes, 1,2-bis(2-chloroethoxy)ethane (84 mg, 0.449 mmol) was added while maintaining the high temperature, and stirring was continued for 1 hour. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, the combined organic phases were washed with saturated brine, concentrated, and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 70 mg of crude product, which was purified by preparative purification to obtain compounds 171 and 172.
化合物171：LC-MS(ESI)m/z:281.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.90(d,J＝8.7Hz,2H),7.54(d,J＝2.1Hz,2H),7.12(dd,J＝8.8,2.0Hz,2H),4.16(t,J＝5.7Hz,4H),3.60(t,J＝5.7Hz,4H),3.48(s,4H),3.21(s,12H).Compound 171: LC-MS (ESI) m/z: 281.1 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ7.90 (d, J = 8.7Hz, 2H), 7.54 ( d,J＝2.1Hz,2H),7.12(dd,J＝8.8,2.0Hz,2H),4.16(t,J＝5.7Hz,4H),3.60(t,J＝5.7Hz,4H),3.48( s,4H),3.21(s,12H).
化合物172：LC-MS(ESI)m/z:281.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.11(d,J＝9.0Hz,1H),7.89(d,J＝8.8Hz,1H),7.58(d,J＝2.0Hz,1H),7.50(d,J＝2.3Hz,1H),7.26(dd,J＝9.0,2.3Hz,1H),7.12(dd,J＝8.8,2.0Hz,1H),4.35(dd,J＝5.8,3.8Hz,2H),4.22(q,J＝5.8,4.7Hz,2H),3.70–3.63(m,4H),3.54(s,4H),3.29(s,6H),3.20(s,6H).Compound 172: LC-MS (ESI) m/z: 281.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.11(d,J＝9.0Hz,1H),7.89(d,J＝8.8Hz,1H),7.58(d,J＝2.0Hz,1H),7.50(d,J＝2.3Hz,1H),7.26(dd,J＝9.0,2.3Hz,1H),7.12(dd,J＝8.8,2.0Hz,1H),4.35 (dd,J＝5.8,3.8Hz,2H),4.22(q,J＝5.8,4.7Hz,2H),3.70–3.63(m,4H),3.54(s,4H),3.29(s,6H),3.20(s,6H).
实施例173
Embodiment 173
合成路线
Synthetic route
步骤一：化合物173-1的合成Step 1: Synthesis of compound 173-1
室温下，将7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(123-2，300mg，1.34mmol)和4-溴丁酸乙酯(400mg，2.05mmol)溶于5mL干燥的DMF中，加入碳酸钾(550mg，3.99mmol)，升温至100℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相，浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到130mg化合物173-1，收率29％。LC-MS(ESI)m/z:338[M+H]+.At room temperature, 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2, 300 mg, 1.34 mmol) and ethyl 4-bromobutyrate (400 mg, 2.05 mmol) were dissolved in 5 mL of dry DMF, potassium carbonate (550 mg, 3.99 mmol) was added, and the temperature was raised to 100 ° C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine, concentrated and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 130 mg of compound 173-1, with a yield of 29%. LC-MS (ESI) m/z: 338 [M+H] + .
步骤二：化合物173-2的合成Step 2: Synthesis of compound 173-2
室温下，将化合物173-1(130mg，0.385mmol)溶于3mL甲醇和3mL水中，加入氢氧化锂(40mg，1.67mmol)，室温反应2小时。LC-MS监测反应完全。浓缩除去甲醇，加1N的盐酸调节pH至2-3，浓缩后过反向柱(水和乙腈，梯度5-95％，20分钟)得到60mg化合物173-2，收率50％。LC-MS(ESI)m/z:310[M+H]+.At room temperature, compound 173-1 (130 mg, 0.385 mmol) was dissolved in 3 mL of methanol and 3 mL of water, and lithium hydroxide (40 mg, 1.67 mmol) was added. The reaction was allowed to react at room temperature for 2 hours. LC-MS monitored the reaction to be complete. The methanol was removed by concentration, and 1 N hydrochloric acid was added to adjust the pH to 2-3. After concentration, the mixture was passed through a reverse column (water and acetonitrile, gradient 5-95%, 20 minutes) to obtain 60 mg of compound 173-2, with a yield of 50%. LC-MS (ESI) m/z: 310 [M+H] + .
步骤三：化合物173的合成Step 3: Synthesis of compound 173
室温下，将化合物173-2(50mg，0.161mmol)溶于2mL干燥的DMF中，加入DIEA(100mg，0.775mmol)和HATU(62mg，0.163mmol)，室温搅拌20分钟后，加入1-(2-氨基乙基)-7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(150-2，40mg，0.142mmol)，保持室温反应30分钟。LC-MS监测反应完全。反应液经高效液相制备纯化得9mg化合物173，收率10％。LC-MS(ESI)m/z:279.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.17(t,J＝5.9Hz,1H),8.01(d,J＝8.8Hz,1H),7.96(d,J＝8.8Hz,1H),7.71(d,J＝2.0Hz,1H),7.64(d,J＝2.0Hz,1H),7.24(dd,J＝8.8,2.0Hz,1H),7.17(dd,J＝8.8,1.9Hz,1H),4.07(t,J＝6.8Hz,2H),3.96(t,J＝7.8Hz,2H),3.27(s,6H),3.22(s,6H),2.16(t,J＝7.2Hz,2H),2.05-1.95(m,2H),1.82-1.67(m,2H).At room temperature, compound 173-2 (50 mg, 0.161 mmol) was dissolved in 2 mL of dry DMF, DIEA (100 mg, 0.775 mmol) and HATU (62 mg, 0.163 mmol) were added, and after stirring at room temperature for 20 minutes, 1-(2-aminoethyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (150-2, 40 mg, 0.142 mmol) was added, and the reaction was kept at room temperature for 30 minutes. LC-MS monitored the reaction to be complete. The reaction solution was purified by high performance liquid chromatography to obtain 9 mg of compound 173 with a yield of 10%. LC-MS (ESI) m/z: 279.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.17(t,J＝5.9Hz,1H),8.01(d,J＝8.8Hz,1H),7.96(d,J＝8.8Hz,1H),7.71(d,J＝2.0Hz,1H),7.64(d,J＝2.0Hz,1H),7.24(dd,J＝8.8,2.0Hz,1H),7.17(dd,J =8.8,1.9Hz,1H),4.07(t,J＝6.8Hz,2H),3.96(t,J＝7.8Hz,2H),3.27(s,6H),3.22(s,6H),2.16(t,J＝7.2Hz,2H),2.05-1.95(m,2H),1.82-1.67(m,2H).
实施例174
Embodiment 174
合成方法Synthesis method
化合物174的合成方法参照实施例102。区别在于把步骤五中的101-3替换为1-((2-溴噻唑-5-基)甲基)-7-氯-4-(环丙基氨基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:319.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.7(m,1H),δ8.35(d,J＝4.2Hz,1H),8.11(d, J＝8.7Hz,1H),7.89(d,J＝8.7Hz,1H),7.81(d,J＝2.0Hz,1H),7.75(d,J＝1.9Hz,1H),7.40(s,1H),7.27(dd,J＝8.6,1.8Hz,1H),7.19(dd,J＝8.7,1.8Hz,1H),5.35-5.29(m,2H),4.22-4.12(m,1H),3.99-3.85(m,2H),3.72(d,J＝13.2Hz,1H),3.21(s,6H),3.16-3.05(m,1H),3.07-2.99(m,1H),2.82-2.70(m,1H),1.78-1.71(m,3H),0.81-0.76(m,2H),0.68-0.64(m,2H).The synthesis method of compound 174 refers to Example 102. The difference is that 101-3 in step 5 is replaced by 1-((2-bromothiazol-5-yl)methyl)-7-chloro-4-(cyclopropylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 319.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ8.7 (m, 1H), δ8.35 (d, J＝4.2 Hz, 1H), 8.11 (d, J＝8.7Hz,1H),7.89(d,J＝8.7Hz,1H),7.81(d,J＝2.0Hz,1H),7.75(d,J＝1.9Hz,1H),7.40(s,1H),7.27(dd,J＝8.6,1.8Hz,1H),7.19(dd,J＝8.7,1.8Hz,1H),5. 35-5.29(m,2H),4.22-4. 12(m,1H),3.99-3.85(m,2H),3.72(d,J＝13.2Hz,1H),3.21(s,6H),3.16-3.05(m,1H),3.07-2.99(m,1H),2.82-2.70(m,1H),1.78-1.71(m,3H),0.8 1-0.76(m,2H),0.68-0.64(m,2H).
实施例175
Embodiment 175
合成方法Synthesis method
化合物175的合成方法参照实施例123，区别在于把步骤一中的123-2替换为101-2，步骤五中2-氨基-6-溴吡啶替换为2-氨基-4-溴吡啶。LC-MS(ESI)m/z:303.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.35(d,J＝7.1Hz,1H),8.12(q,1H),8.00(d,J＝8.7Hz,1H),7.63(d,J＝2.0Hz,1H),7.32(dd,J＝8.7,2.1Hz,1H),7.23(d,2H),7.04(s,1H),6.80(s,1H),4.30-4.16(m,2H),3.25(s,6H),3.24(s,6H),2.93-2.78(m,2H),2.26-2.10(m,1H),2.04-1.98(m,2H),1.92(d,J＝8.8Hz,1H),1.49-1.41(m,1H).The synthesis method of compound 175 is similar to that of Example 123, except that 123-2 in step 1 is replaced by 101-2, and 2-amino-6-bromopyridine in step 5 is replaced by 2-amino-4-bromopyridine. LC-MS (ESI) m/z: 303.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.35(d,J＝7.1Hz,1H),8.12(q,1H),8.00(d,J＝8.7Hz,1H),7.63(d,J＝2.0Hz,1H),7.32(dd,J＝8.7,2.1Hz,1H),7.23(d,2H),7.04(s,1H),6.80(s,1H),4 .30-4.16(m,2H),3.25(s,6H),3.24(s,6H),2.93-2.78(m,2H),2.26-2.10(m,1H),2.04-1.98(m,2H),1.92(d,J＝8.8Hz,1H),1.49-1.41(m,1H).
实施例176
Embodiment 176
合成路线
Synthetic route
步骤一：化合物176-1的合成Step 1: Synthesis of compound 176-1
室温下，将7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(123-2，1g，4.64mmol)和N-Boc-溴丙胺(2g，8.40mmol)溶于20mL干燥的DMF中，加入碳酸铯(4.4g，13.4mmol)，升温至100℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相，浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到380mg化合物176-1，收率22％。LC-MS(ESI)m/z:381[M+H]+. At room temperature, 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2, 1 g, 4.64 mmol) and N-Boc-bromopropylamine (2 g, 8.40 mmol) were dissolved in 20 mL of dry DMF, cesium carbonate (4.4 g, 13.4 mmol) was added, and the temperature was raised to 100 ° C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine, concentrated and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 380 mg of compound 176-1, with a yield of 22%. LC-MS (ESI) m/z: 381 [M + H] + .
步骤二：化合物176-2的合成Step 2: Synthesis of compound 176-2
室温下，将化合物176-1(380mg，0.997mmol)溶于5mL二氧六环中，滴加5mL盐酸二氧六环溶液(4N)，室温搅拌2小时。LC-MS监测反应完全。过滤得到180mg化合物176-2，收率64％。LC-MS(ESI)m/z:281[M+H]+.At room temperature, compound 176-1 (380 mg, 0.997 mmol) was dissolved in 5 mL of dioxane, and 5 mL of dioxane hydrochloride solution (4N) was added dropwise, and stirred at room temperature for 2 hours. LC-MS monitored the reaction to be complete. 180 mg of compound 176-2 was obtained by filtration, with a yield of 64%. LC-MS (ESI) m/z: 281 [M+H] + .
步骤三：化合物176的合成Step 3: Synthesis of compound 176
室温下，将4-(7-氯-4-(二甲基氨基)-2-氧代喹唑啉-1(2H)-基)丁酸(173-2，50mg，0.161mmol)溶于2mL干燥的DMF中，加入DIEA(100mg，0.775mmol)和HATU(62mg，0.163mmol)，室温搅拌20分钟后，加入化合物176-2(40mg，0.142mmol)，保持室温反应30分钟。LC-MS监测反应完全。反应液经高效液相制备纯化得10mg化合物176，收率12％。LC-MS(ESI)m/z:286.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.01(d,J＝8.6Hz,2H),7.67(d,J＝2.2Hz,1H),7.52(d,J＝2.1Hz,1H),7.23(dt,J＝8.8,2.3Hz,2H),4.10-3.99(m,4H),3.27(d,J＝2.4Hz,12H),3.20-3.13(m,2H),2.30-2.18(m,2H),1.85-1.69(m,4H).At room temperature, 4-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)butanoic acid (173-2, 50 mg, 0.161 mmol) was dissolved in 2 mL of dry DMF, DIEA (100 mg, 0.775 mmol) and HATU (62 mg, 0.163 mmol) were added, and after stirring at room temperature for 20 minutes, compound 176-2 (40 mg, 0.142 mmol) was added, and the reaction was maintained at room temperature for 30 minutes. LC-MS monitored the reaction to be complete. The reaction solution was purified by high performance liquid chromatography to obtain 10 mg of compound 176, with a yield of 12%. LC-MS(ESI)m/z:286.6[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.01(d,J＝8.6Hz,2H),7.67(d,J＝2.2Hz,1H),7.52(d,J＝2.1Hz,1H),7.23(dt,J＝8.8,2.3Hz,2H), 4.10-3.99(m,4H),3.27(d,J＝2.4Hz,12H),3.20-3.13(m,2H),2.30-2.18(m,2H),1.85-1.69(m,4H).
实施例177
Embodiment 177
合成方法Synthesis method
化合物177的合成方法参照实施例102。区别在于把步骤五中的101-3替换为1-((2-溴噻唑-5-基)甲基)-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:303.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.89(dd,J＝8.8,3.3Hz,2H),7.80(d,J＝2.0Hz,1H),7.67(dd,J＝5.8,1.5Hz,2H),7.40(s,1H),7.19(dd,J＝8.6,1.9Hz,2H),5.28(d,J＝6.6Hz,2H),4.22-4.11(m,1H),3.98-3.87(m,2H),3.72(d,J＝13.4Hz,1H),3.64(q,J＝7.0Hz,2H),3.22(s,3H),3.21(s,6H),3.15-3.05(m,1H),2.81-2.69(m,1H),1.76-1.72(m,3H),1.28(t,J＝7.0Hz,3H).The synthesis method of compound 177 refers to Example 102. The difference is that 101-3 in step 5 is replaced by 1-((2-bromothiazol-5-yl)methyl)-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 303.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.89 (dd, J = 8.8, 3.3 Hz, 2H), 7.80 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 5.8, 1.5 Hz, 2H), 7.40 (s, 1H), 7.19 (dd, J = 8.6, 1.9 Hz, 2H), 5.28 (d, J = 6.6 Hz, 2H), 4.22-4.11 (m, 1H), 3. 98-3.87(m,2H),3.72(d,J＝13.4Hz,1H),3.64(q,J＝7.0Hz,2H),3.22(s,3H),3.21(s,6H),3.15-3.05(m,1H),2.81-2.69(m,1H),1.76-1.72(m,3H), 1.28(t,J＝7.0Hz,3H).
实施例178
Embodiment 178
合成方法Synthesis method
化合物178的合成方法参照实施例102。区别在于把步骤三中的二甲胺替换为甲胺盐酸盐。LC-MS(ESI)m/z:313.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.42(d,J＝4.8Hz,1H),8.00(d,J＝8.7Hz,1H),7.90(d,J＝8.8Hz,1H),7.75(dd,J＝4.5,1.9Hz,2H),7.40(s,1H),7.26(dd,J＝8.6,1.8Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),5.28(d,J＝2.7Hz,2H),4.25(s,1H),3.98-3.86(m,2H),3.73(d,J＝13.2Hz,1H),3.63(q,J＝7.0Hz,2H),3.22(s,3H),3.13-3.03(m,1H),2.90(d,J＝4.4Hz,3H),2.83-2.73(m,1H),1.85-1.66(m,3H),1.27(t,J＝7.0Hz,3H).The synthesis method of compound 178 refers to Example 102. The difference is that the dimethylamine in step 3 is replaced by methylamine hydrochloride. LC-MS (ESI) m/z: 313.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.42 (d, J = 4.8 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.75 (dd, J = 4.5, 1.9 Hz, 2H), 7.40 (s, 1H), 7.26 (dd, J = 8.6, 1.8 Hz, 1H), 7.20 (dd, J = 8.8, 2.0 Hz, 1H), 5.28 (d, J = 2.7 Hz, 2H), 4 .25(s,1H),3.98-3.86(m,2H),3.73(d,J＝13.2Hz,1H),3.63(q,J＝7.0Hz,2H),3.22(s,3H),3.13-3.03(m,1H),2.90(d,J＝4.4Hz,3H),2.83-2.73(m,1 H),1.85-1.66(m,3H),1.27(t,J＝7.0Hz,3H).
实施例179
Embodiment 179
合成路线
Synthetic route
步骤一：化合物179-1的合成Step 1: Synthesis of compound 179-1
室温下，将化合物123-2(500mg，2.2mmol)、3-溴-1-丙醇(343mg，2.5mmol)和碳酸钾(930mg，6.6mmol)分散到N,N-二甲基甲酰胺(5mL)溶液中，加热到100℃，反应20分钟。待反应液冷却至室温，经硅胶层析色谱柱(洗脱剂：二氯甲烷/甲醇＝10/1)纯化，得到化合物179-1，200mg，白色固体,收率32％。LC-MS(ESI)m/z:282[M+H]+.At room temperature, compound 123-2 (500 mg, 2.2 mmol), 3-bromo-1-propanol (343 mg, 2.5 mmol) and potassium carbonate (930 mg, 6.6 mmol) were dispersed in N,N-dimethylformamide (5 mL) solution, heated to 100 ° C, and reacted for 20 minutes. After the reaction solution was cooled to room temperature, it was purified by silica gel chromatography column (eluent: dichloromethane/methanol = 10/1) to obtain compound 179-1, 200 mg, white solid, yield 32%. LC-MS (ESI) m/z: 282 [M + H] + .
步骤二：化合物179-2的合成Step 2: Synthesis of compound 179-2
室温下，将化合物179-1(150mg，0.57mmol)分散到乙腈(2.0mL)中，降温到0℃，在氮气保护下向反应液中滴加氯化亚砜(0.20mL)，和一滴N,N-二甲基甲酰胺，加热到50℃，反应2小时。待反应液冷却至室温，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：二氯甲烷/甲醇＝10/1)纯化，得到化合物179-2，90mg，,白色固体，收率53％。LC-MS(ESI)m/z:300[M+H]+.At room temperature, compound 179-1 (150 mg, 0.57 mmol) was dispersed in acetonitrile (2.0 mL), cooled to 0°C, and thionyl chloride (0.20 mL) and a drop of N,N-dimethylformamide were added dropwise to the reaction solution under nitrogen protection, heated to 50°C, and reacted for 2 hours. After the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography column (eluent: dichloromethane/methanol = 10/1) to obtain compound 179-2, 90 mg, white solid, yield 53%. LC-MS (ESI) m/z: 300 [M + H] + .
步骤三：化合物179的合成Step 3: Synthesis of compound 179
室温下，将化合物162-2(59mg，0.20mmol)和碳酸钾(42mg，0.30mmol)分散到N,N-二甲基甲酰胺(1mL)溶液中，加热到100℃，然后迅速加入化合物179-2(30mg，0.10mmol)，100℃搅拌1.5小时。待反应液冷却至室温，用乙酸乙酯(5mL×3)和水(5mL)萃取，合并有机相，饱和食盐水洗涤(5mL)一次，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，经硅胶层析色谱柱(洗脱剂：石油醚/乙酸乙酯＝1/1，二氯甲烷/甲醇＝10/1)纯化，制备液相色谱纯化，制备液冷冻干燥，得到化合物179，5.88mg，,白色固体，收率11％。LC-MS(ESI)m/z:278.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.96(dd,J＝8.8,3.8Hz,2H),7.62(d,J＝2.0Hz,1H),7.55(d,J＝2.0Hz,1H),7.20(qd,J＝8.7,3.9,2.5,1.9Hz,2H),4.29(d,J＝7.0Hz,2H),4.01(t,J＝7.3Hz,2H),3.26-3.24(m,4H),3.23(s,6H),3.21(s,6H),3.16-3.14(m,1H),2.91(t,J＝6.6Hz,3H),1.54(p,J＝6.8Hz,2H).At room temperature, compound 162-2 (59 mg, 0.20 mmol) and potassium carbonate (42 mg, 0.30 mmol) were dispersed in N, N-dimethylformamide (1 mL) solution, heated to 100°C, and then compound 179-2 (30 mg, 0.10 mmol) was quickly added and stirred at 100°C for 1.5 hours. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate (5 mL×3) and water (5 mL), the organic phases were combined, washed once with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was evaporated under reduced pressure. The solution was purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate = 1/1, dichloromethane/methanol = 10/1), purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain compound 179, 5.88 mg, white solid, yield 11%. LC-MS(ESI)m/z:278.6[M/2+H] + . 1 H NMR(600MHz, DMSO-d 6 )δ7.96(dd,J＝8.8,3.8Hz,2H),7.62(d,J＝2.0Hz,1H),7.55(d,J＝2.0Hz,1H),7.20(qd,J＝8.7,3.9,2.5,1.9Hz,2H),4.29(d,J＝7.0Hz,2H),4.01(t,J＝7.3Hz, 2H),3.26-3.24(m,4H),3.23(s,6H),3.21(s,6H),3.16-3.14(m,1H),2.91(t,J＝6.6Hz,3H),1.54(p,J＝6.8Hz,2H).
实施例180
Embodiment 180
合成方法Synthesis method
化合物180的合成方法参照实施例102。区别在于把步骤三中的二甲胺替换为氨的甲醇溶液。LC-MS(ESI)m/z:306.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.11(d,J＝8.6Hz,1H),7.90(d,J＝8.8Hz,1H),7.80(s,1H),7.76(d,J＝2.0Hz,1H),7.41(s,1H),7.30(dd,J＝8.6,1.7Hz,1H),7.21(dd,J＝8.7,2.0Hz,1H),5.31-5.24(m,2H),6.67(s,2H),4.31(s,1H),3.98-3.90(m,2H),3.75(d,J＝13.1Hz,1H),3.64(q,J＝7.0Hz,2H),3.22(s,3H),3.06(t,J＝12.8,3.5Hz,1H),2.79-2.70(m,1H),1.81-1.71(m,3H),1.26(t,J＝7.2Hz,3H).The synthesis method of compound 180 refers to Example 102. The difference is that the dimethylamine in step 3 is replaced by ammonia methanol solution. LC-MS (ESI) m/z: 306.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.11 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.80 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.41 (s, 1H), 7.30 (dd, J = 8.6, 1.7 Hz, 1H), 7.21 (dd, J = 8.7, 2.0 Hz, 1H), 5.31-5.24 (m, 2H), 6.67 (s, 2H ),4.31(s,1H),3.98-3.90(m,2H),3.75(d,J＝13.1Hz,1H),3.64(q,J＝7.0Hz,2H),3.22(s,3H),3.06(t,J＝12.8,3.5Hz,1H),2.79-2.70(m,1H),1.81-1. 71(m,3H),1.26(t,J＝7.2Hz,3H).
实施例181
Embodiment 181
合成路线
Synthetic route
步骤一：化合物181-1的合成Step 1: Synthesis of compound 181-1
室温下，将喹啉-2(1H)-酮(300mg，2.07mmol)和3-(溴甲基)氮杂环丁烷-1-羧酸叔丁酯(400mg，1.60mmol)溶于5mL干燥的DMF中，加入碳酸铯(1.3g，3.96mmol)，升温至100℃搅拌3小时。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相，浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到380mg化合物181-1，收率58％。LC-MS(ESI)m/z:315[M+H]+.At room temperature, quinoline-2(1H)-one (300 mg, 2.07 mmol) and tert-butyl 3-(bromomethyl)azetidine-1-carboxylate (400 mg, 1.60 mmol) were dissolved in 5 mL of dry DMF, cesium carbonate (1.3 g, 3.96 mmol) was added, and the temperature was raised to 100 ° C and stirred for 3 hours. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine, concentrated and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 380 mg of compound 181-1, with a yield of 58%. LC-MS (ESI) m/z: 315 [M+H] + .
步骤二：化合物181-2的合成Step 2: Synthesis of compound 181-2
室温下，将化合物181-1(380mg，0.997mmol)溶于10mL二氯甲烷中，滴加2mL三氟乙酸，室温搅拌2小时。LC-MS监测反应完全。浓缩后冻干得到210mg化合物181-2，收率81％。LC-MS(ESI)m/z:215[M+H]+.At room temperature, compound 181-1 (380 mg, 0.997 mmol) was dissolved in 10 mL of dichloromethane, 2 mL of trifluoroacetic acid was added dropwise, and stirred at room temperature for 2 hours. LC-MS monitored the reaction to be complete. After concentration, lyophilization was performed to obtain 210 mg of compound 181-2, with a yield of 81%. LC-MS (ESI) m/z: 215 [M+H] + .
步骤三：化合物181的合成 Step 3: Synthesis of compound 181
室温下，将化合物181-2(50mg，0.137mmol)和1-(6-溴吡啶-2-基)-7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(123-7，90mg，0.238mmol)溶于2mL干燥的DMF中，加入碳酸铯(230mg，0.701mmol)，升温至100℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到50mg粗品，之后经HPLC制备纯化后得15mg化合物181，收率13％。LC-MS(ESI)m/z:513.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.92(d,J＝9.5Hz,1H),7.77-7.73(m,2H),7.68(d,J＝8.6Hz,1H),7.64-7.61(m,1H),7.27(t,J＝7.4Hz,1H),7.21(dd,J＝8.8,2.1Hz,1H),6.63(dd,J＝11.9,8.4Hz,2H),6.50(d,J＝8.3Hz,1H),6.42(d,J＝2.1Hz,1H),4.64(d,J＝7.4Hz,2H),3.97(t,J＝8.0Hz,2H),3.86(dd,J＝8.1,5.5Hz,2H),3.30(s,6H),3.26-3.17(m,1H).At room temperature, compound 181-2 (50 mg, 0.137 mmol) and 1-(6-bromopyridin-2-yl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-7, 90 mg, 0.238 mmol) were dissolved in 2 mL of dry DMF, cesium carbonate (230 mg, 0.701 mmol) was added, and the temperature was raised to 100 ° C. and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine and concentrated and separated by flash column chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 50 mg of crude product, which was then purified by HPLC to obtain 15 mg of compound 181, with a yield of 13%. LC-MS (ESI) m/z: 513.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.03(d,J＝8.8Hz,1H),7.92(d,J＝9.5Hz,1H),7.77-7.73(m,2H),7.68(d,J＝8.6Hz,1H),7.64-7.61(m,1H),7.27(t,J＝7.4Hz,1H),7.21(dd,J＝8.8,2.1 Hz,1H),6.63(dd,J ＝11.9,8.4Hz,2H),6.50(d,J＝8.3Hz,1H),6.42(d,J＝2.1Hz,1H),4.64(d,J＝7.4Hz,2H),3.97(t,J＝8.0Hz,2H),3.86(dd,J＝8.1,5.5Hz,2H),3.30(s,6H),3. 26-3.17(m,1H).
实施例182
Embodiment 182
合成方法Synthesis method
化合物182的合成方法参照实施例181。区别在于把步骤一中的喹啉-2(1H)-酮替换为7-氯喹啉-2(1H)-酮。LC-MS(ESI)m/z:547.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.93(d,J＝9.5Hz,1H),7.81(d,J＝1.9Hz,1H),7.78-7.73(m,2H),7.32(dd,J＝8.3,1.8Hz,1H),7.21(dd,J＝8.8,2.1Hz,1H),6.66-6.62(m,2H),6.50(d,J＝8.3Hz,1H),6.42(d,J＝2.1Hz,1H),4.63(d,J＝7.5Hz,2H),3.97(t,J＝8.0Hz,2H),3.84(dd,J＝8.1,5.5Hz,2H),3.30(s,6H),3.21-3.16(m,1H).The synthesis method of compound 182 is similar to that of Example 181. The difference is that quinolin-2(1H)-one in step 1 is replaced by 7-chloroquinolin-2(1H)-one. LC-MS (ESI) m/z: 547.1 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.03(d,J＝8.8Hz,1H),7.93(d,J＝9.5Hz,1H),7.81(d,J＝1.9Hz,1H),7.78-7.73(m,2H),7.32(dd,J＝8.3,1.8Hz,1H),7.21(dd,J＝8.8,2.1Hz,1H),6.66-6 .62(m,2H),6.50(d,J＝8.3Hz,1H),6.42(d,J＝2.1Hz,1H),4.63(d,J＝7.5Hz,2H),3.97(t,J＝8.0Hz,2H),3.84(dd,J＝8.1,5.5Hz,2H),3.30(s,6H),3.21-3. 16(m,1H).
实施例183
Embodiment 183
合成方法Synthesis method
化合物183的合成方法参照实施例123。区别在于把步骤五中的2-氨基-6-溴吡啶替换为4-氨基-2-溴吡啶，步骤七中的二甲胺替换为甲胺盐酸盐。LC-MS(ESI)m/z:296.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.25(d,J＝8.7Hz,1H),8.18(d,J＝6.7Hz,1H),8.07(d,J＝8.8Hz,1H),7.73(s,1H),7.40(d,J＝8.6Hz,1H),7.30(q,J＝9.1Hz,1H),7.24(s,1H),7.16(s,1H),7.07(s,1H),6.89(d,J＝6.7Hz,1H),5.27(d,2H),4.29(d,J＝8.3Hz,2H),4.11(m,1H),3.41(q,1H),3.32(s,6H),3.03(d,J＝4.0Hz,3H),2.90(d,J＝6.6Hz,1H),2.63(m,1H),2.04-1.96(m,1H).The synthesis method of compound 183 refers to Example 123. The difference is that 2-amino-6-bromopyridine in step 5 is replaced by 4-amino-2-bromopyridine, and dimethylamine in step 7 is replaced by methylamine hydrochloride. LC-MS (ESI) m/z: 296.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.25 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 6.7 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.73 (s, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.30 (q, J = 9.1 Hz, 1H), 7.24 (s, 1H), 7.16 (s, 1H), 7.07 (s, 1H), 6.8 9(d,J＝6.7Hz,1H),5.27(d,2H),4.29(d,J＝8.3Hz,2H),4.11(m,1H),3.41(q,1H),3.32(s,6H),3.03(d,J＝4.0Hz,3H),2.90(d,J＝6.6Hz,1H),2.63(m,1H ),2.04-1.96(m,1H).
实施例184
Embodiment 184
合成方法Synthesis method
化合物184的合成方法参照实施例123。区别在于把步骤五中的2-氨基-6-溴吡啶替换为2-氨基-4-溴吡啶，步骤七中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:310.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.18(d,J＝6.1Hz,1H),7.98(dd,J＝8.7,1.4Hz,2H),7.60(d,J＝2.0Hz,1H),7.21(td,J＝8.8,2.0Hz,2H),6.58(d,J＝33.8Hz,2H),6.46(s,1H),4.22(ddd,J＝54.3,14.4,7.5Hz,2H),3.70(q,J＝7.0Hz,2H),3.53(s,1H),3.46(s,1H),3.30(s,3H),3.24(s,6H),2.80(s,1H),2.15-2.05(m,1H),1.90-1.81(m,1H),1.31(t,J＝7.0Hz,3H),1.27-1.21(m,2H).The synthesis method of compound 184 refers to Example 123. The difference is that 2-amino-6-bromopyridine in step 5 is replaced by 2-amino-4-bromopyridine, and dimethylamine in step 7 is replaced by methylethylamine. LC-MS (ESI) m/z: 310.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.18 (d, J = 6.1 Hz, 1H), 7.98 (dd, J = 8.7, 1.4 Hz, 2H), 7.60 (d, J = 2.0 Hz, 1H), 7.21 (td, J = 8.8, 2.0 Hz, 2H), 6.58 (d, J = 33.8 Hz, 2H), 6.46 (s, 1H), 4.22 (ddd, J = 54.3, 14.4, 7.5 Hz ,2H),3.70(q,J＝7.0Hz,2H),3.53(s,1H),3.46(s,1H),3.30(s,3H),3.24(s,6H),2.80(s,1H),2.15-2.05(m,1H),1.90-1.81(m,1H),1.31(t,J＝7. 0Hz,3H),1.27-1.21(m,2H).
实施例185
Embodiment 185
合成方法Synthesis method
化合物185的合成方法参照实施例123。区别在于把步骤五中的2-氨基-6-溴吡啶替换为4-氨基-2-溴吡啶，步骤七中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:310.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.24(d,J＝5.2Hz,1H),7.97(dd,J＝8.8,3.5Hz,2H),7.61(d,J＝2.0Hz,1H),7.21(ddd,J＝11.2,8.8,2.0Hz,2H),6.54(d,J＝2.1Hz,1H),6.48(dd,J＝5.3,1.7Hz,1H),6.39(s,1H),4.23(qd,J＝14.4,7.4Hz,2H),3.70(q,J＝7.0Hz,2H),3.55(d,J＝32.2Hz,2H),3.29(s,3H),3.24(s,6H),2.76(s,1H),2.11-2.04(m,1H),1.87-1.77(m,1H),1.31(t,J＝7.1Hz,3H),1.25-1.24(m,2H).The synthesis method of compound 185 refers to Example 123. The difference is that 2-amino-6-bromopyridine in step 5 is replaced by 4-amino-2-bromopyridine, and dimethylamine in step 7 is replaced by methylethylamine. LC-MS (ESI) m/z: 310.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.24 (d, J = 5.2 Hz, 1H), 7.97 (dd, J = 8.8, 3.5 Hz, 2H), 7.61 (d, J = 2.0 Hz, 1H), 7.21 (ddd, J = 11.2, 8.8, 2.0 Hz, 2H), 6.54 (d, J = 2.1 Hz, 1H), 6.48 (dd, J = 5.3, 1.7 Hz, 1H), 6.39 (s, 1H), 4.23 (qd, J＝14.4,7.4Hz,2H),3.70(q,J＝7.0Hz,2H),3.55(d,J＝32.2Hz,2H),3.29(s,3H),3.24(s,6H),2.76(s,1H),2.11-2.04(m,1H),1.87-1.77(m,1H),1.31 (t,J＝7.1Hz,3H),1.25-1.24(m,2H).
实施例186
Embodiment 186
合成方法Synthesis method
化合物186的合成方法参照实施例102。区别在于把步骤三中的二甲胺替换为甲胺盐酸盐，步骤五中的101-3替换为1-((2-溴噻唑-5-基)甲基)-4-(二甲胺基)-7-三氟甲基喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:306.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.42(q,1H),7.99(dd,J＝18.0,8.7Hz,2H),7.75(dd,J＝6.7,2.0Hz,2H),7.40(s,1H),7.26(dd,J＝8.6,1.8Hz,1H),7.20(dd,J＝8.7,1.9Hz,1H),5.32-5.27(m,2H),4.25(s,1H),3.98-3.88(m,2H),3.73(d,J＝13.2Hz,1H),3.24(s,6H),3.13-3.05(m,1H),2.90(d,J＝4.4Hz,3H),2.82-2.73(m,1H),1.80-1.73(m,2H),1.71(d,1H). The synthesis method of compound 186 refers to Example 102. The difference is that the dimethylamine in step 3 is replaced by methylamine hydrochloride, and 101-3 in step 5 is replaced by 1-((2-bromothiazol-5-yl)methyl)-4-(dimethylamino)-7-trifluoromethylquinazolin-2(1H)-one. LC-MS (ESI) m/z: 306.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.42(q,1H),7.99(dd,J＝18.0,8.7Hz,2H),7.75(dd,J＝6.7,2.0Hz,2H),7.40(s,1H),7.26(dd,J＝8.6,1.8Hz,1H),7.20(dd,J＝8.7,1.9Hz,1H),5.32-5.27 (m,2H) ,4.25(s,1H),3.98-3.88(m,2H),3.73(d,J＝13.2Hz,1H),3.24(s,6H),3.13-3.05(m,1H),2.90(d,J＝4.4Hz,3H),2.82-2.73(m,1H),1.80-1.73(m,2H ),1.71(d,1H).
实施例187
Embodiment 187
合成方法Synthesis method
化合物187的合成方法参照实施例162。区别在于把步骤一中的123-2替换为7-氯-4-(甲胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:289.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.04(dd,J＝8.8,7.3Hz,2H),7.75(t,J＝8.3,7.3Hz,1H),7.65(d,J＝1.9Hz,1H),7.27(dd,J＝8.6,1.9Hz,1H),7.21(dd,2H),6.63(d,J＝7.2Hz,1H),6.49(d,J＝8.4Hz,1H),6.42(d,J＝2.1Hz,1H),4.43(d,J＝7.4Hz,2H),3.95(t,J＝8.1Hz,2H),3.82(t,J＝8.1,5.5Hz,2H),3.30(s,6H),3.12(p,J＝6.6Hz,1H),2.92(d,J＝4.4Hz,3H).The synthesis method of compound 187 is similar to that of Example 162. The difference is that 123-2 in step 1 is replaced by 7-chloro-4-(methylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 289.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.04(dd,J＝8.8,7.3Hz,2H),7.75(t,J＝8.3,7.3Hz,1H),7.65(d,J＝1.9Hz,1H),7.27(dd,J＝8.6,1.9Hz,1H),7.21(dd,2H),6.63(d,J＝7.2Hz,1H),6.49(d, J＝8.4Hz,1H),6.42(d,J＝2.1Hz,1H),4.43(d,J＝7.4Hz,2H),3.95(t,J＝8.1Hz,2H),3.82(t,J＝8.1,5.5Hz,2H),3.30(s,6H),3.12(p,J＝6.6Hz,1H),2.92(d ,J＝4.4Hz,3H).
实施例188
Embodiment 188
合成路线
Synthetic route
步骤一：化合物188-1的合成Step 1: Synthesis of compound 188-1
室温下，将7-氯-2-羟基喹啉(200mg，1.11mmol)溶解在5mL N,N-二甲基甲酰胺中，向其中加入1-Boc-3-溴甲基吡咯烷(350mg，1.33mmol)和碳酸钾(1.1g，3.33mmol)，100℃下搅拌16h。TLC监测完全反应，反应体系中加水，用乙酸乙酯(15mLx3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物188-1(272mg，白色固体)，产率68％。LC-MS(ESI)m/z:363[M+H]+.At room temperature, 7-chloro-2-hydroxyquinoline (200 mg, 1.11 mmol) was dissolved in 5 mL of N,N-dimethylformamide, 1-Boc-3-bromomethylpyrrolidine (350 mg, 1.33 mmol) and potassium carbonate (1.1 g, 3.33 mmol) were added thereto, and the mixture was stirred at 100 ° C for 16 h. TLC monitored the complete reaction, water was added to the reaction system, extracted with ethyl acetate (15 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 188-1 (272 mg, white solid) with a yield of 68%. LC-MS (ESI) m/z: 363 [M + H] + .
步骤二：化合物188-2的合成Step 2: Synthesis of compound 188-2
室温下将化合物188-1(272mg，0.75mmol)溶解在4mL 1,4-二氧六环中，向其中加入盐酸-二氧六环溶液4mL，室温下搅拌30min。TLC监测完全反应，浓缩后得到化合物188-2的盐酸盐(203mg，白色固体)，产率99％。LC-MS(ESI)m/z:263[M+H]+.Compound 188-1 (272 mg, 0.75 mmol) was dissolved in 4 mL of 1,4-dioxane at room temperature, 4 mL of hydrochloric acid-dioxane solution was added thereto, and stirred at room temperature for 30 min. TLC monitored the complete reaction, and after concentration, the hydrochloride of compound 188-2 (203 mg, white solid) was obtained with a yield of 99%. LC-MS (ESI) m/z: 263 [M+H] + .
步骤三：化合物188的合成Step 3: Synthesis of compound 188
室温下将化合物123-7(100mg，0.26mmol)溶解在2mL N,N-二甲基甲酰胺中， 向其中加入化合物188-2(104mg，0.39mmol)和碳酸铯(260mg，0.78mmol)。反应混合液在100℃下搅拌16h。LC-MS检测完全反应。经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，HPLC制备后得到化合物188(42.74mg，白色固体)，产率29.4％。LC-MS(ESI)m/z:281.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.27(d,J＝8.9Hz,1H),8.03(d,J＝8.8Hz,1H),7.93(d,J＝8.6Hz,1H),7.79(d,J＝2.1Hz,1H),7.74(dd,J＝8.4,7.3Hz,1H),7.47(dd,J＝8.6,2.1Hz,1H),7.19(dd,J＝8.8,2.1Hz,1H),7.06(d,J＝8.9Hz,1H),6.59(dd,J＝16.3,7.8Hz,2H),6.46(d,J＝2.1Hz,1H),4.46(ddd,J＝44.3,10.7,6.9Hz,2H),3.64(dd,J＝10.7,7.5Hz,1H),3.58-3.50(m,1H),3.45-3.38(m,2H),3.30(s,6H),3.29-3.24(m,1H),2.85(p,J＝7.2Hz,1H),2.25-2.15(m,1H).Compound 123-7 (100 mg, 0.26 mmol) was dissolved in 2 mL of N,N-dimethylformamide at room temperature. Compound 188-2 (104 mg, 0.39 mmol) and cesium carbonate (260 mg, 0.78 mmol) were added thereto. The reaction mixture was stirred at 100°C for 16 h. LC-MS detected the complete reaction. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min). Compound 188 (42.74 mg, white solid) was obtained after HPLC preparation with a yield of 29.4%. LC-MS (ESI) m/z: 281.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.27(d,J＝8.9Hz,1H),8.03(d,J＝8.8Hz,1H),7.93(d,J＝8.6Hz,1H),7.79(d,J＝2.1Hz,1H),7.74(dd,J＝8.4,7.3Hz,1H),7.47(dd,J＝8.6,2.1Hz,1H),7.19 (dd,J＝8.8,2.1Hz,1H),7.06(d,J＝8.9Hz,1H),6.59(dd,J＝16 .3,7.8Hz,2H),6.46(d,J＝2.1Hz,1H),4.46(ddd,J＝44.3,10.7,6.9Hz,2H),3.64(dd,J＝10.7,7.5Hz,1H),3.58-3.50(m,1H),3.45-3.38(m,2H),3.30(s, 6H),3.29-3.24(m,1H),2.85(p,J=7.2Hz,1H),2.25-2.15(m,1H).
实施例189&190
Example 189 & 190
合成方法Synthesis method
化合物189和190的合成方法参照实施例171和172。区别在于把步骤一中的123-2替换为4-(吖啶-1-基)-7-氯喹唑啉-2(1H)-酮。The synthesis of compounds 189 and 190 was carried out by referring to Examples 171 and 172, except that 123-2 in step 1 was replaced by 4-(acridin-1-yl)-7-chloroquinazolin-2(1H)-one.
化合物189：LC-MS(ESI)m/z:293.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.68(d,J＝8.8Hz,2H),7.50(d,J＝2.0Hz,2H),7.10(dd,J＝8.7,2.0Hz,2H),4.51-4.38(m,2H),4.14(t,J＝5.7Hz,4H),3.57(t,J＝5.7Hz,4H),3.46(s,4H),2.42-2.33(m,4H).Compound 189: LC-MS (ESI) m/z: 293.1 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ7.68 (d, J = 8.8Hz, 2H), 7.50 ( d,J＝2.0Hz,2H),7.10(dd,J＝8.7,2.0Hz,2H),4.51-4.38(m,2H),4.14(t,J＝5.7Hz,4H),3.57(t,J =5.7Hz,4H),3.46(s,4H),2.42-2.33(m,4H).
化合物190：LC-MS(ESI)m/z:293.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.83(d,J＝8.9Hz,1H),7.66(d,J＝8.8Hz,1H),7.54(d,J＝2.0Hz,1H),7.46(d,J＝2.2Hz,1H),7.26(dd,J＝8.8,2.3Hz,1H),7.10(dd,J＝8.7,1.9Hz,1H),4.52-4.41(m,2H),4.35-4.31(m,2H),4.20(t,J＝5.9Hz,2H),3.70-3.60(m,4H),3.57-3.51(m,4H),2.45-2.31(m,4H).Compound 190: LC-MS (ESI) m/z: 293.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.83(d,J＝8.9Hz,1H),7.66(d,J＝8.8Hz,1H),7.54(d,J＝2.0Hz,1H),7.46(d,J＝2.2Hz,1H),7.26(dd,J＝8.8,2.3Hz,1H),7.10(dd,J＝8.7,1.9Hz,1H),4.52 -4.41(m,2H),4.35-4.31(m,2H),4.20(t,J＝5.9Hz,2H),3.70-3.60(m,4H),3.57-3.51(m,4H),2.45-2.31(m,4H).
实施例191&192
Example 191 & 192
合成方法Synthesis method
化合物191和192的合成方法参照实施例171和172。区别在于把步骤一中的123-2替换为7-氯-4-(环丙基胺基)喹唑啉-2(1H)-酮。The synthesis method of compounds 191 and 192 refers to Examples 171 and 172, except that 123-2 in step 1 is replaced by 7-chloro-4-(cyclopropylamino)quinazolin-2(1H)-one.
化合物191：LC-MS(ESI)m/z:293.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.26(d,J＝3.8Hz,2H),8.05(d,J＝8.7Hz,2H),7.51(d,J＝1.9Hz,2H),7.18(dd,J＝8.7,1.9Hz,2H),4.17(t,J＝5.7Hz,4H),3.60(t,J＝5.7Hz,4H),3.46(s,4H),3.03-2.96(m,2H),0.81-0.73(m,4H),0.67-0.61(m,4H).Compound 191: LC-MS (ESI) m/z: 293.1 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.26 (d, J = 3.8Hz, 2H), 8.05 ( d,J＝8.7Hz,2H),7.51(d,J＝1.9Hz,2H),7.18(dd,J＝8.7,1.9Hz,2H),4.17(t,J＝5.7Hz,4H),3.60( t,J＝5.7Hz,4H),3.46(s,4H),3.03-2.96(m,2H),0.81-0.73(m,4H),0.67-0.61(m,4H).
化合物192：LC-MS(ESI)m/z:293.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.37(d,J＝3.8Hz,1H),8.27(d,J＝4.1Hz,1H),8.16(d,J＝8.8Hz,1H),8.06(d,J＝8.7Hz, 1H),7.58(d,J＝2.0Hz,1H),7.48(d,J＝2.2Hz,1H),7.33(dd,J＝8.8,2.2Hz,1H),7.20(dd,J＝8.7,1.9Hz,1H),4.36(t,J＝4.8Hz,2H),4.23(t,J＝5.7Hz,2H),3.73-3.63(m,4H),3.58-3.51(m,4H),3.04-2.92(m,2H),0.82-0.73(m,4H),0.68-0.59(m,4H).Compound 192: LC-MS (ESI) m/z: 293.1[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.37 (d, J = 3.8 Hz, 1H), 8.27 ( d,J＝4.1Hz,1H),8.16(d,J＝8.8Hz,1H),8.06(d,J＝8.7Hz, 1H),7.58(d,J＝2.0Hz,1H),7.48(d,J＝2.2Hz,1H),7.33(dd,J＝8.8,2.2Hz,1H),7.20(dd,J＝8.7,1.9 Hz,1H),4.36(t,J＝4.8Hz,2H),4.23(t,J＝5.7Hz,2H),3.73-3.63(m,4H),3.58-3.51(m,4H),3.04-2.92 (m,2H),0.82-0.73(m,4H),0.68-0.59(m,4H).
实施例193
Embodiment 193
合成路线
Synthetic route
步骤一：化合物193-1的合成Step 1: Synthesis of compound 193-1
室温下，将化合物123-2(500mg，2.2mmol)、3-溴丙酸乙酯(446mg，2.5mmol)和碳酸钾(620mg，4.4mmol)分散到N,N-二甲基甲酰胺(8.0mL)溶液中，加热到100℃，反应4个小时。待反应液冷却至室温，用乙酸乙酯(20mL×3)和水(20mL)萃取，合并有机相，饱和食盐水洗涤(20mL)一次，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：乙酸乙酯/石油醚＝100％)纯化，得到化合物193-1，150mg，白色固体,收率21％。LC-MS(ESI)m/z:324[M+H]+.At room temperature, compound 123-2 (500 mg, 2.2 mmol), ethyl 3-bromopropionate (446 mg, 2.5 mmol) and potassium carbonate (620 mg, 4.4 mmol) were dispersed in N,N-dimethylformamide (8.0 mL) solution, heated to 100 ° C, and reacted for 4 hours. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate (20 mL × 3) and water (20 mL), the organic phases were combined, washed with saturated brine (20 mL) once, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography column (eluent: ethyl acetate/petroleum ether = 100%) to obtain compound 193-1, 150 mg, white solid, yield 21%. LC-MS (ESI) m/z: 324 [M + H] + .
步骤二：化合物193-2的合成Step 2: Synthesis of compound 193-2
室温下，将化合物193-1(150mg，0.46mmol)分散到甲醇(4.0mL)中，将氢氧化锂一水合物(39mg，0.92mmol)溶到水(0.30mL)中，并滴加到反应液中。室温搅拌过夜。经减压蒸除大部分溶剂，向残余物中加入少量水，滴加1N稀盐酸，调节溶液pH至3～4，室温搅拌10分钟。用乙酸乙酯(5mL×8)萃取，合并有机相，减压蒸除溶剂，得到化合物193-2，100mg，白色固体，收率73％。LC-MS(ESI)m/z:296[M+H]+.At room temperature, compound 193-1 (150 mg, 0.46 mmol) was dispersed in methanol (4.0 mL), lithium hydroxide monohydrate (39 mg, 0.92 mmol) was dissolved in water (0.30 mL), and added dropwise to the reaction solution. Stir at room temperature overnight. Most of the solvent was evaporated under reduced pressure, a small amount of water was added to the residue, 1N dilute hydrochloric acid was added dropwise, the pH of the solution was adjusted to 3-4, and stirred at room temperature for 10 minutes. Extracted with ethyl acetate (5 mL × 8), the organic phases were combined, and the solvent was evaporated under reduced pressure to obtain compound 193-2, 100 mg, white solid, yield 73%. LC-MS (ESI) m/z: 296 [M + H] + .
步骤三：化合物193的合成Step 3: Synthesis of compound 193
室温下，将化合物193-2(20mg，0.068mmol)溶到N,N-二甲基甲酰胺(0.2mL)中，并滴加DIEA(18mg，0.13mmol)，室温搅拌20分钟。依次向反应液中滴加HATU(31mg，0.082mmol)和化合物162-2(39mg，0.14mmol)的N,N-二甲基甲酰胺溶液，室温搅拌30分钟。反应液经乙酸乙酯(5mL×3)和水(5mL)萃取，合并有机相，饱和食盐水洗涤(5mL)一次，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，经硅胶层析色谱柱(洗脱剂：二氯甲烷/甲醇＝10/1)纯化，制备液相色谱纯化，制备液冷冻干燥，得到化合物193，14.76mg，为白色固体，收率38％。LC-MS(ESI)m/z:285.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.96(d,J＝8.8Hz,2H),7.65(d,J＝2.0Hz, 1H),7.54(d,J＝2.0Hz,1H),7.20(dq,J＝8.8,2.0,1.1Hz,2H),4.39(dd,J＝14.4,7.7Hz,1H),4.29(dd,J＝14.4,7.2Hz,1H),4.19(t,J＝7.6Hz,2H),4.09(t,J＝8.4Hz,1H),3.91(dd,J＝8.5,5.4Hz,1H),3.84(t,J＝8.9Hz,1H),3.72(dd,J＝9.6,5.5Hz,1H),3.22(s,6H),3.22(s,6H),2.97-2.87(m,1H),2.37(h,J＝8.0Hz,2H).At room temperature, compound 193-2 (20 mg, 0.068 mmol) was dissolved in N, N-dimethylformamide (0.2 mL), and DIEA (18 mg, 0.13 mmol) was added dropwise, and the mixture was stirred at room temperature for 20 minutes. HATU (31 mg, 0.082 mmol) and N, N-dimethylformamide solution of compound 162-2 (39 mg, 0.14 mmol) were added dropwise to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate (5 mL × 3) and water (5 mL), the organic phases were combined, washed with saturated brine (5 mL) once, dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was evaporated under reduced pressure, and the mixture was purified by silica gel chromatography (eluent: dichloromethane/methanol = 10/1), purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain compound 193, 14.76 mg, as a white solid, with a yield of 38%. LC-MS (ESI) m/z: 285.6 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ7.96 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 2.0 Hz, 1H),7.54(d,J＝2.0Hz,1H),7.20(dq,J＝8.8,2.0,1.1Hz,2H),4.39(dd,J＝14.4,7.7Hz,1H),4.29(dd,J＝14.4,7.2Hz,1H),4.19(t,J＝7.6Hz,2H),4.09(t,J =8.4Hz,1H),3.91(dd,J＝8.5,5.4Hz,1H),3.84(t,J＝8.9Hz,1H),3.72(dd,J＝9.6,5.5Hz,1H),3.22(s,6H),3.22(s,6H),2.97-2.87(m,1H),2.37(h,J＝8. 0Hz,2H).
实施例194
Embodiment 194
合成方法Synthesis method
化合物194的合成方法参照实施例123。区别在于把步骤五中的2-氨基-6-溴吡啶替换为间胺基碘苯。LC-MS(ESI)m/z:302.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.02(dd,J＝15.0,8.8Hz,2H),7.62(s,1H),7.35(t,J＝8.0Hz,1H),7.21(td,J＝10.8,8.8,2.1Hz,2H),6.62(s,1H),6.47(dd,J＝8.1,2.0Hz,2H),6.36(s,1H),4.22(ddd,J＝43.5,14.3,7.3Hz,2H),3.31(s,6H),3.26(s,6H),3.13(dd,J＝9.8,6.2Hz,1H),2.77(p,1H),2.06(dd,J＝15.6,7.4Hz,1H),2.04-1.95(m,2H),1.84(dq,J＝14.4,7.4Hz,1H).The synthesis method of compound 194 refers to Example 123. The difference is that 2-amino-6-bromopyridine in step 5 is replaced by m-aminoiodobenzene. LC-MS (ESI) m/z: 302.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.02 (dd, J = 15.0, 8.8 Hz, 2H), 7.62 (s, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.21 (td, J = 10.8, 8.8, 2.1 Hz, 2H), 6.62 (s, 1H), 6.47 (dd, J = 8.1, 2.0 Hz, 2H), 6.36 (s, 1H), 4.22 (ddd, J = 43.5,14.3,7.3Hz,2H),3.31(s,6H),3.26(s,6H),3.13(dd,J＝9.8,6.2Hz,1H),2.77(p,1H),2.06(dd,J＝15.6,7.4Hz,1H),2.04-1.95(m,2H),1.84(dq,J =14.4,7.4Hz,1H).
实施例195
Embodiment 195
合成方法Synthesis method
化合物195的合成方法参照实施例162。区别在于把步骤三中的123-7替换为7-氯-4-(二甲胺基)-1-(3-碘苯基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:295.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.99(d,J＝8.8Hz,1H),7.69(d,J＝2.1Hz,1H),7.36(t,J＝8.0Hz,1H),7.26–7.17(m,3H),6.55(dt,J＝8.2,2.3Hz,2H),6.44(d,J＝2.1Hz,1H),4.45(d,J＝7.4Hz,2H),3.87(t,J＝7.6Hz,2H),3.70(t,J＝6.4Hz,2H),3.30(s,6H),3.25(s,6H),3.14(q,1H).The synthesis method of compound 195 is similar to that of Example 162. The difference is that 123-7 in step 3 is replaced by 7-chloro-4-(dimethylamino)-1-(3-iodophenyl)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 295.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.03(d,J＝8.8Hz,1H),7.99(d,J＝8.8Hz,1H),7.69(d,J＝2.1Hz,1H),7.36(t,J＝8.0Hz,1H),7.26–7.17(m,3H),6.55(dt,J＝8.2,2.3Hz,2H),6.44(d,J＝ 2.1Hz, 1H), 4.45 (d, J = 7.4Hz, 2H), 3.87 (t, J = 7.6Hz, 2H), 3.70 (t, J = 6.4Hz, 2H), 3.30 (s, 6H), 3.25 (s, 6H), 3.14 (q, 1H).
实施例196
Embodiment 196
合成路线
Synthetic route
步骤一：化合物196-1的合成Step 1: Synthesis of compound 196-1
室温下，将7-氯-2-羟基喹啉(200mg，1.11mmol)溶解在5mL N,N-二甲基甲酰胺中，向其中加入1-Boc-3-溴甲基吡咯烷(350mg，1.33mmol)和碳酸钾(1.1g，3.33mmol)，100℃下搅拌16h。TLC监测完全反应，反应体系中加水，用乙酸乙酯(15mL x 3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物196-1(120mg，白色固体)，产率30％。LC-MS(ESI)m/z:363[M+H]+.At room temperature, 7-chloro-2-hydroxyquinoline (200 mg, 1.11 mmol) was dissolved in 5 mL of N,N-dimethylformamide, 1-Boc-3-bromomethylpyrrolidine (350 mg, 1.33 mmol) and potassium carbonate (1.1 g, 3.33 mmol) were added thereto, and stirred at 100 ° C for 16 h. TLC monitored the complete reaction, water was added to the reaction system, extracted with ethyl acetate (15 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 196-1 (120 mg, white solid) with a yield of 30%. LC-MS (ESI) m/z: 363 [M + H] + .
步骤二：化合物196-2的合成Step 2: Synthesis of compound 196-2
室温下将化合物196-1(120mg，0.33mmol)溶解在2mL 1,4-二氧六环中，向其中加入盐酸-二氧六环溶液2mL，室温下搅拌30min。TLC监测完全反应，浓缩后得到化合物196-2的盐酸盐(104mg，白色固体)，产率98％。LC-MS(ESI)m/z:263[M+H]+.步骤三：化合物196的合成Compound 196-1 (120 mg, 0.33 mmol) was dissolved in 2 mL of 1,4-dioxane at room temperature, and 2 mL of hydrochloric acid-dioxane solution was added thereto, and stirred at room temperature for 30 min. TLC monitored the complete reaction, and after concentration, the hydrochloride of compound 196-2 (104 mg, white solid) was obtained with a yield of 98%. LC-MS (ESI) m/z: 263 [M+H] + . Step 3: Synthesis of compound 196
室温下将化合物123-7(100mg，0.26mmol)溶解在2mL N,N-二甲基甲酰胺中，向其中加入化合物196-2(104mg，0.39mmol)和碳酸铯(260mg，0.78mmol)。反应混合液在100℃下搅拌16h。LC-MS检测完全反应。经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，HPLC制备后得到化合物196(20.68mg，白色固体)，产率14.20％。LC-MS(ESI)m/z:561.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.03(d,J＝8.9Hz,1H),7.93(d,J＝9.5Hz,1H),7.79-7.69(m,3H),7.31(dd,J＝8.3,1.8Hz,1H),7.20(dd,J＝8.8,2.2Hz,1H),6.64(d,J＝9.5Hz,1H),6.54(td,J＝7.8,5.9Hz,2H),6.46(d,J＝2.1Hz,1H),4.40(ddd,J＝59.4,14.1,7.5Hz,2H),3.58-3.48(m,2H),3.30(s,6H),3.24(dd,J＝10.7,6.7Hz,1H),2.79(p,J＝7.1Hz,1H),2.06-1.94(m,2H),1.90-1.79(m,1H).Compound 123-7 (100 mg, 0.26 mmol) was dissolved in 2 mL of N,N-dimethylformamide at room temperature, and compound 196-2 (104 mg, 0.39 mmol) and cesium carbonate (260 mg, 0.78 mmol) were added thereto. The reaction mixture was stirred at 100 ° C for 16 h. LC-MS detected the complete reaction. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 196 (20.68 mg, white solid) was obtained after HPLC preparation with a yield of 14.20%. LC-MS (ESI) m/z: 561.1 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.03(d,J＝8.9Hz,1H),7.93(d,J＝9.5Hz,1H),7.79-7.69(m,3H),7.31(dd,J＝8.3,1.8Hz,1H),7.20(dd,J＝8.8,2.2Hz,1H),6.64(d,J＝9.5Hz,1H),6.54(t d,J＝7.8,5.9Hz,2H),6.4 6(d,J＝2.1Hz,1H),4.40(ddd,J＝59.4,14.1,7.5Hz,2H),3.58-3.48(m,2H),3.30(s,6H),3.24(dd,J＝10.7,6.7Hz,1H),2.79(p,J＝7.1Hz,1H),2.06-1.94 (m,2H),1.90-1.79(m,1H).
实施例197
Embodiment 197
合成方法Synthesis method
化合物197的合成方法参照实施例193。区别在于把步骤一中的3-溴丙酸乙酯替换为4-溴丁酸甲酯。LC-MS(ESI)m/z:292.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(dd,J＝8.8,4.1Hz,2H),7.75(d,J＝2.0Hz,1H),7.67(d,J＝2.0Hz,1H),7.21(td,J＝8.4,1.9Hz,2H),4.42-4.34(m,2H),4.13(t,J＝8.3Hz,1H),4.01-3.94(m,3H),3.87(t,J＝8.9Hz,1H),3.74(dd,J＝9.5,5.5Hz,1H),3.24(s,6H),3.23(s,6H),3.01-2.94(m,1H),2.17(t,J＝6.9Hz,2H),1.80-1.70(m,2H).The synthesis method of compound 197 is similar to that of Example 193. The difference is that ethyl 3-bromopropionate in step 1 is replaced by methyl 4-bromobutyrate. LC-MS (ESI) m/z: 292.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.97(dd,J＝8.8,4.1Hz,2H),7.75(d,J＝2.0Hz,1H),7.67(d,J＝2.0Hz,1H),7.21(td,J＝8.4,1.9Hz,2H),4.42-4.34(m,2H),4.13(t,J＝8.3Hz,1H),4.01-3 .94(m,3H),3.87(t,J＝8.9Hz,1H),3.74(dd,J＝9.5,5.5Hz,1H),3.24(s,6H),3.23(s,6H),3.01-2.94(m,1H),2.17(t,J＝6.9Hz,2H),1.80-1.70(m,2H).
实施例198
Embodiment 198
合成方法Synthesis method
化合物198的合成方法参照实施例162。区别在于把步骤一中的123-2替换为7-氯-4-(甲胺基)喹唑啉-2(1H)-酮，步骤三中的123-7替换为1-(2-溴吡啶-4-基)-7-氯-4-(甲胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:282.1[M/2+H]+.The synthesis method of compound 198 refers to Example 162. The difference is that 123-2 in step 1 is replaced by 7-chloro-4-(methylamino)quinazolin-2(1H)-one, and 123-7 in step 3 is replaced by 1-(2-bromopyridin-4-yl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 282.1 [M/2+H] + .
实施例199
Embodiment 199
合成方法Synthesis method
化合物199的合成方法参照实施例162。区别在于把步骤三中的123-7替换为1-(4-溴吡啶-2-基)-7-氯-4-(二甲胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:296.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.8Hz,1H),8.04(d,J＝8.9Hz,1H),7.97(d,J＝8.6Hz,1H),7.71(d,J＝2.0Hz,1H),7.21(ddd,J＝8.7,3.2,2.0Hz,2H),6.48(dd,J＝5.8,2.2Hz,1H),6.40(t,J＝2.6Hz,2H),4.46(d,J＝7.7Hz,2H),4.00(t,J＝8.4Hz,2H),3.87-3.81(m,2H),3.30(s,6H),3.23(s,6H),3.19-3.12(m,1H).The synthesis method of compound 199 refers to Example 162. The difference is that 123-7 in step 3 is replaced by 1-(4-bromopyridin-2-yl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 296.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.17(d,J＝5.8Hz,1H),8.04(d,J＝8.9Hz,1H),7.97(d,J＝8.6Hz,1H),7.71(d,J＝2.0Hz,1H),7.21(ddd,J＝8.7,3.2,2.0Hz,2H),6.48(dd,J＝5.8,2.2Hz,1H) ,6.40(t,J＝2.6Hz,2H),4.46(d,J＝7.7Hz,2H),4.00(t,J＝8.4Hz,2H),3.87-3.81(m,2H),3.30(s,6H),3.23(s,6H),3.19-3.12(m,1H).
实施例200&201&202
Embodiment 200&201&202
合成方法Synthesis method
化合物200、201和202的合成方法参照实施例171和172。区别在于把步骤一中的123-2替换为7-氯-2-羟基喹啉。The synthesis method of compounds 200, 201 and 202 refers to Examples 171 and 172, except that 123-2 in step 1 is replaced by 7-chloro-2-hydroxyquinoline.
化合物200：LC-MS(ESI)m/z:473.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.88(d,J＝9.5Hz,2H),7.70-7.63(m,4H),7.23(dd,J＝8.3,1.8Hz,2H),6.60(d,J＝9.5Hz,2H),4.33(t,J＝5.8Hz,4H),3.60(t,J＝5.8Hz,4H),3.47(s,4H).Compound 200: LC-MS (ESI) m/z: 473.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ7.88 (d, J = 9.5Hz, 2H), 7.70-7.63 ( m,4H),7.23(dd,J＝8.3,1.8Hz,2H),6.60(d,J＝9.5Hz,2H),4.33(t,J＝5.8Hz,4H),3.60(t,J＝5.8 Hz,4H),3.47(s,4H).
化合物201：LC-MS(ESI)m/z:473.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.25(d,J＝8.9Hz,1H),7.91(dd,J＝9.0,3.1Hz,2H),7.76(d,J＝2.1Hz,1H),7.75-7.67(m,2H),7.46(dd,J＝8.6,2.1Hz,1H),7.26(dd,J＝8.3,1.9Hz,1H),7.00(d,J＝8.8Hz,1H),6.61(d,J＝9.5Hz,1H),4.49-4.43(m,2H),4.40(t,J＝5.8Hz,2H),3.75-3.66(m,4H),3.55(s,4H).Compound 201: LC-MS (ESI) m/z: 473.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.25(d,J＝8.9Hz,1H),7.91(dd,J＝9.0,3.1Hz,2H),7.76(d,J＝2.1Hz,1H),7.75-7.67(m,2H),7.46(dd,J＝8.6,2.1Hz,1H),7.26(dd,J＝8.3,1.9Hz,1H),7. 00(d,J＝8.8Hz,1H),6.61(d,J＝9.5Hz,1H),4.49-4.43(m,2H),4.40(t,J＝5.8Hz,2H),3.75-3.66(m,4H),3.55(s,4H).
化合物202：LC-MS(ESI)m/z:473.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.25 (d,J＝8.9Hz,2H),7.91(d,J＝8.6Hz,2H),7.77(d,J＝2.1Hz,2H),7.46(dd,J＝8.6,2.1Hz,2H),7.04(d,J＝8.9Hz,2H),4.57-4.49(m,4H),3.84-3.76(m,4H),3.63(s,4H).Compound 202: LC-MS (ESI) m/z: 473.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.25 (d,J＝8.9Hz,2H),7.91(d,J＝8.6Hz,2H),7.77(d,J＝2.1Hz,2H),7.46(dd,J＝8.6,2.1Hz,2H),7.04(d,J＝8.9Hz,2H),4.57-4.49(m,4H),3.84-3.76(m,4H), 3.63(s,4H).
实施例203
Embodiment 203
合成方法Synthesis method
化合物203的合成方法参照实施例162。区别在于把步骤一中的123-2替换为101-2。LC-MS(ESI)m/z:303.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.04(d,J＝8.9Hz,1H),7.89(d,J＝8.8Hz,1H),7.75(t,J＝8.3,7.4Hz,1H),7.67(d,J＝2.0Hz,1H),7.21(dt,J＝8.7,2.0Hz,2H),6.64(d,J＝7.3Hz,1H),6.50(d,J＝8.2Hz,1H),6.42(d,J＝2.1Hz,1H),4.43(d,J＝7.4Hz,2H),3.96(t,J＝8.1Hz,2H),3.81(dd,J＝8.2,5.4Hz,2H),3.62(q,J＝7.0Hz,2H),3.45(t,3H),3.30(s,6H),3.21(s,3H),3.18-3.05(m,1H).The synthesis method of compound 203 refers to Example 162. The difference is that 123-2 in step 1 is replaced by 101-2. LC-MS (ESI) m/z: 303.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ8.04 (d, J=8.9 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.75 (t, J=8.3, 7.4 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.21 (dt, J=8.7, 2.0 Hz, 2H), 6.64 (d, J=7.3 Hz, 1H), 6.50 (d, J=8.2 Hz, 1H), 6. 42(d,J＝2.1Hz,1H),4.43(d,J＝7.4Hz,2H),3.96(t,J＝8.1Hz,2H),3.81(dd,J＝8.2,5.4Hz,2H),3.62(q,J＝7.0Hz,2H),3.45(t,3H),3.30(s,6H),3.21(s, 3H),3.18-3.05(m,1H).
实施例204
Embodiment 204
合成方法Synthesis method
化合物204的合成方法参照实施例176。区别在于把步骤三中的173-2替换为4-(7-氯-4-(二甲胺基)-2-氧代喹唑啉-1(2H)-基)戊酸。LC-MS(ESI)m/z:293.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.96(d,J＝8.8Hz,1H),7.89(d,J＝8.6Hz,1H),7.86(d,J＝8.6Hz,1H),7.55(d,J＝2.0Hz,1H),7.41(d,J＝2.0Hz,1H),7.18(dd,J＝8.8,1.9Hz,1H),7.07(dd,J＝8.7,1.8Hz,1H),3.97(t,J＝7.5Hz,2H),3.22(s,6H),3.20(s,6H),3.14-3.01(m,2H),2.37-2.25(m,1H),2.13-2.04(m,2H),2.00(q,J＝6.9,6.5Hz,2H),1.67-1.53(m,J＝6.7Hz,2H),1.43(d,J＝6.7Hz,3H).The synthesis method of compound 204 refers to Example 176. The difference is that 173-2 in step 3 is replaced by 4-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)pentanoic acid. LC-MS (ESI) m/z: 293.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.96 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.18 (dd, J = 8.8, 1.9 Hz, 1H), 7.07 (dd, J = 8.7, 1.8 Hz, 1H), 3.97 ( t,J＝7.5Hz,2H),3.22(s,6H),3.20(s,6H),3.14-3.01(m,2H),2.37-2.25(m,1H),2.13-2.04(m,2H),2.00(q,J＝6.9,6.5Hz,2H),1.67-1.53(m,J＝6. 7Hz, 2H), 1.43 (d, J = 6.7Hz, 3H).
实施例205
Embodiment 205
合成方法Synthesis method
化合物205的合成方法参照实施例176。区别在于把步骤三中的173-2替换为4-(7-氯-4-(二甲胺基)-2-氧代喹唑啉-1(2H)-基)-2-甲基丁酸。LC-MS(ESI)m/z:293.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.05(t,J＝5.7Hz,1H),7.94(dd,J＝8.8,2.4Hz,2H),7.47(dd,J＝8.7,2.0Hz,2H),7.17(dd,2H),4.15-4.02(m,3H),3.80-3.70(m,1H),3.38(m,2H),3.21(s,12H),2.47-2.33(m,1H),1.89-1.68(m,3H),1.60-1.47(m,1H),1.10(d,J＝6.8Hz,3H). The synthesis method of compound 205 refers to Example 176, except that 173-2 in step 3 is replaced by 4-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)-2-methylbutanoic acid. 1 -4.02( m ,3H),3.80-3.70(m,1H),3.38(m,2H),3.21(s,12H),2.47-2.33(m,1H) , 1.89-1.68(m,3H),1.60-1.47(m,1H),1.10(d,J＝6.8Hz,3H).
实施例206
Embodiment 206
合成方法Synthesis method
化合物206的合成方法参照实施例193。区别在于把步骤一中的3-溴丙酸乙酯替换为4-溴-2-甲基丁酸乙酯。LC-MS(ESI)m/z:299.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.99-7.91(m,2H),7.70(dd,J＝22.2,2.0Hz,1H),7.54(dd,J＝10.5,2.0Hz,1H),7.24-7.15(m,2H),4.49-4.27(m,2H),4.22-4.13(m,1H),4.09-3.92(m,2H),3.89-3.66(m,3H),3.24(s,6H),3.22-3.19(m,6H),3.03-2.92(m,1H),2.48-2.41(m,1H),1.94-1.78(m,1H),1.59-1.43(m,1H),1.05-0.99(m,3H).The synthesis method of compound 206 is similar to that of Example 193. The difference is that ethyl 3-bromopropionate in step 1 is replaced by ethyl 4-bromo-2-methylbutyrate. LC-MS (ESI) m/z: 299.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.99-7.91(m,2H),7.70(dd,J＝22.2,2.0Hz,1H),7.54(dd,J＝10.5,2.0Hz,1H),7.24-7.15(m,2H),4.49-4.27(m,2H),4.22-4.13(m,1H),4.09-3.92( m,2H),3.89-3.66(m,3H),3.24(s,6H),3.22-3.19(m,6H),3.03-2.92(m,1H),2.48-2.41(m,1H),1.94-1.78(m,1H),1.59-1.43(m,1H),1.05-0.9 9(m,3H).
实施例207
Embodiment 207
合成方法Synthesis method
化合物207的合成方法参照实施例176。区别在于把步骤三中的173-2替换为(E)-4-(7-氯-4-(二甲胺基)-2-氧代喹唑啉-1(2H)-基)-2-丁烯酸。LC-MS(ESI)m/z:285.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.03(t,J＝5.7Hz,1H),8.01(d,J＝8.8Hz,1H),7.95(d,J＝8.8Hz,1H),7.43(d,J＝2.0Hz,1H),7.34(d,J＝2.0Hz,1H),7.21(dd,J＝8.7,2.0Hz,1H),7.18(dd,J＝8.8,2.0Hz,1H),6.70(dt,J＝15.5,4.2Hz,1H),5.73(dt,J＝15.5,1.9Hz,1H),4.84(dd,J＝4.3,2.0Hz,2H),4.00(t,J＝7.6Hz,2H),3.26(s,7H),3.21(s,7H),3.16(q,J＝6.7Hz,2H),1.67(p,J＝7.4Hz,2H).The synthesis method of compound 207 is similar to that of Example 176. The difference is that 173-2 in step 3 is replaced by (E)-4-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)-2-butenoic acid. LC-MS (ESI) m/z: 285.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.03(t,J＝5.7Hz,1H),8.01(d,J＝8.8Hz,1H),7.95(d,J＝8.8Hz,1H),7.43(d,J＝2.0Hz,1H),7.34(d,J＝2.0Hz,1H),7.21(dd,J＝8.7,2.0Hz,1H),7.18(dd,J ＝8.8,2.0Hz,1H),6.70 (dt,J＝15.5,4.2Hz,1H),5.73(dt,J＝15.5,1.9Hz,1H),4.84(dd,J＝4.3,2.0Hz,2H),4.00(t,J＝7.6Hz,2H),3.26(s,7H),3.21(s,7H),3.16(q,J＝6.7Hz,2H) ,1.67(p,J＝7.4Hz,2H).
实施例208
Embodiment 208
合成方法Synthesis method
化合物208的合成方法参照实施例193。区别在于把步骤一中的3-溴丙酸乙酯替换为(E)-4-溴丁-2-烯酸乙酯。LC-MS(ESI)m/z:291.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.97(dd,J＝11.5,8.8Hz,2H),7.65(d,J＝2.0Hz,1H),7.39(d,J＝2.1Hz,1H),7.20(dt,J＝8.8,2.2Hz,2H),6.58(dt,J＝15.5,5.0Hz,1H),5.98(dt,J＝15.5,1.8Hz,1H),4.84(dd,2H),4.34(dd,J＝7.5,3.1Hz,2H),4.07(t,J＝8.4Hz,1H),3.95-3.84(m,2H),3.76-3.70(m,1H),3.25(s,6H),3.23(s,6H),2.99-2.90(m,1H).The synthesis method of compound 208 is similar to that of Example 193. The difference is that ethyl 3-bromopropionate in step 1 is replaced by ethyl (E)-4-bromobut-2-enoate. LC-MS (ESI) m/z: 291.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.97(dd,J＝11.5,8.8Hz,2H),7.65(d,J＝2.0Hz,1H),7.39(d,J＝2.1Hz,1H),7.20(dt,J＝8.8,2.2Hz,2H),6.58(dt,J＝15.5,5.0Hz,1H),5.98(dt,J＝15.5 ,1.8Hz,1H),4.84(dd,2H),4.34(dd,J＝7.5,3.1Hz,2H),4.07(t,J＝8.4Hz,1H),3.95-3.84(m,2H),3.76-3.70(m,1H),3.25(s,6H),3.23(s,6H),2.99-2. 90(m,1H).
实施例209
Embodiment 209
合成方法Synthesis method
化合物209的合成方法参照实施例102。区别在于把步骤一中的1-叔丁氧羰基-3-氨基哌啶替换为3-氨基氮杂环庚烷-1-羧酸叔丁酯。LC-MS(ESI)m/z:320.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.09(s,1H),7.98(dd,J＝8.7,2.4Hz,1H),7.91(d,J＝8.7Hz,1H),7.79(d,J＝2.0Hz,1H),7.43(s,1H),7.20(d,2H),5.29(s,2H),4.17(d,J＝12.2Hz,2H),3.90(d,1H),3.25(s,3H),3.24(s,6H),3.23(s,3H),2.33(d,J＝12.3Hz,1H),2.01(t,J＝7.5Hz,1H),1.90-1.67(m,3H),1.45(dd,J＝13.6,6.9Hz,1H),1.41(d,J＝12.4Hz,1H).The synthesis method of compound 209 is similar to that of Example 102. The difference is that 1-tert-butyloxycarbonyl-3-aminopiperidine in step 1 is replaced by tert-butyl 3-aminoazepane-1-carboxylate. LC-MS (ESI) m/z: 320.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.09(s,1H),7.98(dd,J＝8.7,2.4Hz,1H),7.91(d,J＝8.7Hz,1H),7.79(d,J＝2.0Hz,1H),7.43(s,1H),7.20(d,2H),5.29(s,2H),4.17(d,J＝12.2Hz,2H) ,3.90(d,1H),3.25(s,3H),3.24(s,6H),3.23(s,3H),2.33(d,J＝12.3Hz,1H),2.01(t,J＝7.5Hz,1H),1.90-1.67(m,3H),1.45(dd,J＝13.6,6.9Hz,1H),1 .41(d,J＝12.4Hz,1H).
实施例210
Embodiment 210
合成方法Synthesis method
化合物210的合成方法参照实施例123。区别在于把步骤二中的123-2替换为101-2，步骤五中的2-氨基-6-溴吡啶替换为2-溴-4-氨基吡啶，步骤七中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:317.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.24(d,J＝5.3Hz,1H),7.97(d,J＝8.8Hz,1H),7.90(d,J＝8.8Hz,1H),7.61(d,J＝2.0Hz,1H),7.22(ddd,J＝9.1,7.3,2.0Hz,2H),6.55(s,1H),6.44(d,J＝55.7Hz,2H),4.22(ddd,J＝44.5,14.4,7.5Hz,2H),3.70(q,J＝7.0Hz,2H),3.64(q,J＝17.3,7.0Hz,2H),3.29(s,3H),3.21(s,3H),2.76(dd,J＝13.9,6.9Hz,2H),2.11-2.04(m,1H),1.84(p,J＝7.4Hz,1H),1.50-1.42(m,1H),1.31(t,J＝7.0Hz,3H),1.28(t,J＝7.1Hz,3H).The synthesis method of compound 210 is similar to that of Example 123. The difference is that 123-2 in step 2 is replaced by 101-2, 2-amino-6-bromopyridine in step 5 is replaced by 2-bromo-4-aminopyridine, and dimethylamine in step 7 is replaced by methylethylamine. LC-MS (ESI) m/z: 317.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.24(d,J＝5.3Hz,1H),7.97(d,J＝8.8Hz,1H),7.90(d,J＝8.8Hz,1H),7.61(d,J＝2.0Hz,1H),7.22(ddd,J＝9.1,7.3,2.0Hz,2H),6.55(s,1H),6.44(d,J＝55 .7Hz,2H),4.22(ddd,J＝44.5,14.4,7.5Hz,2H),3.70( q,J＝7.0Hz,2H),3.64(q,J＝17.3,7.0Hz,2H),3.29(s,3H),3.21(s,3H),2.76(dd,J＝13.9,6.9Hz,2H),2.11-2.04(m,1H),1.84(p,J＝7.4Hz,1H),1.50-1 .42(m,1H),1.31(t,J＝7.0Hz,3H),1.28(t,J＝7.1Hz,3H).
实施例211
Embodiment 211
合成方法Synthesis method
化合物211的合成方法参照实施例102。区别在于把步骤一中的4-氯-2-氟苯甲酰胺替换为4-环丙基-2-氟苯甲酰胺，步骤五中的101-3替换为1-((2-溴噻唑-5-基)甲基)-4-(二甲胺基)-7-氯喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:316.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.98(d,J＝8.8Hz,1H),7.77(d,J＝2.0Hz,1H),7.74(d,J＝8.4Hz,1H),7.43(s,1H),7.30(s,1H),7.21(dd,J＝8.7,1.9Hz,1H),6.84(dd,J＝8.4,1.5Hz,1H),5.30(s,2H),4.21(t,1H),3.99(dd,J＝11.4Hz,1H),3.89(t,J＝11.7Hz,1H),3.72(d,J＝13.3Hz,1H),3.24(s,7H),3.19(s,6H),3.15-3.08(m,1H),2.88-2.78(m,1H),2.07-2.02(m,1H), 1.80-1.73(m,2H),1.74-1.66(m,2H),1.11-1.02(m,2H),0.93-0.87(m,1H),0.84-0.77(m,1H).The synthesis method of compound 211 is similar to that of Example 102. The difference is that 4-chloro-2-fluorobenzamide in step 1 is replaced by 4-cyclopropyl-2-fluorobenzamide, and 101-3 in step 5 is replaced by 1-((2-bromothiazol-5-yl)methyl)-4-(dimethylamino)-7-chloroquinazolin-2(1H)-one. LC-MS (ESI) m/z: 316.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.98(d,J＝8.8Hz,1H),7.77(d,J＝2.0Hz,1H),7.74(d,J＝8.4Hz,1H),7.43(s,1H),7.30(s,1H),7.21(dd,J＝8.7,1.9Hz,1H),6.84(dd,J＝8.4,1.5Hz,1H), 5.30(s,2H),4 .21(t,1H),3.99(dd,J＝11.4Hz,1H),3.89(t,J＝11.7Hz,1H),3.72(d,J＝13.3Hz,1H),3.24(s,7H),3.19(s,6H),3.15-3.08(m,1H),2.88-2.78(m,1H), 2.07-2.02(m,1H), 1.80-1.73(m,2H),1.74-1.66(m,2H),1.11-1.02(m,2H),0.93-0.87(m,1H),0.84-0.77(m,1H).
实施例212
Embodiment 212
合成方法Synthesis method
化合物212的合成方法参照实施例193。区别在于把步骤一中的3-溴丙酸乙酯替换为4-溴戊酸乙酯。LC-MS(ESI)m/z:299.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.96(d,J＝8.8Hz,1H),7.89(dd,J＝11.8,8.7Hz,1H),7.68–7.61(m,2H),7.21(dd,J＝8.7,1.9Hz,1H),7.16(ddd,J＝10.7,8.6,1.9Hz,1H),4.32(t,J＝10.2,7.5Hz,2H),3.87(d,J＝6.9Hz,1H),3.84-3.75(m,1H),3.67(dt,J＝9.9,5.1Hz,1H),3.23(s,6H),3.20(s,3H),3.18(s,3H),2.80(dd,J＝14.5,7.0Hz,1H),2.24(dd,J＝14.4,6.6Hz,1H),2.08(q,J＝6.9Hz,1H),2.00(dq,J＝13.4,7.0,6.5Hz,4H),1.42(d,J＝6.7Hz,3H).The synthesis method of compound 212 refers to Example 193. The difference is that ethyl 3-bromopropionate in step 1 is replaced by ethyl 4-bromovalerate. LC-MS (ESI) m/z: 299.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.96 (d, J = 8.8 Hz, 1H), 7.89 (dd, J = 11.8, 8.7 Hz, 1H), 7.68–7.61 (m, 2H), 7.21 (dd, J = 8.7, 1.9 Hz, 1H), 7.16 (ddd, J = 10.7, 8.6, 1.9 Hz, 1H), 4.32 (t, J = 10.2, 7.5 Hz, 2H), 3.87 (d, J = 6.9 Hz, 1H), 3.84–3.75 (m, 1H) ,3.67(dt,J＝9.9,5.1Hz,1H),3.23(s,6H),3.20(s,3H),3.18(s,3H),2.80(dd,J＝14.5,7.0Hz,1H),2.24(dd,J＝14.4,6.6Hz,1H),2.08(q,J＝6.9Hz,1H),2 .00(dq,J＝13.4,7.0,6.5Hz,4H),1.42(d,J＝6.7Hz,3H).
实施例213
Embodiment 213
合成方法Synthesis method
化合物213的合成方法参照实施例176。区别在于把步骤一种的N-Boc-溴丙胺替换为(3-溴-1-甲基丙基)氨基甲酸叔丁酯，步骤三中的173-2替换为4-(7-氯-4-(二甲胺基)-2-氧代喹唑啉-1(2H)-基)戊酸。LC-MS(ESI)m/z:300.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.95(dd,J＝8.7,2.1Hz,1H),7.89(d,J＝8.7Hz,1H),7.83(d,J＝8.6Hz,1H),7.55(d,1H),7.34(dd,J＝39.1,1.9Hz,1H),7.23-7.12(m,2H),3.96(dq,J＝15.1,7.0Hz,1H),3.92-3.79(m,2H),3.22(s,3H),3.21(s,3H),3.20(s,6H),2.15-2.05(m,3H),2.00(dt,J＝18.6,7.1Hz,2H),1.66-1.55(m,2H),1.44(dd,J＝10.6,6.7Hz,3H),1.05(d,J＝6.6Hz,1H),1.01(d,J＝6.6Hz,1H),0.86(t,J＝6.9Hz,1H).The synthesis method of compound 213 is similar to that of Example 176. The difference is that N-Boc-bromopropylamine in step 1 is replaced by (3-bromo-1-methylpropyl)carbamic acid tert-butyl ester, and 173-2 in step 3 is replaced by 4-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)pentanoic acid. LC-MS (ESI) m/z: 300.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.95(dd,J＝8.7,2.1Hz,1H),7.89(d,J＝8.7Hz,1H),7.83(d,J＝8.6Hz,1H),7.55(d,1H),7.34(dd,J＝39.1,1.9Hz,1H),7.23-7.12(m,2H),3.96(dq,J＝15 .1,7.0Hz,1H),3.92-3.79(m,2H),3.22(s, 3H),3.21(s,3H),3.20(s,6H),2.15-2.05(m,3H),2.00(dt,J＝18.6,7.1Hz,2H),1.66-1.55(m,2H),1.44(dd,J＝10.6,6.7Hz,3H),1.05(d,J＝6.6Hz,1H ),1.01(d,J＝6.6Hz,1H),0.86(t,J＝6.9Hz,1H).
实施例214
Embodiment 214
合成路线
Synthetic route
步骤一：化合物214的合成Step 1: Synthesis of compound 214
室温下，将1-(3-氨基丙基)-7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(176-2，30mg，0.107mmol)溶于2mL DCM和2mL饱和的碳酸氢钠水溶液中，降温至0℃，加入三光气(15mg，0.0505mmol)，升至室温反应30分钟。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相浓缩后溶于0.5mL THF中，滴加至1-(2-氨基乙基)-7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(150-2，30mg，0.112mmol)和三乙胺(32mg，0.317mmol)的THF溶液中，室温搅拌30分钟。LCMS监测反应完全。反应液浓缩后经高压制备液相分离纯化得20mg化合物214，收率33％。LC-MS(ESI)m/z:287.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(d,J＝8.9Hz,1H),7.93(d,J＝8.7Hz,1H),7.79(d,J＝2.0Hz,1H),7.48(d,J＝2.0Hz,1H),7.20(dd,J＝8.7,1.9Hz,1H),7.15(dd,J＝8.8,2.0Hz,1H),6.26(t,J＝6.1Hz,1H),6.15(t,J＝5.8Hz,1H),4.07-3.99(m,4H),3.23(s,6H),3.22-3.18(m,8H),3.10-3.05(m,2H),1.72-1.62(m,2H).At room temperature, 1-(3-aminopropyl)-7-chloro-4-(dimethylamino)quinazoline-2(1H)-one (176-2, 30 mg, 0.107 mmol) was dissolved in 2 mL DCM and 2 mL saturated sodium bicarbonate aqueous solution, cooled to 0 ° C, triphosgene (15 mg, 0.0505 mmol) was added, and the reaction was heated to room temperature for 30 minutes. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine and concentrated and dissolved in 0.5 mL THF, and added dropwise to a THF solution of 1-(2-aminoethyl)-7-chloro-4-(dimethylamino)quinazoline-2(1H)-one (150-2, 30 mg, 0.112 mmol) and triethylamine (32 mg, 0.317 mmol), and stirred at room temperature for 30 minutes. LCMS monitored the reaction to be complete. The reaction solution was concentrated and purified by high pressure preparative liquid separation to obtain 20 mg of compound 214 with a yield of 33%. LC-MS (ESI) m/z: 287.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.97(d,J＝8.9Hz,1H),7.93(d,J＝8.7Hz,1H),7.79(d,J＝2.0Hz,1H),7.48(d,J＝2.0Hz,1H),7.20(dd,J＝8.7,1.9Hz,1H),7.15(dd,J＝8.8,2.0Hz,1H),6.26 (t,J＝6.1Hz,1H),6.15(t,J＝5.8Hz,1H),4.07-3.99(m,4H),3.23(s,6H),3.22-3.18(m,8H),3.10-3.05(m,2H),1.72-1.62(m,2H).
实施例215
Embodiment 215
合成方法Synthesis method
化合物215的合成方法参照实施例176。区别在于把步骤一中的N-Boc-溴丙胺替换为(3-溴-1-甲基丙基)氨基甲酸叔丁酯，步骤三中的173-2替换为4-(7-氯-4-(二甲胺基)-2-氧代喹唑啉-1(2H)-基)-2-甲基丁酸。LC-MS(ESI)m/z:300.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(s,1H),7.96(s,1H),7.50(d,J＝2.0Hz,1H),7.44(d,J＝2.0Hz,1H),7.20(dt,J＝8.7,2.3Hz,2H),4.14-4.10(m,1H),4.05-3.95(m,3H),3.79-3.71(m,1H),3.22(s,12H),2.45-2.37(m,1H),1.87-1.80(m,1H),1.75-1.67(m,2H),1.60-1.51(m,1H),1.14(dd,J＝8.8,6.8Hz,6H).The synthesis method of compound 215 refers to Example 176. The difference is that N-Boc-bromopropylamine in step 1 is replaced by (3-bromo-1-methylpropyl)carbamic acid tert-butyl ester, and 173-2 in step 3 is replaced by 4-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)-2-methylbutanoic acid. LC-MS (ESI) m/z: 300.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.97(s,1H),7.96(s,1H),7.50(d,J＝2.0Hz,1H),7.44(d,J＝2.0Hz,1H),7.20(dt,J＝8.7,2.3Hz,2H),4.14-4.10(m,1H),4.05-3.95(m,3H),3.79-3. 71(m,1H),3.22(s,12H),2.45-2.37(m,1H),1.87-1.80(m,1H),1.75-1.67(m,2H),1.60-1.51(m,1H),1.14(dd,J＝8.8,6.8Hz,6H).
实施例216
Embodiment 216
合成方法Synthesis method
化合物216的合成方法参照实施例176。区别在于把步骤一中的N-Boc-溴丙胺替换为(3-溴-1-甲基丙基)氨基甲酸叔丁酯，步骤三中的173-2替换为(E)-4-(7-氯-4-(二甲胺基)-2-氧代喹唑啉-1(2H)-基)-2-丁烯酸。LC-MS(ESI)m/z:292.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.93(t,J＝8.4Hz,2H),7.54(d,J＝2.0Hz,1H),7.38(dd,J＝4.7,2.0Hz, 1H),7.22(dd,J＝8.8,2.0Hz,1H),7.14(dt,J＝8.8,1.8Hz,2H),6.49(d,J＝14.2Hz,1H),5.97(dt,J＝14.7,7.7Hz,1H),4.08-3.92(m,3H),3.25(s,6H),3.21(s,6H),3.16-3.12(m,2H),1.72(q,J＝7.4Hz,2H),1.16(d,J＝6.6Hz,3H).The synthesis method of compound 216 refers to Example 176. The difference is that N-Boc-bromopropylamine in step 1 is replaced by (3-bromo-1-methylpropyl)carbamic acid tert-butyl ester, and 173-2 in step 3 is replaced by (E)-4-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)-2-butenoic acid. LC-MS (ESI) m/z: 292.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.93 (t, J = 8.4 Hz, 2H), 7.54 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 4.7, 2.0 Hz, 1H),7.22(dd,J＝8.8,2.0Hz,1H),7.14(dt,J＝8.8,1.8Hz,2H),6.49(d,J＝14.2Hz,1H),5.97(dt,J＝14.7,7.7Hz,1H),4.08-3.92(m,3H),3.25(s,6H),3.2 1(s,6H),3.16-3.12(m,2H),1.72(q,J＝7.4Hz,2H),1.16(d,J＝6.6Hz,3H).
实施例217
Embodiment 217
合成方法Synthesis method
化合物217的合成方法参照实施例193。区别在于把步骤一中的123-2替换为102-2，步骤一中的3-溴丙酸乙酯替换为4-溴丁酸乙酯。LC-MS(ESI)m/z:299.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.98(d,J＝8.8Hz,1H),7.90(d,J＝8.8Hz,1H),7.76(d,J＝2.0Hz,1H),7.68(d,J＝2.0Hz,1H),7.22(ddd,J＝8.7,4.7,1.9Hz,2H),4.38(dd,J＝7.5,3.0Hz,2H),4.13(t,J＝8.3Hz,1H),3.97(dt,J＝14.5,8.1Hz,3H),3.87(t,J＝8.9Hz,1H),3.74(dd,J＝9.5,5.5Hz,1H),3.63(q,J＝7.0Hz,2H),3.24(s,6H),3.21(s,3H),2.97(ddd,J＝13.6,8.1,5.6Hz,1H),2.18(t,J＝6.8Hz,2H),1.76(dp,J＝13.6,6.6Hz,2H),1.26(t,J＝7.1Hz,3H).The synthesis method of compound 217 is similar to that of Example 193. The difference is that 123-2 in step 1 is replaced by 102-2, and 3-bromopropionic acid ethyl ester in step 1 is replaced by 4-bromobutyric acid ethyl ester. LC-MS (ESI) m/z: 299.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.98(d,J＝8.8Hz,1H),7.90(d,J＝8.8Hz,1H),7.76(d,J＝2.0Hz,1H),7.68(d,J＝2.0Hz,1H),7.22(ddd,J＝8.7,4.7,1.9Hz,2H),4.38(dd,J＝7.5,3.0Hz,2H) ,4.13(t,J＝8.3Hz,1H),3.97(dt,J＝14.5,8.1Hz,3H),3 .87(t,J＝8.9Hz,1H),3.74(dd,J＝9.5,5.5Hz,1H),3.63(q,J＝7.0Hz,2H),3.24(s,6H),3.21(s,3H),2.97(ddd,J＝13.6,8.1,5.6Hz,1H),2.18(t,J＝6.8Hz, 2H), 1.76 (dp, J＝13.6, 6.6Hz, 2H), 1.26 (t, J＝7.1Hz, 3H).
实施例218
Embodiment 218
合成方法Synthesis method
化合物218的合成方法参照实施例176。区别在于把步骤三中的173-2替换为4-(7-氯-4-(甲乙胺基)-2-氧代喹唑啉-1(2H)-基)丁酸。LC-MS(ESI)m/z:293.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.01(t,J＝5.7Hz,1H),7.96(d,J＝8.8Hz,1H),7.89(d,J＝8.8Hz,1H),7.62(d,J＝2.0Hz,1H),7.47(d,J＝2.0Hz,1H),7.18(ddd,J＝8.6,6.5,1.9Hz,2H),4.05(t,J＝7.6Hz,2H),4.00(t,J＝7.8Hz,2H),3.62(q,J＝7.0Hz,2H),3.22(s,6H),3.20(s,3H),3.17(q,J＝6.5Hz,2H),2.23(t,J＝7.1Hz,2H),1.81(q,J＝7.5Hz,2H),1.72(q,J＝7.1Hz,2H),1.26(t,J＝7.1Hz,3H).The synthesis method of compound 218 refers to Example 176. The difference is that 173-2 in step 3 is replaced by 4-(7-chloro-4-(methylethylamino)-2-oxoquinazolin-1(2H)-yl)butanoic acid. LC-MS (ESI) m/z: 293.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.01 (t, J = 5.7 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.18 (ddd, J = 8.6, 6.5, 1.9 Hz, 2H), 4.05 (t, J = 7.6 Hz, 2H), 4.00 ( t,J＝7.8Hz,2H),3.62(q,J＝7.0Hz,2H),3.22(s,6H),3.20(s,3H),3.17(q,J＝6.5Hz,2H),2.23(t,J＝7.1Hz,2H),1.81(q,J＝7.5Hz,2H),1.72(q,J＝7.1Hz, 2H),1.26(t,J=7.1Hz,3H).
实施例219
Embodiment 219
合成方法Synthesis method
化合物219的合成方法参照实施例176。区别在于把步骤一中的N-Boc-溴丙胺替换为(3-溴-1-甲基丙基)氨基甲酸叔丁酯。LC-MS(ESI)m/z:293.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.97-7.94(m,3H),7.62(d,J＝2.0Hz,1H),7.41(d,J＝2.0Hz,1H),7.17(ddd,J＝8.9,7.2,1.9Hz,2H),4.01(dd,J＝9.7,5.8Hz,4H),3.93(p,J＝6.8Hz,1H),3.22 (d,J＝5.3Hz,12H),2.23(td,J＝7.1,3.9Hz,2H),1.81(q,J＝7.8Hz,2H),1.69(q,J＝7.3Hz,2H),1.12(d,J＝6.6Hz,3H).The synthesis method of compound 219 refers to Example 176. The difference is that N-Boc-bromopropylamine in step 1 is replaced by (3-bromo-1-methylpropyl)carbamic acid tert-butyl ester. LC-MS (ESI) m/z: 293.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ7.97-7.94 (m, 3H), 7.62 (d, J=2.0 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.17 (ddd, J=8.9, 7.2, 1.9 Hz, 2H), 4.01 (dd, J=9.7, 5.8 Hz, 4H), 3.93 (p, J=6.8 Hz, 1H), 3.22 (d,J＝5.3Hz,12H),2.23(td,J＝7.1,3.9Hz,2H),1.81(q,J＝7.8Hz,2H),1.69(q,J＝7.3Hz,2H),1.12(d,J＝6.6Hz,3H).
实施例220
Embodiment 220
合成路线
Synthetic route
步骤一：化合物220-1的合成Step 1: Synthesis of compound 220-1
室温下，将化合物162-2(40mg，0.14mmol)、3-溴甲基环丁酮(27mg，0.16mmol)溶到甲醇(1mL)溶液中，然后加入一滴醋酸，室温搅拌10分钟，向反应液中加入氰基硼氢化钠(58mg，0.28mmol)。反应结束后，反应液经减压浓缩，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝1/10)纯化，得到化合物220-1的粗品，41mg，为淡黄色固体。LC-MS(ESI)m/z:439[M+H]+.At room temperature, compound 162-2 (40 mg, 0.14 mmol) and 3-bromomethylcyclobutanone (27 mg, 0.16 mmol) were dissolved in a methanol (1 mL) solution, and then a drop of acetic acid was added. The mixture was stirred at room temperature for 10 minutes, and sodium cyanoborohydride (58 mg, 0.28 mmol) was added to the reaction solution. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography column (eluent: methanol/dichloromethane = 1/10) to obtain a crude product of compound 220-1, 41 mg, as a light yellow solid. LC-MS (ESI) m/z: 439 [M+H] + .
步骤二：化合物220的合成Step 2: Synthesis of compound 220
室温下，将化合物220-1(41mg，0.094mmol)、化合物123-2(21mg，0.094mmol)和碳酸铯(92mg，0.28mmol)溶到N,N-二甲基甲酰胺(1.5mL)中，加热到120℃，搅拌过夜。待反应液冷却至室温，用乙酸乙酯(5mL×3)和水(5mL)萃取，合并有机相，饱和食盐水洗涤(5mL×2),无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝1/10)纯化，得到标题化合物的粗品，再经制备液相色谱纯化，制备液冷冻干燥，得到化合物220，3.5mg，为白色固体，收率5.4％。LC-MS(ESI)m/z:291.6[M/2+H]+.At room temperature, compound 220-1 (41 mg, 0.094 mmol), compound 123-2 (21 mg, 0.094 mmol) and cesium carbonate (92 mg, 0.28 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), heated to 120°C and stirred overnight. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate (5 mL×3) and water (5 mL), the organic phases were combined, washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: methanol/dichloromethane=1/10) to obtain a crude product of the title compound, which was then purified by preparative liquid chromatography. The preparative solution was freeze-dried to obtain compound 220, 3.5 mg, as a white solid, with a yield of 5.4%. LC-MS (ESI) m/z: 291.6 [M/2+H] + .
实施例221
Embodiment 221
合成方法Synthesis method
化合物221的合成方法参照实施例102。区别在于把步骤五中的101-3替换为1-((2- 溴噻唑-5-基)甲基)-7-环丙基-4-(二甲胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:316.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.89(d,J＝8.7Hz,1H),7.82(d,2H),7.41(s,1H),7.30(d,J＝1.6Hz,1H),7.19(dd,J＝8.7,1.8Hz,1H),6.84(dd,J＝8.4,1.5Hz,1H),5.35-5.25(m,2H),4.21-4.12(m,1H),4.00-3.84(m,2H),3.70(d,J＝13.2Hz,1H),3.21(s,6H),3.21(s,6H),3.16-3.06(m,1H),2.83-2.70(m,1H),2.13-2.04(m,1H),1.77-1.72(m,2H),1.11-1.03(m,2H),0.88-0.82(m,2H).The synthesis method of compound 221 is similar to that of Example 102. The difference is that 101-3 in step 5 is replaced by 1-((2- LC-MS (ESI) m/z: 316.1 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ7.89 (d, J=8.7 Hz, 1H), 7.82 (d, 2H), 7.41 (s, 1H), 7.30 (d, J=1.6 Hz, 1H), 7.19 (dd, J=8.7, 1.8 Hz, 1H), 6.84 (dd, J=8.4, 1.5 Hz, 1H), 5.35-5.25 (m, 2H), 4.21-4.12 (m, 1H), 4.00-3 .84(m,2H),3.70(d,J＝13.2Hz,1H),3.21(s,6H),3.21(s,6H),3.16-3.06(m,1H),2.83-2.70(m,1H),2.13-2.04(m,1H),1.77-1.72(m,2H),1.11-1 .03(m,2H),0.88-0.82(m,2H).
实施例222
Embodiment 222
合成方法Synthesis method
化合物222的合成方法参照实施例168。区别在于把步骤一中的2,4-二氯吡啶并[2,3-d]嘧啶替换为2,4-二氯喹啉。LC-MS(ESI)m/z:295.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.89(d,J＝8.7Hz,1H),7.84(dd,J＝8.1,1.5Hz,1H),7.81-7.78(m,2H),7.59(ddd,J＝8.6,7.2,1.5Hz,1H),7.41(s,1H),7.27-7.23(m,1H),7.19(dd,J＝8.7,1.8Hz,1H),5.94(s,1H),5.51-5.36(m,2H),4.21-4.13(m,1H),3.94-3.88(m,2H),3.76-3.69(m,1H),3.25-3.17(m,7H),3.13-3.05(m,1H),2.86(s,6H),2.79-2.69(m,1H),1.76-1.72(m,2H).The synthesis method of compound 222 refers to Example 168. The difference is that 2,4-dichloropyrido[2,3-d]pyrimidine in step 1 is replaced by 2,4-dichloroquinoline. LC-MS (ESI) m/z: 295.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ7.89 (d, J＝8.7 Hz, 1H), 7.84 (dd, J＝8.1, 1.5 Hz, 1H), 7.81-7.78 (m, 2H), 7.59 (ddd, J＝8.6, 7.2, 1.5 Hz, 1H), 7.41 (s, 1H), 7.27-7.23 (m, 1H), 7.19 (dd, J＝8.7, 1.8 Hz, 1H), 5.94 (s,1H),5.51-5.36(m,2H),4.21-4.13(m,1H),3.94-3.88(m,2H),3.76-3.69(m,1H),3.25-3.17(m,7H),3.13-3.05(m,1H),2.86(s,6H),2.79-2.6 9(m,1H),1.76-1.72(m,2H).
实施例223
Embodiment 223
合成方法Synthesis method
化合物223的合成方法参照实施例123。区别在于把步骤一中的二甲胺替换为N-甲基环丙胺，步骤五中的2-氨基-6-溴吡啶替换为4-氨基-2-溴吡啶，步骤七中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:323.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.39(d,J＝8.9Hz,1H),8.22(d,J＝5.6Hz,1H),7.98(d,J＝8.8Hz,1H),7.59(s,1H),7.23(dd,J＝8.8,2.1Hz,1H),7.19(dd,J＝8.8,1.9Hz,2H),7.17(d,1H),6.66(s,1H),4.28-4.17(m,2H),3.70(q,J＝7.0Hz,2H),3.57(d,J＝32.7Hz,2H),3.47-3.42(m,2H),3.30(s,3H),3.17(s,3H),2.83-2.73(m,1H),2.00-1.97(m,2H),1.88-1.80(m,1H),1.47(q,J＝7.2Hz,2H),1.31(t,J＝7.0Hz,3H),0.86(td,J＝6.8,3.2Hz,2H).The synthesis method of compound 223 is similar to that of Example 123. The difference is that the dimethylamine in step 1 is replaced by N-methylcyclopropylamine, the 2-amino-6-bromopyridine in step 5 is replaced by 4-amino-2-bromopyridine, and the dimethylamine in step 7 is replaced by methylethylamine. LC-MS (ESI) m/z: 323.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.39(d,J＝8.9Hz,1H),8.22(d,J＝5.6Hz,1H),7.98(d,J＝8.8Hz,1H),7.59(s,1H),7.23(dd,J＝8.8,2.1Hz,1H),7.19(dd,J＝8.8,1.9Hz,2H),7.17(d,1H), 6.66(s,1H),4.28-4.17(m,2H),3.70(q,J＝7.0Hz, 2H),3.57(d,J＝32.7Hz,2H),3.47-3.42(m,2H),3.30(s,3H),3.17(s,3H),2.83-2.73(m,1H),2.00-1.97(m,2H),1.88-1.80(m,1H),1.47(q,J＝7.2 Hz,2H),1.31(t,J＝7.0Hz,3H),0.86(td,J＝6.8,3.2Hz,2H).
实施例224
Embodiment 224
合成方法Synthesis method
化合物224的合成方法参照实施例162。区别在于把步骤一中的123-2替换为101-2，步骤三中的123-7替换为1-(4-溴吡啶-2-基)-7-氯-4-(二甲胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:303.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.20(d,J＝6.0Hz,1H),7.98(dd,2H),7.73(d,1H),7.27-7.18(m,2H),6.59(d,J＝78.8Hz,2H),6.47(s,1H),4.45(dd,J＝16.5,7.5Hz,2H),4.12-3.99(m,2H),3.94-3.84(m,2H),3.71(q,J＝7.0Hz,2H),3.31(s,3H),3.24(s,6H),1.49-1.44(m,1H),1.31(t,3H).The synthesis method of compound 224 refers to Example 162, except that 123-2 in step 1 is replaced by 101-2, and 123-7 in step 3 is replaced by 1-(4-bromopyridin-2-yl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 303.1[M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ8.20 (d, J = 6.0 Hz, 1H), 7.98 (dd, 2H), 7.73 (d, 1H), 7.27-7.18 (m, 2H), 6.59 (d, J = 78.8Hz, 2H), 6. 47(s,1H),4.45(dd,J＝16.5,7.5Hz,2H),4.12-3.99(m,2H),3.94-3.84(m,2H),3.71(q,J＝7.0Hz,2H),3.31(s,3H),3.24(s,6H),1.49-1.44(m,1H),1.3 1(t,3H).
实施例225
Embodiment 225
合成路线
Synthetic route
步骤一：化合物225-1的合成Step 1: Synthesis of compound 225-1
室温下，将7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(123-2，1g，4.46mmol)和2-(2-溴乙基)环氧乙烷(2g，13.2mmol)溶于10mL干燥的DMF中，加入碳酸铯(4.4g，13.4mmol)，室温搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相，浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到320mg化合物225-1，收率24％。LC-MS(ESI)m/z:294[M+H]+.At room temperature, 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2, 1 g, 4.46 mmol) and 2-(2-bromoethyl)oxirane (2 g, 13.2 mmol) were dissolved in 10 mL of dry DMF, cesium carbonate (4.4 g, 13.4 mmol) was added, and stirred at room temperature overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine, concentrated, and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 320 mg of compound 225-1, with a yield of 24%. LC-MS (ESI) m/z: 294 [M+H] + .
步骤二：化合物225的合成Step 2: Synthesis of compound 225
室温下，将化合物225-1(40mg，0.137mmol)和176-2(40mg，0.142mmol)溶于2mL DMF中，升温至80℃过夜。LC-MS监测有产物生成。将反应液湿法上样经中压flash纯化后得20mg粗品，后经高压制备液相分离纯化得5mg化合物225，收率24％。LC-MS(ESI)m/z:287.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.99(dd,2H),7.59(d,1H),7.54(d,1H),7.23(dd,J＝8.8Hz,2H),4.22-4.05(m,2H),3.85-3.72(m,1H),3.23(d,12H),3.00-2.85(m,4H),1.95-1.88(m,2H),184-1.72(m,2H),1.50-1.42(m,2H).At room temperature, compounds 225-1 (40 mg, 0.137 mmol) and 176-2 (40 mg, 0.142 mmol) were dissolved in 2 mL of DMF and heated to 80 °C overnight. LC-MS monitored the formation of products. The reaction solution was wet loaded and purified by medium pressure flash to obtain 20 mg of crude product, which was then purified by high pressure preparative liquid phase separation to obtain 5 mg of compound 225, with a yield of 24%. LC-MS(ESI)m/z:287.6[M/2+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ7.99(dd,2H),7.59(d,1H),7.54(d,1H),7.23(dd,J＝8.8Hz,2H),4.22-4.05(m,2H),3.85-3.72 (m,1H),3.23(d,12H),3.00-2.85(m,4H),1.95-1.88(m,2H),184-1.72(m,2H),1.50-1.42(m,2H).
实施例226
Embodiment 226
合成路线
Synthetic route
步骤一：化合物226-1的合成Step 1: Synthesis of compound 226-1
室温下，将7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(123-2，300mg，1.34mmol)和2-(氯甲基)环氧乙烷(400mg，4.32mmol)溶于5mL干燥的DMF中，加入碳酸铯(1.3g，3.96mmol)，升温至50℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-30％,10min)得到180mg化合物226-1，收率48％。LC-MS(ESI)m/z:280[M+H]+.At room temperature, 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2, 300 mg, 1.34 mmol) and 2-(chloromethyl)oxirane (400 mg, 4.32 mmol) were dissolved in 5 mL of dry DMF, cesium carbonate (1.3 g, 3.96 mmol) was added, and the temperature was raised to 50 ° C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine and concentrated and separated by flash chromatography (DCM: MeOH, 0-30%, 10 min) to obtain 180 mg of compound 226-1, with a yield of 48%. LC-MS (ESI) m/z: 280 [M + H] + .
步骤二：化合物226-2的合成Step 2: Synthesis of compound 226-2
室温下，将化合物226-1(180mg，0.643mmol)溶于5mL氨水中，室温搅拌1小时。LC-MS监测反应完全。浓缩后经快速色谱柱层析分离(DCM:MeOH,0-30％,10min)得到80mg化合物226-2，收率42％。LC-MS(ESI)m/z:297[M+H]+.At room temperature, compound 226-1 (180 mg, 0.643 mmol) was dissolved in 5 mL of ammonia water and stirred at room temperature for 1 hour. LC-MS monitored the reaction to be complete. After concentration, the product was separated by flash chromatography (DCM: MeOH, 0-30%, 10 min) to obtain 80 mg of compound 226-2 with a yield of 42%. LC-MS (ESI) m/z: 297 [M+H] + .
步骤三：化合物226的合成Step 3: Synthesis of compound 226
室温下，将4-(7-氯-4-(二甲基氨基)-2-氧代喹唑啉-1(2H)-基)丁酸(30mg，0.0971mmol)、EDCI(30mg，0.156mmol)、HOBT(25mg，0.185mmol)和DIEA(40mg，0.310mmol)溶于1mL DMF中，加入化合物226-2(30mg，0.101mmol)，保持室温反应过夜。LC-MS监测有产物生成。将反应液湿法上样经中压flash纯化后得20mg粗品，后经高压制备液相分离纯化得4mg化合物，收率8％。LC-MS(ESI)m/z:294.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.98(d,J＝8.8Hz,2H),7.63(d,J＝2.0Hz,2H),7.21(d,J＝2.0Hz,2H),4.21-4.18(m,4H),4.09-4.07(m,2H),3.21(s,12H),1.88-1.85(m,2H),1.47-1.45(m,2H).At room temperature, 4-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)butanoic acid (30 mg, 0.0971 mmol), EDCI (30 mg, 0.156 mmol), HOBT (25 mg, 0.185 mmol) and DIEA (40 mg, 0.310 mmol) were dissolved in 1 mL of DMF, and compound 226-2 (30 mg, 0.101 mmol) was added, and the reaction was kept at room temperature overnight. LC-MS monitoring showed that the product was generated. The reaction solution was wet loaded and purified by medium pressure flash to obtain 20 mg of crude product, and then purified by high pressure preparative liquid phase separation to obtain 4 mg of compound, with a yield of 8%. LC-MS (ESI) m/z: 294.6 [M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ7.98 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 2.0 Hz, 2H), 7.21 (d, J = 2.0 Hz, 2H), 4.21-4.18 (m, 4H), 4.09- 4.07(m,2H),3.21(s,12H),1.88-1.85(m,2H),1.47-1.45(m,2H).
实施例227
Embodiment 227
合成路线
Synthetic route
化合物227的合成方法参照实施例207。LC-MS(ESI)m/z:301.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.09(t,J＝5.7Hz,1H),7.95(dd,J＝12.9,8.8,1.0Hz,2H),7.60(d,J＝2.0Hz,1H),7.47(d,J＝1.6Hz,1H),7.18(qd,J＝8.7,4.6,2.0Hz,2H),4.34(dd,J＝15.0,8.4Hz,1H),4.10(dd,J＝14.6,4.3Hz,1H),4.04(dd,J＝9.2,6.3Hz,2H),3.95(p,1H),3.23(s,6H),3.22(s,6H),3.18-3.14(m,5H),2.43(dd,J＝14.6,6.9Hz,1H),2.33(dd,J＝14.6,5.5Hz,1H),1.71(p,2H).The synthesis method of compound 227 refers to Example 207. LC-MS (ESI) m/z: 301.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ8.09 (t, J=5.7 Hz, 1H), 7.95 (dd, J=12.9, 8.8, 1.0 Hz, 2H), 7.60 (d, J=2.0 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.18 (qd, J=8.7, 4.6, 2.0 Hz, 2H), 4.34 (dd, J=15.0, 8.4 Hz, 1H), 4.10 (dd, J=13.3, 13.9 Hz, 2H). ＝14.6,4.3Hz,1H),4.04(dd,J＝9.2,6.3Hz,2H),3.95(p,1H),3.23(s,6H),3.22(s,6H),3.18-3.14(m,5H),2.43(dd,J＝14.6,6.9Hz,1H),2.33(dd,J＝14. 6,5.5Hz,1H),1.71(p,2H).
实施例228
Embodiment 228
合成方法Synthesis method
化合物228的合成方法参照实施例162。区别在于把步骤一中的123-2替换为101-2，步骤三中的123-7替换为1-(4-溴吡啶-2-基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:310.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.17(d,J＝5.7Hz,1H),7.97(d,J＝8.8Hz,1H),7.90(d,J＝8.8Hz,1H),7.70(d,J＝1.9Hz,1H),7.23(d,J＝1.9Hz,1H),7.20(d,J＝2.1Hz,1H),6.48(dd,J＝5.7,2.2Hz,1H),6.40(dd,J＝6.4,2.2Hz,2H),4.46(d,J＝7.4Hz,2H),4.00(t,J＝8.1Hz,2H),3.88–3.82(m,2H),3.70(q,J＝6.9Hz,2H),3.63(q,J＝7.1Hz,2H),3.30(s,3H),3.22(s,3H),3.19-3.14(m,1H),1.47(q,J＝7.2Hz,6H).The synthesis method of compound 228 is similar to that of Example 162. The difference is that 123-2 in step 1 is replaced by 101-2, and 123-7 in step 3 is replaced by 1-(4-bromopyridin-2-yl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 310.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.17(d,J＝5.7Hz,1H),7.97(d,J＝8.8Hz,1H),7.90(d,J＝8.8Hz,1H),7.70(d,J＝1.9Hz,1H),7.23(d,J＝1.9Hz,1H),7.20(d,J＝2.1Hz,1H),6.48(dd,J＝5.7 ,2.2Hz,1H),6.40(dd,J＝6.4,2. 2Hz,2H),4.46(d,J＝7.4Hz,2H),4.00(t,J＝8.1Hz,2H),3.88–3.82(m,2H),3.70(q,J＝6.9Hz,2H),3.63(q,J＝7.1Hz,2H),3.30(s,3H),3.22(s,3H),3.19- 3.14(m,1H),1.47(q,J＝7.2Hz,6H).
实施例229
Embodiment 229
合成路线
Synthetic route
步骤一：化合物229-1的合成Step 1: Synthesis of compound 229-1
将1-(Boc-氨基)环丙基甲醇(2.0g，9.95mmol)溶解在20mL二氯甲烷中，降温至0℃后加入四溴化碳(5.0g，14.93mmol)和三苯基磷(4.0g，14.93mmol)，反应混合液在室温下搅拌30min，TLC监测完全反应。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-50％，15min)得到化合物229-1(2.0g，淡黄色油状液体)，产率76％。LC-MS(ESI)m/z:264[M+H]+.1-(Boc-amino)cyclopropylmethanol (2.0 g, 9.95 mmol) was dissolved in 20 mL of dichloromethane, and carbon tetrabromide (5.0 g, 14.93 mmol) and triphenylphosphine (4.0 g, 14.93 mmol) were added after cooling to 0°C. The reaction mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 0-50%, 15 min) to obtain compound 229-1 (2.0 g, light yellow oily liquid) with a yield of 76%. LC-MS (ESI) m/z: 264 [M+H] + .
步骤二：化合物229-2的合成Step 2: Synthesis of compound 229-2
室温下，将化合物123-2(1.0g，4.48mmol)溶解在10mL N,N-二甲基甲酰胺中，向其中加入化合物229-1(1.4g，5.38mmol)和碳酸钾(1.9g，13.44mmol)，室温下搅拌16h。TLC监测完全反应，反应体系中加水，用乙酸乙酯(30mL x 3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物229-2(350mg，白色固体)，产率20％。LC-MS(ESI)m/z:409[M+H]+.At room temperature, compound 123-2 (1.0 g, 4.48 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and compound 229-1 (1.4 g, 5.38 mmol) and potassium carbonate (1.9 g, 13.44 mmol) were added thereto, and stirred at room temperature for 16 h. TLC monitored the complete reaction, water was added to the reaction system, extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 229-2 (350 mg, white solid), with a yield of 20%. LC-MS (ESI) m/z: 409 [M + H] + .
步骤三：化合物229-3的合成Step 3: Synthesis of compound 229-3
室温下将化合物229-2(350mg，0.86mmol)溶解在4mL 1,4-二氧六环中，向其中加入盐酸-二氧六环溶液4mL，室温下搅拌30min。TLC监测完全反应，浓缩后得到化合物229-3的盐酸盐(265mg，白色固体)，产率100％。LC-MS(ESI)m/z:309[M+H]+.Compound 229-2 (350 mg, 0.86 mmol) was dissolved in 4 mL of 1,4-dioxane at room temperature, 4 mL of hydrochloric acid-dioxane solution was added thereto, and stirred at room temperature for 30 min. TLC monitored the complete reaction, and after concentration, the hydrochloride of compound 229-3 (265 mg, white solid) was obtained with a yield of 100%. LC-MS (ESI) m/z: 309 [M+H] + .
步骤四：化合物229-4的合成Step 4: Synthesis of compound 229-4
室温下，将化合物123-2(1.0g，4.46mmol)溶解在10mL N,N-二甲基甲酰胺中，向其中加入4-溴丁-2-烯酸乙酯(1.3g，6.70mmol)和碳酸钾(1.8g，13.38mmol)，100℃下搅拌16h。TLC监测完全反应，反应体系中加水，用乙酸乙酯(30mL x 3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物229-4(517mg，白色固体)，产率35％。LC-MS(ESI)m/z:336[M+H]+.At room temperature, compound 123-2 (1.0 g, 4.46 mmol) was dissolved in 10 mL of N, N-dimethylformamide, 4-bromobut-2-enoic acid ethyl ester (1.3 g, 6.70 mmol) and potassium carbonate (1.8 g, 13.38 mmol) were added thereto, and stirred at 100 ° C for 16 h. TLC monitored the complete reaction, water was added to the reaction system, extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 229-4 (517 mg, white solid) with a yield of 35%. LC-MS (ESI) m/z: 336 [M + H] + .
步骤五：化合物229-5的合成Step 5: Synthesis of compound 229-5
室温下将化合物229-4(517mg，1.54mmol)溶解在5mL甲醇中，向其中加入水5mL后加入氢氧化锂(363mg，7.72mmol)，室温下搅拌2h。TLC监测完全反应， 浓缩除去体系中的甲醇后用稀盐酸(1M)调节pH至4。粗产品通过硅胶柱层析(二氯甲烷：甲醇，0-10％，10min)后得到化合物229-5(306mg，白色固体)，产率65％。LC-MS(ESI)m/z:308[M+H]+.Compound 229-4 (517 mg, 1.54 mmol) was dissolved in 5 mL of methanol at room temperature, 5 mL of water was added, and then lithium hydroxide (363 mg, 7.72 mmol) was added, and stirred at room temperature for 2 h. The reaction was monitored by TLC. After the methanol in the system was removed by concentration, the pH was adjusted to 4 with dilute hydrochloric acid (1 M). The crude product was chromatographed on a silica gel column (dichloromethane:methanol, 0-10%, 10 min) to give compound 229-5 (306 mg, white solid) with a yield of 65%. LC-MS (ESI) m/z: 308 [M+H] + .
步骤六：化合物229的合成Step 6: Synthesis of compound 229
室温下将化合物229-5(40mg，0.13mmol)溶解在1mL N,N-二甲基甲酰胺中，向其中加入DIEA(84mg，0.65mmol)，室温下搅拌20min后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(50mg，0.13mmol)和化合物229-3(40mg，0.13mmol)。反应混合液在室温下搅拌1h。LC-MS检测完全反应。经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，HPLC制备纯化后得到化合物229(1.50mg，白色固体)，产率1.93％。LC-MS(ESI)m/z:298.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.15(t,J＝5.7Hz,1H),8.03(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.37(d,J＝2.0Hz,1H),7.35(d,J＝2.0Hz,1H),7.23(dd,J＝8.8,2.0Hz,1H),7.14(dd,J＝8.8,1.9Hz,1H),6.73(dt,J＝15.6,4.2Hz,1H),5.81(dt,J＝15.5,1.9Hz,1H),4.86(d,2H),4.18(s,2H),3.28(s,6H),3.26(s,1H),3.23(s,1H),3.22(s,6H),3.06(d,J＝5.6Hz,2H),1.47(q,J＝7.2Hz,1H),1.29(q,J＝6.3Hz,1H).Compound 229-5 (40 mg, 0.13 mmol) was dissolved in 1 mL of N,N-dimethylformamide at room temperature, DIEA (84 mg, 0.65 mmol) was added thereto, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (50 mg, 0.13 mmol) and compound 229-3 (40 mg, 0.13 mmol) were added after stirring at room temperature for 20 min. The reaction mixture was stirred at room temperature for 1 h. LC-MS detected the complete reaction. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 229 (1.50 mg, white solid) was obtained after HPLC preparation and purification, with a yield of 1.93%. LC-MS (ESI) m/z: 298.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.15(t,J＝5.7Hz,1H),8.03(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.37(d,J＝2.0Hz,1H),7.35(d,J＝2.0Hz,1H),7.23(dd,J＝8.8,2.0Hz,1H),7.14(dd,J ＝8.8,1.9Hz,1H),6.73(dt,J＝15.6 ,4.2Hz,1H),5.81(dt,J＝15.5,1.9Hz,1H),4.86(d,2H),4.18(s,2H),3.28(s,6H),3.26(s,1H),3.23(s,1H),3.22(s,6H),3.06(d,J＝5.6Hz,2H),1.4 7(q,J＝7.2Hz,1H),1.29(q,J＝6.3Hz,1H).
实施例230
Embodiment 230
合成路线
Synthetic route
步骤一：化合物230-1的合成Step 1: Synthesis of compound 230-1
室温下，将化合物229-1(1.0g，4.48mmol)溶解在10mL N,N-二甲基甲酰胺中，向其中加入化合物1(1.4g，5.38mmol)和碳酸钾(1.9g，13.44mmol)，室温下搅拌16h。TLC监测完全反应，反应体系中加水，用乙酸乙酯(30mL x 3)萃取，氯化钠溶液洗涤有机相。分离后的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物230-1(392mg，白色固体)，产率22％。LC-MS(ESI)m/z:407[M+H]+. At room temperature, compound 229-1 (1.0 g, 4.48 mmol) was dissolved in 10 mL of N, N-dimethylformamide, compound 1 (1.4 g, 5.38 mmol) and potassium carbonate (1.9 g, 13.44 mmol) were added thereto, and stirred at room temperature for 16 h. TLC monitored the complete reaction, water was added to the reaction system, extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 230-1 (392 mg, white solid) with a yield of 22%. LC-MS (ESI) m/z: 407 [M + H] + .
步骤二：化合物230-2的合成Step 2: Synthesis of compound 230-2
室温下将化合物230-1(392mg，0.97mmol)溶解在4mL 1,4-二氧六环中，向其中加入盐酸-二氧六环溶液4mL，室温下搅拌30min。TLC监测完全反应，浓缩后得到化合物230-2的盐酸盐(271mg，白色固体)，产率100％。LC-MS(ESI)m/z:307[M+H]+.Compound 230-1 (392 mg, 0.97 mmol) was dissolved in 4 mL of 1,4-dioxane at room temperature, 4 mL of hydrochloric acid-dioxane solution was added thereto, and stirred at room temperature for 30 min. TLC monitored the complete reaction, and after concentration, the hydrochloride of compound 230-2 (271 mg, white solid) was obtained with a yield of 100%. LC-MS (ESI) m/z: 307 [M+H] + .
步骤三：化合物230的合成Step 3: Synthesis of compound 230
室温下将化合物229-5(40mg，0.13mmol)溶解在1mL N,N-二甲基甲酰胺中，向其中加入DIEA(84mg，0.65mmol)，室温下搅拌20min后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(50mg，0.13mmol)和化合物230-2(40mg，0.13mmol)。混合液在室温下搅拌1h。LC-MS检测完全反应。经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，HPLC制备纯化后得到化合物230(13.51mg，白色固体)，产率17.4％。LC-MS(ESI)m/z:298.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.11(d,J＝9.0Hz,1H),8.03-7.99(m,2H),7.49(d,J＝2.2Hz,1H),7.33(d,J＝2.0Hz,1H),7.26(dd,J＝9.0,2.3Hz,1H),7.21(dd,J＝8.6,2.1Hz,2H),5.74(d,J＝15.6Hz,1H),4.82(d,2H),4.09(s,2H),3.30(s,6H),3.26(s,6H),3.19(d,J＝5.8Hz,2H),1.46(q,2H),0.52(d,J＝5.2Hz,2H).Compound 229-5 (40 mg, 0.13 mmol) was dissolved in 1 mL of N,N-dimethylformamide at room temperature, DIEA (84 mg, 0.65 mmol) was added thereto, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (50 mg, 0.13 mmol) and compound 230-2 (40 mg, 0.13 mmol) were added after stirring at room temperature for 20 min. The mixture was stirred at room temperature for 1 h. LC-MS detected the complete reaction. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 230 (13.51 mg, white solid) was obtained after HPLC preparation and purification, with a yield of 17.4%. LC-MS (ESI) m/z: 298.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.11(d,J＝9.0Hz,1H),8.03-7.99(m,2H),7.49(d,J＝2.2Hz,1H),7.33(d,J＝2.0Hz,1H),7.26(dd,J＝9.0,2.3Hz,1H),7.21(dd,J＝8.6,2.1Hz,2H),5.74(d ,J＝15.6Hz,1H),4.82(d,2H),4.09(s,2H),3.30(s,6H),3.26(s,6H),3.19(d,J＝5.8Hz,2H),1.46(q,2H),0.52(d,J＝5.2Hz,2H).
实施例231
Embodiment 231
合成方法Synthesis method
化合物231的合成方法参照实施例229。区别在于把步骤四中的4-溴丁-2-烯酸乙酯替换为4-溴丁酸乙酯。LC-MS(ESI)m/z:299.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.06(t,J＝5.8Hz,1H),7.93(d,J＝8.9Hz,1H),7.82(d,J＝8.7Hz,1H),7.35(d,J＝2.1Hz,1H),7.28(s,1H),7.15-7.09(m,1H),7.04(dd,J＝8.7,2.0Hz,1H),4.19(s,2H),3.81(t,2H),3.27(s,6H),3.20(s,6H),2.24(t,J＝6.7Hz,2H),1.69(p,J＝6.8Hz,2H),1.32-1.21(m,2H),0.59(d,J＝3.2Hz,4H).The synthesis method of compound 231 is similar to that of Example 229. The difference is that 4-bromobut-2-enoic acid ethyl ester in step 4 is replaced by 4-bromobutyric acid ethyl ester. LC-MS (ESI) m/z: 299.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.06(t,J＝5.8Hz,1H),7.93(d,J＝8.9Hz,1H),7.82(d,J＝8.7Hz,1H),7.35(d,J＝2.1Hz,1H),7.28(s,1H),7.15-7.09(m,1H),7.04(dd,J＝8.7,2.0Hz,1H) ,4.19(s,2H),3.81(t,2H),3.27(s,6H),3.20(s,6H),2.24(t,J＝6.7Hz,2H),1.69(p,J＝6.8Hz,2H),1.32-1.21(m,2H),0.59(d,J＝3.2Hz,4H).
实施例232
Embodiment 232
合成方法Synthesis method
化合物232的合成方法参照实施例230。LC-MS(ESI)m/z:299.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.11(t,J＝5.7Hz,1H),7.97(d,J＝8.8Hz,1H),7.93(d,J＝8.8Hz,1H),7.62(d,J＝2.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.19(dd,J＝8.8,2.0Hz,1H),7.16(dd,J＝8.8,2.0Hz,1H),4.24(s,2H),4.02(t,2H),3.23(s,12H),3.06(d,J＝5.6Hz,2H),2.28(t,J＝7.2Hz,2H),1.80(p,J＝7.3Hz,2H),0.45-0.37(m,4H). The synthesis method of compound 232 refers to Example 230. LC-MS (ESI) m/z: 299.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.11(t,J＝5.7Hz,1H),7.97(d,J＝8.8Hz,1H),7.93(d,J＝8.8Hz,1H),7.62(d,J＝2.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.19(dd,J＝8.8,2.0Hz,1H),7.16(dd,J ＝8.8,2.0Hz,1H),4.24(s,2H),4.02(t,2H),3.23(s,12H),3.06(d,J＝5.6Hz,2H),2.28(t,J＝7.2Hz,2H),1.80(p,J＝7.3Hz,2H),0.45-0.37(m,4H).
实施例233
Embodiment 233
合成方法Synthesis method
化合物233的合成方法参照实施例214。区别在于把步骤一中的150-2替换为7-氯-4-(二甲胺基)-1-(2-(甲胺基)乙基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:294.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.98(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.68(d,J＝2.0Hz,1H),7.46(d,J＝2.1Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),7.15(dd,J＝8.8,1.9Hz,1H),6.50(t,J＝5.6Hz,1H),4.11(t,J＝6.8Hz,2H),4.05(t,J＝7.3Hz,2H),3.41(t,J＝6.7Hz,2H),3.23(s,6H),3.19(s,6H),3.08(q,J＝6.6Hz,2H),2.82(s,3H),1.70(p,J＝7.0Hz,2H).The synthesis method of compound 233 refers to Example 214. The difference is that 150-2 in step 1 is replaced by 7-chloro-4-(dimethylamino)-1-(2-(methylamino)ethyl)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 294.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.98(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.68(d,J＝2.0Hz,1H),7.46(d,J＝2.1Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),7.15(dd,J＝8.8,1.9Hz,1H),6.50 (t,J＝5.6Hz,1H),4.11(t,J＝6.8Hz,2H),4.05(t,J＝7.3Hz,2H),3.41(t,J＝6.7Hz,2H),3.23(s,6H),3.19(s,6H),3.08(q,J＝6.6Hz,2H),2.82(s,3H),1. 70(p,J＝7.0Hz,2H).
实施例234
Embodiment 234
合成方法Synthesis method
化合物234的合成方法参照实施例214。区别在于把步骤一中的150-2替换为1-(2-氨基乙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:294.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝8.8Hz,1H),7.86(d,J＝8.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.49(d,J＝1.9Hz,1H),7.18(ddd,J＝15.4,8.8,1.9Hz,2H),6.29(t,J＝5.9Hz,1H),6.18(t,J＝5.8Hz,1H),4.02(q,J＝7.4Hz,4H),3.61(q,J＝7.0Hz,2H),3.23(s,6H),3.21-3.17(m,5H),3.08(q,J＝6.6Hz,2H),1.67(p,J＝7.1Hz,2H),1.26(t,J＝7.0Hz,3H).The synthesis method of compound 234 is similar to that of Example 214. The difference is that 150-2 in step 1 is replaced by 1-(2-aminoethyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 294.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.97(d,J＝8.8Hz,1H),7.86(d,J＝8.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.49(d,J＝1.9Hz,1H),7.18(ddd,J＝15.4,8.8,1.9Hz,2H),6.29(t,J＝5.9Hz,1H),6. 18(t,J＝5.8Hz,1H),4.02(q,J＝7.4Hz,4H),3.61(q,J＝7.0Hz,2H),3.23(s,6H),3.21-3.17(m,5H),3.08(q,J＝6.6Hz,2H),1.67(p,J＝7.1Hz,2H),1.26(t, J＝7.0Hz,3H).
实施例235
Embodiment 235
合成方法Synthesis method
化合物235的合成方法参照实施例214。区别在于把步骤一中的176-2替换为1-(2-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:294.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.93(d,J＝8.8Hz,1H),7.90(d,J＝8.8Hz,1H),7.79(s,1H),7.48(d,J＝2.0Hz,1H),7.15(dd,J＝8.7,1.9Hz,1H),6.67(s,2H),6.56(d,1H),4.03(t,J＝7.2Hz,4H),3.63(q,J＝7.1Hz,2H),3.21(s,6H),3.21(s,3H),3.08(q,J＝6.4Hz,2H),1.68(q,J＝7.1Hz,2H),1.47(q,J＝7.3Hz,2H),1.17(t,3H).The synthesis method of compound 235 refers to Example 214. The difference is that 176-2 in step 1 is replaced by 1-(2-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 294.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.93(d,J＝8.8Hz,1H),7.90(d,J＝8.8Hz,1H),7.79(s,1H),7.48(d,J＝2.0Hz,1H),7.15(dd,J＝8.7,1.9Hz,1H),6.67(s,2H),6.56(d,1H),4.03(t,J＝7. 2Hz, 4H), 3.63 (q, J = 7.1Hz, 2H), 3.21 (s, 6H), 3.21 (s, 3H), 3.08 (q, J = 6.4Hz, 2H), 1.68 (q, J = 7.1Hz, 2H), 1.47 (q, J = 7.3Hz, 2H), 1.17 (t, 3H).
实施例236
Embodiment 236
合成方法Synthesis method
化合物236的合成方法参照实施例214。区别在于把步骤一中的176-2替换为1-(2-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮，步骤一中的150-2替换为1-(2-氨基乙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:301.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.90(d,J＝8.8Hz,1H),7.86(d,J＝8.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.48(d,J＝2.0Hz,1H),7.21(dd,J＝8.7,1.9Hz,1H),7.16(dd,J＝8.8,1.9Hz,1H),6.26(t,1H),6.15(t,J＝5.8Hz,1H),4.02(q,J＝6.8Hz,4H),3.62(p,4H),3.21(s,3H),3.20(s,3H),3.08(q,J＝6.6Hz,2H),1.68(p,J＝7.0Hz,2H),1.47(q,J＝7.2Hz,2H),1.27(t,J＝7.1Hz,6H).The synthesis method of compound 236 refers to Example 214. The difference is that 176-2 in step 1 is replaced by 1-(2-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one, and 150-2 in step 1 is replaced by 1-(2-aminoethyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 301.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.90(d,J＝8.8Hz,1H),7.86(d,J＝8.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.48(d,J＝2.0Hz,1H),7.21(dd,J＝8.7,1.9Hz,1H),7.16(dd,J＝8.8,1.9Hz,1H),6.26 (t,1H),6.15( t,J＝5.8Hz,1H),4.02(q,J＝6.8Hz,4H),3.62(p,4H),3.21(s,3H),3.20(s,3H),3.08(q,J＝6.6Hz,2H),1.68(p,J＝7.0Hz,2H),1.47(q,J＝7.2Hz,2H),1.2 7(t,J＝7.1Hz,6H).
实施例237
Embodiment 237
合成方法Synthesis method
化合物237的合成方法参照实施例176。区别在于把步骤一中的123-2替换为101-2，步骤三中的173-2替换为(E)-4-(7-氯-4-(二甲胺基)-2-氧代喹唑啉-1(2H)-基)-2-丁烯酸。LC-MS(ESI)m/z:292.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.04(t,J＝5.5Hz,1H),8.01(d,J＝8.8Hz,1H),7.88(d,J＝8.8Hz,1H),7.43(d,J＝2.0Hz,1H),7.34(d,J＝2.0Hz,1H),7.24-7.15(m,2H),6.70(dt,J＝15.6,4.2Hz,1H),5.72(dt,1H),4.84(dd,J＝4.2,1.9Hz,2H),3.99(t,J＝7.6Hz,2H),3.61(q,J＝7.0Hz,2H),3.26(s,6H),3.19(s,3H),3.17-3.12(m,2H),1.67(p,J＝7.2Hz,2H),1.25(d,J＝4.7Hz,3H).The synthesis method of compound 237 is referred to Example 176. The difference is that 123-2 in step 1 is replaced by 101-2, and 173-2 in step 3 is replaced by (E)-4-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)-2-butenoic acid. LC-MS (ESI) m/z: 292.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.04(t,J＝5.5Hz,1H),8.01(d,J＝8.8Hz,1H),7.88(d,J＝8.8Hz,1H),7.43(d,J＝2.0Hz,1H),7.34(d,J＝2.0Hz,1H),7.24-7.15(m,2H),6.70(dt,J＝15.6 ,4.2Hz,1H),5.72(d t,1H),4.84(dd,J＝4.2,1.9Hz,2H),3.99(t,J＝7.6Hz,2H),3.61(q,J＝7.0Hz,2H),3.26(s,6H),3.19(s,3H),3.17-3.12(m,2H),1.67(p,J＝7.2Hz,2H),1. 25(d,J＝4.7Hz,3H).
实施例238
Embodiment 238
合成方法Synthesis method
化合物238的合成方法参照实施例214。区别是把步骤一中的176-2替换为7-氯-4-(二甲胺基)-1-(3-(甲胺基)丙基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:294.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝8.8Hz,1H),7.85(d,J＝8.8Hz,1H),7.73(d,J＝2.0Hz,1H),7.44(d,J＝2.1Hz,1H),7.20(dd,J＝8.7,2.0Hz,1H),7.06(dd,J＝8.7,1.9Hz,1H),6.70(t,J＝5.5Hz,1H),4.03(t,J＝6.8Hz,2H),3.93(t,J＝7.8Hz,2H),3.30-3.24(m,4H),3.23(s,6H),3.20(s,6H),2.78(s,3H),1.64(p,J＝7.7Hz,2H).The synthesis method of compound 238 refers to Example 214. The difference is that 176-2 in step 1 is replaced by 7-chloro-4-(dimethylamino)-1-(3-(methylamino)propyl)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 294.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.97(d,J＝8.8Hz,1H),7.85(d,J＝8.8Hz,1H),7.73(d,J＝2.0Hz,1H),7.44(d,J＝2.1Hz,1H),7.20(dd,J＝8.7,2.0Hz,1H),7.06(dd,J＝8.7,1.9Hz,1H),6.70 (t,J＝5.5Hz,1H),4.03(t,J＝6.8Hz,2H),3.93(t,J＝7.8Hz,2H),3.30-3.24(m,4H),3.23(s,6H),3.20(s,6H),2.78(s,3H),1.64(p,J＝7.7Hz,2H).
实施例239
Embodiment 239
合成方法Synthesis method
化合物239的合成方法参照实施例176。区别在于把步骤一中的N-Boc-溴丙胺替换为(3-溴丁基)氨基甲酸叔丁酯，步骤三中的173-2替换为(E)-4-(7-氯-4-(二甲胺基)-2-氧代喹唑啉-1(2H)-基)-2-丁烯酸。LC-MS(ESI)m/z:292.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.10(d,J＝9.0Hz,1H),8.01(d,J＝8.8Hz,1H),7.95(t,J＝5.5Hz,1H),7.48(d,J＝2.3Hz,1H),7.33(d,J＝2.0Hz,1H),7.25(dd,J＝8.9,2.3Hz,1H),7.21(dd,J＝8.8,2.0Hz,1H),6.67(dt,J＝15.5,4.2Hz,1H),5.67(d,J＝15.6Hz,1H),5.15(q,J＝6.2Hz,1H),4.83(d,2H),3.28(s,6H),3.26(s,6H),3.16(dq,J＝13.5,6.9Hz,2H),2.05-1.99(m,2H),1.80(dt,J＝14.0,6.8Hz,1H),1.69(dt,J＝13.2,6.5Hz,1H),1.46(t,J＝7.2Hz,1H).The synthesis method of compound 239 refers to Example 176. The difference is that N-Boc-bromopropylamine in step 1 is replaced by (3-bromobutyl)carbamic acid tert-butyl ester, and 173-2 in step 3 is replaced by (E)-4-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)-2-butenoic acid. LC-MS (ESI) m/z: 292.6 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.10(d,J＝9.0Hz,1H),8.01(d,J＝8.8Hz,1H),7.95(t,J＝5.5Hz,1H),7.48(d,J＝2.3Hz,1H),7.33(d,J＝2.0Hz,1H),7.25(dd,J＝8.9,2.3Hz,1H),7.21(dd,J ＝8.8,2.0Hz,1H),6.67(dt,J＝15.5,4.2Hz,1H),5.67(d ,J＝15.6Hz,1H),5.15(q,J＝6.2Hz,1H),4.83(d,2H),3.28(s,6H),3.26(s,6H),3.16(dq,J＝13.5,6.9Hz,2H),2.05-1.99(m,2H),1.80(dt,J＝14.0,6.8 Hz,1H),1.69(dt,J＝13.2,6.5Hz,1H),1.46(t,J＝7.2Hz,1H).
实施例240
Embodiment 240
合成方法Synthesis method
化合物240的合成方法参照实施例176。区别在于把步骤一中的N-Boc-溴丙胺替换为(3-(溴甲基)环丁基)氨基甲酸叔丁酯，步骤三中的173-2替换为(E)-4-(7-氯-4-(二甲胺基)-2-氧代喹唑啉-1(2H)-基)-2-丁烯酸。LC-MS(ESI)m/z:298.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.13(d,J＝7.8Hz,1H),8.01(d,J＝8.7Hz,1H),7.95(d,J＝8.8Hz,1H),7.42(d,J＝2.0Hz,1H),7.31(d,J＝2.0Hz,1H),7.22(dd,J＝8.7,2.0Hz,1H),7.18(dd,J＝8.7,1.9Hz,1H),6.70-6.62(m,1H),5.60(d,J＝15.6Hz,1H),5.33(t,J＝4.8Hz,1H),4.82(s,2H),4.10(d,J＝6.3Hz,2H),3.99(q,J＝8.2Hz,1H),3.27(s,6H),3.21(s,6H),2.22-2.15(m,2H),1.73-1.61(m,2H).The synthesis method of compound 240 refers to Example 176. The difference is that N-Boc-bromopropylamine in step 1 is replaced by tert-butyl (3-(bromomethyl)cyclobutyl)carbamate, and 173-2 in step 3 is replaced by (E)-4-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)-2-butenoic acid. LC-MS (ESI) m/z: 298.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.13(d,J＝7.8Hz,1H),8.01(d,J＝8.7Hz,1H),7.95(d,J＝8.8Hz,1H),7.42(d,J＝2.0Hz,1H),7.31(d,J＝2.0Hz,1H),7.22(dd,J＝8.7,2.0Hz,1H),7.18(dd,J＝ 8.7,1.9Hz,1H),6.70-6 .62(m,1H),5.60(d,J＝15.6Hz,1H),5.33(t,J＝4.8Hz,1H),4.82(s,2H),4.10(d,J＝6.3Hz,2H),3.99(q,J＝8.2Hz,1H),3.27(s,6H),3.21(s,6H),2.22-2 .15(m,2H),1.73-1.61(m,2H).
实施例241
Embodiment 241
合成方法Synthesis method
化合物241的合成方法参照实施例214。区别在于把步骤一中的176-2替换为7-氯-4-(二甲胺基)-1-(3-(甲胺基)丙基)喹唑啉-2(1H)-酮，步骤一中的150-2替换为7-氯-4-(二 甲胺基)-1-(2-(甲胺基)乙基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:301.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.96(d,J＝8.9Hz,1H),7.92(d,J＝8.4Hz,1H),7.71(d,J＝2.0Hz,1H),7.51(d,J＝2.0Hz,1H),7.17(ddd,J＝18.8,8.7,1.9Hz,2H),4.17(t,J＝7.0Hz,2H),4.00(t,J＝7.7Hz,2H),3.28(t,J＝7.0Hz,2H),3.22(s,6H),3.20(s,6H),3.14(t,J＝7.2Hz,2H),2.86(s,3H),2.70(s,3H),1.79-1.71(m,2H).The synthesis method of compound 241 refers to Example 214. The difference is that 176-2 in step 1 is replaced by 7-chloro-4-(dimethylamino)-1-(3-(methylamino)propyl)quinazolin-2(1H)-one, and 150-2 in step 1 is replaced by 7-chloro-4-(dimethylamino)-1-(3-(methylamino)propyl)quinazolin-2(1H)-one. 1H NMR (600MHz, DMSO- d 6 )δ7.96(d,J＝8.9Hz,1H),7.92(d,J＝8.4Hz,1H),7.71(d,J＝2.0Hz,1H),7.51(d,J＝2.0Hz,1H),7.17(ddd,J＝18.8,8.7,1.9Hz,2H),4.17(t,J＝7.0Hz,2H),4. 00(t,J＝7.7Hz,2H),3.28(t,J＝7.0Hz,2H),3.22(s,6H),3.20(s,6H),3.14(t,J＝7.2Hz,2H),2.86(s,3H),2.70(s,3H),1.79-1.71(m,2H).
实施例242
Embodiment 242
合成方法Synthesis method
化合物242的合成方法参照实施例176。区别在于把步骤一中的N-Boc-溴丙胺替换为(3-溴丙基)(甲基)甲酸叔丁酯，步骤三中的173-2替换为(E)-4-(7-氯-4-(二甲胺基)-2-氧代喹唑啉-1(2H)-基)-2-丁烯酸。LC-MS(ESI)m/z:292.6[M/2+H]+.The synthesis method of compound 242 refers to Example 176. The difference is that N-Boc-bromopropylamine in step 1 is replaced by (3-bromopropyl)(methyl)formic acid tert-butyl ester, and 173-2 in step 3 is replaced by (E)-4-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)-2-butenoic acid. LC-MS (ESI) m/z: 292.6 [M/2+H] + .
实施例243
Embodiment 243
合成方法Synthesis method
化合物243的合成方法参照实施例176。区别在于把步骤一中的N-Boc-溴丙胺替换为(3-溴丙基)(甲基)甲酸叔丁酯，步骤三中的173-2替换为(E)-4-(7-氯-4-(甲乙胺基)-2-氧代喹唑啉-1(2H)-基)-2-丁烯酸。LC-MS(ESI)m/z:299.6[M/2+H]+.The synthesis method of compound 243 is referred to Example 176. The difference is that N-Boc-bromopropylamine in step 1 is replaced by (3-bromopropyl)(methyl)formic acid tert-butyl ester, and 173-2 in step 3 is replaced by (E)-4-(7-chloro-4-(methylethylamino)-2-oxoquinazoline-1(2H)-yl)-2-butenoic acid. LC-MS (ESI) m/z: 299.6 [M/2+H] + .
实施例244
Embodiment 244
合成方法Synthesis method
化合物244的合成方法参照实施例225。区别在于把步骤一中的176-2替换为7-氯-4-(二甲胺基)-1-(3-(甲胺基)丙基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:294.6[M/2+H]+.The synthesis method of compound 244 refers to Example 225. The difference is that 176-2 in step 1 is replaced by 7-chloro-4-(dimethylamino)-1-(3-(methylamino)propyl)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 294.6 [M/2+H] + .
实施例245
Embodiment 245
合成方法Synthesis method
化合物245的合成方法参照实施例176。区别在于把步骤一中的123-2替换为101-2，步骤一中的N-Boc-溴丙胺替换为(3-溴丙基)(甲基)甲酸叔丁酯，步骤三中的173-2替换为(E)-4-(7-氯-4-(甲乙胺基)-2-氧代喹唑啉-1(2H)-基)-2-丁烯酸。LC-MS(ESI)m/z:306.6[M/2+H]+.The synthesis method of compound 245 is referred to Example 176. The difference is that 123-2 in step 1 is replaced by 101-2, N-Boc-bromopropylamine in step 1 is replaced by (3-bromopropyl)(methyl)formic acid tert-butyl ester, and 173-2 in step 3 is replaced by (E)-4-(7-chloro-4-(methylethylamino)-2-oxoquinazoline-1(2H)-yl)-2-butenoic acid. LC-MS (ESI) m/z: 306.6 [M/2+H] + .
实施例246
Embodiment 246
合成方法Synthesis method
化合物246的合成方法参照实施例176。区别在于把步骤一中的123-2替换为101-2，步骤三中的173-2替换为(E)-4-(7-氯-4-(甲乙胺基)-2-氧代喹唑啉-1(2H)-基)-2-丁烯酸。LC-MS(ESI)m/z:299.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.05(t,J＝5.6Hz,1H),7.93(d,J＝8.8Hz,1H),7.88(d,J＝8.8Hz,1H),7.43(d,J＝2.0Hz,1H),7.34(d,J＝2.1Hz,1H),7.20(ddd,J＝14.7,8.8,2.0Hz,2H),6.70(dt,J＝15.7,4.2Hz,1H),5.71(dt,J＝15.6,1.8Hz,1H),4.83(dd,J＝4.3,1.9Hz,2H),3.99(t,J＝7.6Hz,2H),3.63(dq,J＝21.0,7.0Hz,4H),3.24(s,3H),3.19(s,3H),3.15(t,J＝6.5Hz,2H),1.66(p,J＝7.2Hz,2H),1.25(t,J＝6.8Hz,6H).The synthesis method of compound 246 refers to Example 176. The difference is that 123-2 in step 1 is replaced by 101-2, and 173-2 in step 3 is replaced by (E)-4-(7-chloro-4-(methylethylamino)-2-oxoquinazolin-1(2H)-yl)-2-butenoic acid. LC-MS (ESI) m/z: 299.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.05(t,J＝5.6Hz,1H),7.93(d,J＝8.8Hz,1H),7.88(d,J＝8.8Hz,1H),7.43(d,J＝2.0Hz,1H),7.34(d,J＝2.1Hz,1H),7.20(ddd,J＝14.7,8.8,2.0Hz,2H),6. 70(dt,J＝15.7,4.2Hz,1H),5.71(dt,J＝ 15.6,1.8Hz,1H),4.83(dd,J＝4.3,1.9Hz,2H),3.99(t,J＝7.6Hz,2H),3.63(dq,J＝21.0,7.0Hz,4H),3.24(s,3H),3.19(s,3H),3.15(t,J＝6.5Hz,2H),1.66 (p,J＝7.2Hz,2H),1.25(t,J＝6.8Hz,6H).
实施例247
Embodiment 247
合成方法Synthesis method
化合物247的合成方法参照实施例176。区别在于把步骤三中的173-2替换为(E)-4-(7-氯-4-(甲乙胺基)-2-氧代喹唑啉-1(2H)-基)-2-丁烯酸。LC-MS(ESI)m/z:292.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.05(t,J＝5.6Hz,1H),7.94(dd,J＝8.8,5.9Hz,2H),7.43(d,J＝2.0Hz,1H),7.34(d,J＝2.1Hz,1H),7.22(dd,J＝8.8,2.0Hz,1H),7.17(dd,J＝8.7,2.0Hz,1H),6.70(dt,J＝15.5,4.1Hz,1H),5.71(dt,J＝15.5,1.9Hz,1H),4.83(dd,J＝4.2,1.9Hz,2H),3.99(t,J＝7.6Hz,2H),3.65(q,J＝7.0Hz,2H),3.24(s,3H),3.21(s,6H),3.17-3.11(m,2H),1.71-1.61(m,2H),1.28(t,J＝7.0Hz,3H).The synthesis method of compound 247 is similar to that of Example 176. The difference is that 173-2 in step 3 is replaced by (E)-4-(7-chloro-4-(methylethylamino)-2-oxoquinazolin-1(2H)-yl)-2-butenoic acid. LC-MS (ESI) m/z: 292.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.05(t,J＝5.6Hz,1H),7.94(dd,J＝8.8,5.9Hz,2H),7.43(d,J＝2.0Hz,1H),7.34(d,J＝2.1Hz,1H),7.22(dd,J＝8.8,2.0Hz,1H),7.17(dd,J＝8.7,2.0Hz,1H), 6.70(dt,J=15.5,4.1Hz,1H),5. 71(dt,J＝15.5,1.9Hz,1H),4.83(dd,J＝4.2,1.9Hz,2H),3.99(t,J＝7.6Hz,2H),3.65(q,J＝7.0Hz,2H),3.24(s,3H),3.21(s,6H),3.17-3.11(m,2H),1.7 1-1.61(m,2H),1.28(t,J=7.0Hz,3H).
实施例248
Embodiment 248
合成方法Synthesis method
化合物248的合成方法参照实施例176。区别在于把步骤一中的N-Boc-溴丙胺替换 为(1-(溴甲基)环丁基)氨基甲酸叔丁酯，步骤三中的173-2替换为(E)-4-(7-氯-4-(二甲胺基)-2-氧代喹唑啉-1(2H)-基)-2-丁烯酸。LC-MS(ESI)m/z:298.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.29(s,1H),8.01(d,J＝8.7Hz,1H),7.88(dd,J＝8.6,5.3Hz,1H),7.58(d,J＝2.0Hz,1H),7.25(d,J＝2.0Hz,1H),7.21(dd,J＝8.7,2.0Hz,1H),7.05(dd,J＝8.7,1.9Hz,1H),6.74(dt,J＝15.6,4.5Hz,1H),5.67(d,J＝15.6Hz,1H),4.82(s,2H),4.39(s,2H),3.26(s,6H),3.23(s,6H),2.20-2.11(m,2H),1.96-1.88(m,2H),1.49-1.41(m,2H).The synthesis method of compound 248 refers to Example 176. The difference is that N-Boc-bromopropylamine in step 1 is replaced For tert-butyl (1-(bromomethyl)cyclobutyl)carbamate, 173-2 in step 3 is replaced by (E)-4-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)-2-butenoic acid. LC-MS (ESI) m/z: 298.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.29 (s, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.88 (dd, J = 8.6, 5.3 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 8.7, 2.0 Hz, 1H), 7.05 (dd, J = 8.7, 1.9 Hz, 1 H),6.74(dt,J＝15.6,4.5Hz,1H),5.67(d,J＝15.6Hz,1H),4.82(s,2H),4.39(s,2H),3.26(s,6H),3.23(s,6H),2.20-2.11(m,2H),1.96-1.88(m,2H), 1.49-1.41(m,2H).
实施例249
Embodiment 249
合成方法Synthesis method
化合物249的合成方法参照实施例225。区别在于把步骤一中的176-2替换为7-氯-4-(甲乙胺基)-1-(3-(甲胺基)丙基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:301.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.90(d,J＝8.8Hz,1H),7.85(d,J＝8.8Hz,1H),7.53(d,J＝2.0Hz,1H),7.48(d,J＝2.0Hz,1H),7.14(dd,J＝8.7,2.0Hz,1H),7.08(dd,J＝8.7,2.0Hz,1H),4.23-4.13(m,1H),4.11-4.02(m,1H),4.00-3.88(m,2H),3.78-3.69(m,1H),3.66-3.56(m,2H),3.20(d,J＝1.8Hz,9H),2.46-2.32(m,4H),2.23(s,3H),1.91-1.81(m,1H),1.74-1.63(m,2H),1.61-1.54(m,1H),1.27(t,J＝7.0Hz,3H).The synthesis method of compound 249 refers to Example 225. The difference is that 176-2 in step 1 is replaced by 7-chloro-4-(methylethylamino)-1-(3-(methylamino)propyl)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 301.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.90(d,J＝8.8Hz,1H),7.85(d,J＝8.8Hz,1H),7.53(d,J＝2.0Hz,1H),7.48(d,J＝2.0Hz,1H),7.14(dd,J＝8.7,2.0Hz,1H),7.08(dd,J＝8.7,2.0Hz,1H),4.23 -4.13(m,1H),4.11-4.02(m,1H),4 .00-3.88(m,2H),3.78-3.69(m,1H),3.66-3.56(m,2H),3.20(d,J＝1.8Hz,9H),2.46-2.32(m,4H),2.23(s,3H),1.91-1.81(m,1H),1.74-1.63(m,2H ),1.61-1.54(m,1H),1.27(t,J=7.0Hz,3H).
实施例250
Embodiment 250
合成方法Synthesis method
化合物250的合成方法参照实施例176。区别在于把步骤一中的123-2替换为101-2，步骤一中的N-Boc-溴丙胺替换为(3-溴丙基)(甲基)氨基甲酸叔丁酯，步骤三中的173-2替换为(E)-4-(7-氯-4-(二甲胺基)-2-氧代喹唑啉-1(2H)-基)-2-丁烯酸。LC-MS(ESI)m/z:299.6[M/2+H]+.The synthesis method of compound 250 refers to Example 176. The difference is that 123-2 in step 1 is replaced by 101-2, N-Boc-bromopropylamine in step 1 is replaced by (3-bromopropyl)(methyl)carbamic acid tert-butyl ester, and 173-2 in step 3 is replaced by (E)-4-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)-2-butenoic acid. LC-MS (ESI) m/z: 299.6 [M/2+H] + .
实施例251
Embodiment 251
合成方法Synthesis method
化合物251的合成方法参照实施例176。区别在于把步骤一中的123-2替换为101-2，步骤一中的N-Boc-溴丙胺替换为N-{[1-(溴甲基)环丙基]甲基}氨基甲酸叔丁酯，步骤三 中的173-2替换为(E)-4-(7-氯-4-(二甲胺基)-2-氧代喹唑啉-1(2H)-基)-2-丁烯酸。LC-MS(ESI)m/z:305.6[M/2+H]+.The synthesis method of compound 251 refers to Example 176. The difference is that 123-2 in step 1 is replaced by 101-2, N-Boc-bromopropylamine in step 1 is replaced by N-{[1-(bromomethyl)cyclopropyl]methyl}carbamic acid tert-butyl ester, and step 3 173-2 in the reaction mixture was replaced with (E)-4-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)-2-butenoic acid. LC-MS (ESI) m/z: 305.6 [M/2+H] + .
实施例252&253
Embodiment 252 & 253
合成方法Synthesis method
化合物252和253的合成方法参照实施例171和172。区别在于把步骤一中的1,2-双(2-氯乙氧基)乙烷替换为1,8-二溴辛烷。The synthesis method of compounds 252 and 253 refers to Examples 171 and 172, except that 1,2-bis(2-chloroethoxy)ethane in step 1 is replaced by 1,8-dibromooctane.
化合物252：LC-MS(ESI)m/z:279.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.12(d,J＝9.0Hz,1H),7.96(dd,J＝8.8,3.7Hz,1H),7.52(d,J＝2.3Hz,1H),7.47(d,J＝2.2Hz,1H),7.25(dd,J＝8.9,2.3Hz,1H),7.18(dd,J＝8.7,2.0Hz,1H),4.28(t,J＝6.6Hz,2H),4.01(t,J＝7.7Hz,2H),3.40-3.36(m,2H),3.30(s,6H),3.21(s,7H),1.75-1.67(m,2H),1.56-1.52(m,2H),1.42-1.38(m,2H),1.29-1.21(m,4H).Compound 252: LC-MS (ESI) m/z: 279.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.12(d,J＝9.0Hz,1H),7.96(dd,J＝8.8,3.7Hz,1H),7.52(d,J＝2.3Hz,1H),7.47(d,J＝2.2Hz,1H),7.25(dd,J＝8.9,2.3Hz,1H),7.18(dd,J＝8.7,2.0Hz,1H), 4.28(t,J＝6.6Hz,2H),4.01(t,J＝7.7Hz,2H),3.40-3.36(m,2H),3.30(s,6H),3.21(s,7H),1.75-1.67(m,2H),1.56-1.52(m,2H),1.42-1.38(m,2H), 1.29-1.21(m,4H).
化合物253：LC-MS(ESI)m/z:279.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.11(d,J＝8.9Hz,2H),7.52(d,J＝2.3Hz,2H),7.25(dd,J＝8.9,2.3Hz,2H),4.28(t,J＝6.6Hz,4H),3.30(s,12H),1.77-1.66(m,4H),1.43-1.34(m,8H).Compound 253: LC-MS (ESI) m/z: 279.1 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.11 (d, J = 8.9Hz, 2H), 7.52 ( d,J＝2.3Hz,2H),7.25(dd,J＝8.9,2.3Hz,2H),4.28(t,J＝6.6Hz,4H),3.30(s,12H),1.77-1.66(m,4H ),1.43-1.34(m,8H).
实施例254
Embodiment 254
合成方法Synthesis method
化合物254的合成方法参照实施例176。区别在于把步骤一中的N-Boc-溴丙胺替换为N-{[1-(溴甲基)环丙基]甲基}氨基甲酸叔丁酯，步骤三中的173-2替换为(E)-4-(7-氯-4-(甲乙胺基)-2-氧代喹唑啉-1(2H)-基)-2-丁烯酸。LC-MS(ESI)m/z:305.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.17(t,J＝5.7Hz,1H),7.95(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.36(dd,J＝15.6,2.0Hz,2H),7.24(dd,J＝8.8,2.0Hz,1H),7.14(dd,J＝8.8,1.9Hz,1H),6.73(dt,J＝15.6,4.2Hz,1H),5.81(dt,J＝15.5,1.9Hz,1H),4.85(d,J＝3.7Hz,2H),4.18(s,2H),3.67(q,J＝7.0Hz,2H),3.26(s,3H),3.22(s,6H),3.06(d,J＝5.6Hz,2H),1.30(t,J＝7.0Hz,4H),1.17(t,3H).The synthesis method of compound 254 is similar to that of Example 176. The difference is that N-Boc-bromopropylamine in step 1 is replaced by tert-butyl N-{[1-(bromomethyl)cyclopropyl]methyl}carbamate, and 173-2 in step 3 is replaced by (E)-4-(7-chloro-4-(methylethylamino)-2-oxoquinazolin-1(2H)-yl)-2-butenoic acid. LC-MS (ESI) m/z: 305.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.17(t,J＝5.7Hz,1H),7.95(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.36(dd,J＝15.6,2.0Hz,2H),7.24(dd,J＝8.8,2.0Hz,1H),7.14(dd,J＝8.8,1.9Hz,1H) ,6.73(dt,J=15.6,4.2H z,1H),5.81(dt,J＝15.5,1.9Hz,1H),4.85(d,J＝3.7Hz,2H),4.18(s,2H),3.67(q,J＝7.0Hz,2H),3.26(s,3H),3.22(s,6H),3.06(d,J＝5.6Hz,2H),1.30( t,J＝7.0Hz,4H),1.17(t,3H).
实施例255
Embodiment 255
合成方法Synthesis method
化合物255的合成方法参照实施例176。区别在于把步骤一中的123-2替换为101-2，步骤一中的N-Boc-溴丙胺替换为N-{[1-(溴甲基)环丙基]甲基}氨基甲酸叔丁酯。LC-MS(ESI)m/z:306.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.12(t,J＝5.7Hz,1H),7.96(d,J＝8.8Hz,1H),7.85(d,J＝8.8Hz,1H),7.62(d,J＝2.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.17(td,J＝8.7,1.9Hz,2H),4.24(s,2H),4.02(t,J＝7.7Hz,2H),3.61(q,J＝7.0Hz,2H),3.20(s,3H),3.06(d,J＝5.7Hz,2H),2.27(t,J＝7.1Hz,2H),1.79(p,J＝7.3Hz,2H),1.25(t,3H),0.46-0.35(m,4H).The synthesis method of compound 255 is similar to that of Example 176. The difference is that 123-2 in step 1 is replaced by 101-2, and N-Boc-bromopropylamine in step 1 is replaced by tert-butyl N-{[1-(bromomethyl)cyclopropyl]methyl}carbamate. LC-MS (ESI) m/z: 306.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.12(t,J＝5.7Hz,1H),7.96(d,J＝8.8Hz,1H),7.85(d,J＝8.8Hz,1H),7.62(d,J＝2.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.17(td,J＝8.7,1.9Hz,2H),4.24(s,2 H),4.02(t,J＝7.7Hz,2H),3.61(q,J＝7.0Hz,2H),3.20(s,3H),3.06(d,J＝5.7Hz,2H),2.27(t,J＝7.1Hz,2H),1.79(p,J＝7.3Hz,2H),1.25(t,3H),0.46-0. 35(m,4H).
实施例256
Embodiment 256
合成方法Synthesis method
化合物256的合成方法参照实施例176。区别在于把步骤一中的N-Boc-溴丙胺替换为(3-(溴甲基)环丙基)氨基甲酸叔丁酯。LC-MS(ESI)m/z:299.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.96(d,J＝8.8Hz,2H),7.63(dd,J＝4.4,2.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.19(ddd,J＝8.7,3.7,1.9Hz,2H),4.14(d,J＝6.4Hz,2H),4.05-3.99(m,1H),3.99-3.94(m,2H),3.22(d,J＝2.6Hz,12H),2.31-2.26(m,1H),2.26-2.19(m,2H),2.19-2.13(m,2H),1.78-1.69(m,4H).The synthesis method of compound 256 is similar to that of Example 176. The difference is that N-Boc-bromopropylamine in step 1 is replaced by tert-butyl (3-(bromomethyl)cyclopropyl)carbamate. LC-MS (ESI) m/z: 299.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.96(d,J＝8.8Hz,2H),7.63(dd,J＝4.4,2.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.19(ddd,J＝8.7,3.7,1.9Hz,2H),4.14(d,J＝6.4Hz,2H),4.05-3.99(m,1H),3 .99-3.94(m,2H),3.22(d,J＝2.6Hz,12H),2.31-2.26(m,1H),2.26-2.19(m,2H),2.19-2.13(m,2H),1.78-1.69(m,4H).
实施例257
Embodiment 257
合成方法Synthesis method
化合物257的合成方法参照实施例225。区别在于把步骤二中的176-2替换为1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:294.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(d,J＝8.8Hz,1H),7.89(d,J＝8.8Hz,1H),7.58(d,J＝2.0Hz,1H),7.55(d,J＝2.0Hz,1H),7.20(dd,J＝8.8,1.9Hz,2H),5.17(s,1H),4.18-4.01 (m,4H),3.75-3.68(m,1H),3.62(q,J＝7.0Hz,2H),3.22(s,6H),3.20(s,3H),2.75-2.61(m,4H),1.82-1.76(m,2H),1.66-1.55(m,1H),1.26(t,J＝7.1Hz,3H).The synthesis method of compound 257 refers to Example 225. The difference is that 176-2 in step 2 is replaced by 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 294.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.97 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.20 (dd, J = 8.8, 1.9 Hz, 2H), 5.17 (s, 1H), 4.18-4.01 (m,4H),3.75-3.68(m,1H),3.62(q,J＝7.0Hz,2H),3.22(s,6H),3.20(s,3H),2.75-2.61(m,4H),1.82-1.76(m,2H),1.66-1.55(m,1H),1.26(t,J＝7. 1Hz,3H).
实施例258
Embodiment 258
合成方法Synthesis method
化合物258的合成方法参照实施例176。区别在于把步骤一中的123-2替换为101-2，步骤一中的N-Boc-溴丙胺替换为N-{[1-(溴甲基)环丙基]甲基}氨基甲酸叔丁酯，把步骤三中的173-2替换为4-(7-氯-4-(甲乙胺基)-2-氧代喹唑啉-1(2H)-基)丁酸。LC-MS(ESI)m/z:313.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.12(t,J＝5.7Hz,1H),7.89(d,J＝8.7Hz,1H),7.85(d,J＝8.8Hz,1H),7.62(d,J＝2.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.17(ddd,J＝18.2,8.8,1.8Hz,2H),4.24(s,2H),4.01(t,J＝7.8Hz,2H),3.62(qd,J＝7.1,2.6Hz,4H),3.20(s,3H),3.20(s,3H),3.06(d,J＝5.7Hz,2H),2.28(t,J＝7.2Hz,2H),1.80(p,J＝7.3Hz,2H),1.27(t,6H),0.46-0.35(m,4H).The synthesis method of compound 258 refers to Example 176. The difference is that 123-2 in step 1 is replaced by 101-2, N-Boc-bromopropylamine in step 1 is replaced by N-{[1-(bromomethyl)cyclopropyl]methyl}carbamic acid tert-butyl ester, and 173-2 in step 3 is replaced by 4-(7-chloro-4-(methylethylamino)-2-oxoquinazolin-1(2H)-yl)butanoic acid. LC-MS (ESI) m/z: 313.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.12(t,J＝5.7Hz,1H),7.89(d,J＝8.7Hz,1H),7.85(d,J＝8.8Hz,1H),7.62(d,J＝2.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.17(ddd,J＝18.2,8.8,1.8Hz,2H),4. 24(s,2H),4.01( t,J＝7.8Hz,2H),3.62(qd,J＝7.1,2.6Hz,4H),3.20(s,3H),3.20(s,3H),3.06(d,J＝5.7Hz,2H),2.28(t,J＝7.2Hz,2H),1.80(p,J＝7.3Hz,2H),1.27(t,6H ),0.46-0.35(m,4H).
实施例259
Embodiment 259
合成方法Synthesis method
化合物259的合成方法参照实施例176。区别在于把把步骤三中的173-2替换为3-(7-氯-4-(甲乙胺基)-2-氧代喹唑啉-1(2H)-基)丙酸。LC-MS(ESI)m/z:279.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.12(t,J＝5.7Hz,1H),7.97(d,J＝8.7Hz,1H),7.91(d,J＝8.7Hz,1H),7.53(d,J＝2.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.20(dd,J＝8.7,1.9Hz,1H),7.11(dd,J＝8.7,1.9Hz,1H),4.22(t,J＝7.2Hz,2H),3.99(t,J＝7.6Hz,2H),3.23(s,6H),3.19(s,6H),3.11(q,J＝6.7Hz,2H),2.44(t,J＝7.3Hz,2H),1.63(p,J＝7.3Hz,2H).The synthesis method of compound 259 refers to Example 176. The difference is that 173-2 in step 3 is replaced by 3-(7-chloro-4-(methylethylamino)-2-oxoquinazolin-1(2H)-yl)propanoic acid. LC-MS (ESI) m/z: 279.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.12(t,J＝5.7Hz,1H),7.97(d,J＝8.7Hz,1H),7.91(d,J＝8.7Hz,1H),7.53(d,J＝2.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.20(dd,J＝8.7,1.9Hz,1H),7.11(dd,J ＝8.7,1.9Hz,1H),4.22(t,J＝7.2Hz,2H),3.99(t,J＝7.6Hz,2H),3.23(s,6H),3.19(s,6H),3.11(q,J＝6.7Hz,2H),2.44(t,J＝7.3Hz,2H),1.63(p,J＝7.3Hz ,2H).
实施例260
Embodiment 260
合成方法Synthesis method
化合物260的合成方法参照实施例176。区别在于把步骤一中的N-Boc-溴丙胺替换为N-{[1-(溴甲基)环丙基]甲基}氨基甲酸叔丁酯，步骤三中的173-2替换为4-(7-氯-4-(甲乙胺基)-2-氧代喹唑啉-1(2H)-基)丁酸。LC-MS(ESI)m/z:306.6[M/2+H]+.1H NMR(600 MHz,DMSO-d6)δ8.13(t,J＝5.7Hz,1H),7.92(d,J＝8.7Hz,1H),7.89(d,J＝8.9Hz,1H),7.62(d,J＝2.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.19(dd,J＝8.7,1.9Hz,1H),7.15(dd,J＝8.7,1.9Hz,1H),4.24(s,2H),4.01(t,J＝7.8Hz,2H),3.62(q,J＝7.0Hz,2H),3.20(s,3H),3.06(d,J＝5.6Hz,2H),2.28(t,J＝7.2Hz,2H),1.80(p,J＝7.3Hz,2H),1.27(t,J＝7.0Hz,3H),0.48-0.35(m,4H).The synthesis method of compound 260 is referred to Example 176. The difference is that N-Boc-bromopropylamine in step 1 is replaced by tert-butyl N-{[1-(bromomethyl)cyclopropyl]methyl}carbamate, and 173-2 in step 3 is replaced by 4-(7-chloro-4-(methylethylamino)-2-oxoquinazolin-1(2H)-yl)butanoic acid. LC-MS (ESI) m/z: 306.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.13(t,J＝5.7Hz,1H),7.92(d,J＝8.7Hz,1H),7.89(d,J＝8.9Hz,1H),7.62(d,J＝2.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.19(dd,J＝8.7,1.9Hz,1H ),7.15(dd,J＝8.7,1.9Hz,1H),4.2 4(s,2H),4.01(t,J＝7.8Hz,2H),3.62(q,J＝7.0Hz,2H),3.20(s,3H),3.06(d,J＝5.6Hz,2H),2.28(t,J＝7.2Hz,2H),1.80(p,J＝7.3Hz,2H),1.27(t,J＝7.0Hz ,3H),0.48-0.35(m,4H).
实施例261&262
Example 261 & 262
合成方法Synthesis method
化合物261和262的合成方法参照实施例171和172。区别在于把步骤一中的1,2-双(2-氯乙氧基)乙烷替换为1-溴-3-(3-溴丙氧基)丙烷。The synthesis method of compounds 261 and 262 refers to Examples 171 and 172, except that 1,2-bis(2-chloroethoxy)ethane in step 1 is replaced by 1-bromo-3-(3-bromopropoxy)propane.
化合物261：LC-MS(ESI)m/z:273.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.95(d,J＝8.7Hz,2H),7.51(d,J＝2.0Hz,2H),7.18(dd,J＝8.7,1.9Hz,2H),4.10(t,J＝7.1Hz,4H),3.43(t,J＝6.0Hz,4H),3.21(s,12H),1.85(p,J＝6.6Hz,4H).Compound 261: LC-MS (ESI) m/z: 273.1 [M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ7.95 (d, J = 8.7Hz, 2H), 7.51 ( d,J＝2.0Hz,2H),7.18(dd,J＝8.7,1.9Hz,2H),4.10(t,J＝7.1Hz,4H),3.43(t,J＝6.0Hz,4H),3.21( s,12H),1.85(p,J＝6.6Hz,4H).
化合物262：LC-MS(ESI)m/z:273.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.12(d,J＝9.0Hz,1H),7.94(d,J＝8.7Hz,1H),7.48(dd,J＝4.2,2.1Hz,2H),7.27(dd,J＝8.9,2.3Hz,1H),7.16(dd,J＝8.7,1.9Hz,1H),4.42(t,J＝6.5Hz,2H),4.05(t,J＝8.4,6.2Hz,2H),3.53(t,J＝6.2Hz,2H),3.46(t,J＝5.9Hz,2H),3.32(s,6H),3.22(s,6H),2.03-1.97(m,2H),1.85-1.74(m,2H).Compound 262: LC-MS (ESI) m/z: 273.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.12(d,J＝9.0Hz,1H),7.94(d,J＝8.7Hz,1H),7.48(dd,J＝4.2,2.1Hz,2H),7.27(dd,J＝8.9,2.3Hz,1H),7.16(dd,J＝8.7,1.9Hz,1H),4.42(t,J＝6.5Hz,2H), 4.05(t,J＝8.4,6.2Hz,2H),3.53(t,J＝6.2Hz,2H),3.46(t,J＝5.9Hz,2H),3.32(s,6H),3.22(s,6H),2.03-1.97(m,2H),1.85-1.74(m,2H).
实施例263
Embodiment 263
合成路线
Synthetic route
步骤一：化合物263-1的合成Step 1: Synthesis of compound 263-1
将3-(2-羟基乙基)氮杂丁烷-1-羧酸叔丁酯(2.0g，9.94mmol)溶解在20mL二氯甲烷中，降温至0℃后加入四溴化碳(5.0g，14.93mmol)和三苯基磷(4.0g，14.93mmol)，反应混合液在室温下搅拌30min，TLC监测完全反应。反应体系中加入40mL水，用二氯甲烷(50mL×3)萃取，合并有机相用水(100mL×3)洗涤，无水硫酸钠干燥。过滤，有机相浓缩后粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-50％，15min)得到化合物263-1，2.1g，淡黄色油状液体，产率80％。LC-MS(ESI)m/z:264[M+H]+.3-(2-hydroxyethyl)azetidine-1-carboxylic acid tert-butyl ester (2.0 g, 9.94 mmol) was dissolved in 20 mL of dichloromethane, and carbon tetrabromide (5.0 g, 14.93 mmol) and triphenylphosphine (4.0 g, 14.93 mmol) were added after cooling to 0 ° C. The reaction mixture was stirred at room temperature for 30 min, and TLC monitored the complete reaction. 40 mL of water was added to the reaction system, extracted with dichloromethane (50 mL × 3), and the combined organic phases were washed with water (100 mL × 3) and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated and the crude product was chromatographed on a silica gel column (petroleum ether: ethyl acetate, 0-50%, 15 min) to obtain compound 263-1, 2.1 g, light yellow oily liquid, with a yield of 80%. LC-MS (ESI) m/z: 264 [M + H] + .
步骤二：化合物263-2的合成Step 2: Synthesis of compound 263-2
室温下，将化合物123-2(1.0g，4.48mmol)溶解在10mL N,N-二甲基甲酰胺中，向其中加入化合物263-1(1.4g，5.38mmol)和碳酸钾(1.9g，13.44mmol)，室温下搅拌16h。TLC监测完全反应。反应体系中加入40mL水，用乙酸乙酯(40mL×3)萃取，合并有机相用饱和氯化钠溶液(80mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物263-2，380mg，白色固体，产率21％。LC-MS(ESI)m/z:407[M+H]+.At room temperature, compound 123-2 (1.0 g, 4.48 mmol) was dissolved in 10 mL of N, N-dimethylformamide, and compound 263-1 (1.4 g, 5.38 mmol) and potassium carbonate (1.9 g, 13.44 mmol) were added thereto, and stirred at room temperature for 16 h. TLC monitored the complete reaction. 40 mL of water was added to the reaction system, extracted with ethyl acetate (40 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (80 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 263-2, 380 mg, white solid, yield 21%. LC-MS (ESI) m/z: 407 [M + H] + .
步骤三：化合物263-3的合成Step 3: Synthesis of compound 263-3
室温下将化合物263-2(380mg，0.93mmol)溶解在4mL 1,4-二氧六环中，向其中加入4M的盐酸-二氧六环溶液4mL，室温下搅拌30min。TLC监测完全反应，浓缩后得到化合物263-3的盐酸盐，274mg，白色固体，产率100％。LC-MS(ESI)m/z:307[M+H]+.Compound 263-2 (380 mg, 0.93 mmol) was dissolved in 4 mL of 1,4-dioxane at room temperature, 4 mL of 4M hydrochloric acid-dioxane solution was added thereto, and stirred at room temperature for 30 min. TLC monitored the complete reaction, and after concentration, the hydrochloride of compound 263-3 was obtained, 274 mg, white solid, with a yield of 100%. LC-MS (ESI) m/z: 307 [M + H] + .
步骤四：化合物263-4的合成Step 4: Synthesis of compound 263-4
室温下，将化合物263-3(1.0g，4.46mmol)溶解在10mL N,N-二甲基甲酰胺中，向其中加入溴乙酸乙酯(1.1g，6.70mmol)和碳酸钾(1.8g，13.38mmol)，100℃下搅拌16h。TLC监测完全反应。反应体系中加入40mL水，用乙酸乙酯(40mL×3)萃取，合并有机相用饱和氯化钠溶液(80mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物263-4，394mg，白色固体，产率29％。LC-MS(ESI)m/z:310[M+H]+.At room temperature, compound 263-3 (1.0 g, 4.46 mmol) was dissolved in 10 mL of N, N-dimethylformamide, ethyl bromoacetate (1.1 g, 6.70 mmol) and potassium carbonate (1.8 g, 13.38 mmol) were added thereto, and stirred at 100 ° C for 16 h. TLC monitored the complete reaction. 40 mL of water was added to the reaction system, extracted with ethyl acetate (40 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (80 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 263-4, 394 mg, white solid, yield 29%. LC-MS (ESI) m/z: 310 [M + H] + .
步骤五：化合物263-5的合成 Step 5: Synthesis of compound 263-5
室温下将化合物263-4(394mg，1.28mmol)溶解在5mL甲醇中，向其中加入水5mL后加入氢氧化锂(107mg，2.55mmol)，室温下搅拌2h。TLC监测完全反应。浓缩除去体系中的甲醇后用稀盐酸(1M)调节pH至4。粗产品通过硅胶柱层析(二氯甲烷：甲醇，0-10％，10min)后得到化合物263-5，319mg，白色固体，产率88％。LC-MS(ESI)m/z:282[M+H]+。Compound 263-4 (394 mg, 1.28 mmol) was dissolved in 5 mL of methanol at room temperature, 5 mL of water was added thereto, and lithium hydroxide (107 mg, 2.55 mmol) was added thereto, and stirred at room temperature for 2 h. TLC monitored the complete reaction. After concentrating and removing the methanol in the system, the pH was adjusted to 4 with dilute hydrochloric acid (1 M). The crude product was chromatographed on a silica gel column (dichloromethane: methanol, 0-10%, 10 min) to obtain compound 263-5, 319 mg, white solid, with a yield of 88%. LC-MS (ESI) m/z: 282 [M+H] + .
步骤六：化合物263的合成Step 6: Synthesis of compound 263
室温下将化合物263-5(40mg，0.14mmol)溶解在1mL N,N-二甲基甲酰胺中，向其中加入N,N-二异丙基乙胺(56mg，0.42mmol)，室温下搅拌20min后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(54mg，0.14mmol)和化合物263-3(44mg，0.14mmol)。反应混合液在室温下搅拌1h。LC-MS检测完全反应。经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，HPLC制备纯化后得到化合物263，8.64mg，白色固体，产率1.9％。LC-MS(ESI)m/z:285.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.98(dd,J＝12.1,8.8Hz,2H),7.58(d,J＝2.0Hz,1H),7.37(d,J＝2.0Hz,1H),7.20(ddd,J＝16.4,8.7,2.0Hz,2H),4.69(s,2H),4.36(t,J＝8.4Hz,1H),4.08(hept,J＝7.1Hz,2H),4.01-3.92(m,2H),3.58(q,J＝9.6,5.7Hz,1H),3.25(s,6H),3.23(s,6H),2.75-2.67(m,1H),1.94(q,J＝7.2Hz,2H).Compound 263-5 (40 mg, 0.14 mmol) was dissolved in 1 mL of N,N-dimethylformamide at room temperature, N,N-diisopropylethylamine (56 mg, 0.42 mmol) was added thereto, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (54 mg, 0.14 mmol) and compound 263-3 (44 mg, 0.14 mmol) were added after stirring at room temperature for 20 min. The reaction mixture was stirred at room temperature for 1 h. LC-MS detected the complete reaction. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 263 was obtained after HPLC preparation and purification, 8.64 mg, white solid, yield 1.9%. LC-MS (ESI) m/z: 285.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.98(dd,J＝12.1,8.8Hz,2H),7.58(d,J＝2.0Hz,1H),7.37(d,J＝2.0Hz,1H),7.20(ddd,J＝16.4,8.7,2.0Hz,2H),4.69(s,2H),4.36(t,J＝8.4Hz,1H),4.08 (hept,J＝7.1Hz,2H),4.01-3.92(m,2H),3.58(q,J＝9.6,5.7Hz,1H),3.25(s,6H),3.23(s,6H),2.75-2.67(m,1H),1.94(q,J＝7.2Hz,2H).
实施例264
Embodiment 264
合成路线
Synthetic route
步骤一：化合物264的合成Step 1: Synthesis of compound 264
室温下，将化合物193-2(100mg，0.32mmol)和1-甲基咪唑(80mg，0.96mmol)溶到乙腈(1.0mL)中，降温至0゜C，向反应液中加入对甲苯磺酰氯(75mg，0.065mmol)，搅拌30分钟。在0゜C下，向反应液中滴加7-氯-4-(二甲胺基)-1-(3-羟基丙基)喹唑啉-2(1H)-酮(50mg，0.16mmol)的乙腈(0.5mL)混合物，搅拌1.5个小时。反应液经减压浓缩后，经柱层析纯化(洗脱剂：甲醇/二氯甲烷，10％)，得到化合物264的粗品。粗品再经制备液相色谱纯化，制备液冷冻干燥，得到化合物264，4.5mg，产率1.8％。LC-MS(ESI)m/z:287.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.96(dd,J＝8.7,6.1Hz,2H),7.60(d,J＝2.0Hz,1H),7.51(d,J＝2.0Hz,1H),7.18(td,J＝8.6,1.9Hz,2H),4.12(dt,J＝12.1,6.5Hz,4H),4.03(t,J＝7.7Hz,2H),3.22(s,6H),3.21(s,6H),2.44(t,J＝7.1Hz,2H),1.91(p,J＝6.6Hz,2H),1.82(p,J＝7.2Hz,2H).At room temperature, compound 193-2 (100 mg, 0.32 mmol) and 1-methylimidazole (80 mg, 0.96 mmol) were dissolved in acetonitrile (1.0 mL), cooled to 0°C, p-toluenesulfonyl chloride (75 mg, 0.065 mmol) was added to the reaction solution, and stirred for 30 minutes. At 0°C, a mixture of 7-chloro-4-(dimethylamino)-1-(3-hydroxypropyl)quinazolin-2(1H)-one (50 mg, 0.16 mmol) in acetonitrile (0.5 mL) was added dropwise to the reaction solution, and stirred for 1.5 hours. After the reaction solution was concentrated under reduced pressure, it was purified by column chromatography (eluent: methanol/dichloromethane, 10%) to obtain a crude product of compound 264. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain compound 264, 4.5 mg, with a yield of 1.8%. LC-MS (ESI) m/z: 287.1 [M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ7.96 (dd, J = 8.7, 6.1Hz, 2H), 7.60 (d, J = 2.0Hz, 1H), 7.51 (d, J = 2.0Hz, 1H), 7.18 (td, J = 8.6, 1.9Hz, 2H), 4.12(dt,J＝12.1,6.5Hz,4H),4.03(t,J＝7.7Hz,2H),3.22(s,6H),3.21(s,6H),2.44(t,J＝7.1Hz,2H),1.91(p,J＝6.6Hz,2H),1.82(p,J＝7.2Hz,2H).
实施例265
Embodiment 265
合成方法Synthesis method
化合物265的合成方法参照实施例263。区别在于把步骤二和步骤四中的123-2替换为101-2。LC-MS(ESI)m/z:299.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.90(dd,J＝8.8,6.5Hz,2H),7.58(d,J＝2.0Hz,1H),7.36(d,J＝2.0Hz,1H),7.21(ddd,J＝11.9,8.8,2.0Hz,2H),4.68(s,2H),4.35(t,J＝8.3Hz,1H),4.13-4.03(m,2H),4.00-3.91(m,2H),3.68-3.61(m,4H),3.61-3.54(m,1H),3.23(s,3H),3.21(s,3H),2.76-2.66(m,1H),1.94(q,J＝7.4Hz,2H),1.27(t,J＝7.0Hz,6H).The synthesis method of compound 265 refers to Example 263. The difference is that 123-2 in step 2 and step 4 is replaced by 101-2. LC-MS (ESI) m/z: 299.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.90(dd,J＝8.8,6.5Hz,2H),7.58(d,J＝2.0Hz,1H),7.36(d,J＝2.0Hz,1H),7.21(ddd,J＝11.9,8.8,2.0Hz,2H),4.68(s,2H),4.35(t,J＝8.3Hz,1H),4.13- 4.03(m,2H),4.00-3.91(m,2H),3.68-3.61(m,4H),3.61-3.54(m,1H),3.23(s,3H),3.21(s,3H),2.76-2.66(m,1H),1.94(q,J＝7.4Hz,2H),1.27(t ,J＝7.0Hz,6H).
实施例266
Embodiment 266
合成方法Synthesis method
化合物266的合成方法参照实施例263。区别在于把步骤四中的123-2替换为101-2。LC-MS(ESI)m/z:292.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ.98(d,J＝8.8Hz,1H),7.90(d,J＝8.8Hz,1H),7.58(d,J＝2.0Hz,1H),7.36(d,J＝2.1Hz,1H),7.20(td,J＝8.7,2.0Hz,2H),4.68(s,2H),4.35(t,J＝8.4Hz,1H),4.13-4.03(m,2H),3.96(q,J＝8.6,7.0Hz,2H),3.64(q,J＝7.0Hz,2H),3.58(dd,J＝9.6,5.7Hz,1H),3.23(s,9H),2.78-2.65(m,1H),1.94(q,J＝7.2Hz,2H),1.27(t,J＝7.0Hz,3H).The synthesis method of compound 266 refers to Example 263. The difference is that 123-2 in step 4 is replaced by 101-2. LC-MS (ESI) m/z: 292.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ.98 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.36 (d, J=2.1 Hz, 1H), 7.20 (td, J=8.7, 2.0 Hz, 2H), 4.68 (s, 2H), 4.35 (t, J=8.4 Hz, 1H), 4.13-4.0 3(m,2H),3.96(q,J＝8.6,7.0Hz,2H),3.64(q,J＝7.0Hz,2H),3.58(dd,J＝9.6,5.7Hz,1H),3.23(s,9H),2.78-2.65(m,1H),1.94(q,J＝7.2Hz,2H),1.27(t ,J＝7.0Hz,3H).
实施例267
Embodiment 267
合成方法Synthesis method
化合物267的合成方法参照实施例263。区别在于把步骤二中的123-2替换为101-2。LC-MS(ESI)m/z:292.6[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.96(d,J＝8.8Hz,1H),7.91(d,J＝8.8Hz,1H),7.58(d,J＝2.0Hz,1H),7.37(d,J＝2.0Hz,1H),7.20(ddd,J＝14.2,8.7,1.9Hz,2H),4.68(s,2H),4.35(t,J＝8.3Hz,1H),4.13-4.04(m,2H),4.00–3.91(m,2H),3.63(q,J＝7.3Hz,2H),3.60–3.55(m,1H),3.24(s,6H),3.21(s,3H),2.77-2.68(m,1H),1.94(q,J＝7.4Hz,2H),1.27(t,J＝7.0Hz,3H).The synthesis method of compound 267 refers to Example 263. The difference is that 123-2 in step 2 is replaced by 101-2. LC-MS (ESI) m/z: 292.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ7.96 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.20 (ddd, J=14.2, 8.7, 1.9 Hz, 2H), 4.68 (s, 2H), 4.35 (t, J=8.3 Hz, 1H), 4. 13-4.04(m,2H),4.00–3.91(m,2H),3.63(q,J＝7.3Hz,2H),3.60–3.55(m,1H),3.24(s,6H),3.21(s,3H),2.77-2.68(m,1H),1.94(q,J＝7.4Hz,2H),1 .27(t,J＝7.0Hz,3H).
实施例268
Embodiment 268
合成路线
Synthetic route
步骤一：化合物268-1的合成Step 1: Synthesis of compound 268-1
取2-羟基喹啉(0.50g，3.4mmol)、N-Boc-3-氨基丙基溴(1.6g，6.8mmol)和碳酸铯(3.3g，10.2mmol)分散到1,4-二氧六环(10mL)溶液中，加热到100゜C，搅拌过夜。反应混合物用乙酸乙酯(20mL×3)和水(20mL)萃取，合并有机相，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：乙酸乙酯/石油醚)纯化，得到化合物268-1，0.75g。产率72％。LC-MS(ESI)m/z:303[M+H]+.Take 2-hydroxyquinoline (0.50g, 3.4mmol), N-Boc-3-aminopropyl bromide (1.6g, 6.8mmol) and cesium carbonate (3.3g, 10.2mmol) and disperse them in 1,4-dioxane (10mL) solution, heat to 100°C, and stir overnight. The reaction mixture was extracted with ethyl acetate (20mL×3) and water (20mL), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography column (eluent: ethyl acetate/petroleum ether) to obtain compound 268-1, 0.75g. Yield 72%. LC-MS (ESI) m/z: 303[M+H] + .
步骤二：化合物268-2的合成Step 2: Synthesis of compound 268-2
取化合物268-1(750mg，2.5mmol)分散到1,4-二氧六环(5.0mL)中，室温下，向反应液中滴加盐酸的二氧六环溶液(5.0mL)。室温搅拌3个小时。反应液经减压浓缩后，得到化合物268-2的粗品，直接用于下一步。LC-MS(ESI)m/z:203[M+H]+.Compound 268-1 (750 mg, 2.5 mmol) was dispersed in 1,4-dioxane (5.0 mL). A solution of hydrochloric acid in dioxane (5.0 mL) was added dropwise to the reaction solution at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product of compound 268-2, which was used directly in the next step. LC-MS (ESI) m/z: 203 [M+H] + .
步骤三：化合物268的合成Step 3: Synthesis of compound 268
取化合物225-1(50mg，0.17mmol)、化合物268-2(32mg，0.17mmol)和三乙胺(52mg，0.51mmol)分散到乙醇(1.0mL)溶液中，加热到50゜C，搅拌过夜。反应液经减压浓缩后，经柱层析纯化(MeOH/DCM＝1:10)，得到化合物268的粗品。粗品再经制备液相色谱纯化，制备液冷冻干燥，得到产物268，3.46mg，产率4.1％。LC-MS(ESI)m/z:496.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.99(d,J＝8.8Hz,1H),7.95(d,J＝9.4Hz,1H),7.76(d,J＝7.7Hz,1H),7.63(s,1H),7.54(d,J＝2.0Hz,1H),7.29(p,J＝7.9,4.1Hz,1H),7.22(dd,J＝8.7,1.9Hz,1H),6.64(d,J＝9.5Hz,1H),5.45(s,1H),5.33(t,J＝4.8Hz,1H),4.32(t,2H),4.12(q,J＝8.4Hz,2H),3.81-3.71(m,1H),3.23(s,6H),2.98-2.90(m,3H),2.80(t,J＝10.5Hz,1H),2.01(t,2H),1.85-1.72(m,1H),1.69-1.56(m,1H).Compound 225-1 (50 mg, 0.17 mmol), compound 268-2 (32 mg, 0.17 mmol) and triethylamine (52 mg, 0.51 mmol) were dispersed in an ethanol (1.0 mL) solution, heated to 50°C, and stirred overnight. The reaction solution was concentrated under reduced pressure and purified by column chromatography (MeOH/DCM=1:10) to obtain a crude product of compound 268. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain product 268, 3.46 mg, with a yield of 4.1%. LC-MS (ESI) m/z: 496.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.16(s,1H),7.99(d,J＝8.8Hz,1H),7.95(d,J＝9.4Hz,1H),7.76(d,J＝7.7Hz,1H),7.63(s,1H),7.54(d,J＝2.0Hz,1H),7.29(p,J＝7.9,4.1Hz,1H),7.22 (dd,J＝8.7,1.9Hz,1H),6.64(d,J＝9.5Hz,1H), 5.45(s,1H),5.33(t,J＝4.8Hz,1H),4.32(t,2H),4.12(q,J＝8.4Hz,2H),3.81-3.71(m,1H),3.23(s,6H),2.98-2.90(m,3H),2.80(t,J＝10.5Hz,1H),2 .01(t,2H),1.85-1.72(m,1H),1.69-1.56(m,1H).
实施例269
Embodiment 269
合成方法Synthesis method
化合物269的合成方法参照实施例268。区别在于把步骤一中的2-羟基喹啉替换为7-氯-2-羟基喹啉。LC-MS(ESI)m/z:530.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.99(dd,J＝13.4,9.1Hz,2H),7.80(d,J＝8.3Hz,1H),7.74(d,J＝1.8Hz,1H),7.54(d,J＝2.0Hz,1H),7.36(dd,J＝8.3,1.8Hz,1H),7.24(dd,J＝8.8,1.9Hz,1H),6.66(d,J＝9.5Hz,1H),5.61(s,1H)，5.32(t,J＝4.9Hz,1H),4.31(t,J＝7.2Hz,2H),4.22-4.08(m,2H),3.80(t,1H),3.24(s,6H),3.14-2.95(m,3H),2.89(m,1H),2.02(d,J＝7.3Hz,2H),1.84-1.72(m,1H),1.71-1.58(m,1H).The synthesis method of compound 269 refers to Example 268. The difference is that 2-hydroxyquinoline in step 1 is replaced by 7-chloro-2-hydroxyquinoline. LC-MS (ESI) m/z: 530.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ7.99 (dd, J=13.4, 9.1 Hz, 2H), 7.80 (d, J=8.3 Hz, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.36 (dd, J=8.3, 1.8 Hz, 1H), 7.24 (dd, J=8.8, 1.9 Hz, 1H), 6.66 (d, J=9.5 Hz, 1H), 5.61 (s, 1H), 5.32(t,J＝4.9Hz,1H),4.31(t,J＝7.2Hz,2H),4.22-4.08(m,2H),3.80(t,1H),3.24(s,6H),3.14-2.95(m,3H),2.89(m,1H),2.02(d,J＝7.3Hz,2H ),1.84-1.72(m,1H),1.71-1.58(m,1H).
实施例270
Embodiment 270
合成方法Synthesis method
化合物270的合成方法参照实施例225。区别在于把步骤一中的123-2替换为101-2，步骤二中的176-2替换为1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:301.6[M/2+H]+.The synthesis method of compound 270 refers to Example 225. The difference is that 123-2 in step 1 is replaced by 101-2, and 176-2 in step 2 is replaced by 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 301.6 [M/2+H] + .
实施例271
Embodiment 271
合成方法Synthesis method
化合物271的合成方法参照实施例225。区别在于把步骤一中的123-2替换为101-2，步骤二中的176-2替换为1-((1-(氨基甲基)环丙基)甲基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:314.6[M/2+H]+.The synthesis method of compound 271 refers to Example 225. The difference is that 123-2 in step 1 is replaced by 101-2, and 176-2 in step 2 is replaced by 1-((1-(aminomethyl)cyclopropyl)methyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 314.6 [M/2+H] + .
实施例272
Embodiment 272
合成方法Synthesis method
化合物272的合成方法参照实施例261。LC-MS(ESI)m/z:287.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.88(d,J＝8.8Hz,2H),7.51(d,J＝2.0Hz,2H),7.18(dd,J＝8.7,1.9Hz,2H),4.09(t,J＝7.1Hz,4H),3.60(q,J＝7.0Hz,5H),3.43(t,4H),3.18(s,6H),1.85(q,4H),1.24(t,6H).The synthesis method of compound 272 refers to Example 261. LC-MS (ESI) m/z: 287.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.88 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 2.0 Hz, 2H), 7.18 (dd, J = 8.7, 1.9 Hz, 2H), 4.09 (t, J = 7.1 Hz, 4H), 3.60 (q, J = 7.0 Hz, 5H), 3.43 (t, 4H), 3.18 (s, 6H), 1.85 (q, 4H), 1.24 (t, 6H).
实施例273
Embodiment 273
合成路线
Synthetic route
步骤一：化合物273-1的合成Step 1: Synthesis of compound 273-1
取2-羟基-7-氯喹啉(0.61g，3.4mmol)、N-Boc-3-氨基丙基溴(1.6g，6.8mmol)和碳酸铯(3.3g，10.2mmol)分散到1,4-二氧六环(10mL)溶液中，加热到100゜C，搅拌过夜。反应混合物用乙酸乙酯(20mL×3)和水(20mL)萃取，合并有机相，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：乙酸乙酯/石油醚)纯化，得到化合物273-1，0.84g。产率72％。LC-MS(ESI)m/z:337[M+H]+.2-Hydroxy-7-chloroquinoline (0.61 g, 3.4 mmol), N-Boc-3-aminopropyl bromide (1.6 g, 6.8 mmol) and cesium carbonate (3.3 g, 10.2 mmol) were dispersed in a 1,4-dioxane (10 mL) solution, heated to 100 °C, and stirred overnight. The reaction mixture was extracted with ethyl acetate (20 mL × 3) and water (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate/petroleum ether) to obtain compound 273-1, 0.84 g. Yield 72%. LC-MS (ESI) m/z: 337 [M + H] + .
步骤二：化合物273-2的合成Step 2: Synthesis of compound 273-2
取化合物273-1(840mg，2.5mmol)分散到1,4-二氧六环(5.0mL)中，室温下，向反应液中滴加盐酸的二氧六环溶液(5.0mL)。室温搅拌3个小时。反应液经减压浓缩后，得到化合物273-2的粗品，直接用于下一步。LC-MS(ESI)m/z:237[M+H]+.Compound 273-1 (840 mg, 2.5 mmol) was dispersed in 1,4-dioxane (5.0 mL). A solution of hydrochloric acid in dioxane (5.0 mL) was added dropwise to the reaction solution at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product of compound 273-2, which was used directly in the next step. LC-MS (ESI) m/z: 237 [M+H] + .
步骤三：化合物273的合成Step 3: Synthesis of compound 273
取化合物225-1(50mg，0.17mmol)、化合物273-2(40mg，0.17mmol)和三乙胺(52mg，0.51mmol)分散到乙醇(1.0mL)溶液中，加热到50゜C，搅拌过夜。 反应液经减压浓缩后，经柱层析纯化(MeOH/DCM＝1:10)，得到化合物273的粗品。粗品再经制备液相色谱纯化，制备液冷冻干燥，得到产物273，8.81mg，产率9.8％。LC-MS(ESI)m/z:530.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.25(d,J＝2.1Hz,1H),7.94(dd,J＝16.6,8.6Hz,2H),7.76(d,J＝2.1Hz,1H),7.55(d,J＝2.0Hz,1H),7.46(dd,J＝8.6,2.2Hz,1H),7.19(dd,J＝8.7,1.9Hz,1H),7.03(d,J＝8.8Hz,1H),5.31(t,J＝4.6Hz,1H),5.08(s,1H),4.47(t,J＝6.3Hz,2H),4.14-4.06(m,2H),3.73-3.67(m,1H),3.22(s,6H),2.81(t,J＝7.0Hz,2H),2.71-2.64(m,2H),1.99(t,J＝7.0Hz,2H),1.83-1.71(m,1H),1.68-1.54(m,1H).Compound 225-1 (50 mg, 0.17 mmol), compound 273-2 (40 mg, 0.17 mmol) and triethylamine (52 mg, 0.51 mmol) were dispersed in an ethanol (1.0 mL) solution, heated to 50° C., and stirred overnight. The reaction solution was concentrated under reduced pressure and purified by column chromatography (MeOH/DCM=1:10) to obtain a crude product of compound 273. The crude product was further purified by preparative liquid chromatography and the preparative solution was freeze-dried to obtain product 273, 8.81 mg, with a yield of 9.8%. LC-MS (ESI) m/z: 530.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.25(d,J＝2.1Hz,1H),7.94(dd,J＝16.6,8.6Hz,2H),7.76(d,J＝2.1Hz,1H),7.55(d,J＝2.0Hz,1H),7.46(dd,J＝8.6,2.2Hz,1H),7.19(dd,J＝8.7,1.9Hz,1H), 7.03(d,J＝8.8Hz,1H),5.31(t,J＝4.6H z,1H),5.08(s,1H),4.47(t,J＝6.3Hz,2H),4.14-4.06(m,2H),3.73-3.67(m,1H),3.22(s,6H),2.81(t,J＝7.0Hz,2H),2.71-2.64(m,2H),1.99(t,J＝7 .0Hz,2H),1.83-1.71(m,1H),1.68-1.54(m,1H).
实施例274
Embodiment 274
合成路线
Synthetic route
步骤一：化合物274-1的合成Step 1: Synthesis of compound 274-1
室温下，将7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(123-2，500mg，2.23mmol)和5-溴戊醇(700mg，4.46mmol)溶于10mL干燥的二氧六环中，加入碳酸铯(2.2g，6.71mmol)，升温至100℃搅拌过夜。LC-MS监测反应完全。反应液浓缩后，经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到350mg化合物274-1，收率53％。LC-MS(ESI)m/z:310[M+H]+.At room temperature, 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2, 500 mg, 2.23 mmol) and 5-bromopentanol (700 mg, 4.46 mmol) were dissolved in 10 mL of dry dioxane, cesium carbonate (2.2 g, 6.71 mmol) was added, and the temperature was raised to 100 ° C and stirred overnight. LC-MS monitored the reaction to be complete. After the reaction solution was concentrated, it was separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 350 mg of compound 274-1, with a yield of 53%. LC-MS (ESI) m/z: 310 [M + H] + .
步骤二：化合物274-2的合成Step 2: Synthesis of compound 274-2
室温下，将化合物274-1(220mg，0.710mmol)溶于5mL无水乙腈中，加入一滴DMF，之后冰浴下加入0.2mL氯化亚砜，之后升温至50℃搅拌1小时。LC-MS监测反应完全。加饱和碳酸氢钠溶液和EA萃取三次，合并有机相，浓缩后经快速色谱柱层析分离(PE:EA,0-100％,10min)得到170mg化合物274-2，收率73％。LC-MS(ESI)m/z:328[M+H]+.At room temperature, compound 274-1 (220 mg, 0.710 mmol) was dissolved in 5 mL of anhydrous acetonitrile, and one drop of DMF was added. Then, 0.2 mL of thionyl chloride was added under ice bath, and then the temperature was raised to 50 ° C and stirred for 1 hour. LC-MS monitored the reaction to be complete. Saturated sodium bicarbonate solution and EA were added for extraction three times, and the organic phases were combined, concentrated, and separated by flash chromatography (PE: EA, 0-100%, 10 min) to obtain 170 mg of compound 274-2, with a yield of 73%. LC-MS (ESI) m/z: 328 [M + H] + .
步骤三：化合物274的合成Step 3: Synthesis of compound 274
室温下，将化合物150-2(100mg，0.375mmol)溶于3mL干燥的DMF中，冰浴降温至0℃后缓慢加入氢化钠(30mg，0.75mmol)，室温搅拌1小时后加入化合物274-2(120mg，0.366mmol)，升温至90℃反应2小时。LC-MS监测反应为脱烷基化产物。反应液浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到60mg粗品， 后经高压制备液相分离得12mg化合物274，收率8％。LC-MS(ESI)m/z:265.6[M/2+H]+.At room temperature, compound 150-2 (100 mg, 0.375 mmol) was dissolved in 3 mL of dry DMF, cooled to 0°C in an ice bath, and then sodium hydride (30 mg, 0.75 mmol) was slowly added. After stirring at room temperature for 1 hour, compound 274-2 (120 mg, 0.366 mmol) was added, and the temperature was raised to 90°C for 2 hours. LC-MS monitored the reaction to be a dealkylation product. After the reaction solution was concentrated, it was separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 60 mg of crude product. After high pressure preparative liquid separation, 12 mg of compound 274 was obtained with a yield of 8%. LC-MS (ESI) m/z: 265.6 [M/2+H] + .
实施例275
Embodiment 275
合成方法Synthesis method
化合物275的合成方法参照实施例225。区别在于把步骤二中的176-2替换为3-(6-氯-1H吡咯[2,3-b]吡啶-1-基)-1-丙胺。LC-MS(ESI)m/z:503.2[M+H]+.The synthesis method of compound 275 refers to Example 225. The difference is that 176-2 in step 2 is replaced by 3-(6-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-1-propylamine. LC-MS (ESI) m/z: 503.2 [M+H] + .
实施例276
Embodiment 276
合成路线
Synthetic route
步骤一：化合物276-1的合成Step 1: Synthesis of compound 276-1
室温下，将7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(500mg，2.23mmol)溶于10mL干燥的DMF中，加入4-氯丁烯-2-烯-1-醇(500mg，4.81mmol)和碳酸铯(2.2g，6.71mmol),升温至100℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相，浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到220mg化合物276-1，收率34％。LC-MS(ESI)m/z:292[M+H]+.At room temperature, 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (500 mg, 2.23 mmol) was dissolved in 10 mL of dry DMF, 4-chlorobutene-2-ene-1-ol (500 mg, 4.81 mmol) and cesium carbonate (2.2 g, 6.71 mmol) were added, and the mixture was heated to 100°C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine, concentrated, and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 220 mg of compound 276-1, with a yield of 34%. LC-MS (ESI) m/z: 292 [M+H] + .
步骤二：化合物276-2的合成Step 2: Synthesis of compound 276-2
室温下，将化合物276-1(220mg，0.753mmol)溶于5mL干燥的乙腈中，加入0.2mL二氯亚砜和0.1mL DMF，升温至50℃搅拌1小时。LC-MS监测反应完全。浓缩除去大量二氯亚砜，加饱和碳酸氢钠水溶液和EA萃取三次，饱和食盐水洗涤合并的有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到80mg化合物276-2，收率34％。LC-MS(ESI)m/z:310[M+H]+.At room temperature, compound 276-1 (220 mg, 0.753 mmol) was dissolved in 5 mL of dry acetonitrile, 0.2 mL of dichlorothionyl and 0.1 mL of DMF were added, and the temperature was raised to 50 ° C and stirred for 1 hour. LC-MS monitored the reaction to be complete. Concentrate to remove a large amount of dichlorothionyl, add saturated sodium bicarbonate aqueous solution and EA to extract three times, wash with saturated brine, concentrate the combined organic phase, and separate it by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 80 mg of compound 276-2, with a yield of 34%. LC-MS (ESI) m/z: 310 [M + H] + .
步骤三：化合物276的合成 Step 3: Synthesis of compound 276
室温下，将化合物276-2(50mg，0.161mmol)和化合物1-(2-氨基乙基)-7-氯-4-(二甲胺基)喹唑啉-2(1H)-酮(50mg，0.187mmol)溶于2mL干燥的乙腈中，加入碳酸钾(70mg，0.507mmol),升温至70℃搅拌过夜。LCMS监测反应完全。反应液直接浓缩后，经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到10mg粗品，后经高效液相色谱柱层析分离得到8mg化合物276，收率8％。LC-MS(ESI)m/z:270.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.95(d,J＝8.8Hz,1H),7.91(d,J＝8.7Hz,1H),7.47(d,J＝2.0Hz,1H),7.42(d,J＝2.0Hz,1H),7.16(dd,J＝8.7,1.9Hz,1H),7.05(dd,J＝8.8,2.0Hz,1H),4.90(s,2H),4.02(t,J＝7.2Hz,2H),3.41-3.37(m,4H),3.24(d,J＝8.8Hz,12H),2.69(t,J＝7.2Hz,2H).At room temperature, compound 276-2 (50 mg, 0.161 mmol) and compound 1-(2-aminoethyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (50 mg, 0.187 mmol) were dissolved in 2 mL of dry acetonitrile, potassium carbonate (70 mg, 0.507 mmol) was added, and the temperature was raised to 70°C and stirred overnight. LCMS monitored the reaction to be complete. The reaction solution was directly concentrated and separated by flash column chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 10 mg of crude product, which was then separated by high performance liquid chromatography column chromatography to obtain 8 mg of compound 276, with a yield of 8%. LC-MS (ESI) m/z: 270.6 [M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ7.95 (d, J = 8.8Hz, 1H), 7.91 (d, J = 8.7Hz, 1H), 7.47 (d, J = 2.0Hz, 1H), 7.42 (d, J = 2.0Hz, 1H), 7.16 ( dd,J＝8.7,1.9Hz,1H),7.05(dd,J＝8.8,2.0Hz,1H),4.90(s,2H),4.02(t,J＝7.2Hz,2H),3.41-3.37(m,4H),3.24(d,J＝8.8Hz,12H),2.69(t,J＝7.2Hz,2H).
实施例277
Embodiment 277
合成方法Synthesis method
化合物277的合成方法参照实施例225。区别在于把步骤二中的176-2替换为1-(3-氨基丙基)-7-氟-3,4-二氢喹啉-2(1H)-酮。LC-MS(ESI)m/z:516.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.16(s,1H),7.99(d,J＝8.7Hz,1H),7.96(s,1H),7.53(s,1H),7.26(t,J＝7.4Hz,1H),7.23(d,J＝8.7Hz,1H),7.10(dd,J＝11.5,2.4Hz,1H),6.85(td,J＝8.4,2.3Hz,1H),4.20-4.06(m,2H),4.00-3.88(m,2H),3.81(d,J＝9.4Hz,1H),3.23(s,6H),3.00(d,J＝12.3Hz,1H),2.84(q,J＝6.6,5.6Hz,4H),2.56(t,J＝8.6,6.3Hz,3H),1.95-1.83(m,J＝6.8Hz,2H),1.82-1.74(m,1H),1.67-1.58(m,1H).The synthesis method of compound 277 is similar to that of Example 225. The difference is that 176-2 in step 2 is replaced by 1-(3-aminopropyl)-7-fluoro-3,4-dihydroquinolin-2(1H)-one. LC-MS (ESI) m/z: 516.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.16(s,1H),7.99(d,J＝8.7Hz,1H),7.96(s,1H),7.53(s,1H),7.26(t,J＝7.4Hz,1H),7.23(d,J＝8.7Hz,1H),7.10(dd,J＝11.5,2.4Hz,1H),6.85(td,J＝ 8.4,2.3Hz,1H),4.20-4.06(m,2H),4.00- 3.88(m,2H),3.81(d,J＝9.4Hz,1H),3.23(s,6H),3.00(d,J＝12.3Hz,1H),2.84(q,J＝6.6,5.6Hz,4H),2.56(t,J＝8.6,6.3Hz,3H),1.95-1.83(m,J＝6.8Hz, 2H),1.82-1.74(m,1H),1.67-1.58(m,1H).
实施例278
Embodiment 278
合成方法Synthesis method
化合物278的合成方法参照实施例225。区别在于把步骤二中的176-2替换为1-(3-氨基丙基)-7-环丙基喹喔啉-2(1H)-酮。LC-MS(ESI)m/z:537.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.12(s,1H),7.96(d,J＝8.7Hz,1H),7.69(d,J＝8.3Hz,1H),7.54(d,J＝2.1Hz,1H),7.35(s,1H),7.18(dd,J＝8.8,1.8Hz,1H),7.02(dd,J＝8.4,1.5Hz,1H),5.32(t,J＝4.6,1H),5.03(s,1H),4.27(t,J＝7.1Hz,2H),4.17-4.02(m,2H),3.73-3.68(m,1H),3.21(s,6H),2.78-2.57(m,4H),2.16-2.06(m,1H),1.91-1.80(m,2H),1.80-1.71(m,1H),1.64-1.51(m,1H),1.09-0.99(m,2H),0.88-0.79(m,2H).The synthesis method of compound 278 refers to Example 225. The difference is that 176-2 in step 2 is replaced by 1-(3-aminopropyl)-7-cyclopropylquinoxaline-2(1H)-one. LC-MS (ESI) m/z: 537.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.12(s,1H),7.96(d,J＝8.7Hz,1H),7.69(d,J＝8.3Hz,1H),7.54(d,J＝2.1Hz,1H),7.35(s,1H),7.18(dd,J＝8.8,1.8Hz,1H),7.02(dd,J＝8.4,1.5Hz,1H), 5.32(t,J＝4.6,1H),5.03(s,1H),4.27(t,J ＝7.1Hz,2H),4.17-4.02(m,2H),3.73-3.68(m,1H),3.21(s,6H),2.78-2.57(m,4H),2.16-2.06(m,1H),1.91-1.80(m,2H),1.80-1.71(m,1H),1.64- 1.51(m,1H),1.09-0.99(m,2H),0.88-0.79(m,2H).
实施例279
Embodiment 279
合成方法Synthesis method
化合物279的合成方法参照实施例123。区别在于把步骤一中的二甲胺替换为N-甲乙胺，步骤七中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:317.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.96(d,J＝8.8Hz,1H),7.88(d,J＝8.8Hz,1H),7.71(t,1H),7.61(d,J＝2.0Hz,1H),7.20(dd,J＝8.9,2.2Hz,2H),6.54(t,J＝8.0,6.2Hz,2H),6.44(d,J＝2.1Hz,1H),4.21(ddd,J＝49.1,14.2,7.3Hz,2H),3.69(q,J＝6.9Hz,4H),3.65-3.57(m,2H),3.55-3.47(m,2H),3.29(s,3H),3.20(s,3H),2.09-1.92(m,2H),1.89-1.73(m,1H),1.30(t,J＝7.0Hz,3H),1.26(t,J＝6.9Hz,3H).The synthesis method of compound 279 refers to Example 123. The difference is that the dimethylamine in step 1 is replaced by N-methylethylamine, and the dimethylamine in step 7 is replaced by methylethylamine. LC-MS (ESI) m/z: 317.1 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ7.96 (d, J=8.8 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.71 (t, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.9, 2.2 Hz, 2H), 6.54 (t, J=8.0, 6.2 Hz, 2H), 6.44 (d, J=2.1 Hz, 1H), 4.21 (ddd, J=49.1, 14. 2,7.3Hz,2H),3.69(q,J=6.9Hz,4H),3.65-3.57(m,2H),3.55-3.47(m,2H),3.29(s,3H),3.20(s,3H),2.09-1.92(m,2H),1.89-1.73(m,1H),1.30(t ,J＝7.0Hz,3H),1.26(t,J＝6.9Hz,3H).
实施例280
Embodiment 280
合成方法Synthesis method
化合物280的合成方法参照实施例123。区别在于把步骤三中的1-Boc-3-溴甲基吡咯烷替换为1-Boc-3-氟-3-溴甲基吡咯烷，步骤七中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:320.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.96(dd,J＝16.1,8.8Hz,2H),7.76(t,J＝7.9Hz,1H),7.74(d,J＝2.1Hz,1H),7.21(dt,J＝8.7,2.8Hz,2H),6.60(t,J＝7.6Hz,2H),6.40(d,J＝2.1Hz,1H),4.69(d,J＝18.5Hz,2H),3.81-3.56(m,5H),3.44-3.38(m,1H),3.30(s,3H),3.24(s,6H),1.31(t,J＝7.0Hz,3H),1.25-1.23(m,2H).The synthesis method of compound 280 is similar to that of Example 123. The difference is that 1-Boc-3-bromomethylpyrrolidine in step 3 is replaced by 1-Boc-3-fluoro-3-bromomethylpyrrolidine, and dimethylamine in step 7 is replaced by methylethylamine. LC-MS (ESI) m/z: 320.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.96(dd,J＝16.1,8.8Hz,2H),7.76(t,J＝7.9Hz,1H),7.74(d,J＝2.1Hz,1H),7.21(dt,J＝8.7,2.8Hz,2H),6.60(t,J＝7.6Hz,2H),6.40(d,J＝2.1Hz,1H),4. 69(d,J＝18.5Hz,2H),3.81-3.56(m,5H),3.44-3.38(m,1H),3.30(s,3H),3.24(s,6H),1.31(t,J＝7.0Hz,3H),1.25-1.23(m,2H).
实施例281
Embodiment 281
合成路线
Synthetic route
步骤一：化合物281-1的合成Step 1: Synthesis of compound 281-1
室温下，将7-氯喹啉-2(1H)-酮(500mg，2.79mmol)溶于10mL干燥的乙腈中，加入DMAP(350mg，2.87mmol)和炔丙酸甲酯(350mg，4.17mmol),室温搅拌10分钟。LC-MS监测反应完全。反应液浓缩后经快速色谱柱层析分离(PE:EA,0-30％,10min)得到420mg化合物281-1，收率57％。LC-MS(ESI)m/z:264[M+H]+.At room temperature, 7-chloroquinoline-2(1H)-one (500 mg, 2.79 mmol) was dissolved in 10 mL of dry acetonitrile, and DMAP (350 mg, 2.87 mmol) and methyl propargyl ester (350 mg, 4.17 mmol) were added, and stirred at room temperature for 10 minutes. LC-MS monitored the reaction to be complete. After the reaction solution was concentrated, it was separated by flash chromatography (PE:EA, 0-30%, 10 min) to obtain 420 mg of compound 281-1, with a yield of 57%. LC-MS (ESI) m/z: 264 [M+H] + .
步骤二：化合物281-2的合成Step 2: Synthesis of compound 281-2
室温下，将化合物281-1(300mg，1.14mmol)溶于5mL甲醇中，将水合氢氧化锂(200mg，4.88mmol)溶于1mL水中滴加至反应液中，室温反应30分钟。LC-MS监测反应完全。浓缩除去多余甲醇，用1N的稀盐酸调pH至2-3后过滤得到100mg化合物281-2，收率35％。LC-MS(ESI)m/z:250[M+H]+.At room temperature, compound 281-1 (300 mg, 1.14 mmol) was dissolved in 5 mL of methanol, hydrated lithium hydroxide (200 mg, 4.88 mmol) was dissolved in 1 mL of water and added dropwise to the reaction solution, and reacted at room temperature for 30 minutes. LC-MS monitored the reaction to be complete. The excess methanol was removed by concentration, and the pH was adjusted to 2-3 with 1N dilute hydrochloric acid and filtered to obtain 100 mg of compound 281-2, with a yield of 35%. LC-MS (ESI) m/z: 250 [M + H] + .
步骤三：化合物281的合成Step 3: Synthesis of compound 281
室温下，将化合物281-2(45mg，0.160mmol)和化合物176-3(50mg，0.178mmol)溶于2mL干燥的DCE中，加入DMAP(11mg，0.090mmol)和DCC(55mg，0.267mmol),室温搅拌过夜。LC-MS监测反应完全。反应液直接浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到30mg粗品，后经高效液相色谱柱层析分离得到20mg化合物281，收率22％。LC-MS(ESI)m/z:513.4[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.46(t,J＝5.6Hz,1H),7.98(t,J＝8.7Hz,2H),7.82(d,J＝8.3Hz,1H),7.55-7.47(m,3H),7.40(dd,J＝8.3,1.9Hz,1H),7.20(dd,J＝8.7,1.9Hz,1H),6.68(dd,2H),4.10(t,J＝7.5Hz,2H),3.34-3.30(m,2H),3.22(s,6H),1.80(p,J＝7.2Hz,2H).At room temperature, compound 281-2 (45 mg, 0.160 mmol) and compound 176-3 (50 mg, 0.178 mmol) were dissolved in 2 mL of dry DCE, and DMAP (11 mg, 0.090 mmol) and DCC (55 mg, 0.267 mmol) were added, and stirred at room temperature overnight. LC-MS monitored the reaction to be complete. The reaction solution was directly concentrated and separated by flash chromatography column chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 30 mg of crude product, which was then separated by HPLC column chromatography to obtain 20 mg of compound 281, with a yield of 22%. LC-MS(ESI)m/z:513.4[M+H] + . 1 H NMR (600MHz, DMSO-d 6 )δ8.46(t,J＝5.6Hz,1H),7.98(t,J＝8.7Hz,2H),7.82(d,J＝8.3Hz,1H),7.55-7.47(m,3H),7.40(dd,J＝ 8.3,1.9Hz,1H),7.20(dd,J＝8.7,1.9Hz,1H),6.68(dd,2H),4.10(t,J＝7.5Hz,2H),3.34-3.30(m,2H),3.22(s,6H),1.80(p,J＝7.2Hz,2H).
实施例282
Embodiment 282
合成方法Synthesis method
化合物282的合成方法参照实施例123。区别在于把步骤一中的二甲胺替换为N-甲乙胺。LC-MS(ESI)m/z:310.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.89(d,J＝8.8Hz,1H),7.72(t,J＝7.9Hz,1H),7.61(d,J＝2.0Hz,1H),7.20(d,2H),6.54(t,J＝7.7Hz,2H),6.45(d,J＝2.1Hz,1H),4.21(ddd,J＝72.1,14.4,7.4Hz,2H),3.71(q,J＝6.9Hz,2H),3.68-3.58(m,2H),3.55-3.49(m,2H),3.31(s,6H),3.20(s,3H),2.08-1.95(m,2H),1.82(dq,J＝15.4,8.1Hz,1H),1.26(t,J＝7.1Hz,3H). The synthesis method of compound 282 refers to Example 123. The difference is that the dimethylamine in step 1 is replaced by N-methylethylamine. LC-MS (ESI) m/z: 310.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.03 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.20 (d, 2H), 6.54 (t, J = 7.7 Hz, 2H), 6.45 (d, J = 2.1 Hz, 1H), 4.21 (ddd, J = 72.1, 14 .4,7.4Hz,2H),3.71(q,J＝6.9Hz,2H),3.68-3.58(m,2H),3.55-3.49(m,2H),3.31(s,6H),3.20(s,3H),2.08-1.95(m,2H),1.82(dq,J＝15.4,8.1Hz,1H ),1.26(t,J＝7.1Hz,3H).
实施例283
Embodiment 283
合成方法Synthesis method
化合物283的合成方法参照实施例123。区别在于把步骤五中的2-氨基-6-溴吡啶替换为2-氨基-5-氟-6-溴吡啶。LC-MS(ESI)m/z:312.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.97(d,J＝8.8Hz,1H),7.67-7.58(m,2H),7.20(ddd,J＝8.3,5.9,2.0Hz,2H),6.59(dd,J＝8.0,2.1Hz,1H),6.51(d,J＝2.1Hz,1H),4.21(ddd,J＝80.6,14.4,7.4Hz,2H),3.75-3.68(m,1H),3.65(td,J＝8.8,8.2,3.9Hz,1H),3.56-3.47(m,1H),3.30(s,6H),3.22(s,6H),2.66(p,J＝7.1Hz,1H),2.00-1.94(m,2H),1.76(dq,J＝12.3,7.8Hz,1H).The synthesis method of compound 283 refers to Example 123. The difference is that 2-amino-6-bromopyridine in step 5 is replaced by 2-amino-5-fluoro-6-bromopyridine. LC-MS (ESI) m/z: 312.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.03 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.67-7.58 (m, 2H), 7.20 (ddd, J = 8.3, 5.9, 2.0 Hz, 2H), 6.59 (dd, J = 8.0, 2.1 Hz, 1H), 6.51 (d, J = 2.1 Hz, 1H), 4.21 (ddd, J = 80.6, 14.4, 7 .4Hz,2H),3.75-3.68(m,1H),3.65(td,J＝8.8,8.2,3.9Hz,1H),3.56-3.47(m,1H),3.30(s,6H),3.22(s,6H),2.66(p,J＝7.1Hz,1H),2.00-1.94(m,2H ),1.76(dq,J＝12.3,7.8Hz,1H).
实施例284
Embodiment 284
合成方法Synthesis method
化合物284的合成方法参照实施例123。区别在于把步骤七中的二甲胺替换为N-甲乙胺。LC-MS(ESI)m/z:310.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(d,J＝8.8Hz,2H),7.72(t,J＝7.8Hz,1H),7.61(d,J＝2.0Hz,1H),7.20(ddd,J＝8.9,6.7,2.0Hz,2H),6.54(t,J＝7.9Hz,2H),6.44(d,J＝2.1Hz,1H),4.22(ddd,J＝59.7,14.4,7.4Hz,2H),3.70(q,J＝7.0Hz,2H),3.57-3.48(m,2H),3.30(s,3H),3.23(s,6H),3.20(dd,J＝10.8,6.9Hz,2H),2.03-1.96(m,2H),1.82(dq,J＝15.5,7.9Hz,1H),1.31(t,J＝7.0Hz,3H).The synthesis method of compound 284 refers to Example 123. The difference is that the dimethylamine in step 7 is replaced by N-methylethylamine. LC-MS (ESI) m/z: 310.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.97 (d, J = 8.8 Hz, 2H), 7.72 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.20 (ddd, J = 8.9, 6.7, 2.0 Hz, 2H), 6.54 (t, J = 7.9 Hz, 2H), 6.44 (d, J = 2.1 Hz, 1H), 4.22 (ddd, J = 59.7, 14.4, 7. 4Hz,2H),3.70(q,J＝7.0Hz,2H),3.57-3.48(m,2H),3.30(s,3H),3.23(s,6H),3.20(dd,J＝10.8,6.9Hz,2H),2.03-1.96(m,2H),1.82(dq,J＝15.5,7.9Hz ,1H),1.31(t,J＝7.0Hz,3H).
实施例285
Embodiment 285
合成方法Synthesis method
化合物285的合成方法参照实施例123。区别在于把步骤三中的1-Boc-3-溴甲基吡咯烷替换为(3S)-3-溴甲基-1-吡咯烷甲酸叔丁酯。LC-MS(ESI)m/z:303.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.97(d,J＝8.8Hz,1H),7.72(dd,J＝8.4,7.3Hz,1H),7.61(d,J＝2.0Hz,1H),7.20(dt,J＝8.7,2.2Hz,2H),6.54(t,J＝7.9,5.7Hz,2H),6.45(d,J＝2.2Hz,1H),4.22(ddd,J＝59.2,14.4,7.5Hz,2H),3.57-3.48(m,2H),3.30(s,6H),3.23(s,6H),3.19(dd,J＝10.7,6.9Hz,2H),2.07-1.95(m,2H),1.82(dq,J＝15.8,7.9Hz,1H).The synthesis method of compound 285 refers to Example 123. The difference is that 1-Boc-3-bromomethylpyrrolidine in step 3 is replaced by (3S)-3-bromomethyl-1-pyrrolidinecarboxylic acid tert-butyl ester. LC-MS (ESI) m/z: 303.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.03 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.4, 7.3 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.20 (dt, J = 8.7, 2.2 Hz, 2H), 6.54 (t, J = 7.9, 5.7 Hz, 2H), 6.45 (d, J = 2.2 Hz,1H),4.22(ddd,J＝59.2,14.4,7.5Hz,2H),3.57-3.48(m,2H),3.30(s,6H),3.23(s,6H),3.19(dd,J＝10.7,6.9Hz,2H),2.07-1.95(m,2H),1.82(dq,J =15.8,7.9Hz,1H).
实施例286
Embodiment 286
合成方法Synthesis method
化合物286的合成方法参照实施例123。区别在于把步骤三中的1-Boc-3-溴甲基吡咯烷替换为(3R)-3-溴甲基-1-吡咯烷甲酸叔丁酯。LC-MS(ESI)m/z:303.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.97(d,J＝8.8Hz,1H),7.72(dd,J＝8.4,7.3Hz,1H),7.61(d,J＝2.0Hz,1H),7.20(dt,J＝8.7,2.2Hz,2H),6.54(t,J＝7.9,5.7Hz,2H),6.45(d,J＝2.2Hz,1H),4.22(ddd,J＝59.2,14.4,7.5Hz,2H),3.57-3.48(m,2H),3.30(s,6H),3.23(s,6H),3.19(dd,J＝10.7,6.9Hz,2H),2.07-1.95(m,2H),1.82(dq,J＝15.8,7.9Hz,1H).The synthesis method of compound 286 refers to Example 123. The difference is that 1-Boc-3-bromomethylpyrrolidine in step 3 is replaced by (3R)-3-bromomethyl-1-pyrrolidinecarboxylic acid tert-butyl ester. LC-MS (ESI) m/z: 303.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.03 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.4, 7.3 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.20 (dt, J = 8.7, 2.2 Hz, 2H), 6.54 (t, J = 7.9, 5.7 Hz, 2H), 6.45 (d, J = 2.2 Hz,1H),4.22(ddd,J＝59.2,14.4,7.5Hz,2H),3.57-3.48(m,2H),3.30(s,6H),3.23(s,6H),3.19(dd,J＝10.7,6.9Hz,2H),2.07-1.95(m,2H),1.82(dq,J =15.8,7.9Hz,1H).
实施例287
Embodiment 287
合成方法Synthesis method
化合物287的合成方法参照实施例123。区别在于把步骤一中的二甲胺替换为N-甲乙胺，步骤五中的2-氨基-6-溴吡啶替换为2-氨基-5-氟-6-溴吡啶。LC-MS(ESI)m/z:319.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.89(d,J＝8.7Hz,1H),7.66-7.59(m,2H),7.20(dd,J＝8.8,1.8Hz,2H),6.59(dd,J＝8.0,2.2Hz,1H),6.51(d,J＝2.1Hz,1H),4.20(ddd,J＝86.8,14.4,7.5Hz,2H),3.74-3.65(m,2H),3.64-3.58(m,2H),3.51(q,2H),3.30(s,6H),3.20(s,3H),2.00-1.93(m,2H),1.80-1.72(m,1H),1.26(t,3H).The synthesis method of compound 287 is similar to that of Example 123. The difference is that dimethylamine in step 1 is replaced by N-methylethylamine, and 2-amino-6-bromopyridine in step 5 is replaced by 2-amino-5-fluoro-6-bromopyridine. LC-MS (ESI) m/z: 319.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.03(d,J＝8.8Hz,1H),7.89(d,J＝8.7Hz,1H),7.66-7.59(m,2H),7.20(dd,J＝8.8,1.8Hz,2H),6.59(dd,J＝8.0,2.2Hz,1H),6.51(d,J＝2.1Hz,1H),4.20(dd d,J＝86.8,14.4,7.5Hz,2H),3.74-3.65(m,2H),3.64-3.58(m,2H),3.51(q,2H),3.30(s,6H),3.20(s,3H),2.00-1.93(m,2H),1.80-1.72(m,1H),1 .26(t,3H).
实施例288
Embodiment 288
合成方法Synthesis method
化合物288的合成方法参照实施例123。区别在于把步骤五中的2-氨基-6-溴吡啶替换为2-氨基-5-甲基-6-溴吡啶。LC-MS(ESI)m/z:310.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.02(d,J＝8.8Hz,1H),7.96(d,J＝8.7Hz,1H),7.60(d,J＝2.0Hz,1H),7.56(d,J＝7.5Hz,1H),7.18(dd,J＝8.8,2.0Hz,2H),6.62(d,J＝7.4Hz,1H),6.43(d,J＝2.1Hz,1H),4.27(dd,J＝14.4,7.8Hz,1H),4.10(dd,J＝14.3,6.9Hz,1H),3.71-3.61(m,1H),3.55-3.45(m,2H),3.32-3.31(m,1H),3.30(s,6H),3.22(s,6H),2.64-2.58(m,1H),2.42(s,3H),1.92(dq,J＝12.3,6.4Hz,1H),1.73(dd,J＝12.3,7.4Hz,1H). The synthesis method of compound 288 refers to Example 123. The difference is that 2-amino-6-bromopyridine in step 5 is replaced by 2-amino-5-methyl-6-bromopyridine. LC-MS (ESI) m/z: 310.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ8.02 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.18 (dd, J=8.8, 2.0 Hz, 2H), 6.62 (d, J=7.4 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 4.27 (dd, J=14.4, 7.8 Hz, 1H), 4.1 0(dd,J＝14.3,6.9Hz,1H),3.71-3.61(m,1H),3.55-3.45(m,2H),3.32-3.31(m,1H),3.30(s,6H),3.22(s,6H),2.64-2.58(m,1H),2.42(s,3H),1.92 (dq,J＝12.3,6.4Hz,1H),1.73(dd,J＝12.3,7.4Hz,1H).
实施例289
Embodiment 289
合成方法Synthesis method
化合物289的合成方法参照实施例123。区别在于把步骤七中的二甲胺替换为N-甲乙胺，步骤三中的1-Boc-3-溴甲基吡咯烷替换为1-Boc-3-甲基-3-溴甲基吡咯烷。LC-MS(ESI)m/z:317.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.96(d,J＝8.8Hz,1H),7.90(d,J＝8.7Hz,1H),7.73-7.66(m,2H),7.21(dd,J＝8.8,2.2Hz,1H),7.16(dd,J＝8.7,1.8Hz,1H),6.54(d,J＝7.3Hz,1H),6.50-6.44(m,2H),4.44-4.32(m,1H),4.20-4.03(m,1H),3.70(q,J＝7.1Hz,2H),3.53-3.44(m,1H),3.42-3.35(m,2H),3.30(s,3H),3.22(s,6H),3.13(d,J＝10.8Hz,1H),1.31(t,J＝7.0Hz,3H),1.26-1.20(m,2H),1.08(s,3H).The synthesis method of compound 289 refers to Example 123. The difference is that the dimethylamine in step 7 is replaced by N-methylethylamine, and the 1-Boc-3-bromomethylpyrrolidine in step 3 is replaced by 1-Boc-3-methyl-3-bromomethylpyrrolidine. LC-MS (ESI) m/z: 317.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.96(d,J＝8.8Hz,1H),7.90(d,J＝8.7Hz,1H),7.73-7.66(m,2H),7.21(dd,J＝8.8,2.2Hz,1H),7.16(dd,J＝8.7,1.8Hz,1H),6.54(d,J＝7.3Hz,1H),6.50-6. 44(m,2H),4.44-4.32(m,1H), 4.20-4.03(m,1H),3.70(q,J＝7.1Hz,2H),3.53-3.44(m,1H),3.42-3.35(m,2H),3.30(s,3H),3.22(s,6H),3.13(d,J＝10.8Hz,1H),1.31(t,J＝7.0Hz, 3H),1.26-1.20(m,2H),1.08(s,3H).
实施例290
Embodiment 290
合成方法Synthesis method
化合物290的合成方法参照实施例123。区别在于把步骤五中的2-氨基-6-溴吡啶替换为2-氨基-3-甲基-6-溴吡啶。LC-MS(ESI)m/z:310.1[M/2+H]+.The synthesis method of compound 290 refers to Example 123. The difference is that 2-amino-6-bromopyridine in step 5 is replaced by 2-amino-3-methyl-6-bromopyridine. LC-MS (ESI) m/z: 310.1 [M/2+H] + .
实施例291
Embodiment 291
合成路线
Synthetic route
步骤一：化合物291-1的合成Step 1: Synthesis of compound 291-1
室温下，将2,4,7-三氯喹啉(1.6g，6.93mmol)溶于30mL冰醋酸中，升温至100 ℃搅拌过夜。LC-MS监测反应完全。浓缩除去大量冰醋酸，加DCM打浆过滤得到1.2g化合物291-1，收率81％。LC-MS(ESI)m/z:214[M+H]+.At room temperature, 2,4,7-trichloroquinoline (1.6 g, 6.93 mmol) was dissolved in 30 mL of glacial acetic acid and the temperature was raised to 100 ℃ and stirred overnight. LC-MS monitored the reaction to be complete. Concentrate to remove a large amount of glacial acetic acid, add DCM to slurry and filter to obtain 1.2 g of compound 291-1, with a yield of 81%. LC-MS (ESI) m/z: 214 [M+H] + .
步骤二：化合物291-2的合成Step 2: Synthesis of compound 291-2
室温下，将化合物291-1(500mg，2.34mmol)溶于10mL NMP中，加入甲基乙基胺(1.4g，23.73mmol)，160℃微波反应1小时。LC-MS监测反应完全。反应液搅拌中加入适量水后有大量固体析出，过滤得460mg化合物291-2，收率83％。LC-MS(ESI)m/z:237[M+H]+.At room temperature, compound 291-1 (500 mg, 2.34 mmol) was dissolved in 10 mL NMP, methylethylamine (1.4 g, 23.73 mmol) was added, and microwave reaction was performed at 160°C for 1 hour. LC-MS monitored the reaction to be complete. After adding an appropriate amount of water to the reaction solution during stirring, a large amount of solid precipitated, which was filtered to obtain 460 mg of compound 291-2, with a yield of 83%. LC-MS (ESI) m/z: 237 [M+H] + .
步骤三：化合物291-3的合成Step 3: Synthesis of compound 291-3
室温下，将化合物291-2(530mg，2.24mmol)溶于10mL干燥的乙腈中，加入DMAP(273mg，2.24mmol)和炔丙酸甲酯(280mg，3.33mmol),室温搅拌10分钟。LC-MS监测反应完全。反应液浓缩后，经快速色谱柱层析分离(PE:EA,0-30％,10min)得到450mg化合物291-3，收率63％。LC-MS(ESI)m/z:321[M+H]+.At room temperature, compound 291-2 (530 mg, 2.24 mmol) was dissolved in 10 mL of dry acetonitrile, DMAP (273 mg, 2.24 mmol) and methyl propargyl ester (280 mg, 3.33 mmol) were added, and stirred at room temperature for 10 minutes. LC-MS monitored the reaction to be complete. After the reaction solution was concentrated, it was separated by flash chromatography (PE: EA, 0-30%, 10 min) to obtain 450 mg of compound 291-3, with a yield of 63%. LC-MS (ESI) m/z: 321 [M+H] + .
步骤四：化合物291-4的合成Step 4: Synthesis of compound 291-4
室温下，将化合物291-3(450mg，1.40mmol)溶于10mL甲醇中，将水合氢氧化锂(350mg，8.54mmol)溶于2mL水中滴加至反应液中，室温反应30分钟。LC-MS监测反应完全。浓缩除去多余甲醇，用1N的稀盐酸调pH至2-3后过滤得到260mg化合物291-4，收率60％。LC-MS(ESI)m/z:307[M+H]+.At room temperature, compound 291-3 (450 mg, 1.40 mmol) was dissolved in 10 mL of methanol, hydrated lithium hydroxide (350 mg, 8.54 mmol) was dissolved in 2 mL of water and added dropwise to the reaction solution, and reacted at room temperature for 30 minutes. LC-MS monitored the reaction to be complete. Concentrate to remove excess methanol, adjust the pH to 2-3 with 1N dilute hydrochloric acid, and filter to obtain 260 mg of compound 291-4, with a yield of 60%. LC-MS (ESI) m/z: 307 [M + H] + .
步骤五：化合物291的合成Step 5: Synthesis of compound 291
室温下，将化合物291-4(50mg，0.163mmol)和化合物176-2(46mg，0.164mmol)溶于2mL干燥的DCE中，加入DMAP(10mg，0.082mmol)和DCC(50mg，0.243mmol),室温搅拌过夜。LC-MS监测反应完全。反应液直接浓缩后，经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到30mg粗品，后经高效液相色谱柱层析分离得到14mg化合物291，收率15％。LC-MS(ESI)m/z:569.2[M+H]+.At room temperature, compound 291-4 (50 mg, 0.163 mmol) and compound 176-2 (46 mg, 0.164 mmol) were dissolved in 2 mL of dry DCE, and DMAP (10 mg, 0.082 mmol) and DCC (50 mg, 0.243 mmol) were added and stirred at room temperature overnight. LC-MS monitored the reaction to be complete. After the reaction solution was directly concentrated, it was separated by flash chromatography column chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 30 mg of crude product, and then separated by high-performance liquid chromatography column chromatography to obtain 14 mg of compound 291, with a yield of 15%. LC-MS (ESI) m/z: 569.2 [M+H] + .
实施例292
Embodiment 292
合成方法Synthesis method
化合物292的合成方法参照实施例123。区别在于把步骤五中的2-氨基-6-溴吡啶替换为2-氨基-4-甲基-6-溴吡啶。LC-MS(ESI)m/z:310.1[M/2+H]+.1H NMR(600MHz,Chloroform-d)δ7.71(d,J＝8.6Hz,1H),7.64(d,J＝12.8Hz,1H),7.53(s,1H),7.34(s,1H),7.23(d,J＝8.8Hz,2H),6.88(d,J＝13.7Hz,1H),6.10(s,1H),4.39-4.26(m,2H),3.78-3.42(m,12H),3.33-3.28(m,3H),2.97-3.06(m,2H),3.03(s,2H),2.92(s,3H),2.16-2.05(m,2H).The synthesis method of compound 292 refers to Example 123, except that 2-amino-6-bromopyridine in step 5 is replaced by 2-amino-4-methyl-6-bromopyridine. LC-MS(ESI)m/z:310.1[M/2+H] + . 1 H NMR(600MHz,Chloroform-d)δ7.71(d,J＝8.6Hz,1H),7.64(d,J＝12.8Hz,1H),7.53(s,1H),7.34(s,1H),7.23(d,J＝8.8Hz,2H), 6.88(d,J＝13.7Hz,1H),6.10(s,1H),4.39-4.26(m,2H),3.78-3.42(m,12H),3.33-3.28(m,3H),2.97-3.06(m,2H),3.03(s,2H),2.92(s,3H),2.16-2 .05(m,2H).
实施例293
Embodiment 293
合成路线
Synthetic route
步骤一：化合物293-1的合成Step 1: Synthesis of compound 293-1
室温下，将6-溴-3,3-二甲基吲哚-2-酮(500mg，2.08mmol)溶于10mL干燥的DMF中，加入3-(溴甲基)吡咯烷-1-甲酸叔丁酯(820mg，3.11mmol)和碳酸钾(860g，6.23mmol),升温至100℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相，浓缩后经快速色谱柱层析分离(PE:EA,0-30％,10min)得到800mg化合物293-1，收率91％。LC-MS(ESI)m/z:423[M+H]+.At room temperature, 6-bromo-3,3-dimethylindole-2-one (500 mg, 2.08 mmol) was dissolved in 10 mL of dry DMF, tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate (820 mg, 3.11 mmol) and potassium carbonate (860 g, 6.23 mmol) were added, and the mixture was heated to 100 °C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine, concentrated, and separated by flash chromatography (PE:EA, 0-30%, 10 min) to obtain 800 mg of compound 293-1, with a yield of 91%. LC-MS (ESI) m/z: 423 [M + H] + .
步骤二：化合物293-2的合成Step 2: Synthesis of compound 293-2
室温下，将化合物293-1(300mg，0.709mmol)溶于8mL二氧六环和2mL水中，加入Pd(dppf)Cl2(60mg，0.0734mmol)，环丙基硼酸频哪醇酯(180mg，1.07mmol)和碳酸钾(300mg，2.17mmol),升温至100℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相浓缩后经快速色谱柱层析分离(PE:EA,0-30％,10min)得到170mg化合物293-2，收率62％。LC-MS(ESI)m/z:385[M+H]+.At room temperature, compound 293-1 (300 mg, 0.709 mmol) was dissolved in 8 mL of dioxane and 2 mL of water, and Pd(dppf)Cl 2 (60 mg, 0.0734 mmol), cyclopropylboronic acid pinacol ester (180 mg, 1.07 mmol) and potassium carbonate (300 mg, 2.17 mmol) were added, and the temperature was raised to 100°C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine and concentrated and separated by flash chromatography (PE:EA, 0-30%, 10 min) to obtain 170 mg of compound 293-2, with a yield of 62%. LC-MS (ESI) m/z: 385 [M+H] + .
步骤三：化合物293-3的合成Step 3: Synthesis of compound 293-3
室温下，将化合物293-2溶于3mL干燥的二氧六环中，滴加1mL盐酸二氧六环溶液，室温搅拌3小时。LC-MS监测反应完全。反应液过滤后冻干得到100mg化合物293-3，收率80％。LC-MS(ESI)m/z:285[M+H]+.At room temperature, compound 293-2 was dissolved in 3 mL of dry dioxane, 1 mL of dioxane hydrochloride solution was added dropwise, and stirred at room temperature for 3 hours. LC-MS monitored the reaction to be complete. The reaction solution was filtered and freeze-dried to obtain 100 mg of compound 293-3, with a yield of 80%. LC-MS (ESI) m/z: 285 [M+H] + .
步骤四：化合物293的合成Step 4: Synthesis of compound 293
室温下，将化合物293-3(50mg，0.176mmol)和1-(6-溴吡啶-2-基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮(75mg，0.191mmol)溶于2mL干燥的DMF中，加入碳酸铯(175mg，0.534mmol),升温至120℃微波反应2小时。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相，浓缩后经快速色谱柱层析分离(DCM:MeOH,0-15％,10min)得到30mg粗品，后经高效液相色谱柱层析分离得到18mg化合物293，收率17％。LC-MS(ESI)m/z:597.3[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.96(d,J＝8.8Hz,1H),7.72(dd,J＝8.4,7.3Hz,1H),7.23-7.15(m,2H),6.80(d,J＝1.4 Hz,1H),6.76(dd,J＝7.6,1.5Hz,1H),6.54(dd,J＝10.8,7.8Hz,2H),6.44(d,J＝2.1Hz,1H),3.82-3.67(m,4H),3.55-3.47(m,2H),3.14(dd,J＝10.6,7.0Hz,1H),2.81-2.67(m,1H),1.95-1.83(m,1H),1.79-1.67(m,1H),1.30(t,J＝7.0Hz,3H),1.23(d,J＝8.3Hz,6H),0.94-0.85(m,2H),0.73-0.65(m,2H).At room temperature, compound 293-3 (50 mg, 0.176 mmol) and 1-(6-bromopyridin-2-yl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one (75 mg, 0.191 mmol) were dissolved in 2 mL of dry DMF, cesium carbonate (175 mg, 0.534 mmol) was added, and the temperature was raised to 120°C for microwave reaction for 2 hours. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine, concentrated, and separated by flash chromatography (DCM: MeOH, 0-15%, 10 min) to obtain 30 mg of crude product, which was then separated by high performance liquid chromatography to obtain 18 mg of compound 293, with a yield of 17%. LC-MS (ESI) m/z: 597.3[M+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ7.96 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.4, 7.3 Hz, 1H), 7.23-7.15 (m, 2H), 6.80 (d, J = 1.4 Hz,1H),6.76(dd,J＝7.6,1.5Hz,1H),6.54(dd,J＝10.8,7.8Hz,2H),6.44(d,J＝2.1Hz,1H),3.82-3.67(m,4H),3.55-3.47(m,2H),3.14(dd,J＝10.6,7.0Hz,1 H),2.81-2.67(m,1H),1.95-1.83(m,1H),1.79-1.67(m,1H),1.30(t,J＝7.0Hz,3H),1.23(d,J＝8.3Hz,6H),0.94-0.85(m,2H),0.73-0.65(m,2H).
实施例294
Embodiment 294
合成方法Synthesis method
化合物294的合成方法参照实施例123。区别在于把步骤五中的2-氨基-6-溴吡啶替换为2-氨基-3-氟-6-溴吡啶。LC-MS(ESI)m/z:312.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.12(d,J＝8.8Hz,1H),7.97(d,J＝8.8Hz,1H),7.67-7.58(m,2H),7.20(ddd,J＝8.3,5.9,2.0Hz,2H),6.59(dd,J＝8.0,2.1Hz,1H),6.51(d,J＝2.1Hz,1H),4.21(ddd,J＝80.6,14.4,7.4Hz,2H),3.75-3.68(m,1H),3.65(td,J＝8.8,8.2,3.9Hz,1H),3.56-3.47(m,1H),3.30(s,6H),3.22(s,6H),2.66(p,J＝7.1Hz,1H),2.00-1.94(m,2H),1.76(dq,J＝12.3,7.8Hz,1H).The synthesis method of compound 294 refers to Example 123. The difference is that 2-amino-6-bromopyridine in step 5 is replaced by 2-amino-3-fluoro-6-bromopyridine. LC-MS (ESI) m/z: 312.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.12 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.67-7.58 (m, 2H), 7.20 (ddd, J = 8.3, 5.9, 2.0 Hz, 2H), 6.59 (dd, J = 8.0, 2.1 Hz, 1H), 6.51 (d, J = 2.1 Hz, 1H), 4.21 (ddd, J = 80.6, 14.4, 7 .4Hz,2H),3.75-3.68(m,1H),3.65(td,J＝8.8,8.2,3.9Hz,1H),3.56-3.47(m,1H),3.30(s,6H),3.22(s,6H),2.66(p,J＝7.1Hz,1H),2.00-1.94(m,2H ),1.76(dq,J＝12.3,7.8Hz,1H).
实施例295
Embodiment 295
合成路线
Synthetic route
步骤一：化合物295的合成Step 1: Synthesis of compound 295
室温下，将化合物293-3(20mg，0.0704mmol)和化合物291-4(22mg，0.0719mmol)溶于2mL干燥的DCE中，加入DMAP(5mg，0.0410mmol)和DCC(22mg，0.107mmol),室温搅拌过夜。LC-MS监测反应完全。反应液直接浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到30mg粗品，后经高效液相色谱柱层析分离得到13mg化合物295，收率34％。LC-MS(ESI)m/z:573.3[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.76(d,J＝8.7Hz,1H),7.56(dd,J＝13.9,3.3Hz,1H),7.51(dd,J＝4.9,2.0Hz,1H),7.37(dt,J＝8.7,2.3Hz,1H),7.19(dd,J＝13.2,7.6Hz,1H),6.91(dd,J＝29.7,13.9Hz,1H),6.82(d,J＝7.3Hz,1H),6.77(ddd,J＝17.3,7.6,1.5Hz,1H),5.90(d,J＝3.4Hz,1H),3.80-3.67(m,3H),3.64-3.48(m,2H),3.43-3.36(m,2H),3.22(q,J＝10.0,5.0Hz,2H),2.83(s,3H),2.73(p,J＝7.1Hz,1H),2.69-2.59(m,1H),2.04-1.96(m,1H),1.76-1.60 (m,1H),1.27-1.20(m,9H),0.98-0.87(m,2H),0.77-0.66(m,2H).At room temperature, compound 293-3 (20 mg, 0.0704 mmol) and compound 291-4 (22 mg, 0.0719 mmol) were dissolved in 2 mL of dry DCE, and DMAP (5 mg, 0.0410 mmol) and DCC (22 mg, 0.107 mmol) were added, and stirred at room temperature overnight. LC-MS monitored the reaction to be complete. The reaction solution was directly concentrated and separated by flash column chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 30 mg of crude product, which was then separated by HPLC column chromatography to obtain 13 mg of compound 295, with a yield of 34%. LC-MS (ESI) m/z: 573.3 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.76(d,J＝8.7Hz,1H),7.56(dd,J＝13.9,3.3Hz,1H),7.51(dd,J＝4.9,2.0Hz,1H),7.37(dt,J＝8.7,2.3Hz,1H),7.19(dd,J＝13.2,7.6Hz,1H),6.91(dd,J＝29 .7,13.9Hz,1H),6.82(d,J＝7.3Hz,1H),6.77(ddd,J＝17. 3,7.6,1.5Hz,1H),5.90(d,J＝3.4Hz,1H),3.80-3.67(m,3H),3.64-3.48(m,2H),3.43-3.36(m,2H),3.22(q,J＝10.0,5.0Hz,2H),2.83(s,3H),2.73(p ,J＝7.1Hz,1H),2.69-2.59(m,1H),2.04-1.96(m,1H),1.76-1.60 (m,1H),1.27-1.20(m,9H),0.98-0.87(m,2H),0.77-0.66(m,2H).
实施例296
Embodiment 296
合成路线
Synthetic route
步骤一：化合物296-1的合成Step 1: Synthesis of compound 296-1
取6-氯氧化吲哚(0.50g，3.0mmol)、N-Boc-3-氨基丙基溴(1.4g，6.0mmol)和碳酸钾(1.3g，9.0mmol)分散到N,N-二甲基甲酰胺(10mL)溶液中，加热到100゜C，搅拌过夜。冷却至室温后，反应混合物用乙酸乙酯(20mL×3)和水(20mL)萃取，合并有机相，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝1/20)纯化，得到化合物296-1的粗品。LC-MS(ESI)m/z:269[M-56+H]+.6-Chloroindole (0.50 g, 3.0 mmol), N-Boc-3-aminopropyl bromide (1.4 g, 6.0 mmol) and potassium carbonate (1.3 g, 9.0 mmol) were dispersed in N,N-dimethylformamide (10 mL) solution, heated to 100 °C and stirred overnight. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (20 mL × 3) and water (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography column (eluent: methanol/dichloromethane = 1/20) to obtain the crude product of compound 296-1. LC-MS (ESI) m/z: 269 [M-56 + H] + .
步骤二：化合物296-2的合成Step 2: Synthesis of compound 296-2
取化合物296-1(30mg，0.093mmol)分散到1,4-二氧六环(1.0mL)中，室温下，向反应液中滴加盐酸的二氧六环溶液(1.0mL)，室温搅拌过夜。反应液经减压浓缩后，得到化合物296-2的粗品，直接用于下一步。LC-MS(ESI)m/z:225[M+H]+.Compound 296-1 (30 mg, 0.093 mmol) was dispersed in 1,4-dioxane (1.0 mL). A solution of hydrochloric acid in dioxane (1.0 mL) was added dropwise to the reaction solution at room temperature and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product of compound 296-2, which was used directly in the next step. LC-MS (ESI) m/z: 225 [M+H] + .
步骤三：化合物296的合成Step 3: Synthesis of compound 296
将化合物296-2(24mg，0.11mmol)、化合物291-4(33mg，0.11mmol)，DCC(33mg，0.16mmol)分散到1,2-二氯乙烷(1.0mL)溶液中，向反应混合物中加入4-二甲氨基吡啶(7.0mg，0.055mmol)，室温搅拌2个小时。反应混合物用二氯甲烷(5mL×3)和水(5mL)萃取，合并有机相，饱和食盐水洗涤(5mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝1/12)纯化，得到化合物296的粗品。粗品再经制备液相色谱纯化，制备液冷冻干燥，得到产物296，14.06mg，产率26％。LC-MS(ESI)m/z:513.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.32(t,J＝5.6Hz,1H),7.76(d,J＝8.7Hz,1H),7.56(d,J＝14.2Hz,1H),7.50(d,J＝2.0Hz,1H),7.38(dd,J＝8.7,2.0Hz,1H),7.27(d,J＝7.9Hz,1H),7.21(d,J＝1.9Hz,1H),7.04(dd,J＝7.8,1.9Hz,1H),6.66(d,J＝14.2Hz,1H),3.72(t,J＝7.2Hz,2H),3.57(s,2H),3.24(dq,J＝13.9,6.9Hz,4H),2.83(s,3H),1.78(p,J＝7.2Hz,2H),1.21(t,J ＝7.1Hz,3H).Compound 296-2 (24 mg, 0.11 mmol), compound 291-4 (33 mg, 0.11 mmol), and DCC (33 mg, 0.16 mmol) were dispersed in a 1,2-dichloroethane (1.0 mL) solution, and 4-dimethylaminopyridine (7.0 mg, 0.055 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was extracted with dichloromethane (5 mL × 3) and water (5 mL), and the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: methanol/dichloromethane = 1/12) to obtain a crude product of compound 296. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain product 296, 14.06 mg, with a yield of 26%. LC-MS (ESI) m/z: 513.1[M+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ8.32 (t, J = 5.6 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 14.2 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.38 (dd,J＝8.7,2.0Hz,1H),7.27(d,J＝7.9Hz,1H),7.21(d,J＝1.9Hz,1H ),7.04(dd,J＝7.8,1.9Hz,1H),6.66(d,J＝14.2Hz,1H),3.72(t,J＝7.2Hz,2H),3.57(s,2H),3.24(dq,J＝13.9,6.9Hz,4H),2.83(s,3H),1.78(p,J＝7.2Hz,2H ),1.21(t,J =7.1Hz,3H).
实施例297
Embodiment 297
合成路线
Synthetic route
步骤一：化合物297-1的合成Step 1: Synthesis of compound 297-1
将1-羟基甲基-1-(叔丁氧基羰基氨基甲基)环丙烷(2.0g，9.95mmol)溶解在20mL二氯甲烷中，降温至0℃后加入四溴化碳(5.0g，14.93mmol)和三苯基磷(4.0g，14.93mmol)，反应混合液在室温下搅拌30min，TLC监测完全反应。1-Hydroxymethyl-1-(tert-butoxycarbonylaminomethyl)cyclopropane (2.0 g, 9.95 mmol) was dissolved in 20 mL of dichloromethane, and the temperature was cooled to 0°C. Carbon tetrabromide (5.0 g, 14.93 mmol) and triphenylphosphine (4.0 g, 14.93 mmol) were added. The reaction mixture was stirred at room temperature for 30 min and the reaction was monitored by TLC.
反应体系中加入40mL水，用二氯甲烷(50mL×3)萃取，合并有机相用水(100mL×3)洗涤，无水硫酸钠干燥。过滤，有机相浓缩后粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-50％，15min)得到化合物297-1，2.1g，淡黄色油状液体，产率80％。LC-MS(ESI)m/z:264[M+H]+.40 mL of water was added to the reaction system, extracted with dichloromethane (50 mL × 3), the combined organic phases were washed with water (100 mL × 3), and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated and the crude product was chromatographed on a silica gel column (petroleum ether: ethyl acetate, 0-50%, 15 min) to obtain compound 297-1, 2.1 g, light yellow oily liquid, with a yield of 80%. LC-MS (ESI) m/z: 264 [M + H] + .
步骤二：化合物297-2的合成Step 2: Synthesis of compound 297-2
室温下，将6-溴-3，3-二甲基吲哚啉-2-酮(1.0g，4.17mmol)溶解在10mLN,N-二甲基甲酰胺中，向其中加入化合物297-1(1.6g，6.25mmol)和碳酸钾(1.7g，12.51mmol)，100℃下搅拌16h。TLC监测完全反应。反应体系中加入40mL水，用乙酸乙酯(40mL×3)萃取，合并有机相，用饱和氯化钠溶液(80mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物297-2，677mg，白色固体，产率38％。LC-MS(ESI)m/z:423[M+H]+.At room temperature, 6-bromo-3,3-dimethylindolin-2-one (1.0 g, 4.17 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and compound 297-1 (1.6 g, 6.25 mmol) and potassium carbonate (1.7 g, 12.51 mmol) were added thereto, and stirred at 100 ° C for 16 h. TLC monitored the complete reaction. 40 mL of water was added to the reaction system, extracted with ethyl acetate (40 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (80 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 297-2, 677 mg, white solid, yield 38%. LC-MS (ESI) m/z: 423 [M + H] + .
步骤三：化合物297-3的合成Step 3: Synthesis of compound 297-3
室温下将化合物279-2(677mg，1.60mmol)、环丙基硼酸频哪醇酯(674mg，4.01mmol)、碳酸钾(662mg，4.80mmol)溶解在10mL1，4-二氧六环中，向其中加入[1，1’-双(二苯基磷)二茂铁]二氯化钯二氯甲烷络合物(131mg，0.16mmol)并加入水1mL，氮气保护下升温至100℃搅拌16h。TLC监测完全反应。反应体系中加入40mL水，用乙酸乙酯(40mL×3)萃取，合并有机相，用饱和氯化钠溶液(80mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物279-3，593mg，白色固体，产率96％。LC-MS(ESI)m/z:385[M+H]+.步骤四：化合物297-4的合成 Compound 279-2 (677 mg, 1.60 mmol), cyclopropylboronic acid pinacol ester (674 mg, 4.01 mmol), potassium carbonate (662 mg, 4.80 mmol) were dissolved in 10 mL 1,4-dioxane at room temperature, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (131 mg, 0.16 mmol) and 1 mL of water were added thereto, and the temperature was raised to 100°C under nitrogen protection and stirred for 16 h. TLC monitored the complete reaction. 40 mL of water was added to the reaction system, extracted with ethyl acetate (40 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (80 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was chromatographed on a silica gel column (petroleum ether: ethyl acetate, 0-100%, 20 min) to give compound 279-3, 593 mg, white solid, yield 96%. LC-MS (ESI) m/z: 385 [M+H] + . Step 4: Synthesis of compound 297-4
室温下将化合物279-3(593mg，1.54mmol)溶解在1,4-二氧六环(6mL)中，向其中加入4M的盐酸-二氧六环溶液6mL，室温下搅拌30min。TLC监测完全反应，浓缩后得到化合物279-4的盐酸盐，599mg，白色固体，产率99％。LC-MS(ESI)m/z:285[M+H]+.Compound 279-3 (593 mg, 1.54 mmol) was dissolved in 1,4-dioxane (6 mL) at room temperature, 6 mL of 4M hydrochloric acid-dioxane solution was added thereto, and stirred at room temperature for 30 min. TLC monitored the complete reaction, and after concentration, the hydrochloride of compound 279-4 was obtained, 599 mg, white solid, with a yield of 99%. LC-MS (ESI) m/z: 285 [M + H] + .
步骤五：化合物297的合成Step 5: Synthesis of compound 297
室温下将化合物291-4(22mg，0.07mmol)、化合物297-4(20mg，0.07mmol)、4-二甲氨基吡啶(5mg，0.04mmol)溶解在1mL二氯乙烷中，搅拌加入N,N-二环己基碳二亚胺(22mg，0.11mmol)。反应混合液在室温下搅拌1h。LC-MS检测完全反应。经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，HPLC制备纯化后得到化合物297，6.18mg，白色固体，产率15.4％。LC-MS(ESI)m/z:573.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.35(t,J＝5.4Hz,1H),7.77(d,J＝8.7Hz,1H),7.59(d,J＝14.2Hz,1H),7.54(d,J＝2.0Hz,1H),7.39(dd,J＝8.7,2.0Hz,1H),7.18(d,J＝7.5Hz,1H),6.83-6.71(m,3H),5.92(s,1H),3.76(s,2H),3.22(q,J＝7.1Hz,2H),3.15(d,J＝5.4Hz,2H),2.83(s,3H),2.06-1.95(m,3H),1.89(ddd,J＝13.4,8.6,5.1Hz,1H),1.50-1.41(m,1H),1.20(t,J＝7.1Hz,3H),0.94-0.82(m,4H),0.71-0.62(m,2H),0.58-0.45(m,4H).Compound 291-4 (22 mg, 0.07 mmol), compound 297-4 (20 mg, 0.07 mmol), and 4-dimethylaminopyridine (5 mg, 0.04 mmol) were dissolved in 1 mL of dichloroethane at room temperature, and N,N-dicyclohexylcarbodiimide (22 mg, 0.11 mmol) was added with stirring. The reaction mixture was stirred at room temperature for 1 h. LC-MS detected the complete reaction. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min), and compound 297 was obtained after HPLC preparation and purification, 6.18 mg, white solid, yield 15.4%. LC-MS (ESI) m/z: 573.3 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.35(t,J＝5.4Hz,1H),7.77(d,J＝8.7Hz,1H),7.59(d,J＝14.2Hz,1H),7.54(d,J＝2.0Hz,1H),7.39(dd,J＝8.7,2.0Hz,1H),7.18(d,J＝7.5Hz,1H),6.83-6. 71(m,3H),5.92(s,1H),3.76(s,2H),3.22(q,J＝ 7.1Hz,2H),3.15(d,J＝5.4Hz,2H),2.83(s,3H),2.06-1.95(m,3H),1.89(ddd,J＝13.4,8.6,5.1Hz,1H),1.50-1.41(m,1H),1.20(t,J＝7.1Hz,3H),0.94-0 .82(m,4H),0.71-0.62(m,2H),0.58-0.45(m,4H).
实施例298
Embodiment 298
合成路线
Synthetic route
步骤一：化合物298-1的合成Step 1: Synthesis of compound 298-1
室温下，将6-溴-3,3-二甲基吲哚-2-酮(1g，4.17mmol)溶于20mL干燥的乙腈中，加入DMAP(500mg，4.10mmol)和炔丙酸甲酯(500mg，5.95mmol),室温搅拌10分钟。LC-MS监测反应完全。反应液浓缩后，经快速色谱柱层析分离(PE:EA,0-30％,10min)得到1.2g化合物298-1，收率89％。LC-MS(ESI)m/z:324[M+H]+.At room temperature, 6-bromo-3,3-dimethylindole-2-one (1 g, 4.17 mmol) was dissolved in 20 mL of dry acetonitrile, and DMAP (500 mg, 4.10 mmol) and methyl propargyl ester (500 mg, 5.95 mmol) were added, and stirred at room temperature for 10 minutes. LC-MS monitored the reaction to be complete. After the reaction solution was concentrated, it was separated by flash column chromatography (PE:EA, 0-30%, 10 min) to obtain 1.2 g of compound 298-1, with a yield of 89%. LC-MS (ESI) m/z: 324 [M+H] + .
步骤二：化合物298-2的合成Step 2: Synthesis of compound 298-2
室温下，将化合物298-1(700mg，2.16mmol)溶于8mL二氧六环和2mL水中，加入Pd(dppf)Cl2(190mg，0.233mmol)，环丙基硼酸频哪醇酯(560mg，3.33mmol)和碳酸钾(900mg，6.52mmol),升温至100℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相，浓缩后经快速色谱柱层析分离 (PE:EA,0-30％,10min)得到530mg化合物298-2，收率86％。LC-MS(ESI)m/z:286[M+H]+.At room temperature, compound 298-1 (700 mg, 2.16 mmol) was dissolved in 8 mL of dioxane and 2 mL of water, and Pd(dppf)Cl 2 (190 mg, 0.233 mmol), cyclopropylboronic acid pinacol ester (560 mg, 3.33 mmol) and potassium carbonate (900 mg, 6.52 mmol) were added, and the temperature was raised to 100°C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine, concentrated, and separated by flash chromatography. (PE:EA, 0-30%, 10min) 530mg of compound 298-2 was obtained with a yield of 86%. LC-MS (ESI) m/z: 286 [M+H] + .
步骤三：化合物298-3的合成Step 3: Synthesis of compound 298-3
室温下，将化合物298-2(300mg，1.05mmol)溶于MeOH/THF(6mL,1:1)中，将氢氧化钠(80mg，2.00mmol)溶于0.5mL水中滴加至反应液中，升温至50℃反应30分钟。LCMS监测反应完全。用1N的稀盐酸调pH至2-3后浓缩，经快速色谱柱层析分离(DCM:MeOH,0-15％,10min)得到30mg化合物298-3收率11％。LC-MS(ESI)m/z:272[M+H]+.At room temperature, compound 298-2 (300 mg, 1.05 mmol) was dissolved in MeOH/THF (6 mL, 1:1), sodium hydroxide (80 mg, 2.00 mmol) was dissolved in 0.5 mL of water and added dropwise to the reaction solution, and the temperature was raised to 50°C for 30 minutes. LCMS monitored the reaction to be complete. The pH was adjusted to 2-3 with 1N dilute hydrochloric acid and then concentrated. After flash column chromatography (DCM: MeOH, 0-15%, 10 min), 30 mg of compound 298-3 was obtained with a yield of 11%. LC-MS (ESI) m/z: 272 [M+H] + .
步骤四：化合物298的合成Step 4: Synthesis of compound 298
室温下，将化合物298-3(15mg，0.055mmol)和化合物293-3(15mg，0.053mmol)溶于1mL干燥的DCE中，加入DMAP(4mg，0.0328mmol)和DCC(22mg，0.107mmol),室温搅拌过夜。LC-MS监测反应完全。反应液直接浓缩后，经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到15mg粗品，后经高效液相色谱柱层析分离得到7mg化合物298，收率25％。LC-MS(ESI)m/z:538.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.24-7.17(m,2H),6.98-6.93(m,1H),6.84-6.67(m,4H),5.86-5.78(m,1H),3.77-3.59(m,3H),3.30-3.17(m,2H),2.77-2.61(m,2H),1.98-1.78(m,4H),1.26-1.21(m,12H),0.96-0.89(m,4H),0.73-0.63(m,4H).At room temperature, compound 298-3 (15 mg, 0.055 mmol) and compound 293-3 (15 mg, 0.053 mmol) were dissolved in 1 mL of dry DCE, and DMAP (4 mg, 0.0328 mmol) and DCC (22 mg, 0.107 mmol) were added, and stirred at room temperature overnight. LC-MS monitored the reaction to be complete. The reaction solution was directly concentrated and separated by flash column chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 15 mg of crude product, which was then separated by HPLC column chromatography to obtain 7 mg of compound 298, with a yield of 25%. LC-MS(ESI)m/z:538.3[M+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ7.24-7.17(m,2H),6.98-6.93(m,1H),6.84-6.67(m,4H),5.86-5.78(m,1H),3.77-3.59(m,3H) ,3.30-3.17(m,2H),2.77-2.61(m,2H),1.98-1.78(m,4H),1.26-1.21(m,12H),0.96-0.89(m,4H),0.73-0.63(m,4H).
实施例299
Embodiment 299
合成方法Synthesis method
化合物299的合成方法参照实施例291。区别在于把步骤五中的176-2替换为1-((1-(氨基甲基)环丙基)甲基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:305.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.46(t,J＝5.5Hz,1H),7.85(d,J＝8.8Hz,1H),7.77(d,J＝8.7Hz,1H),7.60(d,J＝14.2Hz,1H),7.51(dd,J＝9.4,2.0Hz,2H),7.39(dd,J＝8.7,2.0Hz,1H),7.18(dd,J＝8.8,1.9Hz,1H),6.76(d,J＝14.2Hz,1H),5.92(s,1H),4.27(s,2H),3.61(q,J＝7.0Hz,2H),3.23(q,J＝7.1Hz,3H),3.21-3.17(m,5H),2.84(s,3H),2.05-1.93(m,3H),1.45(q,1H),1.27(t,3H),0.89-0.81(m,2H).The synthesis method of compound 299 refers to Example 291. The difference is that 176-2 in step 5 is replaced by 1-((1-(aminomethyl)cyclopropyl)methyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 305.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.46(t,J＝5.5Hz,1H),7.85(d,J＝8.8Hz,1H),7.77(d,J＝8.7Hz,1H),7.60(d,J＝14.2Hz,1H),7.51(dd,J＝9.4,2.0Hz,2H),7.39(dd,J＝8.7,2.0Hz,1H),7.1 8(dd,J＝8.8,1.9Hz,1H),6.76( d,J＝14.2Hz,1H),5.92(s,1H),4.27(s,2H),3.61(q,J＝7.0Hz,2H),3.23(q,J＝7.1Hz,3H),3.21-3.17(m,5H),2.84(s,3H),2.05-1.93(m,3H),1.45(q ,1H),1.27(t,3H),0.89-0.81(m,2H).
实施例300
Embodiment 300
合成路线
Synthetic route
步骤一：化合物300-1的合成Step 1: Synthesis of compound 300-1
室温下，将7-氯喹啉-2(1H)-酮(300mg，1.68mmol)溶于10mL干燥的DMF中，加入3-(溴甲基)-3-氟吡咯烷-1-羧酸叔丁酯(700mg，2.48mmol)和碳酸铯(1.6g，4.88mmol),升温至100℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相，浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到330mg化合物300-1，收率52％。LC-MS(ESI)m/z:381[M+H]+.At room temperature, 7-chloroquinoline-2(1H)-one (300 mg, 1.68 mmol) was dissolved in 10 mL of dry DMF, tert-butyl 3-(bromomethyl)-3-fluoropyrrolidine-1-carboxylate (700 mg, 2.48 mmol) and cesium carbonate (1.6 g, 4.88 mmol) were added, and the mixture was heated to 100°C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine, concentrated, and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 330 mg of compound 300-1, with a yield of 52%. LC-MS (ESI) m/z: 381 [M+H] + .
步骤二：化合物300-2的合成Step 2: Synthesis of compound 300-2
室温下，将化合物300-1(330mg，0.866mmol)溶于5mL干燥的二氧六环中，滴加2mL盐酸二氧六环溶液，室温搅拌3小时。LC-MS监测反应完全。反应液过滤后冻干得到240mg化合物300-2，收率99％。LC-MS(ESI)m/z:281[M+H]+.At room temperature, compound 300-1 (330 mg, 0.866 mmol) was dissolved in 5 mL of dry dioxane, and 2 mL of dioxane hydrochloride solution was added dropwise, and stirred at room temperature for 3 hours. LC-MS monitored the reaction to be complete. The reaction solution was filtered and freeze-dried to obtain 240 mg of compound 300-2, with a yield of 99%. LC-MS (ESI) m/z: 281 [M+H] + .
步骤三：化合物300的合成Step 3: Synthesis of compound 300
室温下将化合物300-2(50mg，0.178mmol)和1-(6-溴吡啶-2-基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮(70mg，0.179mmol)溶于2mL干燥的DMF中，加入碳酸铯(170mg，0.518mmol),升温至120℃搅拌过夜。LC-MS监测反应完全。反应液直接浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到20mg粗品，后经高效液相色谱柱层析分离得到7mg化合物300，收率7％。LC-MS(ESI)m/z:593.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.98(dd,J＝9.2,2.0Hz,2H),7.87(t,J＝2.2Hz,1H),7.79-7.73(m,2H),7.32(dd,J＝8.3,1.8Hz,1H),7.21(dd,J＝8.8,2.2Hz,1H),6.68(d,J＝9.4Hz,1H),6.60(dd,J＝12.5,7.8Hz,2H),6.41(d,J＝2.1Hz,1H),4.94-4.77(m,2H),3.87-3.60(m,6H),3.42-3.37(m,2H),3.30(s,3H),1.31(t,J＝7.0Hz,3H).Compound 300-2 (50 mg, 0.178 mmol) and 1-(6-bromopyridin-2-yl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one (70 mg, 0.179 mmol) were dissolved in 2 mL of dry DMF at room temperature, cesium carbonate (170 mg, 0.518 mmol) was added, and the temperature was raised to 120°C and stirred overnight. LC-MS monitored the reaction to be complete. The reaction solution was directly concentrated and separated by flash column chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 20 mg of crude product, which was then separated by high performance liquid chromatography column chromatography to obtain 7 mg of compound 300, with a yield of 7%. LC-MS (ESI) m/z: 593.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.98(dd,J＝9.2,2.0Hz,2H),7.87(t,J＝2.2Hz,1H),7.79-7.73(m,2H),7.32(dd,J＝8.3,1.8Hz,1H),7.21(dd,J＝8.8,2.2Hz,1H),6.68(d,J＝9.4Hz,1H),6.6 0(dd,J＝12.5,7.8Hz,2H),6.41(d,J＝2.1Hz,1H),4.94-4.77(m,2H),3.87-3.60(m,6H),3.42-3.37(m,2H),3.30(s,3H),1.31(t,J＝7.0Hz,3H).
实施例301
Embodiment 301
合成方法Synthesis method
化合物301的合成方法参照实施例291。LC-MS(ESI)m/z:580.3[M+H]+.The synthesis method of compound 301 refers to Example 291. LC-MS (ESI) m/z: 580.3 [M+H] + .
实施例302
Embodiment 302
合成路线
Synthetic route
步骤一：化合物302的合成Step 1: Synthesis of compound 302
取化合物123-4(40mg，0.13mmol)、化合物291-4(40mg，0.13mmol)，DCC(40mg，0.20mmol)分散到1,2-二氯乙烷(1.0mL)溶液中，向反应混合物中加入4-二甲氨基吡啶(8.0mg，0.065mmol)，室温搅拌2小时。反应混合物用二氯甲烷(5mL×3)和水(5mL)萃取，合并有机相，饱和食盐水洗涤(5mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝1/12)纯化，得到化合物302的粗品。粗品再经制备液相色谱纯化，制备液冷冻干燥，得到产物302，5.77mg，产率7.4％。LC-MS(ESI)m/z:298.1[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ7.97(t,J＝8.1Hz,1H),7.75(d,J＝8.7Hz,1H),7.63(dd,J＝12.3,2.0Hz,1H),7.55(dd,J＝13.9,2.6Hz,1H),7.50(dd,J＝4.9,2.0Hz,1H),7.36(dd,J＝8.7,2.0Hz,1H),7.20(td,J＝8.9,1.8Hz,1H),6.90(dd,J＝20.7,13.9Hz,1H),4.29-4.09(m,2H),3.76-3.65(m,1H),3.62-3.48(m,1H),3.43-3.37(m,2H),3.25-3.18(m,8H),2.82(s,3H),2.66(dp,J＝31.1,7.2Hz,1H),2.07-1.87(m,1H),1.83-1.64(m,1H),1.21(t,J＝7.1,6.2Hz,3H).Compound 123-4 (40 mg, 0.13 mmol), compound 291-4 (40 mg, 0.13 mmol), and DCC (40 mg, 0.20 mmol) were dispersed in a 1,2-dichloroethane (1.0 mL) solution, and 4-dimethylaminopyridine (8.0 mg, 0.065 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was extracted with dichloromethane (5 mL × 3) and water (5 mL), and the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: methanol/dichloromethane = 1/12) to obtain a crude compound 302. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain the product 302, 5.77 mg, with a yield of 7.4%. LC-MS (ESI) m/z: 298.1 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ7.97(t,J＝8.1Hz,1H),7.75(d,J＝8.7Hz,1H),7.63(dd,J＝12.3,2.0Hz,1H),7.55(dd,J＝13.9,2.6Hz,1H),7.50(dd,J＝4.9,2.0Hz,1H ),7.36(dd,J＝8.7,2.0Hz,1H),7.20(td,J＝8.9,1.8Hz,1H),6.90(dd,J＝20.7,13 .9Hz,1H),4.29-4.09(m,2H),3.76-3.65(m,1H),3.62-3.48(m,1H),3.43-3.37(m,2H),3.25-3.18(m,8H),2.82(s,3H),2.66(dp,J＝31.1,7.2Hz,1H ),2.07-1.87(m,1H),1.83-1.64(m,1H),1.21(t,J=7.1,6.2Hz,3H).
实施例303
Embodiment 303
合成方法Synthesis method
化合物303的合成方法参照实施例300。区别在于把步骤一中的7-氯喹啉-2(1H)-酮替换为7-氯-4-(甲乙胺基)喹啉-2(1H)-酮，步骤三中的1-(6-溴吡啶-2-基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮替换为1-(6-溴吡啶-2-基)-7-氯-4-(二甲胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:318.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.04(d,J＝8.8Hz,1H),7.83(s,1H),7.79-7.71(m,2H),7.29(dd,J＝8.7,1.9Hz,1H),7.21(dd,J＝8.8,2.1Hz,1H),6.60(t,J＝7.7Hz,2H),6.41(s,1H),6.00(s,1H),4.78(d,2H),3.74(dd,2H),3.64(t,J＝9.6Hz,1H),3.31(s,6H),3.15(q,J＝7.1Hz,2H),2.79(s,3H),2.04-1.96(m,2H),1.19(t,J＝7.1Hz,3H),0.86(t,J＝6.9Hz,1H).The synthesis method of compound 303 refers to Example 300. The difference is that 7-chloroquinoline-2(1H)-one in step 1 is replaced by 7-chloro-4-(methylethylamino)quinoline-2(1H)-one, and 1-(6-bromopyridin-2-yl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one in step 3 is replaced by 1-(6-bromopyridin-2-yl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 318.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.04(d,J＝8.8Hz,1H),7.83(s,1H),7.79-7.71(m,2H),7.29(dd,J＝8.7,1.9Hz,1H),7.21(dd,J＝8.8,2.1Hz,1H),6.60(t,J＝7.7Hz,2H),6.41(s,1H),6. 00(s,1H), 4.78(d,2H),3.74(dd,2H),3.64(t,J＝9.6Hz,1H),3.31(s,6H),3.15(q,J＝7.1Hz,2H),2.79(s,3H),2.04-1.96(m,2H),1.19(t,J＝7.1Hz,3H),0.86(t, J＝6.9Hz,1H).
实施例304
Embodiment 304
合成方法Synthesis method
化合物304的合成方法参照实施例123。区别在于把步骤一中的二甲胺替换为氮杂环丁烷。LC-MS(ESI)m/z:309.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.04(t,J＝10.9,8.7Hz,2H),7.73(q,J＝7.9,7.0Hz,1H),7.43(d,J＝1.8Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),7.16(d,J＝8.4Hz,1H),6.58-6.49(m,2H),6.45(d,J＝2.0Hz,1H),4.12(ddd,J＝44.4,14.8,7.4Hz,2H),3.76(t,J＝5.8Hz,2H),3.31(s,6H),3.58-3.45(m,4H),3.25-3.15(m,2H),2.77-2.69(m,1H),1.82(p,J＝6.5Hz,3H),1.46(q,J＝7.2Hz,1H).The synthesis method of compound 304 refers to Example 123. The difference is that the dimethylamine in step 1 is replaced by azetidine. LC-MS (ESI) m/z: 309.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.04 (t, J = 10.9, 8.7 Hz, 2H), 7.73 (q, J = 7.9, 7.0 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.20 (dd, J = 8.8, 2.0 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.58-6.49 (m, 2H), 6.45 (d, J = 2.0 Hz, 1H), 4.12(ddd,J＝44.4,14.8,7.4Hz,2H),3.76(t,J＝5.8Hz,2H),3.31(s,6H),3.58-3.45(m,4H),3.25-3.15(m,2H),2.77-2.69(m,1H),1.82(p,J＝6.5Hz,3 H),1.46(q,J＝7.2Hz,1H).
实施例305
Embodiment 305
合成方法Synthesis method
化合物305的合成方法参照实施例293。区别在于把步骤一中的3-(溴甲基)吡咯烷-1-甲酸叔丁酯替换为3-(溴甲基)-3-氟吡咯烷-1-羧酸叔丁酯。LC-MS(ESI)m/z:615.3[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(dd,J＝8.8,1.2Hz,1H),7.77(t,J＝7.8,7.2,1.2Hz,1H),7.21(dd,J＝8.9,1.7Hz,1H),7.18(dd,J＝7.6,1.3Hz,1H),6.81(s,1H),6.78(dd,J＝7.7,1.5Hz,1H),6.62(d,J＝7.3Hz,1H),6.58(d,1H),6.42(d,J＝2.0Hz,1H),4.24-4.13(m,2H),3.70(q,J＝7.2Hz,3H),3.67-3.60(m,3H),3.30(s,3H),2.36-2.21(m,1H),2.21-2.13(m,1H),1.92-1.85(m,1H),1.30(t,J＝7.0Hz,3H),1.26(s,3H),1.24(s,3H),0.90-0.86(m,2H),0.68-0.60(m,2H).The synthesis method of compound 305 is similar to that of Example 293. The difference is that tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate in step 1 is replaced by tert-butyl 3-(bromomethyl)-3-fluoropyrrolidine-1-carboxylate. LC-MS (ESI) m/z: 615.3 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.97(dd,J＝8.8,1.2Hz,1H),7.77(t,J＝7.8,7.2,1.2Hz,1H),7.21(dd,J＝8.9,1.7Hz,1H),7.18(dd,J＝7.6,1.3Hz,1H),6.81(s,1H),6.78(dd,J＝7.7,1.5Hz ,1H),6.62(d,J＝7.3Hz,1H),6.58(d,1H),6.42(d,J＝2.0Hz,1H) ,4.24-4.13(m,2H),3.70(q,J＝7.2Hz,3H),3.67-3.60(m,3H),3.30(s,3H),2.36-2.21(m,1H),2.21-2.13(m,1H),1.92-1.85(m,1H),1.30(t,J＝7.0 Hz,3H),1.26(s,3H),1.24(s,3H),0.90-0.86(m,2H),0.68-0.60(m,2H).
实施例306
Embodiment 306
合成路线
Synthetic route
步骤一：化合物306-1的合成Step 1: Synthesis of compound 306-1
室温下，将7-氯-4-(二甲基氨基)喹唑啉-2(1H)-酮(123-2，500mg，2.23mmol)溶于10mL干燥的乙腈中，加入DMAP(270mg，2.21mmol)和炔丙酸甲酯(300mg，3.57mmol),升温至70℃搅拌过夜。LC-MS监测有产物生成。反应液浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,15min)得到150mg化合物306-1，收率22％。LC-MS(ESI)m/z:308[M+H]+.At room temperature, 7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (123-2, 500 mg, 2.23 mmol) was dissolved in 10 mL of dry acetonitrile, DMAP (270 mg, 2.21 mmol) and methyl propargyl ester (300 mg, 3.57 mmol) were added, and the temperature was raised to 70°C and stirred overnight. LC-MS monitored the formation of the product. After the reaction solution was concentrated, it was separated by flash chromatography (DCM: MeOH, 0-10%, 15 min) to obtain 150 mg of compound 306-1, with a yield of 22%. LC-MS (ESI) m/z: 308 [M+H] + .
步骤二：化合物306-2的合成Step 2: Synthesis of compound 306-2
室温下，将化合物306-1(150mg，0.487mmol)溶于3mL乙醇，将氢氧化锂(60mg，1.46mmol)溶于0.5mL水中滴加至反应液中，室温反应30分钟。LC-MS监测反应完全。室温浓缩除去乙醇，加水稀释体系，用1N的稀盐酸调pH至2-3后过滤得到30mg化合物306-2，收率21％。LC-MS(ESI)m/z:294[M+H]+.At room temperature, compound 306-1 (150 mg, 0.487 mmol) was dissolved in 3 mL of ethanol, and lithium hydroxide (60 mg, 1.46 mmol) was dissolved in 0.5 mL of water and added dropwise to the reaction solution. The reaction was allowed to react at room temperature for 30 minutes. LC-MS monitored the reaction to be complete. The ethanol was removed by concentration at room temperature, and the system was diluted with water. The pH was adjusted to 2-3 with 1N dilute hydrochloric acid and filtered to obtain 30 mg of compound 306-2, with a yield of 21%. LC-MS (ESI) m/z: 294 [M+H] + .
步骤三：化合物306的合成Step 3: Synthesis of compound 306
室温下，将化合物306-2(15mg，0.051mmol)和1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮(15mg，0.051mmol)溶于1mL干燥的DCE中，加入DMAP(4mg，0.0328mmol)和DCC(22mg，0.107mmol)，室温搅拌2小时。LC-MS监测反应完全。反应液直接浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到15mg粗品，后经高效液相色谱柱层析分离得到7mg化合物306，收率24％。LC-MS(ESI)m/z:570.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.29(t,J＝5.6Hz,1H),7.99(d,J＝8.7Hz,1H),7.90(d,J＝8.8Hz,1H),7.72(d,J＝14.2Hz,1H),7.53(dd,J＝8.0,2.0Hz,2H),7.34(dd,J＝8.7,2.0Hz,1H),7.21(dd,J＝8.8,1.9Hz,1H),6.68(d,J＝14.2Hz,1H),4.08(t,J＝7.6Hz,2H),3.62(q,J＝7.0Hz,2H),3.31-3.25(m,8H),3.20(s,3H),1.84-1.71(m,2H),1.26(t,3H).At room temperature, compound 306-2 (15 mg, 0.051 mmol) and 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one (15 mg, 0.051 mmol) were dissolved in 1 mL of dry DCE, and DMAP (4 mg, 0.0328 mmol) and DCC (22 mg, 0.107 mmol) were added, and the mixture was stirred at room temperature for 2 hours. LC-MS monitored the reaction to be complete. The reaction solution was directly concentrated and separated by flash column chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 15 mg of crude product, which was then separated by HPLC column chromatography to obtain 7 mg of compound 306, with a yield of 24%. LC-MS (ESI) m/z: 570.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.29(t,J＝5.6Hz,1H),7.99(d,J＝8.7Hz,1H),7.90(d,J＝8.8Hz,1H),7.72(d,J＝14.2Hz,1H),7.53(dd,J＝8.0,2.0Hz,2H),7.34(dd,J＝8.7,2.0Hz,1H),7.2 1(dd,J＝8.8,1.9Hz,1H),6.68(d,J＝14.2Hz,1H),4.08(t,J＝7.6Hz,2H),3.62 (q,J＝7.0Hz,2H),3.31-3.25(m,8H),3.20(s,3H),1.84-1.71(m,2H),1.26(t ,3H).
实施例307
Embodiment 307
合成方法Synthesis method
化合物307的合成方法参照实施例306。区别在于把步骤三中的1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮替换为123-4。LC-MS(ESI)m/z:291.6[M/2+H]+.1H  NMR(400MHz,DMSO-d6)δ8.01-7.94(m,2H),7.71(d,J＝13.9Hz,1H),7.63(dd,J＝8.4,2.0Hz,1H),7.55(dd,J＝8.6,2.0Hz,1H),7.33(dd,J＝8.7,2.0Hz,1H),7.20(ddd,J＝8.9,7.2,1.9Hz,1H),6.88(dd,J＝16.4,13.8Hz,1H),4.19(qt,J＝14.7,8.3Hz,2H),3.75-3.42(m,4H),3.29(s,6H),3.23(d,J＝7.1Hz,6H),2.76-2.55(m,2H),1.85-1.64(m,1H).The synthesis method of compound 307 is similar to that of Example 306. The difference is that 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one in step 3 is replaced by 123-4. LC-MS (ESI) m/z: 291.6 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.01-7.94(m,2H),7.71(d,J＝13.9Hz,1H),7.63(dd,J＝8.4,2.0Hz,1H),7.55(dd,J＝8.6,2.0Hz,1H),7.33(dd,J＝8.7,2.0Hz,1H),7.20(ddd,J＝8.9,7.2,1 .9Hz,1H),6.88(dd,J＝16.4,13.8Hz,1H),4.19(qt,J＝14.7,8.3Hz,2H),3.75-3.42(m,4H),3.29(s,6H),3.23(d,J＝7.1Hz,6H),2.76-2.55(m,2H),1.85 -1.64(m,1H).
实施例308
Embodiment 308
合成路线
Synthetic route
步骤一：化合物308-1的合成Step 1: Synthesis of compound 308-1
室温下，将7-氯喹啉-2(1H)-酮(500mg，2.78mmol)溶于10mL干燥的DMF中，加入2-溴-6-碘吡啶(1.2g，4.23mmol)、碳酸铯(2.7g，8.23mmol)、碘化亚铜(60mg，0.316mmol)和,升温至100℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤合并的有机相，浓缩后经快速色谱柱层析分离(PE:EA,0-100％,10min)得到330mg化合物308-1，收率52％。LC-MS(ESI)m/z:381[M+H]+.At room temperature, 7-chloroquinoline-2(1H)-one (500mg, 2.78mmol) was dissolved in 10mL of dry DMF, 2-bromo-6-iodopyridine (1.2g, 4.23mmol), cesium carbonate (2.7g, 8.23mmol), cuprous iodide (60mg, 0.316mmol) and were added, and the mixture was heated to 100°C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and the combined organic phase was washed with saturated brine, concentrated, and separated by flash chromatography (PE:EA, 0-100%, 10min) to obtain 330mg of compound 308-1, with a yield of 52%. LC-MS (ESI) m/z: 381[M+H] + .
步骤二：化合物308的合成Step 2: Synthesis of compound 308
室温下，将化合物308-1(70mg，0.209mmol)和化合物123-4(50mg，0.163mmol)溶于2mL干燥的DMF中，加入碳酸铯(160mg，0.488mmol)，升温至120℃搅拌过夜。LC-MS监测反应完全。反应液直接浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到20mg粗品，后经高效液相色谱柱层析分离得到15mg化合物308，收率13％。LC-MS(ESI)m/z:561.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.05(d,J＝9.6Hz,1H),7.96(d,J＝8.8Hz,1H),7.82(d,J＝8.4Hz,1H),7.76(t,J＝7.9Hz,1H),7.61(d,J＝2.0Hz,1H),7.31(dd,J＝8.4,2.0Hz,1H),7.19(dd,J＝8.7,1.9Hz,1H),6.68(d,J＝9.6Hz,1H),6.59(dd,J＝7.8,3.4Hz,2H),6.50(d,J＝2.0Hz,1H),4.32-4.08(m,2H),3.58-3.48(m,2H),3.28-3.15(m,8H),2.79-2.64(m,1H),2.08-1.95(m,1H),1.88-1.76(m,1H).At room temperature, compound 308-1 (70 mg, 0.209 mmol) and compound 123-4 (50 mg, 0.163 mmol) were dissolved in 2 mL of dry DMF, cesium carbonate (160 mg, 0.488 mmol) was added, and the temperature was raised to 120°C and stirred overnight. LC-MS monitored the reaction to be complete. The reaction solution was directly concentrated and separated by flash column chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 20 mg of crude product, which was then separated by HPLC column chromatography to obtain 15 mg of compound 308, with a yield of 13%. LC-MS (ESI) m/z: 561.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.05(d,J＝9.6Hz,1H),7.96(d,J＝8.8Hz,1H),7.82(d,J＝8.4Hz,1H),7.76(t,J＝7.9Hz,1H),7.61(d,J＝2.0Hz,1H),7.31(dd,J＝8.4,2.0Hz,1H),7.19(dd,J＝ 8.7,1.9Hz,1H),6.68(d ,J＝9.6Hz,1H),6.59(dd,J＝7.8,3.4Hz,2H),6.50(d,J＝2.0Hz,1H),4.32-4.08(m,2H),3.58-3.48(m,2H),3.28-3.15(m,8H),2.79-2.64(m,1H),2.08-1 .95(m,1H),1.88-1.76(m,1H).
实施例309
Embodiment 309
合成方法Synthesis method
化合物309的合成方法参照实施例123。区别在于把步骤一中的2,4,7-三氯喹唑啉 替换为2,4-二氯-7-三氟甲基喹唑啉。LC-MS(ESI)m/z:320.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.16(d,J＝8.4Hz,1H),8.03(d,J＝8.8Hz,1H),7.76(s,1H),7.71(t,J＝7.9Hz,1H),7.45(d,1H),7.20(dd,J＝8.9,2.2Hz,1H),6.54(t,J＝7.4Hz,2H),6.44(d,J＝2.1Hz,1H),4.29(ddd,J＝42.0,14.5,7.2Hz,2H),3.-3.48(m,2H),3.30(s,6H),3.26(s,6H),3.24-3.16(m,2H),1.89-1.77(m,1H),1.51-1.41(m,2H).The synthesis method of compound 309 refers to Example 123. The difference is that 2,4,7-trichloroquinazoline in step 1 Replaced with 2,4-dichloro-7-trifluoromethylquinazoline. LC-MS (ESI) m/z: 320.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.16(d,J＝8.4Hz,1H),8.03(d,J＝8.8Hz,1H),7.76(s,1H),7.71(t,J＝7.9Hz,1H),7.45(d,1H),7.20(dd,J＝8.9,2.2Hz,1H),6.54(t,J＝7.4Hz,2H),6.44 (d,J＝2.1Hz,1H),4.29(ddd,J＝42.0,14.5,7.2Hz,2H),3.-3.48(m,2H),3.30(s,6H),3.26(s,6H),3.24-3.16(m,2H),1.89-1.77(m,1H),1.51-1.41( m,2H).
实施例310
Embodiment 310
合成方法Synthesis method
化合物310的合成方法参照实施例123。区别在于把步骤七中的二甲胺替换为N-甲乙胺，步骤三中的1-Boc-3-溴甲基吡咯烷替换为1-Boc-3-氟-3-溴甲基吡咯烷，把步骤五中的2-氨基-6-溴吡啶替换为2-氨基-4-甲基-6-溴吡啶。LC-MS(ESI)m/z:326.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.95(t,J＝8.5Hz,2H),7.71(t,J＝1.9Hz,1H),7.58(d,J＝7.6Hz,1H),7.20(dt,J＝8.8,1.8Hz,2H),6.66(d,J＝7.5Hz,1H),6.40(d,J＝2.1Hz,1H),4.77-4.57(m,2H),3.94(dd,J＝35.9,12.7Hz,1H),3.76-3.58(m,5H),3.29(s,3H),3.24(s,6H),2.41(s,3H),2.30-2.07(m,2H),1.30(t,3H).The synthesis method of compound 310 is similar to that of Example 123. The difference is that dimethylamine in step 7 is replaced by N-methylethylamine, 1-Boc-3-bromomethylpyrrolidine in step 3 is replaced by 1-Boc-3-fluoro-3-bromomethylpyrrolidine, and 2-amino-6-bromopyridine in step 5 is replaced by 2-amino-4-methyl-6-bromopyridine. LC-MS (ESI) m/z: 326.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.95(t,J＝8.5Hz,2H),7.71(t,J＝1.9Hz,1H),7.58(d,J＝7.6Hz,1H),7.20(dt,J＝8.8,1.8Hz,2H),6.66(d,J＝7.5Hz,1H),6.40(d,J＝2.1Hz,1H),4.77-4.5 7(m,2H),3.94(dd,J＝35.9,12.7Hz,1H),3.76-3.58(m,5H),3.29(s,3H),3.24(s,6H),2.41(s,3H),2.30-2.07(m,2H),1.30(t,3H).
实施例311
Embodiment 311
合成方法Synthesis method
化合物311的合成方法参照实施例295。区别在于把步骤一中的293-3替换为6-环丙基-1-((3-氟吡咯烷-3-基)甲基)-3,3-二甲基吲哚啉-2-酮。LC-MS(ESI)m/z:591.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.76(dd,J＝8.7,1.7Hz,1H),7.59(d,J＝13.9Hz,1H),7.51(t,J＝2.2Hz,1H),7.37(dt,1H),7.19(t,J＝7.5Hz,1H),6.96(d,J＝13.8Hz,1H),6.89-6.76(m,2H),4.16(dd,J＝18.8,15.5Hz,2H),3.93-3.75(m,2H),3.75-3.54(m,2H),3.22(qd,J＝7.0,2.6Hz,2H),2.83(d,J＝2.6Hz,3H),2.28-2.06(m,2H),1.96-1.85(m,1H),1.29-1.27(m,3H),1.27-1.18(m,6H),0.98-0.89(m,2H),0.74-0.62(m,2H).The synthesis method of compound 311 is similar to that of Example 295. The difference is that 293-3 in step 1 is replaced by 6-cyclopropyl-1-((3-fluoropyrrolidin-3-yl)methyl)-3,3-dimethylindolin-2-one. LC-MS (ESI) m/z: 591.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.76(dd,J＝8.7,1.7Hz,1H),7.59(d,J＝13.9Hz,1H),7.51(t,J＝2.2Hz,1H),7.37(dt,1H),7.19(t,J＝7.5Hz,1H),6.96(d,J＝13.8Hz,1H),6.89-6.76(m, 2H),4.16(dd,J＝18.8,15.5Hz,2H),3.93-3 .75(m,2H),3.75-3.54(m,2H),3.22(qd,J＝7.0,2.6Hz,2H),2.83(d,J＝2.6Hz,3H),2.28-2.06(m,2H),1.96-1.85(m,1H),1.29-1.27(m,3H),1.27-1. 18(m,6H),0.98-0.89(m,2H),0.74-0.62(m,2H).
实施例312
Embodiment 312
合成方法Synthesis method
化合物312的合成方法参照实施例123。区别在于把步骤七中的二甲胺替换为N- 甲乙胺，把步骤五中的2-氨基-6-溴吡啶替换为2-氨基-4-甲基-6-溴吡啶。LC-MS(ESI)m/z:317.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ7.95(dd,J＝8.8,2.1Hz,2H),7.60(d,J＝2.0Hz,1H),7.55(d,J＝7.5Hz,1H),7.18(dt,2H),6.62(d,J＝7.4Hz,1H),6.42(d,J＝2.1Hz,1H),4.18(ddd,J＝67.4,14.3,7.4Hz,2H),3.69(q,J＝7.1Hz,2H),3.57-3.44(m,3H),3.29(s,3H),3.21(s,6H),2.59(q,J＝7.0Hz,2H),2.41(s,3H),1.95-1.85(m,1H),1.80-1.67(m,1H),1.30(t,J＝7.0Hz,3H).The synthesis method of compound 312 is similar to that of Example 123. The difference is that the dimethylamine in step 7 is replaced by N- Methylethylamine, replace 2-amino-6-bromopyridine in step 5 with 2-amino-4-methyl-6-bromopyridine. LC-MS (ESI) m/z: 317.1 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ7.95 (dd, J=8.8, 2.1 Hz, 2H), 7.60 (d, J=2.0 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.18 (dt, 2H), 6.62 (d, J=7.4 Hz, 1H), 6.42 (d, J=2.1 Hz, 1H), 4.18 (ddd, J=67.4, 14.3, 7.4 Hz, 2H),3.69(q,J＝7.1Hz,2H),3.57-3.44(m,3H),3.29(s,3H),3.21(s,6H),2.59(q,J＝7.0Hz,2H),2.41(s,3H),1.95-1.85(m,1H),1.80-1.67(m,1H), 1.30(t,J＝7.0Hz,3H).
实施例313
Embodiment 313
合成路线
Synthetic route
步骤一：化合物313-1的合成Step 1: Synthesis of compound 313-1
取7-溴-1H-吡咯并[3,2-C]吡啶(2.0g，10mmol)、溴甲基环丙烷(1.6g，12mmol)和碳酸钾(4.2g，30mmol)分散到N,N-二甲基甲酰胺(20mL)溶液中，加热到100゜C，搅拌过夜。反应混合物用乙酸乙酯(50mL×3)和水(50mL)萃取，合并有机相，饱和食盐水洗涤(50mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：乙酸乙酯/石油醚)纯化，得到化合物313-1，2.1g。产率81％。LC-MS(ESI)m/z:251[M+H]+.7-Bromo-1H-pyrrolo[3,2-C]pyridine (2.0 g, 10 mmol), bromomethylcyclopropane (1.6 g, 12 mmol) and potassium carbonate (4.2 g, 30 mmol) were dispersed in N,N-dimethylformamide (20 mL) solution, heated to 100 °C and stirred overnight. The reaction mixture was extracted with ethyl acetate (50 mL × 3) and water (50 mL), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography column (eluent: ethyl acetate/petroleum ether) to obtain compound 313-1, 2.1 g. Yield 81%. LC-MS (ESI) m/z: 251 [M + H] + .
步骤二：化合物313-2的合成Step 2: Synthesis of compound 313-2
在封管中加入化合物313-1(50mg，0.20mmol)、氯化亚铜(36mg，0.38mmol)和铜粉(11mg，0.18mmol)和氨水(7.0mL)，密闭后，加热到120゜C，搅拌过夜。反应混合物减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：乙酸乙酯/石油醚)纯化，得到化合物313-2的粗品，44mg，直接用于下一步。LC-MS(ESI)m/z:188[M+H]+.Compound 313-1 (50 mg, 0.20 mmol), cuprous chloride (36 mg, 0.38 mmol), copper powder (11 mg, 0.18 mmol) and ammonia water (7.0 mL) were added to the sealed tube, sealed, heated to 120°C, and stirred overnight. The reaction mixture was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel chromatography (eluent: ethyl acetate/petroleum ether) to obtain a crude product of compound 313-2, 44 mg, which was directly used in the next step. LC-MS (ESI) m/z: 188 [M+H] + .
步骤三：化合物313-3的合成Step 3: Synthesis of compound 313-3
取化合物313-2(0.80g，1.9mmol)、丙炔酸甲酯(0.32g，2.8mmol)和三乙胺 (0.57g，5.7mmol)分散到N,N-二甲基甲酰胺(8.0mL)溶液中。向反应液中加入碘化亚铜(36mg，0.019mmol)和双三苯基磷二氯化钯(0.13g，0.019mmol)，用氮气吹气三分钟。加热到60゜C，搅拌过夜。反应混合物用乙酸乙酯(5mL×3)和水(5mL)萃取，合并有机相，饱和食盐水洗涤(5mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝3/100)纯化，得到化合物313-3，0.40g，产率56％。LC-MS(ESI)m/z:382[M+H]+.Take compound 313-2 (0.80 g, 1.9 mmol), methyl propiolate (0.32 g, 2.8 mmol) and triethylamine (0.57g, 5.7mmol) was dispersed in N,N-dimethylformamide (8.0mL) solution. Cuprous iodide (36mg, 0.019mmol) and bistriphenylphosphine palladium dichloride (0.13g, 0.019mmol) were added to the reaction solution and purged with nitrogen for three minutes. Heat to 60°C and stir overnight. The reaction mixture was extracted with ethyl acetate (5mL×3) and water (5mL), the organic phases were combined, washed with saturated brine (5mL), dried over anhydrous sodium sulfate, the desiccant was filtered out, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography column (eluent: methanol/dichloromethane = 3/100) to obtain compound 313-3, 0.40g, yield 56%. LC-MS (ESI) m/z: 382[M+H] + .
步骤四：化合物313-4的合成Step 4: Synthesis of compound 313-4
室温下，将化合物313-3(0.40g，1.0mmol)分散到四氢呋喃(4.0mL)中，将氢氧化锂一水合物(0.088g，2.0mmol)溶到水(0.40mL)中，并逐滴滴加到反应液中。室温搅拌过夜。反应液经减压蒸除大部分溶剂，向残余物中加入少量水，用1N稀盐酸调节溶液pH至3～4，室温搅拌10分钟。用乙酸乙酯(20mL×6)和水(20mL)萃取，合并有机相，减压蒸除溶剂，得到化合物313-4的粗品，0.20g，为淡黄色固体，可直接用于下一步。LC-MS(ESI)m/z:368[M+H]+.At room temperature, compound 313-3 (0.40 g, 1.0 mmol) was dispersed in tetrahydrofuran (4.0 mL), lithium hydroxide monohydrate (0.088 g, 2.0 mmol) was dissolved in water (0.40 mL), and added dropwise to the reaction solution. Stir overnight at room temperature. Most of the solvent was evaporated from the reaction solution under reduced pressure, a small amount of water was added to the residue, and the pH of the solution was adjusted to 3-4 with 1N dilute hydrochloric acid, and stirred at room temperature for 10 minutes. Extracted with ethyl acetate (20 mL × 6) and water (20 mL), the organic phases were combined, and the solvent was evaporated under reduced pressure to obtain a crude product of compound 313-4, 0.20 g, as a light yellow solid, which can be directly used in the next step. LC-MS (ESI) m/z: 368 [M + H] + .
步骤五：化合物313的合成Step 5: Synthesis of compound 313
室温下，将化合物313-4(90mg，0.25mmol)溶到N,N-二甲基甲酰胺(0.5mL)中，并滴加DIEA(120mg，0.74mmol)，室温搅拌30分钟。依次向反应液中滴加HATU(100mg，0.30mmol)和化合物313-2(44mg，0.25mmol)的N,N-二甲基甲酰胺溶液，室温搅拌30分钟。反应液用乙酸乙酯(10mL×3)和水(10mL)萃取，合并有机相，再用饱和食盐水洗涤(10mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝1/50)纯化，得到化合物313，40mg，为红色固体，收率31％。LC-MS(ESI)m/z:537.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.14(d,J＝7.9Hz,1H),8.10(d,J＝8.8Hz,1H),7.67(t,J＝7.8Hz,1H),7.58(d,J＝2.7Hz,1H),7.38(d,J＝7.2Hz,1H),7.34(dd,1H),7.24(dd,J＝8.8,2.1Hz,1H),7.16(s,1H),6.70(d,J＝7.2Hz,1H),6.47(dd,J＝7.8,2.4Hz,2H),4.23(dd,J＝16.2,7.2Hz,2H),3.34(s,6H),1.99(dt,J＝13.1,7.0Hz,1H),0.29-0.13(m,2H),0.13-0.02(m,2H).At room temperature, compound 313-4 (90 mg, 0.25 mmol) was dissolved in N, N-dimethylformamide (0.5 mL), and DIEA (120 mg, 0.74 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. HATU (100 mg, 0.30 mmol) and N, N-dimethylformamide solution of compound 313-2 (44 mg, 0.25 mmol) were added dropwise to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate (10 mL × 3) and water (10 mL), and the organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the desiccant was filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: methanol/dichloromethane = 1/50) to obtain compound 313, 40 mg, as a red solid, with a yield of 31%. LC-MS (ESI) m/z: 537.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.54 (s, 1H), 8.14 (d, J = 7.9Hz, 1H), 8.10 (d, J = 8.8Hz, 1H), 7.67 (t, J = 7.8Hz, 1H), 7.58 (d, J = 2.7 Hz,1H),7.38(d,J＝7.2Hz,1H),7.34(dd,1H),7.24(dd,J＝8.8,2.1Hz,1H),7 .16(s,1H),6.70(d,J＝7.2Hz,1H),6.47(dd,J＝7.8,2.4Hz,2H),4.23(dd,J＝16.2,7.2Hz,2H),3.34(s,6H),1.99(dt,J＝13.1,7.0Hz,1H),0.29-0.13(m,2 H),0.13-0.02(m,2H).
实施例314
Embodiment 314
合成路线
Synthetic route
步骤一：化合物314-1的合成Step 1: Synthesis of compound 314-1
取7-溴-2(1H)-喹喔啉酮(0.50g，3.6mmol)、3-(溴甲基)吡咯烷-1-甲酸叔丁酯(1.2 g，7.2mmol)和碳酸铯(2.2g，10.8mmol)分散到N,N-二甲基甲酰胺(10mL)溶液中，加热到100゜C，搅拌过夜。反应混合物用乙酸乙酯(20mL×3)和水(20mL)萃取，合并有机相，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：乙酸乙酯/石油醚)纯化，得到化合物314-1，0.88g，产率97％。LC-MS(ESI)m/z:408[M+H]+.Take 7-bromo-2(1H)-quinoxalinone (0.50 g, 3.6 mmol), tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate (1.2 g, 7.2mmol) and cesium carbonate (2.2g, 10.8mmol) were dispersed in N,N-dimethylformamide (10mL) solution, heated to 100°C, and stirred overnight. The reaction mixture was extracted with ethyl acetate (20mL×3) and water (20mL), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography column (eluent: ethyl acetate/petroleum ether) to obtain compound 314-1, 0.88g, yield 97%. LC-MS (ESI) m/z: 408[M+H] + .
步骤二：化合物314-2的合成Step 2: Synthesis of compound 314-2
将化合物314-1(0.20g，0.49mmol)和环丙基硼酸频哪醇酯(0.21g，1.2mmol)溶到1,4-二氧六环(2.0mL)溶液中，向反应液中加入碳酸钾(0.21g，1.5mmol)的水(0.30mL)溶液，氮气吹气三分钟，然后加入1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.40g，0.049mmol)。加热到100゜C，搅拌过夜。待反应液冷却至室温，反应液经硅藻土过滤，用乙酸乙酯洗涤，滤液经减压浓缩，残余物用乙酸乙酯(10mL×3)和水(10mL)萃取，合并有机相，饱和食盐水洗涤(10mL)一次，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：乙酸乙酯/石油醚)纯化，得到化合物314-2，0.12g，产率66％。LC-MS(ESI)m/z:314[M+H-56]+.Compound 314-1 (0.20 g, 0.49 mmol) and cyclopropylboronic acid pinacol ester (0.21 g, 1.2 mmol) were dissolved in 1,4-dioxane (2.0 mL) solution, potassium carbonate (0.21 g, 1.5 mmol) in water (0.30 mL) was added to the reaction solution, nitrogen was blown for three minutes, and then 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.40 g, 0.049 mmol) was added. Heat to 100°C and stir overnight. After the reaction solution was cooled to room temperature, the reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate (10 mL×3) and water (10 mL). The organic phases were combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/petroleum ether) to obtain compound 314-2, 0.12 g, with a yield of 66%. LC-MS (ESI) m/z: 314 [M+H-56] + .
步骤三：化合物314-3的合成Step 3: Synthesis of compound 314-3
取化合物314-2(0.12g，0.32mmol)分散到1,4-二氧六环(2.0mL)中，室温下，向反应液中滴加盐酸的二氧六环溶液(2.0mL)。室温搅拌过夜。反应液经减压浓缩后，得到化合物314-3的粗品，直接用于下一步。LC-MS(ESI)m/z:270[M+H]+.Compound 314-2 (0.12 g, 0.32 mmol) was dispersed in 1,4-dioxane (2.0 mL). A solution of hydrochloric acid in dioxane (2.0 mL) was added dropwise to the reaction solution at room temperature. The mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product of compound 314-3, which was used directly in the next step. LC-MS (ESI) m/z: 270 [M+H] + .
步骤四：化合物314的合成Step 4: Synthesis of compound 314
取化合物314-3(60mg，0.22mmol)、1-(6-溴吡啶-2-基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮(72mg，0.22mmol)和碳酸铯(0.22g，0.66mmol)分散到N,N-二甲基甲酰胺(2.0mL)溶液中，加热到120゜C，搅拌过夜。反应混合物用乙酸乙酯(5mL×3)和水(5mL)萃取，合并有机相，饱和食盐水洗涤(5mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝1/12)纯化，得到化合物314的粗品。粗品再经制备液相色谱纯化，制备液冷冻干燥，得到产物314，6.51mg，产率5.0％。LC-MS(ESI)m/z:582.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.97(d,J＝8.8Hz,1H),7.73(d,1H),7.69(d,J＝8.5Hz,1H),7.36(d,J＝1.7Hz,1H),7.21(dd,J＝8.8,2.1Hz,1H),7.02(dd,J＝8.3,1.6Hz,1H),6.55(dd,J＝8.0,6.5Hz,2H),6.44(d,J＝2.1Hz,1H),4.37(ddd,J＝43.1,13.9,7.4Hz,2H),3.69(q,J＝7.0Hz,2H),3.56(dt,J＝10.2,4.8Hz,2H),3.29(s,3H),3.24(dd,J＝10.7,6.8Hz,1H),2.82(q,J＝7.2Hz,1H),2.15-1.96(m,3H),1.91-1.79(m,1H),1.31(t,J＝7.0Hz,3H),1.03(dd,J＝8.3,2.0Hz,2H),0.86-0.81(m,2H).Compound 314-3 (60 mg, 0.22 mmol), 1-(6-bromopyridin-2-yl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one (72 mg, 0.22 mmol) and cesium carbonate (0.22 g, 0.66 mmol) were dispersed in N,N-dimethylformamide (2.0 mL) solution, heated to 120°C and stirred overnight. The reaction mixture was extracted with ethyl acetate (5 mL×3) and water (5 mL), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography column (eluent: methanol/dichloromethane = 1/12) to obtain a crude product of compound 314. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain product 314, 6.51 mg, with a yield of 5.0%. LC-MS(ESI)m/z:582.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.13(s,1H),7.97(d,J＝8.8Hz,1H),7.73(d,1H),7.69(d,J＝8.5Hz,1H),7.36(d,J＝1.7Hz,1H),7.2 1(dd,J＝8.8,2.1Hz,1H),7.02(dd,J＝8.3,1.6Hz,1H),6.55(dd,J＝8.0,6.5Hz,2H),6.44(d,J＝2.1Hz,1H),4.37(ddd,J＝43.1,13.9,7.4 Hz,2H),3.69(q,J＝7.0Hz,2H),3.56(dt,J＝10.2,4.8Hz,2H),3.29(s,3H),3.24(dd,J＝10.7,6.8Hz,1H),2.82(q,J＝7.2Hz,1H),2.15-1.96(m,3H),1.91- 1.79(m,1H),1.31(t,J＝7.0Hz,3H),1.03(dd,J＝8.3,2.0Hz,2H),0.86-0.81(m,2H).
实施例315
Embodiment 315
合成方法Synthesis method
化合物315的合成方法参照实施例123。区别在于把步骤七中的二甲胺替换为N-甲乙胺。LC-MS(ESI)m/z:310.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.96(d,J＝8.8Hz,1H),7.78(d,J＝8.7Hz,1H),7.74(dd,J＝8.4,7.2Hz,1H),7.61(d,J＝2.0Hz,1H),7.27(dd,J＝8.7,2.1Hz,1H),7.19(dd,J＝8.8,1.9Hz,1H),6.56(t,J＝7.8Hz,2H),6.49(d,J＝ 2.1Hz,1H),5.97(s,1H),4.31-4.12(m,2H),3.58-3.47(m,4H),3.25-3.18(m,9H),2.84(s,3H),2.77-2.66(m,2H),1.25(t,3H).The synthesis method of compound 315 refers to Example 123. The difference is that the dimethylamine in step 7 is replaced by N-methylethylamine. LC-MS (ESI) m/z: 310.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ7.96 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.74 (dd, J=8.4, 7.2 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.27 (dd, J=8.7, 2.1 Hz, 1H), 7.19 (dd, J=8.8, 1.9 Hz, 1H), 6.56 (t, J=7.8 Hz, 2H), 6.49 (d, J= 2.1Hz,1H),5.97(s,1H),4.31-4.12(m,2H),3.58-3.47(m,4H),3.25-3.18(m,9H),2.84(s,3H),2.77-2.66(m,2H),1.25(t,3H).
实施例316
Embodiment 316
合成方法Synthesis method
化合物316的合成方法参照实施例123。区别在于把步骤一中的2,4,7-三氯喹唑啉替换为2,4-二氯-7-三氟甲基喹唑啉，步骤七中的二甲胺替换为N-甲乙胺，把步骤五中的2-氨基-6-溴吡啶替换为2-氨基-4-甲基-6-溴吡啶。LC-MS(ESI)m/z:334.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.16(d,J＝8.4Hz,1H),7.94(d,J＝8.8Hz,1H),7.77(s,1H),7.56(d,J＝7.5Hz,1H),7.43(d,J＝8.4Hz,1H),7.18(dd,J＝8.8,2.2Hz,1H),6.63(d,J＝7.4Hz,1H),6.40(d,J＝2.1Hz,1H),4.27(ddd,J＝80.9,14.4,7.3Hz,2H),3.69(q,J＝7.2Hz,2H),3.54-3.45(m,2H),3.29(s,3H),3.25(s,6H),2.41(s,3H),2.04(m,1H),1.96-1.90(m,1H),1.76(dd,J＝12.3,7.0Hz,1H),1.46(t,J＝7.2Hz,2H),0.86(t,J＝6.9Hz,3H).The synthesis method of compound 316 refers to Example 123. The difference is that 2,4,7-trichloroquinazoline in step 1 is replaced by 2,4-dichloro-7-trifluoromethylquinazoline, dimethylamine in step 7 is replaced by N-methylethylamine, and 2-amino-6-bromopyridine in step 5 is replaced by 2-amino-4-methyl-6-bromopyridine. LC-MS (ESI) m/z: 334.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.16(d,J＝8.4Hz,1H),7.94(d,J＝8.8Hz,1H),7.77(s,1H),7.56(d,J＝7.5Hz,1H),7.43(d,J＝8.4Hz,1H),7.18(dd,J＝8.8,2.2Hz,1H),6.63(d,J＝7.4Hz,1 H), 6.40 (d, J = 2.1Hz, 1H), 4.27 (ddd, J = 80.9, 14. 4,7.3Hz,2H),3.69(q,J＝7.2Hz,2H),3.54-3.45(m,2H),3.29(s,3H),3.25(s,6H),2.41(s,3H),2.04(m,1H),1.96-1.90(m,1H),1.76(dd,J＝12.3,7.0 Hz,1H),1.46(t,J＝7.2Hz,2H),0.86(t,J＝6.9Hz,3H).
实施例317
Embodiment 317
合成方法Synthesis method
化合物317的合成方法参照实施例123。区别在于把步骤一中的2,4,7-三氯喹唑啉替换为2,4-二氯-7-环丙基喹唑啉，步骤七中的二甲胺替换为N-甲乙胺，把步骤五中的2-氨基-6-溴吡啶替换为2-氨基-4-甲基-6-溴吡啶。LC-MS(ESI)m/z:320.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.95(d,J＝8.8Hz,1H),7.80(d,J＝8.5Hz,1H),7.55(d,J＝7.5Hz,1H),7.19(dd,J＝8.8,2.2Hz,1H),7.14(s,1H),6.79(d,J＝8.5Hz,1H),6.63(d,J＝7.4Hz,1H),6.43(d,J＝2.2Hz,1H),4.20(ddd,J＝98.5,14.0,7.0Hz,2H),3.69(q,J＝7.1Hz,2H),3.55-3.47(m,2H),3.29(s,3H),3.19(s,6H),2.63(q,J＝6.6Hz,2H),2.42(s,3H),1.92(dt,J＝12.5,6.3Hz,1H),1.75(dt,J＝12.4,7.2Hz,1H),1.49-1.43(m,1H),1.30(t,J＝7.0Hz,3H),0.99(p,J＝7.6Hz,2H),0.86(t,J＝6.9Hz,1H),0.84-0.73(m,2H).The synthesis method of compound 317 is similar to that of Example 123. The difference is that 2,4,7-trichloroquinazoline in step 1 is replaced by 2,4-dichloro-7-cyclopropylquinazoline, dimethylamine in step 7 is replaced by N-methylethylamine, and 2-amino-6-bromopyridine in step 5 is replaced by 2-amino-4-methyl-6-bromopyridine. LC-MS (ESI) m/z: 320.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.95(d,J＝8.8Hz,1H),7.80(d,J＝8.5Hz,1H),7.55(d,J＝7.5Hz,1H),7.19(dd,J＝8.8,2.2Hz,1H),7.14(s,1H),6.79(d,J＝8.5Hz,1H),6.63(d,J＝7.4Hz,1 H),6.43(d,J＝2.2Hz,1H),4.20(ddd,J＝98.5,14.0,7.0Hz,2H),3.69(q,J＝7.1Hz,2H),3.5 5-3.47(m,2H),3.29(s,3H),3.19(s,6H),2.63(q,J＝6.6Hz,2H),2.42(s,3H),1.92(dt,J＝12.5,6.3Hz,1H),1.75(dt,J＝12.4,7.2Hz,1H),1.49-1.43 (m,1H),1.30(t,J＝7.0Hz,3H),0.99(p,J＝7.6Hz,2H),0.86(t,J＝6.9Hz,1H),0.84-0.73(m,2H).
实施例318
Embodiment 318
合成方法Synthesis method
化合物318的合成方法参照实施例123。区别在于把步骤一中的二甲胺替换为氮杂 环丁烷，步骤三中的1-Boc-3-溴甲基吡咯烷替换为1-Boc-3-氟-3-溴甲基吡咯烷，步骤七中的二甲胺替换为N-甲乙胺。LC-MS(ESI)m/z:325.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.06(d,J＝8.5Hz,1H),7.98(d,J＝8.8Hz,1H),7.77(t,1H),7.57(s,1H),7.22(dd,J＝8.8,2.2Hz,1H),7.17(dd,J＝8.5,1.8Hz,1H),6.62(d,J＝7.3Hz,1H),6.60(d,J＝8.2Hz,1H),6.42(d,J＝2.2Hz,1H),4.58(d,J＝18.9Hz,2H),3.84-3.76(m,3H),3.70(q,J＝6.9Hz,2H),3.64(t,J＝9.8Hz,2H),3.50(t,J＝5.6Hz,2H),3.30(s,3H),2.34-2.27(m,1H),2.00-1.96(m,2H),1.84(p,J＝5.7Hz,2H),1.49-1.42(m,1H),1.31(t,J＝7.0Hz,3H).The synthesis method of compound 318 refers to Example 123. The difference is that the dimethylamine in step 1 is replaced by aza Cyclobutane, 1-Boc-3-bromomethylpyrrolidine in step 3 was replaced by 1-Boc-3-fluoro-3-bromomethylpyrrolidine, and dimethylamine in step 7 was replaced by N-methylethylamine. LC-MS (ESI) m/z: 325.1 [M/2 + H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.06(d,J＝8.5Hz,1H),7.98(d,J＝8.8Hz,1H),7.77(t,1H),7.57(s,1H),7.22(dd,J＝8.8,2.2Hz,1H),7.17(dd,J＝8.5,1.8Hz,1H),6.62(d,J＝7.3Hz,1H), 6.60(d,J＝8.2Hz,1H),6.42(d,J＝2.2Hz,1H),4.58(d,J＝18 .9Hz,2H),3.84-3.76(m,3H),3.70(q,J＝6.9Hz,2H),3.64(t,J＝9.8Hz,2H),3.50(t,J＝5.6Hz,2H),3.30(s,3H),2.34-2.27(m,1H),2.00-1.96(m,2H), 1.84(p,J＝5.7Hz,2H),1.49-1.42(m,1H),1.31(t,J＝7.0Hz,3H).
实施例319
Embodiment 319
合成路线
Synthetic route
步骤一：化合物319-1的合成Step 1: Synthesis of compound 319-1
取7-溴-3,4-二氢-2(1H)-喹啉酮(0.50g，2.2mmol)、3-(溴甲基)吡咯烷-1-甲酸叔丁酯(1.2g，4.4mmol)和碳酸铯(2.2g，6.6mmol)分散到1,4-二氧六环(10mL)溶液中，加热到100゜C，搅拌过夜。反应混合物用乙酸乙酯(20mL×3)和水(20mL)萃取，合并有机相，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：乙酸乙酯/石油醚)纯化，得到化合物319-1，0.86g，产率95％。LC-MS(ESI)m/z:353[M-56+H]+.7-Bromo-3,4-dihydro-2(1H)-quinolinone (0.50 g, 2.2 mmol), tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate (1.2 g, 4.4 mmol) and cesium carbonate (2.2 g, 6.6 mmol) were dispersed in a 1,4-dioxane (10 mL) solution, heated to 100 °C, and stirred overnight. The reaction mixture was extracted with ethyl acetate (20 mL × 3) and water (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate/petroleum ether) to obtain compound 319-1, 0.86 g, yield 95%. LC-MS (ESI) m/z: 353 [M-56 + H] + .
步骤二：化合物319-2的合成Step 2: Synthesis of compound 319-2
将化合物319-1(0.86g，2.1mmol)和环丙基硼酸频哪醇酯(0.89g，5.3mmol)溶到1,4-二氧六环(10mL)溶液中，向反应液中加入碳酸钾(0.2g，6.3mmol)的水(2.0mL)溶液，氮气吹气三分钟，然后加入1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.17g，0.21mmol)。加热到100゜C，搅拌过夜。待反应液冷却至室温，反应液经硅藻土过滤，用乙酸乙酯洗涤，滤液经减压浓缩，残余物用乙酸乙酯(20mL×3)和水(20mL)萃取，合并有机相，饱和食盐水洗涤(20mL)一次，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：乙酸乙酯/石油醚)纯化，得到化合物319-2，0.77g，产率99％。LC-MS(ESI)m/z:315[M-56+H]+.Compound 319-1 (0.86 g, 2.1 mmol) and cyclopropylboronic acid pinacol ester (0.89 g, 5.3 mmol) were dissolved in 1,4-dioxane (10 mL) solution, potassium carbonate (0.2 g, 6.3 mmol) in water (2.0 mL) was added to the reaction solution, nitrogen was blown for three minutes, and then 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.17 g, 0.21 mmol) was added. Heat to 100°C and stir overnight. After the reaction solution was cooled to room temperature, the reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate (20 mL×3) and water (20 mL). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/petroleum ether) to obtain compound 319-2, 0.77 g, yield 99%. LC-MS (ESI) m/z: 315 [M-56+H] + .
步骤三：化合物319-3的合成Step 3: Synthesis of compound 319-3
取化合物319-2(0.44g，1.1mmol)分散到1,4-二氧六环(5.0mL)中，室温下，向反应液中滴加盐酸的二氧六环溶液(5.0mL)。室温搅拌过夜。反应液经减压浓缩后， 得到化合物319-3的粗品，直接用于下一步。LC-MS(ESI)m/z:271[M+H]+.Compound 319-2 (0.44 g, 1.1 mmol) was dispersed in 1,4-dioxane (5.0 mL). A solution of hydrochloric acid in dioxane (5.0 mL) was added dropwise to the reaction solution at room temperature. The mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. The crude product of compound 319-3 was obtained and used directly in the next step. LC-MS (ESI) m/z: 271 [M+H] + .
步骤四：化合物319的合成Step 4: Synthesis of compound 319
取化合物319-3(80mg，0.30mmol)、1-(6-溴吡啶-2-基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮(96mg，0.30mmol)和碳酸铯(0.29g，0.90mmol)分散到N,N-二甲基甲酰胺(2.0mL)溶液中，加热到120゜C，搅拌过夜。反应混合物用乙酸乙酯(5mL×3)和水(5mL)萃取，合并有机相，饱和食盐水洗涤(5mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝1/16)纯化，得到化合物319的粗品。粗品再经制备液相色谱纯化，制备液冷冻干燥，得到产物319，9.22mg，产率5.3％。LC-MS(ESI)m/z:583.3[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(d,J＝8.8Hz,1H),7.72(dd,J＝8.4,7.3Hz,1H),7.21(dd,J＝8.8,2.2Hz,1H),7.07(d,J＝7.7Hz,1H),6.90(d,J＝1.6Hz,1H),6.67(dd,J＝7.7,1.5Hz,1H),6.55(t,J＝8.3Hz,2H),6.45(d,J＝2.1Hz,1H),4.15(dd,J＝14.3,8.0Hz,1H),3.96(dd,J＝14.2,6.8Hz,1H),3.70(q,J＝7.0Hz,2H),3.52-3.44(m,2H),3.33-3.30(m,1H),3.30(s,3H),3.15(dd,J＝10.6,6.5Hz,1H),2.79(t,J＝7.3Hz,2H),2.64-2.57(m,1H),2.54-2.51(m,2H),2.00-1.96(m,1H),1.92-1.84(m,1H),1.80-1.69(m,1H),1.31(t,J＝7.0Hz,3H),0.88(dd,J＝8.3,2.2Hz,2H),0.69-0.61(m,2H).Compound 319-3 (80 mg, 0.30 mmol), 1-(6-bromopyridin-2-yl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one (96 mg, 0.30 mmol) and cesium carbonate (0.29 g, 0.90 mmol) were dispersed in N,N-dimethylformamide (2.0 mL) solution, heated to 120°C, and stirred overnight. The reaction mixture was extracted with ethyl acetate (5 mL×3) and water (5 mL), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography column (eluent: methanol/dichloromethane = 1/16) to obtain a crude product of compound 319. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain product 319, 9.22 mg, with a yield of 5.3%. LC-MS(ESI)m/z:583.3[M+H] + . 1 H NMR(600MHz, DMSO-d 6 )δ7.97(d,J＝8.8Hz,1H),7.72(dd,J＝8.4,7.3Hz,1H),7.21(dd,J＝8.8,2.2Hz,1H),7.07(d,J＝7.7Hz,1H),6.90(d,J＝1.6Hz,1H),6.67(dd,J＝7.7,1.5Hz,1H), 6.55(t,J＝8.3Hz,2H),6.45(d,J＝2.1Hz,1H),4.15(dd,J＝14.3,8.0Hz,1H),3.96(dd,J＝14.2,6.8Hz,1H),3.70(q,J＝7.0H z,2H),3.52-3.44(m,2H),3.33-3.30(m,1H),3.30(s,3H),3.15(dd,J＝10.6,6.5Hz,1H),2.79(t,J＝7.3Hz,2H),2.64-2.57(m,1H),2.54-2.51(m,2H), 2.00-1.96(m,1H),1.92-1.84(m,1H),1.80-1.69(m,1H),1.31(t,J＝7.0Hz,3H),0.88(dd,J＝8.3,2.2Hz,2H),0.69-0.61(m,2H).
实施例320
Embodiment 320
合成方法Synthesis method
化合物320的合成方法参照实施例123。区别在于把步骤一中的二甲胺替换为甲乙胺，步骤三中的1-Boc-3-溴甲基吡咯烷替换为1-Boc-3-氟-3-溴甲基吡咯烷。LC-MS(ESI)m/z:319.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.04(d,J＝8.8Hz,1H),7.87(d,J＝8.8Hz,1H),7.76(t,1H),7.74(t,J＝2.0Hz,1H),7.21(td,J＝8.7,6.4,2.1Hz,2H),6.60(t,J＝7.8Hz,2H),6.42(d,J＝2.1Hz,1H),4.69(d,J＝20.1Hz,2H),3.77-3.59(m,5H),3.43-3.38(m,1H),3.31(s,6H),3.22(s,3H),2.36-2.22(m,2H),1.26(t,3H).The synthesis method of compound 320 is similar to that of Example 123. The difference is that dimethylamine in step 1 is replaced by methylethylamine, and 1-Boc-3-bromomethylpyrrolidine in step 3 is replaced by 1-Boc-3-fluoro-3-bromomethylpyrrolidine. LC-MS (ESI) m/z: 319.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.04(d,J＝8.8Hz,1H),7.87(d,J＝8.8Hz,1H),7.76(t,1H),7.74(t,J＝2.0Hz,1H),7.21(td,J＝8.7,6.4,2.1Hz,2H),6.60(t,J＝7.8Hz,2H),6.42(d,J＝2 .1Hz,1H),4.69(d,J＝20.1Hz,2H),3.77-3.59(m,5H),3.43-3.38(m,1H),3.31(s,6H),3.22(s,3H),2.36-2.22(m,2H),1.26(t,3H).
实施例321
Embodiment 321
合成方法Synthesis method
化合物321的合成方法参照实施例300。区别在于把步骤一中的7-氯喹啉-2(1H)-酮替换为7-氯喹唑啉-2(1H)-酮，步骤一中的1-Boc-3-氟-3-溴甲基吡咯烷替换为1-Boc-3-溴甲基吡咯烷。LC-MS(ESI)m/z:576.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ9.49(s,1H),8.13(d,J＝8.6Hz,1H),7.97(d,J＝8.8Hz,1H),7.86(d,J＝2.0Hz,1H),7.74(t,J＝7.9Hz,1H),7.60(dd,J＝8.6,2.0Hz,1H),7.20(dd,J＝8.8,2.2Hz,1H),6.62(d,J＝8.4Hz,1H),6.58(d,J＝7.3Hz,1H),6.45(d,J＝2.1Hz,1H),4.56-4.48(m,1H),4.48-4.38(m,1H),3.70(q,J＝7.0Hz,2H),3.67-3.61(m,1H),3.57-3.52(m,1H),3.44-3.39(m,2H),3.29(s,3H),2.93-2.82(m,1H),2.25-2.16(m,1H),1.96-1.89(m,1H),1.31(t,J＝7.0Hz,3H). The synthesis method of compound 321 refers to Example 300. The difference is that 7-chloroquinoline-2(1H)-one in step 1 is replaced by 7-chloroquinazoline-2(1H)-one, and 1-Boc-3-fluoro-3-bromomethylpyrrolidine in step 1 is replaced by 1-Boc-3-bromomethylpyrrolidine. LC-MS (ESI) m/z: 576.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ9.49(s,1H),8.13(d,J＝8.6Hz,1H),7.97(d,J＝8.8Hz,1H),7.86(d,J＝2.0Hz,1H),7.74(t,J＝7.9Hz,1H),7.60(dd,J＝8.6,2.0Hz,1H),7.20(dd,J＝8.8,2. 2Hz,1H),6.62(d,J＝8.4Hz,1H),6.58(d,J＝7.3Hz,1H),6.45(d,J＝2 .1Hz,1H),4.56-4.48(m,1H),4.48-4.38(m,1H),3.70(q,J＝7.0Hz,2H),3.67-3.61(m,1H),3.57-3.52(m,1H),3.44-3.39(m,2H),3.29(s,3H),2.93 -2.82(m,1H),2.25-2.16(m,1H),1.96-1.89(m,1H),1.31(t,J＝7.0Hz,3H).
实施例322
Embodiment 322
合成方法Synthesis method
化合物322的合成方法参照实施例123。区别在于把步骤一中的2,4,7-三氯喹唑啉替换为2,4-二氯-7-三氟甲基喹唑啉，步骤一中的二甲胺替换为氮杂环丁烷，步骤七中的二甲胺替换为N-甲乙胺，把步骤五中的2-氨基-6-溴吡啶替换为2-氨基-4-甲基-6-溴吡啶。LC-MS(ESI)m/z:340.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝8.2Hz,1H),7.93(d,J＝8.9Hz,1H),7.61(s,1H),7.56(d,J＝7.6Hz,1H),7.41(d,1H),7.17(dd,J＝8.8,2.1Hz,1H),6.64(d,J＝7.4Hz,1H),6.37(d,J＝2.1Hz,1H),4.17(ddd,J＝50.7,14.7,7.4Hz,2H),3.77(t,J＝6.2Hz,2H),3.68(q,J＝7.0Hz,2H),3.55-3.41(m,4H),3.28(s,3H),2.65-2.56(m,1H),2.41(s,3H),2.03-1.98(m,2H),1.83(q,J＝5.7Hz,2H),1.81-1.71(m,1H),1.45(t,J＝7.1Hz,1H),1.29(t,J＝7.0Hz,3H).The synthesis method of compound 322 refers to Example 123. The difference is that 2,4,7-trichloroquinazoline in step 1 is replaced by 2,4-dichloro-7-trifluoromethylquinazoline, dimethylamine in step 1 is replaced by azetidine, dimethylamine in step 7 is replaced by N-methylethylamine, and 2-amino-6-bromopyridine in step 5 is replaced by 2-amino-4-methyl-6-bromopyridine. LC-MS (ESI) m/z: 340.1 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.24(d,J＝8.2Hz,1H),7.93(d,J＝8.9Hz,1H),7.61(s,1H),7.56(d,J＝7.6Hz,1H),7.41(d,1H),7.17(dd,J＝8.8,2.1Hz,1H),6.64(d,J＝7.4Hz,1H),6.37 (d,J＝2.1Hz,1H),4.17(ddd,J＝50.7,14.7,7.4Hz,2H),3.7 7(t,J＝6.2Hz,2H),3.68(q,J＝7.0Hz,2H),3.55-3.41(m,4H),3.28(s,3H),2.65-2.56(m,1H),2.41(s,3H),2.03-1.98(m,2H),1.83(q,J＝5.7Hz,2H), 1.81-1.71(m,1H),1.45(t,J＝7.1Hz,1H),1.29(t,J＝7.0Hz,3H).
实施例323
Embodiment 323
合成方法Synthesis method
化合物323的合成方法参照实施例123。区别在于把步骤一中的2,4,7-三氯喹唑啉替换为2,4-二氯-7-环丙基喹唑啉。LC-MS(ESI)m/z:306.1[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.81(d,J＝8.5Hz,1H),7.71(t,1H),7.24-7.14(m,2H),6.78(dd,J＝8.5,1.5Hz,1H),6.54(dd,J＝7.8,3.0Hz,2H),6.44(d,J＝2.2Hz,1H),4.22(ddd,J＝49.3,14.1,7.1Hz,2H),3.54-3.47(m,2H),3.29(s,6H),3.19(s,6H),2.79-2.69(m,2H),1.88-1.77(m,1H),1.51-1.40(m,2H),1.02(dd,J＝8.2,2.4Hz,2H),0.84-0.78(m,3H).The synthesis method of compound 323 refers to Example 123. The difference is that 2,4,7-trichloroquinazoline in step 1 is replaced by 2,4-dichloro-7-cyclopropylquinazoline. LC-MS (ESI) m/z: 306.1 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.03 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.71 (t, 1H), 7.24-7.14 (m, 2H), 6.78 (dd, J = 8.5, 1.5 Hz, 1H), 6.54 (dd, J = 7.8, 3.0 Hz, 2H), 6.44 (d, J = 2.2 Hz, 1H), 4.22 (ddd, J = 49.3,14.1,7.1Hz,2H),3.54-3.47(m,2H),3.29(s,6H),3.19(s,6H),2.79-2.69(m,2H),1.88-1.77(m,1H),1.51-1.40(m,2H),1.02(dd,J＝8.2,2.4 Hz,2H),0.84-0.78(m,3H).
实施例324
Embodiment 324
合成方法Synthesis method
化合物324的合成方法参照实施例298。区别在于把步骤一中的6-溴-3,3-二甲基吲哚-2-酮替换为6'-溴螺[环丙烷-1,3'-吲哚啉]-2'-酮，步骤四中的293-3替换为6'-环丙基-1'-(吡咯烷-3-基甲基)螺[环丙烷-1,3'-吲哚啉]-2'-酮。LC-MS(ESI)m/z:534.3[M+H]+.1H NMR(600MHz,DMSO-d6)δδ7.81(d,J＝13.9Hz,1H),7.17(d,J＝13.1Hz,1H),7.06 (dd,J＝21.3,13.9Hz,1H),6.99(d,J＝7.7Hz,1H),6.91-6.83(m,3H),6.73(ddd,J＝14.4,7.7,1.5Hz,1H),3.86-3.77(m,2H),3.76-3.68(m,1H),3.59-3.53(m,1H),3.25-3.19(m,1H),2.68-2.60(m,1H),2.08-1.96(m,3H),1.71-1.60(m,5H),1.58-1.43(m,5H),1.010.89(m,4H),0.80-0.66(m,4H).The synthesis method of compound 324 refers to Example 298. The difference is that 6-bromo-3,3-dimethylindol-2-one in step 1 is replaced by 6'-bromospiro[cyclopropane-1,3'-indolin]-2'-one, and 293-3 in step 4 is replaced by 6'-cyclopropyl-1'-(pyrrolidin-3-ylmethyl)spiro[cyclopropane-1,3'-indolin]-2'-one. LC-MS (ESI) m/z: 534.3 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δδ7.81 (d, J＝13.9 Hz, 1H), 7.17 (d, J＝13.1 Hz, 1H), 7.06 (d, J＝13.7 Hz, 1H). (dd,J＝21.3,13.9Hz,1H),6.99(d,J＝7.7Hz,1H),6.91-6.83(m,3H),6.73(ddd,J＝14.4,7.7,1.5Hz,1H),3.86-3.77(m,2H),3.76-3.68(m,1H),3.59-3.53 (m,1H),3.25-3.19(m,1H),2.68-2.60(m,1H),2.08-1.96(m,3H),1.71-1.60(m,5H),1.58-1.43(m,5H),1.010.89(m,4H),0.80-0.66(m,4H).
实施例325
Embodiment 325
合成方法Synthesis method
化合物325的合成方法参照实施例298。区别在于把步骤一中的6-溴-3,3-二甲基吲哚-2-酮替换为6'-溴螺[环丙烷-1,3'-吲哚啉]-2'-酮，步骤四中的293-3替换为1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:546.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.26(t,J＝5.8Hz,1H),7.90(d,J＝8.7Hz,1H),7.79(d,J＝14.3Hz,1H),7.51(d,J＝2.1Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),7.15(s,1H),6.99(d,J＝7.7Hz,1H),6.88(d,J＝7.8Hz,1H),6.83(d,J＝14.3Hz,1H),4.08(t,J＝7.6Hz,2H),3.62(q,J＝7.0Hz,2H),3.29(q,J＝6.7Hz,2H),3.20(s,3H),2.03-1.98(m,1H),1.82-1.75(m,2H),1.69-1.60(m,4H),1.26(t,J＝7.1Hz,3H),1.03-0.94(m,2H),0.80-0.72(m,2H).The synthesis method of compound 325 refers to Example 298. The difference is that 6-bromo-3,3-dimethylindol-2-one in step 1 is replaced by 6'-bromospiro[cyclopropane-1,3'-indolline]-2'-one, and 293-3 in step 4 is replaced by 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 546.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.26(t,J＝5.8Hz,1H),7.90(d,J＝8.7Hz,1H),7.79(d,J＝14.3Hz,1H),7.51(d,J＝2.1Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),7.15(s,1H),6.99(d,J＝7.7Hz, 1H),6.88(d,J＝7.8Hz,1H),6.83(d,J＝14.3Hz,1 H),4.08(t,J＝7.6Hz,2H),3.62(q,J＝7.0Hz,2H),3.29(q,J＝6.7Hz,2H),3.20(s,3H),2.03-1.98(m,1H),1.82-1.75(m,2H),1.69-1.60(m,4H),1.26(t, J＝7.1Hz,3H),1.03-0.94(m,2H),0.80-0.72(m,2H).
实施例326
Embodiment 326
合成方法Synthesis method
化合物326的合成方法参照实施例123。区别在于把步骤三中的1-Boc-3-溴甲基吡咯烷替换为1-(溴甲基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯。LC-MS(ESI)m/z:309.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.96(d,J＝8.8Hz,1H),7.70(dd,J＝8.4,7.3Hz,1H),7.66(d,J＝2.0Hz,1H),7.20(ddd,J＝8.8,4.0,2.0Hz,2H),6.57(d,J＝7.3Hz,1H),6.53(d,J＝8.5Hz,1H),6.39(d,J＝2.1Hz,1H),4.51-4.39(m,2H),3.62(d,J＝10.5Hz,1H),3.54(d,J＝10.2Hz,1H),3.30(s,6H),3.21(s,6H),1.73(d,J＝5.8Hz,1H),1.46(p,J＝7.2Hz,1H),0.89(dd,J＝8.3,4.6Hz,1H),0.86(t,J＝6.9Hz,1H),0.45(t,J＝4.4Hz,1H).The synthesis method of compound 326 refers to Example 123. The difference is that 1-Boc-3-bromomethylpyrrolidine in step 3 is replaced by 1-(bromomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester. LC-MS (ESI) m/z: 309.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.03(d,J＝8.8Hz,1H),7.96(d,J＝8.8Hz,1H),7.70(dd,J＝8.4,7.3Hz,1H),7.66(d,J＝2.0Hz,1H),7.20(ddd,J＝8.8,4.0,2.0Hz,2H),6.57(d,J＝7.3Hz,1H) ,6.53(d,J＝8.5Hz,1H),6.39(d,J＝2.1Hz,1H),4.51 -4.39(m,2H),3.62(d,J＝10.5Hz,1H),3.54(d,J＝10.2Hz,1H),3.30(s,6H),3.21(s,6H),1.73(d,J＝5.8Hz,1H),1.46(p,J＝7.2Hz,1H),0.89(dd,J＝8.3,4 .6Hz,1H),0.86(t,J＝6.9Hz,1H),0.45(t,J＝4.4Hz,1H).
实施例327
Embodiment 327
合成方法Synthesis method
化合物327的合成方法参照实施例123。区别在于把步骤一中的2,4,7-三氯喹唑啉 替换为2,4-二氯吡啶并[2,3-d]嘧啶，步骤七中的二甲胺替换为N-甲乙胺。LC-MS(ESI)m/z:293.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.60(dd,J＝4.7,1.6Hz,1H),8.40(dd,J＝8.1,1.7Hz,1H),7.96(d,J＝8.8Hz,1H),7.71(t,J＝7.9Hz,1H),7.23-7.17(m,2H),6.56-6.51(m,2H),6.43(d,J＝2.1Hz,1H),4.39-4.27(m,2H),3.69(q,J＝7.0Hz,2H),3.56-3.49(m,1H),3.49-3.42(m,1H),3.32-3.30(m,1H),3.29(s,3H),3.28(s,6H),3.24-3.19(m,1H),2.89-2.80(m,1H),2.03-1.97(m,1H),1.85-1.73(m,1H),1.31(t,J＝7.0Hz,3H).The synthesis method of compound 327 is similar to that of Example 123. The difference is that 2,4,7-trichloroquinazoline in step 1 Replaced with 2,4-dichloropyrido[2,3-d]pyrimidine, dimethylamine in step 7 was replaced with N-methylethylamine. LC-MS (ESI) m/z: 293.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.60 (dd, J = 4.7, 1.6 Hz, 1H), 8.40 (dd, J = 8.1, 1.7 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.23-7.17 (m, 2H), 6.56-6.51 (m, 2H), 6.43 (d, J = 2.1 Hz, 1H), 4.39-4.27 (m, 2H), 3.69 (q, J ＝7.0Hz,2H),3.56-3.49(m,1H),3.49-3.42(m,1H),3.32-3.30(m,1H),3.29(s,3H),3.28(s,6H),3.24-3.19(m,1H),2.89-2.80(m,1H),2.03-1.97 (m,1H),1.85-1.73(m,1H),1.31(t,J＝7.0Hz,3H).
实施例328
Embodiment 328
合成方法Synthesis method
化合物328的合成方法参照实施例293。区别在于把步骤四中的293-3替换为5-氯-3-(吡咯烷-3-基甲基)氯苯并[d]恶唑-2(3H)-酮。LC-MS(ESI)m/z:565.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(d,J＝8.8Hz,1H),7.73(t,J＝7.8Hz,1H),7.62(d,J＝2.2Hz,1H),7.37(d,J＝8.5Hz,1H),7.19(ddd,J＝18.5,8.7,2.2Hz,2H),6.56(d,J＝7.7Hz,2H),6.43(d,J＝2.1Hz,1H),3.97-3.88(m,2H),3.70(q,J＝7.0Hz,2H),3.61-3.50(m,2H),3.32-3.30(m,1H),3.30(s,3H),3.19-3.13(m,1H),2.86-2.78(m,1H),2.13-2.05(m,1H),1.86-1.76(m,1H),1.31(t,J＝7.0Hz,4H).The synthesis method of compound 328 refers to Example 293. The difference is that 293-3 in step 4 is replaced by 5-chloro-3-(pyrrolidin-3-ylmethyl)chlorobenzo[d]oxazol-2(3H)-one. LC-MS (ESI) m/z: 565.1 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.97 (d, J = 8.8 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.19 (ddd, J = 18.5, 8.7, 2.2 Hz, 2H), 6.56 (d, J = 7.7 Hz, 2H), 6.43 (d, J = 2.1 Hz, 1H), 3.97-3. 1.8 6-1.76(m,1H),1.31(t,J＝7.0Hz,4H).
实施例329
Embodiment 329
合成路线
Synthetic route
步骤一：化合物329-1的合成Step 1: Synthesis of compound 329-1
在封管中加入双三甲基硅基胺基锂的四氢呋喃溶液(5.8mL)，通入氮气后密封。向封管中依次加入化合物313-1(0.58g，2.3mmol)的N,N-二甲基乙酰胺(2.0mL)溶液、醋酸钯(30mg，0.13mmol)和(R)-(-)-1-[(S)-2-(二环己基膦)二茂铁]乙基二叔丁基膦(70mg，0.13mmol)的N,N-二甲基乙酰胺(0.8mL)混合液和丙炔胺(0.15g， 2.8mmol)，加热到60゜C，搅拌过夜。待反应液冷却至室温后，用乙酸乙酯(20mL×3)和水(20mL)萃取，合并有机相，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：乙酸乙酯/石油醚)纯化，得到化合物329-1，200mg，产率38％。LC-MS(ESI)m/z:226[M+H]+.A tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (5.8 mL) was added to the sealed tube, and nitrogen was introduced and sealed. A solution of compound 313-1 (0.58 g, 2.3 mmol) in N,N-dimethylacetamide (2.0 mL), palladium acetate (30 mg, 0.13 mmol) and a mixture of (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyl di-tert-butylphosphine (70 mg, 0.13 mmol) in N,N-dimethylacetamide (0.8 mL) and propargylamine (0.15 g, 0.13 mmol) were added to the sealed tube in sequence. 2.8mmol), heated to 60°C, and stirred overnight. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate (20mL×3) and water (20mL), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, the desiccant was filtered out, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography column (eluent: ethyl acetate/petroleum ether) to obtain compound 329-1, 200mg, yield 38%. LC-MS (ESI) m/z: 226[M+H] + .
步骤二：化合物329的合成Step 2: Synthesis of compound 329
室温下，将化合物329-1(0.12g，0.53mmol)和1-(6-溴吡啶-2-基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮(0.30g，0.77mmol)溶到N,N-二甲基乙酰胺(2.0mL)中，向反应液中加入1,4－二氮杂二环〔2.2.2〕辛烷(10mg，0.089mmol)、碳酸钾(0.22g，1.6mmol)和醋酸钯(0.020g，0.089mmol)中，通入氮气后，密封。加热到125゜C，搅拌过夜。反应混合物用乙酸乙酯(5mL×3)和水(5mL)萃取，合并有机相，饱和食盐水洗涤(5mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝1/16)纯化，得到化合物329的粗品。粗品再经制备液相色谱纯化，制备液冷冻干燥，得到产物329，18.8mg，产率6.6％。LC-MS(ESI)m/z:538.2[M+H]+。1H NMR(600MHz,DMSO-d6)δ8.24(s,1H),8.08(t,J＝7.8Hz,1H),8.05(d,J＝8.8Hz,1H),7.99(d,J＝7.9Hz,1H),7.84(d,J＝7.2Hz,1H),7.73(d,J＝7.2Hz,1H),7.31-7.17(m,4H),6.56(d,J＝2.2Hz,1H),4.61(d,J＝7.2Hz,2H),3.76(q,J＝7.0Hz,2H),3.36(s,3H),2.45-2.43(m,2H),1.51-1.45(m,1H),1.35(t,J＝6.9Hz,3H),0.58-0.47(m,4H).At room temperature, compound 329-1 (0.12 g, 0.53 mmol) and 1-(6-bromopyridin-2-yl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one (0.30 g, 0.77 mmol) were dissolved in N,N-dimethylacetamide (2.0 mL), 1,4-diazabicyclo〔2.2.2〕octane (10 mg, 0.089 mmol), potassium carbonate (0.22 g, 1.6 mmol) and palladium acetate (0.020 g, 0.089 mmol) were added to the reaction solution, nitrogen was introduced, and the mixture was sealed. Heat to 125°C and stir overnight. The reaction mixture was extracted with ethyl acetate (5 mL×3) and water (5 mL), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: methanol/dichloromethane = 1/16) to obtain a crude product of compound 329. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain the product 329, 18.8 mg, yield 6.6%. LC-MS (ESI) m/z: 538.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.24(s,1H),8.08(t,J＝7.8Hz,1H),8.05(d,J＝8.8Hz,1H),7.99(d,J＝7.9Hz,1H),7.84(d,J＝7.2Hz,1H),7.73(d,J＝7.2Hz,1H),7.31-7.17(m,4H),6.5 6(d,J＝2.2Hz,1H),4.61(d,J＝7.2Hz,2H),3.76(q,J＝7.0Hz,2H),3.36(s,3H),2.45-2.43(m,2H),1.51-1.45(m,1H),1.35(t,J＝6.9Hz,3H),0.58-0.47 (m,4H).
实施例330
Embodiment 330
合成方法Synthesis method
化合物330的合成方法参照实施例307。LC-MS(ESI)m/z:300.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(dd,2H),7.74(dd,2H),7.58(dd,J＝13.2,2.0Hz,1H),7.34(dt,J＝8.7,2.2Hz,1H),7.22(dd,J＝8.3,6.2,2.0Hz,1H),6.88(dd,J＝52.3,13.8Hz,1H),4.66(t,J＝20.6Hz,2H),3.97-3.37(m,4H),3.30(s,3H),3.30(s,3H),3.27(s,3H),3.25(s,3H),2.32-2.13(m,2H).The synthesis method of compound 330 refers to Example 307. LC-MS (ESI) m/z: 300.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.97(dd,2H),7.74(dd,2H),7.58(dd,J＝13.2,2.0Hz,1H),7.34(dt,J＝8.7,2.2Hz,1H),7.22(dd,J＝8.3,6.2,2.0Hz,1H),6.88(dd,J＝52.3,13.8Hz,1H),4. 66(t,J＝20.6Hz,2H),3.97-3.37(m,4H),3.30(s,3H),3.30(s,3H),3.27(s,3H),3.25(s,3H),2.32-2.13(m,2H).
实施例331
Embodiment 331
合成方法Synthesis method
化合物331的合成方法参照实施例306。区别在于把步骤三中的1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮替换为1-((1-(氨基甲基)环丙基)甲基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:298.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.37(t,J＝5.7Hz,1H),8.00(d,J＝8.7Hz,1H),7.86(d,J＝8.7Hz,1H),7.73(d,J＝14.2Hz,1H),7.56(d,J＝2.0Hz,1H),7.50(d,J＝2.0Hz,1H),7.35(dd,J＝8.7,2.0Hz,1H), 7.19(dd,J＝8.7,2.0Hz,1H),6.75(d,J＝14.2Hz,1H),4.27(s,2H),3.62(q,J＝7.1Hz,2H),3.32(s,6H),3.20(s,3H),3.18(d,J＝5.6Hz,2H),1.26(t,J＝7.0Hz,3H),0.42-0.50(m,4H).The synthesis method of compound 331 refers to Example 306, except that 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one in step 3 is replaced by 1-((1-(aminomethyl)cyclopropyl)methyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 298.6 [M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ8.37 (t, J = 5.7Hz, 1H), 8.00 (d, J = 8.7Hz, 1H), 7.86 (d, J = 8.7Hz, 1H), 7.73 (d, J = 14.2Hz, 1H), 7. 56(d,J＝2.0Hz,1H),7.50(d,J＝2.0Hz,1H),7.35(dd,J＝8.7,2.0Hz,1H), 7.19(dd,J＝8.7,2.0Hz,1H),6.75(d,J＝14.2Hz,1H),4.27(s,2H),3.62(q,J＝7.1Hz,2H),3.32(s,6H),3.20(s,3H),3.18(d,J＝5.6Hz,2H),1.26(t,J＝7. 0Hz,3H),0.42-0.50(m,4H).
实施例332
Embodiment 332
合成路线
Synthetic route
步骤一：化合物332-1的合成Step 1: Synthesis of compound 332-1
取2-氨基-4-溴苯甲酸甲酯(5.0g，22mmol)溶于四氢呋喃(40mL)中，降温到0゜C，向反应液中滴加甲基溴化镁的乙醚溶液(22mL，3.0M)，升温至室温，搅拌1.5个小时。TLC监测原料消失后，反应混合物用乙酸乙酯(20mL×3)和水(20mL)萃取，合并有机相，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，得到化合物332-1的粗品，4.8g，可直接用于下一步。LC-MS(ESI)m/z:230[M+H]+.Take methyl 2-amino-4-bromobenzoate (5.0 g, 22 mmol) and dissolve it in tetrahydrofuran (40 mL), cool it to 0 ° C, add methyl magnesium bromide in ether solution (22 mL, 3.0 M) to the reaction solution, warm it to room temperature, and stir for 1.5 hours. After TLC monitoring the disappearance of the raw material, the reaction mixture was extracted with ethyl acetate (20 mL × 3) and water (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was evaporated under reduced pressure to obtain a crude product of compound 332-1, 4.8 g, which can be directly used in the next step. LC-MS (ESI) m/z: 230 [M + H] + .
步骤二：化合物332-2的合成Step 2: Synthesis of compound 332-2
将化合物332-1(4.8g，21mmol)溶于四氢呋喃(40mL)中，向反应液中加入N,N'-羰基二咪唑(3.9g，25mmol)，升温到60゜C，搅拌过夜。反应液经减压浓缩，残余物用乙酸乙酯(50mL×3)和水(50mL)萃取，合并有机相，饱和食盐水洗涤(50mL)一次，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物用乙酸乙酯打浆，得到化合物332-2，4.2g，为白色固体，产率95％。LC-MS(ESI)m/z:256[M+H]+.Compound 332-1 (4.8 g, 21 mmol) was dissolved in tetrahydrofuran (40 mL), N, N'-carbonyldiimidazole (3.9 g, 25 mmol) was added to the reaction solution, the temperature was raised to 60 ° C, and stirred overnight. The reaction solution was concentrated under reduced pressure, the residue was extracted with ethyl acetate (50 mL × 3) and water (50 mL), the organic phases were combined, washed with saturated brine (50 mL) once, dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was evaporated under reduced pressure, and the residue was slurried with ethyl acetate to obtain compound 332-2, 4.2 g, as a white solid, with a yield of 95%. LC-MS (ESI) m/z: 256 [M + H] + .
步骤三：化合物332-3的合成Step 3: Synthesis of compound 332-3
取化合物332-2(0.50g，2.0mmol)、3-(溴甲基)吡咯烷-1-甲酸叔丁酯(1.0g，4.0mmol)和碳酸铯(1.9g，6.0mmol)分散到N,N-二甲基甲酰胺(10mL)溶液中，加热到100゜C，搅拌过夜。反应混合物用乙酸乙酯(20mL×3)和水(20mL)萃取，合并有机相，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：乙酸乙酯/石油醚＝21％)纯化，得到化合物332-3，0.67g，产率77％。LC-MS(ESI)m/z:383[M-56+H]+. Compound 332-2 (0.50 g, 2.0 mmol), tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate (1.0 g, 4.0 mmol) and cesium carbonate (1.9 g, 6.0 mmol) were dispersed in N,N-dimethylformamide (10 mL) solution, heated to 100 ° C, and stirred overnight. The reaction mixture was extracted with ethyl acetate (20 mL × 3) and water (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography column (eluent: ethyl acetate/petroleum ether = 21%) to obtain compound 332-3, 0.67 g, yield 77%. LC-MS (ESI) m/z: 383 [M-56 + H] + .
步骤四：化合物332-4的合成Step 4: Synthesis of compound 332-4
取化合物332-3(0.20g，0.46mmol)分散到1,4-二氧六环(2.0mL)中，室温下，向反应液中滴加盐酸的二氧六环溶液(2.0mL)。室温搅拌3个小时。反应液经减压浓缩后，得到化合物332-4的粗品，直接用于下一步。LC-MS(ESI)m/z:339[M+H]+.Compound 332-3 (0.20 g, 0.46 mmol) was dispersed in 1,4-dioxane (2.0 mL). A solution of hydrochloric acid in dioxane (2.0 mL) was added dropwise to the reaction solution at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product of compound 332-4, which was used directly in the next step. LC-MS (ESI) m/z: 339 [M+H] + .
步骤五：化合物332的合成Step 5: Synthesis of compound 332
取化合物332-4(60mg，0.18mmol)、1-(6-溴吡啶-2-基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮(70mg，0.18mmol)和碳酸铯(0.17g，0.53mmol)分散到N,N-二甲基甲酰胺(2.0mL)溶液中，加热到120゜C，搅拌过夜。反应混合物用乙酸乙酯(5mL×3)和水(5mL)萃取，合并有机相，饱和食盐水洗涤(5mL)，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝1/16)纯化，得到化合物332的粗品。粗品再经制备液相色谱纯化，制备液冷冻干燥，得到产物332，25.62mg，产率22％。LC-MS(ESI)m/z:651.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(d,J＝8.8Hz,1H),7.73(t,J＝8.4,7.2Hz,1H),7.49(d,J＝1.5Hz,1H),7.34-7.27(m,2H),7.21(dd,J＝8.8,2.2Hz,1H),6.56(dd,J＝15.1,7.8Hz,2H),6.46(d,J＝2.1Hz,1H),4.07(ddd,J＝56.4,14.7,7.4Hz,2H),3.70(q,J＝7.0Hz,2H),3.59-3.47(m,2H),3.16(dd,J＝10.7,6.9Hz,1H),2.70(p,J＝7.3Hz,1H),2.12-2.03(m,1H),1.84-1.75(m,1H),1.60(s,3H),1.59(s,3H),1.31(t,J＝7.0Hz,3H),1.27-1.21(m,1H).Compound 332-4 (60 mg, 0.18 mmol), 1-(6-bromopyridin-2-yl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one (70 mg, 0.18 mmol) and cesium carbonate (0.17 g, 0.53 mmol) were dispersed in N,N-dimethylformamide (2.0 mL) solution, heated to 120°C and stirred overnight. The reaction mixture was extracted with ethyl acetate (5 mL×3) and water (5 mL), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography column (eluent: methanol/dichloromethane=1/16) to obtain a crude product of compound 332. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain product 332, 25.62 mg, with a yield of 22%. LC-MS (ESI) m/z: 651.1[M+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ7.97 (d, J = 8.8Hz, 1H), 7.73 (t, J = 8.4, 7.2Hz, 1H), 7.49 (d, J = 1.5Hz, 1H), 7.34-7.27 (m, 2H), 7.21 ( dd,J＝8.8,2.2Hz,1H),6.56(dd,J＝15.1,7.8Hz,2H),6.46(d,J＝2.1Hz,1H),4.07(ddd,J＝56.4,14.7,7.4Hz ,2H),3.70(q,J＝7.0Hz,2H),3.59-3.47(m,2H),3.16(dd,J＝10.7,6.9Hz,1H),2.70(p,J＝7.3Hz,1H),2.12-2.03(m,1H),1.84-1.75(m,1H),1.60(s,3H ),1.59(s,3H),1.31(t,J＝7.0Hz,3H),1.27-1.21(m,1H).
实施例333
Embodiment 333
合成方法Synthesis method
化合物333的合成方法参照实施例306。区别在于把步骤三中的1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮替换为332-4。LC-MS(ESI)m/z:614.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.98(dd,J＝8.7,1.8Hz,1H),7.72(dd,J＝13.8,7.5Hz,1H),7.56(dd,J＝6.6,2.0Hz,1H),7.51(dd,J＝16.9,1.6Hz,1H),7.36-7.29(m,3H),6.89(dd,J＝13.8,5.0Hz,1H),4.13-3.96(m,2H),3.75-3.64(m,1H),3.64-3.56(m,1H),3.51(dt,J＝9.8,7.6Hz,1H),3.30(d,J＝2.8Hz,6H),3.19(dd,J＝12.1,7.3Hz,1H),2.72-2.54(m,1H),2.00-1.92(m,1H),1.80-1.64(m,1H),1.61(t,J＝8.8,7.4Hz,6H).The synthesis method of compound 333 is similar to that of Example 306. The difference is that 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one in step 3 is replaced by 332-4. LC-MS (ESI) m/z: 614.1 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.98(dd,J＝8.7,1.8Hz,1H),7.72(dd,J＝13.8,7.5Hz,1H),7.56(dd,J＝6.6,2.0Hz,1H),7.51(dd,J＝16.9,1.6Hz,1H),7.36-7.29(m,3H),6.89(dd,J＝13.8, 5.0Hz,1H),4.13-3.96(m,2H),3.75-3. 64(m,1H),3.64-3.56(m,1H),3.51(dt,J＝9.8,7.6Hz,1H),3.30(d,J＝2.8Hz,6H),3.19(dd,J＝12.1,7.3Hz,1H),2.72-2.54(m,1H),2.00-1.92(m,1H), 1.80-1.64(m,1H),1.61(t,J=8.8,7.4Hz,6H).
实施例334
Embodiment 334
合成方法Synthesis method
化合物334的合成方法参照实施例293。区别在于把步骤四中的293-3替换为6-氯-3-(丙烷-2-亚烷基)-1-(吡咯烷-3-基甲基)吲哚啉-2-酮。LC-MS(ESI)m/z:603.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(d,J＝8.9Hz,1H),7.72(dd,J＝8.4,7.3Hz,1H),7.59(d,J＝8.3Hz,1H),7.30(d,J＝2.0Hz,1H),7.21(dd,J＝8.8,2.2Hz,1H),7.06(dd,J＝8.2,2.0Hz,1H),6.58-6.52(m,2H),6.44(d,J＝2.2Hz,1H),3.88-3.79(m,2H),3.70(q,J＝ 7.0Hz,2H),3.56-3.46(m,2H),3.32-3.31(m,1H),3.30(s,3H),3.18-3.11(m,1H),2.78-2.70(m,1H),2.54(s,3H),2.34(s,3H),1.81-1.72(m,1H),1.50-1.41(m,1H),1.31(t,J＝7.0Hz,3H).The synthesis method of compound 334 refers to Example 293, except that 293-3 in step 4 is replaced by 6-chloro-3-(propane-2-ylidene)-1-(pyrrolidin-3-ylmethyl)indolin-2-one. LC-MS (ESI) m/z: 603.2[M+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ7.97 (d, J = 8.9 Hz, 1H), 7.72 (dd, J = 8.4, 7.3 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.2 1(dd,J＝8.8,2.2Hz,1H),7.06(dd,J＝8.2,2.0Hz,1H),6.58-6.52(m,2H),6.44(d,J＝2.2Hz,1H),3.88-3.79(m,2H),3.70(q,J＝ 7.0Hz,2H),3.56-3.46(m,2H),3.32-3.31(m,1H),3.30(s,3H),3.18-3.11(m,1H),2.78-2.70(m,1H),2.54(s,3H),2.34(s,3H),1.81-1.72(m,1H), 1.50-1.41(m,1H),1.31(t,J=7.0Hz,3H).
实施例335
Embodiment 335
合成方法Synthesis method
化合物335的合成方法参照实施例123。区别在于把步骤一中的2,4,7-三氯喹唑啉替换为2,4-二氯-7-三氟甲基喹唑啉，步骤三中1-Boc-3-溴甲基吡咯烷替换为(S)-3-(溴甲基)吡咯烷-1-羧酸叔丁酯，步骤七中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:327.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.17(d,J＝8.4Hz,1H),7.97(d,J＝8.8Hz,1H),7.77(s,1H),7.72(t,J＝7.8Hz,1H),7.46(d,J＝8.5Hz,1H),7.21(dd,J＝8.8,2.1Hz,1H),6.55(d,J＝7.3Hz,1H),6.53(d,J＝8.4Hz,1H),6.44(d,J＝2.1Hz,1H),4.30(ddd,J＝60.9,14.5,7.3Hz,2H),3.70(q,J＝7.0Hz,2H),3.56-3.48(m,2H),3.30(s,3H),3.26(s,6H),3.21(dd,J＝10.6,6.9Hz,1H),2.76-2.68(m,1H),2.04-1.96(m,2H),1.88-1.78(m,1H),1.31(t,J＝7.0Hz,3H).The synthesis method of compound 335 refers to Example 123. The difference is that 2,4,7-trichloroquinazoline in step 1 is replaced by 2,4-dichloro-7-trifluoromethylquinazoline, 1-Boc-3-bromomethylpyrrolidine in step 3 is replaced by (S)-3-(bromomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester, and dimethylamine in step 7 is replaced by methylethylamine. LC-MS (ESI) m/z: 327.1 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.17(d,J＝8.4Hz,1H),7.97(d,J＝8.8Hz,1H),7.77(s,1H),7.72(t,J＝7.8Hz,1H),7.46(d,J＝8.5Hz,1H),7.21(dd,J＝8.8,2.1Hz,1H),6.55(d,J＝7.3Hz,1H ),6.53(d,J＝8.4Hz,1H),6.44(d,J＝2.1Hz,1H),4.30( ddd,J＝60.9,14.5,7.3Hz,2H),3.70(q,J＝7.0Hz,2H),3.56-3.48(m,2H),3.30(s,3H),3.26(s,6H),3.21(dd,J＝10.6,6.9Hz,1H),2.76-2.68(m,1H),2.0 4-1.96(m,2H),1.88-1.78(m,1H),1.31(t,J=7.0Hz,3H).
实施例336
Embodiment 336
合成方法Synthesis method
化合物336的合成方法参照实施例123。区别在于把步骤一中的2,4,7-三氯喹唑啉替换为2,4-二氯-7-三氟甲基喹唑啉，步骤三中1-Boc-3-溴甲基吡咯烷替换为(R)-3-(溴甲基)吡咯烷-1-羧酸叔丁酯，步骤七中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:327.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.17(d,J＝8.4Hz,1H),7.97(d,J＝8.8Hz,1H),7.77(s,1H),7.72(t,J＝7.8Hz,1H),7.46(d,J＝8.5Hz,1H),7.21(dd,J＝8.8,2.1Hz,1H),6.55(d,J＝7.3Hz,1H),6.53(d,J＝8.4Hz,1H),6.44(d,J＝2.1Hz,1H),4.30(ddd,J＝60.9,14.5,7.3Hz,2H),3.70(q,J＝7.0Hz,2H),3.56-3.48(m,2H),3.30(s,3H),3.26(s,6H),3.21(dd,J＝10.6,6.9Hz,1H),2.76-2.68(m,1H),2.04-1.96(m,2H),1.88-1.78(m,1H),1.31(t,J＝7.0Hz,3H).The synthesis method of compound 336 refers to Example 123. The difference is that 2,4,7-trichloroquinazoline in step 1 is replaced by 2,4-dichloro-7-trifluoromethylquinazoline, 1-Boc-3-bromomethylpyrrolidine in step 3 is replaced by (R)-3-(bromomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester, and dimethylamine in step 7 is replaced by methylethylamine. LC-MS (ESI) m/z: 327.1 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.17(d,J＝8.4Hz,1H),7.97(d,J＝8.8Hz,1H),7.77(s,1H),7.72(t,J＝7.8Hz,1H),7.46(d,J＝8.5Hz,1H),7.21(dd,J＝8.8,2.1Hz,1H),6.55(d,J＝7.3Hz,1H ),6.53(d,J＝8.4Hz,1H),6.44(d,J＝2.1Hz,1H),4.30( ddd,J＝60.9,14.5,7.3Hz,2H),3.70(q,J＝7.0Hz,2H),3.56-3.48(m,2H),3.30(s,3H),3.26(s,6H),3.21(dd,J＝10.6,6.9Hz,1H),2.76-2.68(m,1H),2.0 4-1.96(m,2H),1.88-1.78(m,1H),1.31(t,J=7.0Hz,3H).
实施例337
Embodiment 337
合成路线
Synthetic route
步骤一：化合物337-1的合成Step 1: Synthesis of compound 337-1
室温下，将间碘硝基苯(800mg，5.80mmol)溶于20mL干燥的DCE中，降温至0℃后缓慢滴入草酰氯(1.1g，8.66mmol)，然后升温至70℃搅拌3小时。TLC检测反应完全，浓缩除去大量草酰氯后溶于2mL DCE中，缓慢滴入2-氟-4-氯苯甲酰胺(1g，5.75mmol)的DCE(40mL)溶液中，室温搅拌30min。LC-MS监测反应完全。过滤得到1.8g化合物337-1。LC-MS(ESI)m/z:338[M+H]+，收率：92％。At room temperature, m-iodonitrobenzene (800 mg, 5.80 mmol) was dissolved in 20 mL of dry DCE, cooled to 0 °C, and then slowly dripped into oxalyl chloride (1.1 g, 8.66 mmol), then heated to 70 °C and stirred for 3 hours. TLC detected that the reaction was complete, concentrated to remove a large amount of oxalyl chloride, dissolved in 2 mL of DCE, slowly dripped into a DCE (40 mL) solution of 2-fluoro-4-chlorobenzamide (1 g, 5.75 mmol), and stirred at room temperature for 30 min. LC-MS monitored the reaction to be complete. Filtration gave 1.8 g of compound 337-1. LC-MS (ESI) m/z: 338 [M+H] + , yield: 92%.
步骤二：化合物337-2的合成Step 2: Synthesis of compound 337-2
室温下，将化合物337-1(1.8g，5.34mmol)溶于20mL干燥的DMF中，降温至0℃后缓慢加入氢化钠(430mg，10.8mmol)，然后升温至90℃搅拌2小时。TLC检测反应完全，加入氯化铵溶液淬灭反应，之后用稀盐酸调节pH至6-7，过滤得到1.6g化合物337-2。LC-MS(ESI)m/z:318[M+H]+，收率：94％。At room temperature, compound 337-1 (1.8 g, 5.34 mmol) was dissolved in 20 mL of dry DMF, cooled to 0°C, and sodium hydride (430 mg, 10.8 mmol) was slowly added, and then heated to 90°C and stirred for 2 hours. TLC detected that the reaction was complete, and ammonium chloride solution was added to quench the reaction, and then the pH was adjusted to 6-7 with dilute hydrochloric acid, and filtered to obtain 1.6 g of compound 337-2. LC-MS (ESI) m/z: 318 [M+H] + , yield: 94%.
步骤三：化合物337-3的合成Step 3: Synthesis of compound 337-3
室温下，将化合物337-2(1.6g，5.03mmol)溶于30mL干燥的乙腈中，加入PyBOP(4.2g，8.08mmol)和二甲胺的四氢呋喃溶液(7mL)，然后缓慢滴加DBU(2.8g，18.4mmol)，之后室温搅拌20分钟。TLC检测反应完全，浓缩后直接柱层析分离(DCM：MeOH,0-10％,20min)得到2g化合物337-3。LC-MS(ESI)m/z:345[M+H]+.At room temperature, compound 337-2 (1.6 g, 5.03 mmol) was dissolved in 30 mL of dry acetonitrile, PyBOP (4.2 g, 8.08 mmol) and a tetrahydrofuran solution of dimethylamine (7 mL) were added, and then DBU (2.8 g, 18.4 mmol) was slowly added dropwise, and then stirred at room temperature for 20 minutes. TLC detected that the reaction was complete, and after concentration, column chromatography was directly separated (DCM: MeOH, 0-10%, 20 min) to obtain 2 g of compound 337-3. LC-MS (ESI) m/z: 345 [M+H] + .
步骤四：化合物337-4的合成Step 4: Synthesis of compound 337-4
室温下，将化合物337-3(2g粗品)溶于40mL乙醇和10mL水中，加入Fe粉(1.5g，26.8mmol)和氯化铵(1.5g，26.8mmol)，升温至79℃搅拌2小时。TLC检测反应完全，过滤除去铁粉，浓缩后直接经反向柱层析分离(H2O：MeCN,0-100％,20min)得到1.3g化合物337-4。LC-MS(ESI)m/z:315[M+H]+.At room temperature, compound 337-3 (2 g crude product) was dissolved in 40 mL ethanol and 10 mL water, and Fe powder (1.5 g, 26.8 mmol) and ammonium chloride (1.5 g, 26.8 mmol) were added, and the temperature was raised to 79°C and stirred for 2 hours. TLC detected that the reaction was complete, and the iron powder was removed by filtration. After concentration, the mixture was directly separated by reverse column chromatography (H 2 O: MeCN, 0-100%, 20 min) to obtain 1.3 g of compound 337-4. LC-MS (ESI) m/z: 315 [M+H] + .
步骤五：化合物337-5的合成Step 5: Synthesis of compound 337-5
室温下，将7-溴-1H-吡咯并[3,2-c]吡啶(1g，5.10mmol)和3-溴甲基环丙烷(1g，7.46mmol)溶于15mL干燥的DMF中，加入碳酸钾(2.1g，15.2mmol)，升温至100℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤两次，合并有机相浓缩后经快速色谱柱层析分离(PE:EA,0-50％,10min)得到800mg化合物337-5。LC-MS(ESI)m/z:251[M+H]+，收率：62％。 At room temperature, 7-bromo-1H-pyrrolo[3,2-c]pyridine (1 g, 5.10 mmol) and 3-bromomethylcyclopropane (1 g, 7.46 mmol) were dissolved in 15 mL of dry DMF, potassium carbonate (2.1 g, 15.2 mmol) was added, and the temperature was raised to 100°C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, saturated brine was washed twice, the organic phases were combined and concentrated, and then separated by flash chromatography (PE:EA, 0-50%, 10 min) to obtain 800 mg of compound 337-5. LC-MS (ESI) m/z: 251 [M+H] + , yield: 62%.
步骤六：化合物337-6的合成Step 6: Synthesis of compound 337-6
室温下，将化合物337-5(300mg，1.20mmol)和丙炔酸甲酯(310mg，3.60mmol)溶于5mL干燥的DMF中，加入醋酸钯(30mg，0.134mmol)和DABCO(30mg，0.268mmol)，升温至120℃搅拌过夜。LC-MS监测反应完全。加水和EA萃取三次，饱和食盐水洗涤两次，合并有机相浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到280mg化合物337-6。LC-MS(ESI)m/z:257[M+H]+，收率：91％。At room temperature, compound 337-5 (300 mg, 1.20 mmol) and methyl propiolate (310 mg, 3.60 mmol) were dissolved in 5 mL of dry DMF, palladium acetate (30 mg, 0.134 mmol) and DABCO (30 mg, 0.268 mmol) were added, and the temperature was raised to 120°C and stirred overnight. LC-MS monitored the reaction to be complete. Water and EA were added for extraction three times, and saturated brine was washed twice. The organic phases were combined and concentrated, and then separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 280 mg of compound 337-6. LC-MS (ESI) m/z: 257 [M+H] + , yield: 91%.
步骤七：化合物337-7的合成Step 7: Synthesis of compound 337-7
室温下，将化合物337-6(280mg，1.09mmol)溶于5mL乙醇和1mL水中，将氢氧化锂(130mg，3.17mmol)溶于0.5mL水中滴加至反应液中，室温反应2小时。LC-MS监测反应完全。用1N的稀盐酸调pH至2-3后浓缩，经快速色谱柱层析分离(DCM:MeOH,0-15％,10min)得到150mg化合物337-7。LC-MS(ESI)m/z:243[M+H]+，收率：57％。At room temperature, compound 337-6 (280 mg, 1.09 mmol) was dissolved in 5 mL of ethanol and 1 mL of water, and lithium hydroxide (130 mg, 3.17 mmol) was dissolved in 0.5 mL of water and added dropwise to the reaction solution. The reaction was allowed to react at room temperature for 2 hours. LC-MS monitored the reaction to be complete. The pH was adjusted to 2-3 with 1N dilute hydrochloric acid and then concentrated. The mixture was separated by flash chromatography (DCM: MeOH, 0-15%, 10 min) to obtain 150 mg of compound 337-7. LC-MS (ESI) m/z: 243 [M+H] + , yield: 57%.
步骤八：化合物337的合成Step 8: Synthesis of compound 337
室温下，将化合物337-7(40mg，0.165mmol)和化合物337-4(56mg，0.178mmol)溶于2mL干燥的DCE中，加入DMAP(10mg，0.0820mmol)和DCC(50mg，0.243mmol),室温搅拌过夜。LC-MS监测反应完全。反应液直接浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到30mg粗品，后经高效液相色谱柱层析分离得到20mg化合物337。LC-MS(ESI)m/z:539.2[M+H]+，收率：23％。1H NMR(600MHz,DMSO-d6)δ10.67(s,1H),8.82(s,1H),8.35(s,1H),8.32(d,J＝15.3Hz,1H),8.05(d,J＝8.8Hz,1H),7.79(d,J＝2.1Hz,1H),7.72(dd,J＝8.3,2.1Hz,1H),7.58(t,J＝8.0Hz,1H),7.53(d,J＝3.2Hz,1H),7.22(dd,J＝8.8,2.1Hz,1H),7.03(dd,J＝7.8,2.0Hz,1H),6.80(d,J＝15.2Hz,1H),6.68(d,J＝3.2Hz,1H),6.42(d,J＝2.1Hz,1H),4.21(d,J＝6.8Hz,2H),3.31(s,6H),1.23-1.20(m,1H),0.54-0.48(m,2H),0.40-0.34(m,2H).At room temperature, compound 337-7 (40 mg, 0.165 mmol) and compound 337-4 (56 mg, 0.178 mmol) were dissolved in 2 mL of dry DCE, and DMAP (10 mg, 0.0820 mmol) and DCC (50 mg, 0.243 mmol) were added, and stirred at room temperature overnight. LC-MS monitored the reaction to be complete. The reaction solution was directly concentrated and separated by flash column chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 30 mg of crude product, which was then separated by HPLC column chromatography to obtain 20 mg of compound 337. LC-MS (ESI) m/z: 539.2 [M+H] + , yield: 23%. 1 H NMR (600 MHz, DMSO-d 6 )δ10.67(s,1H),8.82(s,1H),8.35(s,1H),8.32(d,J＝15.3Hz,1H),8.05(d,J＝8.8Hz,1H),7.79(d,J＝2.1Hz,1H),7.72(dd,J＝8.3,2.1Hz,1H),7.58(t,J＝ 8.0Hz,1H),7.53(d,J＝3.2Hz,1H),7.22(dd,J＝8.8, 2.1Hz,1H),7.03(dd,J＝7.8,2.0Hz,1H),6.80(d,J＝15.2Hz,1H),6.68(d,J＝3.2Hz,1H),6.42(d,J＝2.1Hz,1H),4.21(d,J＝6.8Hz,2H),3.31(s,6H),1.23-1 .20(m,1H),0.54-0.48(m,2H),0.40-0.34(m,2H).
实施例338
Embodiment 338
合成方法Synthesis method
化合物338的合成方法参照实施例123。区别在于把步骤一中的2,4,7-三氯喹唑啉替换为2,4-二氯-6-氟喹唑啉，步骤七中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:302.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(d,J＝8.8Hz,1H),7.77(dd,J＝9.8,2.7Hz,1H),7.72(dd,J＝8.4,7.3Hz,1H),7.62-7.53(m,2H),7.21(dd,J＝8.8,2.1Hz,1H),6.55(dd,J＝7.8,3.8Hz,2H),6.43(d,J＝2.1Hz,1H),4.31-4.16(m,2H),3.70(q,J＝7.0Hz,2H),3.52(td,J＝11.7,10.6,8.1Hz,2H),3.34-3.29(m,1H),3.30(s,3H),3.23(s,6H),3.23-3.18(m,1H),2.72(p,J＝7.2Hz,1H),2.03(dd,J＝13.8,6.7Hz,1H),1.82(dd,J＝12.1,8.2Hz,1H),1.31(t,J＝7.0Hz,3H).The synthesis method of compound 338 is similar to that of Example 123. The difference is that 2,4,7-trichloroquinazoline in step 1 is replaced by 2,4-dichloro-6-fluoroquinazoline, and dimethylamine in step 7 is replaced by methylethylamine. LC-MS (ESI) m/z: 302.1 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.97(d,J＝8.8Hz,1H),7.77(dd,J＝9.8,2.7Hz,1H),7.72(dd,J＝8.4,7.3Hz,1H),7.62-7.53(m,2H),7.21(dd,J＝8.8,2.1Hz,1H),6.55(dd,J＝7.8,3.8Hz,2H) ,6.43(d,J＝2.1Hz,1H),4.31-4.16(m,2H),3.70(q,J＝7. 0Hz,2H),3.52(td,J＝11.7,10.6,8.1Hz,2H),3.34-3.29(m,1H),3.30(s,3H),3.23(s,6H),3.23-3.18(m,1H),2.72(p,J＝7.2Hz,1H),2.03(dd,J＝13.8, 6.7Hz, 1H), 1.82 (dd, J＝12.1, 8.2Hz, 1H), 1.31 (t, J＝7.0Hz, 3H).
实施例339
Embodiment 339
合成方法Synthesis method
化合物339的合成方法参照实施例123。区别在于把步骤一中的2,4,7-三氯喹唑啉替换为2,4-二氯-5-氟喹唑啉，步骤七中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:302.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.96(dd,J＝8.9,1.9Hz,1H),7.71(dd,1H),7.70-7.64(m,1H),7.33(dd,J＝8.9,4.3Hz,1H),7.21(dd,J＝8.8,2.2Hz,1H),7.01(dd,J＝11.2,8.1Hz,1H),6.54(t,J＝7.7Hz,2H),6.42(t,J＝2.7Hz,1H),4.26-4.18(m,2H),3.85-3.67(m,6H),3.17(dd,J＝5.3,2.0Hz,3H),3.05(d,J＝3.3Hz,6H),2.76-2.68(m,1H),2.01(t,J＝7.5Hz,1H),1.98(q,J＝5.4,4.4Hz,1H),1.30(t,J＝7.1,3.1Hz,3H).The synthesis method of compound 339 refers to Example 123. The difference is that 2,4,7-trichloroquinazoline in step 1 is replaced by 2,4-dichloro-5-fluoroquinazoline, and dimethylamine in step 7 is replaced by methylethylamine. LC-MS (ESI) m/z: 302.1 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.96 (dd, J = 8.9, 1.9 Hz, 1H), 7.71 (dd, 1H), 7.70-7.64 (m, 1H), 7.33 (dd, J = 8.9, 4.3 Hz, 1H), 7.21 (dd, J = 8.8, 2.2 Hz, 1H), 7.01 (dd, J = 11.2, 8.1 Hz, 1H), 6.54 (t, J = 7.7 Hz, 2H), 6.42 (t, J = 2.7 Hz ,1H),4.26-4.18(m,2H),3.85-3.67(m,6H),3.17(dd,J＝5.3,2.0Hz,3H),3.05(d,J＝3.3Hz,6H),2.76-2.68(m,1H),2.01(t,J＝7.5Hz,1H),1.98(q,J＝5 .4,4.4Hz,1H),1.30(t,J=7.1,3.1Hz,3H).
实施例340&341
Embodiment 340 & 341
将化合物282通过SFC拆分得到单一构型化合物340和341。Compound 282 was resolved by SFC to give single-configuration compounds 340 and 341.
实施例342
Embodiment 342
合成方法Synthesis method
化合物342的合成方法参照实施例298。区别在于把步骤四中的293-3替换为1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:548.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.27(t,J＝5.8Hz,1H),7.90(d,J＝8.8Hz,1H),7.71(d,J＝14.3Hz,1H),7.51(d,J＝2.0Hz,1H),7.32(d,J＝7.7Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),7.08(s,1H),6.92(dd,J＝7.7,1.5Hz,1H),6.84(d,J＝14.3Hz,1H),4.08(t,J＝7.6Hz,2H),3.62(q,J＝7.0Hz,2H),3.29(q,J＝6.6Hz,2H),3.20(s,3H),2.04-1.96(m,1H),1.78(h,J＝7.2Hz,2H),1.32(s,6H),1.26(t,J＝7.1Hz,3H),1.01-0.94(m,2H),0.79-0.74(m,2H).The synthesis method of compound 342 is similar to that of Example 298. The difference is that 293-3 in step 4 is replaced by 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 548.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.27(t,J＝5.8Hz,1H),7.90(d,J＝8.8Hz,1H),7.71(d,J＝14.3Hz,1H),7.51(d,J＝2.0Hz,1H),7.32(d,J＝7.7Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),7.08(s, 1H),6.92(dd,J＝7.7,1.5Hz,1H),6.84(d,J＝14.3H z,1H),4.08(t,J＝7.6Hz,2H),3.62(q,J＝7.0Hz,2H),3.29(q,J＝6.6Hz,2H),3.20(s,3H),2.04-1.96(m,1H),1.78(h,J＝7.2Hz,2H),1.32(s,6H),1.26(t ,J＝7.1Hz,3H),1.01-0.94(m,2H),0.79-0.74(m,2H).
实施例343
Embodiment 343
合成方法Synthesis method
化合物343的合成方法参照实施例332。区别在于把步骤一中的2-氨基-4-溴苯甲酸甲酯换成2-氨基-4-氯苯甲酸甲酯。LC-MS(ESI)m/z:607.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.97(d,J＝8.8Hz,1H),7.73(t,J＝7.9Hz,1H),7.38(d,J＝1.9Hz,1H),7.36(d,J＝8.2Hz,1H),7.21(dd,J＝8.8,2.2Hz,1H),7.18(dd,J＝8.2,1.9Hz,1H),6.57(d,J＝7.3Hz,1H),6.54(d,J＝8.4Hz,1H),6.45(d,J＝2.1Hz,1H),4.07(ddd,J＝55.4,14.8,7.4Hz,2H),3.70(q,J＝7.0Hz,2H),3.59-3.48(m,2H),3.30(s,3H),3.16(dd,J＝10.6,6.9Hz,1H),2.71(h,J＝7.0Hz,1H),2.10-2.04(m,1H),2.03-1.97(m,1H),1.84-1.73(m,1H),1.60(s,3H),1.60(s,3H),1.31(t,J＝7.0Hz,3H).The synthesis method of compound 343 is similar to that of Example 332. The difference is that 2-amino-4-bromobenzoic acid methyl ester in step 1 is replaced by 2-amino-4-chlorobenzoic acid methyl ester. LC-MS (ESI) m/z: 607.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.97(d,J＝8.8Hz,1H),7.73(t,J＝7.9Hz,1H),7.38(d,J＝1.9Hz,1H),7.36(d,J＝8.2Hz,1H),7.21(dd,J＝8.8,2.2Hz,1H),7.18(dd,J＝8.2,1.9Hz,1H),6.57 (d,J＝7.3Hz,1H),6.54(d,J＝8.4Hz,1H),6.45(d,J＝2.1Hz,1H),4.07(ddd,J＝55 .4,14.8,7.4Hz,2H),3.70(q,J＝7.0Hz,2H),3.59-3.48(m,2H),3.30(s,3H),3.16(dd,J＝10.6,6.9Hz,1H),2.71(h,J＝7.0Hz,1H),2.10-2.04(m,1H),2. 03-1.97(m,1H),1.84-1.73(m,1H),1.60(s,3H),1.60(s,3H),1.31(t,J＝7.0Hz,3H).
实施例344
Embodiment 344
合成方法Synthesis method
化合物344的合成方法参照实施例306。区别在于把步骤三中的1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮替换为7-氯-4,4-二甲基-1-(吡咯烷-3-基甲基)-1,4-二氢-2H-苯并[d][1,3]噁嗪-2-酮。LC-MS(ESI)m/z:570.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.98(dd,J＝8.7,1.8Hz,1H),7.72(dd,J＝13.8,7.2Hz,1H),7.56(dd,J＝7.0,2.0Hz,1H),7.39(dd,2H),7.33(qd,J＝8.8,3.5,2.0Hz,1H),7.22-7.17(m,1H),6.89(dd,J＝13.8,4.5Hz,1H),4.12-3.98(m,2H),3.76-3.65(m,1H),3.64-3.57(m,1H),3.51(q,J＝8.1Hz,1H),3.30(s,3H),3.30(s,3H),3.19(dd,J＝12.1,7.3Hz,1H),2.73-2.55(m,1H),2.09-1.91(m,1H),1.81-1.64(m,1H),1.62(dd,J＝8.9,7.1Hz,6H).The synthesis method of compound 344 refers to Example 306. The difference is that 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one in step 3 is replaced by 7-chloro-4,4-dimethyl-1-(pyrrolidin-3-ylmethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one. LC-MS (ESI) m/z: 570.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.98(dd,J＝8.7,1.8Hz,1H),7.72(dd,J＝13.8,7.2Hz,1H),7.56(dd,J＝7.0,2.0Hz,1H),7.39(dd,2H),7.33(qd,J＝8.8,3.5,2.0Hz,1H),7.22-7.17(m,1H), 6.89(dd,J＝13.8,4.5Hz,1H),4.12-3.98(m,2H) ,3.76-3.65(m,1H),3.64-3.57(m,1H),3.51(q,J＝8.1Hz,1H),3.30(s,3H),3.30(s,3H),3.19(dd,J＝12.1,7.3Hz,1H),2.73-2.55(m,1H),2.09-1.91 (m,1H),1.81-1.64(m,1H),1.62(dd,J＝8.9,7.1Hz,6H).
实施例345
Embodiment 345
合成方法Synthesis method
化合物345的合成方法参照实施例306。区别在于把步骤三中的1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮替换为1-(3-氨基丙基)-7-氯-4,4-二甲基-1,4-二氢-2H-苯并[d][1,3]噁嗪-2-酮。LC-MS(ESI)m/z:544.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.31(t,J＝5.6Hz,1H),7.99(d,J＝8.7Hz,1H),7.72(d,J＝14.2Hz,1H),7.54(d,J＝2.0Hz,1H),7.36(d,J＝8.2Hz,1H),7.34(dd,J＝8.7,2.0Hz,1H),7.26(d,J＝1.9Hz,1H),7.20-7.16(m,1H),6.68(d,J＝14.2Hz,1H),3.96(t,J＝8.5,7.6Hz,2H),3.30(s,6H),3.27(t,J＝6.5Hz,2H),1.80(p,J＝7.3Hz,2H),1.60(s,6H).The synthesis method of compound 345 refers to Example 306. The difference is that 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one in step 3 is replaced by 1-(3-aminopropyl)-7-chloro-4,4-dimethyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one. LC-MS (ESI) m/z: 544.1 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.31(t,J＝5.6Hz,1H),7.99(d,J＝8.7Hz,1H),7.72(d,J＝14.2Hz,1H),7.54(d,J＝2.0Hz,1H),7.36(d,J＝8.2Hz,1H),7.34(dd,J＝8.7,2.0Hz,1H),7.26(d, J＝1.9Hz,1H),7.20-7.16(m,1H),6.68(d,J＝14.2Hz,1H),3.96(t,J＝8.5,7.6Hz,2H),3.30(s,6H),3.27(t,J＝6.5Hz,2H),1.80(p,J＝7.3Hz,2H),1.60(s ,6H).
实施例346
Embodiment 346
合成方法Synthesis method
化合物346的合成方法参照实施例306。区别在于把步骤三中的1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮替换为1-(3-氨基丙基)-7-环丙基-4,4-二甲基-1,4-二氢-2H-苯并[d][1,3]噁嗪-2-酮。LC-MS(ESI)m/z:550.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.33(t,J＝5.7Hz,1H),7.99(d,J＝8.7Hz,1H),7.73(d,J＝14.2Hz,1H),7.55(d,J＝2.0Hz,1H),7.34(dd,J＝8.7,2.0Hz,1H),7.18(d,J＝7.9Hz,1H),6.82(d,J＝1.6Hz,1H),6.77(dd,J＝7.9,1.5Hz,1H),6.69(d,J＝14.2Hz,1H),3.94(t,J＝7.5Hz,2H),3.34(s,6H),3.29-3.25(m,2H),1.98-1.91(m,1H),1.81(p,J＝7.2Hz,2H),1.57(s,6H),0.95-0.89(m,2H),0.74-0.68(m,2H).The synthesis method of compound 346 refers to Example 306. The difference is that 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one in step 3 is replaced by 1-(3-aminopropyl)-7-cyclopropyl-4,4-dimethyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one. LC-MS (ESI) m/z: 550.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.33(t,J＝5.7Hz,1H),7.99(d,J＝8.7Hz,1H),7.73(d,J＝14.2Hz,1H),7.55(d,J＝2.0Hz,1H),7.34(dd,J＝8.7,2.0Hz,1H),7.18(d,J＝7.9Hz,1H),6.82(d,J ＝1.6Hz,1H),6.77(dd,J＝7.9 ,1.5Hz,1H),6.69(d,J＝14.2Hz,1H),3.94(t,J＝7.5Hz,2H),3.34(s,6H),3.29-3.25(m,2H),1.98-1.91(m,1H),1.81(p,J＝7.2Hz,2H),1.57(s,6H),0. 95-0.89(m,2H),0.74-0.68(m,2H).
实施例347
Embodiment 347
合成方法Synthesis method
化合物347的合成方法参照实施例123。区别在于把步骤一中的2,4,7-三氯喹唑啉替换为2,4-二氯吡啶并[3,2-d]嘧啶，步骤七中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:293.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.48(d,J＝4.2Hz,1H),8.04(d,J＝8.8Hz,1H),7.98(dd,J＝8.9,2.3Hz,1H),7.76-7.68(m,2H),7.22(dd,J＝8.8,2.2Hz,1H),6.56(t,J＝7.7Hz,2H),6.43(d,J＝2.2Hz,1H),4.31-4.14(m,2H),3.90-3.76(m,2H),3.70(q,J＝7.1Hz,3H),3.57-3.49(m,2H),3.36-3.27(m,6H),3.26-3.17(m,2H),2.70(t,J＝7.5Hz,1H),2.11-2.02(m,1H),1.91-1.77(m,1H),1.31(t,J＝7.0Hz,3H).The synthesis method of compound 347 is similar to that of Example 123. The difference is that 2,4,7-trichloroquinazoline in step 1 is replaced by 2,4-dichloropyrido[3,2-d]pyrimidine, and dimethylamine in step 7 is replaced by methylethylamine. LC-MS (ESI) m/z: 293.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.48(d,J＝4.2Hz,1H),8.04(d,J＝8.8Hz,1H),7.98(dd,J＝8.9,2.3Hz,1H),7.76-7.68(m,2H),7.22(dd,J＝8.8,2.2Hz,1H),6.56(t,J＝7.7Hz,2H),6.43(d, J＝2.2Hz,1H),4.31-4.14(m,2 H),3.90-3.76(m,2H),3.70(q,J＝7.1Hz,3H),3.57-3.49(m,2H),3.36-3.27(m,6H),3.26-3.17(m,2H),2.70(t,J＝7.5Hz,1H),2.11-2.02(m,1H),1.9 1-1.77(m,1H),1.31(t,J=7.0Hz,3H).
实施例348
Embodiment 348
合成方法Synthesis method
化合物348的合成方法参照实施例298。区别在于把步骤一中的6-溴-3,3-二甲基吲哚-2-酮替换为6'-溴螺[环丙烷-1,3'-吲哚啉]-2'-酮，步骤四中的293-3替换为7-氯-4-(甲乙胺基)-1-(吡咯烷-3-基甲基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:572.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.90(dd,J＝8.8,5.0Hz,1H),7.80(dd,J＝13.9,5.0Hz,1H),7.64(dd,J＝9.4,2.0Hz,1H),7.22(ddd,J＝13.3,8.7,1.9Hz,1H),7.17(dd,J＝15.1,1.4Hz,1H),7.07(dd,J＝13.9,10.3Hz,1H),6.99(d,J＝7.8Hz,1H),6.86(ddd,J＝7.8,4.0,1.4Hz,1H),4.28-4.10(m,2H),3.78-3.51(m,6H),3.27-3.23(m,1H),3.22(d,J＝5.1Hz,3H),1.70-1.66(m,2H),1.65-1.60(m,2H),1.28(t,J＝6.9Hz,3H),1.00-0.94(m,2H),0.86(t,J＝ 7.0Hz,1H),0.78-0.71(m,2H).The synthesis method of compound 348 refers to Example 298. The difference is that 6-bromo-3,3-dimethylindol-2-one in step 1 is replaced by 6'-bromospiro[cyclopropane-1,3'-indolline]-2'-one, and 293-3 in step 4 is replaced by 7-chloro-4-(methylethylamino)-1-(pyrrolidin-3-ylmethyl)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 572.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.90(dd,J＝8.8,5.0Hz,1H),7.80(dd,J＝13.9,5.0Hz,1H),7.64(dd,J＝9.4,2.0Hz,1H),7.22(ddd,J＝13.3,8.7,1.9Hz,1H),7.17(dd,J＝15.1,1.4Hz,1H),7. 07(dd,J＝13.9,10.3Hz,1H),6.99(d,J＝7.8Hz,1H ),6.86(ddd,J＝7.8,4.0,1.4Hz,1H),4.28-4.10(m,2H),3.78-3.51(m,6H),3.27-3.23(m,1H),3.22(d,J＝5.1Hz,3H),1.70-1.66(m,2H),1.65-1.60(m ,2H),1.28(t,J＝6.9Hz,3H),1.00-0.94(m,2H),0.86(t,J＝ 7.0 Hz, 1H), 0.78-0.71 (m, 2H).
实施例349
Embodiment 349
合成方法Synthesis method
化合物349的合成方法参照实施例298。区别在于把步骤四中的293-3替换为7-氯-4-(甲乙胺基)-1-(吡咯烷-3-基甲基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:574.3[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.90(dd,J＝8.8,4.3Hz,1H),7.71(dd,J＝14.0,5.2Hz,1H),7.64(dd,J＝10.6,2.1Hz,1H),7.32(d,J＝7.7Hz,1H),7.21(ddd,J＝14.3,8.6,2.0Hz,1H),7.12-7.03(m,2H),6.90(dt,J＝8.3,2.4Hz,1H),4.27-4.10(m,2H),3.78-3.68(m,1H),3.64(dt,J＝12.8,4.3Hz,2H),3.56(dd,J＝11.3,7.8Hz,1H),3.44(dd,J＝10.1,6.5Hz,1H),3.22(d,J＝3.7Hz,3H),2.71(q,J＝6.9Hz,1H),2.60(d,J＝7.3Hz,1H),1.94-1.87(m,1H),1.81(dt,J＝12.3,7.6Hz,1H),1.71(dd,J＝12.6,7.3Hz,1H),1.32(d,J＝3.3Hz,6H),1.28(d,J＝6.4Hz,3H),0.96(qd,J＝5.8,3.0Hz,2H),0.76(pd,J＝5.1,3.3,2.2Hz,2H).The synthesis method of compound 349 refers to Example 298. The difference is that 293-3 in step 4 is replaced by 7-chloro-4-(methylethylamino)-1-(pyrrolidin-3-ylmethyl)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 574.3 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.90(dd,J＝8.8,4.3Hz,1H),7.71(dd,J＝14.0,5.2Hz,1H),7.64(dd,J＝10.6,2.1Hz,1H),7.32(d,J＝7.7Hz,1H),7.21(ddd,J＝14.3,8.6,2.0Hz,1H),7.12-7 .03(m,2H),6.90(dt,J＝8.3,2.4Hz,1H),4.27-4.10(m,2H),3.78-3.68(m,1H),3.64(dt,J＝12.8,4.3Hz,2H),3.56(dd,J＝11.3,7.8Hz ,1H),3.44(dd,J＝10.1,6.5Hz,1H),3.22(d,J＝3.7Hz,3H),2.71(q,J＝6.9Hz,1H),2.60(d,J＝7.3Hz,1H),1.94-1.87(m,1H),1.81(dt,J＝12.3,7.6Hz,1H) ,1.71(dd,J＝12.6,7.3Hz,1H),1.32(d,J＝3.3Hz,6H),1.28(d,J＝6.4Hz,3H),0.96(qd,J＝5.8,3.0Hz,2H),0.76(pd,J＝5.1,3.3,2.2Hz,2H).
实施例350
Embodiment 350
合成方法Synthesis method
化合物350的合成方法参照实施例298。区别在于把步骤四中的298-3替换为(E)-3-(6-氯-3,3-二甲基-2-氧代吲哚烷-1-基)丙烯酸，步骤四中的293-3替换为1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:542.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.24(t,J＝5.6Hz,1H),7.89(d,J＝8.7Hz,1H),7.70(d,J＝14.4Hz,1H),7.55-7.49(m,3H),7.27(dd,J＝8.0,1.8Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),6.80(d,J＝14.4Hz,1H),4.08(t,J＝7.6Hz,2H),3.62(q,J＝7.0Hz,2H),3.30(q,J＝6.7Hz,2H),3.20(s,3H),1.78(p,J＝7.0Hz,2H),1.36(s,6H),1.26(t,J＝7.1Hz,3H).The synthesis method of compound 350 refers to Example 298. The difference is that 298-3 in step 4 is replaced by (E)-3-(6-chloro-3,3-dimethyl-2-oxoindole-1-yl)acrylic acid, and 293-3 in step 4 is replaced by 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 542.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.24(t,J＝5.6Hz,1H),7.89(d,J＝8.7Hz,1H),7.70(d,J＝14.4Hz,1H),7.55-7.49(m,3H),7.27(dd,J＝8.0,1.8Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),6.80( d,J＝14.4Hz,1H),4.08(t,J＝7.6Hz,2H),3.62(q,J＝7.0Hz,2H),3.30(q,J＝6.7Hz,2H),3.20(s,3H),1.78(p,J＝7.0Hz,2H),1.36(s,6H),1.26(t,J＝7.1Hz ,3H).
实施例351
Embodiment 351
合成路线
Synthetic route
步骤一：化合物351-1的合成Step 1: Synthesis of compound 351-1
取化合物7-氯-4,4-二甲基-1,4-二氢-2H-苯并[d][1,3]噁嗪-2-酮(0.10g，0.47mmol)、4-二甲氨基吡啶(0.58g，0.47mmol)和分散到乙腈(1.5mL)溶液中，在搅拌状态下向反应液中滴加叔丁基丙炔酸酯(0.090g，0.71mmol)，室温搅拌3个小时。TLC监测原料消失后，反应混合物经减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：乙酸乙酯/石油醚＝10％)纯化，得到化合物351-1，0.11g，为白色固体，产率69％。LC-MS(ESI)m/z:282[M-56+H]+.Take compound 7-chloro-4,4-dimethyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (0.10 g, 0.47 mmol), 4-dimethylaminopyridine (0.58 g, 0.47 mmol) and disperse them in acetonitrile (1.5 mL) solution, add tert-butyl propiolate (0.090 g, 0.71 mmol) dropwise to the reaction solution under stirring, and stir at room temperature for 3 hours. After TLC monitoring the disappearance of the raw material, the reaction mixture was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel chromatography column (eluent: ethyl acetate/petroleum ether = 10%) to obtain compound 351-1, 0.11 g, as a white solid, with a yield of 69%. LC-MS (ESI) m/z: 282 [M-56 + H] + .
步骤二：化合物351-2的合成Step 2: Synthesis of compound 351-2
取化合物351-1(0.11g，0.33mmol)分散到二氯甲烷(2.0mL)中，室温下，向反应液中滴加三氟乙酸(2.0mL)。室温搅拌20分钟。反应液经减压浓缩，残余物经硅胶层析色谱柱(洗脱剂：乙酸乙酯/石油醚＝40％)纯化，得到化合物351-2，0.06g，为白色固体。LC-MS(ESI)m/z:282[M+H]+.Compound 351-1 (0.11 g, 0.33 mmol) was dispersed in dichloromethane (2.0 mL). Trifluoroacetic acid (2.0 mL) was added dropwise to the reaction solution at room temperature. The mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate/petroleum ether = 40%) to obtain compound 351-2, 0.06 g, as a white solid. LC-MS (ESI) m/z: 282 [M+H] + .
步骤三：化合物351的合成Step 3: Synthesis of compound 351
取化合物351-2(60mg，0.21mmol)、1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮(60mg，0.21mmol)和4-二甲氨基吡啶(12mg，0.11mmol)分散到1,2-二氯乙烷(2.0mL)溶液中，向反应混合物中加入N,N'-二环己基碳二亚胺(63mg，0.33mmol)，室温搅拌过夜。反应液经减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝1/16)纯化，得到化合物351的粗品。粗品再经制备液相色谱纯化，制备液冷冻干燥，得到产物351，15.85mg，产率13％。LC-MS(ESI)m/z:558.2[M+H]+。1H NMR(600MHz,DMSO-d6)δ8.27(t,J＝5.7Hz,1H),7.90(d,J＝8.8Hz,1H),7.63(d,J＝14.1Hz,1H),7.49(t,2H),7.40–7.35(m,2H),7.21(dd,J＝8.8,2.0Hz,1H),6.59(d,J＝14.1Hz,1H),4.07(t,J＝7.6Hz,2H),3.62(q,J＝7.0Hz,2H),3.27(q,J＝6.5Hz,2H),3.20(s,3H),1.76(p,J＝7.2Hz,2H),1.65(s,6H),1.26(t,J＝7.0Hz,3H).Compound 351-2 (60 mg, 0.21 mmol), 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one (60 mg, 0.21 mmol) and 4-dimethylaminopyridine (12 mg, 0.11 mmol) were dispersed in 1,2-dichloroethane (2.0 mL) solution, and N,N'-dicyclohexylcarbodiimide (63 mg, 0.33 mmol) was added to the reaction mixture, and stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel chromatography column (eluent: methanol/dichloromethane = 1/16) to obtain a crude product of compound 351. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain product 351, 15.85 mg, with a yield of 13%. LC-MS (ESI) m/z: 558.2 [M+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ8.27(t,J＝5.7Hz,1H),7.90(d,J＝8.8Hz,1H),7.63(d,J＝14.1Hz,1H),7.49(t,2H),7.40–7.35(m,2H),7.21(dd,J＝8.8,2.0Hz,1H), 6.59(d,J＝14.1Hz,1H),4.07(t,J＝7.6Hz,2H),3.62(q,J＝7.0Hz,2H),3.27(q ,J＝6.5Hz,2H),3.20(s,3H),1.76(p,J＝7.2Hz,2H),1.65(s,6H),1.26(t,J＝7 .0Hz,3H).
实施例352
Embodiment 352
合成方法Synthesis method
化合物352的合成方法参照实施例306。区别在于把步骤三中的1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮替换为4-(二甲胺基)-1-(吡咯烷-3-基甲基)-7-(三氟甲基) 喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:308.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.18(t,J＝7.9Hz,1H),7.98(dd,J＝8.7,1.8Hz,1H),7.78(d,J＝10.9Hz,1H),7.71(d,J＝13.8Hz,1H),7.55(dd,J＝12.2,2.0Hz,1H),7.47(t,J＝9.0Hz,1H),7.33(dd,J＝8.7,1.7Hz,1H),6.88(dd,J＝25.7,13.8Hz,1H),4.36-4.19(m,2H),3.74-3.64(m,1H),3.64-3.54(m,1H),3.53-3.47(m,1H),3.42-3.37(m,1H),3.30(s,6H),3.28(s,3H),3.26(s,3H),2.76-2.57(m,1H),2.08-1.96(m,1H),1.85-1.67(m,1H).The synthesis method of compound 352 is similar to that of Example 306. The difference is that 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one in step 3 is replaced by 4-(dimethylamino)-1-(pyrrolidin-3-ylmethyl)-7-(trifluoromethyl) Quinazolin-2(1H)-one. LC-MS(ESI)m/z:308.6[M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 )δ8.18(t,J＝7.9Hz,1H),7.98(dd,J＝8.7,1.8Hz,1H),7.78(d,J＝10.9Hz,1H),7.71(d,J＝13.8Hz,1H) ,7.55(dd,J＝12.2,2.0Hz,1H),7.47(t,J＝9.0Hz,1H),7.33(dd,J＝8.7,1.7Hz,1H),6.88(dd,J＝25.7,13 .8Hz,1H),4.36-4.19(m,2H),3.74-3.64(m,1H),3.64-3.54(m,1H),3.53-3.47(m,1H),3.42-3.37(m,1H),3.30(s,6H),3.28(s,3H),3.26(s,3H), 2.76-2.57(m,1H),2.08-1.96(m,1H),1.85-1.67(m,1H).
实施例353
Embodiment 353
合成路线
Synthetic route
步骤一：化合物353-1的合成Step 1: Synthesis of compound 353-1
取5-氯-2-苯并噁唑酮(0.30g，1.8mmol)和4-二甲氨基吡啶(0.22g，1.8mmol)分散到乙腈(3.0mL)溶液中，在搅拌状态下向反应液中滴加叔丁基丙炔酸酯(0.34g，2.7mmol)，室温搅拌0.5个小时。TLC监测原料消失后，反应混合物经减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：乙酸乙酯/石油醚＝10％)纯化，得到化合物353-1，0.49g，为白色固体，产率94％。LC-MS(ESI)m/z:240[M-56+H]+.5-Chloro-2-benzoxazolone (0.30 g, 1.8 mmol) and 4-dimethylaminopyridine (0.22 g, 1.8 mmol) were dispersed in acetonitrile (3.0 mL) solution, tert-butyl propiolate (0.34 g, 2.7 mmol) was added dropwise to the reaction solution under stirring, and stirred at room temperature for 0.5 hours. After TLC monitoring of the disappearance of the raw material, the reaction mixture was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel chromatography column (eluent: ethyl acetate/petroleum ether = 10%) to obtain compound 353-1, 0.49 g, as a white solid, with a yield of 94%. LC-MS (ESI) m/z: 240 [M-56 + H] + .
步骤二：化合物353-2的合成Step 2: Synthesis of compound 353-2
取化合物353-1(0.49g，1.7mmol)分散到二氯甲烷(5.0mL)中，室温下，向反应液中滴加三氟乙酸(5.0mL)。室温搅拌20分钟。反应液经减压浓缩，得到化合物353-2的粗品，0.40g，可直接用于下一步，为白色固体。LC-MS(ESI)m/z:240[M+H]+.步骤三：化合物353的合成Compound 353-1 (0.49 g, 1.7 mmol) was dispersed in dichloromethane (5.0 mL), and trifluoroacetic acid (5.0 mL) was added dropwise to the reaction solution at room temperature. Stir at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure to obtain a crude product of compound 353-2, 0.40 g, which can be directly used in the next step as a white solid. LC-MS (ESI) m/z: 240 [M+H] + . Step 3: Synthesis of compound 353
取化合物353-2(50mg，0.21mmol)、1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮(62mg，0.21mmol)和4-二甲氨基吡啶(13mg，0.11mmol)分散到1,2-二氯乙烷(2.0mL)溶液中，向反应混合物中加入N,N'-二环己基碳二亚胺(65mg，0.33mmol)，室温搅拌过夜。反应液经减压蒸除溶剂，残余物经硅胶层析色谱柱(洗脱剂：甲醇/二氯甲烷＝1/16)纯化，得到化合物353的粗品。粗品再经制备液相色谱纯化，制备液冷冻干燥，得到产物353，14.13mg，产率13％。LC-MS(ESI)m/z:516.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.26(t,J＝5.7Hz,1H),7.90(d,J＝8.7Hz,1H),7.79(d,J＝2.1Hz,1H),7.65(d,J＝14.3Hz,1H),7.53(d,J＝2.0Hz,1H),7.49(d,J＝8.6Hz,1H),7.34(dd,J＝8.5,2.1Hz,1H),7.21(dd,J＝8.7,1.9Hz,1H),6.77(d,J＝14.3Hz,1H),4.09(t,J＝7.5Hz,2H),3.62(q,J＝7.0Hz,2H),3.31(q,2H),3.21(s,3H),1.79(p,J＝7.1Hz,2H),1.26(t,J＝7.0Hz,3H).Compound 353-2 (50 mg, 0.21 mmol), 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one (62 mg, 0.21 mmol) and 4-dimethylaminopyridine (13 mg, 0.11 mmol) were dispersed in 1,2-dichloroethane (2.0 mL) solution, and N,N'-dicyclohexylcarbodiimide (65 mg, 0.33 mmol) was added to the reaction mixture, and stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel chromatography column (eluent: methanol/dichloromethane = 1/16) to obtain a crude product of compound 353. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain product 353, 14.13 mg, with a yield of 13%. LC-MS (ESI) m/z: 516.1[M+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ8.26 (t, J = 5.7Hz, 1H), 7.90 (d, J = 8.7Hz, 1H), 7.79 (d, J = 2.1Hz, 1H), 7.65 (d, J = 14.3Hz, 1H), 7.53 (d,J＝2.0Hz,1H),7.49(d,J＝8.6Hz,1H),7.34(dd,J＝8.5,2.1Hz,1H), 7.21(dd,J＝8.7,1.9Hz,1H),6.77(d,J＝14.3Hz,1H),4.09(t,J＝7.5Hz,2H),3.62(q,J＝7.0Hz,2H),3.31(q,2H),3.21(s,3H),1.79(p,J＝7.1Hz,2H),1.26 (t,J＝7.0Hz,3H).
实施例354
Embodiment 354
合成方法Synthesis method
化合物354的合成方法参照实施例298。区别在于把步骤四中的298-3替换为(E)-3-(6'-氯-2'-氧代螺[环丙烷-1,3'-吲哚啉]-1'-基)丙烯酸，步骤四中的293-3替换为1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:540.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.24(t,J＝5.7Hz,1H),7.90(d,J＝8.8Hz,1H),7.77(d,J＝14.4Hz,1H),7.58(d,J＝1.7Hz,1H),7.52(d,J＝2.0Hz,1H),7.22(ddd,J＝20.4,8.4,1.9Hz,2H),7.17(d,J＝8.0Hz,1H),6.80(d,J＝14.4Hz,1H),5.58(d,J＝8.0Hz,1H),4.08(t,J＝7.6Hz,2H),3.62(q,J＝7.0Hz,2H),3.30(q,J＝6.6Hz,2H),3.20(s,3H),1.79-1.78(m,2H),1.71-1.68(m,2H),1.62(dt,J＝13.2,4.1Hz,2H),1.26(t,J＝7.0Hz,3H).The synthesis method of compound 354 is similar to that of Example 298. The difference is that 298-3 in step 4 is replaced by (E)-3-(6'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)acrylic acid, and 293-3 in step 4 is replaced by 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 540.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.24(t,J＝5.7Hz,1H),7.90(d,J＝8.8Hz,1H),7.77(d,J＝14.4Hz,1H),7.58(d,J＝1.7Hz,1H),7.52(d,J＝2.0Hz,1H),7.22(ddd,J＝20.4,8.4,1.9Hz,2H),7 .17(d,J＝8.0Hz,1H),6.80(d,J＝14.4Hz,1H ),5.58(d,J＝8.0Hz,1H),4.08(t,J＝7.6Hz,2H),3.62(q,J＝7.0Hz,2H),3.30(q,J＝6.6Hz,2H),3.20(s,3H),1.79-1.78(m,2H),1.71-1.68(m,2H),1.62(d t,J＝13.2,4.1Hz,2H),1.26(t,J＝7.0Hz,3H).
实施例355
Embodiment 355
合成方法Synthesis method
化合物355的合成方法参照实施例353。区别在于把步骤一中的5-氯-2-苯并噁唑酮替换为5-氯-1-甲基-1,3-二氢-2H-苯并[d]咪唑-2-酮。LC-MS(ESI)m/z:529.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.19(t,J＝5.7Hz,1H),7.90(d,J＝8.7Hz,1H),7.82(d,1H),7.66(s,1H),7.52(d,J＝2.0Hz,1H),7.31(s,2H),7.20(dd,J＝8.8,2.0Hz,1H),6.72(d,J＝14.5Hz,1H),4.09(t,J＝7.5Hz,2H),3.62(q,J＝7.0Hz,2H),3.37(s,3H),3.30(q,J＝6.3Hz,2H),3.20(s,3H),1.78(p,J＝7.2Hz,2H),1.26(t,3H).The synthesis method of compound 355 is similar to that of Example 353. The difference is that 5-chloro-2-benzoxazolone in step 1 is replaced by 5-chloro-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one. LC-MS (ESI) m/z: 529.1 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.19(t,J＝5.7Hz,1H),7.90(d,J＝8.7Hz,1H),7.82(d,1H),7.66(s,1H),7.52(d,J＝2.0Hz,1H),7.31(s,2H),7.20(dd,J＝8.8,2.0Hz,1H),6.72(d,J＝14 .5Hz,1H),4.09(t,J＝7.5Hz,2H),3.62(q,J＝7.0Hz,2H),3.37(s,3H),3.30(q,J＝6.3Hz,2H),3.20(s,3H),1.78(p,J＝7.2Hz,2H),1.26(t,3H).
实施例356
Embodiment 356
合成方法Synthesis method
化合物356的合成方法参照实施例353。区别在于把步骤一中的5-氯-2-苯并噁唑酮替换为6-氯-3,3-二甲基-1,3-二氢-2H-吡咯并[2,3-b]吡啶-2-酮。LC-MS(ESI)m/z:543.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.41(t,J＝5.7Hz,1H),7.95(d,J＝7.7Hz,1H),7.89(d,J＝8.8Hz,1H),7.79(d,J＝14.3Hz,1H),7.51(d,J＝2.0Hz,1H),7.34(d,J＝7.7Hz,1H),7.20(dd,J＝8.7,1.9Hz,1H),7.12(d,J＝14.3Hz,1H),4.07(t,J＝7.6Hz,2H),3.61(q,J＝7.0Hz,2H),3.29(p,J＝6.5Hz,2H),3.20(s,3H),1.77(p,J＝7.1Hz,2H),1.39(s,6H),1.26(t,J＝7.1Hz,3H).The synthesis method of compound 356 refers to Example 353. The difference is that 5-chloro-2-benzoxazolone in step 1 is replaced by 6-chloro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one. LC-MS (ESI) m/z: 543.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.41 (t, J = 5.7 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 14.3 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.20 (dd, J = 8.7, 1.9 Hz, 1H ),7.12(d,J＝14.3Hz,1H),4.07(t,J＝7.6Hz,2H),3.61(q,J＝7.0Hz,2H),3.29(p,J＝6.5Hz,2H),3.20(s,3H),1.77(p,J＝7.1Hz,2H),1.39(s,6H),1.26(t, J＝7.1Hz,3H).
实施例357
Embodiment 357
合成方法Synthesis method
化合物357的合成方法参照实施例298。区别在于把步骤一中的6-溴-3,3-二甲基吲哚-2-酮替换为6'-溴螺[环丙烷-1,3'-吲哚啉]-2'-酮，步骤四中的293-3替换为1-(3-氨基丙基)-7-三氟甲基-4-(甲乙胺基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:580.3[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.27(t,J＝5.7Hz,1H),8.10(d,J＝8.5Hz,1H),7.78(d,J＝14.3Hz,1H),7.67(d,J＝1.8Hz,1H),7.46(dd,J＝8.6,1.7Hz,1H),7.14(d,J＝1.4Hz,1H),6.99(d,J＝7.7Hz,1H),6.88(dd,J＝7.8,1.4Hz,1H),6.81(d,J＝14.3Hz,1H),4.16(t,J＝7.5Hz,2H),3.65(q,J＝7.0Hz,2H),3.30(q,J＝6.6Hz,2H),2.01(tt,J＝8.4,5.1Hz,1H),1.80(p,J＝7.0Hz,2H),1.68(q,J＝4.1,3.2Hz,2H),1.62(q,J＝4.8,3.9Hz,2H),1.28(t,J＝7.1Hz,3H),1.00-0.95(m,2H),0.78-0.74(m,2H).The synthesis method of compound 357 refers to Example 298. The difference is that 6-bromo-3,3-dimethylindol-2-one in step 1 is replaced by 6'-bromospiro[cyclopropane-1,3'-indolline]-2'-one, and 293-3 in step 4 is replaced by 1-(3-aminopropyl)-7-trifluoromethyl-4-(methylethylamino)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 580.3 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.27(t,J＝5.7Hz,1H),8.10(d,J＝8.5Hz,1H),7.78(d,J＝14.3Hz,1H),7.67(d,J＝1.8Hz,1H),7.46(dd,J＝8.6,1.7Hz,1H),7.14(d,J＝1.4Hz,1H),6.99(d, J＝7.7Hz,1H),6.88(dd,J＝7.8,1.4Hz,1H),6.81(d,J＝14.3Hz,1H),4.16(t ,J＝7.5Hz,2H),3.65(q,J＝7.0Hz,2H),3.30(q,J＝6.6Hz,2H),2.01(tt,J＝8.4,5.1Hz,1H),1.80(p,J＝7.0Hz,2H),1.68(q,J＝4.1,3.2Hz,2H),1.62(q,J＝4 .8,3.9Hz,2H),1.28(t,J＝7.1Hz,3H),1.00-0.95(m,2H),0.78-0.74(m,2H).
实施例358
Embodiment 358
合成方法Synthesis method
化合物358的合成方法参照实施例353。区别在于把步骤一中的5-氯-2-苯并噁唑酮替换为6-氯-3,3-二甲基吲哚啉-2-酮，把步骤三中的1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮替换为7-氯-4-(甲乙胺基)-1-(3-(甲胺基)丙基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:556.2[M+H]+.The synthesis method of compound 358 refers to Example 353. The difference is that 5-chloro-2-benzoxazolone in step 1 is replaced by 6-chloro-3,3-dimethylindolin-2-one, and 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one in step 3 is replaced by 7-chloro-4-(methylethylamino)-1-(3-(methylamino)propyl)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 556.2 [M+H] + .
实施例359
Embodiment 359
合成方法Synthesis method
化合物359的合成方法参照实施例306。区别在于把步骤三中的1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮替换为1'-(3-氨基丙基)-6'-氯螺[环丙烷-1,3'-吲哚啉]-2'-酮。LC-MS(ESI)m/z:526.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.24(t,J＝5.5Hz,1H),7.99(d,J＝8.7Hz,1H),7.70(d,J＝14.1Hz,1H),7.53(d,J＝2.0Hz,1H),7.34(dd,J＝8.7,2.0Hz,1H),7.30(d,J＝1.1Hz,1H),7.05(d,J＝1.4Hz,2H),6.68(d,J＝14.2Hz,1H),3.81(t,J＝7.2Hz,2H),3.30(s,6H),3.23(q,J＝6.6Hz,2H),1.83-1.76(m,2H),1.65 (q,J＝3.9Hz,2H),1.55(q,J＝3.8Hz,2H).The synthesis method of compound 359 refers to Example 306. The difference is that 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one in step 3 is replaced by 1'-(3-aminopropyl)-6'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one. LC-MS (ESI) m/z: 526.1 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.24(t,J＝5.5Hz,1H),7.99(d,J＝8.7Hz,1H),7.70(d,J＝14.1Hz,1H),7.53(d,J＝2.0Hz,1H),7.34(dd,J＝8.7,2.0Hz,1H),7.30(d,J＝1.1Hz,1H),7.05(d, J＝1.4Hz,2H),6.68(d,J＝14.2Hz,1H),3.81(t,J＝7.2Hz,2H),3.30(s,6H),3.23(q,J＝6.6Hz,2H),1.83-1.76(m,2H),1.65 (q,J＝3.9Hz,2H),1.55(q,J＝3.8Hz,2H).
实施例360
Embodiment 360
合成方法Synthesis method
化合物360的合成方法参照实施例306。区别在于把步骤三中的1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮替换为7-环丙基-4-(二甲胺基)-1-(吡咯烷-3-基甲基)喹唑啉-2(1H)-酮。LC-MS(ESI)m/z:294.6[M/2+H]+.1H NMR(600MHz,DMSO-d6)δδ7.98(dd,J＝8.7,2.8Hz,1H),7.83(dd,J＝8.5,7.2Hz,1H),7.72(dd,J＝13.8,2.6Hz,1H),7.56(dd,J＝19.1,2.0Hz,1H),7.33(dt,J＝8.7,2.4Hz,1H),7.19(dd,J＝12.0,1.6Hz,1H),6.88(dd,J＝30.3,13.9Hz,1H),6.80(ddd,J＝16.5,8.5,1.6Hz,1H),4.29-4.10(m,2H),3.73-3.47(m,2H),3.42-3.37(m,1H),3.32(s,6H),3.25(dd,1H),3.22(s,3H),3.20(s,3H),2.77-2.59(m,1H),2.16-2.05(m,1H),2.04-1.95(m,1H),1.84-1.68(m,1H),1.12-1.01(m,2H),0.92-0.79(m,2H).The synthesis method of compound 360 refers to Example 306. The difference is that 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one in step 3 is replaced by 7-cyclopropyl-4-(dimethylamino)-1-(pyrrolidin-3-ylmethyl)quinazolin-2(1H)-one. LC-MS (ESI) m/z: 294.6 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δδ7.98(dd,J＝8.7,2.8Hz,1H),7.83(dd,J＝8.5,7.2Hz,1H),7.72(dd,J＝13.8,2.6Hz,1H),7.56(dd,J＝19.1,2.0Hz,1H),7.33(dt,J＝8.7,2.4Hz,1H),7.19(dd, J＝12.0,1.6Hz,1H),6.88(dd,J＝30.3,13.9Hz,1H),6.80(ddd,J＝16.5,8.5,1 .6Hz,1H),4.29-4.10(m,2H),3.73-3.47(m,2H),3.42-3.37(m,1H),3.32(s,6H),3.25(dd,1H),3.22(s,3H),3.20(s,3H),2.77-2.59(m,1H),2.16-2 .05(m,1H),2.04-1.95(m,1H),1.84-1.68(m,1H),1.12-1.01(m,2H),0.92-0.79(m,2H).
实施例361
Embodiment 361
合成方法Synthesis method
化合物361的合成方法参照实施例298。区别在于把步骤四中的298-3替换为(E)-3-(6'-氯-2'-氧代螺[环丙烷-1,3'-吲哚啉]-1'-基)丙烯酸，步骤四中的293-3替换为1'-(3-氨基丙基)-6'-氯螺[环丙烷-1,3'-吲哚啉]-2'-酮。LC-MS(ESI)m/z:502.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.20(t,J＝5.6Hz,1H),7.77(d,J＝14.3Hz,1H),7.30(d,J＝1.4Hz,1H),7.14(d,J＝1.4Hz,1H),7.05(d,J＝1.5Hz,2H),6.99(d,J＝7.7Hz,1H),6.88(dd,J＝7.8,1.4Hz,1H),6.82(d,J＝14.3Hz,1H),3.81(t,J＝7.2Hz,2H),3.24(q,J＝6.6Hz,2H),2.05-1.99(m,1H),1.80(p,J＝7.1Hz,2H),1.70-1.64(m,4H),1.64-1.60(m,2H),1.55(q,J＝3.8Hz,2H),1.00-0.95(m,2H),0.79-0.73(m,2H).The synthesis method of compound 361 refers to Example 298. The difference is that 298-3 in step 4 is replaced by (E)-3-(6'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)acrylic acid, and 293-3 in step 4 is replaced by 1'-(3-aminopropyl)-6'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one. LC-MS (ESI) m/z: 502.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.20(t,J＝5.6Hz,1H),7.77(d,J＝14.3Hz,1H),7.30(d,J＝1.4Hz,1H),7.14(d,J＝1.4Hz,1H),7.05(d,J＝1.5Hz,2H),6.99(d,J＝7.7Hz,1H),6.88(dd,J＝7. 8,1.4Hz,1H),6.82(d,J＝14.3Hz,1 H),3.81(t,J＝7.2Hz,2H),3.24(q,J＝6.6Hz,2H),2.05-1.99(m,1H),1.80(p,J＝7.1Hz,2H),1.70-1.64(m,4H),1.64-1.60(m,2H),1.55(q,J＝3.8Hz,2H) ,1.00-0.95(m,2H),0.79-0.73(m,2H).
实施例362
Embodiment 362
合成方法 Synthesis method
化合物362的合成方法参照实施例337，区别在于把步骤五中的7-溴-1H-吡咯并[3,2-c]吡啶替换为7-溴-1H-吡唑并[4,3-C]吡啶。LC-MS(ESI)m/z:540.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ10.66(s,1H),9.17(s,1H),8.57(s,1H),8.43(s,1H),8.24(d,J＝15.3Hz,1H),8.07(d,J＝8.8Hz,1H),7.82(d,J＝2.1Hz,1H),7.74(dd,J＝8.1,2.1Hz,1H),7.59(t,J＝8.0Hz,1H),7.23(dd,J＝8.8,2.1Hz,1H),7.06(dd,J＝7.8,2.0Hz,1H),6.90(d,J＝15.3Hz,1H),6.43(d,J＝2.1Hz,1H),4.47(d,J＝6.9Hz,2H),3.32(s,6H),0.86(t,J＝6.9Hz,1H),0.52-0.48(m,2H),0.41-0.36(m,2H).The synthesis method of compound 362 refers to Example 337, except that 7-bromo-1H-pyrrolo[3,2-c]pyridine in step 5 is replaced by 7-bromo-1H-pyrazolo[4,3-c]pyridine. LC-MS (ESI) m/z: 540.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.66 (s, 1H), 9.17 (s, 1H), 8.57 (s, 1H), 8.43 (s, 1H), 8.24 (d, J = 15.3 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 8.1, 2.1 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.23 (dd, J = 8.8,2.1Hz,1H),7.06(dd,J＝7.8,2.0Hz,1H),6.90(d,J＝15.3Hz,1H),6.43(d,J＝2.1Hz,1H),4.47(d,J＝6.9Hz,2H),3.32(s,6H),0.86(t,J＝6.9Hz,1H),0. 52-0.48(m,2H),0.41-0.36(m,2H).
实施例363
Embodiment 363
合成方法Synthesis method
化合物363的合成方法参照实施例123。区别在于把步骤一中的2,4,7-三氯喹唑啉替换为2,4-二氯-8-甲氧基喹唑啉。LC-MS(ESI)m/z:301.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ8.03(d,J＝8.8Hz,1H),7.71(t,J＝8.4,7.3Hz,1H),7.46(dd,J＝8.2,1.3Hz,1H),7.30(d,J＝8.1Hz,1H),7.20(dd,J＝8.8,2.1Hz,1H),7.13(t,J＝8.0Hz,1H),6.53(dd,J＝7.7,2.6Hz,2H),6.43(d,J＝2.1Hz,1H),4.58-4.49(m,2H),3.86(s,3H),3.46-3.40(m,2H),3.32(s,6H),3.16(s,6H),3.12(dd,J＝10.7,7.0Hz,1H),2.03-1.97(m,2H),1.72(dd,J＝12.7,7.6Hz,1H),1.46(q,J＝7.3Hz,1H).The synthesis method of compound 363 refers to Example 123. The difference is that 2,4,7-trichloroquinazoline in step 1 is replaced by 2,4-dichloro-8-methoxyquinazoline. LC-MS (ESI) m/z: 301.1 [M/2+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.03 (d, J = 8.8 Hz, 1H), 7.71 (t, J = 8.4, 7.3 Hz, 1H), 7.46 (dd, J = 8.2, 1.3 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.20 (dd, J = 8.8, 2.1 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.53 (dd, J = 7.7, 2.6 Hz, 2H), 6.43 (d, J＝2.1Hz,1H),4.58-4.49(m,2H),3.86(s,3H),3.46-3.40(m,2H),3.32(s,6H),3.16(s,6H),3.12(dd,J＝10.7,7.0Hz,1H),2.03-1.97(m,2H),1.72(dd,J ＝12.7,7.6Hz,1H),1.46(q,J＝7.3Hz,1H).
实施例364
Embodiment 364
合成方法Synthesis method
化合物364的合成方法参照实施例298。区别在于把步骤四中的293-3替换为1-(3-氨基丙基)-7-氯-4,4-二甲基-1,4-二氢-2H-苯并[d][1,3]噁嗪-2-酮。LC-MS(ESI)m/z:522.2 [M+H]+.1H NMR(600MHz,DMSO-d6)δ8.29(t,J＝5.7Hz,1H),7.70(d,J＝14.3Hz,1H),7.36(d,J＝8.2Hz,1H),7.32(d,J＝7.7Hz,1H),7.25(d,J＝2.0Hz,1H),7.17(dd,J＝8.2,1.9Hz,1H),7.07(d,J＝1.5Hz,1H),6.91(dd,J＝7.8,1.4Hz,1H),6.84(d,J＝14.3Hz,1H),3.94(t,J＝7.5Hz,2H),3.28(q,J＝6.6Hz,2H),2.00(tt,J＝8.5,5.1Hz,1H),1.80(p,J＝7.1Hz,2H),1.60(s,6H),1.32(s,6H),1.00-0.95(m,2H),0.80-0.74(m,2H).The synthesis method of compound 364 is similar to that of Example 298. The difference is that 293-3 in step 4 is replaced by 1-(3-aminopropyl)-7-chloro-4,4-dimethyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one. LC-MS (ESI) m/z: 522.2 [M+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ8.29 (t, J = 5.7Hz, 1H), 7.70 (d, J = 14.3Hz, 1H), 7.36 (d, J = 8.2Hz, 1H), 7.32 (d, J = 7.7Hz, 1H), 7.25 (d, J = 2.0Hz, 1H), 7.1 7(dd,J＝8.2,1.9Hz,1H),7.07(d,J＝1.5Hz,1H),6.91(dd,J＝7.8,1.4Hz ,1H),6.84(d,J＝14.3Hz,1H),3.94(t,J＝7.5Hz,2H),3.28(q,J＝6.6Hz,2H),2.00(tt,J＝8.5,5.1Hz,1H),1.80(p,J＝7.1Hz,2H),1.60(s,6H),1.32(s,6H ),1.00-0.95(m,2H),0.80-0.74(m,2H).
实施例365
Embodiment 365
合成方法Synthesis method
化合物365的合成方法参照实施例298。区别在于把步骤四中的293-3替换为7-氯-4,4-二甲基-1-(吡咯烷-3-基甲基)-1,4-二氢-2H-苯并[d][1,3]噁嗪-2-酮。LC-MS(ESI)m/z:548.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.72(dd,J＝13.9,1.9Hz,1H),7.42(dd,J＝10.7,1.9Hz,1H),7.37(t,J＝7.9Hz,1H),7.32(d,J＝7.7Hz,1H),7.18(ddd,J＝14.5,8.2,1.9Hz,1H),7.10(d,J＝3.4Hz,1H),7.07(d,J＝13.9Hz,1H),6.89(ddd,J＝7.0,5.3,1.4Hz,1H),4.11-3.99(m,2H),3.78-3.70(m,1H),3.63-3.56(m,1H),3.42(m,2H),3.41-3.32(m,1H),2.73-2.55(m,1H),2.07-1.91(m,2H),1.82-1.66(m,1H),1.63(d,J＝4.1Hz,3H),1.61(d,J＝6.7Hz,3H),1.32(d,J＝3.5Hz,6H),0.99-0.94(m,2H),0.79-0.73(m,2H).The synthesis method of compound 365 refers to Example 298. The difference is that 293-3 in step 4 is replaced by 7-chloro-4,4-dimethyl-1-(pyrrolidin-3-ylmethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one. LC-MS (ESI) m/z: 548.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.72(dd,J＝13.9,1.9Hz,1H),7.42(dd,J＝10.7,1.9Hz,1H),7.37(t,J＝7.9Hz,1H),7.32(d,J＝7.7Hz,1H),7.18(ddd,J＝14.5,8.2,1.9Hz,1H),7.10(d,J＝3 .4Hz,1H),7.07(d,J＝13.9Hz,1H),6.89(ddd,J＝7.0,5.3,1.4Hz,1H),4.11-3.99(m, 2H),3.78-3.70(m,1H),3.63-3.56(m,1H),3.42(m,2H),3.41-3.32(m,1H),2.73-2.55(m,1H),2.07-1.91(m,2H),1.82-1.66(m,1H),1.63(d,J＝4 .1Hz,3H),1.61(d,J＝6.7Hz,3H),1.32(d,J＝3.5Hz,6H),0.99-0.94(m,2H),0.79-0.73(m,2H).
实施例366
Embodiment 366
合成方法Synthesis method
化合物366的合成方法参照实施例123。区别在于把步骤三中的1-Boc-3-溴甲基吡咯烷替换为tert-butyl 6-bromo-3-azabicyclo[3.1.0]hexane-3-carboxylate，步骤七中的二甲胺替换为甲乙胺。LC-MS(ESI)m/z:309.1[M/2+H]+.1H NMR(600MHz,DMSO-d6)δ7.96(dd,J＝36.8,8.8Hz,2H),7.78(t,J＝7.9Hz,1H),7.53(s,1H),7.23(d,J＝8.9Hz,2H),6.74(d,J＝8.5Hz,1H),6.66(d,J＝7.3Hz,1H),6.47(s,1H),3.93(d,J＝10.6Hz,2H), 3.72(q,J＝7.1Hz,2H),3.56(m,2H),3.32(s,3H),3.24(s,6H),2.66(s,1H),2.09(s,2H),1.32(t,J＝7.1Hz,3H).The synthesis method of compound 366 refers to Example 123, except that 1-Boc-3-bromomethylpyrrolidine in step 3 is replaced by tert-butyl 6-bromo-3-azabicyclo[3.1.0]hexane-3-carboxylate, and dimethylamine in step 7 is replaced by methylethylamine. LC-MS (ESI) m/z: 309.1[M/2+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ7.96 (dd, J = 36.8, 8.8 Hz, 2H), 7.78 (t, J = 7.9 Hz, 1H), 7.53 (s, 1H), 7.23 (d, J = 8.9 Hz, 2H), 6.74 ( d,J＝8.5Hz,1H),6.66(d,J＝7.3Hz,1H),6.47(s,1H),3.93(d,J＝10.6Hz,2H), 3.72(q,J＝7.1Hz,2H),3.56(m,2H),3.32(s,3H),3.24(s,6H),2.66(s,1H),2.09(s,2H),1.32(t,J＝7.1Hz,3H).
实施例367
Embodiment 367
合成方法Synthesis method
化合物367的合成方法参照实施例298。区别在于把步骤四中的293-3替换为1-((1-(氨基甲基)环丙基)甲基)-6-氯-3,3-二甲基吲哚啉-2-酮。LC-MS(ESI)m/z:526.2[M+H]+.The synthesis method of compound 367 refers to Example 298. The difference is that 293-3 in step 4 is replaced by 1-((1-(aminomethyl)cyclopropyl)methyl)-6-chloro-3,3-dimethylindolin-2-one. LC-MS (ESI) m/z: 526.2 [M+H] + .
实施例368
Embodiment 368
合成路线
Synthetic route
步骤一：化合物368-1的合成Step 1: Synthesis of compound 368-1
室温下，将4-氯-1H-吡咯并[3,2-c]吡啶(300mg，1.97mmol)溶于5mL干燥的DMF中，降温至0℃，加入NaH(160mg，4.00mmol)，在氮气气氛下缓慢滴加溴化 苄(600mg，3.5mmol)，滴加完毕后室温反应1小时。LC-MS监测反应完全。冰浴下滴加饱和氯化铵溶液淬灭反应，加水和乙酸乙酯萃取后合并有机相浓缩，后经快速色谱柱层析分离(PE:EA,0-50％,10min)得到460mg化合物368-1。LC-MS(ESI)m/z:243[M+H]+，收率：96％。At room temperature, 4-chloro-1H-pyrrolo[3,2-c]pyridine (300 mg, 1.97 mmol) was dissolved in 5 mL of dry DMF, cooled to 0°C, and NaH (160 mg, 4.00 mmol) was added. Under a nitrogen atmosphere, bromide was slowly added dropwise. Benzyl (600 mg, 3.5 mmol) was added dropwise and reacted at room temperature for 1 hour. The reaction was complete after LC-MS monitoring. Saturated ammonium chloride solution was added dropwise under ice bath to quench the reaction. After extraction with water and ethyl acetate, the organic phases were combined and concentrated, and then separated by flash chromatography column (PE:EA, 0-50%, 10 min) to obtain 460 mg of compound 368-1. LC-MS (ESI) m/z: 243 [M+H] + , yield: 96%.
步骤二：化合物368-2的合成Step 2: Synthesis of compound 368-2
室温下，将化合物368-1(430mg，1.78mmol)溶于10mL NMP中，加入1-Boc-哌嗪(1.3g，6.99mmol)和三乙胺(710mg，7.03mmol),微波180℃反应1小时。LC-MS监测反应完全。反应液直接经反向柱层析分离(H2O:MeCN,5-95％,10min)得到220mg化合物368-2。LC-MS(ESI)m/z:393[M+H]+，收率：32％。At room temperature, compound 368-1 (430 mg, 1.78 mmol) was dissolved in 10 mL NMP, 1-Boc-piperazine (1.3 g, 6.99 mmol) and triethylamine (710 mg, 7.03 mmol) were added, and the mixture was reacted at 180°C for 1 hour under microwave. The reaction was complete as monitored by LC-MS. The reaction solution was directly separated by reverse column chromatography (H 2 O:MeCN, 5-95%, 10 min) to obtain 220 mg of compound 368-2. LC-MS (ESI) m/z: 393 [M+H] + , yield: 32%.
步骤三：化合物368-3的合成Step 3: Synthesis of compound 368-3
室温下，将化合物368-2(220mg，0.560mmol)溶于5mL DCM中，加入2mL三氟乙酸，室温搅拌2小时。反应液浓缩后得180mg化合物368-3。At room temperature, compound 368-2 (220 mg, 0.560 mmol) was dissolved in 5 mL DCM, 2 mL trifluoroacetic acid was added, and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain 180 mg of compound 368-3.
步骤四：化合物368的合成Step 4: Synthesis of compound 368
室温下，将化合物229-5(30mg，0.102mmol)溶于2mL干燥的DMF中，加入DIEA(40mg，0.310mmol)和HATU(40mg，0.143mmol),室温搅拌5分钟后加入化合物368-3(30mg，0.102mmol)，之后室温搅拌20分钟。LC-MS监测反应完全。加水和乙酸乙酯萃取后合并有机相，用饱和食盐水洗涤有机相两次，浓缩后经快速色谱柱层析分离(DCM:MeOH,0-10％,10min)得到20mg粗品。然后经高效液相色谱柱层析分离得到5mg化合物368。LC-MS(ESI)m/z:568.2[M+H]+，收率：9％。At room temperature, compound 229-5 (30 mg, 0.102 mmol) was dissolved in 2 mL of dry DMF, DIEA (40 mg, 0.310 mmol) and HATU (40 mg, 0.143 mmol) were added, and the mixture was stirred at room temperature for 5 minutes before adding compound 368-3 (30 mg, 0.102 mmol), followed by stirring at room temperature for 20 minutes. LC-MS monitored the reaction to be complete. After extraction with water and ethyl acetate, the organic phases were combined, washed twice with saturated brine, concentrated, and separated by flash chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 20 mg of crude product. Then, 5 mg of compound 368 was obtained by HPLC column chromatography. LC-MS (ESI) m/z: 568.2 [M+H] + , yield: 9%.
实施例369
Embodiment 369
合成方法Synthesis method
化合物369的合成方法参照实施例298。区别在于把步骤一中的5-氯-2-苯并噁唑酮替换为6-溴-3,3-二甲基-1,3-二氢-2H-吡咯并[3,2-b]吡啶-2-酮。LC-MS(ESI)m/z:587.1[M+H]+.1H NMR(600MHz,DMSO-d6)δδ8.26(t,J＝5.7Hz,1H),8.13(s,1H),7.90(d,J＝8.8Hz,1H),7.72(d,J＝14.4Hz,1H),7.65(s,1H),7.52(d,J＝2.0Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),6.84(d,J＝14.4Hz,1H),4.08(t,J＝7.6Hz,2H),3.62(q,J＝7.0Hz,2H), 3.30(q,J＝6.6Hz,2H),3.20(s,3H),1.94(q,J＝4.1Hz,2H),1.75(q,J＝4.0Hz,3H),1.29-1.21(m,6H).The synthesis method of compound 369 refers to Example 298, except that 5-chloro-2-benzoxazolone in step 1 is replaced by 6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one. LC-MS (ESI) m/z: 587.1[M+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ 8.26 (t, J = 5.7 Hz, 1H), 8.13 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 14.4 Hz, 1H), 7.65 (s, 1H) .52(d,J＝2.0Hz,1H),7.20(dd,J＝8.8,2.0Hz,1H),6.84(d,J＝14.4Hz,1H),4.08(t,J＝7.6Hz,2H),3.62(q,J＝7.0Hz,2H), 3.30(q,J＝6.6Hz,2H),3.20(s,3H),1.94(q,J＝4.1Hz,2H),1.75(q,J＝4.0Hz,3H),1.29-1.21(m,6H).
实施例370
Embodiment 370
合成方法Synthesis method
化合物370的合成方法参照实施例298。区别在于把步骤一中的5-氯-2-苯并噁唑酮替换为6'-氯螺[环丙烷-1,3'-吡咯并[3,2-c]吡啶]-2'(1'H)-酮。LC-MS(ESI)m/z:541.1[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.44(d,J＝1.8Hz,1H),8.21(t,J＝5.7Hz,1H),8.11(d,J＝1.8Hz,1H),7.90(d,J＝8.7Hz,1H),7.71(d,J＝14.4Hz,1H),7.52(d,J＝2.0Hz,1H),7.20(dd,J＝8.8,1.9Hz,1H),6.79(d,J＝14.5Hz,1H),4.08(t,J＝7.5Hz,2H),3.62(q,J＝7.0Hz,2H),3.30(q,J＝6.7Hz,2H),3.20(s,3H),1.78(p,J＝7.1Hz,2H),1.37(s,4H),1.26(t,J＝7.1Hz,3H).The synthesis method of compound 370 refers to Example 298. The difference is that 5-chloro-2-benzoxazolone in step 1 is replaced by 6'-chlorospiro[cyclopropane-1,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one. LC-MS (ESI) m/z: 541.1 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.44 (d, J = 1.8 Hz, 1H), 8.21 (t, J = 5.7 Hz, 1H), 8.11 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 14.4 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.20 (dd, J = 8.8, 1.9 Hz, 1H ),6.79(d,J＝14.5Hz,1H),4.08(t,J＝7.5Hz,2H),3.62(q,J＝7.0Hz,2H),3.30(q,J＝6.7Hz,2H),3.20(s,3H),1.78(p,J＝7.1Hz,2H),1.37(s,4H),1.26(t, J＝7.1Hz,3H).
实施例371&372
Example 371 & 372
合成路线
Synthetic route
步骤一：化合物371-1的合成Step 1: Synthesis of compound 371-1
室温下，将2,4-二氯烟醛(2.0g，11.36mmol)溶解在200mL四氢呋喃中，氮气保护下降温至-78℃，逐滴加入环丙基溴化镁(1M)(12.5mL，12.5mmol)，-78℃下搅拌过夜。TLC监测完全反应。At room temperature, 2,4-dichloronicotinaldehyde (2.0 g, 11.36 mmol) was dissolved in 200 mL of tetrahydrofuran, cooled to -78°C under nitrogen protection, cyclopropylmagnesium bromide (1M) (12.5 mL, 12.5 mmol) was added dropwise, and stirred overnight at -78°C. The complete reaction was monitored by TLC.
反应体系升温至-20℃，缓慢加入饱和氯化铵溶液(100mL)淬灭，用乙酸乙酯(150mL×3)萃取，合并有机相用饱和氯化钠溶液(200mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物371-1，997mg，淡黄色油状液体，产率41％。LC-MS(ESI)m/z:218[M+H]+。The reaction system was heated to -20°C, quenched by slowly adding saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (150 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (200 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 371-1, 997 mg, light yellow oily liquid, yield 41%. LC-MS (ESI) m/z: 218 [M+H] + .
步骤二：化合物371-2的合成Step 2: Synthesis of compound 371-2
室温下，将化合物371-1(997mg，4.59mmol)溶解在10mL二氯甲烷中，降温至0℃后加入氯铬酸吡咯烷(2.0g，9.19mmol)，室温下搅拌过夜。TLC监测完全反应。At room temperature, compound 371-1 (997 mg, 4.59 mmol) was dissolved in 10 mL of dichloromethane, cooled to 0°C, and then pyrrolidine chlorochromate (2.0 g, 9.19 mmol) was added, and stirred at room temperature overnight. The reaction was monitored by TLC.
反应体系中加入20mL水，用乙酸乙酯(30mL×3)萃取，合并有机相用饱和氯化钠溶液(50mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物371-2，800mg，淡黄色油状液体，产率81％。LC-MS(ESI)m/z:216[M+H]+。20 mL of water was added to the reaction system, extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 371-2, 800 mg, light yellow oily liquid, yield 81%. LC-MS (ESI) m/z: 216 [M + H] + .
步骤三：化合物371-3的合成Step 3: Synthesis of compound 371-3
室温下，将化合物371-2(800mg，3.72mmol)溶解在1,4-二氧六环(10mL)中，降温至0℃后加入水合肼(80％)8.2mL，室温下搅拌过夜。TLC监测完全反应。At room temperature, compound 371-2 (800 mg, 3.72 mmol) was dissolved in 1,4-dioxane (10 mL), cooled to 0°C, 8.2 mL of hydrazine hydrate (80%) was added, and stirred at room temperature overnight. The complete reaction was monitored by TLC.
反应体系中加入20mL二氯甲烷，浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物371-3，455mg，黄色油状液体，产率63％。LC-MS(ESI)m/z:194[M+H]+。20 mL of dichloromethane was added to the reaction system and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate, 0-100%, 20 min) to obtain compound 371-3, 455 mg, yellow oily liquid, yield 63%. LC-MS (ESI) m/z: 194 [M+H] + .
步骤四：化合物371-4的合成Step 4: Synthesis of compound 371-4
室温下，将化合物371-3(455mg，2.35mmol)溶解在N,N-二甲基甲酰胺(5mL)中，降温至0℃后加入氢化钠(60％)(150mg，3.52mmol)，室温下搅拌20min后滴加2-(三甲基硅烷基)乙氧甲基氯，室温下搅拌2h。TLC监测完全反应。At room temperature, compound 371-3 (455 mg, 2.35 mmol) was dissolved in N,N-dimethylformamide (5 mL), cooled to 0°C, sodium hydride (60%) (150 mg, 3.52 mmol) was added, stirred at room temperature for 20 min, 2-(trimethylsilyl)ethoxymethyl chloride was added dropwise, and stirred at room temperature for 2 h. TLC monitored the complete reaction.
反应体系中加入10mL水，用乙酸乙酯(20mL×3)萃取，合并有机相用饱和氯化钠溶液(30mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(石油醚：乙酸乙酯，0-100％，20min)得到化合物371-4，520mg，淡黄色油状液体，产 率69％。LC-MS(ESI)m/z:324[M+H]+。10 mL of water was added to the reaction system, extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 0-100%, 20 min) to obtain compound 371-4, 520 mg, light yellow oily liquid, yield The rate is 69%. LC-MS(ESI)m/z:324[M+H] + .
步骤五：化合物371-5的合成Step 5: Synthesis of compound 371-5
室温下，将化合物371-4(520mg，1.61mmol)溶解在N-甲基吡咯烷酮(10mL)中，加入1-Boc哌嗪(1.2g，6.44mmol)和三乙胺(500mg，4.83mmol)，微波180℃搅拌1h。TLC监测完全反应。At room temperature, compound 371-4 (520 mg, 1.61 mmol) was dissolved in N-methylpyrrolidone (10 mL), 1-Boc piperazine (1.2 g, 6.44 mmol) and triethylamine (500 mg, 4.83 mmol) were added, and the mixture was stirred at 180° C. for 1 h in a microwave oven. The complete reaction was monitored by TLC.
反应体系中加入10mL水，用乙酸乙酯(20mL×3)萃取，合并有机相用饱和氯化钠溶液(30mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(二氯甲烷：甲醇，0-10％，10min)得到化合物371-5，900mg，淡红色油状液体，产率100％。LC-MS(ESI)m/z:474[M+H]+。10 mL of water was added to the reaction system, extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 10 min) to obtain compound 371-5, 900 mg, light red oily liquid, yield 100%. LC-MS (ESI) m/z: 474 [M+H] + .
步骤六：化合物371-6的合成Step 6: Synthesis of compound 371-6
室温下，将化合物371-5(900mg，1.90mmol)溶解在二氯甲烷(10mL)中，加入三氟乙酸2.5mL，室温下搅拌1h。TLC监测完全反应。At room temperature, compound 371-5 (900 mg, 1.90 mmol) was dissolved in dichloromethane (10 mL), 2.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 h. The complete reaction was monitored by TLC.
反应体系浓缩直接用于下步反应。LC-MS(ESI)m/z:374[M+H]+。The reaction system was concentrated and used directly in the next step. LC-MS (ESI) m/z: 374 [M+H] + .
步骤七：化合物371的合成Step 7: Synthesis of compound 371
室温下将化合物229-5(300mg，1.02mmol)溶解在N,N-二甲基甲酰胺(10mL)中，加入N,N-二异丙基乙胺(396mg，3.07mmol)，室温下搅拌20min后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(389mg，1.02mmol)和化合物371-6(382mg，1.02mmol)，室温下搅拌20min。TLC监测完全反应。Compound 229-5 (300 mg, 1.02 mmol) was dissolved in N,N-dimethylformamide (10 mL) at room temperature, N,N-diisopropylethylamine (396 mg, 3.07 mmol) was added, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (389 mg, 1.02 mmol) and compound 371-6 (382 mg, 1.02 mmol) were added after stirring at room temperature for 20 min, and stirred at room temperature for 20 min. The complete reaction was monitored by TLC.
反应体系中加入20mL水，用乙酸乙酯(20mL×3)萃取，合并有机相用饱和氯化钠溶液(30mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩。粗产品通过硅胶柱层析(二氯甲烷：甲醇，0-10％，10min)得到化合物371，102mg，白色固体，产率15％。LC-MS(ESI)m/z:609.2[M+H]+。1H NMR(600MHz,DMSO-d6)δ7.98(dd,J＝12.7,7.3Hz,1H),7.76(d,J＝13.7Hz,1H),7.57(d,J＝2.0Hz,1H),7.34(dd,J＝8.6,2.1Hz,1H),7.25(s,1H),5.59(s,2H),3.81(s,4H),3.49(t,J＝8.0Hz,2H),3.43(t,J＝5.1Hz,4H),3.32(s,6H),1.09(dt,J＝8.1,3.0Hz,2H),1.03(dq,J＝6.9,4.3,3.8Hz,2H),0.78(t,J＝8.0Hz,2H),0.11(s,12H)20 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 10 min) to obtain compound 371, 102 mg, white solid, yield 15%. LC-MS (ESI) m/z: 609.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.98(dd,J＝12.7,7.3Hz,1H),7.76(d,J＝13.7Hz,1H),7.57(d,J＝2.0Hz,1H),7.34(dd,J＝8.6,2.1Hz,1H),7.25(s,1H),5.59(s,2H),3.81(s,4H),3.49(t ,J＝8.0Hz,2H),3.43(t,J＝5.1Hz,4H),3.32(s,6H),1.09(dt,J＝8.1,3.0Hz,2H),1.03(dq,J＝6.9,4.3,3.8Hz,2H),0.78(t,J＝8.0Hz,2H),0.11(s,12H)
步骤八：化合物372的合成Step 8: Synthesis of compound 372
室温下，将化合物371(102mg，0.15mmol)溶解在1,4-二氧六环(2mL)中，加入盐酸-二氧六环(4M)2mL，室温下搅拌15min。LC-MS检测完全反应。经硅胶柱层析(二氯甲烷：甲醇，0-10％，15min)纯化得到粗产品，HPLC制备后得到化合 物372，32mg，白色固体，产率40％。LC-MS(ESI)m/z:479.2[M+H]+。1H NMR(600MHz,DMSO-d6)δ8.00(d,J＝8.7Hz,1H),7.83(d,J＝6.4Hz,1H),7.77(d,J＝13.7Hz,1H),7.57(d,J＝2.0Hz,1H),7.44(d,J＝1.8Hz,1H),7.38-7.32(m,1H),7.25(t,J＝14.3Hz,2H),3.84(m,6H),3.55(m,2H),3.34(s,6H),2.14(m,1H)1.09-1.02(m,4H)At room temperature, compound 371 (102 mg, 0.15 mmol) was dissolved in 1,4-dioxane (2 mL), and 2 mL of hydrochloric acid-dioxane (4 M) was added, and stirred at room temperature for 15 min. LC-MS detected the complete reaction. The crude product was purified by silica gel column chromatography (dichloromethane: methanol, 0-10%, 15 min). Compound 371 was prepared by HPLC. Product 372, 32 mg, white solid, yield 40%. LC-MS (ESI) m/z: 479.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.00 (d, J = 8.7 Hz, 1H), 7.83 (d, J = 6.4 Hz, 1H), 7.77 (d, J = 13.7 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.38-7.32 (m, 1H), 7.25 (t, J = 14.3 Hz, 2H), 3.84 (m, 6H), 3.55 (m, 2H), 3.34 (s, 6H), 2.14 (m, 1H) 1.09-1.02 (m, 4H)
实施例373
Embodiment 373
合成方法Synthesis method
化合物373的合成方法参照实施例306。区别在于把步骤三中的1-(3-氨基丙基)-7-氯-4-(甲乙胺基)喹唑啉-2(1H)-酮替换为1'-(3-氨基丙基)-6'-环丙基螺[环丙烷-1,3'-吲哚啉]-2'-酮。LC-MS(ESI)m/z:532.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.25(t,J＝5.6Hz,1H),7.99(d,J＝8.7Hz,1H),7.71(d,J＝14.1Hz,1H),7.54(d,J＝2.0Hz,1H),7.34(dd,J＝8.7,2.0Hz,1H),6.88(d,J＝7.6Hz,1H),6.82(d,J＝1.5Hz,1H),6.72(dd,J＝7.7,1.5Hz,1H),6.69(d,J＝14.1Hz,1H),3.79(t,J＝7.2Hz,2H),3.30(s,6H),3.22(q,J＝6.6Hz,2H),1.96-1.91(m,1H),1.80(p,J＝7.2Hz,2H),1.54(q,J＝4.0,3.3Hz,2H),1.48(t,J＝3.4Hz,2H),0.95-0.89(m,2H),0.73-0.66(m,2H)The synthesis method of compound 373 refers to Example 306. The difference is that 1-(3-aminopropyl)-7-chloro-4-(methylethylamino)quinazolin-2(1H)-one in step 3 is replaced by 1'-(3-aminopropyl)-6'-cyclopropylspiro[cyclopropane-1,3'-indolin]-2'-one. LC-MS (ESI) m/z: 532.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ8.25(t,J＝5.6Hz,1H),7.99(d,J＝8.7Hz,1H),7.71(d,J＝14.1Hz,1H),7.54(d,J＝2.0Hz,1H),7.34(dd,J＝8.7,2.0Hz,1H),6.88(d,J＝7.6Hz,1H),6.82(d ,J＝1.5Hz,1H),6.72(dd,J＝7.7,1.5Hz,1H),6.69(d ,J＝14.1Hz,1H),3.79(t,J＝7.2Hz,2H),3.30(s,6H),3.22(q,J＝6.6Hz,2H),1.96-1.91(m,1H),1.80(p,J＝7.2Hz,2H),1.54(q,J＝4.0,3.3Hz,2H),1.48( t,J＝3.4Hz,2H),0.95-0.89(m,2H),0.73-0.66(m,2H)
实施例374
Embodiment 374
合成方法Synthesis method
化合物374的合成方法参照实施例298。区别在于把步骤四中的293-3替换为1-(3-氨基丙基)-7-环丙基-4,4-二甲基-1,4-二氢-2H-苯并[d][1,3]噁嗪-2-酮。LC-MS(ESI)m/z:528.3[M+H]+.1H NMR(600MHz,DMSO-d6)δ8.33(t,J＝5.8Hz,1H),7.72(d,J＝14.3Hz,1H),7.33(d,J＝7.7Hz,1H),7.17(d,J＝7.9Hz,1H),7.09(d,J＝1.5Hz,1H),6.92(dd,J＝7.7,1.5Hz,1H),6.86(d,J＝14.3Hz,1H),6.80(d,J＝1.6Hz,1H),6.75(dd,J＝8.0,1.5 Hz,1H),3.93(t,J＝7.6Hz,2H),3.29(q,J＝6.5Hz,2H),2.00(tt,J＝8.4,5.1Hz,1H),1.93(tt,J＝8.3,5.1Hz,1H),1.80(p,J＝7.0Hz,2H),1.56(s,6H),1.32(s,6H),1.01-0.95(m,2H),0.90-0.83(m,2H),0.80-0.74(m,2H),0.73-0.66(m,2H).The synthesis method of compound 374 refers to Example 298, except that 293-3 in step 4 is replaced by 1-(3-aminopropyl)-7-cyclopropyl-4,4-dimethyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one. LC-MS (ESI) m/z: 528.3[M+H] + . 1 H NMR (600MHz, DMSO-d 6 ) δ8.33 (t, J = 5.8Hz, 1H), 7.72 (d, J = 14.3Hz, 1H), 7.33 (d, J = 7.7Hz, 1H), 7.17 (d, J = 7.9Hz, 1H), 7.09 (d ,J＝1.5Hz,1H),6.92(dd,J＝7.7,1.5Hz,1H),6.86(d,J＝14.3Hz,1H),6.80(d,J＝1.6Hz,1H),6.75(dd,J＝8.0,1.5 Hz,1H),3.93(t,J＝7.6Hz,2H),3.29(q,J＝6.5Hz,2H),2.00(tt,J＝8.4,5.1Hz,1H),1.93(tt,J＝8.3,5.1Hz,1H),1.80(p,J＝7.0Hz,2H),1.56(s,6H),1.32 (s,6H),1.01-0.95(m,2H),0.90-0.83(m,2H),0.80-0.74(m,2H),0.73-0.66(m,2H).
实施例375
Embodiment 375
合成方法Synthesis method
化合物374的合成方法参照实施例298。区别在于把步骤四中的298-3替换为(E)-3-(7-氯-4,4-二甲基-2-氧代-2H-苯并[d][1,3]噁嗪-1(4H)-基)丙烯酸，步骤四中的293-3替换为7氯-4,4-二甲基-1-(吡咯烷-3-基甲基)-1,4-二氢-2H-苯并[d][1,3]噁嗪-2-酮。LC-MS(ESI)m/z:558.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ7.61(d,J＝13.8Hz,1H),7.48(dd,J＝8.7,2.1Hz,1H),7.42-7.35(m,4H),7.19(ddd,J＝11.7,8.2,1.9Hz,1H),6.79(dd,J＝16.1,13.9Hz,1H),4.11-3.96(m,2H),3.73-3.64(m,1H),3.58(dt,J＝11.5,5.6Hz,1H),3.55-3.35(m,1H),3.33-3.16(m,1H),2.62(dp,J＝63.8,7.3Hz,1H),2.09-1.90(m,1H),1.80-1.67(m,1H),1.66(d,J＝3.4Hz,6H),1.63-1.59(m,6H).The synthesis method of compound 374 refers to Example 298. The difference is that 298-3 in step 4 is replaced by (E)-3-(7-chloro-4,4-dimethyl-2-oxo-2H-benzo[d][1,3]oxazin-1(4H)-yl)acrylic acid, and 293-3 in step 4 is replaced by 7-chloro-4,4-dimethyl-1-(pyrrolidin-3-ylmethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one. LC-MS (ESI) m/z: 558.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 )δ7.61(d,J＝13.8Hz,1H),7.48(dd,J＝8.7,2.1Hz,1H),7.42-7.35(m,4H),7.19(ddd,J＝11.7,8.2,1.9Hz,1H),6.79(dd,J＝16.1,13.9Hz,1H),4.11-3.96(m ,2H),3.73-3.64(m,1H) ,3.58(dt,J＝11.5,5.6Hz,1H),3.55-3.35(m,1H),3.33-3.16(m,1H),2.62(dp,J＝63.8,7.3Hz,1H),2.09-1.90(m,1H),1.80-1.67(m,1H),1.66(d,J ＝3.4Hz,6H),1.63-1.59(m,6H).
试验例1：MAT2A酶学活性测试Test Example 1: MAT2A enzymatic activity test
试剂与耗材

Reagents and consumables

检测方法Detection Methods
取4μL MAT2A 2.5X工作液(使用Assay Buffer(50mM Tris,pH 7.5+50mM KCl+10mM MgCl2+0.01％DTT+0.1％BGG)稀释，配置成浓度为75nM的MAT2A工作液)加入到384孔板中(第11孔为阴性对照，不加蛋白溶液，以Assay Buffer代替)，对应孔再加2μL各浓度的5X化合物工作液样品(本发明的化合物以及阳性对照药AG-270(CasNo:2201056-66-6)、AGI-24512(CasNo:2201066-53-5))(使用DMSO稀释，取上一个浓度孔工作液4μL与12μL DMSO混合，4倍稀释8个点，起始浓度为400μM；再使用Assay Buffer 40倍稀释所有浓度点，取2μL已稀释各浓度孔溶液与78μL Assay Buffer混合均匀，配置成起始浓度为10μL的化合物工作液)，1000rpm离心1min，25℃孵育30min；Take 4 μL of MAT2A 2.5X working solution (using Assay Buffer (50 mM Tris, pH 7.5 + 50 mM KCl + 10 mM MgCl 2 + 0.01% DTT+0.1% BGG) was diluted to prepare a MAT2A working solution with a concentration of 75nM) and added to a 384-well plate (the 11th well was a negative control, without adding a protein solution, and replaced with Assay Buffer), and 2μL of 5X compound working solution samples of each concentration (the compound of the present invention and the positive control drug AG-270 (CasNo: 2201056-66-6), AGI-24512 (CasNo: 2201066-53-5)) were added to the corresponding wells (using DMSO to dilute, take 4μL of the working solution of the previous concentration well and mix it with 12μL DMSO, dilute 4 times to 8 points, and the starting concentration is 400μM; then use Assay Buffer to dilute all concentration points 40 times, take 2μL of the diluted solution of each concentration well and mix it evenly with 78μL Assay Buffer to prepare a compound working solution with a starting concentration of 10μL), centrifuge at 1000rpm for 1min, and incubate at 25°C for 30min;
对应每孔加入4μL L-甲硫氨酸/ATP MIX 2.5X工作液(使用Assay Buffer稀释，配置成250μM ATP、250μM L-甲硫氨酸工作液)，1000rpm离心1min，25℃摇晃孵育60min；Add 4 μL L-methionine/ATP MIX 2.5X working solution (diluted with Assay Buffer to prepare 250 μM ATP, 250 μM L-methionine working solution) to each well, centrifuge at 1000 rpm for 1 min, and incubate at 25°C with shaking for 60 min.
每孔加入10μL的Green或3μL的Malachite Green Phosphate Assay Kit工作液，1000rpm离心1min，25℃摇晃孵育20min；Add 10 μL of Green or 3 μL of Malachite Green Phosphate Assay Kit working solution, centrifuge at 1000 rpm for 1 min, and incubate at 25°C with shaking for 20 min;
酶标仪使用波长620nm读取吸光度值，用Excel记录；The absorbance value was read by the microplate reader at a wavelength of 620 nm and recorded in Excel;
数据处理：按如下公式计算各化合物在各浓度点的抑制率，并通过软件Graphpad Prism 8.0进行曲线拟合得到IC50值。
Data processing: The inhibition rate of each compound at each concentration point was calculated according to the following formula, and the IC50 value was obtained by curve fitting using the software Graphpad Prism 8.0.
实验结果如下表所示：




The experimental results are shown in the following table:




注：A+代表IC50≤1nM，A代表1nM﹤IC50≤10nM，B代表10nM﹤IC50≤100nM，C代表100nM﹤IC50≤1μM，D代表1μM﹤IC50≤50μM。Note: A+ represents IC 50 ≤1nM, A represents 1nM﹤IC 50 ≤10nM, B represents 10nM﹤IC 50 ≤100nM, C represents 100nM﹤IC 50 ≤1μM, and D represents 1μM﹤IC50≤50μM.
以上数据表明，本发明化合物对MAT2A具有较强的抑制作用，且多数本发明化合物的酶学活性优于阳性对照化合物AG-270和AGI-24512，可以作为MAT2A相关疾病的治疗药物，其中包括编码甲硫腺苷磷酸化酶(MTAP)的基因缺失和/或未完全发挥功能的一些癌症。 The above data show that the compounds of the present invention have a strong inhibitory effect on MAT2A, and the enzymatic activity of most of the compounds of the present invention is better than that of the positive control compounds AG-270 and AGI-24512, and can be used as therapeutic drugs for MAT2A-related diseases, including some cancers in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted and/or does not fully function.

Claims (23)

  1. 化合物，所述化合物为式(Ⅰ-1)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
    A compound, wherein the compound is a compound represented by formula (I-1), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:
    其中A1和B1各自独立选自式(Ⅱ)、(Ⅲ)、(Ⅳ)、(Ⅴ)、(Ⅵ)、(Ⅶ)和(Ⅷ)：
    wherein A 1 and B 1 are each independently selected from formula (II), (III), (IV), (V), (VI), (VII) and (VIII):
    R1每次出现时不存在或各自独立地选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、C1-6烷基、-S-C1-6烷基、-S(O)-C1-6烷基、-S(O2)-C1-6烷基、-O-C1-6烷基、-O-C1-6卤代烷基、C1-6氘代烷基、3-10元环烷基、3-10元杂环烷基和-NR1aR1b，其中R1a和R1b分别独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个含有1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-10元杂环烷基，其中所述杂环烷基任选地被0、1、2、3或4个独立选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氘代烷基、C1-6烷基、氰基、C1-6氨基烷基、3-10元环烷基、3-10元杂环烷基和羟基的取代基取代；R 1 is absent at each occurrence or is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, -SC 1-6 alkyl, -S(O)-C 1-6 alkyl, -S(O 2 )-C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, C 1-6 deuterated alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and -NR 1a R 1b , wherein R 1a and R 1b are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 1-6 containing 1-3 heteroatoms independently selected from N, O, P and S R 1a and R 1b are C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl, and C 5-10 heteroaryl are optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; or R 1a and R 1b and the nitrogen atom to which it is commonly attached form a 3-10 membered heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl group is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 deuterated alkyl, C 1-6 alkyl , cyano, C 1-6 aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy;
    Z每次出现时各自独立地选自C和N；当Z选自N时，R1不存在；Each occurrence of Z is independently selected from C and N; when Z is selected from N, R 1 is absent;
    R2、R4和R6每次出现时分别独立地选自氢、氘、卤素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、-NHC1-6烷基、-N(C1-6烷基)C1-6烷基、C1-6卤代烷氧基、C1-6卤代烷基氨基、羟基、C2-6烷氧基、3-12元单环的环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-12元单杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的5-12元螺杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的4-12元桥杂环烷基、-S-C1-6烷基、-SO-C1-6烷基、-SO2-C1-6烷基、3-6元环烷基-C1-6亚烷基、3-6元环烷基-O-、3-6元杂环烷基-O-、6-10元单环芳基、8-14元并环芳基、含有1-3个分别独立地选自N、O、P和S杂原子的5-12元单环杂芳基和含有1-3个分别独立地选自N、O、P和S杂原子的8-10元并环杂芳基；优选地，R2、R4和R6每次出现时分别独立地选自氢、卤素、C1-3烷基、C2-3烯基、C2-3炔基、C1-3卤代烷基、-NHC1-6烷基、-N(C1-6烷基)C1-6烷基、C1-6卤代烷氧基、C1-6卤代烷基氨基、3-6元单环的环烷基、含有1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-6元单杂环烷基；R 2 , R 4 and R 6 are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 haloalkylamino, hydroxy, C 2-6 alkoxy, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, -SC The invention relates to a group consisting of : a 6- membered cycloalkyl-C 1-6 alkylene group, a 3-6 -membered cycloalkyl-O-, a 3-6-membered heterocycloalkyl-O-, a 6-10-membered monocyclic aryl group, an 8-14-membered paracyclic aryl group, a 5-12-membered monocyclic heteroaryl group containing 1-3 heteroatoms independently selected from N, O, P and S, and an 8-10-membered paracyclic heteroaryl group containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R 2 , R 4 and R 6 are each independently selected from hydrogen, halogen, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 haloalkylamino, 3-6 membered monocyclic cycloalkyl, 3-6 membered monoheterocyclic alkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S;
    R5选自氢、C1-6烷基、C3-10环烷基、C3-10杂环烷基和C1-6卤代烷基，任选地，所述C1-6烷基、C3-10环烷基、C3-10杂环烷基和C1-6卤代烷基被0-6个独立选自卤素、氘、烷 基、氨基、羟基、氨基烷基、烷基氨基、和烷氧基的取代基取代； R5 is selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl and C1-6 haloalkyl, optionally, the C1-6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl and C1-6 haloalkyl are substituted by 0-6 independently selected from halogen, deuterium, alkane substituted with substituents of alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
    G1和G2每次出现各自独立地选自O、S、和NR2a； G1 and G2 are each independently selected from O, S, and NR2a ;
    E0、E1、E2、E3、E4、E5、E6、E7、E8、E9、M1、M2、M3、M4、M5、M6和E每次出现时分别独立地选自N和CR2a，且E7、E8、和E9不同时为CR2a； E0 , E1 , E2 , E3, E4 , E5 , E6 , E7 , E8 , E9 , M1 , M2 , M3 , M4 , M5 , M6 and E are each independently selected from N and CR2a , and E7 , E8 , and E9 are not CR2a at the same time;
    R2a每次出现时各自独立地选自选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、苯基亚甲基、-CH2OCH2CH2Si(CH3)3、C1-6烷基、C1-6卤代烷基、C1-6烷基-S-、-S(O)-C1-6烷基、-SO2-C1-6烷基、-O-C1-6烷基、-O-C1-6卤代烷基、-NR2bR2c、-C(O)R8c、-C(O)NR8aR8b、-C1-6亚烷基-C3-6环烷基、C3-6环烷基-NR2b-、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基-NR2b-、3-12元单环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的5-12元螺杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的4-12元桥杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基、3-6元卤代环烷基-O-、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-、6-12元单环芳基、8-12元并环芳基、含有1-3个分别独立地选自N、O、P和S的杂原子的5-12元单环杂芳基、和含有1-3个分别独立地选自N、O、P和S的杂原子的8-10元并环杂芳基；优选地，R2a选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷基-S-、-S(O)-C1-6烷基、-SO2-C1-6烷基、-O-C1-6烷基、-O-C1-6卤代烷基、-NHC1-6烷基、-N(C1-6烷基)C1-6烷基、C3-6环烷基和-C1-6亚烷基-C3-6环烷基；优选地，R2a选自氢、卤素、氰基、羟基、氨基、C1-3烷基、C1-3卤代烷基、-C1-3亚烷基-C3-6环烷基、和C3-6环烷基； R2a at each occurrence is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, phenylmethylene, -CH2OCH2CH2Si ( CH3 ) 3 , C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-S-, -S(O) -C1-6 alkyl, -SO2 - C1-6 alkyl, -OC1-6 alkyl, -OC1-6 haloalkyl, -NR2bR2c , -C(O)R8c, -C(O)NR8aR8b, -C1-6 alkylene -C3-6 cycloalkyl, C3-6 cycloalkyl-NR2b-, 3-6 membered heterocycloalkyl-NR2b containing 1-3 heteroatoms independently selected from N , O , P and S -, 3-12 membered monocyclic heterocycloalkyl, 5-12 membered spirocyclic heterocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 6-12 membered monocyclic aryl, 8-12 membered cycloheteroaryl, 5-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, and 8-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-S-, -S(O)-C 1-6 alkyl, -SO 2 -C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 3-6 cycloalkyl and -C 1-6 alkylene-C 3-6 cycloalkyl; preferably, R 2a is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-3 alkyl, C 1-3 haloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, and C 3-6 cycloalkyl;
    R2b和R2c每次出现时各自独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；或R2b和R2c和其共同连接的氮原子组成一个含有1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-10元杂环烷基，其中所述杂环烷基任选地被0、1、2、3或4个独立选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氘代烷基、C1-6烷基、氰基、C1-6氨基烷基、3-10元环烷基、3-10元杂环烷基和羟基的取代基取代；优选R2b和R2c分别独立地选自氢和C1-6烷基；R 2b and R 2c are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl , C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl R 2b and R 2c and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl containing 1, 2 , 3 or 4 heteroatoms independently selected from N, O, P and S , wherein the heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 deuterated alkyl, C 1-6 alkyl, cyano, C 1-6 aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; preferably R 2b and R 2c are independently selected from hydrogen and C 1-6 alkylamino. 1-6 alkyl;
    R8a和R8b每次出现时各自独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；或R8a和R8b和其共同连接的氮原子组成一个含有1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-10元杂环烷基，其中所述杂环烷基任选地被0、1、2、3或4个独立选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氘代 烷基、C1-6烷基、氰基、C1-6氨基烷基、3-10元环烷基、3-10元杂环烷基和羟基的取代基取代；优选R8a和R8b每次出现时分别独立地选自氢、氘、C1-6烷基、C1-6卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、-OR8d和-X2-R8d基团取代；R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl , C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl R 8a and R 8b and the nitrogen atom to which they are attached together form a 3-10 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 deuterated alkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; or R 8a and R 8b and the nitrogen atom to which they are attached together form a 3-10 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 deuterated alkyl, alkyl, C 1-6 alkyl, cyano, C 1-6 aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; preferably R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, the phenyl group is optionally substituted with 0-2 groups selected from C 1-4 alkyl, -OR 8d and -X 2 -R 8d ;
    R8c每次出现时各自独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；优选R8c选自氢、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基和C1-6卤代烷基；R 8c is independently selected at each occurrence from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl R 5-10 heteroaryl is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; preferably R 8c is selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 haloalkyl;
    X2选自C1-6亚烷基和C2-6亚烯基； X2 is selected from C1-6 alkylene and C2-6 alkenylene;
    R8d选自氢、C1-6烷基和C1-6卤代烷基；R 8d is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
    J1和J2分别独立地选自单键、O、S、C(O)、S(O)、S(O2)、C(R1cR1d)、C(＝CR1eR1f)和N(R3)，优选地，J1和J2不同时为单键；J 1 and J 2 are independently selected from a single bond, O, S, C(O), S(O), S(O 2 ), C(R 1c R 1d ), C(═CR 1e R 1f ) and N(R 3 ), preferably, J 1 and J 2 are not single bonds at the same time;
    其中R1c、R1d、R1e和R1f分别独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6氘代烷基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个个独立地选自卤素、氘、C1-6烷基、氨基、羟基、C1-6烷基氨基、C1-6氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和C1-6烷氧基的取代基取代；或R1c和R1d和其共同连接的碳原子组成一个3-10元亚环烷基或含有1-3个分别独立地选自N、O、P和S的杂原子的3-10元亚杂环烷基，其中所述亚环烷基或亚杂环烷基任选地被0、1、2、3或4个独立地选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氨基烷基和羟基的取代基取代；或R1e和R1f和其共同连接的碳原子组成一个3-10元亚环烷基或含有0、1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-10元亚杂环烷基，其中所述亚环烷基或亚杂环烷基任选地被0、1、2、3或4个独立选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氘代烷基、C1-6烷基、氰基、C1-6氨烷基、3-10元环烷基、3-10元杂环烷基和羟基的取代基取代；R3为-X1-R8，X1选自单键、-O-、-S-、C1-6亚烷氧基、C2-6亚烯基和C1-6亚烷基；R8选自氢、氘、卤素、C1-6烷基、C1-6卤代烷基、C6-10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳基；wherein R 1c , R 1d , R 1e and R 1f are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl R 1c and R 1d and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino , C 1-6 aminoalkyl and hydroxy; or R 1e and R 1d and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted by 0, 1 , 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy; wherein 1f and the carbon atom to which it is commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 deuterated alkyl, C 1-6 alkyl, cyano, C 1-6 aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; R 3 is -X 1 -R 8 , X 1 is selected from a single bond, -O-, -S-, C 1-6 alkyleneoxy, C 2-6 alkenylene and C 1-6 alkylene; R 8 is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 6-10 membered aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, and 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S;
    Linker C为连接A1和B1的连接子，为-La-Lb-Lc-Ld-Le-；Linker C is the linker connecting A1 and B1, which is -L a -L b -L c -L d -L e -;
    La、Lc、和Le每次出现时各自独立地选自-(L)n-；L a , L c , and L e at each occurrence are each independently selected from -(L) n -;
    n选自1、2、3、4、5和6；n is selected from 1, 2, 3, 4, 5 and 6;
    L每次出现时独立地选自单键、-O-、-S-、C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、C1-6卤代亚烷基、-N(RL6)C(O)-、-N(RL6)S(O)-、-N(RL6)S(O2)-、-C(O)-、-OC(O)-、-NRL6-、-S(O)-、-S(O2)-、-S(O2)NRL6-、-CRL1RL2-、和C1-6亚烷基羟基，任选地，所述C1-6亚烷 基、C2-6亚烯基、C2-6亚炔基、和C1-6卤代亚烷基各自独立地被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；优选地，L每次出现独立地选自单键、-O-、-S-、C1-4亚烷基、C2-4亚烯基、C2-4亚炔基、-CRL1RL2-、-C(O)N(RL6)-、-C(O)-、-OC(O)-、-NRL6-、-S-、-S(O)-、和-S(O2)-，任选地，所述C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、和C1-6卤代亚烷基各自独立地被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；L is independently selected at each occurrence from a single bond, -O-, -S-, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 haloalkylene, -N(R L6 )C(O)-, -N(R L6 )S(O)-, -N(R L6 )S(O 2 )-, -C(O)-, -OC(O)-, -NR L6 -, -S(O)-, -S(O 2 )-, -S(O 2 )NR L6 -, -CR L1 R L2 -, and C 1-6 alkylene hydroxyl, optionally wherein the C 1-6 alkylene wherein each of the C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, and C 1-6 haloalkylene groups is independently substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and alkoxy; preferably, each occurrence of L is independently selected from a single bond, -O-, -S-, C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -CR L1 R L2 -, -C(O)N(R L6 )-, -C(O)-, -OC(O)-, -NR L6 -, -S-, -S(O)-, and -S(O 2 )-, and optionally , the C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, and C 1-6 haloalkylene groups are independently substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy , alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and alkoxy; preferably, each occurrence of L is independently selected from a single bond, -O-, -S- , 1-6 haloalkylene groups are each independently substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy;
    RL6每次出现时各自独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；优选地，RL6每次出现时各自独立地选自氢、C1-6烷基、C3-10环烷基和C1-6卤代烷基，任选地，所述C1-6烷基、C3-10环烷基和C1-6卤代烷基被0、1、2、3、4、5或6个独立选自卤素、氘、烷基、氨基、羟基、氨基烷基、烷基氨基、和烷氧基的取代基取代；R L6 is independently selected at each occurrence from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl 5-10 heteroaryl is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy; preferably, each occurrence of RL is independently selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl and C1-6 haloalkyl, optionally, the C1-6 alkyl, C3-10 cycloalkyl and C1-6 haloalkyl are substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
    RL1和RL2每次出现时各自独立地选自氢、氘、羟基、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、-XL-ORL3、-XL-NRL4RL5、C1-6氘代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基和C5-10杂芳基，优选地RL1和RL2每次出现时分别独立地选自氢、氘、卤素、C1-6烷基、C1-6卤代烷基、-XL-ORL3、-XL-NRL4RL5和C3-10环烷基；或者RL1和RL2与其共同连接的碳原子形成成一个3-10元亚环烷基或含有1、2或3个分别独立地选自N、O、P和S的杂原子的3-10元亚杂环烷基，其中所述亚环烷基或亚杂环烷基任选地被0、1、2、3或4个独立地选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氨基烷基和羟基的取代基取代；优选地，RL1和RL2和其连接的碳组成3-10元亚环烷基；R L1 and R L2 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, -XL - OR L3 , -XL - NR L4LR L5 , C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, preferably R L1 and R L2 are each independently selected from hydrogen , deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -XL - OR L3 , -XL- NR L4LR L5 and C 3-10 cycloalkyl; or R L1 and R L2 and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1, 2 or 3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy; preferably, RL1 and RL2 and the carbon to which they are attached form a 3-10 membered cycloalkylene;
    XL每次出现时各自独立选自C1-6亚烷基和C2-C6亚烯基； XL at each occurrence is independently selected from C1-6 alkylene and C2 - C6 alkenylene;
    RL3选自氢、氘、C1-6烷基和C1-6卤代烷基； RL3 is selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl;
    RL4和RL5分别独立地选自氢、氘、C1-6烷基和C1-6卤代烷基； RL4 and RL5 are independently selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl;
    Lb、和Ld每次出现时各自独立地选自单键、亚环烷基、亚环烯基、亚杂环烷基、亚芳基、亚杂芳基、和亚稠杂环烷基，所述亚环烷基、亚环烯基、亚杂环烷基、亚芳基、亚杂芳基和亚稠杂环烷基可任选地被0、1、2、3、4、5或6个R9取代；优选地，Lb、Ld每次出现各自独立地选自单键、亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1-4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、3-7元亚杂环烯基、5-6元亚杂芳基和4-12元亚稠杂环烷基，所述亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1-4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、5-6元亚杂芳基和4-12元亚稠杂环烷基任选地被0-6个R9取代；优选且La、Lb、Lc、Ld、和Le不同时为单键；L b , and L d are each independently selected from a single bond, a cycloalkylene group, a cycloalkenylene group, a heterocycloalkylene group, an arylene group, a heteroarylene group, and a fused heterocycloalkylene group, wherein the cycloalkylene group, the cycloalkenylene group, the heterocycloalkylene group, the arylene group, the heteroarylene group, and the fused heterocycloalkylene group may be optionally substituted with 0, 1, 2, 3, 4, 5 or 6 R 9 ; preferably, L b , L d d is independently selected from a single bond, phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene at each occurrence, wherein the phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene are optionally substituted with 0-6 R 9 ; preferably, L a , L b , L c , L d , and L e are not single bonds at the same time;
    R9每次出现时各自独立选自卤素、氘、烷基、卤代烷基、氰基、环烷基、杂环烷基、-S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a和-X4-OR9a；优选地，R9每次出现时分别独立地选自卤素、氘、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自 N、O和S的杂原子的C3-7杂环烷基、-S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a和-X4-OR9a；优选地，R9每次出现时分别独立地选自F、Cl、Br、I、C1-3烷基、和C1-3卤代烷基；R 9 is independently selected from halogen, deuterium, alkyl, haloalkyl, cyano, cycloalkyl, heterocycloalkyl, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; preferably, R 9 is independently selected from halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, 1-3 independently selected N, O and S heteroatom C 3-7 heterocycloalkyl, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; preferably, R 9 at each occurrence is independently selected from F, Cl, Br, I, C 1-3 alkyl, and C 1-3 haloalkyl;
    R9a、R9b和R9c每次出现时各自独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基和C5-10杂芳基；优选地，R9a、R9b和R9c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；R 9a , R 9b and R 9c are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl; preferably, R 9a , R 9b and R 9c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
    X4选自C1-6亚烷基和C2-6亚烯基；X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
    当Lb和Ld各自独立地为亚苯基、或含有1或2个选自N和S的杂原子的5元亚杂芳基时，La和Le其中至少一个不为单键、或当La和Le同时为单键时，Lc选自-S-、C2-6亚烷基、C2-6亚烷氧基、C2-6亚烯基、C2-6亚炔基、C1-6卤代亚烷基、-N(RL6)S(O)-、-N(RL6)S(O2)-、-OC(O)-、-S(O)-、-S(O2)-、-S(O2)NRL6-、-和C1-6亚烷基羟基，任选地，所述C2-6亚烷基、C2-6亚烷氧基、C2-6亚烯基、C2-6亚炔基、和C1-6卤代亚烷基各自独立地被0、1、2、3、4、5或6个独立地选自卤素、氘、烷基、氘代烷基、氨基、羟基、烷基氨基、氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和烷氧基的取代基取代；When L b and L d are each independently a phenylene group, or a 5-membered heteroarylene group containing 1 or 2 heteroatoms selected from N and S, at least one of La and Le is not a single bond, or when La and Le are both single bonds, L c is selected from -S-, C 2-6 alkylene, C 2-6 alkyleneoxy, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 haloalkylene, -N(R L6 )S(O)-, -N(R L6 )S(O 2 )-, -OC(O)-, -S(O)-, -S(O 2 )-, -S(O 2 )NR L6 -, - and C 1-6 alkylenehydroxyl, optionally, the C 2-6 alkylene, C 2-6 alkyleneoxy, C 2-6 alkenylene, C 2-6 alkynylene, and C 1-6 haloalkylene 1-6 haloalkylene groups are each independently substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, alkyl, deuterated alkyl, amino, hydroxy, alkylamino, aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and alkoxy;
    当Linker C为脂肪链时，Linker C为任选被取代的-C8H16-，优选为任选被取代的-(CH2)8-、优选为-(CH2)8-；When Linker C is an aliphatic chain, Linker C is optionally substituted -C 8 H 16 -, preferably optionally substituted -(CH 2 ) 8 -, preferably -(CH 2 ) 8 -;
    当Lb、Ld其中一个为亚苯基或含有3个N原子的6元亚杂芳基，另一个为单键时，La、和Le不同时为单键；和When one of L b and L d is a phenylene group or a 6-membered heteroarylene group containing 3 N atoms, and the other is a single bond, L a and L e are not simultaneously single bonds; and
    当A1和B1均为式(Ⅴ)，且La、和Le不为单键时，则La、和Le至少一个不为-O-。When A1 and B1 are both of formula (V), and La , and Le are not single bonds, then at least one of La , and Le is not -O-.
  2. 如权利要求1所述的化合物，其中Linker C选自式(Ⅸ)、(Ⅹ)、(Ⅺ)和(Ⅻ)：
    The compound according to claim 1, wherein Linker C is selected from the group consisting of formula (IX), (X), (XI) and (XII):
    R7a和R7b分别独立地选自氢、氘、卤素、C1-6烷基、C1-6卤代烷基、-X3-OR7c、-X3-NR7dR7e和C3-10环烷基；X3每次出现时各自独立选自C1-6亚烷基和C2-C6亚烯基；R7c选自氢、氘、C1-6烷基和C1-6卤代烷基；R7d和R7e分别独立地选自氢、氘、C1-6烷基和C1-6卤代烷基；或者R7a和R7b及其连接的碳组成3-10元环烷基；R 7a and R 7b are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl; X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence; R 7c is selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are connected form a 3-10 membered cycloalkyl;
    R7a和R7b每次出现时各自独立地选自氢、氘、羟基、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、-XL-ORL3、-XL-NRL4RL5、C1-6氘代烷基、C3-12环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12杂环烷基、C6-10芳基和C5-10杂芳基，优选地RL1和RL2每次出现时分别独立地选自氢、氘、卤素、C1-6烷基、C1-6卤代烷基、-XL-ORL3、-XL-NRL4RL5和C3-10环烷基；或者R7a和R7b与其共同连接的碳原子形成成一个3-10元亚环烷基或含有1、2或3个分别独立地选自N、O、P和S的杂原子的3-10元亚杂环烷 基，其中所述亚环烷基或亚杂环烷基任选地被0、1、2、3或4个独立地选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氨基烷基和羟基的取代基取代；优选地，R7a和R7b和其连接的碳组成3-10元亚环烷基；R 7a and R 7b are each independently selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, -XL - OR L3 , -XL - NR L4LR L5 , C 1-6 deuterated alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 5-10 heteroaryl, preferably R L1 and R L2 are each independently selected from hydrogen , deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -XL - OR L3 , -XL- NR L4LR L5 and C 3-10 cycloalkyl; or R 7a and R 7b and the carbon atom to which it is commonly connected form a 3-10 membered cycloalkylene group or a 3-10 membered heterocycloalkylene group containing 1, 2 or 3 heteroatoms independently selected from N, O, P and S. wherein the cycloalkylene or heterocycloalkylene is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy; preferably, R 7a and R 7b and the carbon to which they are attached form a 3-10 membered cycloalkylene;
    XL每次出现时各自独立选自C1-6亚烷基和C2-C6亚烯基； XL at each occurrence is independently selected from C1-6 alkylene and C2 - C6 alkenylene;
    RL3选自氢、氘、C1-6烷基和C1-6卤代烷基； RL3 is selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl;
    RL4和RL5分别独立地选自氢、氘、C1-6烷基和C1-6卤代烷基； RL4 and RL5 are independently selected from hydrogen, deuterium, C1-6 alkyl and C1-6 haloalkyl;
    W选自以下基团：
    W is selected from the following groups:
    Q环和R环每次出现时各自独立地选自亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1、2、3或4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、3-7元亚杂环烯基、5-6元亚杂芳基和4-12元亚稠杂环烷基，所述亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1-4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、5-6元亚杂芳基和4-12元亚稠杂环烷基任选地被0-6个R9取代；Q ring and R ring are each independently selected at each occurrence from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene, said phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocycloalkylene optionally substituted with 0-6 R 9 ;
    R9每次出现时各自独立选自卤素、氘、烷基、卤代烷基、氰基、环烷基、杂环烷基、-S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a和-X4-OR9a；优选地，R9每次出现时分别独立地选自卤素、氘、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-7杂环烷基、-S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a和-X4-OR9a；优选地，R9每次出现时分别独立地选自F、Cl、Br、I、C1-3烷基、和C1-3卤代烷基；；R 9 is independently selected from halogen, deuterium, alkyl, haloalkyl, cyano, cycloalkyl, heterocycloalkyl, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; preferably, R 9 is independently selected from halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, C 3-7 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; preferably, R 9 is independently selected from F, Cl, Br, I, C 1-6 C 1-3 alkyl, and C 1-3 haloalkyl;
    R9a、R9b和R9c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；R 9a , R 9b and R 9c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
    X4选自C1-6亚烷基和C2-6亚烯基；X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
    T环和U环每次出现时分别独立地选自亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基，其中所述亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基任选地被0、1、2或3个独立地选自氰基、卤素、氨基、烷基氨基、氨基烷基、羟基、羟烷基、氨基酰基、氨磺酰基、C1-6烷基、C3-6杂环烷基、和C3-6环烷基的取代基取代，优选地，任选被选自F、Cl、Br、I、C1-3烷基、和C1-3卤代烷基地取代基取代；T ring and U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene at each occurrence, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 0, 1, 2 or 3 substituents independently selected from cyano, halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, C 3-6 heterocycloalkyl, and C 3-6 cycloalkyl, preferably, optionally substituted with substituents selected from F, Cl, Br, I, C 1-3 alkyl, and C 1-3 haloalkyl;
    L1选自以下基团：
     L1 is selected from the following groups:
    L2选自以下基团： L2 is selected from the following groups:
    其中Y1、Y2、Y3、Y4、Y5、Y6、和Y7每次出现时分别独立地选自-O-、-NH-、-NHC(O)-、-NHS(O)-、-NHS(O2)-、-CH2-、-C(O)-、-S(O)-、-S(O2)-、-C(O)NH-、-S(O2)NH-、-CH＝CH-、-C≡C-和单键；wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are each independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 —, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH═CH—, —C≡C—, and a single bond;
    a选自0、1、2、3、4和5；b和c分别独立选自0、1、2和3；d和e分别独立选自 0、1和2；a is selected from 0, 1, 2, 3, 4 and 5; b and c are independently selected from 0, 1, 2 and 3; d and e are independently selected from 0, 1, and 2;
    L3选自以下基团： L3 is selected from the following groups:
    Y8、Y9、Y10、Y11和Y12分别独立地选自-O-、-NH-、-NHC(O)-、-NHS(O)-、-NHS(O2)-、-CRY1RY2-、-C(O)-、-S(O)-、-S(O2)-、-C(O)NH-、-S(O2)NH-、-CH＝CH-、-C≡C-、单键、亚苯基、含有1-4个独立地选自N、O、P和S杂原子的3-6元亚杂环烷基和含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂芳基；Y 8 , Y 9 , Y 10 , Y 11 and Y 12 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CR Y1 RY2 -, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH═CH—, —C≡C-, a single bond, phenylene, a 3-6 membered heterocycloalkylene group containing 1-4 heteroatoms independently selected from N, O, P and S, and a 5-6 membered heteroarylene group containing 1-4 heteroatoms independently selected from N, O, P and S;
    RY1和RY2每次出现时分别独立地选自氢和C1-6烷基，或RY1和RY2与其连接的C形成3-6元亚环烷基或3-6元亚杂环烷基；和R Y1 and R Y2 are each independently selected from hydrogen and C 1-6 alkyl, or R Y1 and R Y2 form a 3-6 membered cycloalkylene or 3-6 membered heterocycloalkylene to which they are attached; and
    f、g、h、i和j分别独立选自0、1、2和3。3.如权利要求1或2所述的化合物，其中：f, g, h, i and j are independently selected from 0, 1, 2 and 3. 3. The compound of claim 1 or 2, wherein:
    R1每次出现时不存在或各自独立地选自氢、氘、F、Cl、Br、I、氰基、羟基、酰胺基、磺酰胺基、C1-3烷基、-S-C1-3烷基、-S(O)-C1-3烷基、-S(O2)-C1-3烷基、-O-C1-3烷基、-O-C1-3卤代烷基、C1-3氘代烷基、3-6元环烷基、3-6元杂环烷基和-NR1aR1b，其中R1a和R1b分别独立地选自氢、氘、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、C1-3氘代烷基、C3-6单环环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-6单环杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-3烷基、C1-3烷氧基、C1-3卤代烷基、C3-6单环环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-6单环杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个独立选自F、Cl、Br、I、氘、C1-3烷基、C1-3氘代烷基、氨基、羟基、C1-3烷基氨基、C1-3氨基烷基、氰基、3-6元环烷基、3-6元杂环烷基和C1-3烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个含有1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基，其中所述杂环烷基任选地被0、1、2、3或4个独立选自F、Cl、Br、I、氘、氨基、C1-3烷氧基、C1-3烷基氨基、C1-3氘代烷基、C1-3烷基、氰基、氨基烷基、3-6元环烷基、3-6元杂环烷基和羟基的取代基取代；和/或 R1 is absent at each occurrence or is independently selected from hydrogen, deuterium, F, Cl, Br, I, cyano, hydroxyl, amide, sulfonamide, C1-3 alkyl, -SC1-3 alkyl, -S(O) -C1-3 alkyl, -S( O2 ) -C1-3 alkyl, -OC1-3 alkyl, -OC1-3 haloalkyl, C1-3 deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and -NR1aR1b , wherein R1a and R1b are independently selected from hydrogen, deuterium, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 deuterated alkyl, C3-6 monocyclic cycloalkyl, C3-6 monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C6-10 aryl and C wherein said C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C3-6 monocyclic cycloalkyl, C3-6 monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C6-10 aryl, and C5-10 heteroaryl are optionally substituted with 0, 1 , 2, 3, 4, 5 or 6 substituents independently selected from F, Cl, Br, I, deuterium, C1-3 alkyl, C1-3 deuterated alkyl, amino, hydroxy, C1-3 alkylamino, C1-3 aminoalkyl, cyano, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and C1-3 alkoxy; or R1a and R 1b and the nitrogen atom to which it is commonly attached form a 3-6 membered heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl group is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, I, deuterium, amino, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 deuterated alkyl, C 1-3 alkyl, cyano, aminoalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and hydroxy; and/or
    Z每次出现时各自独立地选自C和N；且当Z为N时，R1不存在；和/或Z is independently selected from C and N at each occurrence; and when Z is N, R 1 is absent; and/or
    R2、R4和R6每次出现时分别独立地选自氢、氘、卤素、C1-3烷基、C2-3烷氧基、C1-3卤代烷基、3-6元单环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子3-6元单杂环烷基、3-6元环烷基-O-、3-6元杂环烷基-O-、和含有1-3个分别独立地选自N、O、P和S杂原子的3-12元单环杂芳基；优选地，R2、R4和R6每次出现时分别独立地选自氢、氘、氯、氟、Br、C1-3烷基、3-6元单环的环烷基、和含有1-3个分别独立地选自N、O、P和S的杂原子3-6元单杂环烷基；和/或R 2 , R 4 and R 6 are each independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 2-3 alkoxy, C 1-3 haloalkyl, 3-6 membered monocyclic cycloalkyl, 3-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, and 3-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R 2 , R 4 and R 6 are each independently selected from hydrogen, deuterium, chlorine, fluorine, Br, C 1-3 alkyl, 3-6 membered monocyclic cycloalkyl, and 3-6 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S; and/or
    R5选自氢、C1-4烷基、C3-6环烷基、C3-6杂环烷基和C1-4卤代烷基；任选地，所述C1-4烷基、C3-6环烷基和C1-4卤代烷基被0-6个独立选自卤素、氘、C1-4烷基、氨基、羟基、和C1-4烷氧基的取代基取代；优选地，R5选自氢、C1-3烷基和C3-6环烷基，任选地，所述C1-3烷基、和C3-6环烷基被0-6个独立选自卤素、氘、C1-6烷基、氨基和羟基的取代基取代；更优选地，R5选自H和C1-3烷基；和/或R 5 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl and C 1-4 haloalkyl; optionally, the C 1-4 alkyl, C 3-6 cycloalkyl and C 1-4 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, C 1-4 alkyl, amino, hydroxyl and C 1-4 alkoxy; preferably, R 5 is selected from hydrogen, C 1-3 alkyl and C 3-6 cycloalkyl, optionally, the C 1-3 alkyl and C 3-6 cycloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, C 1-6 alkyl, amino and hydroxyl; more preferably, R 5 is selected from H and C 1-3 alkyl; and/or
    G1和G2每次出现选自O、S、和NR2a；和/或 G1 and G2 are each selected from O, S, and NR2a ; and/or
    R2a每次出现时各自独立地选自选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、苯基亚甲基、-CH2OCH2CH2Si(CH3)3、C1-3烷基、C1-3卤代烷基、C1-3烷基-S-、-S(O)-C1-3 烷基、-SO2-C1-3烷基、-O-C1-3烷基、-O-C1-3卤代烷基、-NR2bR2c、-C1-3亚烷基-C3-6环烷基、C3-6环烷基-NR2b-、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基-NR2b-、3-6元单环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元单环杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基、3-6元卤代环烷基-O-、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-、6-10元单环芳基、含有1-3个分别独立地选自N、O、P和S的杂原子的5-6元单环杂芳基、和含有1-3个分别独立地选自N、O、P和S的杂原子的8-10元并环杂芳基；优选地，R2a选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、氨基、C1-3烷基、C1-3卤代烷基、C1-3烷基-S-、-S(O)-C1-3烷基、-SO2-C1-3烷基、-O-C1-3烷基、-O-C1-3卤代烷基、-NHC1-3烷基、-N(C1-3烷基)C1-3烷基、C3-6环烷基和-C1-3亚烷基-C3-6环烷基；优选地，R2a选自氢、F、Cl、Br、I、氰基、羟基、氨基、C1-3烷基、C1-3卤代烷基、-C1-3亚烷基-C3-6环烷基、和C3-6环烷基；R2b和R2c分别独立地选自氢和C1-6烷基；和/或R 2a is independently selected at each occurrence from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, phenylmethylene, -CH 2 OCH 2 CH 2 Si(CH 3 ) 3 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-S-, -S(O)-C 1-3 alkyl, -SO2 - C1-3alkyl , -OC1-3alkyl , -OC1-3haloalkyl, -NR2bR2c, -C1-3alkylene-C3-6cycloalkyl, C3-6cycloalkyl-NR2b-, 3-6 membered heterocycloalkyl - NR2b containing 1-3 heteroatoms independently selected from N, O, P and S -, 3-6 membered monocyclic alkyl, 3-6 membered monocyclic heterocyclic alkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated heterocyclic alkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocyclic alkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocyclic alkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 6-10 membered monocyclic aryl, 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, and 8-10 membered cyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; preferably, R R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-S-, -S(O)-C 1-3 alkyl, -SO 2 -C 1-3 alkyl, -OC 1-3 alkyl, -OC 1-3 haloalkyl, -NHC 1-3 alkyl, -N(C 1-3 alkyl)C 1-3 alkyl, C 3-6 cycloalkyl and -C 1-3 alkylene-C 3-6 cycloalkyl; preferably, R 2a is selected from hydrogen, F, Cl, Br, I, cyano, hydroxyl, amino, C 1-3 alkyl, C 1-3 haloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, and C 3-6 cycloalkyl; R 2b and R 2c are each independently selected from hydrogen and C 1-6 alkyl; and/or
    J1和J2分别独立地选自单键、-O-、-S-、-C(O)-、-S(O)-、-S(O2)-、-C(R1cR1d)-、-C(＝CR1eR1f)-和-N(R3)-；优选地，J1和J2不同时为单键；其中R1c、R1d、R1e和R1f分别独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6氘代烷基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0、1、2、3、4、5或6个个独立地选自卤素、氘、C1-6烷基、氨基、羟基、C1-6烷基氨基、C1-6氨基烷基、氰基、3-10元环烷基、3-10元杂环烷基和C1-6烷氧基的取代基取代；或R1c和R1d和其共同连接的碳原子组成一个3-10元亚环烷基或含有1-3个分别独立地选自N、O、P和S的杂原子的3-10元亚杂环烷基，其中所述亚环烷基或亚杂环烷基任选地被0、1、2、3或4个独立地选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氨基烷基和羟基的取代基取代；或R1e和R1f和其共同连接的碳原子组成一个3-10元亚环烷基或含有0、1、2、3或4个分别独立地选自N、O、P和S的杂原子的3-10元亚杂环烷基，其中所述亚环烷基或亚杂环烷基任选地被0、1、2、3或4个独立选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氘代烷基、C1-6烷基、氰基、C1-6氨烷基、3-10元环烷基、3-10元杂环烷基和羟基的取代基取代；和/或 J1 and J2 are independently selected from a single bond, -O-, -S-, -C(O)-, -S(O)-, -S( O2 )-, -C( R1cR1d )-, -C(＝ CR1eR1f )- and -N( R3 )-; preferably, J1 and J2 are not single bonds at the same time; wherein R1c , R1d , R1e and R1f are independently selected from hydrogen, deuterium, C1-6 alkyl, C1-6 alkoxy, C1-6 deuterated alkyl, C3-12 monocyclic, spirocyclic or bridged cycloalkyl, C3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C6-10 aryl and C5-10 heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 deuterated alkyl , C3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C6-10 aryl and C5-10 heteroaryl R 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl, and C 5-10 heteroaryl are optionally substituted with 0, 1, 2, 3, 4, 5 or 6 substituents independently selected from halogen, deuterium, C 1-6 alkyl, amino, hydroxy, C 1-6 alkylamino, C 1-6 aminoalkyl, cyano, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and C 1-6 alkoxy; or R 1c and R R 1e and the carbon atom to which they are attached together form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy; or R 1e and R 1f and the carbon atom to which they are attached together form a 3-10 membered cycloalkylene or a 3-10 membered heterocycloalkylene containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O, P and S, wherein the cycloalkylene or heterocycloalkylene is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 deuterated alkyl, C 1-6 substituted with a substituent selected from the group consisting of C 1-6 alkyl, cyano, C 1-6 aminoalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and hydroxy; and/or
    R3为-X1-R8，X1选自单键、-O-、-S-、C1-3亚烷氧基、C2-3亚烯基和C1-3亚烷基；R8选自氢、氘、卤素、C1-3烷基、C1-3卤代烷基、C6-10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b、C3-6环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-6杂环烷基、和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳基。R 3 is -X 1 -R 8 , X 1 is selected from a single bond, -O-, -S-, C 1-3 alkyleneoxy, C 2-3 alkenylene and C 1-3 alkylene; R 8 is selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b , C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, and 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S.
  3. 如权利要求1-2任一项所述的化合物，所述Q环、R环、Lb和Ld每次出现时各自独立地选自以下基团：
    The compound according to any one of claims 1 to 2, wherein the Q ring, R ring, L b and L d are each independently selected from the following groups:
  4. 如权利要求1-3任一项所述的化合物，所述化合物选自如下结构：
    The compound according to any one of claims 1 to 3, wherein the compound is selected from the following structures:
    优选地：所述化合物选自如下结构：
    Preferably: the compound is selected from the following structures:
    其中，A、B、Linker C、式(Ⅱ)～(Ⅻ)定义同权利要求1-3任一项所述。Wherein, A, B, Linker C, and formulas (II) to (XII) are defined as described in any one of claims 1-3.
  5. 如权利要求1-4任一项所述的化合物，其中Linker C选自以下结构：


    The compound according to any one of claims 1 to 4, wherein Linker C is selected from the following structures:


  6. 化合物，所述化合物为式(Ⅰ)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
    A compound, wherein the compound is a compound represented by formula (I), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:
    其中A环和B环各自独立选自式(Ⅱ)、(Ⅲ)和(Ⅳ)：
    Wherein ring A and ring B are independently selected from formula (II), (III) and (IV):
    其中Linker C为连接A环和B环的连接子，选自式(Ⅴ)、(Ⅵ)和(Ⅶ)：
    Wherein Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI) and (VII):
    其中，R1a、R1b、R1c和R1d分别独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0-6个独立选自卤素、氘、烷基、氨基、羟基、烷基氨基、氨烷基、和烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个3-10元杂环烷基，其中所述杂环烷基任选地被0-3个独立选自卤素、氘、氨基、烷氧基、烷基氨基、氨烷基和羟基的取代基取代；或R1c和R1d和其共同连接 的氮原子组成一个3-10元杂环烷基，其中所述杂环烷基任选地被0-3个独立选自卤素、氘、氨基、烷氧基、氨烷基和羟基的取代基取代；wherein R 1a , R 1b , R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl and alkoxy; or R 1a and R R 1c and R 1d and the nitrogen atom to which they are connected together form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, alkylamino, aminoalkyl and hydroxy; or R 1c and R 1d and the nitrogen atom to which they are connected together form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, alkylamino, aminoalkyl and hydroxy; The nitrogen atom of the cycloalkyl group forms a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, aminoalkyl and hydroxy;
    R2、R4和R6分别独立地选自氢、氘、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6单烷基氨基、C2-6双烷基氨基、C1-6卤代烷基氨基、3-12元单环的环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单杂环烷基、5-12元螺杂环烷基和4-12元桥杂环烷基、C1-6烷基-S-、C1-6烷基-SO-、C1-6烷基-SO2-、3-6元环烷基-O-、3-6元杂环烷基-O-、5-10元单环芳基、5-10元并环芳基、和含有1-3个分别独立地选自N、O、P和S杂原子的3-12元单环杂芳基和7-10元并环杂芳基； R2 , R4 and R6 are independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 monoalkylamino, C2-6 dialkylamino, C1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1-6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cycloaryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S;
    R5选自氢、C1-6烷基、C3-10环烷基和C1-6卤代烷基，任选地，所述C1-6烷基、C3-10环烷基和C1-6卤代烷基被0-6个独立选自卤素、氘、烷基、氨基、羟基、氨基烷基、烷基氨基、和烷氧基的取代基取代；R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
    E、G、J和Z每次出现时分别独立地选自N和CR2a；其中R2a选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、C1-6烷基、C1-6卤代烷基、C1-6烷基-S-、C1-6烷基-SO-、C1-6烷基-SO2-、C1-6烷基-O-、C1-6卤代烷基-O-、-NR2bR2c、C3-6环烷基氨基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基氨基、3-12元单环烷基、5-12元螺环烷基和4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂环烷基、5-12元螺杂环烷基和4-12元桥杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基、3-6元卤代环烷基-O-、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-、5-12元单环芳基、5-12元并环芳基、和含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂芳基和7-10元并环杂芳基；R2b和R2c分别独立地选自氢和C1-6烷基；E, G, J and Z are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -, C 1-6 alkyl-O-, C 1-6 haloalkyl-O-, -NR 2b R 2c , C 3-6 -membered cycloalkylamino, 3-6-membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12-membered monocyclic alkyl, 5-12-membered spirocycloalkyl and 4-12-membered bridged cycloalkyl, 3-12-membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12-membered spirocycloheterocycloalkyl and 4-12-membered bridged heterocycloalkyl, 3-6-membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6-membered R 2b and R 2c are independently selected from hydrogen and C 1-6 alkyl ;
    R3为-X1-R8，X1选自化学键、C2-6亚烯基和C1-6亚烷基；R8选自氢、卤素、C1-6烷基、C1-6卤代烷基、C6-10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳环；R8a和R8b每次出现时分别独立地选自氢、氘、C1-6烷基、C1-6卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、-OR8d和-X2-R8d基团取代；R8c选自氢、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基和C1-6卤代烷基；X2选 自C1-6亚烷基和C2-6亚烯基；R8d选自氢、C1-6烷基和C1-6卤代烷基；R 3 is -X 1 -R 8 , X 1 is selected from a chemical bond, C 2-6 alkenylene and C 1-6 alkylene; R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, the phenyl being optionally substituted with 0-2 groups selected from C 1-4 alkyl, -OR 8d and -X 2 -R 8d ; R 8c is selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-10 aryl. 1-6 haloalkyl; X 2 selected is selected from C 1-6 alkylene and C 2-6 alkenylene; R 8d is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
    R7a和R7b分别独立地选自氢、卤素、C1-6烷基、C1-6卤代烷基、-X3-OR7c、-X3-NR7dR7e和C3-10环烷基；X3每次出现时各自独立选自C1-6亚烷基和C2-C6亚烯基；R7c选自氢、C1-6烷基和C1-6卤代烷基；R7d和R7e分别独立地选自氢、C1-6烷基和C1-6卤代烷基；或者R7a和R7b和其连接的碳组成3-10元环烷基；R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl; X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence; R 7c is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; R 7d and R 7e are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are connected form a 3-10 membered cycloalkyl;
    W环选自以下基团：
    The W ring is selected from the following groups:
    Q环选自含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂环烷基和5-6元亚杂芳基，所述亚杂环烷基和所述亚杂芳基任选地被0-2个R9取代，R9每次出现时分别独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-6杂环烷基、-S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a和-X4-OR9a；R9a、R9b和R9c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；X4选自C1-6亚烷基和C2-6亚烯基；The Q ring is selected from 5-6 membered heterocycloalkylene and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and said heteroarylene are optionally substituted by 0-2 R 9 , R 9 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; R 9a , R 9b and R 9c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
    R环为含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂环烷基或5-6元亚杂芳基，所述亚杂环烷基和亚杂芳基任选地被0-2个R10取代，R10每次出现时分别独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-6杂环烷基、-S(O2)R10a、-NR10bR10c、-X5-NR10bR10c、-OR10a和-X5-OR10a；R10a、R10b和R10c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；X5选自C1-6亚烷基和C2-6亚烯基；The R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , R 10 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c , -X 5 -NR 10b R 10c , -OR 10a and -X 5 -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 5 is selected from C 5 C 1-6 alkylene and C 2-6 alkenylene;
    T环和U环分别独立地选自亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基，其中所述亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基任选地被1-3个独立地选自卤素、氨基、烷基氨基、氨烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的取代基取代；The T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 1-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl and C 3-6 cycloalkyl;
    L1选自以下基团：
     L1 is selected from the following groups:
    L2选自以下基团： L2 is selected from the following groups:
    其中Y1、Y2、Y3、Y4、Y5、Y6、和Y7分别独立地选自-O-、-NH-、-NHC(O)-、-NHS(O)-、-NHS(O2)-、-CH2-、-C(O)-、-S(O)-、-S(O2)-、-C(O)NH-、-S(O2)NH-、-CH＝CH-、-C≡C-和单键，其中所述的氢原子任选地被0-2个独立地选自氘、卤素、氨基、烷基氨基、氨烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的取代基取代；wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 -, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH═CH—, —C≡C—, and a single bond, wherein the hydrogen atom is optionally substituted with 0-2 substituents independently selected from deuterium, halogen, amino, alkylamino, aminoalkyl, hydroxy, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, and C 3-6 cycloalkyl;
    a为0-5的整数；b和c分别为0-3的整数；d和e分别为0-2的整数；和a is an integer from 0 to 5; b and c are integers from 0 to 3; d and e are integers from 0 to 2; and
    L1和L2任选地被1-5个R11取代，R11分别独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自氧、硫和氮的杂原子的3-6元杂环烷基、-S(O2)R11a、NR11bR11c、-X6-NR11bR11c、-OR11a和-X6-OR11a；R11a、R11b和R11c每次出现时各自独立地选自氢、C1-6烷基和C1-6卤代烷基；X6选自C1-6亚烷基和C2-6亚烯基。L 1 and L 2 are optionally substituted by 1-5 R 11 , R 11 are independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O 2 )R 11a , NR 11b R 11c , -X 6 -NR 11b R 11c , -OR 11a and -X 6 -OR 11a ; R 11a , R 11b and R 11c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 6 is selected from C 1-6 alkylene and C 2-6 alkenylene.
  7. 如权利要求6所述的化合物，其中：The compound according to claim 6, wherein:
    R1a和R1b分别独立地选自氢、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、和C1-4烷基，其中C1-4烷基任选地被0-6个独立选自卤素、氘、氨基、羟基、氨烷基和烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个四元、五元或六元杂环烷基，其中所述杂环烷基任选地被0-3个独立地选自卤素、氨基和羟基的取代基取代；或R 1a and R 1b are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
    R2、R4和R6分别独立地选自卤素、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、C1-3单烷基氨基、C1-3双烷基氨基、C1-3卤代烷基氨基、含有3-12元单环的环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子3-12元单杂环烷基、5-12元螺杂环烷基和4-12元桥杂环烷基、C1-C6烷基-S-、C1-6烷基-SO-、C1-6烷基-SO2-、3-6元环烷基-O-、3-6元杂环烷基-O-、5-10元单环芳基、5-10元并环芳基、和含有1-3个分别独立地选自N、O、P和S杂原子的3-12元单环杂芳基和7-10元并环杂芳基；或 R2 , R4 and R6 are independently selected from halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 monoalkylamino, C1-3 dialkylamino, C1-3 haloalkylamino, cycloalkyl containing 3-12 membered monocyclic ring, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1 - C6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cycloheteroaryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; or
    R5选自氢、C1-3烷基和C1-3卤代烷基；或 R5 is selected from hydrogen, C1-3 alkyl and C1-3 haloalkyl; or
    E、G、J和Z分别独立地选自N和CR2a；其中R2a选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、C1-3烷基、C1-3卤代烷基、C1-3烷基-S-、C1-C3烷基-SO-、C1-3烷基-SO2-、 C1-3烷基-O-、C1-3卤代烷基-O-、-NR2bR2c、C3-6环烷基氨基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基氨基、3-6元卤代环烷基、含有1-3个独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-；R2b和R2c分别独立地选自氢和C1-C6烷基；或E, G, J and Z are independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-S-, C 1 -C 3 alkyl-SO-, C 1-3 alkyl-SO 2 -, C 1-3 alkyl-O-, C 1-3 haloalkyl-O-, -NR 2b R 2c , C 3-6 cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halocycloalkyl, 3-6 membered haloheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halocycloalkyl-O-, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C 1 -C 6 alkyl; or
    R3为-X1-R8，X1选自化学键、C2-C4亚烯基和C1-C4亚烷基；R8选自氢、卤素、C1-C3烷基、C1-C3卤代烷基、C6-C10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳环；R8a和R8b每次出现时分别独立地选自氢、氘、C1-C3烷基、C1-C3卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、-OR8d和-X2-R8d基团取代；R8c选自氢、C1-6烷基和C1-6卤代烷基；X2选自C1-6亚烷基和C2-6亚烯基；R8d选自氢、C1-4烷基和C1-4卤代烷基；或 R3 is -X1 - R8 , X1 is selected from a chemical bond, C2 - C4 alkenylene and C1 - C4 alkylene; R8 is selected from hydrogen, halogen, C1 - C3 alkyl, C1 - C3 haloalkyl, C6 - C10 aryl, -NR8aR8b , -C(O) R8c , -C(O) NR8aR8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R8a and R8b are independently selected from hydrogen, deuterium, C1 - C3 alkyl, C1 - C3 haloalkyl and phenyl at each occurrence , the phenyl being optionally substituted with 0-2 groups selected from C1-4 alkyl, -OR8d and -X2 - R8d ; R8c is selected from hydrogen, C1-6 alkyl and C X2 is selected from C1-6 alkylene and C2-6 alkenylene; R8d is selected from hydrogen, C1-4 alkyl and C1-4 haloalkyl; or
    R1c和R1d分别独立地选自氢、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、和C1-4烷基，其中C1-4烷基任选地被0-6个独立选自卤素、氘、氨基、羟基、氨烷基和烷氧基的取代基取代；或R1c和R1d和其共同连接的氮原子组成一个四元、五元或六元杂环烷基，其中所述杂环烷基任选地被0-3个独立地选自卤素、氨基和羟基的取代基取代；或R 1c and R 1d are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
    R7a和R7b分别独立地选自氢、卤素、C1-4烷基和C1-4卤代烷基；或R 7a and R 7b are each independently selected from hydrogen, halogen, C 1-4 alkyl and C 1-4 haloalkyl; or
    Q环任选地被1-2个R9取代，R9每次出现时分别独立地选自卤素、C1-C3烷基、C1-C3卤代烷基、氰基、C3-C6环烷基、含有1-3个杂原子的3-6元杂环烷基，所述杂原子分别独立地选自N、O和S、-S(O2)R9a、NR9bR9c和-OR9a；每个R9a、R9b和R9c每次出现时分别独立地选自氢、C1-3烷基和C1-3卤代烷基；或The Q ring is optionally substituted with 1-2 R 9 , each of which is independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms, each of which is independently selected from N, O and S, -S(O 2 )R 9a , NR 9b R 9c and -OR 9a ; each of R 9a , R 9b and R 9c is independently selected from hydrogen, C 1-3 alkyl and C 1-3 haloalkyl at each occurrence; or
    R环为含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂环烷基或5-6元亚杂芳基，所述亚杂环烷基和亚杂芳基任选地被0-2个R10取代，R10每次出现时分别独立地选自卤素、C1-C3烷基、C1-C3卤代烷基、氰基、C3-C6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-6杂环烷基、-S(O2)R10a、-NR10bR10c和-OR10a；R10a、R10b和R10c每次出现时分别独立地选自氢、C1-C3烷基和C1-C3卤代烷基；或The R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , R 10 is independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, C 3 -6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c and -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl at each occurrence; or
    T环和U环分别独立地选自亚苯基和亚吡啶基，其中所述的亚苯基、亚吡啶基任选地被1-3个独立地选自卤素、氨基、烷基氨基、氨烷基、羟基、羟烷基、氨酰基、氨磺 酰基、C1-6烷基和C3-6环烷基的取代基取代。The T ring and the U ring are independently selected from phenylene and pyridinyl, wherein the phenylene and pyridinyl are optionally substituted by 1-3 groups independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, aminosulfonyl, The substituents are substituted with acyl, C 1-6 alkyl and C 3-6 cycloalkyl.
  8. 如权利要求6-7任一所述的化合物，其中：The compound according to any one of claims 6 to 7, wherein:
    R2选自氢、氟、氯、环丙基、C1-3烷基和C1-3卤代烷基；或 R2 is selected from hydrogen, fluorine, chlorine, cyclopropyl, C1-3 alkyl and C1-3 haloalkyl; or
    R3为氢；或 R3 is hydrogen; or
    R4选自氢、氟、氯、溴和环丙基；或R 4 is selected from hydrogen, fluorine, chlorine, bromine and cyclopropyl; or
    R6选自氢、氟、氯和环丙基；或 R6 is selected from hydrogen, fluorine, chlorine and cyclopropyl; or
    R5选自氢和甲基；或 R5 is selected from hydrogen and methyl; or
    R1c和R1d分别独立地选自氢和C1-C3烷基；优选地，R1c和R1d分别独立地选自氢和甲基；或R 1c and R 1d are independently selected from hydrogen and C 1 -C 3 alkyl; preferably, R 1c and R 1d are independently selected from hydrogen and methyl; or
    所述Q环选自以下基团：
    The Q ring is selected from the following groups:
    其中，所述每个Q环基团左边的连接位点各自独立与式(V)中-CR7aR7b-相连，所述每个Q环基团右边的连接位点各自独立与式(V)中R环相连；或wherein the connection site on the left side of each Q ring group is independently connected to -CR 7a R 7b - in formula (V), and the connection site on the right side of each Q ring group is independently connected to the R ring in formula (V); or
    R环选自以下基团：

    The R ring is selected from the following groups:

    其中，所述每个R环基团的右边的连接位点各自独立与式(Ⅴ)中Q环相连，所述每个R环基团的左边的连接位点各自独立与式Ⅰ中A环或B环相连。The right connecting site of each R ring group is independently connected to the Q ring in formula (V), and the left connecting site of each R ring group is independently connected to the A ring or the B ring in formula I.
  9. 如权利要求6-8任一项所述的化合物，所述化合物选自式(Ⅰ-A)、(Ⅰ-B)、(Ⅰ-C)、(Ⅰ-D)、(Ⅰ-E)、(Ⅰ-F)和(Ⅰ-G)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
    The compound according to any one of claims 6 to 8, wherein the compound is selected from the compounds represented by formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) and (I-G), or their isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates:
    其中，Q环、R环、T环、U环、W环、R1a、R1b、R1c、R1d、R7a、R7b、R2、R3、R4、R5和R6定义同权利要求1或2或3。Wherein, the Q ring, R ring, T ring, U ring, W ring, R 1a , R 1b , R 1c , R 1d , R 7a , R 7b , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in claim 1 , 2 or 3.
  10. 如权利要求6-9任一项所述的化合物，其中，A环、B环各自独立地选自式(Ⅱ-1)、(Ⅳ-1)和(Ⅲ-1)：
    The compound according to any one of claims 6 to 9, wherein the A ring and the B ring are each independently selected from the formula (II-1), (IV-1) and (III-1):
    其中，R1a、R1b、R1c、R1d、R2、R3、R4、R5和R6的定义同权利要求1或2或3。wherein R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 4 , R 5 and R 6 have the same definitions as in claim 1 , 2 or 3.
  11. 如权利要求6-10任一项所述的化合物，其中所述化合物选自式(Ⅰ-A-1)、(Ⅰ-A-2)、(Ⅰ-A-3)、(Ⅰ-A-4)、(Ⅰ-F-1)、(Ⅰ-F-2)、(Ⅰ-F-3)、(Ⅰ-F-4)、(Ⅰ-F-5)、(Ⅰ-F-6)、(Ⅰ-F-7)和(Ⅰ-F-8)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
    A compound according to any one of claims 6 to 10, wherein the compound is selected from the group consisting of compounds represented by formula (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-F-3), (I-F-4), (I-F-5), (I-F-6), (I-F-7) and (I-F-8), or isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates thereof:
    其中Qa环的定义与权利要求1或2或3中Q环的定义一致；Ra环的定义与权利要求1或2或3中R环的定义一致；R1a、R1b、R1c、R1d、R7a、R7b、E、G、J、Z、L2、R2和R6的定义同权利要求1或2或3。The definition of Qa ring is consistent with the definition of Q ring in claim 1, 2 or 3; the definition of Ra ring is consistent with the definition of R ring in claim 1, 2 or 3; R1a , R1b , R1c , R1d , R7a , R7b , E, G, J, Z, L2 , R2 and R6 are defined the same as in claim 1, 2 or 3.
  12. 化合物，所述化合物为式(Ⅰ)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
    A compound, wherein the compound is a compound represented by formula (I), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:
    其中A环和B环相同或不同，A环和B环各自独立选自式(Ⅱ)、(Ⅲ)和(Ⅳ)：
    Wherein ring A and ring B are the same or different, and ring A and ring B are independently selected from formula (II), (III) and (IV):
    其中Linker C为连接A环和B环的连接子，选自式(Ⅴ)、(Ⅵ)、(Ⅵ-2)和(Ⅶ)：
    Wherein Linker C is a linker connecting Ring A and Ring B, selected from Formula (V), (VI), (VI-2) and (VII):
    其中，R1a、R1b、R1c和R1d分别独立地选自氢、氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、羟烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0-6个独立选自卤素、氘、烷基、氨基、羟基、烷基氨基、氨烷基、和烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个3-10元杂环烷基，其中所述杂环烷基任选地被0-3个独立选自卤素、氘、氨基、烷氧基、烷基氨基、氨烷基和羟基的取代基取代；或R1c和R1d和其共同连接的氮原子组成一个3-10元杂环烷基，其中所述杂环烷基任选地被0-3个独立选自卤素、氘、氨基、烷氧基、氨烷基和羟基的取代基取代；wherein R 1a , R 1b , R 1c and R 1d are independently selected from hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyalkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, alkylamino, aminoalkyl and alkoxy; or R 1a and R R 1c and R 1d and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, alkylamino, aminoalkyl and hydroxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, deuterium, amino, alkoxy, aminoalkyl and hydroxy;
    R2、R4和R6分别独立地选自氢、氘、卤素、C1-6烷基、C1-6烯基、C1-6炔基、C1-6烷氧基、C1-6卤代烷基、-NHC1-6烷基、-N(C1-6烷基)C1-6烷基、C1-6卤代烷氧基、C1-6卤代烷基氨基、3-12元单环的环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单杂环烷基、5-12元螺杂环烷基和4-12 元桥杂环烷基、C1-6烷基-S-、C1-6烷基-SO-、C1-6烷基-SO2-、3-6元环烷基-O-、3-6元杂环烷基-O-、5-10元单环芳基、5-10元并环芳基、和含有1-3个分别独立地选自N、O、P和S杂原子的3-12元单环杂芳基和7-10元并环杂芳基；R 2 , R 4 and R 6 are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 haloalkylamino , 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged cycloalkyl. 3-6 membered heterocycloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered paracyclic aryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered paracyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S;
    R5选自氢、C1-6烷基、C3-10环烷基和C1-6卤代烷基，任选地，所述C1-6烷基、C3-10环烷基和C1-6卤代烷基被0-6个独立选自卤素、氘、烷基、氨基、羟基、氨基烷基、烷基氨基、和烷氧基的取代基取代；R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
    E、G、J和Z每次出现时分别独立地选自N和CR2a；其中R2a选自氢、氘、卤素、氰基、羟基、--NHCO-C1-6烷基、-COHN2、-C1-6烷基-COHN2、磺酰胺基、-NHCONH2、-NH-CS-NH2、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷基-S-、C1-6烷基-SO-、C1-6烷基-SO2-、C1-6烷基-O-、C1-6卤代烷基-O-、-NR2bR2c、C1-6烷基氨基、C2-6二烷基氨基、-CONH2、-NHC1-6烷基、-N(C1-6烷基)C1-6烷基、C3-6环烷基氨基、C3-6环烷基烷氧基、羟烷基、羟烷氧基、羟烷基氨基、烷氧基烷基、烷氧基烷氧基、烷氧基烷基氨基、氨基烷基、氨基烷氧基、氨基烷基氨基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基氨基、3-12元单环烷基、5-12元螺环烷基和4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂环烷基、5-12元螺杂环烷基和4-12元桥杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基、3-6元卤代环烷基-O-、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-、5-12元单环芳基、5-12元并环芳基、和含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂芳基和7-10元并环杂芳基；R2b和R2c分别独立地选自氢和C1-6烷基；E, G, J and Z are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, --NHCO-C 1-6 alkyl, -COHN 2 , -C 1-6 alkyl-COHN 2 , sulfonamido, -NHCONH 2 , -NH-CS-NH 2 , amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-S-, C 1-6 alkyl-SO-, C 1-6 alkyl-SO 2 -, C 1-6 alkyl-O-, C 1-6 haloalkyl-O-, -NR 2b R 2c , C 1-6 alkylamino, C 2-6 dialkylamino, -CONH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, C 3-6 cycloalkylamino, C 1-6 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12 membered monocyclic alkyl, 5-12 membered spirocycloalkyl and 4-12 membered bridged cycloalkyl, 3-12 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spirocycloalkyl and 4-12 membered bridged heterocycloalkyl, 1-3 heteroatoms independently selected from N, O, P and S ... 3-6 membered halogenated heterocycloalkyl containing heteroatoms selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered halogenated heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered monocyclic aryl, 5-12 membered paracyclic aryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered paracyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C 1-6 alkyl;
    R3为-X1-R8，X1选自化学键、-O-、-S-、烷氧基、C2-6亚烯基和C1-6亚烷基；R8选自氢、卤素、C1-6烷基、C1-6卤代烷基、C6-10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳环；R8a和R8b每次出现时分别独立地选自氢、氘、C1-6烷基、C1-6卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、卤素、羟基、氰基、氨基、-OR8d和-X2-R8d基团取代；R8c选自氢、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基和C1-6卤代烷基；X2选自C1-6亚烷基和C2-6亚烯基；R8d选自氢、C1-6烷基和C1-6卤代烷基； R 3 is -X 1 -R 8 , X 1 is selected from a chemical bond, -O-, -S-, alkoxy, C 2-6 alkenylene and C 1-6 alkylene; R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, and the phenyl is optionally substituted with 0-2 groups selected from C 1-4 alkyl, halogen, hydroxy, cyano, amino, -OR 8d and -X 2 -R 8d ; R 8c is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 haloalkyl; X 2 is selected from C 1-6 alkylene and C 2-6 alkenylene; R 8d is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
    R7a和R7b分别独立地选自氢、卤素、C1-6烷基、C1-6卤代烷基、-X3-OR7c、-X3-NR7dR7e和C3-10环烷基；X3每次出现时各自独立选自C1-6亚烷基和C2-C6亚烯基；R7c选自氢、氘、C1-6烷基和C1-6卤代烷基；R7d和R7e分别独立地选自氢、氘、C1-6烷基和C1-6卤代烷基；或者R7a和R7b和其连接的碳组成3-10元环烷基；R 7a and R 7b are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl; X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence; R 7c is selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are attached form a 3-10 membered cycloalkyl;
    W选自以下基团：
    W is selected from the following groups:
    Q环选自含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂环烷基和5-6元亚杂芳基，所述亚杂环烷基和所述亚杂芳基任选地被0-2个R9取代，R9每次出现时分别独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-6杂环烷基、-S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a和-X4-OR9a；R9a、R9b和R9c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；X4选自C1-6亚烷基和C2-6亚烯基；The Q ring is selected from 5-6 membered heterocycloalkylene and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, said heterocycloalkylene and said heteroarylene are optionally substituted by 0-2 R 9 , R 9 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; R 9a , R 9b and R 9c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
    R环为含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂环烷基或5-6元亚杂芳基，所述亚杂环烷基和亚杂芳基任选地被0-2个R10取代，R10每次出现时分别独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-6杂环烷基、-S(O2)R10a、-NR10bR10c、-X5-NR10bR10c、-OR10a和-X5-OR10a；R10a、R10b和R10c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；X5选自C1-6亚烷基和C2-6亚烯基；The R ring is a 5-6 membered heterocycloalkylene or a 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , R 10 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c , -X 5 -NR 10b R 10c , -OR 10a and -X 5 -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl at each occurrence; X 5 is selected from C 5 C 1-6 alkylene and C 2-6 alkenylene;
    T环和U环分别独立地选自亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基，其中所述亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基任选地被1-3个独立地选自卤素、氨基、烷基氨基、氨烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的取代基取代；The T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 1-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl and C 3-6 cycloalkyl;
    L1选自以下基团：
     L1 is selected from the following groups:
    L2选自以下基团： L2 is selected from the following groups:
    其中Y1、Y2、Y3、Y4、Y5、Y6、和Y7分别独立地选自-O-、-NH-、-NHC(O)-、-NHS(O)-、-NHS(O2)-、-CH2-、-C(O)-、-S(O)-、-S(O2)-、-C(O)NH-、-S(O2)NH-、-CH＝CH-、-C≡C-和单键，其中所述L2中的氢原子各自独立地被选自氘、卤素、氨基、烷基氨基、氨烷基、-CONH2、-NHCO-C1-6烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的任一取代基取代；wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 —, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH═CH—, —C≡C—, and a single bond, wherein the hydrogen atoms in said L 2 are each independently substituted with any substituent selected from deuterium, halogen, amino, alkylamino, aminoalkyl, —CONH 2 , —NHCO—C 1-6 alkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl, and C 3-6 cycloalkyl;
    a为0-5的整数；b和c分别为0-3的整数；d和e分别为0-2的整数；和a is an integer from 0 to 5; b and c are integers from 0 to 3; d and e are integers from 0 to 2; and
    L1和L2任选地被1-5个R11取代，R11分别独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自氧、硫和氮的杂原子的3-6元杂环烷基、-S(O2)R11a、NR11bR11c、-X6-NR11bR11c、-OR11a和-X6-OR11a；R11a、R11b和R11c每次出现时各自独立地选自氢、C1-6烷基和C1-6卤代烷基；X6选自C1-6亚烷基和C2-6亚烯基。L 1 and L 2 are optionally substituted by 1-5 R 11 , R 11 are independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O 2 )R 11a , NR 11b R 11c , -X 6 -NR 11b R 11c , -OR 11a and -X 6 -OR 11a ; R 11a , R 11b and R 11c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 6 is selected from C 1-6 alkylene and C 2-6 alkenylene.
  13. 如权利要求2所述的化合物，其中：The compound according to claim 2, wherein:
    R1a和R1b分别独立地选自氢、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、和C1-4烷基，其中C1-4烷基任选地被0-6个独立选自卤素、氘、氨基、羟基、氨烷基和烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个四元、五元或六元杂环烷基，其中所述杂环烷基任选地被0-3个独立地选自卤素、氨基和羟基的取代基取代；或R 1a and R 1b are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
    R2、R4和R6分别独立地选自卤素、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、-NHC1-3烷基、-N(C1-3烷基)C1-3烷基、C1-3卤代烷基氨基、含有3-12元单环的环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子3-12元单杂环烷基、5-12元螺杂环烷基和4-12元桥杂环烷基、C1-C6烷基-S-、C1-6烷基-SO-、C1-6烷基-SO2-、3-6元环烷基-O-、3-6元杂环烷基-O-、5-10元单环芳基、5-10元并环芳基、和含有1-3个分别独立地选自N、O、P和S杂原子的3-12元单环杂芳基和7-10元并环杂芳基；或 R2 , R4 and R6 are independently selected from halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, -NHC1-3 alkyl, -N( C1-3 alkyl) C1-3 alkyl, C1-3 haloalkylamino, cycloalkyl containing 3-12 membered monocyclic ring, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl and 4-12 membered bridged heterocycloalkyl, C1 - C6 alkyl-S-, C1-6 alkyl-SO-, C1-6 alkyl- SO2 -, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered cycloheteroaryl, and 3-12 membered monocyclic heteroaryl and 7-10 membered cycloheteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S; or
    R5选自氢、C1-3烷基和C1-3卤代烷基；或 R5 is selected from hydrogen, C1-3 alkyl and C1-3 haloalkyl; or
    E、G、J和Z分别独立地选自N和CR2a；其中R2a选自氢、氘、卤素、氰基、羟基、 -NHCO-C1-6烷基、-CONH2、-C1-6烷基-CONH2、磺酰胺基、C1-3烷基、C1-3卤代烷基、C1-3烷基-S-、C1-C3烷基-SO-、C1-3烷基-SO2-、C1-3烷基-O-、C1-3卤代烷基-O-、-NR2bR2c、C3-6环烷基氨基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基氨基、3-6元卤代环烷基、含有1-3个独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-；R2b和R2c分别独立地选自氢和C1-C6烷基；或E, G, J and Z are independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -NHCO-C 1-6 alkyl, -CONH 2 , -C 1-6 alkyl-CONH 2 , sulfonamide, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl -S-, C 1 -C 3 alkyl-SO-, C 1-3 alkyl-SO 2 -, C 1-3 alkyl-O-, C 1-3 haloalkyl-O-, -NR 2b R 2c , C 3-6 membered cycloalkylamino, 3-6 membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered halogenated cycloalkyl, 3-6 membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6 membered cycloalkyl-O-, 3-6 membered halogenated cycloalkyl-O-, 3-6 membered heterocycloalkyl-O- containing 1-3 heteroatoms independently selected from N, O, P and S; R 2b and R 2c are independently selected from hydrogen and C 1 -C 6 alkyl; or
    R3为-X1-R8，X1选自化学键、C2-C4亚烯基和C1-C4亚烷基；R8选自氢、卤素、C1-C3烷基、C1-C3卤代烷基、C6-C10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳环；R8a和R8b每次出现时分别独立地选自氢、氘、C1-C3烷基、C1-C3卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、-OR8d和-X2-R8d基团取代；R8c选自氢、C1-6烷基和C1-6卤代烷基；X2选自C1-6亚烷基和C2-6亚烯基；R8d选自氢、C1-4烷基和C1-4卤代烷基；或 R3 is -X1 - R8 , X1 is selected from a chemical bond, C2 - C4 alkenylene and C1 - C4 alkylene; R8 is selected from hydrogen, halogen, C1 - C3 alkyl, C1 - C3 haloalkyl, C6 - C10 aryl, -NR8aR8b , -C(O) R8c , -C(O) NR8aR8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R8a and R8b are independently selected from hydrogen, deuterium, C1 - C3 alkyl, C1 - C3 haloalkyl and phenyl at each occurrence , the phenyl being optionally substituted with 0-2 groups selected from C1-4 alkyl, -OR8d and -X2 - R8d ; R8c is selected from hydrogen, C1-6 alkyl and C X2 is selected from C1-6 alkylene and C2-6 alkenylene; R8d is selected from hydrogen, C1-4 alkyl and C1-4 haloalkyl; or
    R1c和R1d分别独立地选自氢、C3-12单环、螺环或桥环的环烷基、C3-12单环、螺环或桥环的杂环烷基、和C1-4烷基，其中C1-4烷基任选地被0-6个独立选自卤素、氘、氨基、羟基、氨烷基和烷氧基的取代基取代；或R1c和R1d和其共同连接的氮原子组成一个四元、五元或六元杂环烷基，其中所述杂环烷基任选地被0-3个独立地选自卤素、氨基和羟基的取代基取代；或R 1c and R 1d are independently selected from hydrogen, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by 0-6 substituents independently selected from halogen, deuterium, amino, hydroxyl, aminoalkyl and alkoxy; or R 1c and R 1d and the nitrogen atom to which they are commonly attached form a four-membered, five-membered or six-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 0-3 substituents independently selected from halogen, amino and hydroxyl; or
    R7a和R7b分别独立地选自氢、氘、卤素、C1-4烷基和C1-4卤代烷基；或R 7a and R 7b are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl and C 1-4 haloalkyl; or
    Q环任选地被1-2个R9取代，R9每次出现时分别独立地选自卤素、C1-C3烷基、C1-C3卤代烷基、氰基、C3-C6环烷基、含有1-3个杂原子的3-6元杂环烷基，所述杂原子分别独立地选自N、O和S、-S(O2)R9a、NR9bR9c和-OR9a；每个R9a、R9b和R9c每次出现时分别独立地选自氢、氘、C1-3烷基和C1-3卤代烷基；或The Q ring is optionally substituted with 1-2 R 9 , each of which is independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms, each of which is independently selected from N, O and S, -S(O 2 )R 9a , NR 9b R 9c and -OR 9a ; each of R 9a , R 9b and R 9c is independently selected from hydrogen, deuterium, C 1-3 alkyl and C 1-3 haloalkyl at each occurrence; or
    R环为含有1-4个独立地选自N、O、P和S杂原子的5-6元亚杂环烷基或5-6元亚杂芳基，所述亚杂环烷基和亚杂芳基任选地被0-2个R10取代，R10每次出现时分别独立地选自卤素、C1-C3烷基、羟基、氨基、C1-C3卤代烷基、氰基、C3-C6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-6杂环烷基、-S(O2)R10a、-NR10bR10c和-OR10a；R10a、R10b和R10c每次出现时分别独立地选自氢、氘、C1-C3烷基和C1-C3卤代烷基；或The R ring is a 5-6 membered heterocycloalkylene or 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from N, O, P and S, the heterocycloalkylene and heteroarylene are optionally substituted by 0-2 R 10 , R 10 is independently selected from halogen, C 1 -C 3 alkyl, hydroxyl, amino, C 1 -C 3 haloalkyl, cyano, C 3 -C 6 cycloalkyl, C 3-6 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 10a , -NR 10b R 10c and -OR 10a ; R 10a , R 10b and R 10c are independently selected from hydrogen, deuterium, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl at each occurrence; or
    T环和U环分别独立地选自含有1、2、3个N、O、S原子的5-6元亚杂环基、亚苯 基和亚吡啶基，其中所述的亚苯基、亚吡啶基任选地被1-3个独立地选自卤素、氨基、烷基氨基、氨烷基、氰基、烷氧基、卤代烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的取代基取代。The T ring and the U ring are independently selected from 5-6 membered heterocyclic groups containing 1, 2, 3 N, O, S atoms, phenylene groups, The phenylene and pyridylene groups are optionally substituted with 1-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, cyano, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl and C 3-6 cycloalkyl.
  14. 如权利要求12所述的化合物，其中：The compound of claim 12, wherein:
    R2选自氢、氟、氯、环丙基、C1-3烷基和C1-3卤代烷基；或 R2 is selected from hydrogen, fluorine, chlorine, cyclopropyl, C1-3 alkyl and C1-3 haloalkyl; or
    R3为氢；或 R3 is hydrogen; or
    R4选自氢、氟、氯、溴和环丙基；或R 4 is selected from hydrogen, fluorine, chlorine, bromine and cyclopropyl; or
    R6选自氢、氟、氯和环丙基；或 R6 is selected from hydrogen, fluorine, chlorine and cyclopropyl; or
    R5选自氢和甲基；或 R5 is selected from hydrogen and methyl; or
    R1c和R1d分别独立地选自氢和C1-C3烷基；优选地，R1c和R1d分别独立地选自氢和甲基；或R 1c and R 1d are independently selected from hydrogen and C 1 -C 3 alkyl; preferably, R 1c and R 1d are independently selected from hydrogen and methyl; or
    所述Q环选自以下基团：
    The Q ring is selected from the following groups:
    其中，所述每个Q环基团左边的连接位点各自独立与式(V)中-CR7aR7b-相连，所述每个Q环基团右边的连接位点各自独立与式(V)中R环相连；或wherein the connection site on the left side of each Q ring group is independently connected to -CR 7a R 7b - in formula (V), and the connection site on the right side of each Q ring group is independently connected to the R ring in formula (V); or
    R环选自以下基团：
    The R ring is selected from the following groups:
    其中，所述每个R环基团的右边的连接位点各自独立与式(Ⅴ)中Q环相连，所述每个R环基团的左边的连接位点各自独立与式Ⅰ中A环或B环相连。The right connecting site of each R ring group is independently connected to the Q ring in formula (V), and the left connecting site of each R ring group is independently connected to the A ring or the B ring in formula I.
  15. 如权利要求12-13任一项所述的化合物，所述化合物选自式(Ⅰ-A)、(Ⅰ-B)、(Ⅰ-C)、(Ⅰ-D)、(Ⅰ-E)、(Ⅰ-F)和(Ⅰ-G)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
    A compound according to any one of claims 12 to 13, wherein the compound is selected from the compounds represented by formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) and (I-G), or their isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates:
    其中，Q环、R环、T环、U环、L1、L2、W、R1a、R1b、R1c、R1d、R7a、R7b、R2、R3、R4、R5和R6定义同权利要求12、13或14。Wherein, Q ring, R ring, T ring, U ring, L 1 , L 2 , W, R 1a , R 1b , R 1c , R 1d , R 7a , R 7b , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in claim 12, 13 or 14.
  16. 如权利要求12-14任一项所述的化合物，其中，A环、B环相同或不同，所述A环和B环各自独立地选自式(Ⅱ-1)、(Ⅳ-1)和(Ⅲ-1)：
    The compound according to any one of claims 12 to 14, wherein the A ring and the B ring are the same or different, and the A ring and the B ring are each independently selected from the formula (II-1), (IV-1) and (III-1):
    其中，R1a、R1b、R1c、R1d、R2、R3、R4、R5和R6的定义同权利要求12或13或14；优选地，所述A环和B环相同。Wherein, R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in claim 12 or 13 or 14; preferably, the A ring and the B ring are the same.
  17. 如权利要求12-15任一项所述的化合物，其中所述化合物选自式(Ⅰ-A-1)、(Ⅰ-A-2)、(Ⅰ-A-3)、(Ⅰ-A-4)、(Ⅰ-F-1)、(Ⅰ-F-2)、(Ⅰ-F-3)、(Ⅰ-F-4)、(Ⅰ-F-5)、(Ⅰ-F-6)、(Ⅰ-F-7)和(Ⅰ-F-8)所示的化合物、或其异构体、同位素衍生物、多晶型物、前药、药学上可接受的盐或溶剂化物：
    A compound according to any one of claims 12 to 15, wherein the compound is selected from the group consisting of compounds represented by formula (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-F-3), (I-F-4), (I-F-5), (I-F-6), (I-F-7) and (I-F-8), or isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates thereof:
  18. 化合物，所述化合物选自如下结构:
    A compound selected from the following structures:
    其中A环和B环各自独立选自式(Ⅱ)、(Ⅲ)、(Ⅳ)、(Ⅴ)、(Ⅵ)、(Ⅶ)和(Ⅷ)：
    Wherein Ring A and Ring B are independently selected from Formula (II), (III), (IV), (V), (VI), (VII) and (VIII):
    其中Linker C为连接A环和B环的连接子，选自式(Ⅸ)、(Ⅹ)、(Ⅺ)和(Ⅻ)：
    Wherein Linker C is a linker connecting Ring A and Ring B, selected from Formula (IX), (X), (XI) and (XII):
    其中，R1选自不存在、氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、C1-6烷基、C1-6卤代烷基、-S-C1-6烷基、-S(O)-C1-6烷基、-S(O2)-C1-6烷基、-O-C1-6烷基、-O-C1-6卤代烷基、C1-6氘代烷基和-NR1aR1b，其中R1a和R1b分别独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6氘代烷基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0-6个独立选自卤素、氘、烷 基、氨基、羟基、烷基氨基、氨烷基、和烷氧基的取代基取代；或R1a和R1b和其共同连接的氮原子组成一个含有1-3个分别独立地选自N、O、P和S的杂原子的3-10元杂环烷基，其中所述杂环烷基任选地被0-3个独立选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6烷基、C1-6氘代烷基、氰基、C1-6氨烷基和羟基的取代基取代；wherein R 1 is selected from the group consisting of absence, hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, C 1-6 alkyl, C 1-6 haloalkyl, -SC 1-6 alkyl, -S(O)-C 1-6 alkyl, -S(O 2 )-C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, C 1-6 deuterated alkyl and -NR 1a R 1b , wherein R 1a and R 1b are independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl, C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl and C 1-12 aryl. wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-12 monocyclic, spirocyclic or bridged cycloalkyl , C 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C 6-10 aryl , and C 5-10 heteroaryl are optionally substituted by 0-6 atoms independently selected from halogen, deuterium, alkane or R 1a and R 1b and the nitrogen atom to which they are commonly attached form a 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 deuterated alkyl, cyano, C 1-6 aminoalkyl and hydroxyl;
    Z选自C和N；当Z选自N时，R1不存在；Z is selected from C and N; when Z is selected from N, R 1 is absent;
    R2、R4和R6分别独立地选自氢、氘、卤素、C1-6烷基、C1-6烯基、C1-6炔基、C1-6烷氧基、C1-6卤代烷基、-NHC1-6烷基、-N(C1-6烷基)C1-6烷基、C1-6卤代烷氧基、C1-6卤代烷基氨基、3-12元单环的环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的5-12元螺杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的4-12元桥杂环烷基、-S-C1-6烷基、-SO-C1-6烷基、-SO2-C1-6烷基、3-6元环烷基-O-、3-6元杂环烷基-O-、5-10元单环芳基、5-10元并环芳基、含有1-3个分别独立地选自N、O、P和S杂原子的3-12元单环杂芳基和含有1-3个分别独立地选自N、O、P和S杂原子的7-10元并环杂芳基； R2 , R4 and R6 are independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl , C1-6 alkoxy, C1-6 haloalkyl, -NHC1-6 alkyl, -N( C1-6 alkyl) C1-6 alkyl, C1-6 haloalkoxy, C1-6 haloalkylamino, 3-12 membered monocyclic cycloalkyl, 5-12 membered spirocycloalkyl, 4-12 membered bridged cycloalkyl, 3-12 membered monoheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12 membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12 membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, -SC1-6 alkyl, -SO-C1-6 alkyl, -S ... 1-6 alkyl, -SO 2 -C 1-6 alkyl, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 5-10 membered monocyclic aryl, 5-10 membered paracyclic aryl, 3-12 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S, and 7-10 membered paracyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, P and S;
    R5选自氢、C1-6烷基、C3-10环烷基和C1-6卤代烷基，任选地，所述C1-6烷基、C3-10环烷基和C1-6卤代烷基被0-6个独立选自卤素、氘、烷基、氨基、羟基、氨基烷基、烷基氨基、和烷氧基的取代基取代；R 5 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl and C 1-6 haloalkyl are substituted with 0-6 substituents independently selected from halogen, deuterium, alkyl, amino, hydroxy, aminoalkyl, alkylamino, and alkoxy;
    G1和G2选自O、S、和NR2a； G1 and G2 are selected from O, S, and NR2a ;
    E0-9、M1-6和E每次出现时分别独立地选自N和CR2a；其中R2a选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷基-S-、-SO-C1-6烷基、-SO2-C1-6烷基、-O-C1-6烷基、-O-C1-6卤代烷基、-NR2bR2c、-NHC1-6烷基、-N(C1-6烷基)C1-6烷基、-C(O)R8c、-C(O)NR8aR8b、-C1-6亚烷基-C1-6环烷基、C3-6环烷基氨基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元杂环烷基氨基、3-12元单环烷基、5-12元螺环烷基、4-12元桥环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的5-12元螺杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的4-12元桥杂环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-6元卤代杂环烷基、3-6元环烷基-O-、3-6元卤代环烷基、3-6元卤代环烷基-O-、含有1-3个分别独立地选自N、 O、P和S的杂原子的3-6元卤代杂环烷基-O-、含有1-3个独立地选自N、O、P和S的杂原子的3-6元杂环烷基-O-、5-12元单环芳基、5-12元并环芳基、含有1-3个分别独立地选自N、O、P和S的杂原子的3-12元单环杂芳基、含有1-3个分别独立地选自N、O、P和S的杂原子的7-10元并环杂芳基；R2b和R2c分别独立地选自氢和C1-6烷基；R8a和R8b每次出现时分别独立地选自氢、氘、C1-6烷基、C1-6卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、-OR8d和-X2-R8d基团取代；R8c选自氢、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基和C1-6卤代烷基；X2选自C1-6亚烷基和C2-6亚烯基；R8d选自氢、C1-6烷基和C1-6卤代烷基；E 0-9 , M 1-6 and E are each independently selected from N and CR 2a ; wherein R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amide, sulfonamide, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl -S-, -SO-C 1-6 alkyl, -SO 2 -C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, -NR 2b R 2c , -NHC 1-6 alkyl, -N(C 1-6 alkyl)C 1-6 alkyl, -C(O)R 8c , -C(O)NR 8a R 8b , -C 1-6 alkylene-C 1-6 cycloalkyl, C 3-6 -membered cycloalkylamino, 3-6-membered heterocycloalkylamino containing 1-3 heteroatoms independently selected from N, O, P and S, 3-12-membered monocyclic alkyl, 5-12-membered spirocycloalkyl, 4-12-membered bridged cycloalkyl, 3-12-membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 5-12-membered spiroheterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 4-12-membered bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6-membered halogenated heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, 3-6-membered cycloalkyl-O-, 3-6-membered halogenated cycloalkyl, 3-6-membered halogenated cycloalkyl-O-, containing 1-3 heteroatoms independently selected from N, R 2b and R 2c are independently selected from hydrogen and C 1-6 alkyl; R 8a and R 8b are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl at each occurrence, and the phenyl group is optionally substituted with 0-2 groups selected from C 1-4 alkyl, -OR 8d and -X 2 -R 8d; R 8c is selected from hydrogen , C 1-6 alkyl, C 1-6 haloalkyl and phenyl . C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 haloalkyl; X 2 is selected from C 1-6 alkylene and C 2-6 alkenylene; R 8d is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
    J1和J2分别独立地选自单键、O、S、C(O)、S(O)、S(O2)、C(R1cR1d)、C(＝CR1eR1f)和N(R3)；其中R1c、R1d、R1e和R1f分别独立地选自氢、氘、C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基和C5-10杂芳基，其中所述C1-6烷基、C1-6烷氧基、C3-12单环、螺环或桥环的环烷基、含有1-3个分别独立地选自N、O、P和S的杂原子的C3-12单环、螺环或桥环的杂环烷基、C6-10芳基、和C5-10杂芳基任选地被0-6个独立地选自卤素、氘、C1-6烷基、氨基、羟基、C1-6烷基氨基、C1-6氨烷基、和C1-6烷氧基的取代基取代；或R1c和R1d和其共同连接的碳原子组成一个3-10元环烷基或含有1-3个分别独立地选自N、O、P和S的杂原子的3-10元杂环烷基，其中所述环烷基或杂环烷基任选地被0-3个独立地选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氨烷基和羟基的取代基取代；或R1e和R1f和其共同连接的碳原子组成一个3-10元环烷基或含有1-3个分别独立地选自N、O、P和S的杂原子的3-10元杂环烷基，其中所述环烷基或杂环烷基任选地被0-3个独立选自卤素、氘、氨基、C1-6烷氧基、C1-6烷基氨基、C1-6氨烷基和羟基的取代基取代； J1 and J2 are independently selected from a single bond, O, S, C(O), S(O), S( O2 ), C( R1cR1d ), C( ═CR1eR1f ) and N( R3 ); wherein R1c , R1d , R1e and R1f are independently selected from hydrogen, deuterium, C1-6 alkyl, C1-6 alkoxy, C3-12 monocyclic, spirocyclic or bridged cycloalkyl, C3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C6-10 aryl and C5-10 heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, C3-12 monocyclic, spirocyclic or bridged cycloalkyl, C3-12 monocyclic, spirocyclic or bridged heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, C6-10 aryl and C5-10 heteroaryl. 3-12 monocyclic, spirocyclic or bridged heterocycloalkyl, C 6-10 aryl, and C 5-10 heteroaryl are optionally substituted with 0-6 substituents independently selected from halogen, deuterium, C 1-6 alkyl, amino, hydroxy, C 1-6 alkylamino, C 1-6 aminoalkyl, and C 1-6 alkoxy; or R 1c and R 1d and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy; or R 1e and R 1d and the carbon atom to which they are commonly attached form a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxy; 1f and the carbon atom to which it is commonly attached form a 3-10 membered cycloalkyl group or a 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O, P and S, wherein the cycloalkyl group or heterocycloalkyl group is optionally substituted with 0-3 substituents independently selected from halogen, deuterium, amino, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 aminoalkyl and hydroxyl;
    R3为-X1-R8，X1选自化学键、-O-、-S-、烷氧基、C2-6亚烯基和C1-6亚烷基；R8选自氢、卤素、C1-6烷基、C1-6卤代烷基、C6-10芳基、-NR8aR8b、-C(O)R8c、-C(O)NR8aR8b和含有1-3个独立地选自N、O、P和S的杂原子的5-10元杂芳环；R8a和R8b每次出现时分别独立地选自氢、氘、C1-6烷基、C1-6卤代烷基和苯基，所述苯基任选被0-2个选自C1-4烷基、卤素、氰基、氨基、-OR8d和-X2-R8d基团取代；R8c选自氢、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基和C1-6卤代烷基；X2选自C1-6亚烷基和C2-6亚烯基；R8d选自氢、C1-6烷基和C1-6卤代烷基； R 3 is -X 1 -R 8 , X 1 is selected from a chemical bond, -O-, -S-, alkoxy, C 2-6 alkenylene and C 1-6 alkylene; R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, -NR 8a R 8b , -C(O)R 8c , -C(O)NR 8a R 8b and a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O, P and S; R 8a and R 8b are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and phenyl, and the phenyl is optionally substituted with 0-2 groups selected from C 1-4 alkyl, halogen, cyano, amino, -OR 8d and -X 2 -R 8d ; R 8c is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 haloalkyl; X 2 is selected from C 1-6 alkylene and C 2-6 alkenylene; R 8d is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
    R7a和R7b分别独立地选自氢、氘、卤素、C1-6烷基、C1-6卤代烷基、-X3-OR7c、-X3-NR7dR7e和C3-10环烷基；X3每次出现时各自独立选自C1-6亚烷基和C2-C6亚烯基；R7c选自氢、氘、C1-6烷基和C1-6卤代烷基；R7d和R7e分别独立地选自氢、氘、C1-6烷基和C1-6卤代烷基；或者R7a和R7b和其连接的碳组成3-10元环烷基；R 7a and R 7b are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -X 3 -OR 7c , -X 3 -NR 7d R 7e and C 3-10 cycloalkyl; X 3 is independently selected from C 1-6 alkylene and C 2 -C 6 alkenylene at each occurrence; R 7c is selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; R 7d and R 7e are independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; or R 7a and R 7b and the carbon to which they are attached form a 3-10 membered cycloalkyl;
    W选自以下基团：
    W is selected from the following groups:
    Q环选自亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1-4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、3-7元亚杂环烯基、5-6元亚杂芳基和4-12元稠杂环，所述亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1-4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、5-6元亚杂芳基和4-12元亚稠杂环任选地被0-6个R9取代，R9每次出现时分别独立地选自卤素、氘、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-7杂环烷基、-S(O2)R9a、-NR9bR9c、-X4-NR9bR9c、-OR9a和-X4-OR9a；R9a、R9b和R9c每次出现时分别独立地选自氢、C1-6烷基和C1-6卤代烷基；X4选自C1-6亚烷基和C2-6亚烯基；The Q ring is selected from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring, wherein the phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring are optionally substituted with 0-6 R 9 , and each occurrence of R 9 is independently selected from halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl , cyano, C 3-6 cycloalkyl, C 3-7 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 )R 9a , -NR 9b R R 9c , -X 4 -NR 9b R 9c , -OR 9a and -X 4 -OR 9a ; R 9a , R 9b and R 9c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 4 is selected from C 1-6 alkylene and C 2-6 alkenylene;
    R环选自亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1-4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、3-7元亚杂环烯基、5-6元亚杂芳基和4-12元稠杂环，所述亚苯基、3-7元亚环烷基、3-7元亚环烯基、含有1-4个独立地选自N、O、P和S杂原子的3-7元亚杂环烷基、3-7元亚杂环烯基、5-6元亚杂芳基和4-12元稠杂环任选地被0-6个R10取代，R10每次出现时分别独立地选自卤素、氘、C1-6烷基、羟基、氨基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自N、O和S的杂原子的C3-7杂环烷基、-S(O2)R10a、-NR10bR10c、-X5-NR10bR10c、-OR10a和-X5-OR10a；R10a、R10b和R10c每次出现时分别独立地选自氢、氘、C1-6烷基和C1-6卤代烷基；X5选自C1-6亚烷基和C2-6亚烯基；The R ring is selected from phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring, wherein the phenylene, 3-7 membered cycloalkylene, 3-7 membered cycloalkenylene, 3-7 membered heterocycloalkylene containing 1-4 heteroatoms independently selected from N, O, P and S, 3-7 membered heterocycloalkenylene, 5-6 membered heteroarylene and 4-12 membered fused heterocyclic ring are optionally substituted with 0-6 R10 , and each occurrence of R10 is independently selected from halogen, deuterium, C1-6 alkyl, hydroxyl, amino, C1-6 haloalkyl, cyano, C3-6 cycloalkyl, C3-7 heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S, -S(O 2 ) R 10a , -NR 10b R 10c , -X 5 -NR 10b R 10c , -OR 10a and -X 5 -OR 10a ; R 10a , R 10b and R 10c are each independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 haloalkyl; X 5 is selected from C 1-6 alkylene and C 2-6 alkenylene;
    T环和U环分别独立地选自亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基，其中所述亚苯基、亚吡啶基、亚嘧啶基和亚吡嗪基任选地被0-3个独立地选自卤素、氨基、烷基氨基、氨烷基、羟基、羟烷基、氨酰基、氨磺酰基、C1-6烷基和C3-6环烷基的取代基取代； The T ring and the U ring are independently selected from phenylene, pyridinylene, pyrimidinylene and pyrazinylene, wherein the phenylene, pyridinylene, pyrimidinylene and pyrazinylene are optionally substituted with 0-3 substituents independently selected from halogen, amino, alkylamino, aminoalkyl, hydroxyl, hydroxyalkyl, aminoacyl, sulfamoyl, C 1-6 alkyl and C 3-6 cycloalkyl;
    L1选自以下基团：
     L1 is selected from the following groups:
    L2选自以下基团： L2 is selected from the following groups:
    其中Y1、Y2、Y3、Y4、Y5、Y6、和Y7分别独立地选自-O-、-NH-、-NHC(O)-、-NHS(O)-、-NHS(O2)-、-CH2-、-C(O)-、-S(O)-、-S(O2)-、-C(O)NH-、-S(O2)NH-、-CH＝CH-、-C≡C-和单键；wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently selected from —O—, —NH—, —NHC(O)—, —NHS(O)—, —NHS(O 2 )—, —CH 2 —, —C(O)—, —S(O)—, —S(O 2 )—, —C(O)NH—, —S(O 2 )NH—, —CH═CH—, —C≡C—, and a single bond;
    a为0-5的整数；b和c分别为0-3的整数；d和e分别为0-2的整数；和a is an integer from 0 to 5; b and c are integers from 0 to 3; d and e are integers from 0 to 2; and
    L1和L2任选地被0-5个R11取代，R11分别独立地选自氘、卤素、C1-6烷基、C1-6卤代烷基、氰基、C3-6环烷基、含有1-3个独立地选自氧、硫和氮的杂原子的3-6元杂环烷基、-S(O2)R11a、NR11bR11c、-X6-NR11bR11c、-OR11a和-X6-OR11a；R11a、R11b和R11c每次出现时各自独立地选自氢、C1-6烷基和C1-6卤代烷基；X6选自C1-6亚烷基和C2-6亚烯基。L 1 and L 2 are optionally substituted by 0-5 R 11 , R 11 are independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, -S(O 2 )R 11a , NR 11b R 11c , -X 6 -NR 11b R 11c , -OR 11a and -X 6 -OR 11a ; R 11a , R 11b and R 11c are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; X 6 is selected from C 1-6 alkylene and C 2-6 alkenylene.
  19. 如权利要求1-17任一项所述的化合物，其中所述化合物选自以下结构：




    The compound according to any one of claims 1 to 17, wherein the compound is selected from the following structures:




  20. 一种药物组合物，其特征在于所述药物组合物中包含治疗有效剂量的权利要求1-18中任一项所述的化合物及药学上可接受的载体或赋形剂。A pharmaceutical composition, characterized in that it contains a therapeutically effective dose of the compound described in any one of claims 1 to 18 and a pharmaceutically acceptable carrier or excipient.
  21. 权利要求1-18中任一项所述的化合物或权利要求19所述的药物组合物用于制备治疗MAT2A相关疾病的药物中的用途；优选地，所述MAT2A相关疾病为癌症或肿瘤。Use of the compound according to any one of claims 1 to 18 or the pharmaceutical composition according to claim 19 for preparing a medicament for treating a MAT2A-related disease; preferably, the MAT2A-related disease is cancer or tumor.
  22. 一种治疗患者的MAT2A相关的疾病的方法，该方法包括向所述患者施用治疗有效量的一种或多种权利要求1-18中任一项所述的化合物或权利要求19所述的药物组合物；优选地，所述MAT2A相关疾病为癌症或肿瘤。A method for treating a MAT2A-related disease in a patient, the method comprising administering to the patient a therapeutically effective amount of one or more compounds according to any one of claims 1 to 18 or the pharmaceutical composition according to claim 19; preferably, the MAT2A-related disease is cancer or tumor.
  23. 权利要求1-18中任一项所述的化合物或权利要求19所述的药物组合物，其用于治疗MAT2A相关疾病；优选地，所述MAT2A相关疾病为癌症或肿瘤。 The compound according to any one of claims 1 to 18 or the pharmaceutical composition according to claim 19, which is used to treat a MAT2A-related disease; preferably, the MAT2A-related disease is cancer or a tumor.
PCT/CN2024/080417 2023-03-06 2024-03-07 Methionine adenosyltransferase 2a inhibitor and medical use thereof WO2024183778A1 (en)

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