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WO2024153143A1 - Nitrogen-containing fused ring compound and use thereof - Google Patents

Nitrogen-containing fused ring compound and use thereof Download PDF

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Publication number
WO2024153143A1
WO2024153143A1 PCT/CN2024/072841 CN2024072841W WO2024153143A1 WO 2024153143 A1 WO2024153143 A1 WO 2024153143A1 CN 2024072841 W CN2024072841 W CN 2024072841W WO 2024153143 A1 WO2024153143 A1 WO 2024153143A1
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Prior art keywords
alkyl
compound
methyl
alkoxy
optionally substituted
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PCT/CN2024/072841
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French (fr)
Chinese (zh)
Inventor
冯捷
蒋蕾
陈亚东
唐锋
余子恒
刘璐
陆涛
唐任宏
韦瑜琛
李桢
毛淋
李正涛
Original Assignee
中国药科大学
南京再明医药有限公司
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Publication of WO2024153143A1 publication Critical patent/WO2024153143A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure belongs to the field of medicine, and specifically relates to a nitrogen-containing cyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof, a pharmaceutical composition containing them, and use of the compound as a DNA polymerase ⁇ inhibitor in preventing or treating related diseases.
  • DNA double-strand break repair is essential for maintaining genome stability and cell survival.
  • HR homologous recombination
  • NHEJ non-homologous end joining
  • alt-MEJ non-conventional non-homologous end joining
  • MMEJ Microhomology-mediated end joining
  • Homologous recombination is a high-fidelity, accurate repair mechanism that can maintain genome stability and avoid inducing cancer.
  • Non-homologous end joining and microhomology-mediated end joining are error-prone repair pathways that can lead to mutations at the repair site.
  • POLQ is a multifunctional enzyme consisting of an N-terminal helicase domain (SF2HEL308-type) and a C-terminal low-fidelity DNA polymerase domain (A-type) (Wood & D.00e DNA Repair (2016), 44, 22-32).
  • the helicase domain mediates the removal of RPA protein from single-stranded DNA and promotes annealing, while the polymerase domain can extend the ends of single-stranded DNA and fill the gaps.
  • the two domains work together to play a role in the microhomology-mediated end-joining repair process.
  • POLQ is essential for cells with homologous recombination defects (such as synthetic lethality with FA/BRCA defects), and that POLQ protein levels are upregulated in tumor cells with homologous recombination defects (Ceccaldi et al. Nature (2015), 518 (7538), 258-262).
  • POLQ is overexpressed in a series of homologous recombination-deficient and poorly prognostic ovarian, uterine and breast cancers (Higgins et al. Oncotarget (2010), 1, 175-184, Lemee et al. PNAS (2010), 107 (30), 13390-13395, Ceccaldi et al. (2015), supra). More importantly, compared with tumor tissues, the expression of POLQ is inhibited in normal tissues (Kawamura et al. International Journal of Cancer (2004), 109(1), 9-16).
  • POLQ is essential for cells with homologous recombination defects, and there is currently an unmet market demand for the treatment of homologous recombination defective tumors. Inhibiting the function of POLQ can inhibit microhomology-mediated end joining repair in cells, and the development of POLQ function inhibitors can provide a new strategy for targeted treatment of homologous recombination defective tumors.
  • the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
  • Q 1 is selected from N, CH or CR 1 ;
  • Q 2 is selected from N, CH or CR 2 ;
  • Q 3 is selected from N, CH or CR 3 ;
  • Q 4 is selected from N or CH
  • the R 1 is selected from halogen, cyano, hydroxyl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocycloalkyl, -Y-NR 1A R 1AA , B(OH) 2 or -Z-5-10 membered heteroaryl, and the 3-12 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted by R 1a ;
  • Y is selected from a bond, C(O), (CH 2 ) p or C 3 -C 8 cycloalkylene;
  • Z is selected from a bond or (CH 2 ) r ;
  • R 1a is selected from halogen, hydroxyl, cyano, amino, oxo, SH, C 1 -C 6 alkyl, -S(O) 2 -R 1a ', -C(O)C 1 -C 6 alkyl, -B(OH) 2 , 5-10 membered heteroaryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, -NHC(O)C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 , said C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, 5-10 membered heteroaryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, -NHC(O)C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl) or -N(
  • R 1A , R 1AA are each independently selected from hydrogen, C 1 -C 6 alkyl, -C(O)H, -C(O)C 1 -C 6 alkyl, -S(O) 2 -R 1A 'or -C(O)OC 1 -C 6 alkyl, said C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl or -C(O)OC 1 -C 6 alkyl are optionally substituted by R 1B ;
  • the R 1B is selected from halogen, hydroxyl, cyano, amino, SH, C 1 -C 6 alkoxy or 4-10 membered heterocycloalkyl, and the 4-10 membered heterocycloalkyl is optionally substituted by R 1C ;
  • the R 2 is selected from halogen, cyano, hydroxyl, -COOH, -CONH 2 , -COOC 1 -C 10 alkyl, -CONH(C 1 -C 10 alkyl), -CON(C 1 -C 10 alkyl) 2 , -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (C 3 -C 6 cycloalkyl), C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocyclyl, -T-NR 2A R 2AA , B(OH) 2 or -L-5-10 membered heteroaryl, the -COOC 1 -C 10 alkyl, -CONH(C 1 -C 10 alkyl), -CON(C 1 -C 10 alkyl) 2 , -S(O) 2 (C 1
  • R 2a is optionally substituted with -S(O) 2 (C 3 -C 6 alkyl), -S(O) 2 (C 3 -C 6 cycloalkyl), C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocyclyl or 5-10 membered heteroaryl;
  • T is selected from a bond, C(O), (CH 2 ) m or C 3 -C 8 cycloalkylene;
  • L is selected from a bond or (CH 2 ) n ;
  • R 2a is selected from halogen, hydroxyl, cyano, amino, oxo, SH, C 1 -C 6 alkyl, -S(O) 2 -R 2a ', -C(O)C 1 -C 6 alkyl, -B(OH) 2 , 5-10 membered heteroaryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, -NHC(O)C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 , said C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, 5-10 membered heteroaryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, -NHC(O)C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl) or -N(
  • R 2A , R 2AA are each independently selected from hydrogen, C 1 -C 6 alkyl, -C(O)H, -C(O)C 1 -C 6 alkyl, -S(O) 2 -R 2A 'or -C(O)OC 1 -C 6 alkyl, said C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl or -C(O)OC 1 -C 6 alkyl are optionally substituted by R 2B ;
  • the R 2B is selected from halogen, hydroxyl, cyano, amino, SH, C 1 -C 6 alkoxy, 4-10 membered heterocycloalkyl, -S(O) 2 -(C 1 -C 6 alkyl) or -S(O) 2 -(C 3 -C 6 cycloalkyl), and the 4-10 membered heterocycloalkyl is optionally substituted by R 2C ;
  • R 1a ', R 1A ', R 2a ', and R 2A ' are each independently selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
  • the R 3 is selected from halogen, hydroxyl, amino, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, -NH(C 1 -C 10 alkyl), -N(C 1 -C 10 alkyl) 2 , 3-12 membered heterocyclyl or -U-5-10 membered heteroaryl, and the C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, -NH(C 1 -C 10 alkyl), -N(C 1 -C 10 alkyl) 2 , 3-12 membered heterocyclyl, 5-10 membered heteroaryl are optionally substituted by R 3a ;
  • U is selected from a bond, (CH 2 ) q or a 3-12 membered heterocycloalkylene group
  • R 1b , R 1c , R 2b , R 2c , and R 3a are each independently selected from halogen, hydroxy, cyano, amino, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or 4-12 membered heterocyclyl, and the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or 4-12 membered heterocyclyl is optionally substituted by R 1c ;
  • R 1c is selected from halogen, hydroxy, amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • X is selected from N or CR 4 ;
  • R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 ; or any two adjacent groups of R 4 , R 5 , R 6 , R 7 and R 8 and the atoms to which they are attached together form a 5-7 membered unsaturated ring, the unsaturated ring optionally containing one or more heteroatoms selected from O, N or S, and the unsaturated ring is optionally substituted by R 4a ;
  • R 4a is selected from C 1 -C 6 alkyl or halogen
  • R 9 is selected from H, halogen, OH, deuterium or C 1 -C 6 alkyl optionally substituted with hydroxyl;
  • R 10 is selected from methyl or deuterated methyl
  • M is selected from N or CR 11 ;
  • R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, -P(O)(C 1 -C 6 alkyl) 2 or NR 11A R 11AA ; or R 13 and R 14 and the carbon atoms to which they are attached together form a 5-10 membered heteroaromatic ring;
  • R 11A and R 11AA are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, -COC 1 -C 6 alkyl or 3-12 membered heterocyclyl, the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl or -COC 1 -C 6 alkyl is optionally substituted by R 11B , the 3-12 membered heterocyclyl is optionally substituted by R 11B ';
  • the R 11B is selected from hydroxyl or amino
  • the R 11B ' is selected from oxo, hydroxyl, C 1 -C 6 alkanol or -COC 1 -C 6 alkyl;
  • p, r, m, n, q are each independently selected from 1, 2, 3, 4, 5 or 6;
  • R 15 when When represents a double bond, R 15 does not exist; when When represents a single bond, R 15 is selected from hydrogen or deuterium.
  • It is a single bond.
  • R 15 when When represents a double bond, R 15 does not exist; when When represents a single bond, R 15 is selected from hydrogen.
  • Q 1 when Q 1 is selected from CR 1 , Q 2 is not CR 2 and Q 3 is not CR 3 .
  • Q 1 is selected from CH or CR 1
  • Q 2 is selected from CH or CR 2
  • Q 3 is selected from CH or CR 3
  • Q 4 is selected from CH; or at least one of Q 1 , Q 2 , Q 3 or Q 4 is selected from N.
  • Q1 is selected from CH or CR1
  • Q2 is selected from CH or CR2
  • Q3 is selected from CH or CR3
  • Q4 is selected from CH
  • one of Q1 , Q2 , Q3 or Q4 is selected from N
  • both Q2 and Q4 are selected from N
  • Q1 is selected from CH or CR1
  • Q3 is selected from CH or CR3 .
  • Q 1 is selected from N or CH.
  • Selected from Wherein * represents connection with N, wherein R 1 , R 2 , and R 3 are as defined above.
  • Selected from Wherein * represents connection with N, wherein R 1 , R 2 , and R 3 are as defined above.
  • Selected from Wherein * represents connection with N, wherein R 1 , R 2 , and R 3 are as defined above.
  • Selected from Wherein * indicates connection with N, wherein R 2 is as defined above.
  • R 1 is selected from halogen, cyano, hydroxy, C 1 -C 6 alkoxy, or -Y-NR 1A R 1AA .
  • R 1 is selected from halogen or -Y-NR 1A R 1AA .
  • Y is selected from a bond.
  • R 1 is selected from halogen or —NR 1A R 1AA .
  • R 1A , R 1AA are each independently selected from hydrogen, C 1 -C 6 alkyl, —S(O) 2 —R 1A ′, or —C(O)OC 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl or —C(O)OC 1 -C 6 alkyl is optionally substituted with R 1B .
  • R 1A , R 1AA are each independently selected from hydrogen or —S(O) 2 —R 1A ′.
  • R 1A is hydrogen and R 1AA is -S(O) 2 -R 1A '.
  • R 1A ′ is selected from C 3 -C 6 cycloalkyl.
  • R 1A ′ is selected from cyclopropyl.
  • R 1 is selected from F, Br or
  • R 1 is selected from F or
  • R 2 is selected from halogen, cyano, hydroxyl, -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocycloalkyl, -T-NR 2A R 2AA , B(OH) 2 , or -L-5-10 membered heteroaryl, and the -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with R 2a .
  • the R 2 is selected from halogen, cyano, hydroxyl, -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 8 alkyl, C 1 -C 8 alkoxy, 3-12 membered heterocyclyl, -T-NR 2A R 2AA , B(OH) 2 or -L-5-10 membered heteroaryl, and the C 1 -C 8 alkyl, C 1 -C 8 alkoxy, -S(O) 2 (C 1 -C 6 alkyl), 3-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted with R 2a .
  • R 2 is selected from halogen, cyano, hydroxyl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocycloalkyl, -T-NR 2A R 2AA , B(OH) 2 or -L-5-10 membered heteroaryl, said 3-12 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted with R 2a .
  • the R 2 is selected from halogen, cyano, hydroxyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, 4-12 membered heterocyclyl, -T-NR 2A R 2AA , B(OH) 2 or -L-5-10 membered heteroaryl, and the C 1 -C 8 alkyl, C 1 -C 8 alkoxy, 4-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted with R 2a .
  • R 2 is selected from halogen, cyano, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, 4-9 membered heterocyclyl, L-5 membered heteroaryl, or -T-NR 2A R 2AA , wherein the C 1 -C 6 alkoxy, C 1 -C 6 alkyl, 4-9 membered heterocyclyl, or 5 membered heteroaryl is optionally substituted with R 2a .
  • R 2 is selected from halogen, cyano, hydroxy, C 1 -C 6 alkoxy, 3-10 membered heterocycloalkyl, or -T-NR 2AR 2AA , said 3-10 membered heterocycloalkyl optionally substituted with R 2a .
  • T is selected from a bond.
  • L is selected from a bond.
  • R 2 is selected from halogen, cyano, hydroxyl, -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, or -NR 2A R 2AA , wherein -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted with R 2a .
  • R2 is selected from Br, Cl, F, cyano, hydroxyl, methoxy, methyl, morpholinyl, piperazinyl, pyrazolyl, thienyl, dihydropyranyl, piperidinyl, azetidinyl, Oxetane, pyrrolidinyl or -NR 2A R 2AA , the methyl, morpholinyl, piperazinyl, pyrazolyl, thienyl, dihydropyranyl, piperidinyl, azetidinyl, The oxetanyl or pyrrolidinyl group is optionally substituted by R 2a .
  • R 2 is selected from Br, Cl, F, cyano, hydroxy, methoxy, methyl, morpholinyl, piperazinyl, pyrazolyl, thienyl, dihydropyranyl, piperidinyl, azetidinyl, Oxetane, pyrrolidinyl or -NR 2A R 2AA , the methyl, morpholinyl, piperazinyl, pyrazolyl, thienyl, dihydropyranyl, piperidinyl, azetidinyl, The oxetanyl or pyrrolidinyl group is optionally substituted by R 2a .
  • R 2 is selected from Br, Cl, F, cyano, hydroxy, methoxy, morpholinyl, piperazinyl, or -NR 2AR 2AA , said morpholinyl or piperazinyl being optionally substituted with R 2a .
  • R 2a is selected from halogen, C 1 -C 6 alkyl, -S(O) 2 -R 2a ′, or -C(O)C 1 -C 6 alkyl, said C 1 -C 6 alkyl or -C(O)C 1 -C 6 alkyl optionally substituted with R 2b .
  • R 2a is selected from C 1 -C 6 alkyl, -S(O) 2 -R 2a ′ or -C(O)C 1 -C 6 alkyl, said C 1 -C 6 alkyl or -C(O)C 1 -C 6 alkyl being optionally substituted with R 2b .
  • R 2a is selected from F, methyl, ethyl, propyl, -S(O) 2 -R 2a ', or -C(O)CH 3 , said methyl, ethyl or propyl being optionally substituted with R 2b .
  • R 2a is selected from methyl, ethyl, -S(O) 2 -R 2a ', or -C(O)CH 3 , wherein the ethyl is optionally substituted with R 2b .
  • R 2a ′ is selected from C 1 -C 6 alkyl.
  • R 2a ′ is selected from methyl.
  • R 1b , R 1c , R 2b , R 2c , R 3a are each independently selected from halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R 2b is selected from hydroxy, cyano, C 1 -C 6 alkoxy, or 4-12 membered heterocyclyl, wherein the C 1 -C 6 alkoxy or 4-12 membered heterocyclyl is optionally substituted with R 1c .
  • R 2b is selected from hydroxy, cyano, C 1 -C 3 alkoxy, or 6-membered heterocyclyl, wherein the C 1 -C 6 alkoxy or 4-12-membered heterocyclyl is optionally substituted with R 1c .
  • R 1c is selected from hydroxy.
  • R 2b is selected from hydroxyl or C 1 -C 6 alkoxy.
  • R 2b is selected from C 1 -C 6 alkoxy.
  • R 2b is selected from methoxy.
  • R 2A , R 2AA are each independently selected from hydrogen, C 1 -C 6 alkyl, —C(O)H, —S(O) 2 —R 2A ′, or —C(O)OC 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl or —C(O)OC 1 -C 6 alkyl is optionally substituted with R 2B .
  • R 2A is selected from hydrogen or C 1 -C 6 alkyl
  • R 2AA is selected from C 1 -C 6 alkyl, -C(O)H, -S(O) 2 -R 2A 'or -C(O)OC 1 -C 6 alkyl
  • said C 1 -C 6 alkyl or -C(O)OC 1 -C 6 alkyl is optionally substituted with R 2B .
  • R 2A ′ is selected from C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl.
  • R 2A ′ is selected from cyclopropyl or n-propyl.
  • R 2A , R 2AA are each independently selected from hydrogen, methyl, -C(O)H, ethyl, The methyl or ethyl group is optionally substituted by R 2B .
  • R 2A is selected from hydrogen or methyl
  • R 2AA is selected from methyl, -C(O)H, ethyl
  • the methyl or ethyl group is optionally substituted by R 2B .
  • R 2A , R 2AA are each independently selected from hydrogen, methyl, -C(O)H, ethyl, The ethyl group is optionally substituted with R 2B .
  • R 2B is selected from halogen, hydroxy, cyano, amino, SH, C 1 -C 6 alkoxy, or 4-10 membered heterocycloalkyl, which is optionally substituted with R 2C .
  • R 2B is selected from C 1 -C 3 alkoxy, 4-6 membered heterocycloalkyl, or -S(O) 2 (C 1 -C 3 alkyl), wherein the 4-6 membered heterocycloalkyl is optionally substituted with R 2C .
  • R 2B is selected from C 1 -C 3 alkoxy or 4-10 membered heterocycloalkyl.
  • R 2C is selected from oxo or hydroxy.
  • R 2B is selected from methoxy
  • R 2B is selected from methoxy or
  • R 2 is selected from Br, Cl, F, CN, OH, methoxy, CF 3 ,
  • R 2 is selected from Br, Cl, F, CN, OH, methoxy, CF 3 ,
  • R2 is selected from Br, Cl, F, CN, OH, methoxy,
  • R 3 is selected from halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, 3-12 membered heterocycloalkyl, or -1-5-10 membered heteroaryl, wherein the C 1 -C 8 alkyl, C 1 -C 8 alkoxy, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl is optionally substituted with R 3a .
  • R 3 is selected from halogen, 3-12 membered heterocycloalkyl, or -1U-5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl is optionally substituted with R 3a .
  • R 3 is selected from halogen, C 1 -C 6 alkyl , or C 1 -C 6 alkyl , which is optionally substituted with R 3a .
  • R 3 is selected from halogen or C 1 -C 3 alkyl.
  • R 3 is selected from halogen.
  • R 3 is selected from Cl, F or methoxy.
  • R 3 is selected from Cl.
  • X is selected from CR 4 .
  • X is selected from CH.
  • R 10 when Selected from When X is N, R 10 is methyl.
  • R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl.
  • R4 is selected from H.
  • R 5 is selected from H, halogen, or C 1 -C 6 alkoxy.
  • R 5 is selected from H or halogen.
  • R 5 is selected from H, F or ethoxy.
  • R 5 is selected from H or F.
  • R 6 is selected from H or halogen.
  • R 6 is selected from H, F or Cl.
  • R 6 is selected from H.
  • R 7 is selected from H, halogen, or C 1 -C 6 alkoxy.
  • R 7 is selected from H or halogen.
  • R 7 is selected from halogen.
  • R 7 is selected from H, F or ethoxy.
  • R7 is selected from H or F.
  • R7 is selected from F.
  • R 8 is selected from H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R 8 is selected from H, halogen, or C 1 -C 6 alkyl.
  • R 8 is selected from H, Cl, F, methyl, or ethoxy.
  • R 8 is selected from H, Cl, F or methyl.
  • R 8 is selected from Cl.
  • R 9 is selected from H, halogen, or OH.
  • R 9 is selected from H, halogen, OH, deuterium, or C 1 -C 6 alkyl.
  • R 9 is selected from H, halogen, OH, deuterium, or C 1 -C 3 alkyl.
  • R 9 is selected from hydrogen, deuterium, OH, or methyl.
  • R 9 is selected from H or OH.
  • R 9 is selected from H.
  • R 10 is selected from methyl or CD 3 .
  • R 10 is selected from methyl.
  • M is selected from CR 11 .
  • R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy , C 3 -C 8 cycloalkyl, or NR 11A R 11AA .
  • R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy or -P(O)(C 1 -C 6 alkyl) 2 ; or R 13 and R 14 and the carbon atoms to which they are attached together form a 5-10 membered heteroaromatic ring.
  • R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy.
  • R 11 is selected from H or CN.
  • R 11 is selected from H.
  • R 12 is selected from C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or -P(O)(C 1 -C 6 alkyl) 2 .
  • R 12 is selected from C 1 -C 6 haloalkyl or C 1 -C 6 alkyl.
  • R 12 is selected from C 1 -C 6 haloalkyl.
  • R 12 is selected from CF 3 , CH 3 or
  • R 12 is selected from CF 3 or CH 3 .
  • R 12 is selected from CF 3 .
  • R 13 is selected from H.
  • R 14 is selected from C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • R 14 is selected from C 1 -C 6 alkyl.
  • R 14 is selected from methyl or CF 3 .
  • R 14 is selected from methyl.
  • R 13 and R 14 together with the carbon atom to which they are attached form a 5-6 membered heteroaryl ring.
  • R 13 and R 14 together with the carbon atom to which they are attached form a 5-membered heteroaryl ring.
  • R 13 and R 14 together with the carbon atom to which they are attached form a furan ring or a thiazole ring.
  • R 15 is selected from hydrogen or deuterium.
  • the compound of formula (I) of the present disclosure or its pharmaceutically acceptable salt or its stereoisomer is selected from the compound of formula (III) or its pharmaceutically acceptable salt or its stereoisomer:
  • the compound of formula (I) of the present disclosure or its pharmaceutically acceptable salt or stereoisomer thereof is selected from the compound of formula (IV) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:
  • the compound of formula (I) of the present disclosure or its pharmaceutically acceptable salt or its stereoisomer is selected from the compound of formula (II) or its pharmaceutically acceptable salt or its stereoisomer:
  • the compound of formula (I) of the present disclosure or its pharmaceutically acceptable salt or its stereoisomer is selected from the following compounds or its pharmaceutically acceptable salt or its stereoisomer:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) of the present disclosure or a pharmaceutically acceptable salt or a stereoisomer thereof and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for preventing or treating a disease mediated by DNA polymerase ⁇ in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.
  • the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, in the preparation of a drug for preventing or treating a disease mediated by DNA polymerase ⁇ .
  • the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, in preventing or treating a disease mediated by DNA polymerase ⁇ .
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof for preventing or treating a disease mediated by DNA polymerase ⁇ .
  • the DNA polymerase theta-mediated disease is a disease in which DNA polymerase theta is overexpressed.
  • the DNA polymerase theta-mediated disease is cancer.
  • the cancer is colorectal adenocarcinoma.
  • connection site such as a connection group It means that the N atom in the linking group is the linking site.
  • tautomer refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present disclosure may exhibit tautomerism.
  • Tautomeric compounds may exist in two or more interconvertible species.
  • Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates.
  • the present disclosure includes all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.
  • the compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E-type and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and their mixtures.
  • asymmetric carbon atoms asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of these isomers and their mixtures involved in all substituents are also included within the definition of the compounds of the present invention.
  • the compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are replaced.
  • an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH 2 CH 2 Cl, etc.), polysubstituted (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2 , etc.) or fully substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3 , etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or cannot be synthesized will be introduced.
  • any variable eg, Ra , Rb
  • its definition is independent at each occurrence. For example, if a group is substituted with 2 Rb , each Rb has an independent option.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
  • L 1 When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary.
  • L 1 When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary.
  • L 1 When L 1 is selected from “C 1 -C 3 alkylene-O", L 1 can connect ring Q and R 1 from left to right to form “ring QC 1 -C 3 alkylene-OR 1 ", or connect ring Q and R 1 from right to left to form “ring QOC 1 -C 3 alkylene-R 1 ".
  • Cm - Cn herein refers to an integer number of carbon atoms in the range of mn.
  • C1 - C10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 , which may be straight-chain or branched.
  • C1 - C10 alkyl may be understood to mean a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl
  • C 1 -C 6 alkyl may be understood to mean an alkyl group having 1 to 6 carbon atoms, and specific examples include, but are not limited to, methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.
  • C 1 -C 3 alkyl may be understood to mean a straight or branched saturated alkyl group having 1 to 3 carbon atoms.
  • the "C 1 -C 10 alkyl” may include “C 1 -C 6 alkyl” or “C 1 -C 3 alkyl” and the “C 1 -C 6 alkyl” may further include “C 1 -C 3 alkyl”.
  • alkoxy refers to a group resulting from the loss of a hydrogen atom from a hydroxyl group of a straight or branched alcohol, and may be understood as an “alkyloxy” or “alkyl-O-".
  • C 1 -C 10 alkoxy may be understood as a “C 1 -C 10 alkyloxy” or “C 1 -C 10 alkyl-O-”;
  • C 1 -C 6 alkoxy may be understood as a "C 1 -C 6 alkyloxy” or "C 1 -C 6 alkyl-O-".
  • the "C 1 -C 10 alkoxy” may include a “C 1 -C 6 alkoxy” and a “C 1 -C 3 alkoxy", and the "C 1 -C 6 alkoxy” may further include a "C 1 -C 3 alkoxy”.
  • haloalkyl is intended to include monohaloalkyl and polyhaloalkyl.
  • C 1-6 haloalkyl means a C 1-6 alkyl as defined above substituted with one or more halogens, specific examples of which include but are not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl and pentachloroethyl, etc.
  • alkanol refers to an alkyl group substituted by a single or multiple hydroxyl groups.
  • C 1 -C 6 alkanol refers to a C 1-6 alkyl group as defined above substituted by one or more hydroxyl groups. Specific examples include, but are not limited to, CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, or CH 2 CH(OH)CH 3 , etc.
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond.
  • C 2 -C 10 alkenyl can be understood to mean a linear or branched unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • C 2 -C 10 alkenyl is preferably "C 2 -C 6 alkenyl", further preferably "C 2 -C 4 alkenyl", and further preferably C 2 or C 3 alkenyl.
  • alkenyl contains more than one double bond
  • the double bonds may be separated or conjugated with each other.
  • alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.
  • cycloalkyl refers to a fully saturated carbocyclic ring that exists in the form of a monocyclic, cyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally a 3- to 10-membered ring.
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monocyclic, cyclic, spirocyclic or bridged ring having 3 to 10 carbon atoms.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like.
  • C 3 -C 10 cycloalkyl may include "C 3 -C 6 cycloalkyl".
  • C 3 -C 6 cycloalkyl may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms. Specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • cycloalkylene refers to a divalent group derived from a “cycloalkyl” group as defined herein.
  • heterocyclyl include morpholine, piperidine (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidone, pyrrolidine (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl), pyrrolidone, azetidine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g., tetrahydropyran-4-yl), imidazoline, imidazolidinone, oxazoline, thiazoline, pyrazolin-2-yl, pyrazolidine, piperazinone
  • heterocyclyl includes both spiro and bridged heterocyclic derivatives.
  • spiro and bridged heterocyclic derivatives include hexahydropyrrolo[2,3-c]pyrrolidinyl, diazaspiro[3.4]octanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[3.4]octanyl, oxa-azaspiro[4.4]nonanyl, tetrahydrofuro[3,4-c]pyrrolidinyl, oxa-azaspiro[3.3]heptyl, diazaspiro[4.5]decanyl, diazaspiro[3.4]octanyl, octahydro-naphthyridinyl, tetrahydropyrazino-oxazinyl, oxadiazolospiro[5.5]undecyl, and oxabicyclo[2.2.1
  • heterocycloalkylene refers to a divalent group derived from a "heterocycloalkyl” group as defined herein.
  • heterocyclylene refers to a divalent radical derived from a "heterocyclyl” group as defined herein.
  • heterocycloalkylene refers to a divalent radical derived from a "heterocycloalkyl” group as defined herein.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group with a conjugated ⁇ electron system.
  • the aryl group may have 6-20 carbon atoms, 6-14 carbon atoms or 6-10 carbon atoms.
  • C 6 -C 14 aryl is understood to mean an aryl group having 6 to 14 carbon atoms.
  • C 6 aryl such as phenyl
  • C 9 aryl such as indanyl or indenyl
  • 10 carbon atoms such as tetrahydronaphthyl, dihydronaphthyl or naphthyl
  • C 13 aryl such as fluorenyl
  • C 14 aryl such as anthracenyl
  • C 6 -C 10 aryl is understood to mean an aryl group having 6 to 10 carbon atoms, in particular a ring having 6 carbon atoms (“C 6 aryl”), such as phenyl; or a ring having 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl; or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C.
  • 5-10 membered heteroaryl is understood to include monocyclic or bicyclic aromatic ring systems: it has 5, 6, 7, 8, 9 or 10 ring atoms, especially 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S.
  • the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or azinyl, in
  • 5-6 membered heteroaryl refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.
  • 9-10 membered heteroaryl refers to an aromatic ring system having 9 or 10 ring atoms, and which contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.
  • 6 membered heteroaryl refers to an aromatic ring system having 6 ring atoms, and which contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.
  • halo or halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to an -OH group.
  • cyano refers to a -CN group.
  • amino refers to a -NH2 group.
  • terapéuticaally effective amount means an amount of a compound of the present disclosure that (i) treats a particular disease, condition or disorder, or (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder.
  • the amount of a compound of the present disclosure that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or an organic acid, and a salt formed between a compound and an inorganic base or an organic base.
  • composition refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient.
  • the purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl , etc., respectively.
  • isotopically-labeled compounds of the disclosure are useful in compound and/or substrate tissue distribution assays.
  • O i.e., 3 H
  • carbon-14 i.e., 14 C
  • isotopes are particularly preferred for their ease of preparation and detectability.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or sugar-coated core.
  • suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.
  • the compound of formula (I) may be administered at a daily dosage of 0.1 mg/kg to 1000 mg/kg body weight in the form of single or divided doses.
  • the compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the embodiments with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.
  • the ratio of mixed solvents is the volume ratio.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the unit of NMR shift is 10 -6 (ppm).
  • the solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • NaH stands for sodium hydride
  • RT stands for retention time
  • TLC stands for thin layer chromatography
  • Step 1 Synthesis of 3-chloro-4-fluoro-N-methylaniline (Intermediate 1-2)
  • Step 2 Synthesis of (S)-1-(tert-butyloxycarbonyl)indoline-2-carboxylic acid (Intermediate 1-3)
  • Step 3 Synthesis of tert-butyl (S)-2-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)indoline-1-carboxylate (Intermediate 1-4)
  • N,N'-dicyclohexylcarbodiimide (929 mg) and 4-dimethylaminopyridine (36 mg) were added to a solution of (S)-1-(tert-butyloxycarbonyl)indoline-2-carboxylic acid (intermediate 1-3) (789 mg) and 3-chloro-4-fluoro-N-methylaniline (intermediate 1-2) (478 mg) in dichloromethane (20 mL).
  • the mixture was stirred at room temperature for 12 h, and the reaction was completed after monitoring by TLC.
  • Step 4 Synthesis of (S)-N-(3-chloro-4-fluorophenyl)-N-methylindoline-2-carboxamide (Intermediate 1-5)
  • Step 5 Synthesis of (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 1)
  • Step 1 Synthesis of 1-(tert-butoxycarbonyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 2-1)
  • Step 2 Synthesis of 1-(tert-butyl)-2-methyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (Intermediate 2-2)
  • Step 3 Synthesis of 1-(tert-butyl)-2-methyl 5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (Intermediate 2-3)
  • Step 4 Synthesis of 1-(tert-butoxycarbonyl)-5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 2-4)
  • Step 5 Synthesis of tert-butyl 2-((5-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 2-5)
  • Step 6 Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-fluoro-N-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Intermediate 2-6)
  • Step 7 Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-fluoro-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 2)
  • the title compound was prepared by referring to the method of Example 1, except that 3-chloro-4-fluoroaniline in step 1 was replaced by 5-chloro-2,4-difluoroaniline.
  • intermediate 10-1 (528 mg), potassium hydroxide (210 mg) and methanol (5 mL) to water (50 mL) and stir at room temperature for 10 h. After the reaction is completed by TLC monitoring, 1N hydrochloric acid is added dropwise to adjust the pH to 3-4, and the mixture is extracted with ethyl acetate (25 mL ⁇ 3). The organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain intermediate 10-2 (423 mg).
  • Step 3 Synthesis of 1-(tert-butyloxycarbonyl)-5-chloroindoline-2-carboxylic acid (Intermediate 10-3)
  • Step 5 Synthesis of tert-butyl 5-chloro-2-((5-chloro-2,4-difluorophenyl)(methyl)carbamoyl)indoline-1-carboxylate (Intermediate 10-5)
  • Step 6 Synthesis of 5-chloro-N-(5-chloro-2,4-difluorophenyl)-N-methylindoline-2-carboxamide (Intermediate 10-6)
  • Step 7 Synthesis of 5-chloro-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 10)
  • the title compound was prepared by referring to the method of Example 10, except that 5-chloroindole-2-carboxylic acid methyl ester in step 1 was replaced by 6-chloroindole-2-carboxylic acid methyl ester.
  • the title compound was prepared by referring to the method of Example 10, except that 5-chloroindole-2-carboxylic acid methyl ester in step 1 was replaced by 4-fluoroindole-2-carboxylic acid methyl ester.
  • the title compound was prepared by referring to the method of Example 10, except that 5-chloroindole-2-carboxylic acid methyl ester was replaced by 5-fluoroindole-2-carboxylic acid methyl ester.
  • the title compound was prepared by referring to the method of Example 10, except that 5-chloroindole-2-carboxylic acid methyl ester was replaced by 4-bromoindole-2-carboxylic acid methyl ester.
  • the title compound was prepared by referring to the method of Example 10, except that 5-chloroindole-2-carboxylic acid methyl ester was replaced by 5-cyanoindole-2-carboxylic acid methyl ester.
  • the title compound was prepared by referring to the method of Example 10, except that 5-chloroindole-2-carboxylic acid methyl ester was replaced by 5-methoxyindole-2-carboxylic acid methyl ester.
  • Step 1 Synthesis of 1-(tert-butyl) 2-ethyl 1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (Intermediate 27-1)
  • Step 2 Synthesis of 1-(tert-butyl) 2-ethyl 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (Intermediate 27-2)
  • intermediate 27-1 1015 mg
  • methanol (20 mL) 5% palladium on carbon (50 mg) was added.
  • the reaction solution was stirred at room temperature under a hydrogen environment for 6 h, and the reaction was completed after monitoring by TLC.
  • Step 3 Synthesis of 1-(tert-butyloxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 27-3)
  • intermediate 27-2 (876 mg), lithium hydroxide (108 mg) and methanol (5 mL) to water (50 mL) and stir at room temperature for 10 h. After TLC monitoring, the reaction was completed, 1N hydrochloric acid was added dropwise to adjust the pH to 3-4, and the mixture was extracted with ethyl acetate (25 mL ⁇ 6). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 27-3 (660 mg).
  • Step 4 Synthesis of tert-butyl 2-((5-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 27-4)
  • Step 5 Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Intermediate 27-5)
  • Intermediate 27-4 (634 mg) was dissolved in 10% trifluoroacetic acid in dichloromethane (15 mL). The reaction solution was stirred at room temperature for 6 h, and the reaction was completed after TLC monitoring. Saturated sodium bicarbonate solution was added dropwise to the reaction solution, and the pH was adjusted to 8-9. The mixture was extracted with ethyl acetate (25 mL ⁇ 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 27-5 (323 mg).
  • Step 6 Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 27)
  • the title compound was prepared by referring to the method of Example 27, except that 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in step 1 was replaced with 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester.
  • the title compound was prepared by referring to the method of Example 27, except that 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester was replaced with 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester.
  • the title compound was prepared by referring to the method of Example 27, except that 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester was replaced with 1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester.
  • Step 3 Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(3-cyano-6-methyl-4-trifluoromethylpyridin-2-yl)indoline-2-carboxamide (Compound 32)
  • Example 1 The method of Example 1 was used with reference to the above, except that 2-chloro-6-methyl-4-(trifluoromethyl)pyridine was replaced by 2-chloro-6-methyl-4-trifluoromethylnicotinonitrile (intermediate 32-2), and 3-chloro-4-fluoroaniline was replaced by 5-chloro-2,4-difluoroaniline to obtain (S)-5-chloro-2,4-difluorophenyl-1-(3-cyano-6-methyl-4-trifluoromethylpyridin-2-yl)-N-methyldihydroindole-2-carboxamide (compound 32).
  • Step 1 Synthesis of tert-butyl 4-chloro-5-hydroxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Intermediate 33-1)
  • Step 2 Synthesis of tert-butyl 5-hydroxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Intermediate 33-2)
  • Step 3 Synthesis of tert-butyl 5-hydroxy-7-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Intermediate 33-3)
  • Step 4 Synthesis of 5-hydroxy-7-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (Intermediate 33-4)
  • Step 5 Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-hydroxy-N-methyl-7-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Compound 33)
  • N,N'-dicyclohexylcarbodiimide (310 mg) and 4-dimethylaminopyridine (13 mg) were added to a solution of intermediate 33-4 (337 mg) and intermediate 10-4 (129 mg) in dichloromethane (15 mL).
  • the mixture was stirred at room temperature for 12 h, and the reaction was completed after monitoring by TLC.
  • Step 1 Synthesis of ethyl 4-chloro-5-hydroxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Intermediate 34-1)
  • Step 2 Synthesis of ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Intermediate 34-2)
  • Step 3 Synthesis of 7-(tert-butyl)-6-ethyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6,7-dicarboxylate (Intermediate 34-3)
  • Step 4 Synthesis of 7-(tert-butyl)-6-ethyl-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine-6,7-dicarboxylate (Intermediate 34-4)
  • Step 5 Synthesis of 7-(tert-butoxycarbonyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (Intermediate 34-5)
  • Step 6 Synthesis of tert-butyl 6-((5-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (Intermediate 34-6)
  • Step 7 Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Intermediate 34-7)
  • Step 8 Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-7-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Compound 34)
  • the title compound was prepared by referring to the synthesis method of Example 27, except that the intermediate 10-4 in step 4 was replaced by 5-chloro-2-fluoro-N-methylaniline.
  • the title compound was prepared by referring to the synthesis method of Example 27, except that the intermediate 10-4 in step 4 was replaced by 6-methyl-2-methylaminopyridine.
  • the title compound was prepared by referring to the synthesis method of Example 27, except that the intermediate 10-4 in step 4 was replaced by 5-chloro-2,4-difluoro-N-(methyl-d 3 )aniline.
  • Step 1 Synthesis of 1-(tert-butyl)-2-ethyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (Intermediate 42-1)
  • Step 2 Synthesis of 1-(tert-butyl)-2-ethyl 5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (Intermediate 42-2)
  • intermediate 42-1 (1005 mg) in methanol (20 mL), 5% palladium on carbon (45 mg) was added.
  • the reaction solution was stirred at room temperature under a hydrogen environment for 6 h, and the reaction was completed after monitoring by TLC.
  • Step 3 Synthesis of 1-(tert-butyloxycarbonyl)-5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 42-3)
  • intermediate 42-2 (896 mg), lithium hydroxide (110 mg) and methanol (5 mL) to water (50 mL) and stir at room temperature for 10 h. After the reaction is completed by TLC monitoring, 1N hydrochloric acid is added dropwise to adjust the pH to 3-4, and the mixture is extracted with ethyl acetate (25 mL ⁇ 6). The organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain intermediate 42-3 (630 mg).
  • Step 4 Synthesis of tert-butyl 2-((5-chloro-2-fluorophenyl)(methyl)carbamoyl)-5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 42-4)
  • Step 5 Synthesis of N-(5-chloro-2-fluorophenyl)-5-fluoro-N-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Intermediate 42-5)
  • Step 6 Synthesis of N-(5-chloro-2-fluorophenyl)-5-fluoro-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 42)
  • the title compound was prepared by referring to the synthesis method of Example 42, except that 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in step 1 was replaced with 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester.
  • the title compound was prepared by referring to the synthesis method of Example 42, except that 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in step 1 was replaced by 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, and 5-chloro-2-fluoro-N-methylaniline in step 4 was replaced by 5-chloro-2,4-difluoroaniline.
  • Step 1 Synthesis of ethyl N-tert-butyloxycarbonyl-5-fluoroindole-2-carboxylate (Intermediate 45-1)
  • Step 2 Synthesis of 1-(tert-butyl)-2-ethyl-5-fluoroindoline-1,2-dicarboxylate (Intermediate 45-2)
  • Step 4 Synthesis of tert-butyl 5-fluoro-2-((2,4,5-trifluorophenyl)carbamoyl)indoline-1-carboxylate (Intermediate 45-4)
  • Step 5 Synthesis of tert-butyl 5-fluoro-2-((methyl-d 3 )(2,4,5-trifluorophenyl)carbamoyl)indoline-1-carboxylate (Intermediate 45-5)
  • Step 6 Synthesis of 5-fluoro-N-(methyl-d 3 )-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Intermediate 45-6)
  • Step 7 Synthesis of 5-fluoro-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 45)
  • Step 8 Synthesis of Compound 45-P1 and Compound 45-P2
  • Compound 45 was prepared and separated by supercritical fluid chromatography (chromatographic column (S,S) Whelk-01 (100mm*4.6mm I.D., 5 ⁇ m)); mobile phase A: carbon dioxide; B: ethanol (0.05% diethanolamine), flow rate 2.5mL/min, to obtain compound 45-P1 (RT: 2.923min) and compound 45-P2 (RT: 3.305min).
  • the title compound was prepared by referring to the synthesis method of Example 45, except that 2,4,5-trifluoroaniline in step 4 was replaced by 6-fluoropyridin-2-amine.
  • the title compound 48 was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced by 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, and 2,4,5-trifluoroaniline in step 4 was replaced by 5-fluoropyridine-2-amine.
  • the title compound was prepared by referring to the synthesis method of Example 45, except that 2,4,5-trifluoroaniline in step 4 was replaced by 5-fluoropyridin-2-amine.
  • the title compound was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced with 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester.
  • the title compound was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced by 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, and 2,4,5-trifluoroaniline in step 4 was replaced by 5-chloro-2,4-difluoroaniline.
  • the title compound was prepared by referring to the synthesis method of Example 45, except that only the hydrogen gas in step 2 was replaced by deuterium gas.
  • Example 54 Synthesis of 5-fluoro-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-2,3-d 2 (Compound 54)
  • the title compound was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced with 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester and hydrogen in step 2 was replaced with deuterium gas.
  • the title compound was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced by 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, the hydrogen in step 2 was replaced by deuterium gas, and the 2,4,5-trifluoroaniline in step 4 was replaced by 5-chloro-2,4-difluoroaniline.
  • the title compound was prepared by referring to the synthesis method of Example 27, except that the intermediate 10-4 in step 4 was replaced by 2,4-difluoro-N-methylaniline.
  • the title compound was prepared by referring to the synthesis method of Example 27, except that the intermediate 10-4 in step 4 was replaced by 3-chloro-2-fluoro-N-methylaniline.
  • Example 27 Referring to the synthesis method of Example 27, the only difference is that the intermediate 10-4 in step 4 is replaced by 4,5-difluoro-N-methylpyridin-2-amine to prepare the title compound).
  • the title compound was prepared by referring to the synthesis method of Example 27, except that the intermediate 10-4 in step 4 was replaced by 2,4,5-trifluoro-N-methyl-aniline.
  • the title compound was prepared by referring to the synthesis method of Example 27, except that the intermediate 10-4 in step 4 was replaced by 3,5-dichloro-2-fluoro-N-methylaniline.
  • Example 61 Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 61)
  • Tris(dibenzylideneacetone)dipalladium (15 mg), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (18 mg) and cesium carbonate (140 mg) were added to a solution of compound 40 (80 mg) and 3-hydroxy-3-aminomethyloxetane (20 mg) in 1,4-dioxane (5 mL).
  • the mixture was stirred at 100°C for 6 h under nitrogen protection, and the reaction was completed after monitoring by TLC.
  • Example 65 Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 65)
  • Example 66 Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-(1-(3-methoxypropyl)-1H-pyrazol-4-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 66)
  • Example 70 Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-5-(4-(2-methoxyethyl)piperidin-1-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 70)
  • the title compound was prepared by referring to the method of Example 1, except that the intermediate 1-2 in step 3 was replaced by 5-chloro-2-fluoro-N-methylaniline.
  • the title compound was prepared by referring to the synthesis method of Example 10, except that 5-chloro-2,4-difluoro-N-methylaniline was replaced by 5-chloro-2-fluoro-N-methylaniline.
  • the title compound was prepared by referring to the synthesis method of Example 27, except that 2-chloro-6-methyl-4-(trifluoromethyl)pyridine in step 6 was replaced by 2-chloro-4,6-bis(trifluoromethyl)pyridine.
  • the title compound was prepared by referring to the synthesis method of Example 27, except that 2-chloro-6-methyl-4-(trifluoromethyl)pyridine in step 6 was replaced by 2-chloro-4,6-dimethylpyridine.
  • Example 10 The synthetic method of Example 10 is referred to, except that 5-chloroindole-2-carboxylic acid methyl ester in step 1 is replaced by 3-methylindole-2-carboxylic acid
  • the title compound was prepared by ethyl ester.
  • Example 77 Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-3-d (Compound 77)
  • Step 1 Synthesis of 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid-3-d-ethyl ester (Intermediate 77-2)
  • Step 2 Synthesis of 1-(tert-butyl)-2-ethyl-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate-3-d (Intermediate 77-3)
  • Step 3 Synthesis of 1-(tert-butyl)-2-ethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate-3-d (Intermediate 77-4)
  • intermediate 77-3 (883 mg) in methanol (20 mL).
  • 5% palladium on carbon 60 mg was added.
  • the reaction solution was stirred at room temperature under a hydrogen environment for 8 h, and the reaction was completed after monitoring by TLC.
  • Step 4 Synthesis of 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid-3-d (Intermediate 77-5)
  • Step 5 Synthesis of tert-butyl 2-((5-chloro-2,4-difluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate-3-d (Intermediate 77-6)
  • N,N'-dicyclohexylcarbodiimide (715 mg) and 4-dimethylaminopyridine (20 mg) were added to a solution of intermediate 77-5 (574 mg) and 5-chloro-2,4-difluoroaniline (398 mg) in dichloromethane (20 mL).
  • the mixture was stirred at room temperature for 12 h.
  • the reaction was completed after monitoring by TLC.
  • Step 6 Synthesis of tert-butyl 2-((5-chloro-2,4-difluorophenyl)(methyl-d 3 )carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate-3-d (77-7)
  • intermediate 77-6 Sodium hydride (35 mg) and deuterated iodomethane (200 mg) were added to a solution of intermediate 77-6 (553 mg) in N,N-dimethylformamide (10 mL). Stir at 0°C for 4 h and monitor the completion of the reaction by TLC. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL ⁇ 4). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 77-7 (528 mg).
  • Step 7 Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-(methyl-d 3 )-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-3-d (Intermediate 77-8)
  • Step 8 Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-3-d (Compound 77)
  • Step 1 Synthesis of 5-bromo-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Intermediate 78-1)
  • Step 2 Synthesis of 5-(4-(2-methoxyethyl)piperazin-1-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl))-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 78)
  • the title compound was prepared by referring to the synthesis method of Example 13, except that 5-chloro-2,4-difluoroaniline was replaced by 4-ethoxy-2,5-difluoroaniline.
  • the title compound was prepared by referring to the synthesis method of Example 13, except that 5-chloro-2,4-difluoroaniline was replaced by 5-ethoxy-2,4-difluoroaniline.
  • the title compound was prepared by referring to the synthesis method of Example 13, except that 5-chloro-2,4-difluoroaniline was replaced by 2-ethoxy-4,5-difluoroaniline.
  • the title compound was prepared by referring to the synthesis method of Example 13, except that 5-chloro-2,4-difluoroaniline was replaced by 2,4,5-trifluoroaniline.
  • the title compound was prepared by referring to the synthesis method of Example 45, except that 2-chloro-6-methyl-4-(trifluoromethyl)pyridine was replaced by 5-chloro-7-(trifluoromethyl)thiazolo[5,4-b]pyridine.
  • the title compound was prepared by referring to the synthesis method of Example 45, except that 2-chloro-6-methyl-4-(trifluoromethyl)pyridine was replaced by 5-chloro-7-(trifluoromethyl)furo[3,2-b]pyridine.
  • Step 2 Synthesis of 5-fluoro-N-(methyl-d 3 )-1-(4-(dimethylphosphoryl)-6-methylpyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 85)
  • the title compound was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced with 5-methanesulfonyl-1H-indole-2-carboxylic acid methyl ester.
  • the title compound was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced with 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester.
  • the title compound was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced with 5-fluoro-6-methoxy-1H-indole-2-carboxylic acid methyl ester.
  • Step 1 Synthesis of (S)-5-bromo-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Intermediate 90-1)
  • Step 2 Synthesis of (S)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(3-(methylsulfonyl)azetidin-1-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 90)
  • the title compound was prepared by referring to the synthesis method of Example 90, except that 3-(methylsulfonyl)azetidine hydrochloride in step 2 was replaced by 2-oxazole-7-azaspiro[3.5]nonane.
  • Step 1 Synthesis of tert-butyl (S)-2-((2,4,5-trifluorophenyl)carbamoyl)indoline-1-carboxylate (Intermediate 92-1)
  • Step 2 Synthesis of (S)-tert-butyl 2-((methyl-d 3 )(2,4,5-trifluorophenyl)carbamoyl)indoline-1-carboxylate (Intermediate 92-2)
  • Step 3 Synthesis of (S)-N-(methyl-d 3 )-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Intermediate 92-3)
  • Step 4 Synthesis of (S)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 92)
  • Step 1 Synthesis of (S)-5-bromo-N-(2,4,5-trifluorophenyl)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Intermediate 93-1)
  • Step 2 Synthesis of (S)-5-(4-(2-methoxyethyl)piperazin-1-yl)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 93)
  • 1,1-Bis(diphenylphosphino)diboraneferronichloridepalladium(10mg) and sodium carbonate(50mg) were added to a solution of intermediate 93-1(80mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-propionitrile(36mg) in 1,4-dioxane(5mL).
  • Step 1 Synthesis of 1-(tert-butoxycarbonyl)-5,6-difluoroindoline-2-carboxylic acid (Intermediate 95-1)
  • Step 2 Synthesis of tert-butyl 5,6-difluoro-2-((2,4,5-trifluorophenyl)carbamoyl)indoline-1-carboxylate (Intermediate 95-2)
  • Step 3 Synthesis of tert-butyl 5,6-difluoro-2-((2,4,5-trifluorophenyl)carbamoyl)indoline-1-carboxylate (Intermediate 95-3)
  • Step 4 Synthesis of 5,6-difluoro-N-methyl-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Intermediate 7-4)
  • Step 5 Synthesis of 5,6-difluoro-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 95)
  • N-terminal active peptide segment (M1-N899) of POLQ with ATPase activity is incubated with the compound, it reacts with the substrate dT50 under the action of ATP to generate ADP, participates in the subsequent NADH oxidation-coupled enzymatic reaction, and catalyzes the reaction of NADH to generate NAD + .
  • the decrease in the OD value of NADH at 340nm is measured using the Envision microplate reader from Perkin Elmer, thereby reflecting the enzyme activity.
  • POLQ enzyme was diluted to 100 nM in reaction buffer (20 mM Tris HCl (pH 7.80), 80 mM KCl, 10 mM MgCl 2 , 1 mM DTT (dithiothreitol), 0.01% w/v bovine serum albumin, 0.01% v/v Tween-20, 5% v/v glycerol).
  • the test compound was diluted to different concentrations in dimethyl sulfoxide (DMSO) using the Echo 650 pipetting system, transferred to a 384-well plate, and 20 ⁇ L/well of 100 nM POLQ was added and incubated at room temperature for 15 minutes.
  • DMSO dimethyl sulfoxide
  • the reaction mixture solution was prepared, and the concentrations of the components in the reaction mixture solution were: 100 ⁇ M ATP, 300 nM dT50, 300 ⁇ M NADH, 6 mM PEP, 10 U/mL lactate dehydrogenase and 20 U/mL pyruvate kinase. 20 ⁇ L/well of the reaction mixture solution was added to start the enzyme reaction. The final concentration of the compound in the reaction system started from 10 ⁇ M, and was diluted 3 times in a gradient, ranging from 10 ⁇ M to 0.0005 ⁇ M, and the final concentration of DMSO in the system was 0.2% v/v. After the 384-well plate was placed at room temperature for 20 minutes, the OD value at 340 nm was read using an Envision microplate reader.
  • the inhibition rate was calculated and the IC 50 of the compound was obtained by fitting using XLfit software.
  • the experiment set up a blank group and a DMSO group.
  • the reaction system of the blank group was 0.2% v/v DMSO and reaction mixture solution, and the inhibition rate was considered to be 100% at this time;
  • the reaction system of the DMSO group was 0.2% v/v DMSO, POLQ (N) (100nM) and reaction mixture solution, and the inhibition rate was considered to be 100% at this time.
  • the rate is 0.
  • Inhibition rate (%) (100-100*(OD max -OD compound )/(OD max -OD min ))%
  • OD max refers to the OD value of the well containing the reactant mixture and 0.2% v/v DMSO
  • OD compound refers to the OD value of the well containing the compound, enzyme and reactant mixture
  • OD min refers to the OD value of the well containing the enzyme, reactant mixture and 0.2% v/v DMSO.
  • Test Example 2 Experiment on the inhibition of tumor cell proliferation by compounds
  • DLD-1 parental cells or DLD-1BRCA2 (-/-) cells were diluted with RPMI 1640 medium containing 10% FBS and added to 96-well plates (90 ⁇ L/well). The number of cells was 600/well or 1200/well, respectively, and cultured in a 37°C, 5% CO 2 incubator overnight.
  • the test compound was diluted to different concentrations in dimethyl sulfoxide (DMSO) and added to the 96-well plate.
  • DMSO dimethyl sulfoxide
  • the final concentration of the compound in the reaction system started from 25 ⁇ M, and the concentration range of the compound was 4 times dilution. The concentration range was 25 ⁇ M to 0.0004 ⁇ M, and the final concentration of DMSO was 0.25% v/v.
  • 50 ⁇ L/well CTG was added and incubated at room temperature for 10 minutes.
  • the light signal value (Lum) was read using an Envision microplate reader, and the inhibition rate and half inhibition concentration (IC 50 ) were calculated.
  • the inhibition rate was calculated and the IC 50 of the compound was obtained by fitting using XLfit software.
  • the experiment set up blank wells and DMSO wells.
  • the blank wells were 100 ⁇ L of RPMI Medium 1640 culture medium containing 10% FBS, and the inhibition rate of the compound on tumor cell growth was considered to be 100% at this time; the DMSO wells were cell wells with 0.25% v/v DMSO added, and the inhibition rate of the compound on tumor cell growth was considered to be 0 at this time.
  • Inhibition rate 100*(Lum max -Lum compound )/(Lum max -Lum min )%
  • Lum max refers to the light signal value of the well containing cells and 0.25% v/v DMSO
  • Lum compound refers to the light signal value of the well containing compound and cells
  • Lum min refers to the light signal value of the well containing culture medium and 0.25% v/v DMSO.
  • the example compounds of the present application have a good inhibitory effect on BRCA2 mutated tumor cells and have good selectivity.

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Abstract

Provided in the present disclosure are a nitrogen-containing fused ring compound as represented by formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, a pharmaceutical composition containing same, and the use thereof in the preparation of a drug for preventing or treating DNA polymerase θ-mediated diseases.

Description

含氮并环类化合物及其应用Nitrogen-containing cyclic compounds and their applications
相关申请的交叉引用CROSS-REFERENCE TO RELATED APPLICATIONS
本公开要求于2023年01月18日向中华人民共和国国家知识产权局提交的第202310201796.6号中国发明专利申请和于2023年09月08日向中华人民共和国国家知识产权局提交的第202311160314.3号中国发明专利申请的权益和优先权，在此将它们的全部内容以援引的方式整体并入本公开中。This disclosure claims the rights and priority of Chinese invention patent application No. 202310201796.6 filed with the State Intellectual Property Office of the People's Republic of China on January 18, 2023, and Chinese invention patent application No. 202311160314.3 filed with the State Intellectual Property Office of the People's Republic of China on September 8, 2023, the entire contents of which are hereby incorporated by reference into this disclosure in their entirety.
技术领域Technical Field
本公开属于医药领域，具体的涉及一种含氮并环类化合物或其药学可接受的盐或其立体异构体、含有它们的药物组合物、以及其作为DNA聚合酶θ抑制剂在预防或治疗相关疾病中的用途。The present disclosure belongs to the field of medicine, and specifically relates to a nitrogen-containing cyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof, a pharmaceutical composition containing them, and use of the compound as a DNA polymerase θ inhibitor in preventing or treating related diseases.
背景技术Background technique
DNA双链断裂修复对于维持基因组稳定性和细胞存活至关重要。DNA双链断裂有三条主要的修复通路：同源重组(HR)、非同源末端连接(NHEJ)和非传统的非同源末端连接(alt-MEJ)。微同源介导的末端连接(MMEJ)是最常见的非同源末端连接和非传统的非同源末端连接。同源重组是一种高保真的、准确无误的修复机制，可以维持基因组稳定性，避免诱发癌症。而非同源末端连接和微同源介导的末端连接属于易错修复通路，会导致修复位点出现突变。DNA double-strand break repair is essential for maintaining genome stability and cell survival. There are three main repair pathways for DNA double-strand breaks: homologous recombination (HR), non-homologous end joining (NHEJ), and non-conventional non-homologous end joining (alt-MEJ). Microhomology-mediated end joining (MMEJ) is the most common non-homologous end joining and non-conventional non-homologous end joining. Homologous recombination is a high-fidelity, accurate repair mechanism that can maintain genome stability and avoid inducing cancer. Non-homologous end joining and microhomology-mediated end joining are error-prone repair pathways that can lead to mutations at the repair site.
与正常细胞不同，肿瘤细胞的生存通常依赖于DNA双链断裂修复的错误调控。同时，异常的DNA双链断裂修复可以使肿瘤细胞对于特定类型的DNA损伤更加敏感。因此，可以利用DNA双链断裂修复缺陷来开发靶向肿瘤治疗。同源重组或非同源末端连接修复受损的肿瘤细胞会更依赖于微同源介导的末端连接修复。遗传学、细胞生物学和生物化学的多重证据表明DNA聚合酶θ(POLQ或POLθ)是微同源介导的末端连接修复过程中的关键蛋白(Kent et al.Nature Structural&Molecular Biology(2015),22(3),230-237,Mateos-Gomez et al.Nature(2015),518(7538),254-257)。Unlike normal cells, the survival of tumor cells often depends on the misregulation of DNA double-strand break repair. At the same time, abnormal DNA double-strand break repair can make tumor cells more sensitive to specific types of DNA damage. Therefore, defects in DNA double-strand break repair can be used to develop targeted tumor therapies. Tumor cells with impaired homologous recombination or non-homologous end joining repair are more dependent on microhomology-mediated end joining repair. Multiple lines of evidence from genetics, cell biology, and biochemistry indicate that DNA polymerase θ (POLQ or POLθ) is a key protein in the microhomology-mediated end joining repair process (Kent et al. Nature Structural & Molecular Biology (2015), 22(3), 230-237, Mateos-Gomez et al. Nature (2015), 518(7538), 254-257).
POLQ是一个由N端的解旋酶结构域(SF2HEL308-type)和C端的低保真DNA聚合酶结构域(A-type)组成的多功能酶(Wood&Doublie DNA Repair(2016),44,22-32)。解旋酶结构域介导了RPA蛋白从单链DNA上的移除并促进退火，聚合酶结构域可以延伸单链DNA末端并填补缝隙，两个结构域共同协作在微同源介导的末端连接修复过程中发挥功能。POLQ is a multifunctional enzyme consisting of an N-terminal helicase domain (SF2HEL308-type) and a C-terminal low-fidelity DNA polymerase domain (A-type) (Wood & Doublie DNA Repair (2016), 44, 22-32). The helicase domain mediates the removal of RPA protein from single-stranded DNA and promotes annealing, while the polymerase domain can extend the ends of single-stranded DNA and fill the gaps. The two domains work together to play a role in the microhomology-mediated end-joining repair process.
研究表明，POLQ对于同源重组缺陷的细胞至关重要(例如与FA/BRCA缺陷的合成致死)，并且POLQ在同源重组缺陷的肿瘤细胞中蛋白水平上调(Ceccaldi et al.Nature(2015),518(7538),258-262)。体内研究结果也表明，POLQ在一系列同源重组缺陷且预后差的卵巢癌、子宫癌和乳腺癌中过表达(Higgins et al.Oncotarget(2010),1,175-184,Lemee et al.PNAS(2010),107(30),13390-13395,Ceccaldi et al.(2015),supra)。更重要的是，与肿瘤组织相比，正常组织中POLQ的表达是被抑制的(Kawamura et al.International Journal of Cancer(2004),109(1),9-16)。Studies have shown that POLQ is essential for cells with homologous recombination defects (such as synthetic lethality with FA/BRCA defects), and that POLQ protein levels are upregulated in tumor cells with homologous recombination defects (Ceccaldi et al. Nature (2015), 518 (7538), 258-262). In vivo studies have also shown that POLQ is overexpressed in a series of homologous recombination-deficient and poorly prognostic ovarian, uterine and breast cancers (Higgins et al. Oncotarget (2010), 1, 175-184, Lemee et al. PNAS (2010), 107 (30), 13390-13395, Ceccaldi et al. (2015), supra). More importantly, compared with tumor tissues, the expression of POLQ is inhibited in normal tissues (Kawamura et al. International Journal of Cancer (2004), 109(1), 9-16).
综上所述，POLQ对于同源重组缺陷的细胞至关重要，目前同源重组缺陷肿瘤的治疗还有未满足的市场需求。抑制POLQ的功能可以抑制细胞的微同源介导的末端连接修复，POLQ功能抑制剂的开发可以为同源重组缺陷肿瘤靶向治疗提供一个全新的策略。In summary, POLQ is essential for cells with homologous recombination defects, and there is currently an unmet market demand for the treatment of homologous recombination defective tumors. Inhibiting the function of POLQ can inhibit microhomology-mediated end joining repair in cells, and the development of POLQ function inhibitors can provide a new strategy for targeted treatment of homologous recombination defective tumors.
发明内容Summary of the invention
本公开涉及式(I)化合物或其药学上可接受的盐或其立体异构体，
The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
其中，代表单键或双键；in, represents a single bond or a double bond;
Q1选自N、CH或CR1；Q 1 is selected from N, CH or CR 1 ;
Q2选自N、CH或CR2；Q 2 is selected from N, CH or CR 2 ;
Q3选自N、CH或CR3；Q 3 is selected from N, CH or CR 3 ;
Q4选自N或CH；Q 4 is selected from N or CH;
所述R1选自卤素、氰基、羟基、C1-C10烷基、C1-C10烷氧基、3-12元杂环烷基、-Y-NR1AR1AA、B(OH)2或-Z-5-10元杂芳基，所述3-12元杂环烷基或5-10元杂芳基任选被R1a取代；The R 1 is selected from halogen, cyano, hydroxyl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocycloalkyl, -Y-NR 1A R 1AA , B(OH) 2 or -Z-5-10 membered heteroaryl, and the 3-12 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted by R 1a ;
Y选自键、C(O)、(CH2)p或C3-C8亚环烷基；Y is selected from a bond, C(O), (CH 2 ) p or C 3 -C 8 cycloalkylene;
Z选自键或(CH2)r；Z is selected from a bond or (CH 2 ) r ;
所述R1a选自卤素、羟基、氰基、氨基、氧代、SH、C1-C6烷基、-S(O)2-R1a’、-C(O)C1-C6烷基、-B(OH)2、5-10元杂芳基、C1-C6烷氧基、C3-C8环烷基、-NHC(O)C1-C6烷基、-NH(C1-C6烷基)或-N(C1-C6烷基)2，所述C1-C6烷基、-C(O)C1-C6烷基、5-10元杂芳基、C1-C6烷氧基、C3-C8环烷基、-NHC(O)C1-C6烷基、-NH(C1-C6烷基)或-N(C1-C6烷基)2任选被R1b取代；Said R 1a is selected from halogen, hydroxyl, cyano, amino, oxo, SH, C 1 -C 6 alkyl, -S(O) 2 -R 1a ', -C(O)C 1 -C 6 alkyl, -B(OH) 2 , 5-10 membered heteroaryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, -NHC(O)C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 , said C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, 5-10 membered heteroaryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, -NHC(O)C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 is optionally substituted by R 1b ;
所述R1A、R1AA各自独立地选自氢、C1-C6烷基、-C(O)H、-C(O)C1-C6烷基、-S(O)2-R1A’或-C(O)OC1-C6烷基，所述C1-C6烷基、-C(O)C1-C6烷基或-C(O)OC1-C6烷基任选被R1B取代；Said R 1A , R 1AA are each independently selected from hydrogen, C 1 -C 6 alkyl, -C(O)H, -C(O)C 1 -C 6 alkyl, -S(O) 2 -R 1A 'or -C(O)OC 1 -C 6 alkyl, said C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl or -C(O)OC 1 -C 6 alkyl are optionally substituted by R 1B ;
所述R1B选自卤素、羟基、氰基、氨基、SH、C1-C6烷氧基或4-10元杂环烷基，所述4-10元杂环烷基任选被R1C取代；The R 1B is selected from halogen, hydroxyl, cyano, amino, SH, C 1 -C 6 alkoxy or 4-10 membered heterocycloalkyl, and the 4-10 membered heterocycloalkyl is optionally substituted by R 1C ;
所述R2选自卤素、氰基、羟基、-COOH、-CONH2、-COOC1-C10烷基、-CONH(C1-C10烷基)、-CON(C1-C10烷基)2、-S(O)2(C1-C6烷基)、-S(O)2(C3-C6环烷基)、C3-C10环烷基、C6-C14芳基、C1-C10烷基、C1-C10烷氧基、3-12元杂环基、-T-NR2AR2AA、B(OH)2或-L-5-10元杂芳基，所述-COOC1-C10烷基、-CONH(C1-C10烷基)、-CON(C1-C10烷基)2、-S(O)2(C1-C6烷基)、-S(O)2(C3-C6环烷基)、C3-C10环烷基、C6-C14芳基、C1-C10烷基、C1-C10烷氧基、3-12元杂环基或5-10元杂芳基任选被R2a取代；The R 2 is selected from halogen, cyano, hydroxyl, -COOH, -CONH 2 , -COOC 1 -C 10 alkyl, -CONH(C 1 -C 10 alkyl), -CON(C 1 -C 10 alkyl) 2 , -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (C 3 -C 6 cycloalkyl), C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocyclyl, -T-NR 2A R 2AA , B(OH) 2 or -L-5-10 membered heteroaryl, the -COOC 1 -C 10 alkyl, -CONH(C 1 -C 10 alkyl), -CON(C 1 -C 10 alkyl) 2 , -S(O) 2 (C 1 -C 6 alkyl ), -S(O) 2 (C 3 -C 6 cycloalkyl), C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocyclyl, -T-NR 2A R 2AA , B(OH) 2 or -L - 5-10 membered heteroaryl. R 2a is optionally substituted with -S(O) 2 (C 3 -C 6 alkyl), -S(O) 2 (C 3 -C 6 cycloalkyl), C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocyclyl or 5-10 membered heteroaryl;
T选自键、C(O)、(CH2)m或C3-C8亚环烷基；T is selected from a bond, C(O), (CH 2 ) m or C 3 -C 8 cycloalkylene;
L选自键或(CH2)n；L is selected from a bond or (CH 2 ) n ;
所述R2a选自卤素、羟基、氰基、氨基、氧代、SH、C1-C6烷基、-S(O)2-R2a’、-C(O)C1-C6烷基、-B(OH)2、5-10元杂芳基、C1-C6烷氧基、C3-C8环烷基、-NHC(O)C1-C6烷基、-NH(C1-C6烷基)或-N(C1-C6烷基)2，所述C1-C6烷基、-C(O)C1-C6烷基、5-10元杂芳基、C1-C6烷氧基、C3-C8环烷基、-NHC(O)C1-C6烷基、-NH(C1-C6烷基)或-N(C1-C6烷基)2任选被R2b取代；Said R 2a is selected from halogen, hydroxyl, cyano, amino, oxo, SH, C 1 -C 6 alkyl, -S(O) 2 -R 2a ', -C(O)C 1 -C 6 alkyl, -B(OH) 2 , 5-10 membered heteroaryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, -NHC(O)C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 , said C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, 5-10 membered heteroaryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, -NHC(O)C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 is optionally substituted by R 2b ;
所述R2A、R2AA各自独立地选自氢、C1-C6烷基、-C(O)H、-C(O)C1-C6烷基、-S(O)2-R2A’或-C(O)OC1-C6烷基，所述C1-C6烷基、-C(O)C1-C6烷基或-C(O)OC1-C6烷基任选被R2B取代；Said R 2A , R 2AA are each independently selected from hydrogen, C 1 -C 6 alkyl, -C(O)H, -C(O)C 1 -C 6 alkyl, -S(O) 2 -R 2A 'or -C(O)OC 1 -C 6 alkyl, said C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl or -C(O)OC 1 -C 6 alkyl are optionally substituted by R 2B ;
所述R2B选自卤素、羟基、氰基、氨基、SH、C1-C6烷氧基、4-10元杂环烷基、-S(O)2-(C1-C6烷基)或-S(O)2-(C3-C6环烷基)，所述4-10元杂环烷基任选被R2C取代；The R 2B is selected from halogen, hydroxyl, cyano, amino, SH, C 1 -C 6 alkoxy, 4-10 membered heterocycloalkyl, -S(O) 2 -(C 1 -C 6 alkyl) or -S(O) 2 -(C 3 -C 6 cycloalkyl), and the 4-10 membered heterocycloalkyl is optionally substituted by R 2C ;
所述R1a’、R1A’、R2a’、R2A’各自独立地选自C1-C6烷基或C3-C6环烷基；The R 1a ', R 1A ', R 2a ', and R 2A ' are each independently selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
所述R3选自卤素、羟基、氨基、C1-C10烷基、C1-C10烷氧基、C3-C10环烷基、-NH(C1-C10烷基)、-N(C1-C10烷基)2、3-12元杂环基或-U-5-10元杂芳基，所述C1-C10烷基、C1-C10烷氧基、C3-C10环烷基、-NH(C1-C10烷基)、-N(C1-C10烷基)2、3-12元杂环基、5-10元杂芳基任选被R3a取代；The R 3 is selected from halogen, hydroxyl, amino, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, -NH(C 1 -C 10 alkyl), -N(C 1 -C 10 alkyl) 2 , 3-12 membered heterocyclyl or -U-5-10 membered heteroaryl, and the C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, -NH(C 1 -C 10 alkyl), -N(C 1 -C 10 alkyl) 2 , 3-12 membered heterocyclyl, 5-10 membered heteroaryl are optionally substituted by R 3a ;
U选自键、(CH2)q或3-12元亚杂环烷基；U is selected from a bond, (CH 2 ) q or a 3-12 membered heterocycloalkylene group;
所述R1b、R1C、R2b、R2C、R3a各自独立地选自卤素、羟基、氰基、氨基、氧代、C1-C6烷基、C1-C6烷氧基或4-12元杂环基，所述C1-C6烷基、C1-C6烷氧基或4-12元杂环基任选被R1c取代；R 1b , R 1c , R 2b , R 2c , and R 3a are each independently selected from halogen, hydroxy, cyano, amino, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or 4-12 membered heterocyclyl, and the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or 4-12 membered heterocyclyl is optionally substituted by R 1c ;
R1c选自卤素、羟基、氨基、C1-C6烷基或C1-C6烷氧基；R 1c is selected from halogen, hydroxy, amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
X选自N或CR4；X is selected from N or CR 4 ;
R4、R5、R6、R7和R8各自独立地选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C3-C8环烷基、C1-C6卤代烷基、-NH(C1-C6烷基)或-N(C1-C6烷基)2；或者R4、R5、R6、R7和R8中任意两个相邻的基团与它们相连的原子共同形成5-7元不饱和环，所述不饱和环任选地包含一个或多个选自O、N或S的杂原子，且所述不饱和环任选被R4a取代； R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 ; or any two adjacent groups of R 4 , R 5 , R 6 , R 7 and R 8 and the atoms to which they are attached together form a 5-7 membered unsaturated ring, the unsaturated ring optionally containing one or more heteroatoms selected from O, N or S, and the unsaturated ring is optionally substituted by R 4a ;
R4a选自C1-C6烷基或卤素；R 4a is selected from C 1 -C 6 alkyl or halogen;
R9选自H、卤素、OH、氘或任选被羟基取代的C1-C6烷基；R 9 is selected from H, halogen, OH, deuterium or C 1 -C 6 alkyl optionally substituted with hydroxyl;
R10选自甲基或氘代甲基；R 10 is selected from methyl or deuterated methyl;
M选自N或CR11；M is selected from N or CR 11 ;
R11、R12、R13和R14各自独立地选自氢、卤素、氰基、C1-C6烷基、C2-C6烯基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C3-C8环烷基、-P(O)(C1-C6烷基)2或NR11AR11AA；或者R13和R14以及它们所连接的碳原子一起形成5-10元杂芳环；R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, -P(O)(C 1 -C 6 alkyl) 2 or NR 11A R 11AA ; or R 13 and R 14 and the carbon atoms to which they are attached together form a 5-10 membered heteroaromatic ring;
R11A、R11AA各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基、C3-C8环烷基、-COC1-C6烷基或3-12元杂环基，所述C1-C6烷基、C1-C6卤代烷基、C3-C8环烷基或-COC1-C6烷基任选被R11B取代，所述3-12元杂环基任选被R11B’取代；R 11A and R 11AA are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, -COC 1 -C 6 alkyl or 3-12 membered heterocyclyl, the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl or -COC 1 -C 6 alkyl is optionally substituted by R 11B , the 3-12 membered heterocyclyl is optionally substituted by R 11B ';
所述R11B选自羟基或氨基；The R 11B is selected from hydroxyl or amino;
所述R11B’选自氧代、羟基、C1-C6烷醇或-COC1-C6烷基；The R 11B ' is selected from oxo, hydroxyl, C 1 -C 6 alkanol or -COC 1 -C 6 alkyl;
p、r、m、n、q各自独立地选自1、2、3、4、5或6；p, r, m, n, q are each independently selected from 1, 2, 3, 4, 5 or 6;
当代表双键时，R15不存在；当代表单键时，R15选自氢或氘。when When represents a double bond, R 15 does not exist; when When represents a single bond, R 15 is selected from hydrogen or deuterium.
在一些实施方案中，是单键。In some embodiments, It is a single bond.
在一些实施方案中，是双键。In some embodiments, It's a double bond.
在一些实施方案中，当代表双键时，R15不存在；当代表单键时，R15选自氢。In some embodiments, when When represents a double bond, R 15 does not exist; when When represents a single bond, R 15 is selected from hydrogen.
在一些实施方案中，当Q1选自CR1时，Q2不是CR2并且Q3不是CR3。In some embodiments, when Q 1 is selected from CR 1 , Q 2 is not CR 2 and Q 3 is not CR 3 .
在一些实施方案中，Q1选自CH或CR1，Q2选自CH或CR2，Q3选自CH或CR3，且Q4选自CH；或者Q1、Q2、Q3或Q4中至少一个选自N。In some embodiments, Q 1 is selected from CH or CR 1 , Q 2 is selected from CH or CR 2 , Q 3 is selected from CH or CR 3 , and Q 4 is selected from CH; or at least one of Q 1 , Q 2 , Q 3 or Q 4 is selected from N.
在一些实施方案中，Q1选自CH或CR1，Q2选自CH或CR2，Q3选自CH或CR3，且Q4选自CH；或者Q1、Q2、Q3或Q4中一个选自N；或者Q2、Q4中均选自N，Q1选自CH或CR1，Q3选自CH或CR3。In some embodiments, Q1 is selected from CH or CR1 , Q2 is selected from CH or CR2 , Q3 is selected from CH or CR3 , and Q4 is selected from CH; or one of Q1 , Q2 , Q3 or Q4 is selected from N; or both Q2 and Q4 are selected from N, Q1 is selected from CH or CR1 , and Q3 is selected from CH or CR3 .
在一些实施方案中，Q1选自N或CH。In some embodiments, Q 1 is selected from N or CH.
在一些实施方案中，选自 其中*表示与N连接，其中，R1、R2、R3如上文的定义。In some embodiments, Selected from Wherein * represents connection with N, wherein R 1 , R 2 , and R 3 are as defined above.
在一些实施方案中，选自 其中*表示与N连接，其中，R1、R2、R3如上文的定义。In some embodiments, Selected from Wherein * represents connection with N, wherein R 1 , R 2 , and R 3 are as defined above.
在一些实施方案中，选自 其中*表示与N连接，其中，R1、R2、R3如上文的定义。In some embodiments, Selected from Wherein * represents connection with N, wherein R 1 , R 2 , and R 3 are as defined above.
在一些实施方案中，选自其中*表示与N连接，其中，R2如上文的定义。In some embodiments, Selected from Wherein * indicates connection with N, wherein R 2 is as defined above.
在一些实施方案中，R1选自卤素、氰基、羟基、C1-C6烷氧基或-Y-NR1AR1AA。In some embodiments, R 1 is selected from halogen, cyano, hydroxy, C 1 -C 6 alkoxy, or -Y-NR 1A R 1AA .
在一些实施方案中，R1选自卤素或-Y-NR1AR1AA。In some embodiments, R 1 is selected from halogen or -Y-NR 1A R 1AA .
在一些实施方案中，Y选自键。In some embodiments, Y is selected from a bond.
在一些实施方案中，R1选自卤素或-NR1AR1AA。In some embodiments, R 1 is selected from halogen or —NR 1A R 1AA .
在一些实施方案中，R1A、R1AA各自独立地选自氢、C1-C6烷基、-S(O)2-R1A’或-C(O)OC1-C6烷基，所述C1-C6烷基或-C(O)OC1-C6烷基任选被R1B取代。In some embodiments, R 1A , R 1AA are each independently selected from hydrogen, C 1 -C 6 alkyl, —S(O) 2 —R 1A ′, or —C(O)OC 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl or —C(O)OC 1 -C 6 alkyl is optionally substituted with R 1B .
在一些实施方案中，R1A、R1AA各自独立地选自氢或-S(O)2-R1A’。In some embodiments, R 1A , R 1AA are each independently selected from hydrogen or —S(O) 2 —R 1A ′.
在一些实施方案中，R1A为氢，R1AA为-S(O)2-R1A’。In some embodiments, R 1A is hydrogen and R 1AA is -S(O) 2 -R 1A '.
在一些实施方案中，R1A’选自C3-C6环烷基。In some embodiments, R 1A ′ is selected from C 3 -C 6 cycloalkyl.
在一些实施方案中，R1A’选自环丙基。In some embodiments, R 1A ′ is selected from cyclopropyl.
在一些实施方案中，R1选自F、Br或 In some embodiments, R 1 is selected from F, Br or
在一些实施方案中，R1选自F或 In some embodiments, R 1 is selected from F or
在一些实施方案中，R2选自卤素、氰基、羟基、-S(O)2(C1-C6烷基)、C1-C10烷基、C1-C10烷氧基、3-12元杂环烷基、-T-NR2AR2AA、B(OH)2或-L-5-10元杂芳基，所述-S(O)2(C1-C6烷基)、C1-C10烷基、C1-C10烷氧基、3-12元杂环烷基或5-10元杂芳基任选被R2a取代。In some embodiments, R 2 is selected from halogen, cyano, hydroxyl, -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocycloalkyl, -T-NR 2A R 2AA , B(OH) 2 , or -L-5-10 membered heteroaryl, and the -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with R 2a .
在一些实施方案中，所述R2选自卤素、氰基、羟基、-S(O)2(C1-C6烷基)、C1-C8烷基、C1-C8烷氧基、3-12元杂环基、-T-NR2AR2AA、B(OH)2或-L-5-10元杂芳基，所述C1-C8烷基、C1-C8烷氧基、-S(O)2(C1-C6烷基)、3-12元杂环基或5-10元杂芳基任选被R2a取代。In some embodiments, the R 2 is selected from halogen, cyano, hydroxyl, -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 8 alkyl, C 1 -C 8 alkoxy, 3-12 membered heterocyclyl, -T-NR 2A R 2AA , B(OH) 2 or -L-5-10 membered heteroaryl, and the C 1 -C 8 alkyl, C 1 -C 8 alkoxy, -S(O) 2 (C 1 -C 6 alkyl), 3-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted with R 2a .
在一些实施方案中，R2选自卤素、氰基、羟基、C1-C10烷基、C1-C10烷氧基、3-12元杂环烷基、 -T-NR2AR2AA、B(OH)2或-L-5-10元杂芳基，所述3-12元杂环烷基或5-10元杂芳基任选被R2a取代。In some embodiments, R 2 is selected from halogen, cyano, hydroxyl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocycloalkyl, -T-NR 2A R 2AA , B(OH) 2 or -L-5-10 membered heteroaryl, said 3-12 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted with R 2a .
在一些实施方案中，所述R2选自卤素、氰基、羟基、C1-C8烷基、C1-C8烷氧基、4-12元杂环基、-T-NR2AR2AA、B(OH)2或-L-5-10元杂芳基，所述C1-C8烷基、C1-C8烷氧基、4-12元杂环基或5-10元杂芳基任选被R2a取代。In some embodiments, the R 2 is selected from halogen, cyano, hydroxyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, 4-12 membered heterocyclyl, -T-NR 2A R 2AA , B(OH) 2 or -L-5-10 membered heteroaryl, and the C 1 -C 8 alkyl, C 1 -C 8 alkoxy, 4-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted with R 2a .
在一些实施方案中，R2选自卤素、氰基、羟基、C1-C6烷氧基、C1-C6烷基、4-9元杂环基、L-5元杂芳基或-T-NR2AR2AA，所述C1-C6烷氧基、C1-C6烷基、4-9元杂环基或5元杂芳基任选被R2a取代。In some embodiments, R 2 is selected from halogen, cyano, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, 4-9 membered heterocyclyl, L-5 membered heteroaryl, or -T-NR 2A R 2AA , wherein the C 1 -C 6 alkoxy, C 1 -C 6 alkyl, 4-9 membered heterocyclyl, or 5 membered heteroaryl is optionally substituted with R 2a .
在一些实施方案中，R2选自卤素、氰基、羟基、C1-C6烷氧基、3-10元杂环烷基或-T-NR2AR2AA，所述3-10元杂环烷基任选被R2a取代。在一些实施方案中，T选自键。In some embodiments, R 2 is selected from halogen, cyano, hydroxy, C 1 -C 6 alkoxy, 3-10 membered heterocycloalkyl, or -T-NR 2AR 2AA , said 3-10 membered heterocycloalkyl optionally substituted with R 2a . In some embodiments, T is selected from a bond.
在一些实施方案中，L选自键。在一些实施方案中，R2选自卤素、氰基、羟基、-S(O)2(C1-C6烷基)、C1-C10烷基、C1-C10烷氧基、3-12元杂环基、5-10元杂芳基或-NR2AR2AA，所述-S(O)2(C1-C6烷基)、C1-C10烷基、C1-C10烷氧基、3-12元杂环基或5-10元杂芳基任选被R2a取代。In some embodiments, L is selected from a bond. In some embodiments, R 2 is selected from halogen, cyano, hydroxyl, -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, or -NR 2A R 2AA , wherein -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted with R 2a .
在一些实施方案中，R2选自Br、Cl、F、氰基、羟基、甲氧基、甲基、吗啉基、哌嗪基、吡唑基、噻吩基、二氢吡喃基、哌啶基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基或-NR2AR2AA，所述甲基、吗啉基、哌嗪基、吡唑基、噻吩基、二氢吡喃基、哌啶基、氮杂环丁烷基、氧杂环丁烷基或吡咯烷基任选被R2a取代。In some embodiments, R2 is selected from Br, Cl, F, cyano, hydroxyl, methoxy, methyl, morpholinyl, piperazinyl, pyrazolyl, thienyl, dihydropyranyl, piperidinyl, azetidinyl, Oxetane, pyrrolidinyl or -NR 2A R 2AA , the methyl, morpholinyl, piperazinyl, pyrazolyl, thienyl, dihydropyranyl, piperidinyl, azetidinyl, The oxetanyl or pyrrolidinyl group is optionally substituted by R 2a .
在一些实施方案中，R2选自Br、Cl、F、氰基、羟基、甲氧基、甲基、吗啉基、哌嗪基、吡唑基、噻吩基、二氢吡喃基、哌啶基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基或-NR2AR2AA，所述甲基、吗啉基、哌嗪基、吡唑基、噻吩基、二氢吡喃基、哌啶基、氮杂环丁烷基、氧杂环丁烷基或吡咯烷基任选被R2a取代。In some embodiments, R 2 is selected from Br, Cl, F, cyano, hydroxy, methoxy, methyl, morpholinyl, piperazinyl, pyrazolyl, thienyl, dihydropyranyl, piperidinyl, azetidinyl, Oxetane, pyrrolidinyl or -NR 2A R 2AA , the methyl, morpholinyl, piperazinyl, pyrazolyl, thienyl, dihydropyranyl, piperidinyl, azetidinyl, The oxetanyl or pyrrolidinyl group is optionally substituted by R 2a .
在一些实施方案中，R2选自Br、Cl、F、氰基、羟基、甲氧基、吗啉基、哌嗪基或-NR2AR2AA，所述吗啉基或哌嗪基任选被R2a取代。In some embodiments, R 2 is selected from Br, Cl, F, cyano, hydroxy, methoxy, morpholinyl, piperazinyl, or -NR 2AR 2AA , said morpholinyl or piperazinyl being optionally substituted with R 2a .
在一些实施方案中，R2a选自卤素、C1-C6烷基、-S(O)2-R2a’或-C(O)C1-C6烷基，所述C1-C6烷基或-C(O)C1-C6烷基任选被R2b取代。In some embodiments, R 2a is selected from halogen, C 1 -C 6 alkyl, -S(O) 2 -R 2a ′, or -C(O)C 1 -C 6 alkyl, said C 1 -C 6 alkyl or -C(O)C 1 -C 6 alkyl optionally substituted with R 2b .
在一些实施方案中，R2a选自C1-C6烷基、-S(O)2-R2a’或-C(O)C1-C6烷基，所述C1-C6烷基或-C(O)C1-C6烷基任选被R2b取代。In some embodiments, R 2a is selected from C 1 -C 6 alkyl, -S(O) 2 -R 2a ′ or -C(O)C 1 -C 6 alkyl, said C 1 -C 6 alkyl or -C(O)C 1 -C 6 alkyl being optionally substituted with R 2b .
在一些实施方案中，R2a选自F、甲基、乙基、丙基、-S(O)2-R2a’或-C(O)CH3，所述甲基、乙基或丙基任选被R2b取代。In some embodiments, R 2a is selected from F, methyl, ethyl, propyl, -S(O) 2 -R 2a ', or -C(O)CH 3 , said methyl, ethyl or propyl being optionally substituted with R 2b .
在一些实施方案中，R2a选自甲基、乙基、-S(O)2-R2a’或-C(O)CH3，所述乙基任选被R2b取代。In some embodiments, R 2a is selected from methyl, ethyl, -S(O) 2 -R 2a ', or -C(O)CH 3 , wherein the ethyl is optionally substituted with R 2b .
在一些实施方案中，R2a’选自C1-C6烷基。In some embodiments, R 2a ′ is selected from C 1 -C 6 alkyl.
在一些实施方案中，R2a’选自甲基。In some embodiments, R 2a ′ is selected from methyl.
在一些实施方案中，R1b、R1C、R2b、R2C、R3a各自独立地选自卤素、羟基、氰基、氨基、C1-C6烷基或C1-C6烷氧基。In some embodiments, R 1b , R 1c , R 2b , R 2c , R 3a are each independently selected from halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
在一些实施方案中，R2b选自羟基、氰基、C1-C6烷氧基或4-12元杂环基，所述C1-C6烷氧基或4-12元杂环基任选被R1c取代。In some embodiments, R 2b is selected from hydroxy, cyano, C 1 -C 6 alkoxy, or 4-12 membered heterocyclyl, wherein the C 1 -C 6 alkoxy or 4-12 membered heterocyclyl is optionally substituted with R 1c .
在一些实施方案中，R2b选自羟基、氰基、C1-C3烷氧基或6元杂环基，所述C1-C6烷氧基或4-12元杂环基任选被R1c取代。 In some embodiments, R 2b is selected from hydroxy, cyano, C 1 -C 3 alkoxy, or 6-membered heterocyclyl, wherein the C 1 -C 6 alkoxy or 4-12-membered heterocyclyl is optionally substituted with R 1c .
在一些实施方案中，R1c选自羟基。In some embodiments, R 1c is selected from hydroxy.
在一些实施方案中，R2b选自羟基或C1-C6烷氧基。In some embodiments, R 2b is selected from hydroxyl or C 1 -C 6 alkoxy.
在一些实施方案中，R2b选自C1-C6烷氧基。In some embodiments, R 2b is selected from C 1 -C 6 alkoxy.
在一些实施方案中，R2b选自甲氧基。In some embodiments, R 2b is selected from methoxy.
在一些实施方案中，R2A、R2AA各自独立地选自氢、C1-C6烷基、-C(O)H、-S(O)2-R2A’或-C(O)OC1-C6烷基，所述C1-C6烷基或-C(O)OC1-C6烷基任选被R2B取代。In some embodiments, R 2A , R 2AA are each independently selected from hydrogen, C 1 -C 6 alkyl, —C(O)H, —S(O) 2 —R 2A ′, or —C(O)OC 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl or —C(O)OC 1 -C 6 alkyl is optionally substituted with R 2B .
在一些实施方案中，R2A选自氢或C1-C6烷基，R2AA选自C1-C6烷基、-C(O)H、-S(O)2-R2A’或-C(O)OC1-C6烷基，所述C1-C6烷基或-C(O)OC1-C6烷基任选被R2B取代。In some embodiments, R 2A is selected from hydrogen or C 1 -C 6 alkyl, R 2AA is selected from C 1 -C 6 alkyl, -C(O)H, -S(O) 2 -R 2A 'or -C(O)OC 1 -C 6 alkyl, said C 1 -C 6 alkyl or -C(O)OC 1 -C 6 alkyl is optionally substituted with R 2B .
在一些实施方案中，R2A’选自C1-C4烷基或C3-C6环烷基。In some embodiments, R 2A ′ is selected from C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl.
在一些实施方案中，R2A’选自环丙基或正丙基。In some embodiments, R 2A ′ is selected from cyclopropyl or n-propyl.
在一些实施方案中，R2A、R2AA各自独立地选自氢、甲基、-C(O)H、乙基、 所述甲基或乙基任选被R2B取代。In some embodiments, R 2A , R 2AA are each independently selected from hydrogen, methyl, -C(O)H, ethyl, The methyl or ethyl group is optionally substituted by R 2B .
在一些实施方案中，R2A选自氢或甲基，R2AA选自甲基、-C(O)H、乙基、 所述甲基或乙基任选被R2B取代。In some embodiments, R 2A is selected from hydrogen or methyl, and R 2AA is selected from methyl, -C(O)H, ethyl, The methyl or ethyl group is optionally substituted by R 2B .
在一些实施方案中，R2A、R2AA各自独立地选自氢、甲基、-C(O)H、乙基、 所述乙基任选被R2B取代。In some embodiments, R 2A , R 2AA are each independently selected from hydrogen, methyl, -C(O)H, ethyl, The ethyl group is optionally substituted with R 2B .
在一些实施方案中，R2B选自卤素、羟基、氰基、氨基、SH、C1-C6烷氧基或4-10元杂环烷基，所述4-10元杂环烷基任选被R2C取代。In some embodiments, R 2B is selected from halogen, hydroxy, cyano, amino, SH, C 1 -C 6 alkoxy, or 4-10 membered heterocycloalkyl, which is optionally substituted with R 2C .
在一些实施方案中，R2B选自C1-C3烷氧基、4-6元杂环烷基或-S(O)2(C1-C3烷基)，所述4-6元杂环烷基任选被R2C取代。In some embodiments, R 2B is selected from C 1 -C 3 alkoxy, 4-6 membered heterocycloalkyl, or -S(O) 2 (C 1 -C 3 alkyl), wherein the 4-6 membered heterocycloalkyl is optionally substituted with R 2C .
在一些实施方案中，R2B选自C1-C3烷氧基或4-10元杂环烷基。In some embodiments, R 2B is selected from C 1 -C 3 alkoxy or 4-10 membered heterocycloalkyl.
在一些实施方案中，R2C选自氧代或羟基。In some embodiments, R 2C is selected from oxo or hydroxy.
在一些实施方案中，R2B选自甲氧基、 In some embodiments, R 2B is selected from methoxy,
在一些实施方案中，R2B选自甲氧基或 In some embodiments, R 2B is selected from methoxy or
在一些实施方案中，R2选自Br、Cl、F、CN、OH、甲氧基、CF3、 In some embodiments, R 2 is selected from Br, Cl, F, CN, OH, methoxy, CF 3 ,
在一些实施方案中，R2选自Br、Cl、F、CN、OH、甲氧基、CF3、 In some embodiments, R 2 is selected from Br, Cl, F, CN, OH, methoxy, CF 3 ,
在一些实施方案中，R2选自Br、Cl、F、CN、OH、甲氧基、 In some embodiments, R2 is selected from Br, Cl, F, CN, OH, methoxy,
在一些实施方案中，R3选自卤素、C1-C8烷基、C1-C8烷氧基、3-12元杂环烷基或-U-5-10元杂芳基，所述C1-C8烷基、C1-C8烷氧基、3-12元杂环烷基、5-10元杂芳基任选被R3a取代。In some embodiments, R 3 is selected from halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, 3-12 membered heterocycloalkyl, or -1-5-10 membered heteroaryl, wherein the C 1 -C 8 alkyl, C 1 -C 8 alkoxy, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl is optionally substituted with R 3a .
在一些实施方案中，R3选自卤素、3-12元杂环烷基或-U-5-10元杂芳基，所述3-12元杂环烷基、5-10元杂芳基任选被R3a取代。In some embodiments, R 3 is selected from halogen, 3-12 membered heterocycloalkyl, or -1U-5-10 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl is optionally substituted with R 3a .
在一些实施方案中，R3选自卤素、C1-C6烷基或C1-C6烷基，所述C1-C6烷基或C1-C6烷基任选被R3a取代。In some embodiments, R 3 is selected from halogen, C 1 -C 6 alkyl , or C 1 -C 6 alkyl , which is optionally substituted with R 3a .
在一些实施方案中，R3选自卤素或C1-C3烷基。In some embodiments, R 3 is selected from halogen or C 1 -C 3 alkyl.
在一些实施方案中，R3选自卤素。In some embodiments, R 3 is selected from halogen.
在一些实施方案中，R3选自Cl、F或甲氧基。In some embodiments, R 3 is selected from Cl, F or methoxy.
在一些实施方案中，R3选自Cl。In some embodiments, R 3 is selected from Cl.
在一些实施方案中，X选自CR4。In some embodiments, X is selected from CR 4 .
在一些实施方案中，X选自CH。In some embodiments, X is selected from CH.
在一些实施方案中，当选自且X是N时，R10是甲基。In some embodiments, when Selected from When X is N, R 10 is methyl.
在一些实施方案中，R4、R5、R6、R7和R8各自独立地选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷氧基或C1-C6卤代烷基。In some embodiments, R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl.
在一些实施方案中，R4选自H。In some embodiments, R4 is selected from H.
在一些实施方案中，R5选自H、卤素或C1-C6烷氧基。In some embodiments, R 5 is selected from H, halogen, or C 1 -C 6 alkoxy.
在一些实施方案中，R5选自H或卤素。In some embodiments, R 5 is selected from H or halogen.
在一些实施方案中，R5选自H、F或乙氧基。In some embodiments, R 5 is selected from H, F or ethoxy.
在一些实施方案中，R5选自H或F。In some embodiments, R 5 is selected from H or F.
在一些实施方案中，R6选自H或卤素。In some embodiments, R 6 is selected from H or halogen.
在一些实施方案中，R6选自H、F或Cl。In some embodiments, R 6 is selected from H, F or Cl.
在一些实施方案中，R6选自H。In some embodiments, R 6 is selected from H.
在一些实施方案中，R7选自H、卤素或C1-C6烷氧基。In some embodiments, R 7 is selected from H, halogen, or C 1 -C 6 alkoxy.
在一些实施方案中，R7选自H或卤素。In some embodiments, R 7 is selected from H or halogen.
在一些实施方案中，R7选自卤素。In some embodiments, R 7 is selected from halogen.
在一些实施方案中，R7选自H、F或乙氧基。In some embodiments, R 7 is selected from H, F or ethoxy.
在一些实施方案中，R7选自H或F。In some embodiments, R7 is selected from H or F.
在一些实施方案中，R7选自F。In some embodiments, R7 is selected from F.
在一些实施方案中，R8选自H、卤素、C1-C6烷基或C1-C6烷氧基。In some embodiments, R 8 is selected from H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
在一些实施方案中，R8选自H、卤素或C1-C6烷基。In some embodiments, R 8 is selected from H, halogen, or C 1 -C 6 alkyl.
在一些实施方案中，R8选自H、Cl、F、甲基或乙氧基。In some embodiments, R 8 is selected from H, Cl, F, methyl, or ethoxy.
在一些实施方案中，R8选自H、Cl、F或甲基。In some embodiments, R 8 is selected from H, Cl, F or methyl.
在一些实施方案中，R8选自Cl。In some embodiments, R 8 is selected from Cl.
在一些实施方案中，R9选自H、卤素或OH。In some embodiments, R 9 is selected from H, halogen, or OH.
在一些实施方案中，R9选自H、卤素、OH、氘或C1-C6烷基。In some embodiments, R 9 is selected from H, halogen, OH, deuterium, or C 1 -C 6 alkyl.
在一些实施方案中，R9选自H、卤素、OH、氘或C1-C3烷基。In some embodiments, R 9 is selected from H, halogen, OH, deuterium, or C 1 -C 3 alkyl.
在一些实施方案中，R9选自氢、氘、OH或甲基。 In some embodiments, R 9 is selected from hydrogen, deuterium, OH, or methyl.
在一些实施方案中，R9选自H或OH。In some embodiments, R 9 is selected from H or OH.
在一些实施方案中，R9选自H。In some embodiments, R 9 is selected from H.
在一些实施方案中，R10选自甲基或CD3。In some embodiments, R 10 is selected from methyl or CD 3 .
在一些实施方案中，R10选自甲基。In some embodiments, R 10 is selected from methyl.
在一些实施方案中，M选自CR11。In some embodiments, M is selected from CR 11 .
在一些实施方案中，R11、R12、R13和R14各自独立地选自氢、卤素、氰基、C1-C6烷基、C2-C6烯基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C3-C8环烷基或NR11AR11AA。In some embodiments, R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy , C 3 -C 8 cycloalkyl, or NR 11A R 11AA .
在一些实施方案中，R11、R12、R13和R14各自独立地选自氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基或-P(O)(C1-C6烷基)2；或者R13和R14以及它们所连接的碳原子一起形成5-10元杂芳环。In some embodiments, R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy or -P(O)(C 1 -C 6 alkyl) 2 ; or R 13 and R 14 and the carbon atoms to which they are attached together form a 5-10 membered heteroaromatic ring.
在一些实施方案中，R11、R12、R13和R14各自独立地选自氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基或C1-C6卤代烷氧基。In some embodiments, R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy.
在一些实施方案中，R11选自H或CN。In some embodiments, R 11 is selected from H or CN.
在一些实施方案中，R11选自H。In some embodiments, R 11 is selected from H.
在一些实施方案中，R12选自C1-C6卤代烷基、C1-C6烷基或-P(O)(C1-C6烷基)2。In some embodiments, R 12 is selected from C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or -P(O)(C 1 -C 6 alkyl) 2 .
在一些实施方案中，R12选自C1-C6卤代烷基或C1-C6烷基。In some embodiments, R 12 is selected from C 1 -C 6 haloalkyl or C 1 -C 6 alkyl.
在一些实施方案中，R12选自C1-C6卤代烷基。In some embodiments, R 12 is selected from C 1 -C 6 haloalkyl.
在一些实施方案中，R12选自CF3、CH3或 In some embodiments, R 12 is selected from CF 3 , CH 3 or
在一些实施方案中，R12选自CF3或CH3。In some embodiments, R 12 is selected from CF 3 or CH 3 .
在一些实施方案中，R12选自CF3。In some embodiments, R 12 is selected from CF 3 .
在一些实施方案中，R13选自H。In some embodiments, R 13 is selected from H.
在一些实施方案中，R14选自C1-C6烷基或C1-C6卤代烷基。In some embodiments, R 14 is selected from C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
在一些实施方案中，R14选自C1-C6烷基。In some embodiments, R 14 is selected from C 1 -C 6 alkyl.
在一些实施方案中，R14选自甲基或CF3。In some embodiments, R 14 is selected from methyl or CF 3 .
在一些实施方案中，R14选自甲基。In some embodiments, R 14 is selected from methyl.
在一些实施方案中，R13和R14以及它们所连接的碳原子一起形成5-6元杂芳环。In some embodiments, R 13 and R 14 together with the carbon atom to which they are attached form a 5-6 membered heteroaryl ring.
在一些实施方案中，R13和R14以及它们所连接的碳原子一起形成5元杂芳环。In some embodiments, R 13 and R 14 together with the carbon atom to which they are attached form a 5-membered heteroaryl ring.
在一些实施方案中，R13和R14以及它们所连接的碳原子一起形成呋喃环或噻唑环。In some embodiments, R 13 and R 14 together with the carbon atom to which they are attached form a furan ring or a thiazole ring.
在一些实施方案中，代表单键，R15选自氢或氘。In some embodiments, represents a single bond, and R 15 is selected from hydrogen or deuterium.
在一些实施方案中，本公开的式(I)化合物或其药学上可接受的盐或其立体异构体选自式(III)化合物或其药学上可接受的盐或其立体异构体：
In some embodiments, the compound of formula (I) of the present disclosure or its pharmaceutically acceptable salt or its stereoisomer is selected from the compound of formula (III) or its pharmaceutically acceptable salt or its stereoisomer:
其中，Q1、Q2、Q3、Q4、X、R5、R6、R7、R8、R9、R10、M、R12、R13、R14、R15如上文所定义。wherein Q 1 , Q 2 , Q 3 , Q 4 , X, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , M, R 12 , R 13 , R 14 and R 15 are as defined above.
在一些实施方案中，本公开的式(I)化合物或其药学上可接受的盐或其立体异构体选自式(IV)化合 物或其药学上可接受的盐或其立体异构体：
In some embodiments, the compound of formula (I) of the present disclosure or its pharmaceutically acceptable salt or stereoisomer thereof is selected from the compound of formula (IV) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:
其中，Q1、Q2、Q3、Q4、X、R5、R6、R7、R8、R9、R10、M、R12、R13、R14如上文所定义。wherein Q 1 , Q 2 , Q 3 , Q 4 , X, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , M, R 12 , R 13 and R 14 are as defined above.
在一些实施方案中，本公开的式(I)化合物或其药学上可接受的盐或其立体异构体选自式(II)化合物或其药学上可接受的盐或其立体异构体：
In some embodiments, the compound of formula (I) of the present disclosure or its pharmaceutically acceptable salt or its stereoisomer is selected from the compound of formula (II) or its pharmaceutically acceptable salt or its stereoisomer:
其中，Q1、Q2、Q3、Q4、X、R5、R6、R7、R8、R9、R10、M、R12、R13、R14如上文所定义。wherein Q 1 , Q 2 , Q 3 , Q 4 , X, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , M, R 12 , R 13 and R 14 are as defined above.
在一些实施方案中，本公开的式(I)化合物或其药学上可接受的盐或其立体异构体选自以下化合物或其药学上可接受的盐或其立体异构体：







In some embodiments, the compound of formula (I) of the present disclosure or its pharmaceutically acceptable salt or its stereoisomer is selected from the following compounds or its pharmaceutically acceptable salt or its stereoisomer:







另一方面，本公开提供药物组合物，其包含本公开的式(I)化合物或其药学上可接受的盐或其立体异构体和药学上可接受的辅料。In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) of the present disclosure or a pharmaceutically acceptable salt or a stereoisomer thereof and a pharmaceutically acceptable excipient.
另一方面，本公开提供预防或者治疗哺乳动物DNA聚合酶θ介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式(I)化合物或其药学上可接受的盐或其立体异构体、或其药物组合物。In another aspect, the present disclosure provides a method for preventing or treating a disease mediated by DNA polymerase θ in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.
另一方面，本公开提供式(Ⅰ)化合物或其药学上可接受的盐或其立体异构体、或其药物组合物在制备预防或者治疗DNA聚合酶θ介导的疾病的药物中的用途。In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, in the preparation of a drug for preventing or treating a disease mediated by DNA polymerase θ.
另一方面，本公开提供式(Ⅰ)化合物或其药学上可接受的盐或其立体异构体、或其药物组合物在预防或者治疗DNA聚合酶θ介导的疾病中的用途。In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, in preventing or treating a disease mediated by DNA polymerase θ.
另一方面，本公开提供预防或者治疗DNA聚合酶θ介导的疾病的式(Ⅰ)化合物或其药学上可接受的盐或其立体异构体、或其药物组合物。In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof for preventing or treating a disease mediated by DNA polymerase θ.
在一些实施方案中，所述DNA聚合酶θ介导的疾病是DNA聚合酶θ过度表达的疾病。In some embodiments, the DNA polymerase theta-mediated disease is a disease in which DNA polymerase theta is overexpressed.
在一些实施方案中，所述DNA聚合酶θ介导的疾病是癌症。In some embodiments, the DNA polymerase theta-mediated disease is cancer.
在一些实施方案中，所述癌症是结直肠腺癌。In some embodiments, the cancer is colorectal adenocarcinoma.
术语定义和说明Definitions and explanations of terms
除非另有说明，本公开中所用的术语具有下列含义，本公开中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise specified, the terms used in this disclosure have the following meanings, and the groups and term definitions recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. A specific term should not be considered as uncertain or unclear in the absence of special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient.
本文中表示连接位点。In this article Indicates the connection site.
本文中表示单键或双键。In this article Indicates a single bond or a double bond.
本文中，合成路线中的双箭头“→→”表示多步反应。 Herein, the double arrows “→→” in the synthetic routes represent multi-step reactions.
本公开中“*”表示其所标识的原子为连接位点，例如连接基团表示该连接基团中的N原子为连接位点。In this disclosure, "*" indicates that the atom it identifies is a connection site, such as a connection group It means that the N atom in the linking group is the linking site.
本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚楔键表示一个立体中心的绝对构型，用黑实键和虚键表示一个立体中心的相对构型(如脂环化合物的顺反构型)。The graphic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the wedge and dashed wedge keys are used. To indicate the absolute configuration of a stereocenter, use black real and imaginary bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本公开化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本公开包含化合物的所有互变异构形式。The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present disclosure includes all tautomeric forms of the compounds.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和非对映异构体。The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.
本公开的化合物可以具有不对称原子如碳原子、硫原子、氮原子、磷原子或不对称双键，因此本公开的化合物可以存在特定的几何或立体异构体形式。特定的几何或立体异构体形式可以是顺式和反式异构体、E型和Z型几何异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，以及其外消旋混合物或其它混合物，例如对映异构体或非对映体富集的混合物，以上所有这些异构体以及它们的混合物都属于本公开化合物的定义范围之内。烷基等取代基中可存在另外的不对称碳原子、不对称硫原子、不对称氮原子或不对称磷原子，所有取代基中涉及到的这些异构体以及它们的混合物，也均包括在本公开化合物的定义范围之内。本公开的含有不对称原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来，光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E-type and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and their mixtures. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of these isomers and their mixtures involved in all substituents are also included within the definition of the compounds of the present invention. The compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxo (ie, =O), it means that two hydrogen atoms are replaced.
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，是指乙基可以是未被取代的(CH2CH3)、单取代的(CH2CH2F、CH2CH2Cl等)、多取代的(CHFCH2F、CH2CHF2、CHFCH2Cl、CH2CHCl2等)或完全被取代的(CF2CF3、CF2CCl3、CCl2CCl3等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence and non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH 2 CH 2 Cl, etc.), polysubstituted (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2 , etc.) or fully substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3 , etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or cannot be synthesized will be introduced.
当任何变量(例如Ra、Rb)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。例如，如果一个基团被2个Rb所取代，则每个Rb都有独立的选项。When any variable (eg, Ra , Rb ) occurs more than once in a compound's composition or structure, its definition is independent at each occurrence. For example, if a group is substituted with 2 Rb , each Rb has an independent option.
当一个连接基团的数量为0时，比如-(CH2)0-，表示该连接基团为键。When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
当其中一个变量选自化学键或不存在时，表示其连接的两个基团直接相连，比如A-L-Z中L代表键时表示该结构实际上是A-Z。When one of the variables is selected from a chemical bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in A-L-Z represents a bond, it means that the structure is actually A-Z.
当本文中涉及到的连接基团若没有指明其连接方向，则其连接方向是任意的。例如当结构单元中的L1选自“C1-C3亚烷基-O”时，此时L1既可以按照与从左到右的方向连接环Q和R1构成“环Q-C1-C3亚烷基-O-R1”，也可以按照从右到左的方向连接环Q和R1构成“环Q-O-C1-C3亚烷基-R1”。When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary. When L 1 is selected from "C 1 -C 3 alkylene-O", L 1 can connect ring Q and R 1 from left to right to form "ring QC 1 -C 3 alkylene-OR 1 ", or connect ring Q and R 1 from right to left to form "ring QOC 1 -C 3 alkylene-R 1 ".
本文中的Cm-Cn是指具有m-n范围中的整数个碳原子。例如“C1-C10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。 Cm - Cn herein refers to an integer number of carbon atoms in the range of mn. For example, " C1 - C10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
术语“烷基”是指通式为CnH2n+1的烃基，该烷基可以是直链或支链的。术语“C1-C10烷基”可理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和烃基。所述烷基的具体实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、 1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1，1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、2，3-二甲基丁基、1，3-二甲基丁基或1，2-二甲基丁基等；术语“C1-C6烷基”可理解为表示具有1至6个碳原子的烷基，具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等。术语“C1-C3烷基”可理解为表示具有1至3个碳原子的直链或支链饱和烷基。所述“C1-C10烷基”可以包含“C1-C6烷基”或“C1-C3烷基”等范围，所述“C1-C6烷基”可以进一步包含“C1-C3烷基”。The term "alkyl" refers to a hydrocarbon group of the general formula CnH2n +1 , which may be straight-chain or branched. The term " C1 - C10 alkyl" may be understood to mean a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, The term "C 1 -C 6 alkyl" may be understood to mean an alkyl group having 1 to 6 carbon atoms, and specific examples include, but are not limited to, methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C 1 -C 3 alkyl" may be understood to mean a straight or branched saturated alkyl group having 1 to 3 carbon atoms. The "C 1 -C 10 alkyl" may include "C 1 -C 6 alkyl" or "C 1 -C 3 alkyl" and the "C 1 -C 6 alkyl" may further include "C 1 -C 3 alkyl".
术语“烷氧基”是指直链或支链醇类失去羟基上的氢原子产生的基团，可理解为“烷基氧基”或“烷基-O-”。术语“C1-C10烷氧基”可理解为“C1-C10烷基氧基”或“C1-C10烷基-O-”；术语“C1-C6烷氧基”可理解为“C1-C6烷基氧基”或“C1-C6烷基-O-”。所述“C1-C10烷氧基”可以包含“C1-C6烷氧基”和“C1-C3烷氧基”等范围，所述“C1-C6烷氧基”可以进一步包含“C1-C3烷氧基”。The term "alkoxy" refers to a group resulting from the loss of a hydrogen atom from a hydroxyl group of a straight or branched alcohol, and may be understood as an "alkyloxy" or "alkyl-O-". The term "C 1 -C 10 alkoxy" may be understood as a "C 1 -C 10 alkyloxy" or "C 1 -C 10 alkyl-O-"; the term "C 1 -C 6 alkoxy" may be understood as a "C 1 -C 6 alkyloxy" or "C 1 -C 6 alkyl-O-". The "C 1 -C 10 alkoxy" may include a "C 1 -C 6 alkoxy" and a "C 1 -C 3 alkoxy", and the "C 1 -C 6 alkoxy" may further include a "C 1 -C 3 alkoxy".
术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“C1-6卤代烷基”意指被一个或多个卤素取代的如上所定义的C1-6烷基，具体实例包括但不限于三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基、三氯甲基、五氟乙基和五氯乙基等。The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-6 haloalkyl" means a C 1-6 alkyl as defined above substituted with one or more halogens, specific examples of which include but are not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl and pentachloroethyl, etc.
术语“烷醇”是指被单个或多个羟基取代的烷基，例如，术语“C1-C6烷醇”是指被一个或多个羟基取代的如上所定义的C1-6烷基，具体实例包括但不限于CH2OH、CH2CH2OH、CH2CH2CH2OH或CH2CH(OH)CH3等。The term "alkanol" refers to an alkyl group substituted by a single or multiple hydroxyl groups. For example, the term "C 1 -C 6 alkanol" refers to a C 1-6 alkyl group as defined above substituted by one or more hydroxyl groups. Specific examples include, but are not limited to, CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, or CH 2 CH(OH)CH 3 , etc.
术语“烯基”是指由碳原子和氢原子组成的直链或支链的且具有至少一个双键的不饱和脂肪族烃基。术语“C2-C10烯基”可理解为表示直链或支链的不饱和烃基，其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子，“C2-C10烯基”优选“C2-C6烯基”，进一步优选“C2-C4烯基”，更进一步优选C2或C3烯基。可理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或共轭。所述烯基的具体实例包括但不限于乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基或(Z)-1-甲基丙-1-烯基等。The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The term "C 2 -C 10 alkenyl" can be understood to mean a linear or branched unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C 2 -C 10 alkenyl" is preferably "C 2 -C 6 alkenyl", further preferably "C 2 -C 4 alkenyl", and further preferably C 2 or C 3 alkenyl. It can be understood that in the case where the alkenyl contains more than one double bond, the double bonds may be separated or conjugated with each other. Specific examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.
术语“环烷基”是指完全饱和的且以单环、并环、桥环或螺环等形式存在的碳环。除非另有指示，该碳环通常为3至10元环。术语“C3-C10环烷基”可理解为表示饱和的单环、并环、螺环或桥环，其具有3～10个碳原子。所述环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基，降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、螺[4.5]癸烷基等。术语“C3-C10环烷基”可以包含“C3-C6环烷基”，术语“C3-C6环烷基”可理解为表示饱和的单环或双环烃环，其具有3～6个碳原子，具体实例包括但不限于环丙基、环丁基、环戊基或环己基等。The term "cycloalkyl" refers to a fully saturated carbocyclic ring that exists in the form of a monocyclic, cyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally a 3- to 10-membered ring. The term "C 3 -C 10 cycloalkyl" is understood to mean a saturated monocyclic, cyclic, spirocyclic or bridged ring having 3 to 10 carbon atoms. Specific examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like. The term "C 3 -C 10 cycloalkyl" may include "C 3 -C 6 cycloalkyl". The term "C 3 -C 6 cycloalkyl" may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms. Specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
术语“亚环烷基”是指衍生自如本文所定义的“环烷基”基团的二价基团。The term "cycloalkylene" refers to a divalent group derived from a "cycloalkyl" group as defined herein.
术语“杂环基”是指单环或双环非芳族、部分饱和或完全饱和环系，其环原子中含有1-5个杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O)2-、-S(＝O)-、-P(＝O)2-、-P(＝O)-、-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-或-NHC(＝O)NH-等。“杂环基”的具体实例包括吗啉、哌啶(例如哌啶‐1‐基、哌啶‐2‐基、哌啶‐3‐基和哌啶‐4‐基)、哌啶酮、吡咯烷(例如吡咯烷‐1‐基、吡咯烷‐2‐基和吡咯烷‐3‐基)、吡咯烷酮、氮杂环丁烷、吡喃(2H‐吡喃或4H‐吡喃)、二氢噻吩、二氢吡喃、二氢呋喃、二氢噻唑、四氢呋喃、四氢噻吩、二噁烷、四氢吡喃(例如四氢吡喃‐4‐基)、咪唑啉、咪唑烷酮、噁唑啉、噻唑啉、吡唑啉‐2‐基、吡唑烷、哌嗪酮和哌嗪。术语“杂环基”包括所涉及的螺和桥接杂环衍生物。这类螺和桥接杂环衍生物的实例包括：六氢吡咯并[2，3‐c]吡咯烷基、二氮杂螺[3.4]辛烷基、二氮杂螺[4.4]壬烷基、氧杂‐氮杂螺[3.4]辛烷基、氧杂‐氮杂螺[4.4]壬烷基、四氢呋喃并[3，4‐c]吡咯烷基、氧杂‐氮杂螺[3.3]庚基、二氮杂螺[4.5]癸烷基、二氮杂螺[3.4]辛烷基、八氢‐萘啶基、四氢吡嗪并‐噁嗪基、噁二唑并螺[5.5]十一烷基和氧杂双环[2.2.1]庚烷基。The term "heterocyclyl" refers to a monocyclic or bicyclic non-aromatic, partially saturated or fully saturated ring system, whose ring atoms contain 1-5 heteroatoms or heteroatom groups (i.e., an atom group containing heteroatoms), and the "heteroatoms or heteroatom groups" include but are not limited to nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(＝O)2-, -S(＝O)-, -P(＝O)2-, -P(＝O)-, -NH-, -S(＝O)(＝NH)-, -C(＝O)NH- or -NHC(＝O)NH-, etc. Specific examples of "heterocyclyl" include morpholine, piperidine (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidone, pyrrolidine (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl), pyrrolidone, azetidine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g., tetrahydropyran-4-yl), imidazoline, imidazolidinone, oxazoline, thiazoline, pyrazolin-2-yl, pyrazolidine, piperazinone, and piperazine. The term "heterocyclyl" includes both spiro and bridged heterocyclic derivatives. Examples of such spiro and bridged heterocyclic derivatives include hexahydropyrrolo[2,3-c]pyrrolidinyl, diazaspiro[3.4]octanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[3.4]octanyl, oxa-azaspiro[4.4]nonanyl, tetrahydrofuro[3,4-c]pyrrolidinyl, oxa-azaspiro[3.3]heptyl, diazaspiro[4.5]decanyl, diazaspiro[3.4]octanyl, octahydro-naphthyridinyl, tetrahydropyrazino-oxazinyl, oxadiazolospiro[5.5]undecyl, and oxabicyclo[2.2.1]heptanyl.
术语“杂环烷基”是指完全饱和的且以单环、并环、桥环或螺环等形式存在的环状基团，其环的环原子中含有1-5个杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O)2-、-S(＝O)-、-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-或-NHC(＝O)NH-等。术语“杂亚环烷基”是指衍生自如本文所定义的“杂环烷基”基团的二价基团。 The term "heterocycloalkyl" refers to a fully saturated cyclic group in the form of a monocyclic, fused, bridged or spirocyclic ring, wherein the ring atoms of the ring contain 1 to 5 heteroatoms or heteroatomic groups (i.e., heteroatomic groups containing heteroatoms), wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O) 2- , -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-, etc. The term "heterocycloalkylene" refers to a divalent group derived from a "heterocycloalkyl" group as defined herein.
术语“亚杂环基”是指衍生自如本文所定义的“杂环基”基团的二价基团。术语“亚杂环烷基”是指衍生自如本文所定义的“杂环烷基”基团的二价基团。The term "heterocyclylene" refers to a divalent radical derived from a "heterocyclyl" group as defined herein. The term "heterocycloalkylene" refers to a divalent radical derived from a "heterocycloalkyl" group as defined herein.
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。芳基可以具有6-20个碳原子，6-14个碳原子或6-10个碳原子。术语“C6-C14芳基”可理解为具有6～14个碳原子的芳基。特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或者具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基；或者具有13个碳原子的环(“C13芳基”)，例如芴基；或者是具有14个碳原子的环(“C14芳基”)，例如蒽基。术语“C6-C10芳基”可理解为具有6～10个碳原子的芳基。特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或者具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基。The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group with a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms or 6-10 carbon atoms. The term "C 6 -C 14 aryl" is understood to mean an aryl group having 6 to 14 carbon atoms. In particular, it refers to a ring having 6 carbon atoms ("C 6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C 9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring having 13 carbon atoms ("C 13 aryl"), such as fluorenyl; or a ring having 14 carbon atoms ("C 14 aryl"), such as anthracenyl. The term "C 6 -C 10 aryl" is understood to mean an aryl group having 6 to 10 carbon atoms, in particular a ring having 6 carbon atoms ("C 6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C 9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
术语“杂芳基”是指具有芳香性的单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C的芳香环基。术语“5-10元杂芳基”可理解为包括这样的单环或双环芳族环系：其具有5、6、7、8、9或10个环原子，特别是5或6或9或10个环原子，且其包含1-5个，优选1-3个独立选自N、O和S的杂原子。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基或噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基或异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基等以及它们的苯并衍生物，例如喹啉基、喹唑啉基或异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基或吩噁嗪基等。术语“5-6元杂芳基”指具有5或6个环原子的芳族环系，且其包含1-3个，优选1-2个独立选自N、O和S的杂原子。术语“9-10元杂芳基”指具有9或10个环原子的芳族环系，且其包含1-3个，优选1-2个独立选自N、O和S的杂原子。“6元杂芳基”是指具有6个环原子的芳族环系，且其包含1-3个，优选1-2个独立选自N、O和S的杂原子。The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems: it has 5, 6, 7, 8, 9 or 10 ring atoms, especially 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or azinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S. The term "9-10 membered heteroaryl" refers to an aromatic ring system having 9 or 10 ring atoms, and which contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S. "6 membered heteroaryl" refers to an aromatic ring system having 6 ring atoms, and which contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.
术语“卤”或“卤素”是指氟、氯、溴或碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“羟基”是指-OH基团。The term "hydroxy" refers to an -OH group.
术语“氰基”是指-CN基团。The term "cyano" refers to a -CN group.
术语“氨基”是指-NH2基团。The term "amino" refers to a -NH2 group.
术语“治疗有效量”意指(i)治疗特定疾病、病况或病症，或(ii)减轻、改善或消除特定疾病、病况或病症的一种或多种症状的本公开化合物的用量。构成“治疗有效量”的本公开化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition or disorder, or (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指药学上可接受的酸或碱的盐，包括化合物与无机酸或有机酸形成的盐，以及化合物与无机碱或有机碱形成的盐。The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or an organic acid, and a salt formed between a compound and an inorganic base or an organic base.
术语“药物组合物”是指一种或多种本公开的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本公开的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising可理解为开放的、非排他性的意义，即“包括但不限于”。The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be construed as having an open, non-exclusive meaning, ie, "including but not limited to".
本公开还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl , etc., respectively.
某些同位素标记的本公开化合物(例如用3H及14C标记)可用于化合物和/或底物组织分布分析中。氚 化(即3H)和碳-14(即14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本公开化合物。Certain isotopically-labeled compounds of the disclosure (eg, with 3 H and 14 C) are useful in compound and/or substrate tissue distribution assays. O (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as 15 O, 13 N, 11 C and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.
本公开的药物组合物可通过将本公开的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
给予本公开化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes of administration of the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
本公开的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、乳化法、冷冻干燥法等。The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本公开的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂或矫味剂等。Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or sugar-coated core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.
本文所述的通式(Ⅰ)化合物的所有施用方法中，每天给药的剂量可以为0.1mg/kg到1000mg/kg体重，以单独或分开剂量的形式。In all the administration methods described herein, the compound of formula (I) may be administered at a daily dosage of 0.1 mg/kg to 1000 mg/kg body weight in the form of single or divided doses.
本公开的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其它化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本公开的实施例。The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the embodiments with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.
本公开具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本公开的化学变化及其所需的试剂和物料。为了获得本公开的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.
具体实施方式Detailed ways
下面通过实施例对发明进行详细描述，但并不意味着对本公开任何不利限制。本文已经详细地描述了本公开，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本公开精神和范围的情况下针对本公开具体实施方式进行各种改变和改进将是显而易见的。本公开所使用的所有试剂是市售的，无需进一步纯化即可使用。The invention is described in detail below by way of examples, but this does not mean any adverse limitation to the present disclosure. The present disclosure has been described in detail herein, and specific embodiments thereof are also disclosed therein, and it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.
除非另作说明，混合溶剂表示的比例是体积混合比例。例如，“石油醚/乙酸乙酯＝60/1”表示石油醚和乙酸乙酯的体积比是60：1。Unless otherwise specified, the ratio of mixed solvents is the volume ratio. For example, "petroleum ether/ethyl acetate = 60/1" means that the volume ratio of petroleum ether to ethyl acetate is 60:1.
化合物经手工或软件命名，市售化合物采用供应商目录名称。Compounds are manually or The software names were used, and commercially available compounds were named using the supplier's catalog names.
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10-6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)；“IC50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
本公开采用下述缩略词：NaH代表氢化钠；RT代表保留时间。TLC代表薄层色谱层析。The present disclosure uses the following abbreviations: NaH stands for sodium hydride; RT stands for retention time; and TLC stands for thin layer chromatography.
实施例1、(S)-N-(3-氯-4-氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物1)的合成
Example 1. Synthesis of (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 1)
步骤1：3-氯-4-氟-N-甲基苯胺(中间体1-2)的合成Step 1: Synthesis of 3-chloro-4-fluoro-N-methylaniline (Intermediate 1-2)
将3-氯-4-氟苯胺(1.50g)溶于N,N-二甲基甲酰胺(10mL)中，加入碳酸钾(1.66g)，在冰浴中滴加碘甲烷(1.42g)之后把反应液升温至40℃，搅拌6h。向反应液中加入水(150mL)，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝60/1)纯化，得到中间体1-2(1.16g)。3-Chloro-4-fluoroaniline (1.50 g) was dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (1.66 g) was added, iodomethane (1.42 g) was added dropwise in an ice bath, the reaction solution was heated to 40°C and stirred for 6 h. Water (150 mL) was added to the reaction solution, and it was extracted with ethyl acetate (25 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=60/1) to obtain intermediate 1-2 (1.16 g).
LC-MS(ESI):m/z＝160.03[M+H]+ LC-MS(ESI):m/z＝160.03[M+H] +
步骤2：(S)-1-(叔丁氧羰基)吲哚啉-2-羧酸(中间体1-3)的合成Step 2: Synthesis of (S)-1-(tert-butyloxycarbonyl)indoline-2-carboxylic acid (Intermediate 1-3)
向二氯甲烷(20mL)中加入(S)-吲哚啉-2-羧酸(816mg)和三乙胺(760mg)，慢慢滴加二碳酸二叔丁酯(1637mg)。反应液在室温下搅拌2h，TLC监测反应完成。向反应液中加入水(100mL)，用1N盐酸调节pH＝5-6，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，得到中间体1-3(1162mg)。Add (S)-indoline-2-carboxylic acid (816 mg) and triethylamine (760 mg) to dichloromethane (20 mL), and slowly add di-tert-butyl dicarbonate (1637 mg). The reaction solution was stirred at room temperature for 2 h, and the reaction was completed by TLC monitoring. Water (100 mL) was added to the reaction solution, and the pH was adjusted to 5-6 with 1N hydrochloric acid, and extracted with ethyl acetate (25 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 1-3 (1162 mg).
LC-MS(ESI):m/z＝264.12[M+H]+ LC-MS(ESI):m/z＝264.12[M+H] +
步骤3：(S)-2-((3-氯-4-氟苯基)(甲基)氨甲酰基)二氢吲哚-1-甲酸叔丁酯(中间体1-4)的合成Step 3: Synthesis of tert-butyl (S)-2-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)indoline-1-carboxylate (Intermediate 1-4)
在(S)-1-(叔丁氧羰基)吲哚啉-2-羧酸(中间体1-3)(789mg)和3-氯-4-氟-N-甲基苯胺(中间体1-2)(478mg)的二氯甲烷(20mL)溶液中加入N,N'-二环己基碳二亚胺(929mg)和4-二甲氨基吡啶(36mg)。室温条件下搅拌12h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝20/1)纯化，得到中间体1-4(953mg)。N,N'-dicyclohexylcarbodiimide (929 mg) and 4-dimethylaminopyridine (36 mg) were added to a solution of (S)-1-(tert-butyloxycarbonyl)indoline-2-carboxylic acid (intermediate 1-3) (789 mg) and 3-chloro-4-fluoro-N-methylaniline (intermediate 1-2) (478 mg) in dichloromethane (20 mL). The mixture was stirred at room temperature for 12 h, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1) to obtain intermediate 1-4 (953 mg).
LC-MS(ESI):m/z＝405.13[M+H]+ LC-MS(ESI):m/z＝405.13[M+H] +
步骤4：(S)-N-(3-氯-4-氟苯基)-N-甲基二氢吲哚-2-甲酰胺(中间体1-5)的合成Step 4: Synthesis of (S)-N-(3-chloro-4-fluorophenyl)-N-methylindoline-2-carboxamide (Intermediate 1-5)
将(S)-2-((3-氯-4-氟苯基)(甲基)氨甲酰基)二氢吲哚-1-甲酸叔丁酯(中间体1-4)(953mg)溶解在10％三氟乙酸的二氯甲烷溶液(15mL)中。反应液在室温条件下搅拌6h，TLC监测反应完成。向反应液中滴 加饱和碳酸氢钠溶液，调节pH＝8-9，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，得到中间体1-5(560mg)。Dissolve (S)-tert-butyl 2-((3-chloro-4-fluorophenyl)(methyl)carbamoyl)indoline-1-carboxylate (Intermediate 1-4) (953 mg) in 10% trifluoroacetic acid in dichloromethane (15 mL). Stir the reaction mixture at room temperature for 6 h. The reaction was completed after TLC monitoring. Saturated sodium bicarbonate solution was added to adjust pH=8-9, extracted with ethyl acetate (25 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 1-5 (560 mg).
LC-MS(ESI):m/z＝305.08[M+H]+ LC-MS(ESI):m/z＝305.08[M+H] +
步骤5：(S)-N-(3-氯-4-氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物1)的合成Step 5: Synthesis of (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 1)
在(S)-N-(3-氯-4-氟苯基)-N-甲基二氢吲哚-2-甲酰胺(中间体1-5)(560mg)和2-氯-6-甲基-4-(三氟甲基)吡啶(337mg)的1,4-二氧六环(20mL)溶液中加入三(二亚苄基丙酮)二钯(80mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(100mg)和碳酸铯(733mg)。在氮气保护，100℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到化合物1(445mg)。Tris(dibenzylideneacetone)dipalladium (80 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (100 mg) and cesium carbonate (733 mg) were added to a solution of (S)-N-(3-chloro-4-fluorophenyl)-N-methylindoline-2-carboxamide (intermediate 1-5) (560 mg) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (337 mg) in 1,4-dioxane (20 mL). Stirred at 100° C. for 8 h under nitrogen protection, and the reaction was completed by TLC monitoring. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain compound 1 (445 mg).
LC-MS(ESI):m/z＝464.11[M+H]+ LC-MS(ESI):m/z＝464.11[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.65(d,J＝6.5Hz,1H),7.53(d,J＝8.1Hz,1H),7.39(t,J＝4.3Hz,1H),7.31–7.15(m,4H),7.00–6.87(m,2H),5.16(m,1H),3.35(s,3H),3.31–3.11(m,2H),2.65(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.65(d,J＝6.5Hz,1H),7.53(d,J＝8.1Hz,1H),7.39(t,J＝4.3Hz,1H),7.31– 7.15(m,4H),7.00–6.87(m,2H),5.16(m,1H),3.35(s,3H),3.31–3.11(m,2H),2.65(s,3H).
实施例2、N-(5-氯-2,4-二氟苯基)-5-氟-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物2)的合成
Example 2. Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-fluoro-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 2)
步骤1：1-(叔丁氧基羰基)-1H-吡咯并[2,3-b]吡啶-2-羧酸(中间体2-1)的合成Step 1: Synthesis of 1-(tert-butoxycarbonyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 2-1)
将5-氟-1H-吡咯并[2,3-b]吡啶-2-甲酸(900mg)和N,N-二异丙基乙胺(968mg)溶于二氯甲烷(20mL)中，滴加二碳酸二叔丁酯(1637mg)。反应液在室温下搅拌10h，TLC监测反应完成。向反应液中加入水(150mL)，用1N盐酸调节pH＝5-6，用乙酸乙酯(30mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，得到中间体2-1(1015mg)。5-Fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (900 mg) and N,N-diisopropylethylamine (968 mg) were dissolved in dichloromethane (20 mL), and di-tert-butyl dicarbonate (1637 mg) was added dropwise. The reaction solution was stirred at room temperature for 10 h, and the reaction was completed after TLC monitoring. Water (150 mL) was added to the reaction solution, and the pH was adjusted to 5-6 with 1N hydrochloric acid, and extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 2-1 (1015 mg).
LC-MS(ESI):m/z＝281.09[M+H]+ LC-MS(ESI):m/z＝281.09[M+H] +
步骤2：1-(叔丁基)-2-甲基-5-氟-1H-吡咯并[2,3-b]吡啶-1,2-二羧酸酯(中间体2-2)的合成Step 2: Synthesis of 1-(tert-butyl)-2-methyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (Intermediate 2-2)
将中间体2-1(1015mg)溶于甲醇(20mL)中，滴加二氯亚砜(650mg)。反应液在室温下搅拌10h，TLC监测反应完成。向反应液中加入饱和碳酸氢钠溶液，调节pH＝7-8，用乙酸乙酯(30mL×3)萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到中间体2-2(928mg)。Intermediate 2-1 (1015 mg) was dissolved in methanol (20 mL), and thionyl chloride (650 mg) was added dropwise. The reaction solution was stirred at room temperature for 10 h, and the reaction was completed after TLC monitoring. Saturated sodium bicarbonate solution was added to the reaction solution, pH was adjusted to 7-8, and extracted with ethyl acetate (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain intermediate 2-2 (928 mg).
LC-MS(ESI):m/z＝295.10[M+H]+ LC-MS(ESI):m/z＝295.10[M+H] +
步骤3：1-(叔丁基)-2-甲基5-氟-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1,2-二羧酸酯(中间体2-3)的合成Step 3: Synthesis of 1-(tert-butyl)-2-methyl 5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (Intermediate 2-3)
向中间体2-2(928mg)的甲醇(20mL)溶液中，加入5％钯碳(50mg)。反应液在氢气环境，室温 条件下搅拌6h，TLC监测反应完成。将反应液过滤，滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化，得到中间体2-3(735mg)。To a solution of intermediate 2-2 (928 mg) in methanol (20 mL) was added 5% palladium on carbon (50 mg). The reaction solution was stirred at room temperature under a hydrogen atmosphere. The mixture was stirred for 6 h under the conditions of 4% to 5% ethyl acetate, and the reaction was completed after monitoring by TLC. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain intermediate 2-3 (735 mg).
LC-MS(ESI):m/z＝297.12[M+H]+ LC-MS(ESI):m/z＝297.12[M+H] +
步骤4：1-(叔丁氧基羰基)-5-氟-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-羧酸(中间体2-4)的合成Step 4: Synthesis of 1-(tert-butoxycarbonyl)-5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 2-4)
向水(50mL)中加入中间体2-3(735mg)、氢氧化锂(90mg)和甲醇(5mL)室温下搅拌10h。TLC监测反应完成，滴加1N盐酸调节pH＝3-4，用乙酸乙酯(25mL×6)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂得到中间体2-4(440mg)。Add intermediate 2-3 (735 mg), lithium hydroxide (90 mg) and methanol (5 mL) to water (50 mL) and stir at room temperature for 10 h. TLC monitors the reaction completion, add 1N hydrochloric acid dropwise to adjust pH=3-4, extract with ethyl acetate (25 mL×6), dry the organic phase with anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain intermediate 2-4 (440 mg).
LC-MS(ESI):m/z＝283.10[M+H]+ LC-MS(ESI):m/z＝283.10[M+H] +
步骤5：2-((5-氯-2,4-二氟苯基)(甲基)氨基甲酰基)-5-氟-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-羧酸叔丁酯(中间体2-5)的合成Step 5: Synthesis of tert-butyl 2-((5-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 2-5)
在中间体2-4(440mg)和中间体10-4(304mg)的二氯甲烷(20mL)溶液中加入N,N'-二环己基碳二亚胺(483mg)和4-二甲氨基吡啶(20mg)。室温条件下搅拌12h，TLC监测反应完成。将反应液过滤，滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化，得到中间体2-5(415mg)。N,N'-dicyclohexylcarbodiimide (483 mg) and 4-dimethylaminopyridine (20 mg) were added to a solution of intermediate 2-4 (440 mg) and intermediate 10-4 (304 mg) in dichloromethane (20 mL). The mixture was stirred at room temperature for 12 h, and the reaction was completed after monitoring by TLC. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain intermediate 2-5 (415 mg).
LC-MS(ESI):m/z＝442.11[M+H]+ LC-MS(ESI):m/z＝442.11[M+H] +
步骤6：N-(5-氯-2,4-二氟苯基)-5-氟-N-甲基-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(中间体2-6)的合成Step 6: Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-fluoro-N-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Intermediate 2-6)
将中间体2-5(415mg)溶解在10％三氟乙酸的二氯甲烷溶液(15mL)中。反应液在室温条件下搅拌6h，TLC监测反应完成。向反应液中滴加饱和碳酸氢钠溶液，调节pH＝8-9，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，得到中间体2-6(203mg)。Intermediate 2-5 (415 mg) was dissolved in 10% trifluoroacetic acid in dichloromethane (15 mL). The reaction solution was stirred at room temperature for 6 h, and the reaction was completed after TLC monitoring. Saturated sodium bicarbonate solution was added dropwise to the reaction solution, and the pH was adjusted to 8-9. The mixture was extracted with ethyl acetate (25 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 2-6 (203 mg).
LC-MS(ESI):m/z＝342.06[M+H]+ LC-MS(ESI):m/z＝342.06[M+H] +
步骤7：N-(5-氯-2,4-二氟苯基)-5-氟-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物2)的合成Step 7: Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-fluoro-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 2)
在中间体2-6(203mg)和2-氯-6-甲基-4-(三氟甲基)吡啶(129mg)的1,4-二氧六环(15mL)溶液中加入三(二亚苄基丙酮)二钯(30mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(50mg)和碳酸铯(295mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到化合物2(90mg)。Tris(dibenzylideneacetone)dipalladium (30 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (50 mg) and cesium carbonate (295 mg) were added to a solution of intermediate 2-6 (203 mg) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (129 mg) in 1,4-dioxane (15 mL). Stirred for 8 h at 110 ° C under nitrogen protection, and the reaction was completed by TLC monitoring. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 2 (90 mg).
LC-MS(ESI):m/z＝501.08[M+H]+ LC-MS(ESI):m/z＝501.08[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.10–7.93(m,1H),7.46–7.30(m,2H),7.25–7.12(m,1H),6.95(m,1H),6.82(m,1H),5.15(m,1H),3.24(s,3H),3.23–3.03(m,2H),2.55(s,3H). 1 H NMR(300MHz,Chloroform-d)δ8.10–7.93(m,1H),7.46–7.30(m,2H),7.25–7.12(m,1H),6.95(m,1H),6.82(m, 1H),5.15(m,1H),3.24(s,3H),3.23–3.03(m,2H),2.55(s,3H).
实施例3、(S)-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物3)的合成
Example 3. Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 3)
参照实施例1的方法，区别仅在于将步骤1中的3-氯-4-氟苯胺替换成5-氯-2,4-二氟苯胺，制备得到标题化合物。The title compound was prepared by referring to the method of Example 1, except that 3-chloro-4-fluoroaniline in step 1 was replaced by 5-chloro-2,4-difluoroaniline.
LC-MS(ESI):m/z＝482.10[M+H]+ LC-MS(ESI):m/z＝482.10[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.98–7.68(m,1H),7.47–7.29(m,1H),7.26–7.07(m,3H),7.02–6.85(m,3H),5.06(m,1H),3.65–3.32(m,1H),3.27(s,3H),3.22–3.05(m,1H),2.59(s,3H). 1 H NMR (300MHz, Chloroform-d) δ7.98–7.68(m,1H),7.47–7.29(m,1H),7.26–7.07(m,3H),7.02–6.85(m,3H),5.06( m,1H),3.65–3.32(m,1H),3.27(s,3H),3.22–3.05(m,1H),2.59(s,3H).
实施例4、(S)-5-溴-N-(3-氯-4-氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物4)的合成
Example 4. Synthesis of (S)-5-bromo-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 4)
将化合物1(463mg)溶于N,N-二甲基甲酰胺(10mL)，加入N-溴代丁二酰亚胺(214mg)室温下搅拌6h，TLC监测反应完成。向反应液中加入水(150mL)，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，将滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝15/1)纯化，得到化合物4(480mg)。Compound 1 (463 mg) was dissolved in N, N-dimethylformamide (10 mL), N-bromosuccinimide (214 mg) was added and stirred at room temperature for 6 h, and the reaction was completed by TLC monitoring. Water (150 mL) was added to the reaction solution, and it was extracted with ethyl acetate (25 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15/1) to obtain compound 4 (480 mg).
LC-MS(ESI):m/z＝542.02[M+H]+ LC-MS(ESI):m/z＝542.02[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.60–7.53(m,1H),7.47(d,J＝8.6Hz,1H),7.35–7.29(m,2H),7.28–7.23(m,2H),7.03(s,1H),6.89(s,1H),5.07(m,1H),3.30(s,3H),3.27–3.07(m,2H),2.60(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.60–7.53(m,1H),7.47(d,J＝8.6Hz,1H),7.35–7.29(m,2H),7.28–7.23(m,2H) ,7.03(s,1H),6.89(s,1H),5.07(m,1H),3.30(s,3H),3.27–3.07(m,2H),2.60(s,3H).
实施例5、(S)-5-溴-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物5)的合成
Example 5. Synthesis of (S)-5-bromo-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 5)
将化合物3(482mg)溶于N,N-二甲基甲酰胺(10mL)，加入N-溴代丁二酰亚胺(214mg)室温下搅拌6h，TLC监测反应完成。向反应液中加入水(150mL)，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，将滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝15/1)纯化，得到化合物5(505mg)。Compound 3 (482 mg) was dissolved in N, N-dimethylformamide (10 mL), N-bromosuccinimide (214 mg) was added and stirred at room temperature for 6 h, and the reaction was completed by TLC monitoring. Water (150 mL) was added to the reaction solution, and it was extracted with ethyl acetate (25 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15/1) to obtain compound 5 (505 mg).
LC-MS(ESI):m/z＝560.01[M+H]+ LC-MS(ESI):m/z＝560.01[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.88–7.79(m,1H),7.50–7.45(m,1H),7.33–7.29(m,1H),7.19–7.09(m,1H),6.91–6.81(m,3H),5.15(m,1H),3.27(s,3H),3.19–2.93(m,2H),2.50(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.88–7.79(m,1H),7.50–7.45(m,1H),7.33–7.29(m,1H),7.19–7.09(m,1H),6.91– 6.81(m,3H),5.15(m,1H),3.27(s,3H),3.19–2.93(m,2H),2.50(s,3H).
实施例6、(S)-N-(3-氯-4-氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-吗啉基二氢吲哚-2-甲酰胺(化合物6)的合成
Example 6. Synthesis of (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-morpholinoindoline-2-carboxamide (Compound 6)
在化合物4(136mg)和吗啉(26mg)的1,4-二氧六环(10mL)溶液中加入醋酸钯(3mg)、1,1'-联萘-2,2'-双二苯膦(16mg)和碳酸铯(122mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化，得到化合物6(37mg)。Palladium acetate (3 mg), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (16 mg) and cesium carbonate (122 mg) were added to a solution of compound 4 (136 mg) and morpholine (26 mg) in 1,4-dioxane (10 mL). Stir at 110°C for 8 h under nitrogen protection, and the reaction was complete after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 6 (37 mg).
LC-MS(ESI):m/z＝549.16[M+H]+ LC-MS(ESI):m/z＝549.16[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.64–7.50(m,1H),7.46(m,1H),7.35–7.29(m,1H),7.27–7.16(m,1H),7.08(s,1H),6.78(m,3H),5.06(m,1H),3.94–3.81(m,4H),3.30(s,3H),3.27–3.11(m,2H),3.10–3.03(m,4H),2.58(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.64–7.50(m,1H),7.46(m,1H),7.35–7.29(m,1H),7.27–7.16(m,1H),7.08(s, 1H),6.78(m,3H),5.06(m,1H),3.94–3.81(m,4H),3.30(s,3H),3.27–3.11(m,2H),3.10–3.03(m,4H) ,2.58(s,3H).
实施例7、(S)-N-(3-氯-4-氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(4-甲基哌嗪-1-基)二氢吲哚-2-甲酰胺(化合物7)的合成
Example 7. Synthesis of (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(4-methylpiperazin-1-yl)indoline-2-carboxamide (Compound 7)
在化合物4(136mg)和N-甲基哌嗪(30mg)的1,4-二氧六环(10mL)溶液中加入醋酸钯(3mg)、1,1'-联萘-2,2'-双二苯膦(16mg)和碳酸铯(122mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到化合物7(60mg)。Palladium acetate (3 mg), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (16 mg) and cesium carbonate (122 mg) were added to a solution of compound 4 (136 mg) and N-methylpiperazine (30 mg) in 1,4-dioxane (10 mL). Stir at 110°C for 8 h under nitrogen protection, and the reaction was complete after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain compound 7 (60 mg).
LC-MS(ESI):m/z＝562.19[M+H]+ LC-MS(ESI):m/z＝562.19[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.54(m,1H),7.44(m,1H),7.27–6.98(m,3H),6.79(m,3H),5.02(m,1H),3.30(d,J＝4.8Hz,3H),3.27–3.05(m,2H),3.16–3.10(m,4H),2.61(m,4H),2.56(s,3H),2.38(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.54(m,1H),7.44(m,1H),7.27–6.98(m,3H),6.79(m,3H),5.02(m,1H),3.30 (d,J＝4.8Hz,3H),3.27–3.05(m,2H),3.16–3.10(m,4H),2.61(m,4H),2.56(s,3H),2.38(s,3H).
实施例8、(S)-N-(3-氯-4-氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(N-甲基甲酰胺)二氢吲哚-2-甲酰胺(化合物8)的合成
Example 8. Synthesis of (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(N-methylformamide)indoline-2-carboxamide (Compound 8)
在化合物4(136mg)和N-甲基甲酰胺(18mg)的甲苯(10mL)溶液中加入三(二亚苄基丙酮)二钯(10mg)、2-二环己基膦-2',4',6'-三异丙基联苯(20mg)和碳酸铯(122mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化，得到化合物8(58mg)。Tris(dibenzylideneacetone)dipalladium (10 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (20 mg) and cesium carbonate (122 mg) were added to a toluene (10 mL) solution of compound 4 (136 mg) and N-methylformamide (18 mg). Stir at 110°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 8 (58 mg).
LC-MS(ESI):m/z＝521.13[M+H]+ LC-MS(ESI):m/z＝521.13[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.37(s,1H),7.69–7.49(m,2H),7.37–7.29(m,1H),7.28(s,1H),7.20–7.01(m,2H),7.01–6.85(m,2H),5.07(m,1H),3.34(m,1H),3.31(s,3H),3.29(s,3H),3.17(m,1H),2.68(s,3H). 1 H NMR(300MHz,Chloroform-d)δ8.37(s,1H),7.69–7.49(m,2H),7.37–7.29(m,1H),7.28(s,1H),7.20–7.01(m, 2H),7.01–6.85(m,2H),5.07(m,1H),3.34(m,1H),3.31(s,3H),3.29(s,3H),3.17(m,1H),2.68(s ,3H).
实施例9、N-(3-氯-4-氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-1H-吲哚-2-甲酰胺(化合物9)的合成
Example 9. Synthesis of N-(3-chloro-4-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1H-indole-2-carboxamide (Compound 9)
在化合物1(116mg)的冰醋酸(10mL)溶液中加入三氧化铬(50mg)，室温条件下搅拌2h，TLC监测反应完成。向反应液中滴加饱和碳酸氢钠溶液，调节pH＝8-9，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，将滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝15/1)纯化，得到化合物9(40mg)。Chromium trioxide (50 mg) was added to a solution of compound 1 (116 mg) in glacial acetic acid (10 mL), stirred at room temperature for 2 h, and the reaction was monitored by TLC to be complete. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust the pH to 8-9, extracted with ethyl acetate (25 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15/1) to obtain compound 9 (40 mg).
LC-MS(ESI):m/z＝462.09[M+H]+ LC-MS(ESI):m/z＝462.09[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.60–7.51(m,3H),7.39–7.29(m,3H),7.27–7.17(m,2H),6.99(t,J＝8.7Hz,1H),6.54(s,1H),3.44(s,3H),2.69(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.60–7.51(m,3H),7.39–7.29(m,3H),7.27–7.17(m,2H),6.99(t,J＝8.7Hz,1H) ,6.54(s,1H),3.44(s,3H),2.69(s,3H).
实施例10、5-氯-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物10)的合成
Example 10. Synthesis of 5-chloro-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 10)
步骤1：5-氯二氢吲哚-2-羧酸甲酯(中间体10-1)的合成Step 1: Synthesis of methyl 5-chloroindoline-2-carboxylate (Intermediate 10-1)
将5-氯吲哚-2-羧酸甲酯(836mg)溶于甲醇(20mL)中，加入镁条(384mg)，在氮气保护，室温下搅拌6h。TLC监测反应完成，向反应液中滴加氨水，调节pH＝8-9，再用1N盐酸调节pH＝4-5，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝20/1)纯化，得到中间体10-1(560mg)。Dissolve 5-chloroindole-2-carboxylic acid methyl ester (836 mg) in methanol (20 mL), add magnesium stick (384 mg), and stir at room temperature under nitrogen protection for 6 h. TLC monitors the completion of the reaction, and drips ammonia water into the reaction solution to adjust the pH to 8-9, and then adjust the pH to 4-5 with 1N hydrochloric acid, extract with ethyl acetate (25 mL×3), dry the organic phase with anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to obtain intermediate 10-1 (560 mg).
LC-MS(ESI):m/z＝212.04[M+H]+ LC-MS(ESI): m/z＝212.04[M+H] +
步骤2：5-氯二氢吲哚-2-羧酸(中间体10-2)的合成Step 2: Synthesis of 5-chloroindoline-2-carboxylic acid (Intermediate 10-2)
向水(50mL)中加入中间体10-1(528mg)、氢氧化钾(210mg)和甲醇(5mL)室温下搅拌10h。TLC监测反应完成，滴加1N盐酸调节pH＝3-4，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂得到中间体10-2(423mg)。Add intermediate 10-1 (528 mg), potassium hydroxide (210 mg) and methanol (5 mL) to water (50 mL) and stir at room temperature for 10 h. After the reaction is completed by TLC monitoring, 1N hydrochloric acid is added dropwise to adjust the pH to 3-4, and the mixture is extracted with ethyl acetate (25 mL×3). The organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain intermediate 10-2 (423 mg).
LC-MS(ESI):m/z＝198.02[M+H]+ LC-MS(ESI):m/z＝198.02[M+H] +
步骤3：1-(叔丁氧羰基)-5-氯二氢吲哚-2-羧酸(中间体10-3)的合成Step 3: Synthesis of 1-(tert-butyloxycarbonyl)-5-chloroindoline-2-carboxylic acid (Intermediate 10-3)
向二氯甲烷(20mL)中加入中间体10-2(396mg)和三乙胺(304mg)，慢慢滴加二碳酸二叔丁酯(655mg)。反应液在室温下搅拌2h，TLC监测反应完成。向反应液中加入水(100mL)，用1N盐酸调节pH＝5-6，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，得到中间体10-3(580mg)。Add intermediate 10-2 (396 mg) and triethylamine (304 mg) to dichloromethane (20 mL), and slowly add di-tert-butyl dicarbonate (655 mg). The reaction solution was stirred at room temperature for 2 h, and the reaction was completed by TLC monitoring. Water (100 mL) was added to the reaction solution, and the pH was adjusted to 5-6 with 1N hydrochloric acid, and extracted with ethyl acetate (25 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 10-3 (580 mg).
LC-MS(ESI):m/z＝298.08[M+H]+ LC-MS(ESI):m/z＝298.08[M+H] +
步骤4：5-氯-2,4-二氟-N-甲基苯胺(中间体10-4)的合成Step 4: Synthesis of 5-chloro-2,4-difluoro-N-methylaniline (Intermediate 10-4)
参照中间体1-2的合成方法，区别仅在于将3-氯-4-氟苯胺替换成5-氯-2,4-二氟苯胺，制备得到5-氯-2,4- 二氟-N-甲基苯胺(中间体10-4)Referring to the synthesis method of intermediate 1-2, the only difference is that 3-chloro-4-fluoroaniline is replaced by 5-chloro-2,4-difluoroaniline to prepare 5-chloro-2,4- Difluoro-N-methylaniline (Intermediate 10-4)
LC-MS(ESI):m/z＝178.02[M+H]+ LC-MS(ESI):m/z＝178.02[M+H] +
步骤5：5-氯-2-((5-氯-2,4-二氟苯基)(甲基)氨甲酰基)二氢吲哚-1-羧酸叔丁酯(中间体10-5)的合成Step 5: Synthesis of tert-butyl 5-chloro-2-((5-chloro-2,4-difluorophenyl)(methyl)carbamoyl)indoline-1-carboxylate (Intermediate 10-5)
在中间体10-3(298mg)和中间体10-4(177mg)的二氯甲烷(20mL)溶液中加入N,N'-二环己基碳二亚胺(309mg)和4-二甲氨基吡啶(13mg)。室温条件下搅拌12h，TLC监测反应完成。将反应液过滤，滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝20/1)纯化，得到中间体10-5(365mg)。N, N'-dicyclohexylcarbodiimide (309 mg) and 4-dimethylaminopyridine (13 mg) were added to a solution of intermediate 10-3 (298 mg) and intermediate 10-4 (177 mg) in dichloromethane (20 mL). The mixture was stirred at room temperature for 12 h, and the reaction was completed after monitoring by TLC. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1) to obtain intermediate 10-5 (365 mg).
LC-MS(ESI):m/z＝457.09[M+H]+ LC-MS(ESI):m/z＝457.09[M+H] +
步骤6：5-氯-N-(5-氯-2,4-二氟苯基)-N-甲基二氢吲哚-2-甲酰胺(中间体10-6)的合成Step 6: Synthesis of 5-chloro-N-(5-chloro-2,4-difluorophenyl)-N-methylindoline-2-carboxamide (Intermediate 10-6)
将中间体10-5(365mg)溶解在10％三氟乙酸的二氯甲烷溶液(15mL)中。反应液在室温条件下搅拌6h，TLC监测反应完成。向反应液中滴加饱和碳酸氢钠溶液，调节pH＝8-9，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，得到中间体10-6(267mg)。Intermediate 10-5 (365 mg) was dissolved in 10% trifluoroacetic acid in dichloromethane (15 mL). The reaction solution was stirred at room temperature for 6 h, and the reaction was completed after TLC monitoring. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust pH to 8-9, and extracted with ethyl acetate (25 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 10-6 (267 mg).
LC-MS(ESI):m/z＝357.03[M+H]+ LC-MS(ESI):m/z＝357.03[M+H] +
步骤7：5-氯-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物10)的合成Step 7: Synthesis of 5-chloro-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 10)
在中间体10-6(267mg)和2-氯-6-甲基-4-(三氟甲基)吡啶(147mg)的1,4-二氧六环(10mL)溶液中加入三(二亚苄基丙酮)二钯(10mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(20mg)和碳酸铯(367mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到化合物10(359mg)。To a solution of intermediate 10-6 (267 mg) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (147 mg) in 1,4-dioxane (10 mL) were added tris(dibenzylideneacetone)dipalladium (10 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (20 mg) and cesium carbonate (367 mg). Stirred at 110°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain compound 10 (359 mg).
LC-MS(ESI):m/z＝516.06[M+H]+ LC-MS(ESI):m/z＝516.06[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.90–7.80(m,1H),7.48–7.35(m,2H),7.19–7.11(m,1H),6.52–6.71(m,3H),5.11(m,1H),3.57–3.35(m,1H),3.25(s,3H),3.24–3.02(m,1H),2.51(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.90–7.80(m,1H),7.48–7.35(m,2H),7.19–7.11(m,1H),6.52–6.71(m,3H),5.11( m,1H),3.57–3.35(m,1H),3.25(s,3H),3.24–3.02(m,1H),2.51(s,3H).
实施例11、6-氯-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物11)的合成
Example 11. Synthesis of 6-chloro-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 11)
参照实施例10的方法，区别仅在于将步骤1中的5-氯吲哚-2-羧酸甲酯替换成6-氯吲哚-2-羧酸甲酯，制备得到标题化合物。The title compound was prepared by referring to the method of Example 10, except that 5-chloroindole-2-carboxylic acid methyl ester in step 1 was replaced by 6-chloroindole-2-carboxylic acid methyl ester.
LC-MS(ESI):m/z＝516.06[M+H]+ LC-MS(ESI):m/z＝516.06[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.83(m,1H),7.51(m,1H),7.20–6.98(m,3H),6.94–6.84(m,2H),5.04(m,1H),3.60–3.29(m,1H),3.26(s,3H),3.15(m,1H),2.61(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.83(m,1H),7.51(m,1H),7.20–6.98(m,3H),6.94–6.84(m,2H),5.04(m,1H) ,3.60–3.29(m,1H),3.26(s,3H),3.15(m,1H),2.61(s,3H).
实施例12、4-氟-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物12)的合成
Example 12. Synthesis of 4-fluoro-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 12)
参照实施例10的方法，区别仅在于将步骤1中的5-氯吲哚-2-羧酸甲酯替换成4-氟吲哚-2-羧酸甲酯，制备得到标题化合物。The title compound was prepared by referring to the method of Example 10, except that 5-chloroindole-2-carboxylic acid methyl ester in step 1 was replaced by 4-fluoroindole-2-carboxylic acid methyl ester.
LC-MS(ESI):m/z＝500.09[M+H]+ LC-MS(ESI):m/z＝500.09[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.89(m,1H),7.27(s,1H),7.23–6.96(m,3H),6.91(s,1H),6.63(m,1H),5.10(m,1H),3.28(s,3H),3.25–3.09(m,2H),2.59(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.89(m,1H),7.27(s,1H),7.23–6.96(m,3H),6.91(s,1H),6.63(m,1H),5.10 (m,1H),3.28(s,3H),3.25–3.09(m,2H),2.59(s,3H).
实施例13、5-氟-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物13)的合成
Example 13. Synthesis of 5-fluoro-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 13)
参照实施例10的方法，区别仅在于将5-氯吲哚-2-羧酸甲酯替换成5-氟吲哚-2-羧酸甲酯，制备得到标题化合物。The title compound was prepared by referring to the method of Example 10, except that 5-chloroindole-2-carboxylic acid methyl ester was replaced by 5-fluoroindole-2-carboxylic acid methyl ester.
LC-MS(ESI):m/z＝500.09[M+H]+ LC-MS(ESI):m/z＝500.09[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.91–7.78(m,1H),7.46–7.39(m,1H),7.18–7.10(m,1H),7.04–6.91(m,1H),6.91–6.81(m,3H),5.06(m,1H),3.63–3.31(m,1H),3.27(s,3H),3.24–3.02(m,1H),2.59(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.91–7.78(m,1H),7.46–7.39(m,1H),7.18–7.10(m,1H),7.04–6.91(m,1H),6.91– 6.81(m,3H),5.06(m,1H),3.63–3.31(m,1H),3.27(s,3H),3.24–3.02(m,1H),2.59(s,3H).
实施例14、4-溴-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物14)的合成
Example 14. Synthesis of 4-bromo-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 14)
参照实施例10的方法，区别仅在于将5-氯吲哚-2-羧酸甲酯替换成4-溴吲哚-2-羧酸甲酯，制备得到标题化合物。The title compound was prepared by referring to the method of Example 10, except that 5-chloroindole-2-carboxylic acid methyl ester was replaced by 4-bromoindole-2-carboxylic acid methyl ester.
LC-MS(ESI):m/z＝560.01[M+H]+ LC-MS(ESI):m/z＝560.01[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.55(m,1H),7.33(m,1H),7.18–6.96(m,3H),6.90–6.64(m,2H),5.11(m,1H),3.25(s,3H),3.25–3.09(m,2H),2.51(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.55(m,1H),7.33(m,1H),7.18–6.96(m,3H),6.90–6.64(m,2H),5.11(m,1H) ,3.25(s,3H),3.25–3.09(m,2H),2.51(s,3H).
实施例15、N-(5-氯-2,4-二氟苯基)-5-氰基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物15)的合成
Example 15. Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-cyano-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 15)
参照实施例10的方法，区别仅在于将5-氯吲哚-2-羧酸甲酯替换成5-氰基吲哚-2-羧酸甲酯，制备得到标题化合物。The title compound was prepared by referring to the method of Example 10, except that 5-chloroindole-2-carboxylic acid methyl ester was replaced by 5-cyanoindole-2-carboxylic acid methyl ester.
LC-MS(ESI):m/z＝507.09[M+H]+ LC-MS(ESI):m/z＝507.09[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.88–7.58(m,1H),7.44–7.28(m,2H),7.14(m,1H),7.08–6.71(m,3H),4.91(m,1H),3.67–3.16(m,1H),3.12(s,3H),3.03(m,1H),2.46(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.88–7.58(m,1H),7.44–7.28(m,2H),7.14(m,1H),7.08–6.71(m,3H),4.91(m, 1H),3.67–3.16(m,1H),3.12(s,3H),3.03(m,1H),2.46(s,3H).
实施例16、N-(5-氯-2,4-二氟苯基)-5-甲氧基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物16)的合成
Example 16. Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-methoxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 16)
参照实施例10的方法，区别仅在于将5-氯吲哚-2-羧酸甲酯替换成5-甲氧基吲哚-2-羧酸甲酯，制备得到标题化合物。The title compound was prepared by referring to the method of Example 10, except that 5-chloroindole-2-carboxylic acid methyl ester was replaced by 5-methoxyindole-2-carboxylic acid methyl ester.
LC-MS(ESI):m/z＝512.11[M+H]+ LC-MS(ESI):m/z＝512.11[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.93–7.68(m,1H),7.39(m,1H),7.19(s,1H),7.17–7.08(m,1H),6.84(m,1H),6.79–6.69(m,2H),5.22–4.88(m,1H),3.79(s,3H),3.26(s,3H),3.23–3.03(m,2H),2.57(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.93–7.68(m,1H),7.39(m,1H),7.19(s,1H),7.17–7.08(m,1H),6.84(m,1H) ,6.79–6.69(m,2H),5.22–4.88(m,1H),3.79(s,3H),3.26(s,3H),3.23–3.03(m,2H),2.57(s,3H).
实施例17、N-(5-氯-2,4-二氟苯基)-5-羟基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物17)的合成
Example 17. Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-hydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 17)
将化合物16(150mg)溶解在二氯甲烷(10mL)中，在0℃，氮气保护条件下滴加0.59mL的三溴化硼的二氯甲烷溶液(2mol/L)搅拌5h，TLC监测反应完成。向反应液中加入甲醇5mL淬灭三溴化硼，再加入水(100mL)，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到化合物17(128mg)。Compound 16 (150 mg) was dissolved in dichloromethane (10 mL), and 0.59 mL of dichloromethane solution of boron tribromide (2 mol/L) was added dropwise at 0°C under nitrogen protection and stirred for 5 h. The reaction was monitored by TLC to complete. 5 mL of methanol was added to the reaction solution to quench the boron tribromide, and then water (100 mL) was added, and the mixture was extracted with ethyl acetate (25 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain compound 17 (128 mg).
LC-MS(ESI):m/z＝498.10[M+H]+ LC-MS(ESI):m/z＝498.10[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.65–8.00(m,1H),7.88–7.50(m,3H),7.44(s,1H),7.16(m,2H),6.58(m,1H),5.67(m,1H),3.93(s,3H),3.85–3.55(m,2H),3.20(s,3H). 1 H NMR(300MHz,Chloroform-d)δ8.65–8.00(m,1H),7.88–7.50(m,3H),7.44(s,1H),7.16(m,2H),6.58(m,1H) ,5.67(m,1H),3.93(s,3H),3.85–3.55(m,2H),3.20(s,3H).
实施例18：(S)-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-吗啉基二氢吲哚-2-甲酰胺(化合物18)的合成
Example 18: Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-morpholinoindoline-2-carboxamide (Compound 18)
在化合物5(135mg)和吗啉(26mg)的1,4-二氧六环(10mL)溶液中加入醋酸钯(3mg)、1,1'-联萘-2,2'-双二苯膦(16mg)和碳酸铯(122mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化，得到化合物18(48mg)。Palladium acetate (3 mg), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (16 mg) and cesium carbonate (122 mg) were added to a solution of compound 5 (135 mg) and morpholine (26 mg) in 1,4-dioxane (10 mL). Stir at 110°C for 8 h under nitrogen protection, and the reaction was complete after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 18 (48 mg).
LC-MS(ESI):m/z＝567.15[M+H]+ LC-MS(ESI):m/z＝567.15[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.71(m,1H),7.58–7.42(m,1H),7.11–6.98(m,2H),6.80(m,3H),5.18–4.79(m,1H),3.89(m,4H),3.75–3.45(m,1H),3.28(s,3H),3.25–3.12(m,1H),3.09(m,4H),2.55(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.71(m,1H),7.58–7.42(m,1H),7.11–6.98(m,2H),6.80(m,3H),5.18–4.79(m, 1H),3.89(m,4H),3.75–3.45(m,1H),3.28(s,3H),3.25–3.12(m,1H),3.09(m,4H),2.55(s,3H).
实施例19：(S)-N-(5-氯-2,4-二氟苯基)-5-((2-甲氧基乙基)氨基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物19)的合成
Example 19: Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-5-((2-methoxyethyl)amino)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 19)
在化合物5(135mg)和2-甲氧基乙胺(23mg)的甲苯(10mL)溶液中加入三(二亚苄基丙酮)二钯(5mg)、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-联苯]-2-基)膦(10mg)和碳酸铯(122mg)。在氮气保护，120℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到化合物19(60mg)。Tris(dibenzylideneacetone)dipalladium(5mg), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine(10mg) and cesium carbonate(122mg) were added to a toluene(10mL) solution of compound 5(135mg) and 2-methoxyethylamine(23mg). Stirred at 120°C for 8h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate=2/1) to obtain compound 19(60mg).
LC-MS(ESI):m/z＝555.2[M+H]+ LC-MS (ESI): m/z = 555.2 [M + H] +
1H NMR(300MHz,Chloroform-d)δ8.05–7.29(m,2H),7.28–6.97(m,2H),6.97–6.74(m,2H),6.73–6.42(m,2H),5.02(m,1H),3.71–3.55(m,2H),3.41(s,3H),3.29(m,1H),3.27(s,3H),3.24(m,1H),3.17–2.89(m,2H),2.55(s,3H). 1 H NMR (300MHz, Chloroform-d) δ8.05–7.29(m,2H),7.28–6.97(m,2H),6.97–6.74(m,2H),6.73–6.42(m,2H),5.02( m,1H),3.71–3.55(m,2H),3.41(s,3H),3.29(m,1H),3.27(s,3H),3.24(m,1H),3.17–2.89(m,2H) ,2.55(s,3H).
实施例20：(S)-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(4-(甲基磺酰基)哌嗪-1-基)二氢吲哚-2-甲酰胺(化合物20)的合成
Example 20: Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(4-(methylsulfonyl)piperazin-1-yl)indoline-2-carboxamide (Compound 20)
在化合物5(135mg)和1-甲烷磺酰哌嗪(50mg)的1,4-二氧六环(10mL)溶液中加入醋酸钯(3mg)、2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯(18mg)和碳酸铯(122mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到化合物20(37mg)。Palladium acetate (3 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (18 mg) and cesium carbonate (122 mg) were added to a solution of compound 5 (135 mg) and 1-methanesulfonylpiperazine (50 mg) in 1,4-dioxane (10 mL). Stir at 110°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 20 (37 mg).
LC-MS(ESI):m/z＝644.15[M+H]+ LC-MS(ESI):m/z＝644.15[M+H] +
1H NMR(400MHz,Chloroform-d)δ7.75–7.64(m,1H),7.35(m,1H),7.19–6.90(m,3H),6.85–6.69(m,2H),5.12(m,1H),3.38(m,1H),3.24(s,3H),3.22–3.14(m,1H),3.13–3.01(m,4H),2.95(s,3H)2.88–2.75(m,4H),2.54(s,3H). 1 H NMR(400MHz,Chloroform-d)δ7.75–7.64(m,1H),7.35(m,1H),7.19–6.90(m,3H),6.85–6.69(m,2H),5.12(m, 1H),3.38(m,1H),3.24(s,3H),3.22–3.14(m,1H),3.13–3.01(m,4H),2.95(s,3H)2.88–2.75(m,4H), 2.54(s,3H).
实施例21：(S)-N-(5-氯-2,4-二氟苯基)-5-(环丙烷磺酰胺基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物21)的合成
Example 21: Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-5-(cyclopropanesulfonamido)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 21)
在化合物5(135mg)和环丙磺酰胺(36mg)的甲苯(10mL)溶液中加入三(二亚苄基丙酮)二钯(5mg)、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-联苯]-2-基)膦(10mg)和碳酸铯(122mg)。在氮气保护，120℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到化合物21(51mg)。Tris(dibenzylideneacetone)dipalladium(5mg), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine(10mg) and cesium carbonate(122mg) were added to a toluene(10mL) solution of compound 5(135mg) and cyclopropylsulfonamide(36mg). Stirred at 120°C for 8h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate=2/1) to obtain compound 21(51mg).
LC-MS(ESI):m/z＝601.10[M+H]+ LC-MS(ESI):m/z＝601.10[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.92–7.73(m,1H),7.35(m,1H),7.20–7.12(m,2H),7.12–6.85(m,3H),6.46(m,1H),5.03(m,1H),3.65–3.31(m,1H),3.29(s,3H),3.24–3.04(m,1H),2.59(s,3H),2.44(m,1H),1.14(m,2H),0.96(m,2H). 1 H NMR(300MHz,Chloroform-d)δ7.92–7.73(m,1H),7.35(m,1H),7.20–7.12(m,2H),7.12–6.85(m,3H),6.46(m, 1H),5.03(m,1H),3.65–3.31(m,1H),3.29(s,3H),3.24–3.04(m,1H),2.59(s,3H),2.44(m,1H),1.14 (m,2H),0.96(m,2H).
实施例22：(S)-(2-((5-氯-2,4-二氟苯基)(甲基)氨基甲酰基)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-5-基)氨基甲酸叔丁酯(化合物22)的合成
Example 22: Synthesis of tert-butyl (S)-(2-((5-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indolin-5-yl)carbamate (Compound 22)
在化合物5(135mg)和氨基甲酸叔丁酯(40mg)的甲苯(10mL)溶液中加入三(二亚苄基丙酮)二钯(5mg)、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-联苯]-2-基)膦(10mg)和碳酸铯(122mg)。在氮气保护，120℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到化合物22(43mg)。Tris(dibenzylideneacetone)dipalladium(5mg), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine(10mg) and cesium carbonate(122mg) were added to a toluene(10mL) solution of compound 5(135mg) and tert-butyl carbamate(40mg). Stirred at 120°C for 8h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate=5/1) to obtain compound 22(43mg).
LC-MS(ESI):m/z＝597.16[M+H]+LC-MS (ESI): m/z = 597.16 [M + H] +
1H NMR(300MHz,Chloroform-d)δ7.90–7.66(m,1H),7.50–7.40(m,1H),7.36(m,1H),7.21–7.08(m,2H),7.03–6.94(m,1H),6.85(m,1H),6.43(s,1H),5.03(m,1H),3.60–3.31(m,1H),3.26(s,3H),3.21–3.00(m,1H),2.57(s,3H).1.53(s,9H) 1 H NMR(300MHz,Chloroform-d)δ7.90–7.66(m,1H),7.50–7.40(m,1H),7.36(m,1H),7.21–7.08(m,2H),7.03–6.94( m,1H),6.85(m,1H),6.43(s,1H),5.03(m,1H),3.60–3.31(m,1H),3.26(s,3H),3.21–3.00(m,1H) ,2.57(s,3H).1.53(s,9H)
实施例23：(S)-N-(5-氯-2,4-二氟苯基)-5-(4-(2-甲氧基乙基)哌嗪-1-基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物23)的合成
Example 23: Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-5-(4-(2-methoxyethyl)piperazin-1-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 23)
在化合物5(135mg)和1-(2-甲氧基乙基)哌嗪(43mg)的1,4-二氧六环(10mL)溶液中加入醋酸钯(3mg)、2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯(18mg)和碳酸铯(122mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到化合物23(45mg)。Palladium acetate (3 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (18 mg) and cesium carbonate (122 mg) were added to a solution of compound 5 (135 mg) and 1-(2-methoxyethyl)piperazine (43 mg) in 1,4-dioxane (10 mL). Stir at 110°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 23 (45 mg).
LC-MS(ESI):m/z＝624.21[M+H]+ LC-MS(ESI):m/z＝624.21[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.94–7.33(m,1H),7.21(s,1H),7.13(m,1H),6.90(m,1H),6.83(m,2H),6.80–6.72(m,1H),5.06(m,1H),3.62(m,2H),3.42(s,3H),3.27(s,3H),3.23–3.14(m,5H),3.08(m,1H),2.73(m,6H),2.58(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.94–7.33(m,1H),7.21(s,1H),7.13(m,1H),6.90(m,1H),6.83(m,2H),6.80 –6.72(m,1H),5.06(m,1H),3.62(m,2H),3.42(s,3H),3.27(s,3H),3.23–3.14(m,5H),3.08(m,1H ),2.73(m,6H),2.58(s,3H).
实施例24：(S)-5-(4-乙酰哌嗪-1-基)-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物24)的合成
Example 24: Synthesis of (S)-5-(4-acetylpiperazin-1-yl)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 24)
在化合物5(135mg)和乙酰哌嗪(39mg)的1,4-二氧六环(10mL)溶液中加入醋酸钯(3mg)、2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯(18mg)和碳酸铯(122mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到化合物24(53mg)。Palladium acetate (3 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (18 mg) and cesium carbonate (122 mg) were added to a solution of compound 5 (135 mg) and acetylpiperazine (39 mg) in 1,4-dioxane (10 mL). Stir at 110°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain compound 24 (53 mg).
LC-MS(ESI):m/z＝608.18[M+H]+ LC-MS (ESI): m/z = 608.18 [M+H] +
1H NMR(400MHz,Chloroform-d)δ7.87–7.64(m,1H),7.36(m,1H),7.18–6.90(m,2H),6.87–6.71(m,3H),5.02(m,1H),3.77–3.56(m,4H),3.38(m,1H),3.24(s,3H),3.20–3.12(m,1H),3.05(m,4H),2.55(s,3H),2.14(s,3H). 1 H NMR(400MHz,Chloroform-d)δ7.87–7.64(m,1H),7.36(m,1H),7.18–6.90(m,2H),6.87–6.71(m,3H),5.02(m, 1H),3.77–3.56(m,4H),3.38(m,1H),3.24(s,3H),3.20–3.12(m,1H),3.05(m,4H),2.55(s,3H),2.14 (s,3H).
实施例25：(S)-N-(5-氯-2,4-二氟苯基)-5-((2-(1,1-二氧代硫代吗啉)乙基)氨基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物25)的合成
Example 25: Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-5-((2-(1,1-dioxothiomorpholino)ethyl)amino)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 25)
在化合物5(135mg)和4-(2-氨乙基)硫代吗啉-1,1-二氧化物(53mg)的甲苯(10mL)溶液中加入三(二亚苄基丙酮)二钯(5mg)、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-联苯]-2-基)膦(10mg)和碳酸铯(122mg)。在氮气保护，120℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/2)纯化，得到化合物25(43mg)。Tris(dibenzylideneacetone)dipalladium(5mg), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine(10mg) and cesium carbonate(122mg) were added to a toluene(10mL) solution of compound 5(135mg) and 4-(2-aminoethyl)thiomorpholine-1,1-dioxide(53mg). Stirred at 120°C for 8h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate=1/2) to obtain compound 25(43mg).
LC-MS(ESI):m/z＝658.16[M+H]+ LC-MS(ESI):m/z＝658.16[M+H] +
1H NMR(400MHz,Chloroform-d)δ7.94–7.53(m,1H),7.50–7.30(m,1H),7.24–6.93(m,2H),6.85–6.75(m,1H),6.67–6.46(m,2H),5.01(m,1H),3.62–3.29(m,1H),3.25(s,3H),3.18(m,1H),3.08-3.03(m,8H),3.01(m,1H),2.81(m,2H),2.59(s,3H),1.36–1.24(m,2H). 1 H NMR(400MHz,Chloroform-d)δ7.94–7.53(m,1H),7.50–7.30(m,1H),7.24–6.93(m,2H),6.85–6.75(m,1H),6.67– 6.46(m,2H),5.01(m,1H),3.62–3.29(m,1H),3.25(s,3H),3.18(m,1H),3.08-3.03(m,8H),3.01(m, 1H),2.81(m,2H),2.59(s,3H),1.36–1.24(m,2H).
实施例26：(S)-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(丙基磺酰胺)二氢吲哚-2-甲酰胺(化合物26)的合成
Example 26: Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(propylsulfonamide)indoline-2-carboxamide (Compound 26)
在化合物5(135mg)和丙磺酰胺(37mg)的甲苯(10mL)溶液中加入三(二亚苄基丙酮)二钯(5mg)、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-联苯]-2-基)膦(10mg)和碳酸铯(122mg)。在氮气保护，120℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到化合物26(48mg)。Tris(dibenzylideneacetone)dipalladium(5mg), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine(10mg) and cesium carbonate(122mg) were added to a toluene(10mL) solution of compound 5(135mg) and propanesulfonamide(37mg). Stirred at 120°C for 8h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate=2/1) to obtain compound 26(48mg).
LC-MS(ESI):m/z＝603.12[M+H]+ LC-MS(ESI):m/z＝603.12[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.94–7.67(m,1H),7.35(m,1H),7.24–7.05(m,3H),6.96–6.85(m,2H),6.85–6.62(m,1H),5.02(m,1H),3.65–3.32(m,1H),3.30(s,3H),3.25–3.05(m,1H),3.05–2.94(m,2H),2.59(s,3H),1.91–1.81(m,2H),1.03(m,3H). 1 H NMR (300MHz, Chloroform-d) δ7.94–7.67(m,1H),7.35(m,1H),7.24–7.05(m,3H),6.96–6.85(m,2H),6.85–6.62( m,1H),5.02(m,1H),3.65–3.32(m,1H),3.30(s,3H),3.25–3.05(m,1H),3.05–2.94(m,2H),2.59(s, 3H),1.91–1.81(m,2H),1.03(m,3H).
实施例27、N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物27)的合成
Example 27. Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 27)
步骤1：1-(叔丁基)2-乙基1H-吡咯并[2,3-b]吡啶-1,2-二羧酸酯(中间体27-1)的合成Step 1: Synthesis of 1-(tert-butyl) 2-ethyl 1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (Intermediate 27-1)
将1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯(760mg)和4-二甲氨基吡啶(40mg)溶于二氯甲烷(20mL)中，滴加二碳酸二叔丁酯(1746mg)。反应液在室温下搅拌5h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到中间体27-1(1015mg)。1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester (760 mg) and 4-dimethylaminopyridine (40 mg) were dissolved in dichloromethane (20 mL), and di-tert-butyl dicarbonate (1746 mg) was added dropwise. The reaction solution was stirred at room temperature for 5 h, and the reaction was monitored by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain intermediate 27-1 (1015 mg).
LC-MS(ESI):m/z＝291.13[M+H]+ LC-MS(ESI): m/z＝291.13[M+H] +
步骤2：1-(叔丁基)2-乙基2,3-二氢-1H-吡咯并[2,3-b]吡啶-1,2-二羧酸酯(中间体27-2)的合成Step 2: Synthesis of 1-(tert-butyl) 2-ethyl 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (Intermediate 27-2)
向中间体27-1(1015mg)的甲醇(20mL)溶液中，加入5％钯碳(50mg)。反应液在氢气环境，室温条件下搅拌6h，TLC监测反应完成。将反应液过滤，滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到中间体27-2(876mg)。To a solution of intermediate 27-1 (1015 mg) in methanol (20 mL), 5% palladium on carbon (50 mg) was added. The reaction solution was stirred at room temperature under a hydrogen environment for 6 h, and the reaction was completed after monitoring by TLC. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain intermediate 27-2 (876 mg).
LC-MS(ESI):m/z＝293.15[M+H]+ LC-MS(ESI):m/z＝293.15[M+H] +
步骤3：1-(叔丁氧羰基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-羧酸(中间体27-3)的合成Step 3: Synthesis of 1-(tert-butyloxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 27-3)
向水(50mL)中加入中间体27-2(876mg)、氢氧化锂(108mg)和甲醇(5mL)室温下搅拌10h。TLC监测反应完成，滴加1N盐酸调节pH＝3-4，用乙酸乙酯(25mL×6)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂得到中间体27-3(660mg)。Add intermediate 27-2 (876 mg), lithium hydroxide (108 mg) and methanol (5 mL) to water (50 mL) and stir at room temperature for 10 h. After TLC monitoring, the reaction was completed, 1N hydrochloric acid was added dropwise to adjust the pH to 3-4, and the mixture was extracted with ethyl acetate (25 mL×6). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 27-3 (660 mg).
LC-MS(ESI):m/z＝265.11[M+H]+ LC-MS(ESI):m/z＝265.11[M+H] +
步骤4：2-((5-氯-2,4-二氟苯基)(甲基)氨甲酰基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-羧酸叔丁酯(中间体27-4)的合成Step 4: Synthesis of tert-butyl 2-((5-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 27-4)
在中间体27-3(660mg)和中间体10-4(443mg)的二氯甲烷(20mL)溶液中加入N,N'-二环己基碳二亚胺(774mg)和4-二甲氨基吡啶(16mg)。室温条件下搅拌12h，TLC监测反应完成。将反应液过滤，滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝20/1)纯化，得到中间体27-4(634mg)。N, N'-dicyclohexylcarbodiimide (774 mg) and 4-dimethylaminopyridine (16 mg) were added to a solution of intermediate 27-3 (660 mg) and intermediate 10-4 (443 mg) in dichloromethane (20 mL). The mixture was stirred at room temperature for 12 h, and the reaction was completed after monitoring by TLC. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1) to obtain intermediate 27-4 (634 mg).
LC-MS(ESI):m/z＝424.12[M+H]+ LC-MS(ESI):m/z＝424.12[M+H] +
步骤5：N-(5-氯-2，4-二氟苯基)-N-甲基-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(中间体27-5)的合成Step 5: Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Intermediate 27-5)
将中间体27-4(634mg)溶解在10％三氟乙酸的二氯甲烷溶液(15mL)中。反应液在室温条件下搅拌6h，TLC监测反应完成。向反应液中滴加饱和碳酸氢钠溶液，调节pH＝8-9，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，得到中间体27-5(323mg)。Intermediate 27-4 (634 mg) was dissolved in 10% trifluoroacetic acid in dichloromethane (15 mL). The reaction solution was stirred at room temperature for 6 h, and the reaction was completed after TLC monitoring. Saturated sodium bicarbonate solution was added dropwise to the reaction solution, and the pH was adjusted to 8-9. The mixture was extracted with ethyl acetate (25 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 27-5 (323 mg).
LC-MS(ESI):m/z＝324.06[M+H]+ LC-MS(ESI):m/z＝324.06[M+H] +
步骤6：N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物27)的合成Step 6: Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 27)
在中间体27-5(323mg)和2-氯-6-甲基-4-(三氟甲基)吡啶(195mg)的1,4-二氧六环(15mL)溶液 中加入三(二亚苄基丙酮)二钯(20mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(40mg)和碳酸铯(488mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到化合物27(110mg)。A solution of intermediate 27-5 (323 mg) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (195 mg) in 1,4-dioxane (15 mL) Tris(dibenzylideneacetone)dipalladium (20 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (40 mg) and cesium carbonate (488 mg) were added to the mixture. Stirring was carried out at 110°C for 8 h under nitrogen protection. The reaction was completed after monitoring by TLC. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 27 (110 mg).
LC-MS(ESI):m/z＝483.10[M+H]+ LC-MS(ESI):m/z＝483.10[M+H] +
1H NMR(300MHz,Chloroform-d)δ9.10–8.90(m,1H),8.15(m,1H),8.04(m,1H),7.46–7.30(m,1H),7.27–7.12(m,1H),6.93(m,1H),6.77(m,1H),5.32–5.15(m,1H),3.28(s,3H),3.25–3.03(m,2H),2.58(s,3H). 1 H NMR(300MHz,Chloroform-d)δ9.10–8.90(m,1H),8.15(m,1H),8.04(m,1H),7.46–7.30(m,1H),7.27–7.12(m, 1H),6.93(m,1H),6.77(m,1H),5.32–5.15(m,1H),3.28(s,3H),3.25–3.03(m,2H),2.58(s,3H).
实施例28、N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-c]吡啶-2-甲酰胺(化合物28)的合成
Example 28. Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound 28)
参照实施例27的方法，区别仅在于将步骤1中的1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯替换成1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯，制备得到标题化合物。The title compound was prepared by referring to the method of Example 27, except that 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in step 1 was replaced with 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester.
LC-MS(ESI):m/z＝483.10[M+H]+ LC-MS(ESI):m/z＝483.10[M+H] +
1H NMR(300MHz,Chloroform-d)δ9.17(m,1H),8.21(m,1H),7.82(m,1H),7.27–6.99(m,3H),6.94(s,1H),5.03(m,1H),3.63–3.30(m,1H),3.28(s,3H),3.24–3.13(m,1H),2.61(s,3H). 1 H NMR(300MHz,Chloroform-d)δ9.17(m,1H),8.21(m,1H),7.82(m,1H),7.27–6.99(m,3H),6.94(s,1H),5.03 (m,1H),3.63–3.30(m,1H),3.28(s,3H),3.24–3.13(m,1H),2.61(s,3H).
实施例29、N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[3,2-c]吡啶-2-甲酰胺(化合物29)的合成
Example 29. Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide (Compound 29)
参照实施例27的方法，区别仅在于将1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯替换成1H-吡咯并[3,2-c]吡啶-2-羧酸乙酯，制备得到标题化合物。The title compound was prepared by referring to the method of Example 27, except that 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester was replaced with 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester.
LC-MS(ESI):m/z＝483.10[M+H]+ LC-MS(ESI):m/z＝483.10[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.33–8.25(m,1H),8.09–8.03(m,1H),7.18–7.10(m,1H),7.02–6.93(m,2H),6.91–6.81(m,2H),5.10(m,1H),3.48–3.31(m,1H),3.26(s,3H),3.20–3.08(m,1H),2.49(s,3H). 1 H NMR(300MHz,Chloroform-d)δ8.33–8.25(m,1H),8.09–8.03(m,1H),7.18–7.10(m,1H),7.02–6.93(m,2H),6.91– 6.81(m,2H),5.10(m,1H),3.48–3.31(m,1H),3.26(s,3H),3.20–3.08(m,1H),2.49(s,3H).
实施例30、N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[3,2-b]吡啶-2-甲酰胺(化合物30)的合成
Example 30. Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (Compound 30)
参照实施例27的方法，区别仅在于将1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯替换成1H-吡咯并[3,2-b]吡啶-2-羧酸乙酯，制备得到标题化合物。The title compound was prepared by referring to the method of Example 27, except that 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester was replaced with 1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester.
LC-MS(ESI):m/z＝483.10[M+H]+ LC-MS(ESI):m/z＝483.10[M+H] +
1H NMR(400MHz,Chloroform-d)δ8.08–8.02(m,1H),7.86–7.78(m,1H),7.32(m,1H),7.22–7.00(m,3H),6.94(s,1H),5.20–4.88(m,1H),3.64–3.30(m,2H),3.28(s,3H),2.61(s,3H). 1 H NMR(400MHz,Chloroform-d)δ8.08–8.02(m,1H),7.86–7.78(m,1H),7.32(m,1H),7.22–7.00(m,3H),6.94(s, 1H),5.20–4.88(m,1H),3.64–3.30(m,2H),3.28(s,3H),2.61(s,3H).
实施例31：N-(5-氯-2,4-二氟苯基)-4-(环丙烷磺酰胺基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物31)的合成
Example 31: Synthesis of N-(5-chloro-2,4-difluorophenyl)-4-(cyclopropanesulfonamido)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 31)
在化合物14(135mg)和环丙磺酰胺(36mg)的甲苯(10mL)溶液中加入三(二亚苄基丙酮)二钯(5mg)、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-联苯]-2-基)膦(10mg)和碳酸铯(122mg)。在氮气保护，120℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到化合物31(47mg)。Tris(dibenzylideneacetone)dipalladium(5mg), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine(10mg) and cesium carbonate(122mg) were added to a toluene(10mL) solution of compound 14(135mg) and cyclopropylsulfonamide(36mg). Stirred at 120°C for 8h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate=2/1) to obtain compound 31(47mg).
LC-MS(ESI):m/z＝601.10[M+H]+ LC-MS(ESI):m/z＝601.10[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.93–7.31(m,2H),7.27–7.16(m,2H),7.16–6.87(m,3H),6.63(m,1H),5.07(m,1H),3.47–3.31(m,1H),3.27(s,3H),3.24–3.06(m,1H),2.59(s,3H),2.52–2.46(m,1H),1.18(m,2H),1.00(m,2H). 1 H NMR(300MHz,Chloroform-d)δ7.93–7.31(m,2H),7.27–7.16(m,2H),7.16–6.87(m,3H),6.63(m,1H),5.07(m, 1H),3.47–3.31(m,1H),3.27(s,3H),3.24–3.06(m,1H),2.59(s,3H),2.52–2.46(m,1H),1.18(m,2H) ,1.00(m,2H).
实施例32、(S)-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(3-氰基-6-甲基-4-三氟甲基吡啶-2-基)二氢吲哚-2-甲酰胺(化合物32)的合成
Example 32. Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(3-cyano-6-methyl-4-trifluoromethylpyridin-2-yl)indoline-2-carboxamide (Compound 32)
步骤1：6-甲基-2-氧代-4-三氟甲基-1,2-二氢吡啶-3-甲腈(中间体32-1)的合成Step 1: Synthesis of 6-methyl-2-oxo-4-trifluoromethyl-1,2-dihydropyridine-3-carbonitrile (Intermediate 32-1)
将2-氰基乙酰胺(1g)溶解在无水乙醇(20mL)中，向其中加入1，1，1-三氟戊烷-2，4-二酮(500mg)，最后向反应液中滴加二乙胺溶液(300uL)，在70℃下搅拌反应5h，TLC监测反应完成。反应液有晶体析出，进行抽滤，得到中间体32-1(545mg)。2-Cyanoacetamide (1 g) was dissolved in anhydrous ethanol (20 mL), 1,1,1-trifluoropentane-2,4-dione (500 mg) was added thereto, and finally diethylamine solution (300 uL) was added dropwise to the reaction solution, and the reaction was stirred at 70°C for 5 h. The reaction was completed after monitoring by TLC. Crystals precipitated from the reaction solution, which was filtered to obtain intermediate 32-1 (545 mg).
LC-MS(ESI):m/z＝203.04[M+H]+ LC-MS(ESI): m/z＝203.04[M+H] +
步骤2：2-氯-6-甲基-4-三氟甲基烟腈(中间体32-2)的合成Step 2: Synthesis of 2-chloro-6-methyl-4-trifluoromethylnicotinonitrile (Intermediate 32-2)
向6-甲基-2-氧代-4-三氟甲基-1,2-二氢吡啶-3-甲腈(中间体32-1)(545mg)中加入三氯氧磷(4mL)，在110℃下搅拌反应20h，TLC监测反应完成。减压蒸出溶剂，柱层析(石油醚/乙酸乙酯＝30/1)得到中间体32-2(635mg)。Phosphorus oxychloride (4 mL) was added to 6-methyl-2-oxo-4-trifluoromethyl-1,2-dihydropyridine-3-carbonitrile (Intermediate 32-1) (545 mg), and the mixture was stirred at 110°C for 20 h. The reaction was completed after monitoring by TLC. The solvent was evaporated under reduced pressure, and column chromatography (petroleum ether/ethyl acetate = 30/1) was performed to obtain Intermediate 32-2 (635 mg).
LC-MS(ESI):m/z＝221.00[M+H]+ LC-MS(ESI):m/z＝221.00[M+H] +
步骤3：(S)-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(3-氰基-6-甲基-4-三氟甲基吡啶-2-基)二氢吲哚-2-甲酰胺(化合物32)的合成Step 3: Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(3-cyano-6-methyl-4-trifluoromethylpyridin-2-yl)indoline-2-carboxamide (Compound 32)
参照实施例1的方法，区别仅在于将2-氯-6-甲基-4-(三氟甲基)吡啶替换成2-氯-6-甲基-4-三氟甲基烟腈(中间体32-2)，将3-氯-4-氟苯胺替换成5-氯-2,4-二氟苯胺，制备得到(S)-5-氯-2,4-二氟苯基-1-(3-氰基-6-甲基-4-三氟甲基吡啶-2-基)-N-甲基二氢吲哚-2-甲酰胺(化合物32)。The method of Example 1 was used with reference to the above, except that 2-chloro-6-methyl-4-(trifluoromethyl)pyridine was replaced by 2-chloro-6-methyl-4-trifluoromethylnicotinonitrile (intermediate 32-2), and 3-chloro-4-fluoroaniline was replaced by 5-chloro-2,4-difluoroaniline to obtain (S)-5-chloro-2,4-difluorophenyl-1-(3-cyano-6-methyl-4-trifluoromethylpyridin-2-yl)-N-methyldihydroindole-2-carboxamide (compound 32).
LC-MS(ESI):m/z＝507.10[M+H]+LC-MS (ESI): m/z = 507.10 [M+H] +
1H NMR(300MHz,Chloroform-d)δ7.88–7.69(m,1H),7.45–7.29(m,1H),7.21–7.02(m,3H),7.00–6.88(m,2H),5.08(m,1H),3.59–3.35(m,1H),3.26(s,3H),3.21–3.11(m,1H),2.57(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.88–7.69(m,1H),7.45–7.29(m,1H),7.21–7.02(m,3H),7.00–6.88(m,2H),5.08( m,1H),3.59–3.35(m,1H),3.26(s,3H),3.21–3.11(m,1H),2.57(s,3H).
实施例33、N-(5-氯-2,4-二氟苯基)-5-羟基-N-甲基-7-(6-甲基-4-(三氟甲基)吡啶-2-基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物33)的合成
Example 33. Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-hydroxy-N-methyl-7-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Compound 33)
步骤1：4-氯-5-羟基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-6-羧酸叔丁酯(中间体33-1)的合成Step 1: Synthesis of tert-butyl 4-chloro-5-hydroxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Intermediate 33-1)
将4,6-二氯-5-嘧啶甲醛(1770mg)和甘氨酸叔丁酯(1312mg)溶于乙醇(20mL)中，滴加三乙胺(1518mg)。反应液在室温下搅拌12h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到中间体33-1(1135mg)。4,6-Dichloro-5-pyrimidinecarboxaldehyde (1770 mg) and glycine tert-butyl ester (1312 mg) were dissolved in ethanol (20 mL), and triethylamine (1518 mg) was added dropwise. The reaction solution was stirred at room temperature for 12 h, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain intermediate 33-1 (1135 mg).
LC-MS(ESI):m/z＝272.07[M+H]+ LC-MS(ESI):m/z＝272.07[M+H] +
步骤2：5-羟基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-6-羧酸叔丁酯(中间体33-2)的合成Step 2: Synthesis of tert-butyl 5-hydroxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Intermediate 33-2)
向中间体33-1(1135mg)的甲醇(20mL)溶液中，加入5％钯碳(100mg)。反应液在氢气环境，室温条件下搅拌12h，TLC监测反应完成。将反应液过滤，滤液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝20/1)纯化，得到中间体33-2(576mg)。 To a solution of intermediate 33-1 (1135 mg) in methanol (20 mL), 5% palladium on carbon (100 mg) was added. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 12 h, and the reaction was completed after monitoring by TLC. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain intermediate 33-2 (576 mg).
LC-MS(ESI):m/z＝238.12[M+H]+ LC-MS(ESI):m/z＝238.12[M+H] +
步骤3：5-羟基-7-(6-甲基-4-(三氟甲基)吡啶-2-基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-6-羧酸叔丁酯(中间体33-3)的合成Step 3: Synthesis of tert-butyl 5-hydroxy-7-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Intermediate 33-3)
在中间体33-2(576mg)和2-氯-6-甲基-4-(三氟甲基)吡啶(569mg)的1,4-二氧六环(15mL)溶液中加入三(二亚苄基丙酮)二钯(50mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(80mg)和碳酸铯(1188mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到中间体33-3(396mg)。Tris(dibenzylideneacetone)dipalladium (50 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (80 mg) and cesium carbonate (1188 mg) were added to a solution of intermediate 33-2 (576 mg) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (569 mg) in 1,4-dioxane (15 mL). Stir at 110°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain intermediate 33-3 (396 mg).
LC-MS(ESI):m/z＝397.15[M+H]+ LC-MS(ESI):m/z＝397.15[M+H] +
步骤4：5-羟基-7-(6-甲基-4-(三氟甲基)吡啶-2-基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-6-羧酸(中间体33-4)的合成Step 4: Synthesis of 5-hydroxy-7-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (Intermediate 33-4)
将中间体33-3(396mg)溶解在10％三氟乙酸的二氯甲烷溶液(15mL)中。反应液在室温条件下搅拌6h，TLC监测反应完成。减压蒸出溶剂，得到中间体33-4(337mg)。Intermediate 33-3 (396 mg) was dissolved in 10% trifluoroacetic acid in dichloromethane (15 mL). The reaction solution was stirred at room temperature for 6 h, and the reaction was completed after monitoring by TLC. The solvent was evaporated under reduced pressure to obtain intermediate 33-4 (337 mg).
LC-MS(ESI):m/z＝341.08[M+H]+ LC-MS(ESI):m/z＝341.08[M+H] +
步骤5：N-(5-氯-2,4-二氟苯基)-5-羟基-N-甲基-7-(6-甲基-4-(三氟甲基)吡啶-2-基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物33)的合成Step 5: Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-hydroxy-N-methyl-7-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Compound 33)
在中间体33-4(337mg)和中间体10-4(129mg)的二氯甲烷(15mL)溶液中加入N,N'-二环己基碳二亚胺(310mg)和4-二甲氨基吡啶(13mg)。室温条件下搅拌12h，TLC监测反应完成。将反应液过滤，滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到化合物33(115mg)。N,N'-dicyclohexylcarbodiimide (310 mg) and 4-dimethylaminopyridine (13 mg) were added to a solution of intermediate 33-4 (337 mg) and intermediate 10-4 (129 mg) in dichloromethane (15 mL). The mixture was stirred at room temperature for 12 h, and the reaction was completed after monitoring by TLC. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 33 (115 mg).
LC-MS(ESI):m/z＝500.09[M+H]+ LC-MS(ESI):m/z＝500.09[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.11–7.99(m,1H),7.98(m,1H),7.40–7.31(m,1H),7.15(m,2H),6.86(m,1H),5.15(m,1H),3.83–3.71(m,1H),3.24(s,3H),2.50(s,3H). 1 H NMR(300MHz,Chloroform-d)δ8.11–7.99(m,1H),7.98(m,1H),7.40–7.31(m,1H),7.15(m,2H),6.86(m,1H) ,5.15(m,1H),3.83–3.71(m,1H),3.24(s,3H),2.50(s,3H).
实施例34、N-(5-氯-2,4-二氟苯基)-N-甲基-7-(6-甲基-4-(三氟甲基)吡啶-2-基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物34)的合成
Example 34. Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-7-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Compound 34)
步骤1：4-氯-5-羟基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(中间体34-1)的合成Step 1: Synthesis of ethyl 4-chloro-5-hydroxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Intermediate 34-1)
将4,6-二氯-5-嘧啶甲醛(1770mg)和甘氨酸乙酯盐酸盐(1400mg)溶于乙醇(20mL)中，滴加三乙胺(2530mg)。反应液在室温下搅拌12h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到中间体34-1(1055mg)。4,6-Dichloro-5-pyrimidinecarboxaldehyde (1770 mg) and glycine ethyl ester hydrochloride (1400 mg) were dissolved in ethanol (20 mL), and triethylamine (2530 mg) was added dropwise. The reaction solution was stirred at room temperature for 12 h, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain intermediate 34-1 (1055 mg).
LC-MS(ESI):m/z＝244.04[M+H]+ LC-MS(ESI):m/z＝244.04[M+H] +
步骤2：4-氯-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯(中间体34-2)的合成Step 2: Synthesis of ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Intermediate 34-2)
向中间体34-1(1055mg)的N,N-二甲基甲酰胺(15mL)溶液中，加入氢化钠(105mg)。室温条件下搅拌5h，TLC监测反应完成。向反应液中加入水(150mL)，用乙酸乙酯(25mL×3)萃取，有机相 用无水硫酸钠干燥，过滤，蒸出溶剂，得到中间体34-2(657mg)。To a solution of intermediate 34-1 (1055 mg) in N,N-dimethylformamide (15 mL), sodium hydride (105 mg) was added. Stirring was continued at room temperature for 5 h. TLC monitored the completion of the reaction. Water (150 mL) was added to the reaction solution, and the organic phase was extracted with ethyl acetate (25 mL × 3). Drying over anhydrous sodium sulfate, filtering and distilling off the solvent gave Intermediate 34-2 (657 mg).
LC-MS(ESI):m/z＝226.03[M+H]+ LC-MS(ESI):m/z＝226.03[M+H] +
步骤3：7-(叔丁基)-6-乙基-4-氯-7H-吡咯并[2,3-d]嘧啶-6,7-二羧酸酯(中间体34-3)的合成Step 3: Synthesis of 7-(tert-butyl)-6-ethyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6,7-dicarboxylate (Intermediate 34-3)
将中间体34-2(657mg)和4-二甲氨基吡啶(30mg)溶于二氯甲烷(20mL)中，滴加二碳酸二叔丁酯(1275mg)。反应液在室温下搅拌5h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到中间体34-3(815mg)。Intermediate 34-2 (657 mg) and 4-dimethylaminopyridine (30 mg) were dissolved in dichloromethane (20 mL), and di-tert-butyl dicarbonate (1275 mg) was added dropwise. The reaction solution was stirred at room temperature for 5 h, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain intermediate 34-3 (815 mg).
LC-MS(ESI):m/z＝326.09[M+H]+ LC-MS(ESI):m/z＝326.09[M+H] +
步骤4：7-(叔丁基)-6-乙基-5,6-二氢-7H-吡咯并[2,3-d]嘧啶-6,7-二羧酸酯(中间体34-4)的合成Step 4: Synthesis of 7-(tert-butyl)-6-ethyl-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine-6,7-dicarboxylate (Intermediate 34-4)
向中间体34-3(815mg)的甲醇(20mL)溶液中，加入5％钯碳(70mg)。反应液在氢气环境，室温条件下搅拌12h，TLC监测反应完成。将反应液过滤，滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化，得到中间体33-4(461mg)。To a solution of intermediate 34-3 (815 mg) in methanol (20 mL), 5% palladium on carbon (70 mg) was added. The reaction solution was stirred at room temperature under a hydrogen environment for 12 h, and the reaction was completed after monitoring by TLC. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain intermediate 33-4 (461 mg).
LC-MS(ESI):m/z＝294.14[M+H]+ LC-MS(ESI):m/z＝294.14[M+H] +
步骤5：7-(叔丁氧基羰基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-6-羧酸(中间体34-5)的合成Step 5: Synthesis of 7-(tert-butoxycarbonyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (Intermediate 34-5)
向水(50mL)中加入中间体34-4(461mg)、氢氧化锂(57mg)和甲醇(5mL)室温下搅拌12h。TLC监测反应完成，滴加1N盐酸调节pH＝3-4，用乙酸乙酯(25mL×6)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂得到中间体34-5(223mg)。Intermediate 34-4 (461 mg), lithium hydroxide (57 mg) and methanol (5 mL) were added to water (50 mL) and stirred at room temperature for 12 h. The reaction was monitored by TLC, 1N hydrochloric acid was added dropwise to adjust the pH to 3-4, and the mixture was extracted with ethyl acetate (25 mL×6). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 34-5 (223 mg).
LC-MS(ESI):m/z＝266.11[M+H]+ LC-MS(ESI):m/z＝266.11[M+H] +
步骤6：6-((5-氯-2,4-二氟苯基)(甲基)氨基甲酰基)-5,6-二氢-7H-吡咯并[2,3-d]嘧啶-7-羧酸叔丁酯(中间体34-6)的合成Step 6: Synthesis of tert-butyl 6-((5-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (Intermediate 34-6)
在中间体34-5(223mg)和中间体10-4(110mg)的二氯甲烷(15mL)溶液中加入N,N'-二环己基碳二亚胺(263mg)和4-二甲氨基吡啶(10mg)。室温条件下搅拌12h，TLC监测反应完成。将反应液过滤，滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/3)纯化，得到中间体34-6(151mg)。N,N'-dicyclohexylcarbodiimide (263 mg) and 4-dimethylaminopyridine (10 mg) were added to a solution of intermediate 34-5 (223 mg) and intermediate 10-4 (110 mg) in dichloromethane (15 mL). Stirred for 12 h at room temperature, and the reaction was completed after monitoring by TLC. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/3) to obtain intermediate 34-6 (151 mg).
LC-MS(ESI):m/z＝425.11[M+H]+ LC-MS(ESI):m/z＝425.11[M+H] +
步骤7：N-(5-氯-2,4-二氟苯基)-N-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-6-甲酰胺(中间体34-7)的合成Step 7: Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Intermediate 34-7)
将中间体34-6(151mg)溶解在10％三氟乙酸的二氯甲烷溶液(10mL)中。反应液在室温条件下搅拌6h，TLC监测反应完成。向反应液中滴加饱和碳酸氢钠溶液，调节pH＝8-9，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，得到中间体34-7(90mg)。Intermediate 34-6 (151 mg) was dissolved in 10% trifluoroacetic acid in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 6 h, and the reaction was completed after TLC monitoring. Saturated sodium bicarbonate solution was added dropwise to the reaction solution, and the pH was adjusted to 8-9. The mixture was extracted with ethyl acetate (25 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 34-7 (90 mg).
LC-MS(ESI):m/z＝325.06[M+H]+ LC-MS(ESI):m/z＝325.06[M+H] +
步骤8：N-(5-氯-2,4-二氟苯基)-N-甲基-7-(6-甲基-4-(三氟甲基)吡啶-2-基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-6-甲酰胺(化合物34)的合成Step 8: Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-7-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Compound 34)
在中间体34-7(90mg)和2-氯-6-甲基-4-(三氟甲基)吡啶(60mg)的1,4-二氧六环(10mL)溶液中加入三(二亚苄基丙酮)二钯(10mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(30mg)和碳酸铯(137mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到化合物34(51mg)。Tris(dibenzylideneacetone)dipalladium (10 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (30 mg) and cesium carbonate (137 mg) were added to a solution of intermediate 34-7 (90 mg) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (60 mg) in 1,4-dioxane (10 mL). Stirred at 110°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain compound 34 (51 mg).
LC-MS(ESI):m/z＝484.09[M+H]+ LC-MS(ESI):m/z＝484.09[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.54–8.35(m,1H),7.98(m,1H),7.47–7.29(m,2H),7.05(m,1H),6.86(m,1H),5.22–5.05(m,1H),3.23(s,3H),3.19–3.01(m,2H),2.47(s,3H). 1 H NMR(300MHz,Chloroform-d)δ8.54–8.35(m,1H),7.98(m,1H),7.47–7.29(m,2H),7.05(m,1H),6.86(m,1H) ,5.22–5.05(m,1H),3.23(s,3H),3.19–3.01(m,2H),2.47(s,3H).
实施例35：(S)-N-(5-氯-2,4-二氟苯基)-5-(4-(2-(2-羟基乙氧基)乙基)哌嗪-1-基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物35)的合成
Example 35: Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-5-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 35)
在化合物5(86mg)和1-[2-(2-羟基乙氧基)乙基]哌嗪(33mg)的1,4-二氧六环(6mL)溶液中加入醋酸钯(4mg)、1,1'-联萘-2,2'-双二苯膦(18mg)和叔丁醇钾(78mg)。在氮气保护，100℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/2)纯化，得到标题化合物(38mg)。Palladium acetate (4 mg), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (18 mg) and potassium tert-butoxide (78 mg) were added to a solution of compound 5 (86 mg) and 1-[2-(2-hydroxyethoxy)ethyl]piperazine (33 mg) in 1,4-dioxane (6 mL). The mixture was stirred at 100°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/2) to obtain the title compound (38 mg).
LC-MS(ESI):m/z＝654.22[M+H]+ LC-MS(ESI):m/z＝654.22[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.78–7.63(m,1H),7.59–7.42(m,1H),7.11–6.95(m,2H),6.85(m,1H),6.78(m,2H),5.10–4.84(m,1H),4.81(s,1H),3.86–3.51(m,6H),3.27(s,3H),3.14(m,5H),2.86–2.65(m,5H),2.54(s,3H),2.04(m,1H). 1 H NMR(300MHz,Chloroform-d)δ7.78–7.63(m,1H),7.59–7.42(m,1H),7.11–6.95(m,2H),6.85(m,1H),6.78(m, 2H),5.10–4.84(m,1H),4.81(s,1H),3.86–3.51(m,6H),3.27(s,3H),3.14(m,5H),2.86–2.65(m,5H) ,2.54(s,3H),2.04(m,1H).
实施例36：(S)-N-(3-氯-4-氟苯基)-5-(4-(2-甲氧基乙基)哌嗪-1-基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物36)的合成
Example 36: Synthesis of (S)-N-(3-chloro-4-fluorophenyl)-5-(4-(2-methoxyethyl)piperazin-1-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 36)
在化合物4(136mg)和1-(2-甲氧基乙基)哌嗪(26mg)的1,4-二氧六环(8mL)溶液中加入醋酸钯(5mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(21mg)和碳酸铯(147mg)。在氮气保护，100℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/1)纯化，得到标题化合物(66mg)。Palladium acetate (5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21 mg) and cesium carbonate (147 mg) were added to a solution of compound 4 (136 mg) and 1-(2-methoxyethyl)piperazine (26 mg) in 1,4-dioxane (8 mL). Stir at 100°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1) to obtain the title compound (66 mg).
LC-MS(ESI):m/z＝606.22[M+H]+ LC-MS(ESI):m/z＝606.22[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.63–7.51(m,1H),7.42(d,J＝8.5Hz,1H),7.30(m,1H),7.22(t,J＝8.5Hz,1H),7.08(s,1H),6.83–6.75(m,3H),5.05(m,J＝10.6,5.2Hz,1H),3.58(t,J＝5.5Hz,2H),3.39(s,3H),3.29(s,3H),3.26–3.04(m,6H),2.76–2.63(m,6H),2.56(s,3H). 1 H NMR (300MHz, Chloroform-d) δ7.63–7.51(m,1H),7.42(d,J＝8.5Hz,1H),7.30(m,1H),7.22(t,J＝8.5Hz,1H ),7.08(s,1H),6.83–6.75(m,3H),5.05(m,J＝10.6,5.2Hz,1H),3.58(t,J＝5.5Hz,2H),3.39(s,3H) ,3.29(s,3H),3.26–3.04(m,6H),2.76–2.63(m,6H),2.56(s,3H).
实施例37：N-(5-氯-2-氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物37)的合成
Example 37: Synthesis of N-(5-chloro-2-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 37)
参照实施例27的合成方法，区别仅在于将步骤4中的中间体10-4替换成5-氯-2-氟-N-甲基苯胺，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 27, except that the intermediate 10-4 in step 4 was replaced by 5-chloro-2-fluoro-N-methylaniline.
LC-MS(ESI):m/z＝465.10[M+H]+ LC-MS(ESI):m/z＝465.10[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.86(m,1H),8.26–8.10(m,1H),7.94(m,1H),7.49–7.33(m,2H),7.27–7.09(m,1H),6.95(s,1H),6.85–6.73(m,1H),5.37–5.15(m,1H),3.30(s,3H),3.11(d,J＝7.9Hz,2H),2.61(s,3H). 1 H NMR(300MHz,Chloroform-d)δ8.86(m,1H),8.26–8.10(m,1H),7.94(m,1H),7.49–7.33(m,2H),7.27–7.09(m, 1H),6.95(s,1H),6.85–6.73(m,1H),5.37–5.15(m,1H),3.30(s,3H),3.11(d,J＝7.9Hz,2H),2.61(s ,3H).
实施例38：N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(6-甲基吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物38)的合成
Example 38: Synthesis of N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(6-methylpyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 38)
参照实施例27的合成方法，区别仅在于将步骤4中的中间体10-4替换成6-甲基-2-甲氨基吡啶，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 27, except that the intermediate 10-4 in step 4 was replaced by 6-methyl-2-methylaminopyridine.
LC-MS(ESI):m/z＝428.16[M+H]+ LC-MS(ESI):m/z＝428.16[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.86(s,1H),8.20(d,J＝5.2Hz,1H),7.73(t,J＝7.8Hz,1H),7.43(d,J＝7.5Hz,1H),7.23(d,J＝8.0Hz,1H),7.11(d,J＝7.6Hz,1H),6.88(s,1H),6.80(m,1H),5.38(m,1H),3.55–3.35(m,5H),2.58(s,3H),2.50(s,3H). 1 H NMR (300MHz, Chloroform-d) δ8.86 (s, 1H), 8.20 (d, J = 5.2Hz, 1H), 7.73 (t, J = 7.8Hz, 1H), 7.43 (d, J = 7.5 Hz,1H),7.23(d,J＝8.0Hz,1H),7.11(d,J＝7.6Hz,1H),6.88(s,1H),6.80(m,1H),5.38(m,1H), 3.55–3.35(m,5H),2.58(s,3H),2.50(s,3H).
实施例39：N-(5-氯-2,4-二氟苯基)-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物39)的合成
Example 39: Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 39)
参照实施例27的合成方法，区别仅在于将步骤4中的中间体10-4替换成5-氯-2,4-二氟-N-(甲基-d3)苯胺，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 27, except that the intermediate 10-4 in step 4 was replaced by 5-chloro-2,4-difluoro-N-(methyl-d 3 )aniline.
LC-MS(ESI):m/z＝486.11[M+H]+ LC-MS(ESI):m/z＝486.11[M+H] +
1H NMR(400MHz,Chloroform-d)δ8.99(m,1H),8.15(m,1H),8.04(m,1H),7.45–7.33(m,1H),7.21(m,1H),6.93(m,1H),6.77(m,1H),5.24(m,1H),3.38–2.98(m,2H),2.58(s,3H). 1 H NMR(400MHz,Chloroform-d)δ8.99(m,1H),8.15(m,1H),8.04(m,1H),7.45–7.33(m,1H),7.21(m,1H),6.93 (m,1H),6.77(m,1H),5.24(m,1H),3.38–2.98(m,2H),2.58(s,3H).
实施例40：5-溴-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物40)的合成
Example 40: Synthesis of 5-bromo-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 40)
将化合物27(84mg)溶于N,N-二甲基甲酰胺(3mL)，加入N-溴代丁二酰亚胺(41mg)室温下搅拌2h，TLC监测反应完成。向反应液中加入水(30mL)，用乙酸乙酯(10mL×3)萃取，有机相用无水硫酸钠干燥，过滤，将滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到标题化合物(76mg)。Compound 27 (84 mg) was dissolved in N, N-dimethylformamide (3 mL), N-bromosuccinimide (41 mg) was added and stirred at room temperature for 2 h, and the reaction was completed by TLC monitoring. Water (30 mL) was added to the reaction solution, and it was extracted with ethyl acetate (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the title compound (76 mg).
LC-MS(ESI):m/z＝561.00[M+H]+ LC-MS(ESI):m/z＝561.00[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.89(m,1H),8.24–8.13(m,1H),8.01(m,1H),7.51–7.42(m,1H),7.23–7.13(m,1H),6.95(m,1H),5.25(m,1H),3.28(s,3H),3.24–2.96(m,2H),2.57(s,3H). 1 H NMR(300MHz,Chloroform-d)δ8.89(m,1H),8.24–8.13(m,1H),8.01(m,1H),7.51–7.42(m,1H),7.23–7.13(m, 1H),6.95(m,1H),5.25(m,1H),3.28(s,3H),3.24–2.96(m,2H),2.57(s,3H).
实施例41：N-(5-氯-2,4-二氟苯基)-5-(4-(2-甲氧基乙基)哌嗪-1-基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物41)的合成
Example 41: Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-(4-(2-methoxyethyl)piperazin-1-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 41)
在化合物40(73mg)和1-(2-甲氧基乙基)哌嗪(18mg)的1,4-二氧六环(4mL)溶液中加入醋酸钯(3mg)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(13mg)和碳酸铯(112mg)。在氮气保护，100℃条件下搅拌6h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝90/1)纯化，得到标题化合物(42mg)。Palladium acetate (3 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (13 mg) and cesium carbonate (112 mg) were added to a solution of compound 40 (73 mg) and 1-(2-methoxyethyl)piperazine (18 mg) in 1,4-dioxane (4 mL). The mixture was stirred at 100°C for 6 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 90/1) to obtain the title compound (42 mg).
LC-MS(ESI):m/z＝625.20[M+H]+ LC-MS(ESI):m/z＝625.20[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.85(m,1H),7.94(m,1H),7.73(s,1H),7.15–6.90(m,2H),6.79(s,1H),5.20–5.12(m,1H),3.55(m,2H),3.31(s,3H),3.17(s,3H),3.10(m,4H),2.98(m,2H),2.68(m,6H),2.52(s,3H). 1 H NMR(300MHz,Chloroform-d)δ8.85(m,1H),7.94(m,1H),7.73(s,1H),7.15–6.90(m,2H),6.79(s,1H),5.20 –5.12(m,1H),3.55(m,2H),3.31(s,3H),3.17(s,3H),3.10(m,4H),2.98(m,2H),2.68(m,6H), 2.52(s,3H).
实施例42：N-(5-氯-2-氟苯基)-5-氟-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物42)的合成
Example 42: Synthesis of N-(5-chloro-2-fluorophenyl)-5-fluoro-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 42)
步骤1：5-氟-1H-吡咯并[2,3-b]吡啶-1,2-二甲酸1-(叔丁基)-2-乙酯(中间体42-1)的合成Step 1: Synthesis of 1-(tert-butyl)-2-ethyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (Intermediate 42-1)
将5-氟-1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯(700mg)和4-二甲氨基吡啶(46mg)溶于二氯甲烷(20mL)中，滴加二碳酸二叔丁酯(1666mg)。反应液在室温下搅拌5h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到中间体42-1(1005mg)。Dissolve 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester (700 mg) and 4-dimethylaminopyridine (46 mg) in dichloromethane (20 mL), and add di-tert-butyl dicarbonate (1666 mg) dropwise. The reaction solution was stirred at room temperature for 5 h, and the reaction was monitored by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain intermediate 42-1 (1005 mg).
LC-MS(ESI):m/z＝309.12[M+H]+ LC-MS(ESI): m/z＝309.12[M+H] +
步骤2：5-氟-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1,2-二甲酸1-(叔丁基)-2-乙酯(中间体42-2)的合成Step 2: Synthesis of 1-(tert-butyl)-2-ethyl 5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (Intermediate 42-2)
向中间体42-1(1005mg)的甲醇(20mL)溶液中，加入5％钯碳(45mg)。反应液在氢气环境，室温条件下搅拌6h，TLC监测反应完成。将反应液过滤，滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到中间体42-2(896mg)。To a solution of intermediate 42-1 (1005 mg) in methanol (20 mL), 5% palladium on carbon (45 mg) was added. The reaction solution was stirred at room temperature under a hydrogen environment for 6 h, and the reaction was completed after monitoring by TLC. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain intermediate 42-2 (896 mg).
LC-MS(ESI):m/z＝311.13[M+H]+ LC-MS(ESI):m/z＝311.13[M+H] +
步骤3：1-(叔丁氧羰基)-5-氟-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-羧酸(中间体42-3)的合成Step 3: Synthesis of 1-(tert-butyloxycarbonyl)-5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 42-3)
向水(50mL)中加入中间体42-2(896mg)、氢氧化锂(110mg)和甲醇(5mL)室温下搅拌10h。TLC监测反应完成，滴加1N盐酸调节pH＝3-4，用乙酸乙酯(25mL×6)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂得到中间体42-3(630mg)。Add intermediate 42-2 (896 mg), lithium hydroxide (110 mg) and methanol (5 mL) to water (50 mL) and stir at room temperature for 10 h. After the reaction is completed by TLC monitoring, 1N hydrochloric acid is added dropwise to adjust the pH to 3-4, and the mixture is extracted with ethyl acetate (25 mL×6). The organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain intermediate 42-3 (630 mg).
LC-MS(ESI):m/z＝283.10[M+H]+ LC-MS(ESI):m/z＝283.10[M+H] +
步骤4：2-((5-氯-2-氟苯基)(甲基)氨基甲酰基)-5-氟-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-甲酸叔丁酯(中间体42-4)的合成Step 4: Synthesis of tert-butyl 2-((5-chloro-2-fluorophenyl)(methyl)carbamoyl)-5-fluoro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 42-4)
在中间体42-3(630mg)和5-氯-2-氟-N-甲基苯胺(412mg)的四氢呋喃(20mL)溶液中加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(623mg)和1-羟基苯并三唑(325mg)。室温条件下搅拌12h，TLC监测反应完成，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝25/1)纯化，得到中间体42-4(610mg)。1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (623 mg) and 1-hydroxybenzotriazole (325 mg) were added to a tetrahydrofuran (20 mL) solution of intermediate 42-3 (630 mg) and 5-chloro-2-fluoro-N-methylaniline (412 mg). The mixture was stirred at room temperature for 12 h. The reaction was completed after monitoring by TLC. The mixture was extracted with ethyl acetate (25 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=25/1) to obtain intermediate 42-4 (610 mg).
LC-MS(ESI):m/z＝424.12[M+H]+ LC-MS(ESI):m/z＝424.12[M+H] +
步骤5：N-(5-氯-2-氟苯基)-5-氟-N-甲基-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(中间体42-5)的合成Step 5: Synthesis of N-(5-chloro-2-fluorophenyl)-5-fluoro-N-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Intermediate 42-5)
将中间体42-4(610mg)溶解在10％三氟乙酸的二氯甲烷溶液(15mL)中。反应液在室温条件下搅拌6h，TLC监测反应完成。向反应液中滴加饱和碳酸氢钠水溶液，调节pH＝8-9，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，得到中间体42-5(323mg)。Intermediate 42-4 (610 mg) was dissolved in 10% trifluoroacetic acid in dichloromethane (15 mL). The reaction solution was stirred at room temperature for 6 h, and the reaction was completed after TLC monitoring. Saturated sodium bicarbonate aqueous solution was added dropwise to the reaction solution to adjust pH to 8-9, and extracted with ethyl acetate (25 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 42-5 (323 mg).
LC-MS(ESI):m/z＝324.06[M+H]+ LC-MS(ESI):m/z＝324.06[M+H] +
步骤6：N-(5-氯-2-氟苯基)-5-氟-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物42)的合成Step 6: Synthesis of N-(5-chloro-2-fluorophenyl)-5-fluoro-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 42)
在中间体42-5(323mg)和2-氯-6-甲基-4-(三氟甲基)吡啶(195mg)的1,4-二氧六环(15mL)溶液 中加入醋酸钯(20mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(40mg)和碳酸铯(488mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到标题化合物(98mg)。A solution of intermediate 42-5 (323 mg) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (195 mg) in 1,4-dioxane (15 mL) Palladium acetate (20 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (40 mg) and cesium carbonate (488 mg) were added. Stir at 110°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the title compound (98 mg).
LC-MS(ESI):m/z＝483.09[M+H]+ LC-MS(ESI): m/z＝483.09[M+H] +
1H NMR(400MHz,Chloroform-d)δ7.93–7.74(m,1H),7.38(m,1H),7.27–7.10(m,2H),6.93–6.79(m,3H),5.05(m,1H),3.29(s,3H),3.25–3.06(m,2H),2.59(s,3H). 1 H NMR (400MHz, Chloroform-d) δ7.93–7.74(m,1H),7.38(m,1H),7.27–7.10(m,2H),6.93–6.79(m,3H),5.05(m, 1H),3.29(s,3H),3.25–3.06(m,2H),2.59(s,3H).
实施例43：N-(5-氯-2-氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(三氟甲基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物43)的合成
Example 43: Synthesis of N-(5-chloro-2-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 43)
参照实施例42的合成方法，区别在于将步骤1中的5-氟-1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯替换成5-三氟甲基-1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 42, except that 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in step 1 was replaced with 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester.
LC-MS(ESI):m/z＝533.09[M+H]+ LC-MS(ESI):m/z＝533.09[M+H] +
1H NMR(300MHz,Chloroform-d)δ9.04(s,1H),8.45(s,1H),7.92(dd,J＝6.7,2.6Hz,1H),7.54(m,1H),7.45(m,1H),7.26(m,1H),7.01(m,1H),5.40(t,J＝7.7Hz,1H),3.30(s,3H),3.10–3.22(m,2H),2.67(s,3H). 1 H NMR (300MHz, Chloroform-d) δ9.04 (s, 1H), 8.45 (s, 1H), 7.92 (dd, J = 6.7, 2.6Hz, 1H), 7.54 (m, 1H), 7.45 (m ,1H),7.26(m,1H),7.01(m,1H),5.40(t,J＝7.7Hz,1H),3.30(s,3H),3.10–3.22(m,2H),2.67(s, 3H).
实施例44：N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(三氟甲基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物44)的合成
Example 44: Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 44)
参照实施例42的合成方法，区别在于将步骤1中的5-氟-1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯替换成5-三氟甲基-1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯，将步骤4中的5-氯-2-氟-N-甲基苯胺替换成5-氯-2,4-二氟苯胺制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 42, except that 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in step 1 was replaced by 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, and 5-chloro-2-fluoro-N-methylaniline in step 4 was replaced by 5-chloro-2,4-difluoroaniline.
LC-MS(ESI):m/z＝551.08[M+H]+ LC-MS(ESI):m/z＝551.08[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.91(m,1H),8.36(s,1H),7.92(m,1H),7.45(m,1H),7.15–7.01(m,1H),6.92(m,1H),5.35–5.18(m,1H),3.19(s,3H),3.10–3.15(m,2H),2.49(s,3H). 1 H NMR(300MHz,Chloroform-d)δ8.91(m,1H),8.36(s,1H),7.92(m,1H),7.45(m,1H),7.15–7.01(m,1H),6.92 (m,1H),5.35–5.18(m,1H),3.19(s,3H),3.10–3.15(m,2H),2.49(s,3H).
实施例45：5-氟-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物45)的合成
Example 45: Synthesis of 5-fluoro-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 45)
步骤1：N-叔丁氧羰基-5氟吲哚-2-甲酸乙酯(中间体45-1)的合成Step 1: Synthesis of ethyl N-tert-butyloxycarbonyl-5-fluoroindole-2-carboxylate (Intermediate 45-1)
将5-氟-1H-吲哚-2-羧酸乙酯(650mg)和4-二甲氨基吡啶(49mg)溶于二氯甲烷(20mL)中，滴加二碳酸二叔丁酯(1596mg)。反应液在室温下搅拌5h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到中间体45-1(965mg)。Ethyl 5-fluoro-1H-indole-2-carboxylate (650 mg) and 4-dimethylaminopyridine (49 mg) were dissolved in dichloromethane (20 mL), and di-tert-butyl dicarbonate (1596 mg) was added dropwise. The reaction solution was stirred at room temperature for 5 h, and the reaction was completed after TLC monitoring. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain intermediate 45-1 (965 mg).
LC-MS(ESI):m/z＝308.12[M+H]+ LC-MS(ESI):m/z＝308.12[M+H] +
步骤2：1-(叔丁基)-2-乙基-5-氟吲哚啉-1,2-二羧酸酯(中间体45-2)的合成Step 2: Synthesis of 1-(tert-butyl)-2-ethyl-5-fluoroindoline-1,2-dicarboxylate (Intermediate 45-2)
向中间体45-1(965mg)的甲醇(20mL)溶液中，加入5％钯碳(41mg)。反应液在氢气环境，室温条件下搅拌6h，TLC监测反应完成。将反应液过滤，滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到中间体45-2(887mg)。To a solution of intermediate 45-1 (965 mg) in methanol (20 mL), 5% palladium on carbon (41 mg) was added. The reaction solution was stirred at room temperature under a hydrogen environment for 6 h, and the reaction was completed after monitoring by TLC. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain intermediate 45-2 (887 mg).
LC-MS(ESI):m/z＝310.14[M+H]+ LC-MS(ESI):m/z＝310.14[M+H] +
步骤3：1-(叔丁氧基羰基)-5-氟吲哚啉-2-羧酸(中间体45-3)的合成Step 3: Synthesis of 1-(tert-butoxycarbonyl)-5-fluoroindoline-2-carboxylic acid (Intermediate 45-3)
向水(50mL)中加入中间体45-2(887mg)、氢氧化锂(100mg)和甲醇(5mL)室温下搅拌10h。TLC监测反应完成，滴加1N盐酸调节pH＝3-4，用乙酸乙酯(25mL×6)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂得到中间体45-3(635mg)。Intermediate 45-2 (887 mg), lithium hydroxide (100 mg) and methanol (5 mL) were added to water (50 mL) and stirred at room temperature for 10 h. The reaction was monitored by TLC. 1N hydrochloric acid was added dropwise to adjust the pH to 3-4, and the mixture was extracted with ethyl acetate (25 mL×6). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 45-3 (635 mg).
LC-MS(ESI):m/z＝282.11[M+H]+ LC-MS(ESI):m/z＝282.11[M+H] +
步骤4：5-氟-2-((2,4,5-三氟苯基)氨基甲酰基)二氢吲哚-1-甲酸叔丁酯(中间体45-4)的合成Step 4: Synthesis of tert-butyl 5-fluoro-2-((2,4,5-trifluorophenyl)carbamoyl)indoline-1-carboxylate (Intermediate 45-4)
在中间体45-3(635mg)和2,4,5-三氟苯胺(402mg)的二氯甲烷20mL)溶液中加入N,N'-二环己基碳二亚胺(774mg)和4-二甲氨基吡啶(16mg)。室温条件下搅拌12h，TLC监测反应完成，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝25/1)纯化，得到中间体45-4(626mg)。N,N'-dicyclohexylcarbodiimide (774 mg) and 4-dimethylaminopyridine (16 mg) were added to a solution of intermediate 45-3 (635 mg) and 2,4,5-trifluoroaniline (402 mg) in dichloromethane (20 mL). The mixture was stirred at room temperature for 12 h. The reaction was completed after monitoring by TLC. The mixture was extracted with ethyl acetate (25 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 25/1) to obtain intermediate 45-4 (626 mg).
LC-MS(ESI):m/z＝411.13[M+H]+ LC-MS(ESI):m/z＝411.13[M+H] +
步骤5：5-氟-2-((甲基-d3)(2,4,5-三氟苯基)氨基甲酰基)吲哚啉-1-甲酸叔丁酯(中间体45-5)的合成Step 5: Synthesis of tert-butyl 5-fluoro-2-((methyl-d 3 )(2,4,5-trifluorophenyl)carbamoyl)indoline-1-carboxylate (Intermediate 45-5)
将中间体45-4(626mg)溶于N,N-二甲基甲酰胺(5mL)中，加入NaH(101mg)，在冰浴中滴加氘 代碘甲烷(115.62uL)之后把反应液升温至40℃，搅拌6h。向反应液中加入水(100mL)，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝60/1)纯化，得到中间体45-5(594g)。Intermediate 45-4 (626 mg) was dissolved in N,N-dimethylformamide (5 mL), NaH (101 mg) was added, and deuterium was added dropwise in an ice bath. After methyl iodide (115.62uL), the reaction solution was heated to 40°C and stirred for 6h. Water (100mL) was added to the reaction solution, extracted with ethyl acetate (25mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=60/1) to obtain intermediate 45-5 (594g).
LC-MS(ESI):m/z＝428.16[M+H]+ LC-MS(ESI):m/z＝428.16[M+H] +
步骤6：5-氟-N-(甲基-d3)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(中间体45-6)的合成Step 6: Synthesis of 5-fluoro-N-(methyl-d 3 )-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Intermediate 45-6)
将中间体45-5(594mg)溶解在10％三氟乙酸的二氯甲烷溶液(15mL)中。反应液在室温条件下搅拌6h，TLC监测反应完成。向反应液中滴加饱和碳酸氢钠水溶液，调节pH＝8-9，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，得到中间体45-6(333mg)。Intermediate 45-5 (594 mg) was dissolved in 10% trifluoroacetic acid in dichloromethane (15 mL). The reaction solution was stirred at room temperature for 6 h, and the reaction was completed after TLC monitoring. Saturated sodium bicarbonate aqueous solution was added dropwise to the reaction solution to adjust pH to 8-9, and extracted with ethyl acetate (25 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 45-6 (333 mg).
LC-MS(ESI):m/z＝328.11[M+H]+ LC-MS(ESI):m/z＝328.11[M+H] +
步骤7：5-氟-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物45)的合成Step 7: Synthesis of 5-fluoro-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 45)
在中间体45-6(333mg)和2-氯-6-甲基-4-(三氟甲基)吡啶(195mg)的1,4-二氧六环(16mL)溶液中加入醋酸钯(25mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(36mg)和碳酸铯(498mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到化合物45(88mg)。Palladium acetate (25 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (36 mg) and cesium carbonate (498 mg) were added to a solution of intermediate 45-6 (333 mg) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (195 mg) in 1,4-dioxane (16 mL). Stir at 110°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 45 (88 mg).
LC-MS(ESI):m/z＝487.14[M+H]+ LC-MS(ESI):m/z＝487.14[M+H] +
1H NMR(400MHz,Chloroform-d)δ7.84(dd,J＝8.6,4.5Hz,1H),7.69–7.62(m,1H),7.26–7.11(m,1H),7.12–6.97(m,1H),6.99–6.81(m,3H),5.15–4.98(m,1H),3.39–3.16(m,2H),2.61–2.53(m,3H). 1 H NMR (400MHz, Chloroform-d) δ7.84 (dd, J＝8.6, 4.5Hz, 1H), 7.69–7.62 (m, 1H), 7.26–7.11 (m, 1H), 7.12–6.97 (m, 1H),6.99–6.81(m,3H),5.15–4.98(m,1H),3.39–3.16(m,2H),2.61–2.53(m,3H).
步骤8：化合物45-P1和化合物45-P2的合成Step 8: Synthesis of Compound 45-P1 and Compound 45-P2
化合物45经过超临界流体色谱制备拆分(色谱柱(S,S)Whelk-01(100mm*4.6mm I.D.,5μm))；流动相A:二氧化碳；B:乙醇(0.05％二乙醇胺)，流速2.5mL/min，得到化合物45-P1(RT:2.923min)和化合物45-P2(RT:3.305min)。Compound 45 was prepared and separated by supercritical fluid chromatography (chromatographic column (S,S) Whelk-01 (100mm*4.6mm I.D., 5μm)); mobile phase A: carbon dioxide; B: ethanol (0.05% diethanolamine), flow rate 2.5mL/min, to obtain compound 45-P1 (RT: 2.923min) and compound 45-P2 (RT: 3.305min).
化合物45-P1Compound 45-P1
LC-MS(ESI):m/z＝487.14[M+H]+ LC-MS(ESI):m/z＝487.14[M+H] +
1H NMR(400MHz,Chloroform-d)δ7.84(s,1H),7.69–7.62(m,1H),7.26–7.11(m,1H),7.12(s,1H),6.99–6.81(m,3H),5.15–4.98(m,1H),3.39–3.16(m,2H),2.61(s,3H). 1 H NMR(400MHz,Chloroform-d)δ7.84(s,1H),7.69–7.62(m,1H),7.26–7.11(m,1H),7.12(s,1H),6.99–6.81(m, 3H),5.15–4.98(m,1H),3.39–3.16(m,2H),2.61(s,3H).
化合物45-P2Compound 45-P2
LC-MS(ESI):m/z＝487.14[M+H]+ LC-MS(ESI):m/z＝487.14[M+H] +
1H NMR(400MHz,Chloroform-d)δ7.84(s,1H),7.69–7.62(m,1H),7.26–7.11(m,1H),7.12(s,1H),6.99–6.81(m,3H),5.15–4.98(m,1H),3.39–3.16(m,2H),2.61(s,3H). 1 H NMR(400MHz,Chloroform-d)δ7.84(s,1H),7.69–7.62(m,1H),7.26–7.11(m,1H),7.12(s,1H),6.99–6.81(m, 3H),5.15–4.98(m,1H),3.39–3.16(m,2H),2.61(s,3H).
实施例46：5-氟-N-(6-氟吡啶-2-基)-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物46)的合成
Example 46: Synthesis of 5-fluoro-N-(6-fluoropyridin-2-yl)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 46)
参照实施例45的合成方法，区别在于仅将步骤4中的2,4,5-三氟苯胺替换成6-氟吡啶-2-胺制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 45, except that 2,4,5-trifluoroaniline in step 4 was replaced by 6-fluoropyridin-2-amine.
LC-MS(ESI):m/z＝452.15[M+H]+ LC-MS(ESI):m/z＝452.15[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.91–7.85(m,1H),7.67–7.42(m,1H),7.32(d,J＝7.7Hz,1H),7.03–6.85(m,4H),6.81(s,1H),5.41–5.35(m,1H),3.61–3.52(m，1H),3.42–3.27(m,1H),2.49(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.91–7.85(m,1H),7.67–7.42(m,1H),7.32(d,J＝7.7Hz,1H),7.03–6.85(m,4H) ,6.81(s,1H),5.41–5.35(m,1H),3.61–3.52(m,1H),3.42–3.27(m,1H),2.49(s,3H).
实施例48：N-(5-氟吡啶-2-基)-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物48)的合成
Example 48: Synthesis of N-(5-fluoropyridin-2-yl)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 48)
参照实施例45的合成方法，区别在于将步骤1中的5-氟-1H-吲哚-2-羧酸乙酯替换成1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯，将步骤4中的2,4,5-三氟苯胺替换成5-氟吡啶-2-胺制备得到标题化合物48。The title compound 48 was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced by 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, and 2,4,5-trifluoroaniline in step 4 was replaced by 5-fluoropyridine-2-amine.
LC-MS(ESI):m/z＝435.16[M+H]+ LC-MS(ESI):m/z＝435.16[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.91(s,1H),8.47–8.27(m,1H),8.25–8.12(m,1H),7.54(s,2H),7.41(m,1H),6.90(m,1H),6.80(m,1H),5.36–5.25(m,1H),3.54–3.22(m,2H),2.50(s,3H). 1 H NMR(300MHz,Chloroform-d)δ8.91(s,1H),8.47–8.27(m,1H),8.25–8.12(m,1H),7.54(s,2H),7.41(m,1H) ,6.90(m,1H),6.80(m,1H),5.36–5.25(m,1H),3.54–3.22(m,2H),2.50(s,3H).
实施例49：5-氟-N-(5-氟吡啶-2-基)-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物49)的合成
Example 49: Synthesis of 5-fluoro-N-(5-fluoropyridin-2-yl)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 49)
参照实施例45的合成方法，区别在于将步骤4中的2,4,5-三氟苯胺替换成5-氟吡啶-2-胺制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 45, except that 2,4,5-trifluoroaniline in step 4 was replaced by 5-fluoropyridin-2-amine.
LC-MS(ESI):m/z＝452.15[M+H]+ LC-MS(ESI):m/z＝452.15[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.44(m,1H),8.41–8.32(m,1H),7.97(dd,J＝4.1,1.8Hz,1H),7.34–7.25(m,1H),6.96–6.87(m,2H),6.79(m,2H),5.01(m,1H),3.75–3.59(m,1H),3.40–3.25(m,1H),2.56(s,3H). 1 H NMR(300MHz,Chloroform-d)δ8.44(m,1H),8.41–8.32(m,1H),7.97(dd,J＝4.1,1.8Hz,1H),7.34–7.25(m,1H) ,6.96–6.87(m,2H),6.79(m,2H),5.01(m,1H),3.75–3.59(m,1H),3.40–3.25(m,1H),2.56(s,3H).
实施例51：5-氟-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物51)的合成
Example 51: Synthesis of 5-fluoro-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 51)
参照实施例45的合成方法，区别在于仅将步骤1中的5-氟-1H-吲哚-2-羧酸乙酯替换成5-氟-1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced with 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester.
LC-MS(ESI):m/z＝488.13[M+H]+ LC-MS(ESI):m/z＝488.13[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.92–8.82(m,1H),8.05–8.98(m,1H),7.85–7.79(m,1H),7.26–7.10(m,2H),6.94–6.82(m,1H),5.39–5.23(m,1H),3.19–3.05(m,1H),2.65–2.38(m,3H). 1 H NMR(300MHz,Chloroform-d)δ8.92–8.82(m,1H),8.05–8.98(m,1H),7.85–7.79(m,1H),7.26–7.10(m,2H),6.94– 6.82(m,1H),5.39–5.23(m,1H),3.19–3.05(m,1H),2.65–2.38(m,3H).
实施例52：N-(5-氯-2,4-二氟苯基)-5-氟-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物52)的合成
Example 52: Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-fluoro-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 52)
参照实施例45的合成方法，区别在于将步骤1中的5-氟-1H-吲哚-2-羧酸乙酯替换成5-氟-1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯，将步骤4中的2,4,5-三氟苯胺替换成5-氯-2,4-二氟苯胺制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced by 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, and 2,4,5-trifluoroaniline in step 4 was replaced by 5-chloro-2,4-difluoroaniline.
LC-MS(ESI):m/z＝504.10[M+H]+ LC-MS(ESI):m/z＝504.10[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.91–8.82(m,1H),7.99–7.85(m,2H),7.50–7.35(m,1H),7.26–7.10(m,1H),6.92–6.84(m,1H),5.40–5.20(m,1H),3.21–3.05(m,2H),2.62–2.34(m,3H). 1 H NMR(300MHz,Chloroform-d)δ8.91–8.82(m,1H),7.99–7.85(m,2H),7.50–7.35(m,1H),7.26–7.10(m,1H),6.92– 6.84(m,1H),5.40–5.20(m,1H),3.21–3.05(m,2H),2.62–2.34(m,3H).
实施例53：5-氟-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺-2,3-d2(化合物53)的合成
Example 53: Synthesis of 5-fluoro-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide-2,3-d 2 (Compound 53)
参照实施例45的合成方法，区别在于仅将步骤2中的氢气替换成氘气，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 45, except that only the hydrogen gas in step 2 was replaced by deuterium gas.
LC-MS(ESI):m/z＝489.15[M+H]+ LC-MS(ESI):m/z＝489.15[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.65(dt,J＝9.9,7.7Hz,1H),7.49–7.39(m,1H),7.25–6.98(m,2H),6.95–6.79(m,3H),3.27–3.01(m,1H),2.58–2.45(m,3H). 1 H NMR (300MHz, Chloroform-d) δ7.65 (dt, J＝9.9, 7.7Hz, 1H), 7.49–7.39 (m, 1H), 7.25–6.98 (m, 2H), 6.95–6.79 (m, 3H),3.27–3.01(m,1H),2.58–2.45(m,3H).
实施例54：5-氟-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺-2,3-d2(化合物54)的合成
Example 54: Synthesis of 5-fluoro-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-2,3-d 2 (Compound 54)
参照实施例45的合成方法，区别在于仅将步骤1中的5-氟-1H-吲哚-2-羧酸乙酯替换成5-氟-1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯，步骤2中的氢气替换成氘气，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced with 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester and hydrogen in step 2 was replaced with deuterium gas.
LC-MS(ESI):m/z＝490.14[M+H]+ LC-MS(ESI):m/z＝490.14[M+H] +
1H NMR(400MHz,Chloroform-d)δ8.91–8.88(m,1H),8.08–7.89(m,2H),7.26–7.02(m,2H),6.97–6.89(m,1H),3.16–3.05(m,1H),2.62–2.46(m,3H). 1 H NMR (400MHz, Chloroform-d) δ8.91–8.88(m,1H),8.08–7.89(m,2H),7.26–7.02(m,2H),6.97–6.89(m,1H),3.16– 3.05(m,1H),2.62–2.46(m,3H).
实施例55：N-(5-氯-2,4-二氟苯基)-5-氟-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺-2,3-d2(化合物55)的合成
Example 55: Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-fluoro-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-2,3-d 2 (Compound 55)
参照实施例45的合成方法，区别在于将步骤1中的5-氟-1H-吲哚-2-羧酸乙酯替换成5-氟-1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯，步骤2中的氢气替换成氘气，步骤4中的2,4,5-三氟苯胺替换成5-氯-2,4-二氟苯胺制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced by 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, the hydrogen in step 2 was replaced by deuterium gas, and the 2,4,5-trifluoroaniline in step 4 was replaced by 5-chloro-2,4-difluoroaniline.
LC-MS(ESI):m/z＝506.12[M+H]+ LC-MS(ESI):m/z＝506.12[M+H] +
1H NMR(400MHz,Chloroform-d)δ8.91–8.86(m,1H),7.99(dm,1H),7.80(dt,J＝10.0,7.6Hz,1H),7.25–7.08(m,2H),6.97–6.89(m,1H),3.21–3.01(m,1H),2.62–2.44(m,3H). 1 H NMR(400MHz,Chloroform-d)δ8.91–8.86(m,1H),7.99(dm,1H),7.80(dt,J＝10.0,7.6Hz,1H),7.25–7.08(m,2H) ,6.97–6.89(m,1H),3.21–3.01(m,1H),2.62–2.44(m,3H).
实施例56：N-(2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物56)的合成
Example 56: Synthesis of N-(2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 56)
参照实施例27的合成方法，区别仅在于将步骤4中的中间体10-4替换成2,4-二氟-N-甲基苯胺，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 27, except that the intermediate 10-4 in step 4 was replaced by 2,4-difluoro-N-methylaniline.
LC-MS(ESI):m/z＝449.13[M+H]+ LC-MS(ESI):m/z＝449.13[M+H] +
1H NMR(300MHz,Chloroform-d)δ9.00(s,1H),8.24–8.10(m,1H),7.92–7.72(m,1H),7.46–7.31(m,1H),7.13–7.00(m,2H),6.93(s,1H),6.77(dd,J＝7.3,5.2Hz,1H),5.30–5.11(m,1H),3.29(s,3H),3.14–3.03(m,1H),2.59(d,J＝15.9Hz,3H). 1 H NMR(300MHz,Chloroform-d)δ9.00(s,1H),8.24–8.10(m,1H),7.92–7.72(m,1H),7.46–7.31(m,1H),7.13–7.00( m,2H),6.93(s,1H),6.77(dd,J＝7.3,5.2Hz,1H),5.30–5.11(m,1H),3.29(s,3H),3.14–3.03(m,1H) ,2.59(d,J＝15.9Hz,3H).
实施例57、N-(3-氯-2-氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物57)的合成
Example 57. Synthesis of N-(3-chloro-2-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 57)
参照实施例27的合成方法，区别仅在于将步骤4中的中间体10-4替换成3-氯-2-氟-N-甲基苯胺，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 27, except that the intermediate 10-4 in step 4 was replaced by 3-chloro-2-fluoro-N-methylaniline.
LC-MS(ESI):m/z＝465.10[M+H]+ LC-MS(ESI):m/z＝465.10[M+H] +
1H NMR(300MHz,Chloroform-d)δ9.00(m,1H),8.14(m,1H),7.80(m,1H),7.53(m,1H),7.40–7.33(m,1H),7.27–7.18(m,1H),6.92(m,1H),6.76(m,1H),5.36–5.12(m,1H),3.31(s,3H),3.26–3.05(m,2H),2.58(s,3H). 1 H NMR(300MHz,Chloroform-d)δ9.00(m,1H),8.14(m,1H),7.80(m,1H),7.53(m,1H),7.40–7.33(m,1H),7.27 –7.18(m,1H),6.92(m,1H),6.76(m,1H),5.36–5.12(m,1H),3.31(s,3H),3.26–3.05(m,2H),2.58(s ,3H).
实施例58：N-(4,5-二氟吡啶-2-基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基]-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物58)的合成
Example 58: Synthesis of N-(4,5-difluoropyridin-2-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 58)
参照实施例27的合成方法，区别仅在于将步骤4中的中间体10-4替换成4,5-二氟-N-甲基吡啶-2-胺，制备得到)标题化合物。Referring to the synthesis method of Example 27, the only difference is that the intermediate 10-4 in step 4 is replaced by 4,5-difluoro-N-methylpyridin-2-amine to prepare the title compound).
LC-MS(ESI):m/z＝450.13[M+H]+ LC-MS(ESI):m/z＝450.13[M+H] +
1H NMR(300MHz,Chloroform-d)δ9.05(m,1H),8.26(m,1H),8.05–8.11(m,2H),7.80(m,1H),7.40–7.33(m,1H),6.98(m,1H),5.36–5.18(m,1H),3.34(s,3H),3.29–3.05(m,2H),2.60(s,3H). 1 H NMR(300MHz,Chloroform-d)δ9.05(m,1H),8.26(m,1H),8.05–8.11(m,2H),7.80(m,1H),7.40–7.33(m,1H) ,6.98(m,1H),5.36–5.18(m,1H),3.34(s,3H),3.29–3.05(m,2H),2.60(s,3H).
实施例59：N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物59)的合成
Example 59: Synthesis of N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 59)
参照实施例27的合成方法，区别仅在于将步骤4中的中间体10-4替换成2,4,5-三氟-N-甲基-苯胺，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 27, except that the intermediate 10-4 in step 4 was replaced by 2,4,5-trifluoro-N-methyl-aniline.
LC-MS(ESI):m/z＝467.12[M+H]+ LC-MS(ESI):m/z＝467.12[M+H] +
1H NMR(400MHz,Chloroform-d)δ9.02(m,1H),8.18(m,1H),7.79(m,1H),7.37(m,1H),7.19(m,1H),6.95(m,1H),6.78(m,1H),5.29(m,1H),3.29(s,3H),3.11(m,2H),2.63(s,3H). 1 H NMR(400MHz,Chloroform-d)δ9.02(m,1H),8.18(m,1H),7.79(m,1H),7.37(m,1H),7.19(m,1H),6.95(m ,1H),6.78(m,1H),5.29(m,1H),3.29(s,3H),3.11(m,2H),2.63(s,3H).
实施例60：N-(3,5-二氯-2-氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物60)的合成
Example 60: Synthesis of N-(3,5-dichloro-2-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 60)
参照实施例27的合成方法，区别仅在于将步骤4中的中间体10-4替换成3,5-二氯-2-氟-N-甲基苯胺，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 27, except that the intermediate 10-4 in step 4 was replaced by 3,5-dichloro-2-fluoro-N-methylaniline.
LC-MS(ESI):m/z＝499.06[M+H]+ LC-MS(ESI):m/z＝499.06[M+H] +
1H NMR(400MHz,Chloroform-d)δ8.96(m,1H),8.29–8.17(m,1H),7.86(m,1H),7.53(m,1H),7.39(m,1H),6.96(m,1H),6.80(m,1H),5.30(m,1H),3.30(s,3H),3.22–3.07(m,2H),2.65(s,3H). 1 H NMR(400MHz,Chloroform-d)δ8.96(m,1H),8.29–8.17(m,1H),7.86(m,1H),7.53(m,1H),7.39(m,1H),6.96 (m,1H),6.80(m,1H),5.30(m,1H),3.30(s,3H),3.22–3.07(m,2H),2.65(s,3H).
实施例61：N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(2-氧-7-氮杂螺[3.5]壬-7-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物61)的合成
Example 61: Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-oxo-7-azaspiro[3.5]nonan-7-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 61)
在化合物40(70mg)和2-噁唑-7-氮杂螺[3.5]壬烷(20mg)的1,4-二氧六环(4mL)溶液中加入醋酸钯(3mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(13mg)和碳酸铯(120mg)。在氮气保护，100℃条件下搅拌6h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/1)纯化，得到标题化合物(30mg)。Palladium acetate (3 mg), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (13 mg) and cesium carbonate (120 mg) were added to a solution of compound 40 (70 mg) and 2-oxazole-7-azaspiro[3.5]nonane (20 mg) in 1,4-dioxane (4 mL). Stir at 100°C for 6 h under nitrogen protection, and the reaction was completed by TLC monitoring. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1) to obtain the title compound (30 mg).
LC-MS(ESI):m/z＝608.18[M+H]+ LC-MS(ESI):m/z＝608.18[M+H] +
1H NMR(400MHz,Chloroform-d)δ8.98(m,1H),8.19–8.07(m,1H),7.39–7.31(m,1H),7.01(m,1H),6.93(m,1H),6.76(m,1H),5.26(m,1H),4.55–4.44(m,4H),3.26(s,3H),3.03(m,6H),2.56(s,3H),2.07(m,4H). 1 H NMR(400MHz,Chloroform-d)δ8.98(m,1H),8.19–8.07(m,1H),7.39–7.31(m,1H),7.01(m,1H),6.93(m,1H) ,6.76(m,1H),5.26(m,1H),4.55–4.44(m,4H),3.26(s,3H),3.03(m,6H),2.56(s,3H),2.07(m,4H ).
实施例62、N-(5-氯-2,4-二氟苯基)-5-(((3-羟基氧杂环丁烷-3-基)甲基)氨基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物62)的合成
Example 62. Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-(((3-hydroxyoxetane-3-yl)methyl)amino)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 62)
在化合物40(80mg)和3-羟基-3-氨甲基氧杂环丁烷(20mg)的1,4-二氧六环(5mL)溶液中加入三(二亚苄基丙酮)二钯(15mg)、1,1'-联萘-2,2'-双二苯膦(18mg)和碳酸铯(140mg)。在氮气保护，100℃条件下搅拌6h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/1)纯化，得到标题化合物(45mg)。Tris(dibenzylideneacetone)dipalladium (15 mg), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (18 mg) and cesium carbonate (140 mg) were added to a solution of compound 40 (80 mg) and 3-hydroxy-3-aminomethyloxetane (20 mg) in 1,4-dioxane (5 mL). The mixture was stirred at 100°C for 6 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1) to obtain the title compound (45 mg).
LC-MS(ESI):m/z＝584.14[M+H]+ LC-MS(ESI):m/z＝584.14[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.84(m,1H),8.00(m,1H),7.52(m,1H),7.14(m,1H),6.84(m,2H),5.40–5.13(m,1H),4.58(m,2H),4.47(m,2H),3.39(s,2H),3.26(s,3H),3.14–2.92(m,2H),2.51(s,3H). 1 H NMR(300MHz,Chloroform-d)δ8.84(m,1H),8.00(m,1H),7.52(m,1H),7.14(m,1H),6.84(m,2H),5.40–5.13 (m,1H),4.58(m,2H),4.47(m,2H),3.39(s,2H),3.26(s,3H),3.14–2.92(m,2H),2.51(s,3H).
实施例63、N-(5-氯-2,4-二氟苯基)-5-((S)-3-(羟甲基)吡咯烷-1-基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物63)的合成
Example 63. Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 63)
在化合物40(100mg)和(S)-吡咯烷-3-甲醇(20mg)的1,4-二氧六环(5mL)溶液中加入三(二亚苄基丙酮)二钯(16mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(20mg)和碳酸铯(175mg)。在氮气保护，100℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝90/1)纯化，得到化合物63(44mg)。Tris(dibenzylideneacetone)dipalladium (16 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (20 mg) and cesium carbonate (175 mg) were added to a solution of compound 40 (100 mg) and (S)-pyrrolidine-3-methanol (20 mg) in 1,4-dioxane (5 mL). The mixture was stirred at 100°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=90/1) to obtain compound 63 (44 mg).
LC-MS(ESI):m/z＝582.16[M+H]+ LC-MS(ESI):m/z＝582.16[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.96(m,1H),8.03(m,1H),7.52(m,1H),7.14(m,1H),6.81(m,2H), 5.22(m,1H),3.76–3.60(m,2H),3.27(s,3H),3.07(m,6H),2.60(s,3H),2.24–2.09(m,1H),1.81(m,2H). 1 H NMR(300MHz,Chloroform-d)δ8.96(m,1H),8.03(m,1H),7.52(m,1H),7.14(m,1H),6.81(m,2H), 5.22(m,1H),3.76–3.60(m,2H),3.27(s,3H),3.07(m,6H),2.60(s,3H),2.24–2.09(m,1H),1.81(m, 2H).
实施例64、N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(3-(甲磺酰基)氮杂环丁烷-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物64)的合成
Example 64. Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(3-(methylsulfonyl)azetidin-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 64)
在化合物40(50mg)和3-(甲基磺酰基)氮杂环丁烷盐酸盐(20mg)的1,4-二氧六环(4mL)溶液中加入醋酸钯(2mg)、2-二环己基膦-2',4',6'-三异丙基联苯(10mg)和碳酸铯(100mg)。在氮气保护，100℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝90/1)纯化，得到化合物64(20mg)。Palladium acetate (2 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (10 mg) and cesium carbonate (100 mg) were added to a solution of compound 40 (50 mg) and 3-(methylsulfonyl)azetidine hydrochloride (20 mg) in 1,4-dioxane (4 mL). Stirred for 8 h at 100 ° C under nitrogen protection, and the reaction was completed by TLC monitoring. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (dichloromethane/methanol=90/1) to obtain compound 64 (20 mg).
LC-MS(ESI):m/z＝616.11[M+H]+ LC-MS(ESI):m/z＝616.11[M+H] +
1H NMR(400MHz,Chloroform-d)δ8.89(m,1H),8.01(m,1H),7.48–7.36(m,1H),7.21–6.95(m,1H),6.87(m,1H),6.76–6.63(m,1H),5.21(m,1H),4.15(m,5H),3.26(s,3H),3.20–3.02(m,2H),2.98(s,3H),2.55(s,3H). 1 H NMR(400MHz,Chloroform-d)δ8.89(m,1H),8.01(m,1H),7.48–7.36(m,1H),7.21–6.95(m,1H),6.87(m,1H) ,6.76–6.63(m,1H),5.21(m,1H),4.15(m,5H),3.26(s,3H),3.20–3.02(m,2H),2.98(s,3H),2.55(s ,3H).
实施例65：N-(5-氯-2,4-二氟苯基)-5-(1-(2-氰乙基)-1H-吡唑-4-基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物65)的合成
Example 65: Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 65)
在化合物40(80mg)和4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑-1-丙腈(36mg)的1,4-二氧六环(5mL)和水(1mL)中加入1,1-双(二苯基膦)二荗铁二氯化钯(10mg)和碳酸钠(50mg)。在氮气保护，100℃条件下搅拌6h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/1)纯化，得到化合物65(65mg)。1,1-Bis(diphenylphosphine)diborane iron dichloropalladium (10 mg) and sodium carbonate (50 mg) were added to compound 40 (80 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-propionitrile (36 mg) in 1,4-dioxane (5 mL) and water (1 mL). Stirred for 6 h at 100 ° C under nitrogen protection, and the reaction was completed after TLC monitoring. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1) to obtain compound 65 (65 mg).
LC-MS(ESI):m/z＝602.14[M+H]+ LC-MS(ESI):m/z＝602.14[M+H] +
1H NMR(300MHz,Chloroform-d)δ9.02(m,1H),8.29(m,1H),8.06(m,1H),7.75(m,2H),7.46(m,1H),7.21(m,1H),6.95(m,1H),5.39–5.19(m,1H),4.45(m,2H),3.32(s,3H),3.15(m,2H),3.02(m,2H),2.67(s,3H). 1 H NMR(300MHz,Chloroform-d)δ9.02(m,1H),8.29(m,1H),8.06(m,1H),7.75(m,2H),7.46(m,1H),7.21(m ,1H),6.95(m,1H),5.39–5.19(m,1H),4.45(m,2H),3.32(s,3H),3.15(m,2H),3.02(m,2H),2.67( s,3H).
实施例66：N-(5-氯-2,4-二氟苯基)-5-(1-(3-甲氧基丙基)-1H-吡唑-4-基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物66)的合成
Example 66: Synthesis of N-(5-chloro-2,4-difluorophenyl)-5-(1-(3-methoxypropyl)-1H-pyrazol-4-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 66)
在化合物40(50mg)和1-(3-甲氧基丙基)-1H-吡唑-4-硼酸频那醇酯(20mg)的1,4-二氧六环(5mL)和水(1mL)溶液中加入四(三苯基膦)钯(4mg)和碳酸钠(35mg)。在氮气保护，100℃条件下搅拌6h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝90/1)纯化，得到化合物66(50mg)。Tetrakis(triphenylphosphine)palladium (4 mg) and sodium carbonate (35 mg) were added to a solution of compound 40 (50 mg) and 1-(3-methoxypropyl)-1H-pyrazole-4-boronic acid pinacol ester (20 mg) in 1,4-dioxane (5 mL) and water (1 mL). Stirring was carried out at 100°C for 6 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=90/1) to obtain compound 66 (50 mg).
LC-MS(ESI):m/z＝621.17[M+H]+ LC-MS(ESI):m/z＝621.17[M+H] +
1H NMR(300MHz,Chloroform-d)δ9.07(m,1H),8.34(m,1H),8.10(m,1H),7.78(m,1H),7.66(m,1H),7.51(m,1H),7.23(m,1H),6.98(m,1H),5.35(m,1H),4.34(m,2H),3.44(m,5H),3.35(s,3H),3.22–3.15(m,2H),2.70(s,3H),2.24(m,2H). 1 H NMR(300MHz,Chloroform-d)δ9.07(m,1H),8.34(m,1H),8.10(m,1H),7.78(m,1H),7.66(m,1H),7.51(m ,1H),7.23(m,1H),6.98(m,1H),5.35(m,1H),4.34(m,2H),3.44(m,5H),3.35(s,3H),3.22–3.15( m,2H),2.70(s,3H),2.24(m,2H).
实施例67：(S)-N-(5-氯-2,4-二氟苯基)-5-(1-(2-羟乙基)-1H-吡唑-3-基)-N-甲基-1-(6-甲基-4)-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物67)的合成
Example 67: Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-5-(1-(2-hydroxyethyl)-1H-pyrazol-3-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 67)
在化合物5(135mg)和1-(2-(四氢-2H-吡喃-2-基氧)乙基)-1H-4-吡唑硼酸频哪醇酯(86mg)的1,4-二氧六环(10mL)和水(2mL)溶液中加入四(三苯基膦)钯(28mg)、碳酸钾(100mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到化合物67(60mg)。Tetrakis(triphenylphosphine)palladium (28 mg) and potassium carbonate (100 mg) were added to a solution of compound 5 (135 mg) and 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-4-pyrazoleboronic acid pinacol ester (86 mg) in 1,4-dioxane (10 mL) and water (2 mL). Stirring was carried out at 110° C. for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain compound 67 (60 mg).
LC-MS(ESI):m/z＝592.15[M+H]+ LC-MS(ESI):m/z＝592.15[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.01–7.64(m,1H),7.57–7.30(m,2H),7.16(s,2H),7.04(d,J＝7.5Hz,1H),6.90(t,J＝7.4Hz,1H),4.80(d,J＝32.5Hz,1H),3.28(s,3H),3.06(t,J＝13.1Hz,2H),1.61(d,J＝6.7Hz,9H). 1 H NMR(300MHz,Chloroform-d)δ8.01–7.64(m,1H),7.57–7.30(m,2H),7.16(s,2H),7.04(d,J＝7.5Hz,1H),6.90 (t,J＝7.4Hz,1H),4.80(d,J＝32.5Hz,1H),3.28(s,3H),3.06(t,J＝13.1Hz,2H),1.61(d,J＝6.7Hz ,9H).
实施例68:(S)-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(5-(吗啉代甲基)噻吩-2-基)吲哚啉-2-甲酰胺(化合物68)的合成
Example 68: Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(5-(morpholinomethyl)thiophen-2-yl)indoline-2-carboxamide (Compound 68)
在化合物5(135mg)和4-((5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)噻吩-2-基)甲基)吗啉(82mg) 的1,4-二氧六环(10mL)和水(2mL)溶液中加入四(三苯基膦)钯(28mg)、碳酸钾(100mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到化合物68(60mg)。Compound 5 (135 mg) and 4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methyl)morpholine (82 mg) Tetrakis(triphenylphosphine)palladium (28 mg) and potassium carbonate (100 mg) were added to a solution of 1,4-dioxane (10 mL) and water (2 mL). Stirring was carried out at 110°C for 8 h under nitrogen protection. The reaction was completed after monitoring by TLC. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 68 (60 mg).
LC-MS(ESI):m/z＝663.15[M+H]+ LC-MS(ESI):m/z＝663.15[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.89(m,1H),7.82–7.63(m,1H),7.63–7.31(m,3H),7.27–7.10(m,2H),7.09–6.80(m,2H),5.20–4.85(m,1H),3.89–3.66(m,6H),3.63–3.34(m,2H),3.27(m,3H),3.20–3.08(m,2H),2.67–2.44(m,5H). 1 H NMR(300MHz,Chloroform-d)δ7.89(m,1H),7.82–7.63(m,1H),7.63–7.31(m,3H),7.27–7.10(m,2H),7.09–6.80( m,2H),5.20–4.85(m,1H),3.89–3.66(m,6H),3.63–3.34(m,2H),3.27(m,3H),3.20–3.08(m,2H),2.67– 2.44(m,5H).
实施例69:(S)-N-(5-氯-2,4-二氟苯基)-5-(3,6-二氢-2H-吡喃-4-基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)吲哚啉-2-甲酰胺(化合物69)的合成
Example 69: Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-5-(3,6-dihydro-2H-pyran-4-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 69)
在化合物5(135mg)和3,6-二氢-2H-吡喃-4-硼酸频哪醇酯(61mg)的1,4-二氧六环(10mL)和水(2mL)溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(18mg)、碳酸钾(100mg)。在氮气保护，110℃条件下搅拌6h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到化合物69(53mg)。[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (18 mg) and potassium carbonate (100 mg) were added to a solution of compound 5 (135 mg) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (61 mg) in 1,4-dioxane (10 mL) and water (2 mL). Stirring was carried out at 110°C for 6 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 69 (53 mg).
LC-MS(ESI):m/z＝564.14[M+H]+ LC-MS(ESI):m/z＝564.14[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.89–7.73(m,1H),7.44–7.33(m,1H),7.27–7.12(m,3H),7.01–6.92(m,1H),6.87(s,1H),6.04(m,1H),5.17–4.85(m,1H),4.33–4.25(m,2H),3.98–3.85(m,2H),3.27(s,3H),3.22–3.02(m,2H),2.70–2.37(m,5H). 1 H NMR (300MHz, Chloroform-d) δ7.89–7.73(m,1H),7.44–7.33(m,1H),7.27–7.12(m,3H),7.01–6.92(m,1H),6.87( s,1H),6.04(m,1H),5.17–4.85(m,1H),4.33–4.25(m,2H),3.98–3.85(m,2H),3.27(s,3H),3.22–3.02( m,2H),2.70–2.37(m,5H).
实施例70:(S)-N-(5-氯-2,4-二氟苯基)-5-(4-(2-甲氧基乙基)哌啶-1-基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)吲哚啉-2-甲酰胺(化合物70)的合成
Example 70: Synthesis of (S)-N-(5-chloro-2,4-difluorophenyl)-5-(4-(2-methoxyethyl)piperidin-1-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 70)
在化合物5(135mg)和4-(2-甲氧基乙基)哌啶(69mg)的1,4-二氧六环(10mL)溶液中加入醋酸钯(3mg)、2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯(18mg)和碳酸铯(122mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到化合物70(47mg)。Palladium acetate (3 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (18 mg) and cesium carbonate (122 mg) were added to a solution of compound 5 (135 mg) and 4-(2-methoxyethyl)piperidine (69 mg) in 1,4-dioxane (10 mL). Stir at 110°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 70 (47 mg).
LC-MS(ESI):m/z＝623.21[M+H]+ LC-MS(ESI):m/z＝623.21[M+H] +
1H NMR(400MHz,Chloroform-d)δ7.92–7.84(m,1H),7.39–7.24(m,1H),7.24–7.06(m,2H),7.04–6.73(m,3H),5.19–4.89(m,1H),3.62–3.43(m,4H),3.37(s,3H),3.31–3.03(m,5H),2.63–2.24(m,5H),1.88–1.74(m,2H),1.62–1.45(m,3H),1.50–1.37(m,2H). 1 H NMR(400MHz,Chloroform-d)δ7.92–7.84(m,1H),7.39–7.24(m,1H),7.24–7.06(m,2H),7.04–6.73(m,3H),5.19– 4.89(m,1H),3.62–3.43(m,4H),3.37(s,3H),3.31–3.03(m,5H),2.63–2.24(m,5H),1.88–1.74(m,2H), 1.62–1.45(m,3H),1.50–1.37(m,2H).
实施例71:(S)-N-(5-氯-2,4-二氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-((2-(甲磺酰基)乙基)氨基) 吲哚啉-2-甲酰胺(化合物71)的合成
Example 71: (S)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-((2-(methylsulfonyl)ethyl)amino) Synthesis of Indoline-2-carboxamide (Compound 71)
在化合物5(135mg)和2-(甲磺酰基)乙胺(60mg)的1,4-二氧六环(10mL)溶液中加入醋酸钯(3mg)、2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯(18mg)和碳酸铯(122mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到化合物71(42mg)。Palladium acetate (3 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (18 mg) and cesium carbonate (122 mg) were added to a solution of compound 5 (135 mg) and 2-(methylsulfonyl)ethylamine (60 mg) in 1,4-dioxane (10 mL). Stir at 110°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 71 (42 mg).
LC-MS(ESI):m/z＝603.12[M+H]+ LC-MS(ESI):m/z＝603.12[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.98–7.64(m,1H),7..42–7.31(m,1H),7.25–6.94(m,2H),6.85–6.75(m,1H),6.67–6.58(m,2H),5.22–4.85(m,1H),3.85–3.55(m,2H),3.42–3.12(m,7H),2.98(s,3H),2.56(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.98–7.64(m,1H),7..42–7.31(m,1H),7.25–6.94(m,2H),6.85–6.75(m,1H) ,6.67–6.58(m,2H),5.22–4.85(m,1H),3.85–3.55(m,2H),3.42–3.12(m,7H),2.98(s,3H),2.56(s,3H) .
实施例72:(S)-N-(5-氯-2-氟苯基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物72)的合成
Example 72: Synthesis of (S)-N-(5-chloro-2-fluorophenyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 72)
参照实施例1的方法，区别仅在于将步骤3中的中间体1-2替换成5-氯-2-氟-N-甲基苯胺，制备得到标题化合物。The title compound was prepared by referring to the method of Example 1, except that the intermediate 1-2 in step 3 was replaced by 5-chloro-2-fluoro-N-methylaniline.
LC-MS(ESI):m/z＝464.11[M+H]+ LC-MS(ESI):m/z＝464.11[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.92–7.83(m,1H),7.52–7.41(m,2H),7.35–7.22(m,3H),7.05–6.92(m,2H),5.37–5.02(m,1H),3.54–3.18(m,5H),2.79–2.62(m,3H). 1 H NMR(300MHz,Chloroform-d)δ7.92–7.83(m,1H),7.52–7.41(m,2H),7.35–7.22(m,3H),7.05–6.92(m,2H),5.37– 5.02(m,1H),3.54–3.18(m,5H),2.79–2.62(m,3H).
实施例73:N-(5-氯-2-氟苯基)-5-氟-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)吲哚啉-2-甲酰胺(化合物73)的合成
Example 73: Synthesis of N-(5-chloro-2-fluorophenyl)-5-fluoro-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 73)
参照实施例10的合成方法，区别仅在于将5-氯-2,4-二氟-N-甲基苯胺替换成5-氯-2-氟-N-甲基苯胺，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 10, except that 5-chloro-2,4-difluoro-N-methylaniline was replaced by 5-chloro-2-fluoro-N-methylaniline.
LC-MS(ESI):m/z＝482.10[M+H]+ LC-MS(ESI):m/z＝482.10[M+H] +
1H NMR(400MHz,Chloroform-d)δ7.78(dd,J＝6.7,2.7Hz,1H),7.49–7.42(m,1H),7.43–7.34(m,1H),7.27–7.10(m,2H),6.93–6.79(m,3H),5.18–4.92(m,1H),3.29(s,3H),3.25–3.06(m,2H). 1 H NMR (400MHz, Chloroform-d) δ7.78 (dd, J＝6.7, 2.7Hz, 1H), 7.49–7.42 (m, 1H), 7.43–7.34 (m, 1H), 7.27–7.10 (m, 2H),6.93–6.79(m,3H),5.18–4.92(m,1H),3.29(s,3H),3.25–3.06(m,2H).
实施例74:1-(4,6-双(三氟甲基)吡啶-2-基)-N-(5-氯-2,4-二氟苯基)-N-甲基-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物74)的合成
Example 74: Synthesis of 1-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(5-chloro-2,4-difluorophenyl)-N-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 74)
参照实施例27的合成方法，区别仅在于将步骤6中的2-氯-6-甲基-4-(三氟甲基)吡啶替换成2-氯-4,6-双(三氟甲基)吡啶，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 27, except that 2-chloro-6-methyl-4-(trifluoromethyl)pyridine in step 6 was replaced by 2-chloro-4,6-bis(trifluoromethyl)pyridine.
LC-MS(ESI):m/z＝537.07[M+H]+ LC-MS(ESI):m/z＝537.07[M+H] +
1H NMR(300MHz,Chloroform-d)δ9.56(s,1H),8.19(m,1H),7.95(t,J＝7.8Hz,1H),7.47–7.37(m,2H),7.16(m,1H),6.86(m,1H),5.25(m,1H),3.27(s,3H),3.23–3.02(m,2H). 1 H NMR (300MHz, Chloroform-d) δ9.56 (s, 1H), 8.19 (m, 1H), 7.95 (t, J = 7.8Hz, 1H), 7.47–7.37 (m, 2H), 7.16 (m ,1H),6.86(m,1H),5.25(m,1H),3.27(s,3H),3.23–3.02(m,2H).
实施例75:N-(5-氯-2,4-二氟苯基)-1-(4,6-二甲基吡啶-2-基)-N-甲基-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物75)的合成
Example 75: Synthesis of N-(5-chloro-2,4-difluorophenyl)-1-(4,6-dimethylpyridin-2-yl)-N-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 75)
参照实施例27的合成方法，区别仅在于将步骤6中的2-氯-6-甲基-4-(三氟甲基)吡啶替换成2-氯-4,6-二甲基吡啶，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 27, except that 2-chloro-6-methyl-4-(trifluoromethyl)pyridine in step 6 was replaced by 2-chloro-4,6-dimethylpyridine.
LC-MS(ESI):m/z＝429.12[M+H]+ LC-MS(ESI):m/z＝429.12[M+H] +
1H NMR(400MHz,Chloroform-d)δ8.48(s,1H),8.15(t,J＝7.8Hz,1H),8.10(m,1H),7.30(m,1H),7.14(m,1H),6.69(m,1H),6.60(s,1H),5.29(m,1H),3.27(s,3H),3.11–3.01(m,2H),2.53(s,3H),2.36(s,3H). 1 H NMR (400MHz, Chloroform-d) δ8.48 (s, 1H), 8.15 (t, J = 7.8Hz, 1H), 8.10 (m, 1H), 7.30 (m, 1H), 7.14 (m, 1H ),6.69(m,1H),6.60(s,1H),5.29(m,1H),3.27(s,3H),3.11–3.01(m,2H),2.53(s,3H),2.36(s, 3H).
实施例76：N-(5-氯-2,4-二氟苯基)-N,3-二甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物76)的合成
Example 76: Synthesis of N-(5-chloro-2,4-difluorophenyl)-N,3-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 76)
参照实施例10的合成方法，区别仅在于将步骤1中的5-氯吲哚-2-羧酸甲酯替换成3-甲基吲哚-2-甲酸 乙酯，制备得到标题化合物。The synthetic method of Example 10 is referred to, except that 5-chloroindole-2-carboxylic acid methyl ester in step 1 is replaced by 3-methylindole-2-carboxylic acid The title compound was prepared by ethyl ester.
LC-MS(ESI):m/z＝496.11[M+H]+ LC-MS(ESI):m/z＝496.11[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.32(m,1H),7.47–7.30(m,2H),7.27–7.07(m,3H),7.05–6.87(m,2H),5.23(m,1H),4.02–3.58(m,1H),3.56–3.18(m,3H),2.73–2.48(m,3H),1.43(m,3H). 1 H NMR(300MHz,Chloroform-d)δ8.32(m,1H),7.47–7.30(m,2H),7.27–7.07(m,3H),7.05–6.87(m,2H),5.23(m, 1H),4.02–3.58(m,1H),3.56–3.18(m,3H),2.73–2.48(m,3H),1.43(m,3H).
实施例77：N-(5-氯-2,4-二氟苯基)-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺-3-d(化合物77)的合成
Example 77: Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-3-d (Compound 77)
步骤1：1H-吡咯并[2,3-b]吡啶-2-甲酸-3-d-乙酯(中间体77-2)的合成Step 1: Synthesis of 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid-3-d-ethyl ester (Intermediate 77-2)
将中间体27-1(800mg)溶于氘代氯仿(15mL)中，加入氘水(1mL)和三氟甲磺酸银(100mg)。反应液在90℃油浴中搅拌8h，TLC监测反应完成。向反应液中加入水(100mL)，用乙酸乙酯(25mL×4)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂得到中间体77-2(714mg)。Dissolve intermediate 27-1 (800 mg) in deuterated chloroform (15 mL), add deuterated water (1 mL) and silver trifluoromethanesulfonate (100 mg). Stir the reaction solution in a 90°C oil bath for 8 h, and monitor the completion of the reaction by TLC. Add water (100 mL) to the reaction solution, extract with ethyl acetate (25 mL×4), dry the organic phase with anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain intermediate 77-2 (714 mg).
LC-MS(ESI):m/z＝192.08[M+H]+ LC-MS(ESI):m/z＝192.08[M+H] +
步骤2：1-(叔丁基)-2-乙基-1H-吡咯并[2,3-b]吡啶-1,2-二羧酸酯-3-d(中间体77-3)的合成Step 2: Synthesis of 1-(tert-butyl)-2-ethyl-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate-3-d (Intermediate 77-3)
向中间体77-2(714mg)和4-二甲氨基吡啶(50mg)溶于二氯甲烷(20mL)中，滴加二碳酸二叔丁酯(1658mg)。反应液在室温下搅拌5h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到中间体77-3(883mg)。To the intermediate 77-2 (714 mg) and 4-dimethylaminopyridine (50 mg) dissolved in dichloromethane (20 mL), di-tert-butyl dicarbonate (1658 mg) was added dropwise. The reaction solution was stirred at room temperature for 5 h, and the reaction was monitored by TLC. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain intermediate 77-3 (883 mg).
LC-MS(ESI):m/z＝292.13[M+H]+ LC-MS(ESI):m/z＝292.13[M+H] +
步骤3：1-(叔丁基)-2-乙基-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1,2-二羧酸酯-3-d(中间体77-4)的合成Step 3: Synthesis of 1-(tert-butyl)-2-ethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate-3-d (Intermediate 77-4)
向中间体77-3(883mg)的甲醇(20mL)溶液中，加入5％钯碳(60mg)。反应液在氢气环境，室温条件下搅拌8h，TLC监测反应完成。将反应液过滤，滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到中间体77-4(868mg)。To a solution of intermediate 77-3 (883 mg) in methanol (20 mL), 5% palladium on carbon (60 mg) was added. The reaction solution was stirred at room temperature under a hydrogen environment for 8 h, and the reaction was completed after monitoring by TLC. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain intermediate 77-4 (868 mg).
LC-MS(ESI):m/z＝294.15[M+H]+ LC-MS(ESI):m/z＝294.15[M+H] +
步骤4：1-(叔丁氧基羰基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-羧酸-3-d(中间体77-5)的合成Step 4: Synthesis of 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid-3-d (Intermediate 77-5)
向水(50mL)中加入中间体77-4(868mg)、氢氧化锂(106mg)和甲醇(5mL)室温下搅拌10h。TLC监测反应完成，滴加1N盐酸调节pH＝3-4，用乙酸乙酯(25mL×6)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂得到中间体77-5(574mg)。Add intermediate 77-4 (868 mg), lithium hydroxide (106 mg) and methanol (5 mL) to water (50 mL) and stir at room temperature for 10 h. TLC monitors the reaction completion, add 1N hydrochloric acid dropwise to adjust pH=3-4, extract with ethyl acetate (25 mL×6), dry the organic phase with anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain intermediate 77-5 (574 mg).
LC-MS(ESI):m/z＝266.12[M+H]+ LC-MS(ESI):m/z＝266.12[M+H] +
步骤5：2-((5-氯-2,4-二氟苯基)氨基甲酰基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-羧酸叔丁酯-3-d(中间体77-6)的合成Step 5: Synthesis of tert-butyl 2-((5-chloro-2,4-difluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate-3-d (Intermediate 77-6)
在中间体77-5(574mg)和5-氯-2,4-二氟苯胺(398mg)的二氯甲烷(20mL)溶液中加入N,N'-二环己基碳二亚胺(715mg)和4-二甲氨基吡啶(20mg)。室温条件下搅拌12h，TLC监测反应完成。将反应 液过滤，滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝20/1)纯化，得到中间体77-6(553mg)。N,N'-dicyclohexylcarbodiimide (715 mg) and 4-dimethylaminopyridine (20 mg) were added to a solution of intermediate 77-5 (574 mg) and 5-chloro-2,4-difluoroaniline (398 mg) in dichloromethane (20 mL). The mixture was stirred at room temperature for 12 h. The reaction was completed after monitoring by TLC. The filtrate was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to obtain intermediate 77-6 (553 mg).
LC-MS(ESI):m/z＝411.11[M+H]+ LC-MS(ESI):m/z＝411.11[M+H] +
步骤6：2-((5-氯-2,4-二氟苯基)(甲基-d3)氨基甲酰基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-羧酸叔丁酯-3-d(77-7)的合成Step 6: Synthesis of tert-butyl 2-((5-chloro-2,4-difluorophenyl)(methyl-d 3 )carbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate-3-d (77-7)
在中间体77-6(553mg)的N,N-二甲基甲酰胺(10mL)溶液中加入氢化钠(35mg)、氘代碘甲烷(200mg)。在0℃条件下搅拌4h，TLC监测反应完成。向反应液中加入水(100mL)，用乙酸乙酯(25mL×4)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂得到中间体77-7(528mg)。Sodium hydride (35 mg) and deuterated iodomethane (200 mg) were added to a solution of intermediate 77-6 (553 mg) in N,N-dimethylformamide (10 mL). Stir at 0°C for 4 h and monitor the completion of the reaction by TLC. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL×4). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 77-7 (528 mg).
步骤7：N-(5-氯-2,4-二氟苯基)-N-(甲基-d3)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺-3-d(中间体77-8)的合成Step 7: Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-(methyl-d 3 )-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-3-d (Intermediate 77-8)
将中间体77-7(528mg)溶解在10％三氟乙酸的二氯甲烷溶液(15mL)中。反应液在室温条件下搅拌6h，TLC监测反应完成。向反应液中滴加饱和碳酸氢钠溶液，调节pH＝8-9，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，得到中间体77-8(265mg)。Intermediate 77-7 (528 mg) was dissolved in 10% trifluoroacetic acid in dichloromethane (15 mL). The reaction solution was stirred at room temperature for 6 h, and the reaction was completed after TLC monitoring. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust pH to 8-9, and extracted with ethyl acetate (25 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 77-8 (265 mg).
LC-MS(ESI):m/z＝328.09[M+H]+ LC-MS(ESI):m/z＝328.09[M+H] +
步骤8：N-(5-氯-2,4-二氟苯基)-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺-3-d(化合物77)的合成Step 8: Synthesis of N-(5-chloro-2,4-difluorophenyl)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-3-d (Compound 77)
在中间体77-8(265mg)和2-氯-6-甲基-4-(三氟甲基)吡啶(174mg)的1,4-二氧六环(15mL)溶液中加入三(二亚苄基丙酮)二钯(20mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(40mg)和碳酸铯(456mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到化合物77(108mg)。To a solution of intermediate 77-8 (265 mg) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (174 mg) in 1,4-dioxane (15 mL) were added tris(dibenzylideneacetone)dipalladium (20 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (40 mg) and cesium carbonate (456 mg). Stirred at 110°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 77 (108 mg).
LC-MS(ESI):m/z＝487.12[M+H]+ LC-MS(ESI):m/z＝487.12[M+H] +
1H NMR(300MHz,Chloroform-d)δ9.03(m,1H),8.21–8.00(m,2H),7.35(m,1H),7.27–6.98(m,1H),6.95–6.90(m,1H),6.77(m,1H),5.23(m,1H),3.59–3.00(m,1H),2.57(s,3H). 1 H NMR(300MHz,Chloroform-d)δ9.03(m,1H),8.21–8.00(m,2H),7.35(m,1H),7.27–6.98(m,1H),6.95–6.90(m, 1H),6.77(m,1H),5.23(m,1H),3.59–3.00(m,1H),2.57(s,3H).
实施例78、5-(4-(2-甲氧基乙基)哌嗪-1-基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基))-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物78)的合成
Example 78. Synthesis of 5-(4-(2-methoxyethyl)piperazin-1-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl))-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 78)
步骤1：5-溴-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(中间体78-1)的合成Step 1: Synthesis of 5-bromo-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Intermediate 78-1)
将化合物59(124mg)溶于N,N-二甲基甲酰胺(3mL)，加入N-溴代丁二酰亚胺(61mg)室温下搅拌2h，TLC监测反应完成。向反应液中加入水(30mL)，用乙酸乙酯(10mL×3)萃取，有机相用无水硫酸钠干燥，过滤，将滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到中间体78-1(92mg)。Compound 59 (124 mg) was dissolved in N,N-dimethylformamide (3 mL), N-bromosuccinimide (61 mg) was added and stirred at room temperature for 2 h, and the reaction was completed by TLC monitoring. Water (30 mL) was added to the reaction solution, and it was extracted with ethyl acetate (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain intermediate 78-1 (92 mg).
LC-MS(ESI):m/z＝545.03[M+H]+ LC-MS(ESI):m/z＝545.03[M+H] +
步骤2：5-(4-(2-甲氧基乙基)哌嗪-1-基)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基))-2,3-二氢-1H-吡咯并[2,3-b]吡啶-2-甲酰胺(化合物78)的合成Step 2: Synthesis of 5-(4-(2-methoxyethyl)piperazin-1-yl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl))-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 78)
在中间体78-1(90mg)和1-(2-甲氧基乙基)哌嗪(24mg)的1,4-二氧六环(4mL)溶液中加入醋酸钯(5mg)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(17mg)和碳酸铯(138mg)。在氮气保护，100℃条件下搅拌4h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/1)纯化，得到化合物78(38mg)。Palladium acetate (5 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (17 mg) and cesium carbonate (138 mg) were added to a solution of intermediate 78-1 (90 mg) and 1-(2-methoxyethyl)piperazine (24 mg) in 1,4-dioxane (4 mL). The mixture was stirred at 100°C for 4 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1) to obtain compound 78 (38 mg).
LC-MS(ESI):m/z＝609.23[M+H]+ LC-MS(ESI):m/z＝609.23[M+H] +
1H NMR(400MHz,Chloroform-d)δ8.94(m,1H),8.02(m,1H),7.78(m,1H),7.20–7.06(m,2H),6.86(m, 1H),5.21(m,1H),3.58(m,2H),3.39(s,3H),3.26(s,3H),3.14(m,4H),3.06(m,2H),2.68(m,6H),2.54(s,3H). 1 H NMR(400MHz,Chloroform-d)δ8.94(m,1H),8.02(m,1H),7.78(m,1H),7.20–7.06(m,2H),6.86(m, 1H),5.21(m,1H),3.58(m,2H),3.39(s,3H),3.26(s,3H),3.14(m,4H),3.06(m,2H),2.68(m,6H ),2.54(s,3H).
实施例79、N-(4-乙氧基-2,5-二氟苯基)-5-氟-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物79)的合成
Example 79. Synthesis of N-(4-ethoxy-2,5-difluorophenyl)-5-fluoro-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 79)
参照实施例13的合成方法，区别仅在于将5-氯-2,4-二氟苯胺替换成4-乙氧基-2,5-二氟苯胺，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 13, except that 5-chloro-2,4-difluoroaniline was replaced by 4-ethoxy-2,5-difluoroaniline.
LC-MS(ESI):m/z＝510.15[M+H]+ LC-MS(ESI):m/z＝510.15[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.91–7.78(m,1H),7.46–7.39(m,1H),7.18–7.10(m,1H),7.04–6.91(m,1H),6.91–6.81(m,3H),5.06(m,1H),4.19–4.05(m,2H),3.63–3.31(m,1H),3.27(s,3H),3.24–3.02(m,1H),2.59(s,3H),1.55–1.49(m,3H). 1 H NMR(300MHz,Chloroform-d)δ7.91–7.78(m,1H),7.46–7.39(m,1H),7.18–7.10(m,1H),7.04–6.91(m,1H),6.91– 6.81(m,3H),5.06(m,1H),4.19–4.05(m,2H),3.63–3.31(m,1H),3.27(s,3H),3.24–3.02(m,1H),2.59( s,3H),1.55–1.49(m,3H).
实施例80、N-(5-乙氧基-2,4-二氟苯基)-5-氟-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物80)的合成
Example 80. Synthesis of N-(5-ethoxy-2,4-difluorophenyl)-5-fluoro-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 80)
参照实施例13的合成方法，区别仅在于将5-氯-2,4-二氟苯胺替换成5-乙氧基-2,4-二氟苯胺，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 13, except that 5-chloro-2,4-difluoroaniline was replaced by 5-ethoxy-2,4-difluoroaniline.
LC-MS(ESI):m/z＝510.15[M+H]+ LC-MS(ESI):m/z＝510.15[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.02–7.91(m,1H),7.52–7.43(m,1H),7.18–7.11(m,1H),7.08–6.95(m,1H),6.88–6.81(m,3H),5.05(m,1H),4.24–4.15(m,2H),3.62–3.36(m,1H),3.32(s,3H),3.16–3.02(m,1H),2.61(s,3H),1.60–1.51(m,3H). 1 H NMR(300MHz,Chloroform-d)δ8.02–7.91(m,1H),7.52–7.43(m,1H),7.18–7.11(m,1H),7.08–6.95(m,1H),6.88– 6.81(m,3H),5.05(m,1H),4.24–4.15(m,2H),3.62–3.36(m,1H),3.32(s,3H),3.16–3.02(m,1H),2.61( s,3H),1.60–1.51(m,3H).
实施例81、N-(2-乙氧基-4,5-二氟苯基)-5-氟-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(化合物81)的合成
Example 81. Synthesis of N-(2-ethoxy-4,5-difluorophenyl)-5-fluoro-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Compound 81)
参照实施例13的合成方法，区别仅在于将5-氯-2,4-二氟苯胺替换成2-乙氧基-4,5-二氟苯胺，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 13, except that 5-chloro-2,4-difluoroaniline was replaced by 2-ethoxy-4,5-difluoroaniline.
LC-MS(ESI):m/z＝510.15[M+H]+ LC-MS(ESI):m/z＝510.15[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.92–7.81(m,1H),7.47–7.42(m,1H),7.18–7.12(m,1H),7.07–6.97(m,1H),6.88–6.81(m,3H),5.04(m,1H),4.21–4.07(m,2H),3.63–3.34(m,1H),3.30(s,3H),3.16–3.02(m,1H),2.59(s,3H),1.62–1.52(m,3H). 1 H NMR(300MHz,Chloroform-d)δ7.92–7.81(m,1H),7.47–7.42(m,1H),7.18–7.12(m,1H),7.07–6.97(m,1H),6.88– 6.81(m,3H),5.04(m,1H),4.21–4.07(m,2H),3.63–3.34(m,1H),3.30(s,3H),3.16–3.02(m,1H),2.59( s,3H),1.62–1.52(m,3H).
实施例82、5-氟-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物82)的合成
Example 82. Synthesis of 5-fluoro-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 82)
参照实施例13的合成方法，区别仅在于将5-氯-2,4-二氟苯胺替换成2,4,5-三氟苯胺，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 13, except that 5-chloro-2,4-difluoroaniline was replaced by 2,4,5-trifluoroaniline.
LC-MS(ESI):m/z＝484.12[M+H]+ LC-MS(ESI):m/z＝484.12[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.92(dd,J＝8.6,4.5Hz,1H),7.68–7.58(m,1H),7.27–7.12(m,1H),7.12–6.97(m,1H),6.95–6.83(m,3H),5.06–4.98(m,1H),3.39–3.34(m,1H),3.31(s,3H),3.24–3.16(m,1H),2.59(s,3H). 1 H NMR (300MHz, Chloroform-d) δ7.92 (dd, J＝8.6, 4.5Hz, 1H), 7.68–7.58 (m, 1H), 7.27–7.12 (m, 1H), 7.12–6.97 (m, 1H),6.95–6.83(m,3H),5.06–4.98(m,1H),3.39–3.34(m,1H),3.31(s,3H),3.24–3.16(m,1H),2.59(s, 3H).
实施例83、5-氟-N-(甲基-d3)-1-(7-(三氟甲基)噻唑并[5,4-b]吡啶-5-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物83)的合成
Example 83. Synthesis of 5-fluoro-N-(methyl-d 3 )-1-(7-(trifluoromethyl)thiazolo[5,4-b]pyridin-5-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 83)
参照实施例45的合成方法，区别仅在于将2-氯-6-甲基-4-(三氟甲基)吡啶替换成5-氯-7-(三氟甲基)噻唑并[5,4-b]吡啶，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 45, except that 2-chloro-6-methyl-4-(trifluoromethyl)pyridine was replaced by 5-chloro-7-(trifluoromethyl)thiazolo[5,4-b]pyridine.
LC-MS(ESI):m/z＝530.09[M+H]+ LC-MS(ESI):m/z＝530.09[M+H] +
1H NMR(300MHz,Chloroform-d)δ9.00(s,1H),7.63–7.49(m,2H),7.28–7.12(m,2H),7.03–6.89(m,2H),5.20–5.02(m,1H),3.49–3.12(m,2H). 1 H NMR(300MHz,Chloroform-d)δ9.00(s,1H),7.63–7.49(m,2H),7.28–7.12(m,2H),7.03–6.89(m,2H),5.20–5.02( m,1H),3.49–3.12(m,2H).
实施例84、5-氟-N-(甲基-d3)-1-(7-(三氟甲基)呋喃并[3,2-b]吡啶-5-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物84)的合成
Example 84. Synthesis of 5-fluoro-N-(methyl-d 3 )-1-(7-(trifluoromethyl)furo[3,2-b]pyridin-5-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 84)
参照实施例45的合成方法，区别仅在于将2-氯-6-甲基-4-(三氟甲基)吡啶替换成5-氯-7-(三氟甲基)呋喃并[3,2-b]吡啶，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 45, except that 2-chloro-6-methyl-4-(trifluoromethyl)pyridine was replaced by 5-chloro-7-(trifluoromethyl)furo[3,2-b]pyridine.
LC-MS(ESI):m/z＝513.12[M+H]+ LC-MS(ESI):m/z＝513.12[M+H] +
1H NMR(400MHz,Chloroform-d)δ7.96–7.88(m,1H),7.76–7.64(m,1H),7.44–7.36(m,1H),7.26–7.15(m,2H),6.98–6.85(m,3H),5.22–4.98(m,1H),3.47–3.15(m,2H). 1 H NMR(400MHz,Chloroform-d)δ7.96–7.88(m,1H),7.76–7.64(m,1H),7.44–7.36(m,1H),7.26–7.15(m,2H),6.98– 6.85(m,3H),5.22–4.98(m,1H),3.47–3.15(m,2H).
实施例85、5-氟-N-(甲基-d3)-1-(4-(二甲基磷酰基)-6-甲基吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物85)的合成

Example 85. Synthesis of 5-fluoro-N-(methyl-d 3 )-1-(4-(dimethylphosphoryl)-6-methylpyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 85)

步骤1：(2-氯-6-甲基吡啶-4-基)二甲基氧化膦(中间体85-1)的合成Step 1: Synthesis of (2-chloro-6-methylpyridin-4-yl)dimethylphosphine oxide (Intermediate 85-1)
在4-溴-2-氯-6-甲基吡啶(200mg)和二甲基氧化膦(95mg)的二氧六环(10mL)溶液中加入三(二亚苄基丙酮)二钯(44mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(56mg)和磷酸钾(302mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝40/1)纯化，得到中间体85-1(83mg)。Tris(dibenzylideneacetone)dipalladium (44 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (56 mg) and potassium phosphate (302 mg) were added to a solution of 4-bromo-2-chloro-6-methylpyridine (200 mg) and dimethylphosphine oxide (95 mg) in dioxane (10 mL). Stir at 110°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (dichloromethane/methanol=40/1) to obtain intermediate 85-1 (83 mg).
LC-MS(ESI):m/z＝204.03[M+H]+ LC-MS(ESI):m/z＝204.03[M+H] +
步骤2：5-氟-N-(甲基-d3)-1-(4-(二甲基磷酰基)-6-甲基吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物85)的合成Step 2: Synthesis of 5-fluoro-N-(methyl-d 3 )-1-(4-(dimethylphosphoryl)-6-methylpyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 85)
在中间体45-6(90mg)和中间体85-1(67mg)的二氧六环(6mL)溶液中加入三(二亚苄基丙酮)二钯(32mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(25mg)和碳酸铯(269mg)。在氮气保护，100℃条件下搅拌4h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝80/1)纯化，得到化合物85(43mg)。Tris(dibenzylideneacetone)dipalladium (32 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (25 mg) and cesium carbonate (269 mg) were added to a solution of intermediate 45-6 (90 mg) and intermediate 85-1 (67 mg) in dioxane (6 mL). Stirred at 100°C for 4 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (dichloromethane/methanol=80/1) to obtain compound 85 (43 mg).
LC-MS(ESI):m/z＝495.16[M+H]+ LC-MS(ESI):m/z＝495.16[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.12–8.02(m,1H),7.84–7.72(m,1H),7.28–7.15(m,2H),7.01–6.82(m,3H),5.12–5.02(m,1H),3.43–3.12(m,2H),2.60(s,3H),1.82–1.71(m,6H). 1 H NMR(300MHz,Chloroform-d)δ8.12–8.02(m,1H),7.84–7.72(m,1H),7.28–7.15(m,2H),7.01–6.82(m,3H),5.12– 5.02(m,1H),3.43–3.12(m,2H),2.60(s,3H),1.82–1.71(m,6H).
实施例86、N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(甲基磺酰基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物86)的合成
Example 86. Synthesis of N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(methylsulfonyl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 86)
参照实施例45的合成方法，区别在于仅将步骤1中的5-氟-1H-吲哚-2-羧酸乙酯替换成5-甲磺酰基-1H-吲哚-2-羧酸甲酯，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced with 5-methanesulfonyl-1H-indole-2-carboxylic acid methyl ester.
LC-MS(ESI):m/z＝547.12[M+H]+ LC-MS(ESI):m/z＝547.12[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.78(m,2H),7.61(m,2H),7.19(m,2H),6.95(m,1H),5.32–4.94(m,1H),3.44–3.08(m,2H),3.02(s,3H),2.60(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.78(m,2H),7.61(m,2H),7.19(m,2H),6.95(m,1H),5.32–4.94(m,1H),3.44 –3.08(m,2H),3.02(s,3H),2.60(s,3H).
实施例87、6-氯-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)-2,3-二氢-1H-吡咯并 [2,3-b]吡啶-2-甲酰胺(化合物87)的合成
Example 87, 6-chloro-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)-2,3-dihydro-1H-pyrrolo[iota] Synthesis of [2,3-b]pyridine-2-carboxamide (Compound 87)
参照实施例45的合成方法，区别在于仅将步骤1中的5-氟-1H-吲哚-2-羧酸乙酯替换成6-氯-1H-吡咯并[2,3-b]吡啶-2-羧酸乙酯，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced with 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester.
LC-MS(ESI):m/z＝504.10[M+H]+ LC-MS(ESI):m/z＝504.10[M+H] +
1H NMR(300MHz,Chloroform-d)δ8.94–8.88(m,1H),7.75–7.66(m,1H),7.26–7.10(m,2H),7.04–6.96(m,1H),6.85–6.75(m,1H),5.40–5.20(m,1H),3.21–3.05(m,2H),2.62–2.34(m,3H). 1 H NMR(300MHz,Chloroform-d)δ8.94–8.88(m,1H),7.75–7.66(m,1H),7.26–7.10(m,2H),7.04–6.96(m,1H),6.85– 6.75(m,1H),5.40–5.20(m,1H),3.21–3.05(m,2H),2.62–2.34(m,3H).
实施例88、5-氟-6-甲氧基-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物88)的合成
Example 88. Synthesis of 5-fluoro-6-methoxy-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 88)
参照实施例45的合成方法，区别在于仅将步骤1中的5-氟-1H-吲哚-2-羧酸乙酯替换成5-氟-6-甲氧基-1H-吲哚-2-羧酸甲酯，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 45, except that 5-fluoro-1H-indole-2-carboxylic acid ethyl ester in step 1 was replaced with 5-fluoro-6-methoxy-1H-indole-2-carboxylic acid methyl ester.
LC-MS(ESI):m/z＝517.15[M+H]+ LC-MS(ESI):m/z＝517.15[M+H] +
1H NMR(300MHz,Chloroform-d)δ7.75–7.46(m,2H),7.26–7.06(m,2H),6.96–6.76(m,2H),5.20–5.04(m,1H),3.82(s,3H),3.41–3.05(m,2H),2.62–2.54(m,3H). 1 H NMR (300MHz, Chloroform-d) δ7.75–7.46(m,2H),7.26–7.06(m,2H),6.96–6.76(m,2H),5.20–5.04(m,1H),3.82( s,3H),3.41–3.05(m,2H),2.62–2.54(m,3H).
实施例89、(S)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物1)的合成
Example 89. Synthesis of (S)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 1)
参照实施例1的合成方法，区别仅在于将步骤1中的3-氯-4-氟苯胺替换成2,4,5-三氟苯胺，制备得到(S)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物89)。Referring to the synthesis method of Example 1, the only difference is that the 3-chloro-4-fluoroaniline in step 1 is replaced by 2,4,5-trifluoroaniline to prepare (S)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)dihydroindole-2-carboxamide (Compound 89).
LC-MS(ESI):m/z＝466.13[M+H]+LC-MS (ESI): m/z = 466.13 [M + H] +
1H NMR(300MHz,Chloroform-d)δ7.76–7.65(m,1H),7.44–7.28(m,1H),7.20(m,1H),7.14(m,2H),7.01(m,1H),6.88(m,2H),5.09(m,1H),3.25(s,3H),3.22–3.01(m,2H),2.56(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.76–7.65(m,1H),7.44–7.28(m,1H),7.20(m,1H),7.14(m,2H),7.01(m,1H) ,6.88(m,2H),5.09(m,1H),3.25(s,3H),3.22–3.01(m,2H),2.56(s,3H).
实施例90、(S)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(3-(甲基磺酰基)氮杂环丁烷-1-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物90)的合成
Example 90. Synthesis of (S)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(3-(methylsulfonyl)azetidin-1-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 90)
步骤1：(S)-5-溴-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(中间体90-1)的合成Step 1: Synthesis of (S)-5-bromo-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Intermediate 90-1)
将化合物89(950mg)溶于N,N-二甲基甲酰胺(10mL)，加入N-溴代丁二酰亚胺(327mg)室温下搅拌6h，TLC监测反应完成。向反应液中加入水(150mL)，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，将滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝15/1)纯化，得到在中间体90-1(750mg)。Compound 89 (950 mg) was dissolved in N,N-dimethylformamide (10 mL), N-bromosuccinimide (327 mg) was added and stirred at room temperature for 6 h, and the reaction was completed by TLC monitoring. Water (150 mL) was added to the reaction solution, and it was extracted with ethyl acetate (25 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15/1) to obtain intermediate 90-1 (750 mg).
LC-MS(ESI):m/z＝544.04[M+H]+LC-MS (ESI): m/z = 544.04 [M + H] +
步骤2：(S)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(3-(甲基磺酰基)氮杂环丁烷-1-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物90)的合成Step 2: Synthesis of (S)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(3-(methylsulfonyl)azetidin-1-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 90)
在中间体90-1(100mg)和3-(甲磺酰基)氮杂环丁烷盐酸盐(31mg)的1,4-二氧六环(4mL)溶液中加入醋酸钯(2mg)、2-二环己基膦-2',4',6'-三异丙基联苯(10mg)和碳酸铯(100mg)。在氮气保护，100℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝90/1)纯化，得到化合物90(20mg)Palladium acetate (2 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (10 mg) and cesium carbonate (100 mg) were added to a solution of intermediate 90-1 (100 mg) and 3-(methylsulfonyl)azetidine hydrochloride (31 mg) in 1,4-dioxane (4 mL). Stir at 100°C for 8 h under nitrogen protection, and the reaction was completed by TLC monitoring. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 90/1) to obtain compound 90 (20 mg).
LC-MS(ESI):m/z＝599.15[M+H]+LC-MS (ESI): m/z = 599.15 [M + H] +
1H NMR(300MHz,Chloroform-d)δ7.61(m,1H),7.39(s,1H),7.11(m,1H),6.98(m,1H),6.62(m,3H),5.00(m,1H),4.18(m,5H),3.24(s,3H),3.12(m,2H),2.99(s,3H),2.50(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.61(m,1H),7.39(s,1H),7.11(m,1H),6.98(m,1H),6.62(m,3H),5.00(m ,1H),4.18(m,5H),3.24(s,3H),3.12(m,2H),2.99(s,3H),2.50(s,3H).
实施例91、(S)-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-(2-氧杂-7-氮杂螺[3.5]壬-7-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物91)的合成
Example 91. Synthesis of (S)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 91)
参照实施例90的合成方法，区别仅在于将步骤2中的3-(甲基磺酰基)氮杂环丁烷盐酸盐替换成2-噁唑-7-氮杂螺[3.5]壬烷，制备得到标题化合物。The title compound was prepared by referring to the synthesis method of Example 90, except that 3-(methylsulfonyl)azetidine hydrochloride in step 2 was replaced by 2-oxazole-7-azaspiro[3.5]nonane.
LC-MS(ESI):m/z＝591.21[M+H]+LC-MS (ESI): m/z = 591.21 [M + H] +
1H NMR(300MHz,Chloroform-d)δ7.64(m,1H),7.39–7.25(m,1H),7.21–7.07(m,1H),7.07–6.93(m,1H),6.82(m,3H),5.02(m,1H),4.48(m,4H),3.48(m,2H),3.30–3.21(m,3H),3.00(m,4H),2.62–2.48(m,3H),2.04(m,4H). 1 H NMR(300MHz,Chloroform-d)δ7.64(m,1H),7.39–7.25(m,1H),7.21–7.07(m,1H),7.07–6.93(m,1H),6.82(m, 3H),5.02(m,1H),4.48(m,4H),3.48(m,2H),3.30–3.21(m,3H),3.00(m,4H),2.62–2.48(m,3H),2.04 (m,4H).
实施例92、(S)-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物92)的合成
Example 92. Synthesis of (S)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 92)
步骤1：(S)-2-((2,4,5-三氟苯基)氨基甲酰基)二氢吲哚-1-羧酸叔丁酯(中间体92-1)的合成Step 1: Synthesis of tert-butyl (S)-2-((2,4,5-trifluorophenyl)carbamoyl)indoline-1-carboxylate (Intermediate 92-1)
在(S)-1-(叔丁氧羰基)吲哚啉-2-羧酸(900mg)和2，4，5-三氟苯胺(630mg)的二氯甲烷(20mL)溶液中加入N,N'-二环己基碳二亚胺(774mg)和4-二甲氨基吡啶(16mg)。室温条件下搅拌12h，TLC监测反应完成，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝25/1)纯化，得到中间体92-1(1g)。N,N'-dicyclohexylcarbodiimide (774 mg) and 4-dimethylaminopyridine (16 mg) were added to a solution of (S)-1-(tert-butyloxycarbonyl)indoline-2-carboxylic acid (900 mg) and 2,4,5-trifluoroaniline (630 mg) in dichloromethane (20 mL). The mixture was stirred at room temperature for 12 h. The reaction was completed after monitoring by TLC. The mixture was extracted with ethyl acetate (25 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=25/1) to obtain intermediate 92-1 (1 g).
LC-MS(ESI):m/z＝393.13[M+H]+LC-MS (ESI): m/z = 393.13 [M + H] +
步骤2：(S)-2-((甲基-d3)(2,4,5-三氟苯基)氨基甲酰基)二氢吲哚-1-羧酸叔丁酯(中间体92-2)的合成Step 2: Synthesis of (S)-tert-butyl 2-((methyl-d 3 )(2,4,5-trifluorophenyl)carbamoyl)indoline-1-carboxylate (Intermediate 92-2)
将中间体92-1(1g)溶于N,N-二甲基甲酰胺(5mL)中，加入氢化钠(100mg)，在冰浴中滴加氘代碘甲烷(250uL)之后把反应液升温至40℃，搅拌6h。向反应液中加入水(100mL)，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝60/1)纯化，得到中间体92-2(1.1g)。Intermediate 92-1 (1 g) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (100 mg) was added, deuterated iodomethane (250 uL) was added dropwise in an ice bath, the reaction solution was heated to 40°C and stirred for 6 h. Water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (25 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=60/1) to obtain intermediate 92-2 (1.1 g).
LC-MS(ESI):m/z＝410.17[M+H]+LC-MS (ESI): m/z = 410.17 [M+H] +
步骤3：(S)-N-(甲基-d3)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(中间体92-3)的合成Step 3: Synthesis of (S)-N-(methyl-d 3 )-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Intermediate 92-3)
将中间体92-2(1.1g)溶解在10％三氟乙酸的二氯甲烷溶液(15mL)中。反应液在室温条件下搅拌 6h，TLC监测反应完成。向反应液中滴加饱和碳酸氢钠溶液，调节pH＝8-9，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，得到中间体92-3(1g)。Intermediate 92-2 (1.1 g) was dissolved in 10% trifluoroacetic acid in dichloromethane (15 mL). The reaction mixture was stirred at room temperature. After 6 hours, the reaction was completed under TLC monitoring. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust pH to 8-9, extracted with ethyl acetate (25 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 92-3 (1 g).
LC-MS(ESI):m/z＝310.12[M+H]+LC-MS (ESI): m/z = 310.12 [M+H] +
步骤4：(S)-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物92)的合成Step 4: Synthesis of (S)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 92)
在中间体92-3(1g)和2-氯-6-甲基-4-(三氟甲基)吡啶(900mg)的1,4-二氧六环(16mL)溶液中加入醋酸钯(400mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(500mg)和碳酸铯(3g)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到化合物92(700mg)。Palladium acetate (400 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (500 mg) and cesium carbonate (3 g) were added to a solution of intermediate 92-3 (1 g) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (900 mg) in 1,4-dioxane (16 mL). Stir at 110° C. for 8 h under nitrogen protection, and the reaction was completed by TLC monitoring. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain compound 92 (700 mg).
LC-MS(ESI):m/z＝469.15[M+H]+LC-MS (ESI): m/z = 469.15 [M + H] +
1H NMR(300MHz,Chloroform-d)δ7.71(m,1H),7.44(m,1H),7.25–7.11(m,3H),7.03(m,1H),6.95–6.83(m,2H),5.08(m,1H),3.46–3.04(m,2H),2.58(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.71(m,1H),7.44(m,1H),7.25–7.11(m,3H),7.03(m,1H),6.95–6.83(m,2H) ,5.08(m,1H),3.46–3.04(m,2H),2.58(s,3H).
实施例93、(S)-5-(4-(2-甲氧基乙基)哌嗪-1-基)-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物93)的合成
Example 93. Synthesis of (S)-5-(4-(2-methoxyethyl)piperazin-1-yl)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 93)
步骤1：(S)-5-溴-N-(2,4,5-三氟苯基)-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)二氢吲哚-2-甲酰胺(中间体93-1)的合成Step 1: Synthesis of (S)-5-bromo-N-(2,4,5-trifluorophenyl)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)indoline-2-carboxamide (Intermediate 93-1)
将化合物4(800mg)溶于N,N-二甲基甲酰胺(10mL)，加入N-溴代丁二酰亚胺(300mg)室温下搅拌6h，TLC监测反应完成。向反应液中加入水(150mL)，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，将滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝15/1)纯化，得到中间体93-1(500mg)。Compound 4 (800 mg) was dissolved in N,N-dimethylformamide (10 mL), N-bromosuccinimide (300 mg) was added and stirred at room temperature for 6 h, and the reaction was completed by TLC monitoring. Water (150 mL) was added to the reaction solution, and it was extracted with ethyl acetate (25 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15/1) to obtain intermediate 93-1 (500 mg).
LC-MS(ESI):m/z＝547.06[M+H]+LC-MS (ESI): m/z = 547.06 [M + H] +
步骤2：(S)-5-(4-(2-甲氧基乙基)哌嗪-1-基)-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物93)的合成Step 2: Synthesis of (S)-5-(4-(2-methoxyethyl)piperazin-1-yl)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 93)
在中间体93-1(110mg)和1-(2-甲氧基乙基)哌嗪(40mg)的1,4-二氧六环(4mL)溶液中加入醋酸钯(5mg)、2-二环己基膦-2',4',6'-三异丙基联苯(20mg)和碳酸铯(200mg)。在氮气保护，100℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝90/1)纯化，得到化合物93(30mg)Palladium acetate (5 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (20 mg) and cesium carbonate (200 mg) were added to a solution of intermediate 93-1 (110 mg) and 1-(2-methoxyethyl)piperazine (40 mg) in 1,4-dioxane (4 mL). Stir at 100°C for 8 h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 90/1) to obtain compound 93 (30 mg).
LC-MS(ESI):m/z＝611.26[M+H]+LC-MS (ESI): m/z = 611.26 [M + H] +
1H NMR(300MHz,Chloroform-d)δ7.62(m,1H),7.34(m,1H),7.15(m,1H),6.97(m,1H),6.85–6.75(m,3H),5.16–4.87(m,1H),3.58(m,3H),3.42–3.33(m,5H),3.25–3.12(m,7H),2.52–2.02(m,5H). 1 H NMR(300MHz,Chloroform-d)δ7.62(m,1H),7.34(m,1H),7.15(m,1H),6.97(m,1H),6.85–6.75(m,3H),5.16 –4.87(m,1H),3.58(m,3H),3.42–3.33(m,5H),3.25–3.12(m,7H),2.52–2.02(m,5H).
实施例94、(S)-5-(1-(2-氰基乙基)-1H-吡唑-3-基)-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物94)的合成
Example 94. Synthesis of (S)-5-(1-(2-cyanoethyl)-1H-pyrazol-3-yl)-N-(methyl-d 3 )-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 94)
在中间体93-1(80mg)和4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑-1-丙腈(36mg)的1,4-二氧六环(5mL)溶液中加入1,1-双(二苯基膦)二荗铁二氯化钯(10mg)和碳酸钠(50mg)。在氮气保护，100℃条件下搅拌6h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(二氯甲烷/甲醇＝100/1)纯化，得到化合物94(35mg)。1,1-Bis(diphenylphosphino)diboraneferronichloridepalladium(10mg) and sodium carbonate(50mg) were added to a solution of intermediate 93-1(80mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-propionitrile(36mg) in 1,4-dioxane(5mL). Stirred at 100°C for 6h under nitrogen protection, and the reaction was completed after monitoring by TLC. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1) to obtain compound 94(35mg).
LC-MS(ESI):m/z＝588.19[M+H]+LC-MS (ESI): m/z = 588.19 [M + H] +
1H NMR(300MHz,Chloroform-d)δ7.76(m,1H),7.65(m,2H),7.59–7.40(m,1H),7.29(m,1H),7.26–7.22(m,1H),7.20–6.90(m,2H),6.85(m,1H),5.19–4.91(m,1H),4.41(m,2H),3.50–3.06(m,2H),2.96(m,2H),2.56(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.76(m,1H),7.65(m,2H),7.59–7.40(m,1H),7.29(m,1H),7.26–7.22(m,1H) ,7.20–6.90(m,2H),6.85(m,1H),5.19–4.91(m,1H),4.41(m,2H),3.50–3.06(m,2H),2.96(m,2H),2.56 (s,3H).
实施例95、5,6-二氟-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物95)的合成
Example 95. Synthesis of 5,6-difluoro-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 95)
步骤1：1-(叔丁氧基羰基)-5,6-二氟吲哚啉-2-羧酸(中间体95-1)的合成Step 1: Synthesis of 1-(tert-butoxycarbonyl)-5,6-difluoroindoline-2-carboxylic acid (Intermediate 95-1)
向水(50mL)中加入1-(叔丁基)2-乙基5,6-二氟吲哚啉-1,2-二羧酸酯(750mg)、氢氧化锂(90mg)和甲醇(5mL)室温下搅拌10h。TLC监测反应完成，滴加1N盐酸调节pH＝3-4，用乙酸乙酯(25mL×6)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂得到中间体95-1(700mg)。1-(tert-butyl) 2-ethyl 5,6-difluoroindoline-1,2-dicarboxylate (750 mg), lithium hydroxide (90 mg) and methanol (5 mL) were added to water (50 mL) and stirred at room temperature for 10 h. The reaction was completed by TLC monitoring, 1N hydrochloric acid was added dropwise to adjust the pH to 3-4, and the mixture was extracted with ethyl acetate (25 mL×6). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 95-1 (700 mg).
LC-MS(ESI):m/z＝300.10[M+H]+LC-MS (ESI): m/z = 300.10 [M+H] +
步骤2：5,6-二氟-2-((2,4,5-三氟苯基)氨基甲酰基)二氢吲哚-1-羧酸叔丁酯(中间体95-2)的合成Step 2: Synthesis of tert-butyl 5,6-difluoro-2-((2,4,5-trifluorophenyl)carbamoyl)indoline-1-carboxylate (Intermediate 95-2)
在中间体95-1(700mg)和2，4，5-三氟苯胺(460mg)的二氯甲烷(20mL)溶液中加入N,N'-二环己基碳二亚胺(700mg)和4-二甲氨基吡啶(12mg)。室温条件下搅拌12h，TLC监测反应完成，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝25/1)纯化，得到中间体95-2(500mg)。N,N'-dicyclohexylcarbodiimide (700 mg) and 4-dimethylaminopyridine (12 mg) were added to a solution of intermediate 95-1 (700 mg) and 2,4,5-trifluoroaniline (460 mg) in dichloromethane (20 mL). The mixture was stirred at room temperature for 12 h. The reaction was completed after monitoring by TLC. The mixture was extracted with ethyl acetate (25 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 25/1) to obtain intermediate 95-2 (500 mg).
LC-MS(ESI):m/z＝429.12[M+H]+LC-MS (ESI): m/z = 429.12 [M + H] +
步骤3：5,6-二氟-2-((2,4,5-三氟苯基)氨基甲酰基)二氢吲哚-1-羧酸叔丁酯(中间体95-3)的合成Step 3: Synthesis of tert-butyl 5,6-difluoro-2-((2,4,5-trifluorophenyl)carbamoyl)indoline-1-carboxylate (Intermediate 95-3)
将中间体95-2(500mg)溶于N,N-二甲基甲酰胺(5mL)中，加入氢化钠(70mg)，在冰浴中滴加碘甲烷(100uL)之后把反应液升温至40℃，搅拌6h。向反应液中加入水(100mL)，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝60/1)纯化，得到中间体95-3(450mg)。Intermediate 95-2 (500 mg) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (70 mg) was added, iodomethane (100 uL) was added dropwise in an ice bath, the reaction solution was heated to 40°C and stirred for 6 h. Water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (25 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=60/1) to obtain intermediate 95-3 (450 mg).
LC-MS(ESI):m/z＝443.13[M+H]+ LC-MS (ESI): m/z = 443.13 [M + H] +
步骤4：5,6-二氟-N-甲基-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(中间体7-4)的合成Step 4: Synthesis of 5,6-difluoro-N-methyl-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Intermediate 7-4)
将中间体95-3(450mg)溶解在10％三氟乙酸的二氯甲烷溶液(15mL)中。反应液在室温条件下搅拌6h，TLC监测反应完成。向反应液中滴加饱和碳酸氢钠溶液，调节pH＝8-9，用乙酸乙酯(25mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸出溶剂，得到中间体95-4(1g)。Intermediate 95-3 (450 mg) was dissolved in 10% trifluoroacetic acid in dichloromethane (15 mL). The reaction solution was stirred at room temperature for 6 h, and the reaction was completed after TLC monitoring. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust the pH to 8-9, and extracted with ethyl acetate (25 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 95-4 (1 g).
LC-MS(ESI):m/z＝343.08[M+H]+LC-MS (ESI): m/z = 343.08 [M + H] +
步骤5：5,6-二氟-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-N-(2,4,5-三氟苯基)二氢吲哚-2-甲酰胺(化合物95)的合成Step 5: Synthesis of 5,6-difluoro-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)indoline-2-carboxamide (Compound 95)
在中间体95-4(250mg)和2-氯-6-甲基-4-(三氟甲基)吡啶(100mg)的1,4-二氧六环(16mL)溶液中加入醋酸钯(40mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(50mg)和碳酸铯(300mg)。在氮气保护，110℃条件下搅拌8h，TLC监测反应完成。将反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到化合物95(100mg)。Palladium acetate (40 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (50 mg) and cesium carbonate (300 mg) were added to a solution of intermediate 95-4 (250 mg) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (100 mg) in 1,4-dioxane (16 mL). Stir at 110° C. for 8 h under nitrogen protection, and the reaction was completed by TLC monitoring. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain compound 95 (100 mg).
LC-MS(ESI):m/z＝502.11[M+H]+LC-MS (ESI): m/z = 502.11 [M+H] +
1H NMR(300MHz,Chloroform-d)δ7.64–7.44(m,1H),7.10(m,2H),6.91(m,3H),5.02(m,1H),3.25(s,3H),3.21–3.00(m,2H),2.58(s,3H). 1 H NMR(300MHz,Chloroform-d)δ7.64–7.44(m,1H),7.10(m,2H),6.91(m,3H),5.02(m,1H),3.25(s,3H),3.21 –3.00(m,2H),2.58(s,3H).
生物学活性及相关性质测试例Biological activity and related properties test examples
以下测试例中的化合物均根据本公开上述实施例的方法制备获得。The compounds in the following test examples were all prepared according to the methods of the above embodiments of the present disclosure.
测试例1：POLQ酶活性抑制实验Test Example 1: POLQ enzyme activity inhibition experiment
实验原理简介：POLQ具有ATP酶活性的N端活性肽段(M1-N899)与化合物共同孵育后，在ATP的作用下与底物dT50反应生成ADP，参与后续的NADH氧化偶联酶促反应，催化NADH反应生成NAD+。使用Perkin Elmer公司的Envision酶标仪测量NADH在340nm处OD值的减少，从而反映酶活性。Brief introduction to experimental principle: After the N-terminal active peptide segment (M1-N899) of POLQ with ATPase activity is incubated with the compound, it reacts with the substrate dT50 under the action of ATP to generate ADP, participates in the subsequent NADH oxidation-coupled enzymatic reaction, and catalyzes the reaction of NADH to generate NAD + . The decrease in the OD value of NADH at 340nm is measured using the Envision microplate reader from Perkin Elmer, thereby reflecting the enzyme activity.
实验仪器：Labcyte公司Echo 650移液系统；Perkin Elmer公司Envision酶标仪；Eppendorf公司5810R离心机，Boxun公司BSD-YX3400恒温摇床。Experimental instruments: Echo 650 pipetting system from Labcyte; Envision microplate reader from Perkin Elmer; 5810R centrifuge from Eppendorf, and BSD-YX3400 constant temperature shaker from Boxun.
实验材料：
Experimental Materials:
实验方法：用反应缓冲液(20mM Tris HCl(pH 7.80)，80mM KCl，10mM MgCl2，1mM DTT(二硫苏糖醇)，0.01％w/v牛血清蛋白，0.01％v/v吐温-20，5％v/v甘油)将POLQ酶稀释至100nM。用Echo 650移液系统将待测化合物在二甲基亚砜(DMSO)中稀释到不同浓度，转移至384孔板中，加入20μL/孔100nM POLQ，室温孵育15分钟。配置反应混合物溶液，反应混合物溶液中各组分浓度为：100μM ATP，300nM dT50，300μM NADH，6mM PEP，10U/mL乳酸脱氢酶和20U/mL丙酮酸激酶。加入20μL/孔的反应混合物溶液启动酶反应。反应体系中化合物终浓度从10μM起始，3倍梯度稀释，浓度范围为10μM至0.0005μM，体系中DMSO终浓度为0.2％v/v。将384孔板置于室温反应20分钟后，用Envision酶标仪读取340nm处的OD值。Experimental method: POLQ enzyme was diluted to 100 nM in reaction buffer (20 mM Tris HCl (pH 7.80), 80 mM KCl, 10 mM MgCl 2 , 1 mM DTT (dithiothreitol), 0.01% w/v bovine serum albumin, 0.01% v/v Tween-20, 5% v/v glycerol). The test compound was diluted to different concentrations in dimethyl sulfoxide (DMSO) using the Echo 650 pipetting system, transferred to a 384-well plate, and 20 μL/well of 100 nM POLQ was added and incubated at room temperature for 15 minutes. The reaction mixture solution was prepared, and the concentrations of the components in the reaction mixture solution were: 100 μM ATP, 300 nM dT50, 300 μM NADH, 6 mM PEP, 10 U/mL lactate dehydrogenase and 20 U/mL pyruvate kinase. 20 μL/well of the reaction mixture solution was added to start the enzyme reaction. The final concentration of the compound in the reaction system started from 10 μM, and was diluted 3 times in a gradient, ranging from 10 μM to 0.0005 μM, and the final concentration of DMSO in the system was 0.2% v/v. After the 384-well plate was placed at room temperature for 20 minutes, the OD value at 340 nm was read using an Envision microplate reader.
数据分析：data analysis:
计算抑制率，并使用XLfit软件拟合得到化合物的IC50。The inhibition rate was calculated and the IC 50 of the compound was obtained by fitting using XLfit software.
实验设置空白组和DMSO组，空白组反应体系为0.2％v/v DMSO和反应混合物溶液，认为此时抑制率为100％；DMSO组反应体系为0.2％v/v DMSO、POLQ(N)(100nM)和反应混合物溶液，认为此时抑制 率为0。The experiment set up a blank group and a DMSO group. The reaction system of the blank group was 0.2% v/v DMSO and reaction mixture solution, and the inhibition rate was considered to be 100% at this time; the reaction system of the DMSO group was 0.2% v/v DMSO, POLQ (N) (100nM) and reaction mixture solution, and the inhibition rate was considered to be 100% at this time. The rate is 0.
抑制率(％)＝(100-100*(ODmax-OD化合物)/(ODmax-ODmin))％Inhibition rate (%) = (100-100*(OD max -OD compound )/(OD max -OD min ))%
其中，ODmax指含有反应物混合液和0.2％v/v DMSO的孔的OD值，OD化合物指含有化合物、酶及反应物混合液的孔的OD值。ODmin指含有酶、反应物混合液及0.2％v/v DMSO的孔的OD值。Here, OD max refers to the OD value of the well containing the reactant mixture and 0.2% v/v DMSO, OD compound refers to the OD value of the well containing the compound, enzyme and reactant mixture, and OD min refers to the OD value of the well containing the enzyme, reactant mixture and 0.2% v/v DMSO.
本公开实施例化合物的生物活性通过以上的试验进行测定，测得的IC50值见下表1。The biological activities of the compounds of the examples of the present disclosure were determined by the above test, and the measured IC 50 values are shown in Table 1 below.
表1实施例化合物对POLQ酶活性抑制效果

Table 1 Inhibitory effect of the compounds in the examples on POLQ enzyme activity

测试例2：化合物对肿瘤细胞增殖抑制实验Test Example 2: Experiment on the inhibition of tumor cell proliferation by compounds
实验原理简介：将化合物与肿瘤细胞共同孵育7天后，使用Promega公司的CTG试剂盒对活细胞中的ATP进行定量，从而反映化合物对肿瘤细胞增殖的影响。Brief introduction to experimental principle: After the compound is co-incubated with tumor cells for 7 days, the ATP in the living cells is quantified using the CTG kit of Promega, thereby reflecting the effect of the compound on the proliferation of tumor cells.
实验仪器：Perkin Elmer公司Envision酶标仪；Eppendorf公司5810R离心机，Countstar公司自动细胞计数仪。Experimental instruments: Envision microplate reader from Perkin Elmer; 5810R centrifuge from Eppendorf, and automatic cell counter from Countstar.
实验材料：
Experimental Materials:
实验方法：将DLD-1亲本细胞或DLD-1BRCA2(-/-)细胞用含有10％FBS的RPMI 1640培养基稀释后加入96孔板中(90μL/孔)，细胞数分别为600个/孔或1200个/孔，置于37℃、5％CO2培养箱中培养过夜。将待测化合物在二甲基亚砜(DMSO)中稀释到不同浓度后，加入96孔板中，使反应体系中化合物终浓度由25μM起始，4倍梯度稀释，化合物的浓度范围为25μM至0.0004μM，DMSO终浓度为0.25％v/v。孵育7天后，加入50μL/孔CTG室温孵育10分钟后用Envision酶标仪读取光信号值(Lum)，并计算抑制率和半数抑制浓度(IC50)。Experimental method: DLD-1 parental cells or DLD-1BRCA2 (-/-) cells were diluted with RPMI 1640 medium containing 10% FBS and added to 96-well plates (90 μL/well). The number of cells was 600/well or 1200/well, respectively, and cultured in a 37°C, 5% CO 2 incubator overnight. The test compound was diluted to different concentrations in dimethyl sulfoxide (DMSO) and added to the 96-well plate. The final concentration of the compound in the reaction system started from 25 μM, and the concentration range of the compound was 4 times dilution. The concentration range was 25 μM to 0.0004 μM, and the final concentration of DMSO was 0.25% v/v. After incubation for 7 days, 50 μL/well CTG was added and incubated at room temperature for 10 minutes. The light signal value (Lum) was read using an Envision microplate reader, and the inhibition rate and half inhibition concentration (IC 50 ) were calculated.
数据分析：data analysis:
计算抑制率，并使用XLfit软件拟合得到化合物的IC50。The inhibition rate was calculated and the IC 50 of the compound was obtained by fitting using XLfit software.
实验设置空白孔和DMSO孔，空白孔为100μL含有10％FBS的RPMI Medium 1640培养基，认为此时化合物对肿瘤细胞生长的抑制率为100％；DMSO孔为细胞孔中加入0.25％v/v DMSO，认为此时化合物对肿瘤细胞生长的抑制率为0。The experiment set up blank wells and DMSO wells. The blank wells were 100 μL of RPMI Medium 1640 culture medium containing 10% FBS, and the inhibition rate of the compound on tumor cell growth was considered to be 100% at this time; the DMSO wells were cell wells with 0.25% v/v DMSO added, and the inhibition rate of the compound on tumor cell growth was considered to be 0 at this time.
抑制率＝100*(Lummax-Lum化合物)/(Lummax-Lummin)％ Inhibition rate = 100*(Lum max -Lum compound )/(Lum max -Lum min )%
其中，Lummax指含有细胞和0.25％v/v DMSO孔的光信号值，Lum化合物指含有化合物和细胞的孔的光信号值。Lummin指含有培养基及0.25％v/v DMSO孔的光信号值。Wherein, Lum max refers to the light signal value of the well containing cells and 0.25% v/v DMSO, Lum compound refers to the light signal value of the well containing compound and cells, and Lum min refers to the light signal value of the well containing culture medium and 0.25% v/v DMSO.
本申请化合物对肿瘤细胞的生长抑制通过以上的试验进行测定，测得的IC50值见下表2。The inhibitory effect of the compounds of the present application on the growth of tumor cells was determined by the above test, and the measured IC 50 values are shown in Table 2 below.
表2实施例化合物对DLD-1BRCA2-/-细胞增殖抑制活性
Table 2 Inhibitory activity of the compounds in the examples on DLD-1BRCA2-/- cells
本申请的实施例化合物对BRCA2突变的肿瘤细胞有很好的抑制效果，并且有很好的选择性。 The example compounds of the present application have a good inhibitory effect on BRCA2 mutated tumor cells and have good selectivity.

Claims (28)

  1. 式(I)化合物或其药学上可接受的盐或其立体异构体，
    A compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof,
    其中，代表单键或双键；in, represents a single bond or a double bond;
    Q1选自N、CH或CR1；Q 1 is selected from N, CH or CR 1 ;
    Q2选自N、CH或CR2；Q 2 is selected from N, CH or CR 2 ;
    Q3选自N、CH或CR3；Q 3 is selected from N, CH or CR 3 ;
    Q4选自N或CH；Q 4 is selected from N or CH;
    所述R1选自卤素、氰基、羟基、C1-C10烷基、C1-C10烷氧基、3-12元杂环烷基、-Y-NR1AR1AA、B(OH)2或-Z-5-10元杂芳基，所述3-12元杂环烷基或5-10元杂芳基任选被R1a取代；The R 1 is selected from halogen, cyano, hydroxyl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocycloalkyl, -Y-NR 1A R 1AA , B(OH) 2 or -Z-5-10 membered heteroaryl, and the 3-12 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted by R 1a ;
    Y选自键、C(O)、(CH2)p或C3-C8亚环烷基；Y is selected from a bond, C(O), (CH 2 ) p or C 3 -C 8 cycloalkylene;
    Z选自键或(CH2)r；Z is selected from a bond or (CH 2 ) r ;
    所述R1a选自卤素、羟基、氰基、氨基、氧代、SH、C1-C6烷基、-S(O)2-R1a’、-C(O)C1-C6烷基、-B(OH)2、5-10元杂芳基、C1-C6烷氧基、C3-C8环烷基、-NHC(O)C1-C6烷基、-NH(C1-C6烷基)或-N(C1-C6烷基)2，所述C1-C6烷基、-C(O)C1-C6烷基、5-10元杂芳基、C1-C6烷氧基、C3-C8环烷基、-NHC(O)C1-C6烷基、-NH(C1-C6烷基)或-N(C1-C6烷基)2任选被R1b取代；Said R 1a is selected from halogen, hydroxyl, cyano, amino, oxo, SH, C 1 -C 6 alkyl, -S(O) 2 -R 1a ', -C(O)C 1 -C 6 alkyl, -B(OH) 2 , 5-10 membered heteroaryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, -NHC(O)C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 , said C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, 5-10 membered heteroaryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, -NHC(O)C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 is optionally substituted by R 1b ;
    所述R1A、R1AA各自独立地选自氢、C1-C6烷基、-C(O)H、-C(O)C1-C6烷基、-S(O)2-R1A’或-C(O)OC1-C6烷基，所述C1-C6烷基、-C(O)C1-C6烷基或-C(O)OC1-C6烷基任选被R1B取代；Said R 1A , R 1AA are each independently selected from hydrogen, C 1 -C 6 alkyl, -C(O)H, -C(O)C 1 -C 6 alkyl, -S(O) 2 -R 1A 'or -C(O)OC 1 -C 6 alkyl, said C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl or -C(O)OC 1 -C 6 alkyl are optionally substituted by R 1B ;
    所述R1B选自卤素、羟基、氰基、氨基、SH、C1-C6烷氧基或4-10元杂环烷基，所述4-10元杂环烷基任选被R1C取代；The R 1B is selected from halogen, hydroxyl, cyano, amino, SH, C 1 -C 6 alkoxy or 4-10 membered heterocycloalkyl, and the 4-10 membered heterocycloalkyl is optionally substituted by R 1C ;
    所述R2选自卤素、氰基、羟基、-COOH、-CONH2、-COOC1-C10烷基、-CONH(C1-C10烷基)、-CON(C1-C10烷基)2、-S(O)2(C1-C6烷基)、-S(O)2(C3-C6环烷基)、C3-C10环烷基、C6-C14芳基、C1-C10烷基、C1-C10烷氧基、3-12元杂环基、-T-NR2AR2AA、B(OH)2或-L-5-10元杂芳基，所述-COOC1-C10烷基、-CONH(C1-C10烷基)、-CON(C1-C10烷基)2、-S(O)2(C1-C6烷基)、-S(O)2(C3-C6环烷基)、C3-C10环烷基、C6-C14芳基、C1-C10烷基、C1-C10烷氧基、3-12元杂环基或5-10元杂芳基任选被R2a取代；The R 2 is selected from halogen, cyano, hydroxyl, -COOH, -CONH 2 , -COOC 1 -C 10 alkyl, -CONH(C 1 -C 10 alkyl), -CON(C 1 -C 10 alkyl) 2 , -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (C 3 -C 6 cycloalkyl), C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocyclyl, -T-NR 2A R 2AA , B(OH) 2 or -L-5-10 membered heteroaryl, the -COOC 1 -C 10 alkyl, -CONH(C 1 -C 10 alkyl), -CON(C 1 -C 10 alkyl) 2 , -S(O) 2 (C 1 -C 6 alkyl ), -S(O) 2 (C 3 -C 6 cycloalkyl), C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocyclyl, -T-NR 2A R 2AA , B(OH) 2 or -L - 5-10 membered heteroaryl. R 2a is optionally substituted with -S(O) 2 (C 3 -C 6 alkyl), -S(O) 2 (C 3 -C 6 cycloalkyl), C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocyclyl or 5-10 membered heteroaryl;
    T选自键、C(O)、(CH2)m或C3-C8亚环烷基；T is selected from a bond, C(O), (CH 2 ) m or C 3 -C 8 cycloalkylene;
    L选自键或(CH2)n；L is selected from a bond or (CH 2 ) n ;
    所述R2a选自卤素、羟基、氰基、氨基、氧代、SH、C1-C6烷基、-S(O)2-R2a’、-C(O)C1-C6 烷基、-B(OH)2、5-10元杂芳基、C1-C6烷氧基、C3-C8环烷基、-NHC(O)C1-C6烷基、-NH(C1-C6烷基)或-N(C1-C6烷基)2，所述C1-C6烷基、-C(O)C1-C6烷基、5-10元杂芳基、C1-C6烷氧基、C3-C8环烷基、-NHC(O)C1-C6烷基、-NH(C1-C6烷基)或-N(C1-C6烷基)2任选被R2b取代；The R 2a is selected from halogen, hydroxyl, cyano, amino, oxo, SH, C 1 -C 6 alkyl, -S(O) 2 -R 2a ', -C(O)C 1 -C 6 R 2b is selected from the group consisting of: -B(OH) 2 , 5-10 membered heteroaryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, -NHC(O)C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 , wherein the C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, 5-10 membered heteroaryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, -NHC(O)C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 is optionally substituted with R 2b ;
    所述R2A、R2AA各自独立地选自氢、C1-C6烷基、-C(O)H、-C(O)C1-C6烷基、-S(O)2-R2A’或-C(O)OC1-C6烷基，所述C1-C6烷基、-C(O)C1-C6烷基或-C(O)OC1-C6烷基任选被R2B取代；Said R 2A , R 2AA are each independently selected from hydrogen, C 1 -C 6 alkyl, -C(O)H, -C(O)C 1 -C 6 alkyl, -S(O) 2 -R 2A 'or -C(O)OC 1 -C 6 alkyl, said C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl or -C(O)OC 1 -C 6 alkyl are optionally substituted by R 2B ;
    所述R2B选自卤素、羟基、氰基、氨基、SH、C1-C6烷氧基、4-10元杂环烷基、-S(O)2-(C1-C6烷基)或-S(O)2-(C3-C6环烷基)，所述4-10元杂环烷基任选被R2C取代；The R 2B is selected from halogen, hydroxyl, cyano, amino, SH, C 1 -C 6 alkoxy, 4-10 membered heterocycloalkyl, -S(O) 2 -(C 1 -C 6 alkyl) or -S(O) 2 -(C 3 -C 6 cycloalkyl), and the 4-10 membered heterocycloalkyl is optionally substituted by R 2C ;
    所述R1a’、R1A’、R2a’、R2A’各自独立地选自C1-C6烷基或C3-C6环烷基；The R 1a ', R 1A ', R 2a ', and R 2A ' are each independently selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
    所述R3选自卤素、羟基、氨基、C1-C10烷基、C1-C10烷氧基、C3-C10环烷基、-NH(C1-C10烷基)、-N(C1-C10烷基)2、3-12元杂环基或-U-5-10元杂芳基，所述C1-C10烷基、C1-C10烷氧基、C3-C10环烷基、-NH(C1-C10烷基)、-N(C1-C10烷基)2、3-12元杂环基、5-10元杂芳基任选被R3a取代；The R 3 is selected from halogen, hydroxyl, amino, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, -NH(C 1 -C 10 alkyl), -N(C 1 -C 10 alkyl) 2 , 3-12 membered heterocyclyl or -U-5-10 membered heteroaryl, and the C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, -NH(C 1 -C 10 alkyl), -N(C 1 -C 10 alkyl) 2 , 3-12 membered heterocyclyl, 5-10 membered heteroaryl are optionally substituted by R 3a ;
    U选自键、(CH2)q或3-12元亚杂环烷基；U is selected from a bond, (CH 2 ) q or a 3-12 membered heterocycloalkylene group;
    所述R1b、R1C、R2b、R2C、R3a各自独立地选自卤素、羟基、氰基、氨基、氧代、C1-C6烷基、C1-C6烷氧基或4-12元杂环基，所述C1-C6烷基、C1-C6烷氧基或4-12元杂环基任选被R1c取代；R 1b , R 1c , R 2b , R 2c , and R 3a are each independently selected from halogen, hydroxy, cyano, amino, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or 4-12 membered heterocyclyl, and the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or 4-12 membered heterocyclyl is optionally substituted by R 1c ;
    R1c选自卤素、羟基、氨基、C1-C6烷基或C1-C6烷氧基；R 1c is selected from halogen, hydroxy, amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
    X选自N或CR4；X is selected from N or CR 4 ;
    R4、R5、R6、R7和R8各自独立地选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C3-C8环烷基、C1-C6卤代烷基、-NH(C1-C6烷基)或-N(C1-C6烷基)2；或者R4、R5、R6、R7和R8中任意两个相邻的基团与它们相连的原子共同形成5-7元不饱和环，所述不饱和环任选地包含一个或多个选自O、N或S的杂原子，且所述不饱和环任选被R4a取代；R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, -NH(C 1 -C 6 alkyl) or -N(C 1 -C 6 alkyl) 2 ; or any two adjacent groups of R 4 , R 5 , R 6 , R 7 and R 8 and the atoms to which they are attached together form a 5-7 membered unsaturated ring, the unsaturated ring optionally containing one or more heteroatoms selected from O, N or S, and the unsaturated ring is optionally substituted by R 4a ;
    R4a选自C1-C6烷基或卤素；R 4a is selected from C 1 -C 6 alkyl or halogen;
    R9选自H、卤素、OH、氘或任选被羟基取代的C1-C6烷基；R 9 is selected from H, halogen, OH, deuterium or C 1 -C 6 alkyl optionally substituted with hydroxyl;
    R10选自甲基或氘代甲基；R 10 is selected from methyl or deuterated methyl;
    M选自N或CR11；M is selected from N or CR 11 ;
    R11、R12、R13和R14各自独立地选自氢、卤素、氰基、C1-C6烷基、C2-C6烯基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C3-C8环烷基、-P(O)(C1-C6烷基)2或NR11AR11AA；或者R13和R14以及它们所连接的碳原子一起形成5-10元杂芳环；R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, -P(O)(C 1 -C 6 alkyl) 2 or NR 11A R 11AA ; or R 13 and R 14 and the carbon atoms to which they are attached together form a 5-10 membered heteroaromatic ring;
    R11A、R11AA各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基、C3-C8环烷基、-COC1-C6烷基或3-12元杂环基，所述C1-C6烷基、C1-C6卤代烷基、C3-C8环烷基或-COC1-C6烷基任选被R11B取代，所述3-12元杂环基任选被R11B’取代；R 11A and R 11AA are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, -COC 1 -C 6 alkyl or 3-12 membered heterocyclyl, the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl or -COC 1 -C 6 alkyl is optionally substituted by R 11B , the 3-12 membered heterocyclyl is optionally substituted by R 11B ';
    所述R11B选自羟基或氨基；The R 11B is selected from hydroxyl or amino;
    所述R11B’选自氧代、羟基、C1-C6烷醇或-COC1-C6烷基；The R 11B ' is selected from oxo, hydroxyl, C 1 -C 6 alkanol or -COC 1 -C 6 alkyl;
    p、r、m、n、q各自独立地选自1、2、3、4、5或6；p, r, m, n, q are each independently selected from 1, 2, 3, 4, 5 or 6;
    当代表双键时，R15不存在；当代表单键时，R15选自氢或氘。 when When represents a double bond, R 15 does not exist; when When represents a single bond, R 15 is selected from hydrogen or deuterium.
  2. 根据权利要求1所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，当代表双键时，R15不存在；当代表单键时，R15选自氢。The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein When represents a double bond, R 15 does not exist; when When represents a single bond, R 15 is selected from hydrogen.
  3. 根据权利要求1-2任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，选自单键。The compound of formula (I) according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Select from single bonds.
  4. 根据权利要求1-3任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，当Q1选自CR1时，Q2不是CR2并且Q3不是CR3；或者，The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, when Q 1 is selected from CR 1 , Q 2 is not CR 2 and Q 3 is not CR 3 ; or,
    Q1选自CH或CR1，Q2选自CH或CR2，Q3选自CH或CR3，且Q4选自CH；或者，Q 1 is selected from CH or CR 1 , Q 2 is selected from CH or CR 2 , Q 3 is selected from CH or CR 3 , and Q 4 is selected from CH; or,
    Q1、Q2、Q3或Q4中至少一个选自N；或者，At least one of Q 1 , Q 2 , Q 3 or Q 4 is selected from N; or,
    Q1选自CH或CR1，Q2选自CH或CR2，Q3选自CH或CR3，且Q4选自CH；或者，Q 1 is selected from CH or CR 1 , Q 2 is selected from CH or CR 2 , Q 3 is selected from CH or CR 3 , and Q 4 is selected from CH; or,
    Q1、Q2、Q3或Q4中一个选自N；或者，One of Q 1 , Q 2 , Q 3 or Q 4 is selected from N; or,
    Q2、Q4中均选自N，Q1选自CH或CR1，Q3选自CH或CR3；或者，Q 2 and Q 4 are both selected from N, Q 1 is selected from CH or CR 1 , and Q 3 is selected from CH or CR 3 ; or,
    Q1选自N或CH。 Q1 is selected from N or CH.
  5. 根据权利要求1-4任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，选自 其中*表示与N连接，其中，R1、R2、R3如权1-4任一项所定义；或者，The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Selected from Wherein * represents connection with N, wherein R 1 , R 2 , and R 3 are as defined in any one of claims 1 to 4; or,
    选自 其中*表示与N连接，其中，R1、R2、R3如权1-4任一项所定义；或者， Selected from Wherein * represents connection with N, wherein R 1 , R 2 , and R 3 are as defined in any one of claims 1 to 4; or,
    选自 其中*表示与N连接，其中，R1、R2、R3如权1-4任一项所定义；或者， Selected from Wherein * represents connection with N, wherein R 1 , R 2 , and R 3 are as defined in any one of claims 1 to 4; or,
    选自其中*表示与N连接，其中，R2如权1-4任一项所定义。 Selected from Wherein * represents connection with N, wherein R2 is as defined in any one of claims 1-4.
  6. 根据权利要求1-5任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，R1选自卤素、氰基、羟基、C1-C6烷氧基或-Y-NR1AR1AA；或者，R1选自卤素或-Y-NR1AR1AA；或者，R1选自卤素或-NR1AR1AA。The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 1 is selected from halogen, cyano, hydroxyl, C 1 -C 6 alkoxy or -Y-NR 1A R 1AA ; or, R 1 is selected from halogen or -Y-NR 1A R 1AA ; or, R 1 is selected from halogen or -NR 1A R 1AA .
  7. 根据权利要求1-6任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，Y选自键，R1A、R1AA各自独立地选自氢、C1-C6烷基、-S(O)2-R1A’或-C(O)OC1-C6烷基，所述C1-C6烷基或-C(O)OC1-C6烷基任选被R1B取代；或者，Y选自键，R1A、R1AA各自独立地选自氢或-S(O)2-R1A’；或者，Y选自键，R1A为氢，R1AA为-S(O)2-R1A’。The compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 6, wherein Y is selected from a bond, R 1A , R 1AA are each independently selected from hydrogen, C 1 -C 6 alkyl, -S(O) 2 -R 1A 'or -C(O)OC 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl or -C(O)OC 1 -C 6 alkyl is optionally substituted by R 1B ; or, Y is selected from a bond, R 1A , R 1AA are each independently selected from hydrogen or -S(O) 2 -R 1A '; or, Y is selected from a bond, R 1A is hydrogen, and R 1AA is -S(O) 2 -R 1A '.
  8. 根据权利要求1-7任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，R2选自卤素、氰基、羟基、-S(O)2(C1-C6烷基)、C1-C10烷基、C1-C10烷氧基、3-12元杂环烷基、-T-NR2AR2AA、B(OH)2或-L-5-10元杂芳基，所述-S(O)2(C1-C6烷基)、C1-C10烷基、C1-C10烷氧基、3-12元杂环烷基或5-10元杂芳基任选被R2a取代；或者，The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 2 is selected from halogen, cyano, hydroxyl, -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocycloalkyl, -T-NR 2A R 2AA , B(OH) 2 or -L-5-10 membered heteroaryl, wherein -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted by R 2a ; or,
    R2选自卤素、氰基、羟基、-S(O)2(C1-C6烷基)、C1-C8烷基、C1-C8烷氧基、3-12元杂环基、-T-NR2AR2AA、B(OH)2或-L-5-10元杂芳基，所述C1-C8烷基、C1-C8烷氧基、-S(O)2(C1-C6烷基)、3-12元杂环基或5-10元杂芳基任选被R2a取代；或者R 2 is selected from halogen, cyano, hydroxy, -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 8 alkyl, C 1 -C 8 alkoxy, 3-12 membered heterocyclyl, -T-NR 2A R 2AA , B(OH) 2 or -L-5-10 membered heteroaryl, wherein the C 1 -C 8 alkyl, C 1 -C 8 alkoxy, -S(O) 2 (C 1 -C 6 alkyl), 3-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted with R 2a ; or
    R2选自卤素、氰基、羟基、-S(O)2(C1-C6烷基)、C1-C10烷基、C1-C10烷氧基、3-12元杂环基、5-10元杂芳基或-NR2AR2AA，所述-S(O)2(C1-C6烷基)、C1-C10烷基、C1-C10烷氧基、3-12元杂环基或5-10元杂芳基任选被R2a取代；或者，R 2 is selected from halogen, cyano, hydroxyl, -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocyclyl, 5-10 membered heteroaryl or -NR 2A R 2AA , wherein -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 10 alkyl, C 1 -C 10 alkoxy, 3-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by R 2a ; or,
    R2选自Br、Cl、F、氰基、羟基、甲氧基、甲基、吗啉基、哌嗪基、吡唑基、噻吩基、二氢吡喃基、哌啶基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基或-NR2AR2AA，所述甲基、吗啉基、哌嗪基、吡唑基、噻吩基、二氢吡喃基、哌啶基、氮杂环丁烷基、氧杂环丁烷基或吡咯烷基任选被R2a取代。 R2 is selected from Br, Cl, F, cyano, hydroxyl, methoxy, methyl, morpholinyl, piperazinyl, pyrazolyl, thienyl, dihydropyranyl, piperidinyl, azetidinyl, Oxetane, pyrrolidinyl or -NR 2A R 2AA , the methyl, morpholinyl, piperazinyl, pyrazolyl, thienyl, dihydropyranyl, piperidinyl, azetidinyl, The oxetanyl or pyrrolidinyl group is optionally substituted by R 2a .
  9. 根据权利要求1-8任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，T选自键和/或L选自键。A compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein T is selected from a bond and/or L is selected from a bond.
  10. 根据权利要求1-9任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体， 其中，R2a选自卤素、C1-C6烷基、-S(O)2-R2a’或-C(O)C1-C6烷基，所述C1-C6烷基或-C(O)C1-C6烷基任选被R2b取代；或者，R2a选自C1-C6烷基、-S(O)2-R2a’或-C(O)C1-C6烷基，所述C1-C6烷基或-C(O)C1-C6烷基任选被R2b取代；或者，R2a选自F、甲基、乙基、丙基、-S(O)2-R2a’或-C(O)CH3，所述甲基、乙基或丙基任选被R2b取代；或者，R2a选自甲基、乙基、-S(O)2-R2a’或-C(O)CH3，所述乙基任选被R2b取代。A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 2a is selected from halogen, C 1 -C 6 alkyl, -S(O) 2 -R 2a 'or -C(O)C 1 -C 6 alkyl, said C 1 -C 6 alkyl or -C(O)C 1 -C 6 alkyl is optionally substituted by R 2b ; or, R 2a is selected from C 1 -C 6 alkyl, -S(O) 2 -R 2a 'or -C(O)C 1 -C 6 alkyl, said C 1 -C 6 alkyl or -C(O)C 1 -C 6 alkyl is optionally substituted by R 2b ; or, R 2a is selected from F, methyl, ethyl, propyl, -S(O) 2 -R 2a 'or -C(O)CH 3 , said methyl, ethyl or propyl is optionally substituted by R 2b ; or, R 2a is selected from methyl, ethyl, -S(O) 2 -R 2a 'or -C(O)CH 3 , the ethyl group is optionally substituted by R 2b .
  11. 根据权利要求1-10任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，R2b选自羟基、氰基、C1-C6烷氧基或4-12元杂环基，所述C1-C6烷氧基或4-12元杂环基任选被R1c取代；或者，R2b选自羟基、氰基、C1-C3烷氧基或6元杂环基，所述C1-C6烷氧基或4-12元杂环基任选被R1c取代。The compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 10, wherein R 2b is selected from hydroxyl, cyano, C 1 -C 6 alkoxy or 4-12 membered heterocyclyl, and the C 1 -C 6 alkoxy or 4-12 membered heterocyclyl is optionally substituted by R 1c ; or, R 2b is selected from hydroxyl, cyano, C 1 -C 3 alkoxy or 6 membered heterocyclyl, and the C 1 -C 6 alkoxy or 4-12 membered heterocyclyl is optionally substituted by R 1c .
  12. 根据权利要求1-11任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，R2A、R2AA各自独立地选自氢、C1-C6烷基、-C(O)H、-S(O)2-R2A’或-C(O)OC1-C6烷基，所述C1-C6烷基或-C(O)OC1-C6烷基任选被R2B取代；或者，The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 2A , R 2AA are each independently selected from hydrogen, C 1 -C 6 alkyl, -C(O)H, -S(O) 2 -R 2A 'or -C(O)OC 1 -C 6 alkyl, and the C 1 -C 6 alkyl or -C(O)OC 1 -C 6 alkyl is optionally substituted by R 2B ; or,
    R2A选自氢或C1-C6烷基，R2AA选自C1-C6烷基、-C(O)H、-S(O)2-R2A’或-C(O)OC1-C6烷基，所述C1-C6烷基或-C(O)OC1-C6烷基任选被R2B取代；或者，R 2A is selected from hydrogen or C 1 -C 6 alkyl, R 2AA is selected from C 1 -C 6 alkyl, -C(O)H, -S(O) 2 -R 2A 'or -C(O)OC 1 -C 6 alkyl, said C 1 -C 6 alkyl or -C(O)OC 1 -C 6 alkyl is optionally substituted by R 2B ; or,
    R2A、R2AA各自独立地选自氢、甲基、-C(O)H、乙基、所述甲基或乙基任选被R2B取代；或者，R 2A , R 2AA are each independently selected from hydrogen, methyl, -C(O)H, ethyl, The methyl or ethyl group is optionally substituted by R 2B ; or,
    R2A选自氢或甲基，R2AA选自甲基、-C(O)H、乙基、所述甲基或乙基任选被R2B取代；或者，R 2A is selected from hydrogen or methyl, R 2AA is selected from methyl, -C(O)H, ethyl, The methyl or ethyl group is optionally substituted by R 2B ; or,
    R2A、R2AA各自独立地选自氢、甲基、-C(O)H、乙基、所述乙基任选被R2B取代。R 2A , R 2AA are each independently selected from hydrogen, methyl, -C(O)H, ethyl, The ethyl group is optionally substituted with R 2B .
  13. 根据权利要求1-12任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，R2A’选自C1-C4烷基或C3-C6环烷基；或者，R2A’选自环丙基或正丙基。The compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 12, wherein R 2A ' is selected from C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl; or, R 2A ' is selected from cyclopropyl or n-propyl.
  14. 根据权利要求1-13任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，R2B选自卤素、羟基、氰基、氨基、SH、C1-C6烷氧基或4-10元杂环烷基，所述4-10元杂环烷基任选被R2C取代；或者，R2B选自C1-C3烷氧基、4-6元杂环烷基或-S(O)2(C1-C3烷基)，所述4-6元杂环烷基任选被R2C取代；或者，R2B选自C1-C3烷氧基或4-10元杂环烷基。The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 2B is selected from halogen, hydroxyl, cyano, amino, SH, C 1 -C 6 alkoxy or 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted by R 2C ; or, R 2B is selected from C 1 -C 3 alkoxy, 4-6 membered heterocycloalkyl or -S(O) 2 (C 1 -C 3 alkyl), wherein the 4-6 membered heterocycloalkyl is optionally substituted by R 2C ; or, R 2B is selected from C 1 -C 3 alkoxy or 4-10 membered heterocycloalkyl.
  15. 根据权利要求1-14任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，R2选自Br、Cl、F、CN、OH、甲氧基、CF3、 或者，The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 2 is selected from Br, Cl, F, CN, OH, methoxy, CF 3 , or,
    R2选自Br、Cl、F、CN、OH、甲氧基、CF3、 或者，R 2 is selected from Br, Cl, F, CN, OH, methoxy, CF 3 , or,
    R2选自Br、Cl、F、CN、OH、甲氧基、 R2 is selected from Br, Cl, F, CN, OH, methoxy,
  16. 根据权利要求1-15任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体， 其中，R3选自卤素、C1-C8烷基、C1-C8烷氧基、3-12元杂环烷基或-U-5-10元杂芳基，所述C1-C8烷基、C1-C8烷氧基、3-12元杂环烷基、5-10元杂芳基任选被R3a取代；或者，R3选自卤素、3-12元杂环烷基或-U-5-10元杂芳基，所述3-12元杂环烷基、5-10元杂芳基任选被R3a取代；或者，R3选自卤素、C1-C6烷基或C1-C6烷基，所述C1-C6烷基或C1-C6烷基任选被R3a取代；或者，R3选自卤素或C1-C3烷基；或者，R3选自卤素；或者，R3选自Cl、F或甲氧基；或者，R3选自Cl。A compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 3 is selected from halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, 3-12-membered heterocycloalkyl or -U-5-10-membered heteroaryl, wherein the C 1 -C 8 alkyl, C 1 -C 8 alkoxy, 3-12-membered heterocycloalkyl, 5-10-membered heteroaryl is optionally substituted by R 3a ; or, R 3 is selected from halogen, 3-12-membered heterocycloalkyl or -U-5-10-membered heteroaryl, wherein the 3-12-membered heterocycloalkyl, 5-10-membered heteroaryl is optionally substituted by R 3a ; or, R 3 is selected from halogen, C 1 -C 6 alkyl or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl or C 1 -C 6 alkyl is optionally substituted by R 3a ; or, R 3 is selected from halogen or C 1 -C 3 alkyl; or, R 3 is selected from halogen; or, R 3 is selected from Cl, F or methoxy; or, R 3 is selected from Cl.
  17. 根据权利要求1-16任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，X选自CR4；或者，X选自CH。The compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 16, wherein X is selected from CR 4 ; or X is selected from CH.
  18. 根据权利要求1-17任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，R4、R5、R6、R7和R8各自独立地选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷氧基或C1-C6卤代烷基。The compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl.
  19. 根据权利要求1-18任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，R9选自H、卤素、OH、氘或C1-C6烷基；或者，R9选自H、卤素、OH、氘或C1-C3烷基；或者，R9选自氢、氘、OH或甲基。The compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 9 is selected from H, halogen, OH, deuterium or C 1 -C 6 alkyl; or, R 9 is selected from H, halogen, OH, deuterium or C 1 -C 3 alkyl; or, R 9 is selected from hydrogen, deuterium, OH or methyl.
  20. 根据权利要求1-19任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，R10选自甲基或CD3；或者，当选自且X是N时，R10是甲基。The compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 10 is selected from methyl or CD 3 ; or Selected from When X is N, R 10 is methyl.
  21. 根据权利要求1-20任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，M选自CR11。The compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 20, wherein M is selected from CR 11 .
  22. 根据权利要求1-21任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，R11、R12、R13和R14各自独立地选自氢、卤素、氰基、C1-C6烷基、C2-C6烯基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C3-C8环烷基或NR11AR11AA；或者，The compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl or NR 11A R 11AA ; or,
    R11、R12、R13和R14各自独立地选自氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基或-P(O)(C1-C6烷基)2；或者R13和R14以及它们所连接的碳原子一起形成5-10元杂芳环；或者，R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy or -P(O)(C 1 -C 6 alkyl) 2 ; or R 13 and R 14 and the carbon atoms to which they are attached together form a 5-10 membered heteroaromatic ring; or,
    R11、R12、R13和R14各自独立地选自氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基或C1-C6卤代烷氧基。R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy.
  23. 根据权利要求1-22任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，式(I)化合物或其药学上可接受的盐或其立体异构体选自式(III)化合物或其药学上可接受的盐或其立体异构体：
    The compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1 to 22, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the compound of formula (III) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:
    其中，Q1、Q2、Q3、Q4、X、R5、R6、R7、R8、R9、R10、M、R12、R13、R14、R15如权利要求1-22任一项所定义。wherein Q 1 , Q 2 , Q 3 , Q 4 , X, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , M, R 12 , R 13 , R 14 and R 15 are as defined in any one of claims 1 to 22.
  24. 根据权利要求1-22任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，式(I)化合物或其药学上可接受的盐或其立体异构体选自式(IV)化合物或其药学上可接受的盐或其立体异构体：
    The compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1 to 22, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the compound of formula (IV) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:
    其中，Q1、Q2、Q3、Q4、X、R5、R6、R7、R8、R9、R10、M、R12、R13、R14如权利要求1-22任一项所定义。wherein Q 1 , Q 2 , Q 3 , Q 4 , X, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , M, R 12 , R 13 and R 14 are as defined in any one of claims 1 to 22.
  25. 根据权利要求1-22任一项所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，本公开的式(I)化合物或其药学上可接受的盐或其立体异构体选自式(II)化合物或其药学上可接受的盐或其立体异构体：
    The compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1 to 22, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof of the present disclosure is selected from the compound of formula (II) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:
    其中，Q1、Q2、Q3、Q4、X、R5、R6、R7、R8、R9、R10、M、R12、R13、R14如权利要求1-22任一项所述的式(I)化合物所定义。wherein Q 1 , Q 2 , Q 3 , Q 4 , X, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , M, R 12 , R 13 and R 14 are as defined in the compound of formula (I) according to any one of claims 1 to 22.
  26. 根据权利要求1所述的式(I)化合物或其药学上可接受的盐或其立体异构体，其中，本 公开的式(I)化合物或其药学上可接受的盐或其立体异构体选自以下化合物或其药学上可接受的盐或其立体异构体：







    The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein The disclosed compound of formula (I) or its pharmaceutically acceptable salt or its stereoisomer is selected from the following compounds or its pharmaceutically acceptable salt or its stereoisomer:







  27. 一种药物组合物，所述组合物包含权利要求1至26任一项所述的化合物或其药学上可接受的盐或其立体异构体和药学上可接受的辅料。A pharmaceutical composition comprising the compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt or a stereoisomer thereof and a pharmaceutically acceptable excipient.
  28. 权利要求1至26任一项所述的化合物或其药学上可接受的盐或其立体异构体、或权利要求27所述药物组合物在制备预防或者治疗DNA聚合酶θ介导的疾病的药物中的用途。 Use of the compound according to any one of claims 1 to 26 or its pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition according to claim 27 in the preparation of a medicament for preventing or treating a disease mediated by DNA polymerase θ.
PCT/CN2024/072841 2023-01-18 2024-01-17 Nitrogen-containing fused ring compound and use thereof WO2024153143A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013107405A1 (en) * 2012-01-19 2013-07-25 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
WO2021028643A1 (en) * 2019-08-09 2021-02-18 Artios Pharma Limited Heterocyclic compounds for use in the treatment of cancer
WO2021123785A1 (en) * 2019-12-17 2021-06-24 Artios Pharma Limited Dna polymerase theta inhibitors
WO2022026565A1 (en) * 2020-07-29 2022-02-03 Ideaya Biosciences, Inc. Cyclized acetamido derivatives as dna polymerase theta inhibitors
WO2023241322A1 (en) * 2022-06-16 2023-12-21 Danatlas Pharmaceuticals Co., Ltd. Heterocyclic derivatives, compositions and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013107405A1 (en) * 2012-01-19 2013-07-25 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
WO2021028643A1 (en) * 2019-08-09 2021-02-18 Artios Pharma Limited Heterocyclic compounds for use in the treatment of cancer
WO2021123785A1 (en) * 2019-12-17 2021-06-24 Artios Pharma Limited Dna polymerase theta inhibitors
WO2022026565A1 (en) * 2020-07-29 2022-02-03 Ideaya Biosciences, Inc. Cyclized acetamido derivatives as dna polymerase theta inhibitors
WO2023241322A1 (en) * 2022-06-16 2023-12-21 Danatlas Pharmaceuticals Co., Ltd. Heterocyclic derivatives, compositions and uses thereof

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