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WO2022222911A1 - Pyrimidone compound and use thereof - Google Patents

Pyrimidone compound and use thereof Download PDF

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Publication number
WO2022222911A1
WO2022222911A1 PCT/CN2022/087589 CN2022087589W WO2022222911A1 WO 2022222911 A1 WO2022222911 A1 WO 2022222911A1 CN 2022087589 W CN2022087589 W CN 2022087589W WO 2022222911 A1 WO2022222911 A1 WO 2022222911A1
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substituted
alkyl
alkoxy
halogen
cycloalkyl
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PCT/CN2022/087589
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French (fr)
Chinese (zh)
Inventor
张学军
臧杨
李群
常少华
朱圣姬
李莉娥
杨俊�
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武汉人福创新药物研发中心有限公司
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Publication of WO2022222911A1 publication Critical patent/WO2022222911A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the fields of chemistry and medicine, in particular, the present invention relates to pyrimidone compounds and uses thereof.
  • Methionine adenosyltransferase 2A (MAT2A), a member of the MAT family of proteins, is widely distributed in the body and is expressed in non-parenchymal cells of the liver and all extrahepatic tissues (Murray B, et al. World J Gastroenterol 2019;25(31):4300-4319.), the MAT family also has two members, MAT1A and MAT2B.
  • MAT2A inhibitors can reduce S-adenosylmethionine (SAM) levels, so MAT2A inhibitors are also called SAM inhibitors.
  • SAM is the main methyl donor in cells.
  • Protein arginine methyltransferase 5 (PRMT5) is a methylase that utilizes the methyl donor of SAM. SAM plays an important role in the PRMT5 pathway and can affect the activity of PRMT5. Studies have shown that MAT2A is a "synthetic lethal" target in MTAP-deficient tumors.
  • MTA a substrate of the MTAP enzymatic reaction, accumulates abundantly in MTAP-deficient cancers
  • MTA Is a potent and selective inhibitor of PRMT5 resulting in reduced PRMT5 methylation activity in MTAP-deficient cells
  • MAT2A produces PRMT5 substrate SAM
  • MAT2A deletion selectively reduces the growth and PRMT5 methylation activity of MTAP-deficient cells
  • MAT2A is selectively required in MTAP-deficient cancers (Marjon K, et al. Cell Rep. 2016;15(3):574-587).
  • MAT2A inhibitors offer a new treatment option for patients with MTAP-deficient tumors.
  • MAT2A is involved in the metabolism of cancer stem cells, and cancer stem cells require a large amount of methionine to maintain their own histone methylation, which is crucial for the growth and tumorigenicity of cancer stem cells. Inhibition of MAT2A, a key enzyme in the methionine cycle, can significantly inhibit the growth of cancer stem cells and tumor formation. And in human non-small cell lung cancer tissues, MAT2A protein is abnormally high expressed. When tumor stem cells from non-small cell lung cancer were transplanted into mice, MAT2A inhibitor almost completely suppressed tumor growth, while the chemotherapeutic drug cisplatin had little effect (Wang Z, et al. Nature medicine, 2019, 25(5): 1-13.).
  • MAT1A Conversion of MAT1A and MAT2A in liver cancer. Many studies have shown that MAT plays an important role in the occurrence of chronic liver disease and liver cancer. Under normal circumstances, MAT2A is mainly expressed in the fetal liver, and is gradually replaced by MAT1A with growth and development after birth. MAT1A maintains the differentiation state of hepatocytes. There is a dynamic balance between MAT1A and MAT2A in normal hepatocytes, which together maintain the homeostasis of intracellular SAM.
  • MAT1A:MAT2A transition In hepatocellular carcinoma, down-regulation of MAT1A expression levels and up-regulation of MAT2A occur, termed MAT1A:MAT2A transition, which dedifferentiates the liver, reduces SAM biosynthesis, and enhances proliferative signaling in the liver.
  • MAT1A:MAT2A transition In human hepatocellular carcinoma, the expression ratio of MAT1A:MAT2A is negatively correlated with cell growth and genomic instability, and directly correlated with hepatoma cell apoptosis and overall DNA methylation; a reduced ratio is associated with a higher degree of malignancy and a lower survival rate in HCC. prognostic markers.
  • chr9p21 chromosome 9p21
  • the chromosomal chr9p21 locus includes the CDKN2A gene, which encodes the key tumor suppressors p19-ARF and p16-INK4a, and Chr9p21 deletion frequently involves co-deletion of genes proximal to CDKN2A, the most important of which is methylthioadenosine phosphorylase (MTAP) Gene.
  • MTAP methylthioadenosine phosphorylase
  • MTAP deficiency is not only present in tissue culture cells, but also in primary leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, In head and neck cancer, mucinous chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, and mesothelioma.
  • NSC non-small cell lung cancer
  • the present invention aims to provide a compound that can effectively inhibit MAT2A, which can be used as an improvement or replacement of current drugs or MAT2A inhibitors.
  • the present invention proposes a compound shown in formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug :
  • R is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkoxy, cyano, amino, alkane amino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxy Oxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkoxy, heteroarylamino, heterocycloalkyl, heterocyclyloxy , heterocyclylamino, heterocyclylalkoxy, heterocyclyloxyalkoxy, heterocyclyloxyalkoxy, and heterocyclyloxyalkylamino, R is
  • R 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino , alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxy Alkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyl Oxyalkoxy , R is unsubstituted by itself or as part of another group or is substituted by Ra , Rb and/ or Rc independently selected from the group consisting of al
  • R4 and R6 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl;
  • R 1 is selected from cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl or spiroheterocyclyl, wherein aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with Rd , Re and/or Rf ;
  • R 2 is -NR 7 R 8 , where:
  • R is selected from hydrogen, alkyl, deuterated alkyl and cycloalkyl
  • R 8 is selected from hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl, thioureidoalkyl, alkane Sulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl , substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylcycloalkyl, fused cycloalkyl, spirocycloalkyl , spirocycloalkylalkyl, aryl,
  • R 7 , R 8 together with the N atom to which they are commonly attached form a 4-6 membered heterocycloalkyl which is unsubstituted or substituted with R j , R k and/or RL ;
  • R 7 , R 8 together with the N atom to which they are connected together form a 6-12-membered spiro heterocyclyl, a 6-12-membered bridged heterocyclyl, a 6-12-membered heterocycloalkyl, and the 6-12 membered heterocyclyl Member spiroheterocyclyl, 6-12 membered bridged heterocyclyl and 6-12 membered heterocycloalkyl are unsubstituted or substituted by R j , R k and/or RL , the 6-12 1-5 ring atoms of membered spiroheterocyclyl, 6-12 membered bridged heterocyclyl and 6-12 membered heterocycloalkyl are independently selected from N, O and S;
  • R d , Re , R j and R k are each independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxy Alkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocycle carbonyl and urea groups;
  • Rf and RL are each independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino, alkylamino, cycloalkylsulfonylamino, cyano, cyano Alkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl and -Xc-R9, wherein Xc is selected from bond, alkylene and heteroalkylene, and R9 is selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.
  • the present invention proposes a compound, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I Acceptable salts or prodrugs:
  • Y is -C(R 5 );
  • R is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkoxy, cyano, amino, alkane amino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxy Oxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkoxy, heteroarylamino, heterocycloalkyl, heterocyclyloxy , heterocyclylamino, heterocyclylalkoxy, heterocyclyloxyalkoxy, heterocyclyloxyalkoxy, and heterocyclyloxyalkylamino, R is
  • R 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino , alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxy Alkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyl Oxyalkoxy , R is unsubstituted by itself or as part of another group or is substituted by Ra , Rb and/ or Rc independently selected from the group consisting of al
  • R4 and R6 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl;
  • R 1 is selected from cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl or spiroheterocyclyl, wherein aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with Rd , Re and/or Rf ;
  • R 2 is -NR 7 R 8 , where:
  • R is selected from hydrogen, alkyl, deuterated alkyl or cycloalkyl
  • R 8 is selected from hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl, thioureidoalkyl, alkane Sulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl , substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylcycloalkyl, fused cycloalkyl, spirocycloalkyl , spirocycloalkylalkyl, aryl,
  • R 7 , R 8 together with the N atom to which they are commonly attached form a 4-6 membered heterocycloalkyl which is unsubstituted or substituted with R j , R k and/or RL ;
  • R d , Re , R j and R k are each independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxy Alkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocycle carbonyl and urea groups;
  • Rf and RL are each independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino, alkylamino, cycloalkylsulfonylamino, cyano, cyano Alkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl and -Xc-R9, wherein Xc is selected from bond, alkylene and heteroalkylene, and R9 is selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.
  • the alkyl group includes straight chain alkyl group and branched chain alkyl group.
  • R 2 is -NR 7 R 8 , and R 7 and R 8 are not both hydrogen, that is, R 2 is not -NH 2 .
  • R 2 is -NR 7 R 8 , when R 7 and R 8 together with the N atom to which they are connected together form a 6-12-membered spiro heterocyclyl, 6 -12-membered bridged heterocyclyl, 6-12-membered heterocycloalkyl, the R 2 is: wherein Ring A is a 4-6 membered heterocycloalkyl, and R A1 , R A2 and some ring atoms of Ring A are connected to form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, and the 3-7 membered 1-3 ring atoms of heterocycloalkyl are independently selected from N, O and S, and said R 2 is unsubstituted or substituted by R j , R k and/or RL ; undefined groups are as predecessors described in a plan.
  • R 2 is selected from the following groups unsubstituted or substituted by R j , R k and/or RL : wherein R A1 , R A2 and some ring atoms of ring A are connected to form a 3-7-membered cycloalkyl or a 3-7-membered heterocycloalkyl, and 1-3 ring atoms of the 3-7-membered heterocycloalkyl are independent Selected from N, O and S; undefined groups are as described in any of the previous schemes
  • R 2 is selected from the following groups unsubstituted or substituted by R j , R k and/or RL : Undefined groups are as described in any of the previous schemes.
  • R 3 is selected from hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylsulfonyl, halogen, C 1 -C 10 alkyl substituted with 1-5 identical or different halogens, C substituted with 1-5 identical or different halogens 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, cyano, amino, (C 1 -C 10 alkyl)-NH-, N(C 1 -C 10 alkyl) 2 -, aminocarbonyl , (C 1 -C 10 alkyl)-NH-C(O)-, N(C 1 -C 10 alkyl) 2 -C(O)-, C 1 -C 10 substituted by 1-5 hydroxyl groups Alkyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2
  • R 5 is selected from hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylsulfonyl, halogen , C 1 -C 10 alkyl substituted by 1-5 identical or different halogens, C 1 -C 10 alkoxy substituted by 1-5 identical or different halogens, C 3 -C 10 cycloalkyl , cyano, amino, (C 1 -C 10 alkyl)-NH-, N(C 1 -C 10 alkyl) 2 -, (C 1 -C 10 alkoxy)-C(O)-, amino Carbonyl, (C 1 -C 10 alkyl)-aminocarbonyl, (C 1 -C 10 alkyl) 2 -aminocarbonyl, C 1 -C 10 alkyl substituted by 1-5 hydroxy, substituted by 1-5 Hydroxy-
  • R 4 and R 6 are each independently selected from hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 1 -C 10 Alkylthio, C 1 -C 10 alkylsulfonyl, halogen, C 1 -C 10 alkyl substituted with 1-5 identical or different halogens, C 1 substituted with 1-5 identical or different halogens -C 10 alkoxy, C 3 -C 10 cycloalkyl, cyano, amino, (C 1 -C 10 alkyl)-NH-, N(C 1 -C 10 alkyl) 2 -, aminocarbonyl, (C 1 -C 10 alkyl)-aminocarbonyl, (C 1 -C 10 alkyl) 2 -aminocarbonyl;
  • R 1 is selected from C 6 -C 10 aryl, 5-10-membered heteroaryl, 3-10-membered heterocyclyl, 5-10-membered bridged heterocyclyl, 5-10-membered fused heterocyclyl or 5- 10-membered spiro heterocyclyl, wherein C 6 -C 10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl is unsubstituted or substituted by R d , Re and/or R f ;
  • R 2 is -NR 7 R 8 , where:
  • R 7 is selected from hydrogen, C 1 -C 10 alkyl, deuterated C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl;
  • R 8 is selected from hydrogen, C 1 -C 10 alkyl, deuterated C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted with 1-5 identical or different halogens, 1-5 hydroxyl groups Substituted C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted by 1-5 identical or different C 1 -C 10 alkoxy, (substituted by 1-5 identical or different halogen C 1 -C 10 alkoxy)-(C 1 -C 10 alkylene)-, C 1 -C 10 alkyl substituted with 1-5 amino groups, C 1 substituted with 1-5 aminosulfonyl groups -C 10 alkyl, C 1 -C 10 alkyl substituted with 1-5 thiourea groups, C 1 -C 10 alkylsulfonyl, (C 1 -C 10 alkylsulfonyl)-(C 1 - C 10 alkylene)-, C 1 -C 10 al
  • R 7 , R 8 together with the N atom to which they are commonly attached form a 4-6 membered heterocycloalkyl group which is unsubstituted or is replaced by R j , R k and/or R L replaced;
  • R d , R e , R j and R k are each independently selected from C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted with 1-5 identical or different halogens, identical with 1-5 or different halogen substituted C 1 -C 10 alkoxy, C 1 -C 10 alkoxy, hydroxyl, C 1 -C 10 alkylsulfonyl, halogen, cyano, carboxyl, (C 1 -C 10 alkane oxy)-C(O)-, C 1 -C 10 alkyl substituted with 1-5 hydroxyl groups, C 1 -C 10 substituted with 1-5 identical or different C 1 -C 10 alkoxy groups Alkyl, C 1 -C 10 alkyl substituted with 1-5 amino groups, aminosulfonyl, (C 1 -C 10 alkyl)-NH-S(O) 2 -, N(C 1 -C 10 alkane base) 2 -S(O) 2 -
  • R f and RL are each independently selected from C 1 -C 10 alkyl, C 5 -C 10 cycloalkyl, C 1 -C 10 alkyl substituted with 1-5 identical or different halogens, C 1 -C 10 alkyl substituted with 1- 5 identical or different halogen-substituted C 1 -C 10 alkoxy, C 1 -C 10 alkoxy, hydroxy, halogen, amino, (C 1 -C 10 alkyl)-NH-, (C 3 - C 10 cycloalkyl)-S(O) 2 -NH-, cyano, C 1 -C 10 alkyl substituted with 1-5 cyano groups, C 1 -C 10 with 1-5 identical or different C 1 -C 10 alkyl substituted by alkoxycarbonyl, C 1 -C 10 alkyl substituted by carboxyl, C 1 -C 10 alkyl substituted by aminocarbonyl, -X c -R 9 , wherein X
  • R 3 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 alkoxy substituted by 1-5 identical or different halogens, cyano , amino, (C 1 -C 6 alkyl)-NH-, N(C 1 -C 6 alkyl) 2 -, C 1 -C 6 alkyl substituted by 1-3 hydroxyl groups, 1-3 Amino-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy substituted with 1-3 amino groups, (C 1 -C 6 alkyl substituted with 1-3 amino groups)-NH-, R 3 by itself or as part of another group is unsubstituted or substituted with Ra
  • R 5 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfonyl, halogen , C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 alkoxy substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl , cyano, amino, (C 1 -C 6 alkyl)-NH-, N(C 1 -C 6 alkyl) 2 -, (C 1 -C 6 alkoxy)-C(O)-, amino Carbonyl, (C 1 -C 6 alkyl)-aminocarbonyl, (C 1 -C 6 alkyl) 2 -aminocarbonyl, C 1 -C 6 alkyl substituted by 1-3 hydroxy, substituted by 1-3 Hydroxy-
  • R 4 and R 6 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 alkylsulfonyl, halogen, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 substituted with 1-5 identical or different halogens -C 6 alkoxy, C 3 -C 6 cycloalkyl, cyano, amino, (C 1 -C 6 alkyl)-NH-, N(C 1 -C 6 alkyl) 2 -, aminocarbonyl, (C 1 -C 6 alkyl)-aminocarbonyl, (C 1 -C 6 alkyl) 2 -aminocarbonyl;
  • R 1 is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, wherein C 6 -C 10 aryl, or 5-10 membered heteroaryl is unsubstituted or replaced by R d , Re and/or R f replace;
  • R 2 is -NR 7 R 8 , where:
  • R 7 is selected from hydrogen, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
  • R 8 is selected from hydrogen, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, 1-5 hydroxyl groups Substituted C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by 1-3 identical or different C 1 -C 6 alkoxy, (substituted by 1-5 identical or different halogen C 1 -C 6 alkoxy)-(C 1 -C 6 alkylene)-, C 1 -C 6 alkyl substituted with 1-3 amino groups, C 1 substituted with 1-3 aminosulfonyl groups -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-3 thioureido groups, C 1 -C 6 alkylsulfonyl, (C 1 -C 6 alkylsulfonyl)-(C 1 - C 6 alkylene)-, C 1 -C
  • R 7 , R 8 together with the N atom to which they are commonly attached form a 4-6 membered heterocycloalkyl group which is unsubstituted or is replaced by R j , R k and/or R L replaced;
  • R d , Re , R j and R k are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, identical with 1-5 halogens or different halogen substituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, hydroxyl, C 1 -C 6 alkylsulfonyl, halogen, cyano, carboxyl, (C 1 -C 6 alkane oxy)-C(O)-, C 1 -C 6 alkyl substituted with 1-3 hydroxy, C 1 -C 6 substituted with 1-3 identical or different C 1 -C 6 alkoxy Alkyl, C 1 -C 6 alkyl substituted with 1-3 amino groups, aminosulfonyl, (C 1 -C 6 alkyl)-NH-S(O) 2 -, N(C 1 -C 6 alkane base) 2 -S(O) 2 -,
  • R f and RL are each independently selected from C 1 -C 6 alkyl, C 5 -C 10 cycloalkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 alkyl substituted with 1- 5 identical or different halogen-substituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, hydroxy, halogen, amino, (C 1 -C 6 alkyl)-NH-, (C 3 - C 8 cycloalkyl)-S(O) 2 -NH-, cyano, C 1 -C 6 alkyl substituted with 1-3 cyano groups, C 1 -C 6 substituted with 1-3 identical or different C 1 -C 6 groups C 1 -C 6 alkyl substituted by alkoxycarbonyl, C 1 -C 6 alkyl substituted by carboxyl, C 1 -C 6 alkyl substituted by aminocarbonyl, -X c -
  • at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen.
  • R 4 is selected from hydrogen, C 1 -C 6 alkyl, halogen, the same by 1-5 or different halogen substituted C 1 -C 6 alkyl, cyano.
  • R 5 is selected from hydrogen, C 1 -C 6 alkyl, halogen, the same by 1-5 or different halogen-substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, cyano, amino, R 5 is unsubstituted or substituted by R a , R b and/or R c , the R a , R b and/or R c are independently selected from C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens, C 1 -C 3 alkyl
  • R 6 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy , C 1 -C 6 alkylthio, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, cyano.
  • R 1 is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, Pyrazole ring, imidazole ring, and R 1 is unsubstituted or substituted by R d , Re and/or R f , said R d , Re and R f are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 alkoxy substituted with 1-5 identical or different halogens, C
  • R 3 , R 4 , R 5 and R 6 when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, R 2 is -NR 7 R 8 , and R 7 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, said R 8 is selected from hydrogen, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C substituted with 1-5 identical or different halogens 6 alkyl, C 1 -C 6 alkyl substituted by 1-5 hydroxyl groups, C 1 -C 6 alkyl substituted by 1-3 identical or different C 1 -C 6 alkoxy groups, (by 1 -5 identical or different halogen-substituted C 1 -
  • R 2 is -NR 7 R 8 together with the N atom to which they are commonly attached Forms a 4-6 membered heterocycloalkyl group that is unsubstituted or substituted with R j , R k and/or RL , each independently Selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl.
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl base, propyl, isopropyl, cyclopropyl, methyl substituted with 1-3 halogens, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, substituted with 1-3 halogens Isopropyl substituted by one halogen, cyclopropyl substituted by 1-3 halogens; the halogen is selected from fluorine, chlorine, bromine and iodine, preferably,
  • R 1 is selected from a benzene ring substituted by R d , a pyridine ring substituted by R d , the R 1 d is selected from cyano, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methyl substituted with 1-3 halogens, Ethyl substituted by 1-3 halogens, propyl substituted by 1-3 halogens, isopropyl substituted by 1-3 halogens; the halogens are selected from fluorine
  • R 1 is selected from a benzene ring substituted by R d selected from cyano, halogen, Methyl, ethyl, propyl, isopropyl, methyl substituted with 1-3 halogens, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, substituted with 1-3 halogens
  • R d selected from cyano, halogen, Methyl, ethyl, propyl, isopropyl, methyl substituted with 1-3 halogens, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, substituted with 1-3 halogens
  • R 3 , R 4 , R 5 and R 6 when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, R 2 is -NR 7 R 8 , and R 7 is selected from hydrogen, methyl, ethyl, propyl group, the R 8 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, by 1-3 halogen substituted ethyl, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens, cyclopropyl substituted with 1-3 halogens,
  • R 3 , R 4 , R 5 and R 6 when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, R 2 is -NR 7 R 8 , and R 7 is selected from hydrogen, methyl, ethyl, propyl group, the R 8 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, by 1-3 halogen substituted ethyl, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens, cyclopropyl substituted with 1-3 halogens,
  • R 4 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 - substituted by 1-5 identical or different halogens C 6 alkyl, cyano.
  • R 5 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 - substituted by 1-5 identical or different halogens C 6 alkyl, C 3 -C 6 cycloalkyl, cyano, amino, R 5 is unsubstituted or substituted by R a , R b and/or R c , said R a , R b and/or R c independently selected from C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens, C 1 -C 3 alkyl substituted with 1-5 identical or
  • R 6 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio , halogen, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, cyano.
  • R 1 is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, pyrazole ring, imidazole ring, R 1 is unsubstituted or substituted with R d , R e and/or R f each independently selected from C 1 -C 6 alkyl , the same or different by 1-5 C 1 -C 6 alkyl substituted by halogen, C 1 -C 6 alkoxy substituted by 1-5 same or different halogens, C 1 -C 6 alkoxy, hydroxyl, halogen,
  • at least one of R 3 , R 4 and R 5 is not hydrogen.
  • R 5 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C substituted with 1-5 identical or different halogens 6 alkyl, C 3 -C 6 cycloalkyl, cyano, amino, R 5 is unsubstituted or substituted by R a , R b and/or R c , said R a , R b and/or R c independently is selected from the group consisting of C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens, C 1 -C 3 alkyl substituted with 1
  • R 1 is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, pyrazole ring, imidazole ring, R 1 is unsubstituted or substituted by R d , Re and/or R f , each of said R d , Re and R f is independently selected from C 1 -C 6 alkyl, by 1-5 identical or different Halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy substituted with 1-5 identical or different halogens, C 1 -C 6 alkoxy
  • R 5 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C substituted by 1-5 identical or different halogens 6 alkyl, C 3 -C 6 cycloalkyl, cyano, amino, R 5 is unsubstituted or substituted by R a , R b and/or R c , said R a , R b and/or R c independently is selected from the group consisting of C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens, C 1 -C 3 alkyl substituted
  • R 1 is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, pyrazole ring, imidazole ring, R 1 is unsubstituted or substituted by R d , Re and/or R f , each of said R d , Re and R f is independently selected from C 1 -C 6 alkyl, by 1-5 identical or different Halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy substituted with 1-5 identical or different halogens, C 1 -C 6 al
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, cyclic propyl, methyl substituted with 1-3 halo, ethyl substituted with 1-3 halo, propyl substituted with 1-3 halo, isopropyl substituted with 1-3 halo, 1-3 halo substituted -3 halogen-substituted cyclopropyl;
  • the halogen is selected from fluorine, chlorine, bromine, iodine, preferably, the halogen is selected from fluorine, chlorine;
  • R 1 is phenyl or pyridyl; the phenyl or Pyridyl is substituted with 1 or 2 substituents selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 6 alkyl, -OC 1 -C 6 alky
  • R 1 is selected from the following groups substituted by 1, 2 or more halogens: C 6-8 aryl or 5-8 membered heteroaryl
  • R 1 is selected from the following groups substituted with 1 or 2 fluorine or chlorine: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazole group; preferably, R 1 is selected from the following groups substituted by 1 or 2 fluorines: phenyl or pyridyl;
  • R 2 is -NR 7 R 8 , and R 7 is selected from hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl; and R 8 is selected from C 3 -C 12 cycloalkyl substituted by R j ; preferably, R 2 is -NR 7 R 8 , the R 7 is selected from hydrogen, and the R 8 is selected from C 3 -C substituted by R j 6 cycloalkyl; the R j is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl.
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, Cyclopropyl, methyl substituted with 1-3 halogens, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens,
  • the halogen is selected from fluorine, chlorine, bromine and iodine, preferably, the halogen is selected from fluorine and chlorine;
  • R 1 is selected from
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, Cyclopropyl, methyl substituted with 1-3 halogens, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens,
  • the halogen is selected from fluorine, chlorine, bromine, and iodine, preferably, the halogen is selected from fluorine and chlorine;
  • R 1 is selected from
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, Cyclopropyl, methyl substituted with 1-3 halogens, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens,
  • the halogen is selected from fluorine, chlorine, bromine, and iodine, preferably, the halogen is selected from fluorine and chlorine;
  • R 2 is selected from
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, Cyclopropyl, methyl substituted with 1-3 halogens, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens,
  • the halogen is selected from fluorine, chlorine, bromine, and iodine, preferably, the halogen is selected from fluorine and chlorine;
  • R 2 is selected from
  • R 2 is -NHR 8
  • R 8 is selected from C 2 -C 4 alkyl substituted by hydroxy or C 2 -C 4 alkane substituted by cyano group groups; undefined groups are as described in any of the preceding schemes.
  • R 2 is -NHR 8
  • R 8 is selected from C 3 -C 10 cycloalkyl, C 6 -C 10 spirocycloalkyl, bridged C 5 -C 10 cycloalkyl
  • the R 8 is unsubstituted or substituted by R j
  • the R j is independently selected from -F, methyl, methoxy, cyano; undefined groups such as as described in the previous scheme.
  • R 2 is -NHR 8 , and R 8 is selected from cyclopropyl, cyclobutyl,
  • R 8 is unsubstituted or substituted with Rj independently selected from -F, methyl, methoxy, cyano; undefined groups are as described in any of the preceding schemes.
  • R 2 is -NR 7 R 8 , and R 7 and R 8 together with the N atom to which they are connected together form a 4-6 membered heterocycloalkyl, and the said 4-6 membered heterocycloalkyl is unsubstituted or substituted by R j ;
  • R j is selected from -F, cyano, -NH-(C 1 -C 6 alkyl), C 1 -C substituted by hydroxy 6Alkyl ; undefined groups are as described in any of the preceding schemes.
  • R 2 is -NR 7 R 8 , and R 7 and R 8 together with the N atom to which they are connected together form a 4-6 membered heterocycloalkyl, and the said 4-6 membered heterocycloalkyl is simultaneously substituted by R j and RL ;
  • R j is selected from -F, cyano, -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkane substituted by hydroxy group;
  • R L is selected from methyl, hydroxyl; undefined groups are as described in any of the previous schemes.
  • R 2 is -NR 7 R 8 , and R 7 and R 8 together with the N atom to which they are connected together form a 4-6 membered heterocycloalkyl, and the said 4-6 membered heterocycloalkyl is simultaneously substituted by R j , R k and R L ;
  • R j and R k are each independently selected from -F, cyano, -NH-(C 1 -C 6 alkyl), by Hydroxy-substituted C1 - C6 alkyl;
  • R L is selected from methyl, hydroxyl; undefined groups are as described in any of the preceding schemes.
  • R 2 is selected from the following groups unsubstituted or substituted by R j : wherein R A1 , R A2 and some ring atoms of ring A are connected to form a 3-7-membered cycloalkyl or a 3-7-membered heterocycloalkyl, and 1-3 ring atoms of the 3-7-membered heterocycloalkyl are independent Selected from N, O and S; undefined groups are as described in any of the preceding schemes.
  • R 2 is selected from the following groups unsubstituted or substituted by R j : R j is selected from -F, cyano, -N-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted with hydroxy; undefined groups are as described in any of the preceding schemes.
  • the compound shown in formula I is the compound shown in formula Ia:
  • R 5 , R 8 have the above-mentioned definitions; R 1a and R 1b are each independently selected from -H, -F.
  • R 5 is selected from difluoromethyl, trifluoromethyl
  • R 8 is selected from C 2 -C 4 alkyl substituted by hydroxyl or cyano group Substituted C2 - C4 alkyl
  • R 1a and R 1b are each independently selected from -H, -F.
  • R 5 is selected from difluoromethyl, trifluoromethyl
  • R 8 is selected from C 3 -C 10 cycloalkyl, C 6 -C 10 spirocycloalkyl, bridged C 5 -C 10 cycloalkyl, the R 8 is unsubstituted or substituted by R j , the R j is independently selected from -F, methyl, methoxy, cyano; preferably, R 8 is selected from cyclopropyl, cyclobutyl, Said R 8 is unsubstituted or substituted by R j , and said R j is independently selected from -F, methyl, methoxy, cyano; R 1a and R 1b are each independently selected from -H, - F.
  • the compound shown in formula I is the compound shown in formula Ic:
  • R 5 , R 7 , R 8 have the above-mentioned definitions; R 1a and R 1b are each independently selected from -H, -F.
  • R 5 is selected from difluoromethyl, trifluoromethyl; R 7 , R 8 together with the N atom they are connected to together form a 4-6-membered heterocyclic Cycloalkyl, the 4-6 membered heterocycloalkyl is unsubstituted or substituted by R j ; R j is selected from -F, cyano, -NH-(C 1 -C 6 alkyl), hydroxy Substituted C 1 -C 6 alkyl; R 1a and R 1b are each independently selected from -H, -F.
  • R 5 is selected from difluoromethyl, trifluoromethyl; R 7 , R 8 together with the N atom they are connected to together form a 4-6-membered heterocyclic Cycloalkyl, the 4-6 membered heterocycloalkyl is substituted by both R j and R L ; R j is selected from -F, cyano, -NH-(C 1 -C 6 alkyl), hydroxy substituted C 1 -C 6 alkyl; R L is selected from methyl, hydroxyl; R 1a and R 1b are each independently selected from -H, -F.
  • R 5 is selected from difluoromethyl, trifluoromethyl; R 7 , R 8 together with the N atom they are connected to together form a 4-6-membered heterocyclic Cycloalkyl, the 4-6 membered heterocycloalkyl is simultaneously substituted with R j , R k and R L ; R j and R k are each independently selected from -F, cyano, -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted by hydroxyl; R L is selected from methyl, hydroxyl; R 1a and R 1b are each independently selected from -H, -F.
  • the compound represented by formula I is the compound represented by formula If:
  • R 2 , R 5 have the above definitions; R 1a and R 1b are each independently selected from -H, -F.
  • R 5 is selected from difluoromethyl, trifluoromethyl
  • R 2 is selected from the following groups unsubstituted or substituted by R j : wherein R A1 , R A2 and some ring atoms of ring A are connected to form a 3-7-membered cycloalkyl or a 3-7-membered heterocycloalkyl, and 1-3 ring atoms of the 3-7-membered heterocycloalkyl are independent is selected from N, O and S
  • R j is selected from -F, cyano, -N-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted by hydroxy
  • R 1a and R 1b are each independently is selected from -H, -F.
  • R 5 is selected from difluoromethyl, trifluoromethyl
  • R 2 is selected from the following groups unsubstituted or substituted by R j :
  • R j is selected from -F, cyano, -N-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted by hydroxy;
  • R 1a and R 1b are each independently selected from -H, -F .
  • R 2 is selected from Undefined groups are as described in any of the previous schemes.
  • the compound shown in formula I has the structure shown in the following formula Im, In, Ip or Iq:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 independently have the definitions set forth above;
  • R 3 , R 4 and R 6 are hydrogen.
  • the compound of formula I is selected from any of the following compounds, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:
  • the compound of formula I is selected from any of the following compounds, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:
  • the present invention provides an intermediate represented by the formula M-1 for preparing the compound represented by the formula I or the tautomerism of the compound represented by the formula I as described in the first aspect of the present invention
  • Conformer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, the intermediate M-1 has the structure:
  • W, X, Y, Z, and R 1 are as described in the first aspect of the present invention.
  • the present invention provides an intermediate represented by formula M-2 for preparing the compound represented by formula I or the tautomer, stereoisomer, A hydrate, solvate, pharmaceutically acceptable salt or prodrug, the intermediate M-2 has the structure:
  • W, X, Y, Z, and R 1 are as described in the first aspect of the present invention.
  • the present invention provides an intermediate represented by formula M-3 for preparing the compound represented by formula I as described in the first aspect of the present invention or the tautomer, stereoisomer, A hydrate, solvate, pharmaceutically acceptable salt or prodrug, the intermediate M-3 has the structure:
  • the present invention provides an intermediate represented by formula M-3 for preparing the compound represented by formula I as described in the first aspect of the present invention or the tautomer, stereoisomer, A hydrate, solvate, pharmaceutically acceptable salt or prodrug, the intermediate M-3 has the structure:
  • W, X, Y, Z, and R 1 are as described in the first aspect of the present invention.
  • the intermediate M-1 is selected from any of the following compounds:
  • the intermediate M-2 is selected from any of the following compounds:
  • the intermediate M-3 is selected from any of the following compounds:
  • the intermediate M-4 is selected from any of the following compounds:
  • the present invention provides a tautomer, stereoisomer, hydrate, A method for a solvate, pharmaceutically acceptable salt or prodrug, comprising the steps of:
  • the intermediate M-1 is hydrolyzed to obtain the intermediate M-2,
  • the acidic conditions may be provided by inorganic acids and/or organic acids, such as sulfuric acid and acetic acid.
  • inorganic acids and/or organic acids such as sulfuric acid and acetic acid.
  • M-1 is contacted with sulfuric acid and acetic acid, and then the reaction system is heated to 25-90°C, and the reaction is stirred to obtain M-2.
  • the alkaline conditions can be provided by inorganic bases and/or organic bases, such as potassium carbonate, cesium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide Wait.
  • inorganic bases and/or organic bases such as potassium carbonate, cesium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide Wait.
  • organic bases such as potassium carbonate, cesium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide Wait.
  • M-2 Add cesium carbonate to N,N-dimethylformamide, replace nitrogen, heat to 25-75°C, and stir the reaction to obtain M-3, wherein R8 has the above-mentioned definition.
  • the basic conditions may be provided by inorganic bases and/or organic bases, such as cesium carbonate, pyridine and the like.
  • inorganic bases and/or organic bases such as cesium carbonate, pyridine and the like.
  • the preparation method when R 8 contains a hydroxyl group, the preparation method further comprises one or more steps selected from the group consisting of:
  • step (2) Before the step (2), it also includes a step (2-1): protecting the hydroxyl group by a hydroxyl protecting group; and/or
  • Step (3-2) is also included after the step (3): removing the hydroxyl protecting group
  • the hydroxyl protecting group is selected from silyl-containing hydroxyl protecting groups, such as TBS, TMS and the like.
  • the present invention also provides a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound of formula I or a tautomer, stereoisomer, hydrate, solvate, etc.
  • a method of an acceptable salt or prodrug comprising the steps of:
  • R 2 has the definition set forth above.
  • the alkaline condition in step (A), can be provided by an organic base, such as sodium ethoxide, potassium ethoxide and the like.
  • an organic base such as sodium ethoxide, potassium ethoxide and the like.
  • M-2 is contacted with sodium ethoxide, after stirring the reaction, slowly adding thiophosgene, and refluxing to react to obtain M-4.
  • the basic conditions may be provided by inorganic bases and/or organic bases, such as cesium carbonate, pyridine and the like.
  • inorganic bases and/or organic bases such as cesium carbonate, pyridine and the like.
  • M-4, R 2 -H and pyridine are dissolved in tetrahydrofuran, nitrogen is replaced, the temperature is lowered to a low temperature such as 0° C., elemental iodine is slowly added to the reaction system, heated and stirred to obtain the compound represented by formula I.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmacy at least one of the above acceptable salts or prodrugs.
  • the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition may further contain one or more additional therapeutic agents.
  • the present invention provides the compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or said Use of the pharmaceutical composition in the preparation of a medicament for treating or preventing MAT2A-related diseases, the present invention also provides any compound described in the first aspect of the present invention or the pharmaceutical composition described in the fourth aspect of the present invention. Or medicinal use to prevent MAT2A-related diseases.
  • the medicament is for treating or preventing cancer.
  • the cancer is an MTAP-deficient cancer.
  • the cancer is selected from the group consisting of mesothelioma, neuroblastoma, rectal cancer, colon cancer, familiar adenomatous polyposis and hereditary nonpolyposis colorectal cancer, esophageal cancer, lip Cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, intrauterine cancer Membranous cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary cancer, melanoma, brain tumor, lymphoma, head and neck cancer, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) ), acute myeloid leukemia (AML), chronic myeloid leukemia (C ALL), chronic lymphoblastic le
  • the present invention also provides a method for preventing or treating MAT2A-related diseases, comprising administering to a patient a preventive or therapeutically effective amount of the compound represented by formula (I), its tautomer, stereoisomer, hydrate and solvate , at least one of a pharmaceutically acceptable salt or prodrug, or the above-mentioned pharmaceutical composition.
  • the patient mammal preferably a human.
  • the present invention also provides at least one of the compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or a pharmaceutical combination thereof
  • the application of the drug in the treatment or prevention of MAT2A-related diseases is not limited to, butyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N
  • the compounds and/or compositions thereof of the present invention can effectively inhibit the activity of MAT2A enzyme, have a good inhibitory effect on the proliferation of HCT116 MTAP-/- cells and the level of SAM in cells, and have better pharmacological effects.
  • Kinetic properties less side effects, especially reduced gastrointestinal adverse reactions (such as nausea, vomiting, abdominal pain, diarrhea, abdominal distension, loss of appetite, indigestion, etc.). It has broad application prospects in preparing medicines for treating MAT2A-related diseases.
  • groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituents When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 .
  • a number from 1 to 10 should be understood as not only reciting each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also reciting at least that each integer is respectively associated with Sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts or “pharmaceutically acceptable salts thereof” refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
  • salts are also contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the present invention.
  • stereoisomer refers to isomers that result from different arrangements of atoms in a molecule in space.
  • Stereochemical definitions and conventions used herein are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds”, defined by John Wiley & Sons, Inc., New York, 1994.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method Spin body.
  • the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, for example, as pure optical isomers, or as mixtures of isomers, such as racemic and non-isomeric isomers.
  • Optically active I- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques.
  • the substituent may be of E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may be cis or trans (cis- or trans-) structure.
  • Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids. Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
  • optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic
  • resolving agents suitable for fractional crystallization methods include ⁇ -methyl-benzylamine in stereoisomerically pure form (eg, S and R forms or diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.
  • Resolution of the racemic mixture can also be performed by elution on a column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist as two or more interconvertible species.
  • Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the ketone form predominates; in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • composition means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • solvate means that a compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.
  • prodrug refers to a compound of the invention that can be converted under physiological conditions or by solvolysis to a biologically active compound.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds, which modifications can be removed by conventional procedures or in vivo to yield the parent compounds.
  • Prodrugs include compounds formed by connecting a hydroxyl or amino group in the compounds of the present invention to any group. When the prodrugs of the compounds of the present invention are administered to mammalian individuals, the prodrugs are cleaved to form free hydroxyl, free the amino group.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • classes of the term “excipient” include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like.
  • alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to several carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propane base, butyl, pentyl, etc. Those skilled in the art will recognize that the term “alkyl” can include “alkylene” groups.
  • C 1 -C 10 alkyl is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-di
  • the group has 1, 2, 3, 4, 5, 6 carbon atoms (" C1 - C6 alkyl”), eg methyl, ethyl, propyl, butyl, isopropyl , isobutyl, sec-butyl, tert-butyl, more particularly, said groups having 1, 2 or 3 carbon atoms (“ C1 -C3 alkyl”), eg methyl, ethyl, n- propyl or isopropyl.
  • alkylene should be understood to mean a straight-chain saturated divalent hydrocarbon radical having 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical having 3 to 6 carbon atoms, unless otherwise specified, such as methylene, Ethylene, propylene, 1-methylpropylene, butylene, etc.
  • alkenyl refers to a straight-chain monovalent hydrocarbon group with 2 to several carbon atoms containing double bonds or a branched monovalent hydrocarbon group with 3 to several carbon atoms containing double bonds such as propenyl, butenyl, etc. .
  • C 2 -C 10 alkenyl is understood to mean an alkenyl group having 2 to 10 carbon atoms, said alkenyl group being in accordance with the above definition.
  • C 2 -C 6 alkenyl is understood to mean a straight-chain monovalent hydrocarbon group containing one or more carbon-carbon double bonds, having 2, 3, 4, 5 or 6 carbon atoms or a A branched monovalent hydrocarbon group having 3 to 6 carbon atoms of a double bond such as an alkenyl group.
  • alkynyl refers to a straight chain monovalent hydrocarbon group having 2 to several carbon atoms or a branched monovalent hydrocarbon group containing three carbon atoms, such as ethynyl, propynyl, butynyl and the like, containing a triple bond.
  • C 2 -C 10 alkynyl is understood to mean an alkynyl group having 2 to 10 carbon atoms, said alkynyl group being in accordance with the above definition.
  • C 2 -C 6 alkynyl is to be understood as meaning a straight-chain, branched or cyclic hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl and 3-methylbutynyl, etc.
  • Alkoxy refers to an -OR group where R is an alkyl group as defined above, eg, methoxy, ethoxy, propoxy or isopropoxy, and the like.
  • C 1 -C 10 alkoxy should be understood as -O-(C 1-10 alkyl), wherein “C 1-10 alkyl” has the above definition; the term “C 1 -C 6 alkoxy” It should be understood as -O-(C 1-6 alkyl), wherein “C 1-6 alkyl” has the above definition.
  • alkoxyalkyl refers to an alkyl group substituted with one or more alkoxy groups, as defined above, such as 2-methoxyethyl, 1-, 2- or 3-methoxy propyl, 2-ethoxyethyl, etc.
  • alkoxyalkoxy refers to the -OR group, wherein R is an alkoxyalkyl group as defined above, eg, methoxyethoxy, ethoxypropoxy, and the like.
  • alkoxyalkylamino refers to a -NRR' group, wherein R is hydrogen or alkyl, and R' is alkoxyalkyl, each as defined above, eg, methoxyethylamino, methoxypropyl amino, etc.
  • alkylcarbonyl refers to a -C(O)R group, wherein R is an alkyl group as defined herein, eg, methylcarbonyl, ethylcarbonyl, and the like.
  • alkoxycarbonyl refers to a -C(O)OR group, wherein R is an alkyl group as defined above, eg, methoxycarbonyl, ethoxycarbonyl, and the like.
  • alkoxycarboxyalkyl refers to an alkyl group as defined above substituted with an alkoxycarboxy group (eg, methylcarboxymethyl, ethylcarboxyethyl, etc.).
  • alkylthio refers to a -SR group wherein R is an alkyl group as defined above, eg, methylthio, ethylthio, and the like.
  • alkylsulfonyl refers to a -SO2R group, wherein R is an alkyl group as defined above, eg, methylsulfonyl, ethylsulfonyl, and the like.
  • alkylsulfonylalkyl refers to a -(alkylene) -SO2R group, where R is an alkyl group as defined above, eg, methylsulfonylethyl, ethylsulfonylmethyl, etc. .
  • amino refers to -NH2 .
  • alkylamino refers to a -NHR group wherein R is an alkyl group as defined above, eg methylamino, ethylamino, propylamino or 2-propylamino and the like.
  • aminoalkyl refers to an alkyl group substituted with -NR'R", wherein R' and R" are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, or alkylcarbonyl, such as Aminomethyl, aminoethyl, methylaminomethyl, etc.
  • aminoalkoxy refers to the -OR group, wherein R is an aminoalkyl group as defined above, eg, aminoethoxy, methylaminopropoxy, dimethylaminoethoxy, diethylaminopropoxy Base et al.
  • aminoalkylamino refers to a group -NRR', wherein R is hydrogen or alkyl, and R' is aminoalkyl, wherein alkyl, aminoalkyl are as defined above, eg, aminoethylamino, methyl Aminopropylamino, dimethylaminoethylamino, diethylaminopropylamino, etc.
  • aminocarbonyl refers to the -CONH2 group.
  • alkylaminocarbonyl refers to the group -CONHR wherein R is an alkyl group as defined above, eg, methylaminocarbonyl, ethylaminocarbonyl, and the like.
  • aminosulfonyl refers to the -SO2NH2 group.
  • aminosulfonylalkyl refers to a -(alkylene) SO2NRR ' group wherein R is hydrogen or alkyl, R' is hydrogen, alkyl or cycloalkyl, or R and R' are combined with them
  • R is hydrogen or alkyl
  • R' is hydrogen, alkyl or cycloalkyl
  • R and R' are combined with them
  • the attached nitrogen atoms together form a heterocyclyl group, as defined above, eg, methylaminosulfonylethyl, dimethylsulfonylethyl, and the like.
  • alkylaminosulfonyl refers to a -SO2NHR group where R is an alkyl group as defined above, eg, methylaminosulfonyl, ethylaminosulfonyl, and the like.
  • aminocarbonylalkyl refers to a -(alkylene)-CONRR' group, wherein R and R' are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, each as described herein Definition, for example, aminocarbonylethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, etc.
  • aminosulfonylalkyl refers to a -(alkylene) -SO2NRR ' group wherein R and R' are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, Each is as defined herein, eg, aminosulfonylethyl, methylaminosulfonylethyl, dimethylaminosulfonylethyl, and the like.
  • aryl refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group of 6 to several ring atoms.
  • C 6 -C 10 aryl refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 ring atoms, such as phenyl or naphthyl.
  • aralkyl refers to a -(alkylene)-R group, wherein R is an aryl group as defined above, eg, benzyl, phenethyl, and the like.
  • bridged cycloalkyl refers to a saturated monocyclic 5- to 7-membered hydrocarbon group in which two non-adjacent ring atoms are joined by a (CRR')n group, where n is 1 to 3, and each R is independently Ground is H or methyl (also referred to herein as a bridging group).
  • the bridged cycloalkyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy or cyano. Examples of bridged cycloalkyl include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like
  • bridged cycloalkylalkyl refers to a -(alkylene)-R group, wherein R is bridged cycloalkyl as defined above. Examples include, but are not limited to, bicyclo[2.2.1]heptylmethyl and the like.
  • bridged heterocyclyl refers to a saturated monocyclic ring having 5 to 8 ring carbon ring atoms, wherein two non-adjacent ring atoms are connected by a (CRR')n group, where n is 1 to 3, and each R is independently H or methyl (also referred to herein as a "bridging" group), and wherein one or two ring carbon atoms (including atoms in the bridging group) are selected from N , a heteroatom substitution of O or S(O)n, where n is an integer from 0 to 2.
  • Bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy or cyano. Examples include, but are not limited to, 2-azabicyclo[2.2.2]octane, quinoline rings, 7-oxabicyclo[2.2.1]heptane, and the like.
  • bridged heterocyclylalkyl refers to a -(alkylene)-R group, wherein R is a bridged heterocyclyl group as defined above (including specific bridged heterocyclyl rings).
  • cycloalkyl refers to a monocyclic monovalent hydrocarbon group of three to several carbon atoms, which may be saturated or contain one double bond. Cycloalkyl groups may be unsubstituted or substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy or cyano. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocyclopropan-1-yl, 1-cyanomethylcyclopropan-1-yl, 3-fluorocyclohexyl, and the like .
  • C3 - C6cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • cycloalkylalkyl refers to a -(alkylene)-R group, wherein R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, and the like.
  • cycloalkylalkoxy refers to the group -O-R, wherein R is cycloalkylalkyl as defined above. Examples include, but are not limited to, cyclopropylmethoxy, cyclobutylmethoxy, and the like.
  • cycloalkoxyalkyl refers to a -(alkylene)-OR group, wherein R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxyethyl, and the like.
  • cycloalkylsulfonylamino refers to the group -NRSO2 - R', wherein R is hydrogen or alkyl, and R' is cycloalkyl, each as defined above. Examples include, but are not limited to, cyclopropylsulfonylamino and the like.
  • cyanoalkyl refers to an alkyl group as defined above substituted with a cyano group such as cyanomethyl, cyanoethyl and the like.
  • carboxyalkyl refers to an alkyl group as defined above substituted with a carboxyl group such as carboxymethyl, carboxyethyl and the like.
  • deuterated alkyl refers to an alkyl group as defined above wherein 1-6 hydrogen atoms in the alkyl chain are replaced by deuterium atoms. Examples include, but are not limited to, -CD3 , -CH2CHD2 , and the like.
  • dialkylamino refers to a -NRR' group wherein R and R' are alkyl groups as defined above, eg, dimethylamino, methylethylamino, and the like.
  • dialkylaminocarbonyl refers to a -CONRR' group wherein R and R' are alkyl groups as defined above, for example, dimethylaminocarbonyl, diethylaminocarbonyl, and the like.
  • dialkylaminosulfonyl refers to a -SO2NRR ' group, where R and R' are alkyl groups as defined above, eg, dimethylaminosulfonyl, diethylaminosulfonyl, and the like.
  • fused cycloalkyl refers to a saturated monovalent hydrocarbon group of three to six carbon atoms fused to a phenyl or five- or six-membered heteroaryl ring, as defined herein, and optionally surrounded by a , two or three independently selected substituents replace alkyl, halo, alkoxy, haloalkyl, haloalkoxy, hydroxy and cyano. Examples include, but are not limited to, tetrahydronaphthyl, 4,5,6,7-tetrahydro-lH-indolyl, 4,5,6,7-tetrahydrobenzoxazolyl, and the like.
  • fused heterocyclyl refers to a heterocyclyl, as defined herein, fused to a cycloalkyl, phenyl, or five- or six-membered heteroaryl ring, as defined herein.
  • the fused heterocyclyl group is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy or cyano. Examples include, but are not limited to, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro Quinoline-2(1H)-etc.
  • fused heterocyclylalkyl refers to a -(alkylene)-R group, wherein R is a fused heterocyclyloxy group as defined above (including specific fused heterocyclyl rings).
  • halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • fluoroalkyl group When an alkyl group is substituted only with fluorine, it may be referred to as a fluoroalkyl group in this application.
  • haloalkoxy refers to the -OR group, wherein R is a haloalkyl group as defined above, eg, -OCF3 , -OCHF2 , and the like.
  • R is a haloalkyl group in which the alkyl group is substituted only with fluorine, it is referred to in this application as fluoroalkoxy.
  • haloalkoxyalkyl refers to alkyl groups each substituted with a haloalkoxy group as defined above, eg, trifluoromethoxyethyl and the like.
  • heteroalkylene refers to a linear saturated divalent hydrocarbon radical having two to six carbon atoms or a branched saturated divalent hydrocarbon radical having three to six carbon atoms, one of which is replaced by -O-,- NR-, -NR'CO-, -CONR'-, SO2NR'- or -NR'SCh- substituted, unless otherwise specified, wherein R and R' are independently H or alkyl as defined herein, e.g. -CH O-, -OCH 2 -, -(CH 2 ) 2 O-, -O(CH 2 ) 2 -, -(CH 2 ) 2 NH-, -NH(CH 2 ) 2 - and the like.
  • hydroxyalkyl refers to a straight-chain monovalent hydrocarbon group of one or more carbon atoms or a branched-chain monovalent hydrocarbon group of three or six carbons substituted with one or two hydroxy groups, provided that if two are present hydroxyl, they are not atoms on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxy Butyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl.
  • hydroxyalkoxy refers to the -OR group where R is a hydroxyalkyl group as defined above, eg, hydroxyethoxy, hydroxypropoxy, and the like.
  • hydroxyalkylamino refers to a -NRR' group wherein R is hydrogen or alkyl and R' is hydroxyalkyl, each as defined above, eg, hydroxyethylamino, hydroxypropylamino, and the like.
  • heteroaryl refers to a monovalent monocyclic or bicyclic aromatic group having 5 to 10 ring atoms, of which one or more (in one embodiment one, two or three ) ring atoms are selected from N, O, or S, and the remaining ring atoms are carbon.
  • heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnamyl, phthaloyl , benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, isobenzotriazolyl, isobenzotriazolyl, benzotriazolinyl, isobenzotriazolyl, iso Benzotriazolyl.
  • heteroaryl and “aryl” are mutually exclusive. When a heteroaryl ring contains 5 or 6 ring atoms, it is also referred to herein as a 5 or 6 membered heteroaryl.
  • heteroaryl refers to a -(alkylene)-R group, wherein R is a heteroaryl group (including specified rings) as defined above.
  • heteroaryloxy refers to -OR, wherein R is a heteroaryl group (including specified rings) as defined above.
  • heteroarylkoxy refers to the group -O-(alkylene)-R, wherein R is a heteroaryl group (including specified rings) as defined above.
  • heteroarylcarbonyl refers to -COR, wherein R is a heteroaryl group (including specified rings) as defined above.
  • heteroarylamino refers to -NRR' wherein R is hydrogen or alkyl and R' is heteroaryl (including specified rings), as defined above.
  • heterocyclyl refers to a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms, wherein one or two ring atoms are heteroatoms selected from N, O or S(O)n, wherein n is an integer from 0 to 2, and the remaining ring atoms are C. Additionally, one or two ring carbon atoms in the heterocyclyl ring can be optionally substituted with a -CO- group.
  • heterocyclyl includes, but is not limited to, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, Morpholino, piperazinyl, tetrahydropyranyl, thiomorpholino, etc.
  • the heterocyclyl ring When the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, provided that the ring is not aromatic.
  • a heterocyclyl group contains at least one nitrogen atom, it may be referred to herein as a heterocyclylamino group.
  • heterocyclylalkyl refers to a -(alkylene)-R group, wherein R is a heterocyclyl group as defined above (including specified heterocyclyl rings). For example, oxetanylethyl, piperidinylethyl and the like.
  • heterocyclyloxy refers to the -OR group, wherein R is a heterocyclyl group as defined above (including specified heterocyclyl rings).
  • heterocyclylalkoxy refers to the group -O-(alkylene)-R, wherein R is heterocyclyl as defined above (including specified heterocyclyl rings). For example, oxetanylethoxy, piperidinylethoxy, and the like.
  • heterocyclylcarbonyl refers to -COR, wherein R is heterocyclyl (including specified rings) as defined above.
  • heterocyclylamino refers to a -NRR' group wherein R is hydrogen or alkyl and R' is heterocyclyl (including specified heterocyclyl rings), as defined above.
  • heterocyclyloxyalkyl refers to a -(alkylene)-OR group, wherein R is heterocyclyl as defined above (including specified heterocyclyl rings). For example, oxetanyloxyethyl, piperidinyloxyethyl and the like.
  • heterocyclyloxyalkoxy refers to the group -O-(alkylene)-R, wherein R is heterocyclyloxy as defined above (including specified heterocyclyl rings). For example, oxetanyloxyethoxy, piperidinyloxyethoxy, and the like.
  • heterocyclyloxyalkylamino refers to the -NR-(alkylene)-R' group, wherein R is hydrogen or alkyl, and R' is heterocyclyloxy (including specified heterocycles) base ring), as defined above.
  • R is hydrogen or alkyl
  • R' is heterocyclyloxy (including specified heterocycles) base ring), as defined above.
  • bicyclic and fused means that two rings are joined together by a bond between two atoms (eg, naphthalene), and are joined together by a series of atoms to form a bridge (eg, quinuclidine) or single atoms taken together to form spiro compounds (e.g., 1,4-dioxa-8-aza-spiro[4.5]decane and N,3,3-dimethyl-1,5-dioxaspiro [5.5]undecan-9-yl).
  • spiro compounds e.g., 1,4-dioxa-8-aza-spiro[4.5]decane and N,3,3-dimethyl-1,5-dioxaspiro [5.5]undecan-9-yl.
  • 3 to 6 membered heterocycloalkyl refers to a saturated monocyclic group of 3 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, The remainder are carbon atoms; in addition, one or two ring carbon atoms in the heterocyclyl ring may be optionally substituted with a -CO- group.
  • Optional means that the subsequently described event may or may not occur, and that the expression includes instances where the event occurs and instances where it does not.
  • “optionally substituted alkyl” includes “alkyl” and “substituted alkyl” as defined herein.
  • Optionally substituted aryl refers to an aryl group optionally substituted with one, two or three substituents independently selected from alkyl, cycloalkyl, carboxyl, alkoxycarbonyl, hydroxy , hydroxyalkyl, alkoxy, alkylsulfonyl, amino, alkylamino, dialkylamino, halogen, haloalkyl, haloalkoxy, and cyano.
  • Optionally substituted heteroaryl refers to a heteroaryl group as defined above, optionally with 1, 2 or 3 independently selected from the group consisting of alkyl, alkylsulfonyl, cycloalkyl, carboxy, alkoxy Substituent substitution of carbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino and cyano.
  • Optionally substituted heterocyclyl refers to a heterocyclyl group as defined above, optionally with one, two or three independently selected from the group consisting of alkyl, alkylsulfonyl, cycloalkyl, carboxyl, alkoxy Substituents of oxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halogen, haloalkyl, haloalkoxy and cyano, unless otherwise stated.
  • “Spirocycloalkyl” refers to a saturated bicyclic ring having 6 to 10 ring carbon atoms, wherein the rings are joined by only one atom, also known as a spiro atom, most commonly a quaternary carbon (“spirocarbon” ).
  • the spirocycloalkyl ring is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy and cyano.
  • Representative examples include, but are not limited to, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane (1:2:1:1), and the like.
  • Spirocycloalkylalkyl refers to a -(alkylene)-R group, wherein R is a spirocycloalkyl group as defined above (including specific spirocycloalkyl groups).
  • “Spiroheterocyclyl” means a saturated bicyclic ring having 6 to 10 ring atoms, wherein one, two or three ring atoms are selected from N, O or S(O)n, where n is selected from 0 to 2 Integer, the remaining ring atoms are C, and the rings are connected by only one atom, also known as a spiro atom, most commonly a quaternary carbon (“spiro carbon”).
  • Spiroheterocyclyl optionally substituted with one or two substituents
  • Examples include, but are not limited to, representative examples include, but are not limited to: 2,6-diazaspiro[3.3]heptane, 2,6-diaza Spiro[3.4]octane, 2-azaspiro[3.4]octane, 2-azaspiro[3.5]-nonane, 2,7-diazaspiro[4.4]nonane, etc.
  • Spiroheterocyclylalkyl refers to a -(alkylene)-R group, wherein R is a spiroheterocyclyl group as defined above (including specific spiroheterocyclyl groups).
  • “Sulfonylamino” refers to a -NRSO2R ' group, wherein R is hydrogen or alkyl, and R' is alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heteroaryl Cyclic groups, each as defined herein.
  • Substituted cycloalkyl refers to a saturated monocyclic monovalent hydrocarbon group of three to six carbon atoms substituted with one, two or three substituents, wherein two of the three substituents are independently selected from Alkyl, halogen, alkoxy, hydroxy, haloalkyl or haloalkoxy and the third substituent is alkyl, halo, hydroxyalkyl, haloalkyl, haloalkoxy or cyano. Examples include, but are not limited to, 3-hydroxy-3-trifluorocyclobutyl, 2,2-dimethyl-3-hydroxycyclobutyl, and the like.
  • Substituted cycloalkylalkyl refers to -(alkylene)-substituted cycloalkyl, as each term is defined herein. Examples include, but are not limited to, 1-hydroxymethylcyclopropan-1-ylmethyl and the like.
  • “Ureido” refers to a -NHCONRR' group, wherein R and R' are independently hydrogen or alkyl, as defined above, eg, -NHCONHmethyl, -NHCON( CH3 ) 2 , and the like.
  • Thiouranyl refers to a -(alkylene) -NHSO2NRR ' group, wherein R and R' are independently hydrogen or alkyl, as defined above.
  • patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.
  • terapéuticaally effective amount refers to the amount of active compound or drug that a researcher, veterinarian, physician or other clinician is seeking to elicit a biological or medical response in a tissue, system, animal, individual or human, and includes one of the following or more of: (1) Prevention of disease: eg, prevention of disease, disorder or condition in individuals susceptible to a disease, disorder or condition but not yet experiencing or developing disease pathology or symptoms. (2) Inhibiting a disease: eg, inhibiting a disease, disorder or condition (ie preventing further progression of the pathology and/or condition) in an individual who is experiencing or developing the pathology or symptom of the disease, disorder or condition. (3) Alleviating disease: eg, alleviating a disease, disorder or condition (ie, reversing the pathology and/or symptoms) in an individual who is experiencing or experiencing the pathology or symptoms of the disease, disorder or condition.
  • the compounds of the present invention are identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the units of NMR shifts are 10-6 (ppm).
  • the solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • DIPEA can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
  • DMP Dess-Martin oxidizer, also known as Dess-Martin oxidizer
  • EC 80 concentration for 80% of maximal effect, the concentration that can cause 80% of the maximal effect
  • IC 50 half inhibitory concentration, refers to the concentration at which half of the maximum inhibitory effect is achieved
  • N equivalent concentration, for example, 2N hydrochloric acid means 2mol/L hydrochloric acid solution
  • Acid Preparation Method A Welch, Ultimate C 18 column, 10 ⁇ m, 21.2 mm x 250 mm.
  • Mobile phase A is 1 ⁇ trifluoroacetic acid pure aqueous solution
  • mobile phase B is acetonitrile solution.
  • Gradient conditions 0 to 3 minutes, mobile phase A maintained at 90%, 3 to 18 minutes for gradient elution, from 90% to 5%, and 18 to 22 minutes to maintain 5%.
  • the synthetic route of the target compound I-1 is as follows:
  • the first step Synthesis of 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile)(I-1C)
  • the second step Synthesis of 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-1D)
  • the synthetic route of the target compound I-2 is as follows:
  • the first step Synthesis of 2-(2-chlorophenyl)-2-(4-methylpyridin-2-yl)acetonitrile (I-2B)
  • the second step the synthesis of 2-(2-chlorophenyl)-2-(4-methylpyridin-2-yl)acetamide (I-2C)
  • the third step synthesis of 2-(2-chlorophenyl)-N-(methylaminothioformyl)-2-(4-methylpyridin-2-yl)acetamide (I-2D)
  • the fourth step 4-(2-chlorophenyl)-6-methyl-1-(methylamino)-3H-pyrido[1,2-c]pyrimidin-3-one (target compound I-2)
  • the synthetic route of compound I-3 refers to the synthetic method of I-2 to obtain 6-chloro-4-(2-chlorophenyl)-1-(methylamino)-3H-pyrido[1,2-c]pyrimidine -3-keto (I-3)
  • the synthetic route of the target compound I-4 is as follows:
  • the first step Synthesis of 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetonitrile (I-4B)
  • the second step Synthesis of 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetamide (I-4C)
  • the third step synthesis of 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)-N-(methylaminothioformyl)acetamide ((I-4D)
  • the fourth step Synthesis of 4-(2-chlorophenyl)-6-cyclopropyl-1-(methylamino)pyrido[1,2-c]pyrimidin-3-one (I-4)
  • the synthetic route of the target compound I-5 is as follows:
  • the first step Synthesis of 2-(o-tolyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetonitrile (I-5B)
  • the second step Synthesis of 2-(o-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-5C)
  • the third step synthesis of N-(methylaminothioformyl)-2-(o-tolyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetamide (I-5D)
  • the fourth step synthesis of 1-(methylamino)-4-(o-tolyl)-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one (I-5)
  • the synthetic route of the target compound I-6 is as follows:
  • Compound I-7 can be obtained by referring to the synthetic method of I-60 or I-61.
  • Compound I-8 can be obtained by referring to the synthetic method of I-60 or I-61.
  • Compound I-9 can be obtained by referring to the synthetic method of I-70 or I-71.
  • the synthetic route of the target compound I-10 is as follows:
  • the first step the synthesis of 2-(2-methylpyridin-3-yl)acetonitrile (I-10B)
  • the second step Synthesis of 2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-10C)
  • the third step Synthesis of 2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-10D)
  • reaction mixture was diluted with saturated aqueous sodium sulfite solution (200 mL), then extracted with ethyl acetate (100 mL*3), the organic layers were combined, washed with saturated aqueous sodium sulfite solution (200 mL*3), dried over anhydrous sodium sulfate, and filtered.
  • the synthetic route of the target compound I-11 is as follows:
  • the first step Synthesis of 2-(3-chloro-2-pyridin-2-yl)-2-[4-(trifluoromethyl)-2-pyridyl]acetonitrile (I-11B)
  • the second step Synthesis of 2-(3-chloropyridin-2-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-11C)
  • the third step 2-(3-chloro-2-pyridin-2-yl)-N-(methylaminothioformyl)-2-[4-(trifluoromethyl)-2-pyridine-2- Synthesis of Acetamide (I-11D)
  • the fourth step 4-(3-chloropyridin-2-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyridyl[1,2-c]pyrimidin-3-one Synthesis of (Target Compound I-11)
  • Compound I-12 can be obtained by referring to the synthetic method of I-60 or I-61.
  • Compound I-13 can be obtained by referring to the synthetic method of I-60 or I-61.
  • the synthetic route of the target compound I-14 is as follows:
  • the first step Synthesis of 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-14B)
  • o-Chlorophenylacetonitrile 50.0 g, 329.8 mmol
  • potassium hydroxide 27.8 g, 494.8 mmol
  • 2-bromo-4-(trifluoromethyl)pyridine 74.5 g, 329.8 mmol
  • the second step Synthesis of 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)-2-pyridyl)acetamide (I-14C)
  • the fourth step synthesis of tert-butyl-(1-(isothiocyanatomethyl) cyclopropoxy)-dimethyl-silane (I-14D)
  • the sixth step 1-(((1-((tert-butyldimethylsilyl)oxo)cyclopropyl)methyl)amino)-4-(2-chlorophenyl)-6-(tri Synthesis of Fluoromethyl)pyrido[1,2-c]pyrimidin-3-one (I-14F)
  • Step 7 4-(2-Chlorophenyl)-1-(((1-hydroxycyclopropyl)methyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2- c] Pyrimidine-3-one (target compound I-14)
  • the synthetic route of the target compound I-15 is as follows:
  • the first step Synthesis of 2-(2-chlorophenyl)-2-(5-(trifluoromethyl)pyridazin-3-yl)acetonitrile (I-15B)
  • the second step Synthesis of 2-(2-chlorophenyl)-2-(5-(trifluoromethyl)pyridazin-3-yl)acetamide (I-15C)
  • reaction solution was slowly added to an aqueous sodium hydroxide solution (4.00M, 80.0 mL) at 0°C, then extracted with ethyl acetate (20.0 mL*3), the organic layers were combined and dried over anhydrous sodium sulfate , filtered and concentrated to give yellow solid 2-(2-chlorophenyl)-2-(5-(trifluoromethyl)pyridazin-3-yl)acetamide (I-15C) (900.0 mg, 2.85 mmol, yield 94.3%), used directly in the next step.
  • the fourth step 5-(2-chlorophenyl)-8-(methylamino)-3-(trifluoromethyl)-6H-pyrimido[1,6-b]pyridazin-6-one (I -15) synthesis
  • the synthetic route of compound I-16 refers to the synthetic method of I-15 to obtain 5-(2-chlorophenyl)-3-methyl-8-(methylamino)-6H-pyrimido[1,6-b] Pyridazin-6-one (I-16).
  • the synthetic route of compound I-17 refers to the synthetic method of I-15 to obtain 3-chloro-5-(2-chlorophenyl)-8-(methylamino)-6H-pyrimido[1,6-b]pyridin Azin-6-one (I-17).
  • the synthetic route of compound I-18 refers to the synthetic method of I-15 to obtain 5-(2-chlorophenyl)-3-cyclopropyl-8-(methylamino)-6H-pyrimidine[1,6-b]pyridin Azin-6-one (I-18).
  • the synthetic route of compound I-19 refers to the synthetic method of I-15 to obtain 5-(2-chlorophenyl)-8-(cyclopropylamino)-3-(trifluoromethyl)-6H-pyrimidine[1, 6-b]pyridazin-6-one (I-19).
  • the synthetic route of compound I-20 refers to the synthetic method of I-15 to obtain 5-(2-chlorophenyl)-8-(3-hydroxypyrrolidin-1-yl)-3-(trifluoromethyl)-6H - Pyrimidyl[1,6-b]pyridazin-6-one (I-20).
  • the synthetic route of compound I-21 refers to the synthetic method of I-2 to obtain 9-(2-chlorophenyl)-6-(methylamino)-2-(trifluoromethyl)-8H-pyrimidine[1,6 -a]pyrimidin-8-one (I-21).
  • the synthetic route of compound I-22 refers to the synthetic method of I-2 to obtain 4-(2-chlorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrimidine[1,6 -c]pyrimidin-3-one (I-22).
  • the synthetic route of the target compound I-23 is as follows:
  • the first step the synthesis of 2-methoxypyridine-3-carbaldehyde (I-23B)
  • the second step the synthesis of 2-(2-methoxypyridin-3-yl)acetonitrile (I-23C)
  • p-toluenesulfonylmethylisonitrile (6.26 g, 32.1 mmol) was dissolved in ethylene glycol dimethyl ether (50 mL), and tert-butyl was added in portions at -78 to -65 °C under nitrogen protection.
  • reaction solution was quenched with acetic acid (200 mL, 2.0 M) at 0 ⁇ 25 °C, extracted with ethyl acetate (100 mL*2), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated
  • acetic acid 200 mL, 2.0 M
  • ethyl acetate 100 mL*2
  • the third step Synthesis of 2-(2-methoxypyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-23D)
  • Step 6 4-(2-Methoxypyridin-3-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 - Ketone (I-23)
  • the synthetic route of the target compound I-24 is as follows:
  • Step 2 4-(2-Chloropyridin-3-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-24)
  • the synthetic route of the target compound I-25 is as follows:
  • the first step Synthesis of 2-(2,6-dimethylphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-25B)
  • the second step Synthesis of 2-(2,6-dimethylphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-25C)
  • the third step 2-(2,6-dimethylphenyl)-N-(methylaminothioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide ( I-25D) synthesis
  • the first step Synthesis of 2-(p-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-26B)
  • the second step Synthesis of 2-(p-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-26C)
  • the third step synthesis of N-(methylaminothioformyl)-2-(p-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-26D)
  • the fourth step Synthesis of 1-(methylamino)-4-(p-tolyl)-6-(trifluoromethyl)-3H-pyridine[1,2-c]pyrimidin-3-one (I-26)
  • the first step the synthesis of 2-(m-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-27B)
  • the third step synthesis of N-(methylaminothioformyl)-2-(m-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-27D)
  • the synthetic route of the target compound I-28 is as follows:
  • the first step Synthesis of N-(ethylaminothioformyl)-2-(m-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-28A)
  • N-(ethylaminothiocarbonyl)-2-(m-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-28A) (380 mg, 1.0 mmol ) and pyridine (236 mg, 2.99 mmol) were dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, the temperature was lowered to 0°C, and elemental iodine (759 mg, 2.99 mmol) was slowly added to the reaction solution. Stir at room temperature for 14h.
  • the synthetic route of the target compound I-29 is as follows:
  • the first step Synthesis of 2-(3-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-29B)
  • the second step Synthesis of 2-(3-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-29C)
  • the synthetic route of the target compound I-30 is as follows:
  • the first step Synthesis of 2-(3-bromophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-30B)
  • the second step the synthesis of 2-(3-bromophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-30C)
  • reaction solution was slowly added to an aqueous sodium hydroxide solution (4.00M, 80.0 mL) at 0°C, then extracted with ethyl acetate (50.0 mL*3), the organic layers were combined and dried over anhydrous sodium sulfate , filtered, and concentrated to give a yellow solid 2-(3-bromophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-30C) (2.00 g, 5.57 mmol, yielded rate 95.0%), used directly in the next step.
  • the fourth step 4-(3-bromophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I- 30E) synthesis
  • reaction mixture was diluted with saturated aqueous sodium sulfite solution (10.0 mL), then extracted with ethyl acetate (50.0 mL*3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was washed with ethyl acetate (10.0 mL) was beaten to give a yellow solid compound 4-(3-bromophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine- 3-keto (I-30E) (200 mg, 31.0% yield).
  • the synthetic route of the target compound I-31 is as follows:
  • the first step Synthesis of 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-31B)
  • the second step Synthesis of 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-31C)
  • the synthetic route of the target compound I-32 is as follows:
  • the synthetic route is as follows:
  • the first step Synthesis of 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile
  • the second step synthesis of 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
  • N-((2,2-difluoroethyl)carbamoyl)-2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridine-2 -yl)acetamide 100 mg, 237 ⁇ mol
  • elemental iodine 181 mg, 712 ⁇ mol
  • pyridine 93.9 mg, 1.19 mmol
  • the reaction solution was filtered and concentrated to obtain the crude product.
  • the synthetic route of the target compound I-34 is as follows:
  • the first step the synthesis of 2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-34B)
  • Chromatographic column Chiralcel OD-3 50 ⁇ 4.6mm ID, 3 ⁇ m; mobile phase: mobile phase A is CO 2 , mobile phase B is methanol (0.05% diethylamine); gradient elution conditions: 0 ⁇ 1.8min, 5% ⁇ 40%B(v/v); 1.8min ⁇ 2.7min, 40%B(v/v); 2.7min ⁇ 3min, 40% ⁇ 5%B(v/v); flow rate: 3mL/min; detector : PDA; column temperature: 35°C; back pressure: 100Bar;
  • the synthetic route of the target compound I-35 is as follows:
  • the first step the synthesis of N-(ethylaminothioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-35A)
  • the synthetic route is as follows:
  • the first step Synthesis of 2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile
  • the second step synthesis of 2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
  • the third step synthesis of 1,1-difluoro-2-isothiocyanatoethane

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Abstract

Provided is a new compound capable of effectively inhibiting MAT2A, which compound is a compound as shown in formula I, or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof. Specifically, W is -C(R3)= or -N=, X is -C(R4)= or -N=, Y is -C(R5)=, Z is -C(R6)= or -N=, and the definitions of R1, R2, R3, R4, R5 and R6 are as described in the description.

Description

嘧啶酮化合物及其用途Pyrimidone compounds and their uses
本发明要求享有于2021年4月19日向中国国家知识产权局提交的，专利申请号为202110420450.6，名称为“嘧啶酮化合物及其用途”的在先申请、2021年11月3日向中国国家知识产权局提交的，专利申请号为202111294893.1，名称为“嘧啶酮化合物及其用途”的在先申请和2022年1月6日向中国国家知识产权局提交的，专利申请号为202210010065.9，名称为“嘧啶酮化合物及其用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本发明中。The present invention claims to enjoy the patent application No. 202110420450.6, which was submitted to the State Intellectual Property Office of China on April 19, 2021, and is entitled "Pyrimidone Compounds and Their Uses". The patent application No. 202111294893.1 and the previous application titled "Pyrimidone Compounds and Their Uses" and submitted to the State Intellectual Property Office of China on January 6, 2022, the patent application No. 202210010065.9, titled "Pyrimidone Compounds and Their Uses" of the earlier application. The entirety of this prior application is incorporated herein by reference.
技术领域technical field
本发明涉及化学及医药领域，具体地，本发明涉及嘧啶酮化合物及其用途。The present invention relates to the fields of chemistry and medicine, in particular, the present invention relates to pyrimidone compounds and uses thereof.
背景技术Background technique
甲硫氨酸腺苷转移酶2A(methionine adenosyltransferase 2A，MAT2A)是MAT家族蛋白成员之一，体内分布广泛，在肝脏的非实质细胞和所有肝外组织中均有表达(Murray B,et al.World J Gastroenterol 2019；25(31):4300-4319.)，MAT家族还有MAT1A和MAT2B两个成员。MAT2A抑制剂可降低S-腺苷甲硫氨酸(SAM)水平，故MAT2A抑制剂也称为SAM抑制剂。SAM是细胞中主要的甲基供体，蛋白精氨酸甲基转移酶5(PRMT5)是利用SAM的甲基供体的甲基化酶，SAM在PRMT5通路有重要作用，可影响PRMT5活性，研究表明MAT2A是MTAP缺失型肿瘤的“合成致死”靶点。使用shRNA筛选确定MAT2A和PRMT5是MTAP缺失细胞中的易感基因，代谢学和生化研究揭示了这种合成致死性的机制基础：MTAP酶反应的底物MTA在MTAP缺失的癌症中大量积聚，MTA是PRMT5的一种有效的选择性抑制剂，导致MTAP缺失细胞的PRMT5甲基化活性降低，MAT2A产生PRMT5的底物SAM，MAT2A缺失可选择性地降低MTAP缺失细胞的生长和PRMT5甲基化活性，MAT2A在MTAP缺失的癌症中是选择性必需的(Marjon K,et al.Cell Rep.2016；15(3):574-587)。MAT2A抑制剂为MTAP缺失的肿瘤患者提供了一种新的治疗方法。Methionine adenosyltransferase 2A (MAT2A), a member of the MAT family of proteins, is widely distributed in the body and is expressed in non-parenchymal cells of the liver and all extrahepatic tissues (Murray B, et al. World J Gastroenterol 2019;25(31):4300-4319.), the MAT family also has two members, MAT1A and MAT2B. MAT2A inhibitors can reduce S-adenosylmethionine (SAM) levels, so MAT2A inhibitors are also called SAM inhibitors. SAM is the main methyl donor in cells. Protein arginine methyltransferase 5 (PRMT5) is a methylase that utilizes the methyl donor of SAM. SAM plays an important role in the PRMT5 pathway and can affect the activity of PRMT5. Studies have shown that MAT2A is a "synthetic lethal" target in MTAP-deficient tumors. Using shRNA screens to identify MAT2A and PRMT5 as susceptibility genes in MTAP-deficient cells, metabolic and biochemical studies reveal the mechanistic basis of this synthetic lethality: MTA, a substrate of the MTAP enzymatic reaction, accumulates abundantly in MTAP-deficient cancers, MTA Is a potent and selective inhibitor of PRMT5, resulting in reduced PRMT5 methylation activity in MTAP-deficient cells, MAT2A produces PRMT5 substrate SAM, and MAT2A deletion selectively reduces the growth and PRMT5 methylation activity of MTAP-deficient cells , MAT2A is selectively required in MTAP-deficient cancers (Marjon K, et al. Cell Rep. 2016;15(3):574-587). MAT2A inhibitors offer a new treatment option for patients with MTAP-deficient tumors.
MAT2A参与肿瘤干细胞的代谢，肿瘤干细胞需要大量的甲硫氨酸以维持自身组蛋白的甲基化，这对于肿瘤干细胞的生长和致瘤作用至关重要。抑制甲硫氨酸循环上的关键酶MAT2A，可以大幅抑制肿瘤干细胞的生长和肿瘤的形成。并且在人类非小细胞肺癌组织中，MAT2A蛋白有异常高表达。将非小细胞肺癌的肿瘤干细胞移植到小鼠身上，MAT2A抑制剂几乎能完全抑制肿瘤的生长，而化疗药物顺铂几乎没什么效果(Wang Z,et al.Nature medicine,2019,25(5):1-13.)。MAT2A is involved in the metabolism of cancer stem cells, and cancer stem cells require a large amount of methionine to maintain their own histone methylation, which is crucial for the growth and tumorigenicity of cancer stem cells. Inhibition of MAT2A, a key enzyme in the methionine cycle, can significantly inhibit the growth of cancer stem cells and tumor formation. And in human non-small cell lung cancer tissues, MAT2A protein is abnormally high expressed. When tumor stem cells from non-small cell lung cancer were transplanted into mice, MAT2A inhibitor almost completely suppressed tumor growth, while the chemotherapeutic drug cisplatin had little effect (Wang Z, et al. Nature medicine, 2019, 25(5): 1-13.).
肝癌中MAT1A与MAT2A进行转换。许多研究表明MAT在慢性肝病和肝癌的发生中起着重要作用，正常情况下，胎儿肝脏中主要表达MAT2A，出生后随着生长发育逐渐被MAT1A替代，MAT1A维持肝细胞的分化状态。在正常肝细胞中MAT1A与MAT2A存在动态平衡，共同维持细胞内SAM稳态。在肝细胞癌中，发生MAT1A的表达水平下调和MAT2A的上调，被称为MAT1A：MAT2A转换，肝脏去分化，使SAM生物合成减少，增强肝脏的增殖信号。在人类肝癌中，MAT1A：MAT2A的表达比率与细胞生长和基因组不稳定呈负相关，与肝癌细胞凋亡和整体DNA甲基化直接相关；比率降低是肝癌恶性程度更高、生存率更低的预后标志。有研究表明，使用小干扰RNA沉默MAT2A基因能抑制肝癌细胞的生长并诱导细胞凋亡(Liu Q,et al.Hepatol Res.2007；37(5):376-388.)。Conversion of MAT1A and MAT2A in liver cancer. Many studies have shown that MAT plays an important role in the occurrence of chronic liver disease and liver cancer. Under normal circumstances, MAT2A is mainly expressed in the fetal liver, and is gradually replaced by MAT1A with growth and development after birth. MAT1A maintains the differentiation state of hepatocytes. There is a dynamic balance between MAT1A and MAT2A in normal hepatocytes, which together maintain the homeostasis of intracellular SAM. In hepatocellular carcinoma, down-regulation of MAT1A expression levels and up-regulation of MAT2A occur, termed MAT1A:MAT2A transition, which dedifferentiates the liver, reduces SAM biosynthesis, and enhances proliferative signaling in the liver. In human hepatocellular carcinoma, the expression ratio of MAT1A:MAT2A is negatively correlated with cell growth and genomic instability, and directly correlated with hepatoma cell apoptosis and overall DNA methylation; a reduced ratio is associated with a higher degree of malignancy and a lower survival rate in HCC. prognostic markers. Studies have shown that silencing the MAT2A gene using small interfering RNA can inhibit the growth of hepatoma cells and induce apoptosis (Liu Q, et al. Hepatol Res. 2007; 37(5):376-388.).
2018年全球新增1810万例癌症病例，死亡人数达960万。大约15％的人类癌症染色体9p21(chr9p21)基因组纯合缺失，在多形性胶质母细胞瘤中的缺失频率高达>50％。染色体chr9p21位点包括CDKN2A基因，它编码关键的肿瘤抑制因子p19-ARF和p16-INK4a，Chr9p21缺失经常涉及CDKN2A近端基因的共缺失，其中最重要的是甲硫腺苷磷酸化酶(MTAP)基因。研究发现许多人恶性细胞缺乏MTAP活性。MTAP缺陷不仅存在于组织培养细胞中，而且该缺陷也存在于原发性白血病、胶质瘤、黑色素瘤、胰腺癌、非小细胞肺癌(NSLC)、膀胱癌、星形细胞瘤、骨肉瘤、头颈癌、粘液性软骨肉瘤、卵巢癌、子宫内膜癌、乳腺癌、软组织肉瘤、非霍奇金淋巴瘤和间皮瘤中。In 2018, there were 18.1 million new cancer cases globally and 9.6 million deaths. About 15% of human cancers have a homozygous deletion of chromosome 9p21 (chr9p21), with deletion frequencies as high as >50% in glioblastoma multiforme. The chromosomal chr9p21 locus includes the CDKN2A gene, which encodes the key tumor suppressors p19-ARF and p16-INK4a, and Chr9p21 deletion frequently involves co-deletion of genes proximal to CDKN2A, the most important of which is methylthioadenosine phosphorylase (MTAP) Gene. Studies have found that many human malignant cells lack MTAP activity. MTAP deficiency is not only present in tissue culture cells, but also in primary leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, In head and neck cancer, mucinous chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, and mesothelioma.
目前MAT2A抑制剂在癌症等领域的研究取得了一定的进展，但仍需进一步开发新型的药物，优化目前在研MAT2A药物，为癌症治疗领域未被满足的临床需求提供新的治疗选择。At present, the research of MAT2A inhibitors in cancer and other fields has made some progress, but it is still necessary to further develop new drugs, optimize the current MAT2A drugs under research, and provide new treatment options for the unmet clinical needs in the field of cancer treatment.
发明内容SUMMARY OF THE INVENTION
本发明旨在提出一种能够有效抑制MAT2A的化合物，其能够作为目前药物或者MAT2A抑制剂的改进或者替换。The present invention aims to provide a compound that can effectively inhibit MAT2A, which can be used as an improvement or replacement of current drugs or MAT2A inhibitors.
为此，在本发明的第一方面，本发明提出了一种式I所示化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：To this end, in the first aspect of the present invention, the present invention proposes a compound shown in formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug :
Figure PCTCN2022087589-appb-000001
Figure PCTCN2022087589-appb-000001
其中，in,
W是-C(R 3)＝或-N＝；X是-C(R 4)＝或-N＝；Y是-C(R 5)＝；Z是-C(R 6)＝或-N＝；其中： W is -C(R 3 )= or -N=; X is -C(R 4 )= or -N=; Y is -C(R 5 )=; Z is -C(R 6 )= or -N =; where:
R 3选自氢、烷基、烯基、炔基、烷氧基、烷基磺酰基、卤素、卤代烷基、卤代烷氧基、环烷基、环烷基烷氧基、氰基、氨基、烷基氨基、二烷基氨基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、羟基烷基、羟基烷氧基、羟基烷基氨基、烷氧基烷基、烷氧基烷氧基、烷氧基烷基氨基、氨基烷基、氨基烷氧基、氨基烷基氨基、杂芳基、杂芳氧基、杂芳烷氧基、杂芳基氨基、杂环烷基、杂环基氧基、杂环基氨基、杂环基烷氧基、杂环基氧基烷氧基和杂环基氧基烷基氨基，R 3本身或作为另一个基团的一部分是未被取代的或者被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自烷基、环烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤素、氰基、烷氧基羰基、羟烷基、烷氧基烷基和氨基烷基； R is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkoxy, cyano, amino, alkane amino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxy Oxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkoxy, heteroarylamino, heterocycloalkyl, heterocyclyloxy , heterocyclylamino, heterocyclylalkoxy, heterocyclyloxyalkoxy, and heterocyclyloxyalkylamino, R is unsubstituted by itself or as part of another group or is replaced by R a , R b and/ or R c substituted independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano group, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl and aminoalkyl;
R 5选自氢、烷基、烯基、炔基、烷氧基、烷基磺酰基、卤素、卤代烷基、卤代烷氧基、环烷基、氰基、氨基、烷基氨基、二烷基氨基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、羟基烷基、羟基烷氧基、羟基烷基氨基、烷氧基烷基、烷氧基烷氧基、烷氧基烷基氨基、氨基烷基、氨基烷氧基、氨基烷基氨基、杂芳基、杂芳氧基、杂芳基氨基、杂环基、杂环基氧基、杂环基氨基、杂环基氧基烷氧基，R 5本身或作为另一个基团的一部分是未被取代的或者被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自烷基、环烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤素、氰基、羟烷基、烷氧基烷基和氨基烷基； R 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino , alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxy Alkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyl Oxyalkoxy , R is unsubstituted by itself or as part of another group or is substituted by Ra , Rb and/ or Rc independently selected from the group consisting of alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl and aminoalkyl;
R 4和R 6各自独立地选自氢、烷基、烯基、炔基、烷氧基、烷硫基、烷基磺酰基、卤素、卤代烷基、卤代烷氧基、环烷基、氰基、氨基、烷基氨基、二烷基氨基、氨基羰基、烷基氨基羰基或二烷基氨基羰基； R4 and R6 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl;
条件是：(i)W、X和Z中最多一个可以为-N＝，并且(ii)R 3、R 4、R 5和R 6中至少一个 不是氢； Provided that: (i) at most one of W, X, and Z may be -N=, and (ii ) at least one of R3 , R4, R5 , and R6 is not hydrogen ;
R 1选自环烷基、桥连的环烷基、稠合的环烷基、螺环烷基、芳基、杂芳基、杂环基、桥连杂环基、稠合杂环基或螺杂环基，其中芳基、杂芳基或杂环基无取代或被R d、R e和/或R f取代； R 1 is selected from cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl or spiroheterocyclyl, wherein aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with Rd , Re and/or Rf ;
R 2为-NR 7R 8，其中： R 2 is -NR 7 R 8 , where:
R 7选自氢、烷基、氘代烷基和环烷基； R is selected from hydrogen, alkyl, deuterated alkyl and cycloalkyl;
R 8选自氢、烷基、氘代烷基、卤代烷基、羟基烷基、烷氧基烷基、卤代烷氧基烷基、氨基烷基、氨基磺酰基烷基、硫脲基烷基、烷基磺酰基、烷基磺酰基烷基、氰基烷基、烷基羰基、烷氧基羰基、烷基氨基羰基、二烷基氨基羰基、氨基羰基烷基、环烷基、环烷基烷基、取代的环烷基、取代的环烷基烷基、环烷氧基烷基、桥连的环烷基、桥连的环烷基环烷基、稠合的环烷基、螺环烷基，螺环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂芳基羰基、杂环基、杂环基烷基、杂环基羰基、杂环基氧基烷基、稠合的杂环基、稠合的杂环基烷基、桥连的杂环基、桥连的杂环基烷基、螺杂环基和螺杂环基烷基；所述R 8是未被取代的或者被R j、R k和/或R L取代； R 8 is selected from hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl, thioureidoalkyl, alkane Sulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl , substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylcycloalkyl, fused cycloalkyl, spirocycloalkyl , spirocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxy alkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl; the R 8 is unsubstituted or substituted with R j , R k and/or RL ;
或者R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述杂环烷基是未被取代的或者被R j、R k和/或R L取代； or R 7 , R 8 together with the N atom to which they are commonly attached form a 4-6 membered heterocycloalkyl which is unsubstituted or substituted with R j , R k and/or RL ;
或者R 7、R 8与它们共同连接的N原子一起形成6-12元螺杂环基、6-12元桥连的杂环基、6-12元杂并环烷基，所述6-12元螺杂环基、6-12元桥连的杂环基和6-12元杂并环烷基是未被取代的或者被R j、R k和/或R L取代，所述6-12元螺杂环基、6-12元桥连的杂环基和6-12元杂并环烷基的1-5个环原子独立选自N、O和S； Or R 7 , R 8 together with the N atom to which they are connected together form a 6-12-membered spiro heterocyclyl, a 6-12-membered bridged heterocyclyl, a 6-12-membered heterocycloalkyl, and the 6-12 membered heterocyclyl Member spiroheterocyclyl, 6-12 membered bridged heterocyclyl and 6-12 membered heterocycloalkyl are unsubstituted or substituted by R j , R k and/or RL , the 6-12 1-5 ring atoms of membered spiroheterocyclyl, 6-12 membered bridged heterocyclyl and 6-12 membered heterocycloalkyl are independently selected from N, O and S;
R d、R e、R j和R k各自独立地选自烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、烷基磺酰基、卤素、氰基、羧基、烷氧基羰基、羟烷基、烷氧基烷基、氨基烷基、氨基磺酰基、烷基氨基磺酰基、二烷基氨基磺酰基、磺酰基氨基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、杂环羰基和脲基； R d , Re , R j and R k are each independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxy Alkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocycle carbonyl and urea groups;
R f和R L各自独立地选自烷基、环烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤素、氨基、烷基氨基、环烷基磺酰基氨基、氰基、氰基烷基、烷氧基羰基烷基、羧烷基、氨基羰基烷基和-X c-R 9，其中X c选自键、亚烷基和杂亚烷基，R 9选自任选被取代的芳基、任选被取代的杂芳基和任选被取代的杂环基。 Rf and RL are each independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino, alkylamino, cycloalkylsulfonylamino, cyano, cyano Alkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl and -Xc-R9, wherein Xc is selected from bond, alkylene and heteroalkylene, and R9 is selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.
根据本发明的某些实施例，本发明提出了一种化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：According to some embodiments of the present invention, the present invention proposes a compound, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I Acceptable salts or prodrugs:
Figure PCTCN2022087589-appb-000002
Figure PCTCN2022087589-appb-000002
其中，W是-C(R 3)＝或-N＝；X是-C(R 4)＝或-N＝；Y是-C(R 5)；Z是-C(R 6)＝或-N＝；其中： where W is -C(R 3 )= or -N=; X is -C(R 4 )= or -N=; Y is -C(R 5 ); Z is -C(R 6 )= or - N =; where:
R 3选自氢、烷基、烯基、炔基、烷氧基、烷基磺酰基、卤素、卤代烷基、卤代烷氧基、环烷基、环烷基烷氧基、氰基、氨基、烷基氨基、二烷基氨基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、羟基烷基、羟基烷氧基、羟基烷基氨基、烷氧基烷基、烷氧基烷氧基、烷氧基烷基氨基、氨基烷基、氨基烷氧基、氨基烷基氨基、杂芳基、杂芳氧基、杂芳烷氧基、杂芳基氨基、杂环烷基、杂环基氧基、杂环基氨基、杂环基烷氧基、杂环基氧基烷氧基和杂环基氧基烷基氨基，R 3本身或作为另一个基团的一部分是未被取代的或者被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自烷基、环烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤素、 氰基、烷氧基羰基、羟烷基、烷氧基烷基和氨基烷基； R is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkoxy, cyano, amino, alkane amino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxy Oxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkoxy, heteroarylamino, heterocycloalkyl, heterocyclyloxy , heterocyclylamino, heterocyclylalkoxy, heterocyclyloxyalkoxy, and heterocyclyloxyalkylamino, R is unsubstituted by itself or as part of another group or is replaced by R a , R b and/ or R c substituted independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano group, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl and aminoalkyl;
R 5选自氢、烷基、烯基、炔基、烷氧基、烷基磺酰基、卤素、卤代烷基、卤代烷氧基、环烷基、氰基、氨基、烷基氨基、二烷基氨基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、羟基烷基、羟基烷氧基、羟基烷基氨基、烷氧基烷基、烷氧基烷氧基、烷氧基烷基氨基、氨基烷基、氨基烷氧基、氨基烷基氨基、杂芳基、杂芳氧基、杂芳基氨基、杂环基、杂环基氧基、杂环基氨基、杂环基氧基烷氧基，R 5本身或作为另一个基团的一部分是未被取代的或者被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自烷基、环烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤素、氰基、羟烷基、烷氧基烷基和氨基烷基； R 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino , alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxy Alkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyl Oxyalkoxy , R is unsubstituted by itself or as part of another group or is substituted by Ra , Rb and/ or Rc independently selected from the group consisting of alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl and aminoalkyl;
R 4和R 6各自独立地选自氢、烷基、烯基、炔基、烷氧基、烷硫基、烷基磺酰基、卤素、卤代烷基、卤代烷氧基、环烷基、氰基、氨基、烷基氨基、二烷基氨基、氨基羰基、烷基氨基羰基或二烷基氨基羰基； R4 and R6 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl;
条件是：(i)W、X和Z中最多一个可以为-N＝，并且(ii)R 3、R 4、R 5和R 6中至少一个不是氢； Provided that: (i) at most one of W, X, and Z may be -N=, and (ii ) at least one of R3 , R4, R5 , and R6 is not hydrogen ;
R 1选自环烷基、桥连的环烷基、稠合的环烷基、螺环烷基、芳基、杂芳基、杂环基、桥连杂环基、稠合杂环基或螺杂环基，其中芳基、杂芳基或杂环基无取代或被R d、R e和/或R f取代； R 1 is selected from cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl or spiroheterocyclyl, wherein aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with Rd , Re and/or Rf ;
R 2为-NR 7R 8，其中： R 2 is -NR 7 R 8 , where:
R 7选自氢、烷基、氘代烷基或环烷基； R is selected from hydrogen, alkyl, deuterated alkyl or cycloalkyl;
R 8选自氢、烷基、氘代烷基、卤代烷基、羟基烷基、烷氧基烷基、卤代烷氧基烷基、氨基烷基、氨基磺酰基烷基、硫脲基烷基、烷基磺酰基、烷基磺酰基烷基、氰基烷基、烷基羰基、烷氧基羰基、烷基氨基羰基、二烷基氨基羰基、氨基羰基烷基、环烷基、环烷基烷基、取代的环烷基、取代的环烷基烷基、环烷氧基烷基、桥连的环烷基、桥连的环烷基环烷基、稠合的环烷基、螺环烷基，螺环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂芳基羰基、杂环基、杂环基烷基、杂环基羰基、杂环基氧基烷基、稠合的杂环基、稠合的杂环基烷基、桥连的杂环基、桥连的杂环基烷基、螺杂环基和螺杂环基烷基；所述R 8是未被取代的或者被R j、R k和/或R L取代； R 8 is selected from hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl, thioureidoalkyl, alkane Sulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl , substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylcycloalkyl, fused cycloalkyl, spirocycloalkyl , spirocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxy alkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl; the R 8 is unsubstituted or substituted with R j , R k and/or RL ;
或者R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述杂环烷基是未被取代的或者被R j、R k和/或R L取代； or R 7 , R 8 together with the N atom to which they are commonly attached form a 4-6 membered heterocycloalkyl which is unsubstituted or substituted with R j , R k and/or RL ;
R d、R e、R j和R k各自独立地选自烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、烷基磺酰基、卤素、氰基、羧基、烷氧基羰基、羟烷基、烷氧基烷基、氨基烷基、氨基磺酰基、烷基氨基磺酰基、二烷基氨基磺酰基、磺酰基氨基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、杂环羰基和脲基； R d , Re , R j and R k are each independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxy Alkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocycle carbonyl and urea groups;
R f和R L各自独立地选自烷基、环烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤素、氨基、烷基氨基、环烷基磺酰基氨基、氰基、氰基烷基、烷氧基羰基烷基、羧烷基、氨基羰基烷基和-X c-R 9，其中X c选自键、亚烷基和杂亚烷基，R 9选自任选被取代的芳基、任选被取代的杂芳基和任选被取代的杂环基。 Rf and RL are each independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino, alkylamino, cycloalkylsulfonylamino, cyano, cyano Alkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl and -Xc-R9, wherein Xc is selected from bond, alkylene and heteroalkylene, and R9 is selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.
所述烷基包括直链烷基、支链烷基。The alkyl group includes straight chain alkyl group and branched chain alkyl group.
本领域技术人员可以理解，根据本领域中使用的惯例，在本申请的结构式中，
Figure PCTCN2022087589-appb-000003
用于描绘化学键，所述化学键为部分或取代基与核心结构或骨架结构相连的点。 Those skilled in the art can understand that, according to the convention used in the art, in the structural formula of the present application,
Figure PCTCN2022087589-appb-000003
Used to delineate a chemical bond, which is the point at which a moiety or substituent is attached to a core or backbone structure.
根据本发明的某些实施例，式I所示化合物中：R 2为-NR 7R 8，并且R 7和R 8不同时为氢，亦即，R 2不为-NH 2。 According to certain embodiments of the present invention, in the compound of formula I: R 2 is -NR 7 R 8 , and R 7 and R 8 are not both hydrogen, that is, R 2 is not -NH 2 .
根据本发明的某些实施例，式I所示化合物中，W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝。 According to certain embodiments of the present invention, in the compound represented by formula I, W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C (R 6 )=.
根据本发明的某些实施例，式I所示化合物中，W是-N＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z 是-C(R 6)＝。 According to certain embodiments of the present invention, in the compound represented by formula I, W is -N=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 ) =.
根据本发明的某些实施例，式I所示化合物中，W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-N＝。 According to certain embodiments of the present invention, in the compound represented by formula I, W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -N =.
根据本发明的某些实施例，式I所示化合物中，W是-C(R 3)＝，X是-N＝，Y是-C(R 5)＝，Z是-C(R 6)＝。 According to certain embodiments of the present invention, in the compound represented by formula I, W is -C(R 3 )=, X is -N=, Y is -C(R 5 )=, Z is -C(R 6 ) =.
根据本发明的某些实施例，式I所示化合物中，R 2为-NR 7R 8，当R 7、R 8与它们共同连接的N原子一起形成6-12元螺杂环基、6-12元桥连的杂环基、6-12元杂并环烷基时，所述R 2为：
Figure PCTCN2022087589-appb-000004
其中环A为4-6元杂环烷基，R A1、R A2以及环A的部分环原子相连形成3-7元环烷基或3-7元杂环烷基，所述3-7元杂环烷基的1-3个环原子独立选自N、O和S，所述R 2是未被取代的或者被R j、R k和/或R L取代；未定义的基团如前任一方案所述。 According to some embodiments of the present invention, in the compound represented by formula I, R 2 is -NR 7 R 8 , when R 7 and R 8 together with the N atom to which they are connected together form a 6-12-membered spiro heterocyclyl, 6 -12-membered bridged heterocyclyl, 6-12-membered heterocycloalkyl, the R 2 is:
Figure PCTCN2022087589-appb-000004
wherein Ring A is a 4-6 membered heterocycloalkyl, and R A1 , R A2 and some ring atoms of Ring A are connected to form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, and the 3-7 membered 1-3 ring atoms of heterocycloalkyl are independently selected from N, O and S, and said R 2 is unsubstituted or substituted by R j , R k and/or RL ; undefined groups are as predecessors described in a plan.
根据本发明的某些实施例，式I所示化合物中，R 2选自无取代的或被R j、R k和/或R L取代的以下基团：
Figure PCTCN2022087589-appb-000005
Figure PCTCN2022087589-appb-000006
其中R A1、R A2以及环A的部分环原子相连形成3-7元环烷基或3-7元杂环烷基，所述3-7元杂环烷基的1-3个环原子独立选自N、O和S；未定义的基团如前任一方案所述 According to certain embodiments of the present invention, in the compound shown in formula I, R 2 is selected from the following groups unsubstituted or substituted by R j , R k and/or RL :
Figure PCTCN2022087589-appb-000005
Figure PCTCN2022087589-appb-000006
wherein R A1 , R A2 and some ring atoms of ring A are connected to form a 3-7-membered cycloalkyl or a 3-7-membered heterocycloalkyl, and 1-3 ring atoms of the 3-7-membered heterocycloalkyl are independent Selected from N, O and S; undefined groups are as described in any of the previous schemes
根据本发明的某些实施例，式I所示化合物中，R 2选自无取代的或被R j、R k和/或R L取代的以下基团：
Figure PCTCN2022087589-appb-000007
未定义的基团如前任一方案所述。 According to certain embodiments of the present invention, in the compound shown in formula I, R 2 is selected from the following groups unsubstituted or substituted by R j , R k and/or RL :
Figure PCTCN2022087589-appb-000007
Undefined groups are as described in any of the previous schemes.
根据本发明的某些实施例，式I所示化合物中，R 3选自氢、C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 1-C 10烷氧基、C 1-C 10烷基磺酰基、卤素、被1-5个相同或不同的卤素取代的C 1-C 10烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷氧基、C 3-C 10环烷基、氰基、氨基、(C 1-C 10烷基)-NH-、N(C 1-C 10烷基) 2-、氨基羰基、(C 1-C 10烷基)-NH-C(O)-、N(C 1-C 10烷基) 2-C(O)-、被1-5个羟基取代的C 1-C 10烷基、被1-5个羟基取代的C 1-C 10烷氧基、(被1-5个羟基取代的C 1-C 10烷基)-NH-、被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷基、被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷氧基、(被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷基)-NH-、被1-5个氨基取代的C 1-C 10烷基、被1-5个氨基取代的C 1-C 10烷氧基、(被1-5个氨基取代的C 1-C 10烷基)-NH-，R 3本身或作为另一个基团的一部分是未被取代的或者被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自烷基、环烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤素、氰基、烷氧基羰基、羟烷基、烷氧基烷基和氨基烷基； According to certain embodiments of the present invention, in the compound represented by formula I, R 3 is selected from hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylsulfonyl, halogen, C 1 -C 10 alkyl substituted with 1-5 identical or different halogens, C substituted with 1-5 identical or different halogens 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, cyano, amino, (C 1 -C 10 alkyl)-NH-, N(C 1 -C 10 alkyl) 2 -, aminocarbonyl , (C 1 -C 10 alkyl)-NH-C(O)-, N(C 1 -C 10 alkyl) 2 -C(O)-, C 1 -C 10 substituted by 1-5 hydroxyl groups Alkyl, C 1 -C 10 alkoxy substituted with 1-5 hydroxy, (C 1 -C 10 alkyl substituted with 1-5 hydroxy)-NH-, identical or different with 1-5 C 1 -C 10 alkoxy substituted C 1 -C 10 alkyl, C 1 -C 10 alkoxy substituted by 1-5 identical or different C 1 -C 10 alkoxy, ( 5 identical or different C 1 -C 10 alkoxy substituted C 1 -C 10 alkyl)-NH-, C 1 -C 10 alkyl substituted with 1-5 amino groups, C 1 -C 10 alkyl substituted with 1-5 amino groups Substituted C 1 -C 10 alkoxy, (C 1 -C 10 alkyl substituted with 1-5 amino groups)-NH-, R 3 by itself or as part of another group is unsubstituted or by Substituted with R a , R b and / or R c independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl and aminoalkyl;
R 5选自氢、C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 1-C 10烷氧基、C 1-C 10烷基磺酰基、卤素、被1-5个相同或不同的卤素取代的C 1-C 10烷基、被1-5个相同或不同的卤素取代的C 1-C 10 烷氧基、C 3-C 10环烷基、氰基、氨基、(C 1-C 10烷基)-NH-、N(C 1-C 10烷基) 2-、(C 1-C 10烷氧基)-C(O)-、氨基羰基、(C 1-C 10烷基)-氨基羰基、(C 1-C 10烷基) 2-氨基羰基、被1-5个羟基取代的C 1-C 10烷基、被1-5个羟基取代的C 1-C 10烷氧基、(被1-5个羟基取代的C 1-C 10烷基)-NH-、被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷基、被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷氧基、(被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷基)-NH-、被1-5个氨基取代的C 1-C 10烷基、被1-5个氨基取代的C 1-C 10烷氧基、(被1-5个氨基取代的C 1-C 10烷基)-NH-，R 5本身或作为另一个基团的一部分是未被取代的或者被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自烷基、环烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤素、氰基、羟烷基、烷氧基烷基和氨基烷基； R 5 is selected from hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylsulfonyl, halogen , C 1 -C 10 alkyl substituted by 1-5 identical or different halogens, C 1 -C 10 alkoxy substituted by 1-5 identical or different halogens, C 3 -C 10 cycloalkyl , cyano, amino, (C 1 -C 10 alkyl)-NH-, N(C 1 -C 10 alkyl) 2 -, (C 1 -C 10 alkoxy)-C(O)-, amino Carbonyl, (C 1 -C 10 alkyl)-aminocarbonyl, (C 1 -C 10 alkyl) 2 -aminocarbonyl, C 1 -C 10 alkyl substituted by 1-5 hydroxy, substituted by 1-5 Hydroxy-substituted C 1 -C 10 alkoxy, (C 1 -C 10 alkyl substituted with 1-5 hydroxy)-NH-, C 1 -C 10 alkoxy substituted with 1-5 identical or different Substituted C 1 -C 10 alkyl, C 1 -C 10 alkoxy substituted by 1-5 identical or different C 1 -C 10 alkoxy , (by 1-5 identical or different C 1 -C 10 alkoxy substituted C 1 -C 10 alkyl) -NH-, C 1 -C 10 alkyl substituted with 1-5 amino groups, C 1 -C 10 alkane substituted with 1-5 amino groups oxy, (C 1 -C 10 alkyl substituted with 1-5 amino groups)-NH-, R 5 is unsubstituted by itself or as part of another group or is replaced by R a , R b and/or Substituted with R c , the R a , R b and/or R c are independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkane oxyalkyl and aminoalkyl;
R 4和R 6各自独立地选自氢、C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 1-C 10烷氧基、C 1-C 10烷硫基、C 1-C 10烷基磺酰基、卤素、被1-5个相同或不同的卤素取代的C 1-C 10烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷氧基、C 3-C 10环烷基、氰基、氨基、(C 1-C 10烷基)-NH-、N(C 1-C 10烷基) 2-、氨基羰基、(C 1-C 10烷基)-氨基羰基、(C 1-C 10烷基) 2-氨基羰基； R 4 and R 6 are each independently selected from hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 1 -C 10 Alkylthio, C 1 -C 10 alkylsulfonyl, halogen, C 1 -C 10 alkyl substituted with 1-5 identical or different halogens, C 1 substituted with 1-5 identical or different halogens -C 10 alkoxy, C 3 -C 10 cycloalkyl, cyano, amino, (C 1 -C 10 alkyl)-NH-, N(C 1 -C 10 alkyl) 2 -, aminocarbonyl, (C 1 -C 10 alkyl)-aminocarbonyl, (C 1 -C 10 alkyl) 2 -aminocarbonyl;
条件是：(i)W、X和Z中最多一个可以为-N＝，并且(ii)R 3、R 4、R 5和R 6中至少一个不是氢； Provided that: (i) at most one of W, X, and Z may be -N=, and (ii ) at least one of R3 , R4, R5 , and R6 is not hydrogen ;
R 1选自C 6-C 10芳基、5-10元杂芳基、3-10元杂环基、5-10元桥连杂环基、5-10元稠合杂环基或5-10元螺杂环基，其中C 6-C 10芳基、5-10元杂芳基或3-10元杂环基无取代或被R d、R e和/或R f取代； R 1 is selected from C 6 -C 10 aryl, 5-10-membered heteroaryl, 3-10-membered heterocyclyl, 5-10-membered bridged heterocyclyl, 5-10-membered fused heterocyclyl or 5- 10-membered spiro heterocyclyl, wherein C 6 -C 10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl is unsubstituted or substituted by R d , Re and/or R f ;
R 2为-NR 7R 8，其中： R 2 is -NR 7 R 8 , where:
R 7选自氢、C 1-C 10烷基、氘代C 1-C 10烷基或C 3-C 10环烷基； R 7 is selected from hydrogen, C 1 -C 10 alkyl, deuterated C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl;
R 8选自氢、C 1-C 10烷基、氘代C 1-C 10烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷基、被1-5个羟基取代的C 1-C 10烷基、被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷基、(被1-5个相同或不同的卤素取代的C 1-C 10烷氧基)-(C 1-C 10亚烷基)-、被1-5个氨基取代的C 1-C 10烷基、被1-5个氨基磺酰基取代的C 1-C 10烷基、被1-5个硫脲基取代的C 1-C 10烷基、C 1-C 10烷基磺酰基、(C 1-C 10烷基磺酰基)-(C 1-C 10亚烷基)-、被1-5个氰基取代的C 1-C 10烷基、(C 1-C 10烷基)-C(O)-、(C 1-C 10烷氧基)-C(O)-、(C 1-C 10烷基)-NH-C(O)-、N(C 1-C 10烷基) 2-C(O)-、被氨基羰基取代的C 1-C 10烷基、C 3-C 10环烷基、被1-3个C 3-C 10环烷基取代的C 1-C 10烷基、被1-3个C 3-C 10环烷氧基取代的C 1-C 10烷基、桥连的C 5-C 10环烷基、被桥连的C 5-C 10环烷基取代的C 3-C 10环烷基、稠合的C 5-C 10环烷基、C 6-C 10螺环烷基、被C 6-C 10螺环烷基取代的C 1-C 10烷基、C 6-C 10芳基、被1-5个相同或不同的C 6-C 10芳基取代的C 1-C 10烷基、5-10元杂芳基、被1-5个相同或不同的5-10元杂芳基取代的C 1-C 10烷基、(5-10元杂芳基)-C(O)-、3-10元杂环基、被1-5个相同或不同的3-10元杂环基取代的C 1-C 10烷基、(3-10元杂环基)-C(O)-、(3-10元杂环基)-O-(C 1-C 10亚烷基)-、5-10元稠合杂环基、被1-5个相同或不同的5-10元稠合杂环基取代的C 1-C 10烷基、5-10元桥连杂环基、被1-5个相同或不同的5-10元桥连杂环基取代的C 1-C 10烷基、5-10元螺杂环基、被1-5个相同或不同的5-10元螺杂环基取代的C 1-C 10烷基；所述R 8无取代或被R j、R k和/或R L取代； R 8 is selected from hydrogen, C 1 -C 10 alkyl, deuterated C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted with 1-5 identical or different halogens, 1-5 hydroxyl groups Substituted C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted by 1-5 identical or different C 1 -C 10 alkoxy, (substituted by 1-5 identical or different halogen C 1 -C 10 alkoxy)-(C 1 -C 10 alkylene)-, C 1 -C 10 alkyl substituted with 1-5 amino groups, C 1 substituted with 1-5 aminosulfonyl groups -C 10 alkyl, C 1 -C 10 alkyl substituted with 1-5 thiourea groups, C 1 -C 10 alkylsulfonyl, (C 1 -C 10 alkylsulfonyl)-(C 1 - C 10 alkylene)-, C 1 -C 10 alkyl substituted with 1-5 cyano groups, (C 1 -C 10 alkyl)-C(O)-, (C 1 -C 10 alkoxy )-C(O)-, (C 1 -C 10 alkyl)-NH-C(O)-, N(C 1 -C 10 alkyl) 2 -C(O)-, C substituted with aminocarbonyl 1 - C10 alkyl, C3 - C10 cycloalkyl, C1 - C10 alkyl substituted by 1-3 C3 - C10 cycloalkyl, 1-3 C3- C10 ring Alkoxy substituted C 1 -C 10 alkyl, bridged C 5 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl substituted by bridged C 5 -C 10 cycloalkyl, fused C 5 -C 10 cycloalkyl, C 6 -C 10 spiro cycloalkyl, C 1 -C 10 alkyl substituted by C 6 -C 10 spiro cycloalkyl, C 6 -C 10 aryl, 1 -C 1 -C 10 alkyl substituted with 5 identical or different C 6 -C 10 aryl groups, 5-10 membered heteroaryl, substituted by 1-5 identical or different 5-10 membered heteroaryl groups C 1 -C 10 alkyl, (5-10 membered heteroaryl)-C(O)-, 3-10 membered heterocyclyl, substituted by 1-5 same or different 3-10 membered heterocyclyl C 1 -C 10 alkyl, (3-10 membered heterocyclyl)-C(O)-, (3-10 membered heterocyclyl)-O-(C 1 -C 10 alkylene)-, 5- 10-membered fused heterocyclic group, C 1 -C 10 alkyl substituted by 1-5 identical or different 5-10-membered fused heterocyclic groups, 5-10-membered bridged heterocyclic group, 1-5 C 1 -C 10 alkyl substituted by the same or different 5-10 membered bridged heterocyclyl, 5-10 membered spiroheterocyclyl, 5-10 membered spiroheterocyclyl substituted by 1-5 same or different 5-10 membered heterocyclyl Substituted C 1 -C 10 alkyl; said R 8 is unsubstituted or substituted with R j , R k and/or RL ;
或者R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基是未被取代的或者被R j、R k和/或R L取代； Alternatively R 7 , R 8 together with the N atom to which they are commonly attached form a 4-6 membered heterocycloalkyl group which is unsubstituted or is replaced by R j , R k and/or R L replaced;
R d、R e、R j和R k各自独立地选自C 1-C 10烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷氧基、C 1-C 10烷氧基、羟基、C 1-C 10烷基磺酰基、卤素、氰基、羧基、(C 1-C 10烷氧基)-C(O)-、被1-5个羟基取代的C 1-C 10烷基、被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷基、被1-5个氨基取代的C 1-C 10烷基、氨基磺酰基、(C 1-C 10烷基)-NH-S(O) 2-、N(C 1-C 10烷基) 2-S(O) 2-、磺酰基氨基、氨基羰基、(C 1-C 10烷基)-NH-C(O)-、N(C 1-C 10烷基) 2-C(O)-、(3-10元杂环基)-C(O)-和脲基； R d , R e , R j and R k are each independently selected from C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted with 1-5 identical or different halogens, identical with 1-5 or different halogen substituted C 1 -C 10 alkoxy, C 1 -C 10 alkoxy, hydroxyl, C 1 -C 10 alkylsulfonyl, halogen, cyano, carboxyl, (C 1 -C 10 alkane oxy)-C(O)-, C 1 -C 10 alkyl substituted with 1-5 hydroxyl groups, C 1 -C 10 substituted with 1-5 identical or different C 1 -C 10 alkoxy groups Alkyl, C 1 -C 10 alkyl substituted with 1-5 amino groups, aminosulfonyl, (C 1 -C 10 alkyl)-NH-S(O) 2 -, N(C 1 -C 10 alkane base) 2 -S(O) 2 -, sulfonylamino, aminocarbonyl, (C 1 -C 10 alkyl)-NH-C(O)-, N(C 1 -C 10 alkyl) 2 -C( O)-, (3-10 membered heterocyclyl)-C(O)- and ureido;
R f和R L各自独立地选自C 1-C 10烷基、C 5-C 10环烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷氧基、C 1-C 10烷氧基、羟基、卤素、氨基、(C 1-C 10烷基)-NH-、(C 3-C 10环烷基)-S(O) 2-NH-、氰基、被1-5个氰基取代的C 1-C 10烷基、被1-5个相同或不同的C 1-C 10烷氧基羰基取代的C 1-C 10烷基、被羧基取代的C 1-C 10烷基、被氨基羰基取代的C 1-C 10烷基、-X c-R 9，其中X c选自键、C 1-C 5亚烷基和C 1-C 5杂亚烷基，R 9选自任选被取代的C 6-C 10芳基、任选被取代的5-10元杂芳基和任选被取代的5-10元杂环基。 R f and RL are each independently selected from C 1 -C 10 alkyl, C 5 -C 10 cycloalkyl, C 1 -C 10 alkyl substituted with 1-5 identical or different halogens, C 1 -C 10 alkyl substituted with 1- 5 identical or different halogen-substituted C 1 -C 10 alkoxy, C 1 -C 10 alkoxy, hydroxy, halogen, amino, (C 1 -C 10 alkyl)-NH-, (C 3 - C 10 cycloalkyl)-S(O) 2 -NH-, cyano, C 1 -C 10 alkyl substituted with 1-5 cyano groups, C 1 -C 10 with 1-5 identical or different C 1 -C 10 alkyl substituted by alkoxycarbonyl, C 1 -C 10 alkyl substituted by carboxyl, C 1 -C 10 alkyl substituted by aminocarbonyl, -X c -R 9 , wherein X c is selected from Self-bond, C 1 -C 5 alkylene and C 1 -C 5 heteroalkylene, R 9 is selected from optionally substituted C 6 -C 10 aryl, optionally substituted 5-10 membered heteroaryl and optionally substituted 5-10 membered heterocyclyl.
根据本发明的某些实施例，式I所示化合物中，R 3选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、氰基、氨基、(C 1-C 6烷基)-NH-、N(C 1-C 6烷基) 2-、被1-3个羟基取代的C 1-C 6烷基、被1-3个氨基取代的C 1-C 6烷基、被1-3个氨基取代的C 1-C 6烷氧基、(被1-3个氨基取代的C 1-C 6烷基)-NH-，R 3本身或作为另一个基团的一部分是未被取代的或者被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自C 1-C 3烷基、C 3-C 6环烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷氧基、C 1-C 3烷氧基、羟基、卤素、氰基； According to certain embodiments of the present invention, in the compound represented by formula I, R 3 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 alkoxy substituted by 1-5 identical or different halogens, cyano , amino, (C 1 -C 6 alkyl)-NH-, N(C 1 -C 6 alkyl) 2 -, C 1 -C 6 alkyl substituted by 1-3 hydroxyl groups, 1-3 Amino-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy substituted with 1-3 amino groups, (C 1 -C 6 alkyl substituted with 1-3 amino groups)-NH-, R 3 by itself or as part of another group is unsubstituted or substituted with Ra , Rb and /or Rc independently selected from C1 - C3 Alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens, C 1 -C 3 alkane substituted with 1-5 identical or different halogens oxy, C 1 -C 3 alkoxy, hydroxy, halogen, cyano;
R 5选自氢、C 1-C 6烷基、C 2-C 6烯基、C 1-C 6炔基、C 1-C 6烷氧基、C 1-C 6烷基磺酰基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 3-C 6环烷基、氰基、氨基、(C 1-C 6烷基)-NH-、N(C 1-C 6烷基) 2-、(C 1-C 6烷氧基)-C(O)-、氨基羰基、(C 1-C 6烷基)-氨基羰基、(C 1-C 6烷基) 2-氨基羰基、被1-3个羟基取代的C 1-C 6烷基、被1-3个羟基取代的C 1-C 6烷氧基、(被1-3个羟基取代的C 1-C 6烷基)-NH-、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷氧基、(被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基)-NH-、被1-3个氨基取代的C 1-C 6烷基、被1-3个氨基取代的C 1-C 6烷氧基、(被1-3个氨基取代的C 1-C 6烷基)-NH-，R 5本身或作为另一个基团的一部分是未被取代的或者被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自C 1-C 3烷基、C 3-C 6环烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷氧基、C 1-C 3烷氧基、羟基、卤素、氰基、被1-2个羟基取代的C 1-C 3烷基、被1-3个相同或不同的C 1-C 3烷氧基取代的C 1-C 3烷基和被1-2个氨基取代的C 1-C 3烷基； R 5 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfonyl, halogen , C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 alkoxy substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl , cyano, amino, (C 1 -C 6 alkyl)-NH-, N(C 1 -C 6 alkyl) 2 -, (C 1 -C 6 alkoxy)-C(O)-, amino Carbonyl, (C 1 -C 6 alkyl)-aminocarbonyl, (C 1 -C 6 alkyl) 2 -aminocarbonyl, C 1 -C 6 alkyl substituted by 1-3 hydroxy, substituted by 1-3 Hydroxy-substituted C 1 -C 6 alkoxy, (C 1 -C 6 alkyl substituted with 1-3 hydroxy)-NH-, C 1 -C 6 alkoxy substituted with 1-3 same or different Substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy substituted by 1-3 identical or different C 1 -C 6 alkoxy , (by 1-3 identical or different C 1 -C 6 alkoxy substituted C 1 -C 6 alkyl) -NH-, C 1 -C 6 alkyl substituted with 1-3 amino groups, C 1 -C 6 alkane substituted with 1-3 amino groups Oxygen, (C 1 -C 6 alkyl substituted with 1-3 amino groups)-NH-, R 5 is unsubstituted by itself or as part of another group or is unsubstituted by R a , R b and/or R c substituted, said R a , R b and/or R c independently selected from C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C substituted with 1-5 identical or different halogens 1 - C3 alkyl, C1 - C3 alkoxy substituted by 1-5 identical or different halogens, C1 - C3 alkoxy, hydroxy, halogen, cyano, substituted by 1-2 hydroxy Substituted C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted with 1-3 identical or different C 1 -C 3 alkoxy and C 1 -C 3 substituted with 1-2 amino groups alkyl;
R 4和R 6各自独立地选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 6烷基磺酰基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 3-C 6环烷基、氰基、氨基、(C 1-C 6烷基)-NH-、N(C 1-C 6烷基) 2-、氨基羰基、(C 1-C 6烷基)-氨基羰基、(C 1-C 6烷基) 2-氨基羰基； R 4 and R 6 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 alkylsulfonyl, halogen, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 substituted with 1-5 identical or different halogens -C 6 alkoxy, C 3 -C 6 cycloalkyl, cyano, amino, (C 1 -C 6 alkyl)-NH-, N(C 1 -C 6 alkyl) 2 -, aminocarbonyl, (C 1 -C 6 alkyl)-aminocarbonyl, (C 1 -C 6 alkyl) 2 -aminocarbonyl;
条件是：(i)W、X和Z中最多一个可以为-N＝，并且(ii)R 3、R 4、R 5和R 6中至少一个不是氢； Provided that: (i) at most one of W, X, and Z may be -N=, and (ii ) at least one of R3 , R4, R5 , and R6 is not hydrogen ;
R 1选自C 6-C 10芳基、5-10元杂芳基，其中C 6-C 10芳基、或5-10元杂芳基无取代或被R d、R e和/或R f取代； R 1 is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, wherein C 6 -C 10 aryl, or 5-10 membered heteroaryl is unsubstituted or replaced by R d , Re and/or R f replace;
R 2为-NR 7R 8，其中： R 2 is -NR 7 R 8 , where:
R 7选自氢、C 1-C 6烷基、氘代C 1-C 6烷基或C 3-C 6环烷基； R 7 is selected from hydrogen, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
R 8选自氢、C 1-C 6烷基、氘代C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个羟基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、(被1-5个相同或不同的卤素取代的C 1-C 6烷氧基)-(C 1-C 6亚烷基)-、被1-3个氨基取代的C 1-C 6烷基、被1-3个氨基磺酰基取代的C 1-C 6烷基、被1-3个硫脲基取代的C 1-C 6烷基、C 1-C 6烷基磺酰基、(C 1-C 6烷基磺酰基)-(C 1-C 6亚烷基)-、被1-5个氰基取代的C 1-C 6烷基、(C 1-C 6烷基)-C(O)-、(C 1-C 6烷氧基)-C(O)-、(C 1-C 6烷基)-NH-C(O)-、N(C 1-C 6烷基) 2-C(O)-、被氨基羰基取代的C 1-C 6烷基、C 3-C 6环烷基、被1-3个C 3-C 6环烷基取代的C 1-C 6烷基、被1-3个C 3-C 6环烷氧基取代的C 1-C 6烷基、C 6-C 10螺环烷基、被C 6-C 10螺环烷基取代的C 1-C 6烷基、C 6-C 8芳基、被1-3个相同或不 同的C 6-C 8芳基取代的C 1-C 6烷基、5-8元杂芳基、被1-3个相同或不同的5-8元杂芳基取代的C 1-C 6烷基、(5-8元杂芳基)-C(O)-、3-8元杂环基、被1-5个相同或不同的3-8元杂环基取代的C 1-C 6烷基、(3-8元杂环基)-C(O)-、(3-8元杂环基)-O-(C 1-C 6亚烷基)-、5-10元稠合杂环基、被1-3个相同或不同的5-10元稠合杂环基取代的C 1-C 6烷基、5-10元桥连杂环基、被1-3个相同或不同的5-10元桥连杂环基取代的C 1-C 6烷基、5-10元螺杂环基、被1-3个相同或不同的5-10元螺杂环基取代的C 1-C 6烷基；所述R 8无取代或被R j、R k和/或R L取代； R 8 is selected from hydrogen, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, 1-5 hydroxyl groups Substituted C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by 1-3 identical or different C 1 -C 6 alkoxy, (substituted by 1-5 identical or different halogen C 1 -C 6 alkoxy)-(C 1 -C 6 alkylene)-, C 1 -C 6 alkyl substituted with 1-3 amino groups, C 1 substituted with 1-3 aminosulfonyl groups -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-3 thioureido groups, C 1 -C 6 alkylsulfonyl, (C 1 -C 6 alkylsulfonyl)-(C 1 - C 6 alkylene)-, C 1 -C 6 alkyl substituted with 1-5 cyano groups, (C 1 -C 6 alkyl)-C(O)-, (C 1 -C 6 alkoxy )-C(O)-, (C 1 -C 6 alkyl)-NH-C(O)-, N(C 1 -C 6 alkyl) 2 -C(O)-, C substituted with aminocarbonyl 1 - C6 alkyl, C3 - C6 cycloalkyl, C1 - C6 alkyl substituted by 1-3 C3- C6 cycloalkyl, 1-3 C3- C6 ring Alkoxy-substituted C 1 -C 6 alkyl, C 6 -C 10 spirocycloalkyl, C 1 -C 6 alkyl substituted by C 6 -C 10 spirocycloalkyl, C 6 -C 8 aryl , C 1 -C 6 alkyl substituted by 1-3 identical or different C 6 -C 8 aryl groups, 5-8-membered heteroaryl, 5-8-membered heteroaryl substituted by 1-3 identical or different C 6 -C 8 aryl groups C 1 -C 6 alkyl substituted by 1-5-membered heteroaryl, (5-8 membered heteroaryl)-C(O)-, 3-8 membered heterocyclyl, 3-8 membered heterocycle by 1-5 same or different group-substituted C 1 -C 6 alkyl, (3-8 membered heterocyclyl)-C(O)-, (3-8 membered heterocyclyl)-O-(C 1 -C 6 alkylene)- , 5-10-membered fused heterocyclic group, C 1 -C 6 alkyl substituted by 1-3 identical or different 5-10-membered fused heterocyclic groups, 5-10-membered bridged heterocyclic group, C 1 -C 6 alkyl substituted with 1-3 identical or different 5-10-membered bridged heterocyclyls, 5-10-membered spiro heterocyclyl, 5-10-membered spiro substituted by 1-3 identical or different 5-10-membered heterocyclyl groups Heterocyclyl-substituted C 1 -C 6 alkyl; the R 8 is unsubstituted or substituted with R j , R k and/or RL ;
或者R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基是未被取代的或者被R j、R k和/或R L取代； Alternatively R 7 , R 8 together with the N atom to which they are commonly attached form a 4-6 membered heterocycloalkyl group which is unsubstituted or is replaced by R j , R k and/or R L replaced;
R d、R e、R j和R k各自独立地选自C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 1-C 6烷氧基、羟基、C 1-C 6烷基磺酰基、卤素、氰基、羧基、(C 1-C 6烷氧基)-C(O)-、被1-3个羟基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、被1-3个氨基取代的C 1-C 6烷基、氨基磺酰基、(C 1-C 6烷基)-NH-S(O) 2-、N(C 1-C 6烷基) 2-S(O) 2-、磺酰基氨基、氨基羰基、(C 1-C 6烷基)-NH-C(O)-、N(C 1-C 6烷基) 2-C(O)-、(3-10元杂环基)-C(O)-和脲基； R d , Re , R j and R k are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, identical with 1-5 halogens or different halogen substituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, hydroxyl, C 1 -C 6 alkylsulfonyl, halogen, cyano, carboxyl, (C 1 -C 6 alkane oxy)-C(O)-, C 1 -C 6 alkyl substituted with 1-3 hydroxy, C 1 -C 6 substituted with 1-3 identical or different C 1 -C 6 alkoxy Alkyl, C 1 -C 6 alkyl substituted with 1-3 amino groups, aminosulfonyl, (C 1 -C 6 alkyl)-NH-S(O) 2 -, N(C 1 -C 6 alkane base) 2 -S(O) 2 -, sulfonylamino, aminocarbonyl, (C 1 -C 6 alkyl)-NH-C(O)-, N(C 1 -C 6 alkyl) 2 -C( O)-, (3-10 membered heterocyclyl)-C(O)- and ureido;
R f和R L各自独立地选自C 1-C 6烷基、C 5-C 10环烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 1-C 6烷氧基、羟基、卤素、氨基、(C 1-C 6烷基)-NH-、(C 3-C 8环烷基)-S(O) 2-NH-、氰基、被1-3个氰基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基羰基取代的C 1-C 6烷基、被羧基取代的C 1-C 6烷基、被氨基羰基取代的C 1-C 6烷基、-X c-R 9，其中X c选自键、C 1-C 5亚烷基和C 1-C 5杂亚烷基，R 9选自任选被取代的C 6-C 10芳基、任选被取代的5-10元杂芳基和任选被取代的5-10元杂环基。 R f and RL are each independently selected from C 1 -C 6 alkyl, C 5 -C 10 cycloalkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 alkyl substituted with 1- 5 identical or different halogen-substituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, hydroxy, halogen, amino, (C 1 -C 6 alkyl)-NH-, (C 3 - C 8 cycloalkyl)-S(O) 2 -NH-, cyano, C 1 -C 6 alkyl substituted with 1-3 cyano groups, C 1 -C 6 substituted with 1-3 identical or different C 1 -C 6 groups C 1 -C 6 alkyl substituted by alkoxycarbonyl, C 1 -C 6 alkyl substituted by carboxyl, C 1 -C 6 alkyl substituted by aminocarbonyl, -X c -R 9 , wherein X c is selected from Self-bond, C 1 -C 5 alkylene and C 1 -C 5 heteroalkylene, R 9 is selected from optionally substituted C 6 -C 10 aryl, optionally substituted 5-10 membered heteroaryl and optionally substituted 5-10 membered heterocyclyl.
根据本发明的某些实施例，式I所示化合物中，W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 3、R 4、R 5和R 6中至少一个不是氢。 According to certain embodiments of the present invention, in the compound represented by formula I, W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C (R 6 )=, at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 3、R 4、R 5和R 6中至少一个不是氢时，所述R 3选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is - C(R 6 )=, and when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, said R 3 is selected from hydrogen, C 1 -C 6 alkyl, halogen, the same by 1-5 or different halogen substituted C 1 -C 6 alkyl, cyano.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 3、R 4、R 5和R 6中至少一个不是氢时，所述R 4选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is - C(R 6 )=, and when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, said R 4 is selected from hydrogen, C 1 -C 6 alkyl, halogen, the same by 1-5 or different halogen substituted C 1 -C 6 alkyl, cyano.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 3、R 4、R 5和R 6中至少一个不是氢时，所述R 5选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、C 3-C 6环烷基、氰基、氨基，R 5未被取代或被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自C 1-C 3烷基、C 3-C 6环烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷氧基、C 1-C 3烷氧基、羟基、卤素。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is - C(R 6 )=, and when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, said R 5 is selected from hydrogen, C 1 -C 6 alkyl, halogen, the same by 1-5 or different halogen-substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, cyano, amino, R 5 is unsubstituted or substituted by R a , R b and/or R c , the R a , R b and/or R c are independently selected from C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens, C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, halogen substituted with 1-5 identical or different halogens.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 3、R 4、R 5和R 6中至少一个不是氢时，所述R 6选自氢、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is - C(R 6 )=, and when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, said R 6 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy , C 1 -C 6 alkylthio, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, cyano.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 3、R 4、R 5和R 6中至少一个不是氢时，R 1选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环，并且R 1为无取代或被R d、R e和/或R f取代，所述R d、R e和R f各自独立地选自C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is - C(R 6 )=, and when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, R 1 is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, Pyrazole ring, imidazole ring, and R 1 is unsubstituted or substituted by R d , Re and/or R f , said R d , Re and R f are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 alkoxy substituted with 1-5 identical or different halogens, C 1 -C 6 alkoxy, Hydroxyl, halogen, cyano, carboxyl.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 3、R 4、R 5和R 6中至少一个不是氢时，R 2为-NR 7R 8，R 7选自氢、C 1-C 6烷 基、C 3-C 6环烷基，所述R 8选自氢、C 1-C 6烷基、氘代C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个羟基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、(被1-5个相同或不同的卤素取代的C 1-C 6烷氧基)-(C 1-C 6亚烷基)-、C 3-C 6环烷基、被1-3个C 3-C 6环烷基取代的C 1-C 6烷基、被1-5个相同或不同的3-8元杂环基取代的C 1-C 6烷基、(C 1-C 6烷基磺酰基)-(C 1-C 6亚烷基)-，其中R 8无取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is - C(R 6 )=, and when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, R 2 is -NR 7 R 8 , and R 7 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, said R 8 is selected from hydrogen, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C substituted with 1-5 identical or different halogens 6 alkyl, C 1 -C 6 alkyl substituted by 1-5 hydroxyl groups, C 1 -C 6 alkyl substituted by 1-3 identical or different C 1 -C 6 alkoxy groups, (by 1 -5 identical or different halogen-substituted C 1 -C 6 alkoxy)-(C 1 -C 6 alkylene)-, C 3 -C 6 cycloalkyl, substituted by 1-3 C 3 -C C 1 -C 6 alkyl substituted by 6 cycloalkyl, C 1 -C 6 alkyl substituted by 1-5 identical or different 3-8 membered heterocyclic groups, (C 1 -C 6 alkylsulfonyl )-(C 1 -C 6 alkylene)-, wherein R 8 is unsubstituted or substituted by R j , R k and/or RL each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 3、R 4、R 5和R 6中至少一个不是氢时，R 2为-NR 7R 8，所述R 7选自氢、C 1-C 6烷基、C 3-C 6环烷基，所述R 8选自氢、C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个羟基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、(被1-5个相同或不同的卤素取代的C 1-C 6烷氧基)-(C 1-C 6亚烷基)-、C 3-C 6环烷基、被1-3个C 3-C 6环烷基取代的C 1-C 6烷基、被1-5个相同或不同的3-8元杂环基取代的C 1-C 6烷基，其中R 8无取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is - C(R 6 )=, and when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, R 2 is -NR 7 R 8 , and R 7 is selected from hydrogen, C 1 -C 6 alkyl , C 3 -C 6 cycloalkyl, the R 8 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, 1-5 C 1 -C 6 alkyl substituted by 1 hydroxy, C 1 -C 6 alkyl substituted by 1-3 identical or different C 1 -C 6 alkoxy, (by 1-5 identical or different halogen Substituted C 1 -C 6 alkoxy)-(C 1 -C 6 alkylene)-, C 3 -C 6 cycloalkyl, C 1 substituted with 1-3 C 3 -C 6 cycloalkyl -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different 3-8 membered heterocyclyl groups, wherein R 8 is unsubstituted or substituted with R j , R k and/or RL , the R j , R k and RL are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, and carboxyl.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 3、R 4、R 5和R 6中至少一个不是氢时，R 2为-NR 7R 8，所述R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基未被取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is - C(R 6 )=, and when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, R 2 is -NR 7 R 8 together with the N atom to which they are commonly attached Forms a 4-6 membered heterocycloalkyl group that is unsubstituted or substituted with R j , R k and/or RL , each independently Selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl.
根据本发明的某些优选实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝时，R 3、R 4、R 5和R 6中至少一个不是氢；R 3、R 4、R 5和R 6各自独立地选自氢、卤素、甲基、乙基、丙基、异丙基、环丙基、被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、被1-3个卤素取代的环丙基；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯。 According to some preferred embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 5 )= -C(R 6 )=, at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen; R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl base, propyl, isopropyl, cyclopropyl, methyl substituted with 1-3 halogens, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, substituted with 1-3 halogens Isopropyl substituted by one halogen, cyclopropyl substituted by 1-3 halogens; the halogen is selected from fluorine, chlorine, bromine and iodine, preferably, the halogen is selected from fluorine and chlorine.
根据本发明的某些优选实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 3、R 4、R 5和R 6中至少一个不是氢时，R 1选自被R d取代的苯环、被R d取代的吡啶环，所述R d选自氰基、卤素、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯。 According to some preferred embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 5 )= -C(R 6 )=, and when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, R 1 is selected from a benzene ring substituted by R d , a pyridine ring substituted by R d , the R 1 d is selected from cyano, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methyl substituted with 1-3 halogens, Ethyl substituted by 1-3 halogens, propyl substituted by 1-3 halogens, isopropyl substituted by 1-3 halogens; the halogens are selected from fluorine, chlorine, bromine, iodine, preferably, The halogen is selected from fluorine, chlorine.
根据本发明的某些优选实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 3、R 4、R 5和R 6中至少一个不是氢时，R 1选自被R d取代的苯环，所述R d选自氰基、卤素、甲基、乙基、丙基、异丙基、被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯。 According to some preferred embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 5 )= -C(R 6 )=, and when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, R 1 is selected from a benzene ring substituted by R d selected from cyano, halogen, Methyl, ethyl, propyl, isopropyl, methyl substituted with 1-3 halogens, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, substituted with 1-3 halogens A halogen-substituted isopropyl group; the halogen is selected from fluorine, chlorine, bromine and iodine, preferably, the halogen is selected from fluorine and chlorine.
根据本发明的某些优选实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 3、R 4、R 5和R 6中至少一个不是氢时，R 2为-NR 7R 8，所述R 7选自氢、甲基、乙基、丙基，所述R 8选自氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、被1-3个卤素取代的环丙基、被一个羟基取代的丙基、被一个羟基取代的异丙基、被一个羟基取代的正丁基、被一个羟基取代的异丁基、被一个羟基取代的叔丁基、被一个羟基取代的环丙基、被一个羟基取代的环丁基、(C 1-C 3烷基磺酰基)-(C 1-C 3亚烷基)-；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯。 According to some preferred embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 5 )= -C(R 6 )=, and when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, R 2 is -NR 7 R 8 , and R 7 is selected from hydrogen, methyl, ethyl, propyl group, the R 8 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, by 1-3 halogen substituted ethyl, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens, cyclopropyl substituted with 1-3 halogens, propyl substituted with one hydroxy, Isopropyl substituted with one hydroxyl, n-butyl substituted with one hydroxyl, isobutyl substituted with one hydroxyl, tert-butyl substituted with one hydroxyl, cyclopropyl substituted with one hydroxyl, cyclobutyl substituted with one hydroxyl base, (C 1 -C 3 alkylsulfonyl)-(C 1 -C 3 alkylene)-; the halogen is selected from fluorine, chlorine, bromine, iodine, preferably, the halogen is selected from fluorine, chlorine.
根据本发明的某些优选实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 3、R 4、R 5和R 6中至少一个不是氢时，R 2为-NR 7R 8，所述R 7选自 氢、甲基、乙基、丙基，所述R 8选自氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、被1-3个卤素取代的环丙基、被一个羟基取代的丙基、被一个羟基取代的异丙基、被一个羟基取代的正丁基、被一个羟基取代的异丁基、被一个羟基取代的叔丁基、被一个羟基取代的环丙基、被一个羟基取代的环丁基、甲基磺酰基乙基、甲基磺酰基甲基；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯。 According to some preferred embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 5 )= -C(R 6 )=, and when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, R 2 is -NR 7 R 8 , and R 7 is selected from hydrogen, methyl, ethyl, propyl group, the R 8 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, by 1-3 halogen substituted ethyl, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens, cyclopropyl substituted with 1-3 halogens, propyl substituted with one hydroxy, Isopropyl substituted with one hydroxyl, n-butyl substituted with one hydroxyl, isobutyl substituted with one hydroxyl, tert-butyl substituted with one hydroxyl, cyclopropyl substituted with one hydroxyl, cyclobutyl substituted with one hydroxyl group, methylsulfonylethyl, methylsulfonylmethyl; the halogen is selected from fluorine, chlorine, bromine, iodine, preferably, the halogen is selected from fluorine and chlorine.
根据本发明的某些优选实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 3、R 4、R 5和R 6中至少一个不是氢时，R 2为-NR 7R 8，所述R 7选自氢、甲基、乙基、丙基，所述R 8选自氢、甲基、乙基、丙基、异丙基、环丙基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、被1-3个卤素取代的环丙基、被一个羟基取代的丙基、被一个羟基取代的异丙基、被一个羟基取代的环丙基；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯。 According to some preferred embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 5 )= -C(R 6 )=, and when at least one of R 3 , R 4 , R 5 and R 6 is not hydrogen, R 2 is -NR 7 R 8 , and R 7 is selected from hydrogen, methyl, ethyl, propyl, the R8 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, Isopropyl substituted with 1-3 halogens, cyclopropyl substituted with 1-3 halogens, propyl substituted with one hydroxy, isopropyl substituted with one hydroxy, cyclopropyl substituted with one hydroxy; The halogen is selected from fluorine, chlorine, bromine and iodine, preferably, the halogen is selected from fluorine and chlorine.
根据本发明的某些优选实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 3、R 4和R 6为氢；R 5为被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、异丙基、被1-3个卤素取代的环丙基；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯。 According to some preferred embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 5 )= -C(R 6 )=, R 3 , R 4 and R 6 are hydrogen; R 5 is methyl substituted by 1-3 halogens, ethyl substituted by 1-3 halogens, substituted by 1-3 halogens Substituted propyl group, isopropyl group, cyclopropyl group substituted by 1-3 halogens; the halogen is selected from fluorine, chlorine, bromine and iodine, preferably, the halogen is selected from fluorine and chlorine.
根据本发明的某些实施例，式I所示化合物中，当W是-N＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝时，R 4、R 5和R 6中至少一个不是氢。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -N=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 ) )=, at least one of R 4 , R 5 and R 6 is not hydrogen.
根据本发明的某些实施例，式I所示化合物中，当W是-N＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 4、R 5和R 6中至少一个不是氢时，R 4选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -N=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 ) )=, and when at least one of R 4 , R 5 and R 6 is not hydrogen, R 4 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 - substituted by 1-5 identical or different halogens C 6 alkyl, cyano.
根据本发明的某些实施例，式I所示化合物中，当W是-N＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 4、R 5和R 6中至少一个不是氢时，R 5选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、C 3-C 6环烷基、氰基、氨基，R 5未被取代或被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自C 1-C 3烷基、C 3-C 6环烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷氧基、C 1-C 3烷氧基、羟基、卤素。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -N=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 ) )=, and when at least one of R 4 , R 5 and R 6 is not hydrogen, R 5 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 - substituted by 1-5 identical or different halogens C 6 alkyl, C 3 -C 6 cycloalkyl, cyano, amino, R 5 is unsubstituted or substituted by R a , R b and/or R c , said R a , R b and/or R c independently selected from C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens Halogen-substituted C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, halogen.
根据本发明的某些实施例，式I所示化合物中，当W是-N＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 4、R 5和R 6中至少一个不是氢时，R 6选自氢、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -N=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 ) )=, and when at least one of R 4 , R 5 and R 6 is not hydrogen, R 6 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio , halogen, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, cyano.
根据本发明的某些实施例，式I所示化合物中，当W是-N＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 4、R 5和R 6中至少一个不是氢时，R 1选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环，R 1为无取代或被R d、R e和/或R f取代，所述R d、R e和R f各自独立地选自C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -N=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 ) )=, and when at least one of R 4 , R 5 and R 6 is not hydrogen, R 1 is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, pyrazole ring, imidazole ring, R 1 is unsubstituted or substituted with R d , R e and/or R f each independently selected from C 1 -C 6 alkyl , the same or different by 1-5 C 1 -C 6 alkyl substituted by halogen, C 1 -C 6 alkoxy substituted by 1-5 same or different halogens, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl .
根据本发明的某些实施例，式I所示化合物中，当W是-N＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，且R 4、R 5和R 6中至少一个不是氢时，R 2为-NR 7R 8，所述R 7选自氢、C 1-C 6烷基、或C 3-C 6环烷基，所述R 8选自氢、C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个羟基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、(被1-5个相同或不同的卤素取代的C 1-C 6烷氧基)-(C 1-C 6亚烷基)-、C 3-C 6环烷基、被1-3个C 3-C 6环烷基取代的C 1-C 6烷基、被1-5个相同或不同的3-8元杂环基取代的C 1-C 6烷基，其中R 8无取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -N=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 ) )=, and when at least one of R 4 , R 5 and R 6 is not hydrogen, R 2 is -NR 7 R 8 , and R 7 is selected from hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 Cycloalkyl, said R 8 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 substituted with 1-5 hydroxy -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-3 identical or different C 1 -C 6 alkoxy groups, (C 1 -C 6 alkyl substituted with 1-5 identical or different halogens 6 alkoxy)-(C 1 -C 6 alkylene)-, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by 1-3 C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by 1-5 identical or different 3-8 membered heterocyclic groups, wherein R 8 is unsubstituted or substituted by R j , R k and/or RL , the R j , R k and RL are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, halogen, cyano, carboxyl.
根据本发明的某些实施例，式I所示化合物中，当W是-N＝，X是-C(R 4)＝，Y是-C(R 5)＝， Z是-C(R 6)＝，且R 4、R 5和R 6中至少一个不是氢时，R 2为-NR 7R 8，所述R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基未被取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -N=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 ) )=, and when at least one of R 4 , R 5 and R 6 is not hydrogen, R 2 is -NR 7 R 8 , and said R 7 , R 8 together with the N atom to which they are connected together form a 4-6 membered heterocycle Alkyl, the 4-6 membered heterocycloalkyl is unsubstituted or substituted by R j , R k and/or RL each independently selected from C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl.
根据本发明的某些实施例，式I所示化合物中，W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-N＝，R 3、R 4和R 5中至少一个不是氢。 According to certain embodiments of the present invention, in the compound represented by formula I, W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -N =, at least one of R 3 , R 4 and R 5 is not hydrogen.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-N＝，R 3、R 4和R 5中至少一个不是氢时，R 3选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is - N=, when at least one of R 3 , R 4 and R 5 is not hydrogen, R 3 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C substituted with 1-5 identical or different halogens 6 alkyl, cyano.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-N＝，R 3、R 4和R 5中至少一个不是氢时，R 4选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is - N=, when at least one of R 3 , R 4 and R 5 is not hydrogen, R 4 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C substituted with 1-5 identical or different halogens 6 alkyl, cyano.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-N＝，R 3、R 4和R 5中至少一个不是氢时，R 5选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、C 3-C 6环烷基、氰基、氨基，R 5未被取代或被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自C 1-C 3烷基、C 3-C 6环烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷氧基、C 1-C 3烷氧基、羟基、卤素。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is - N=, when at least one of R 3 , R 4 and R 5 is not hydrogen, R 5 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C substituted with 1-5 identical or different halogens 6 alkyl, C 3 -C 6 cycloalkyl, cyano, amino, R 5 is unsubstituted or substituted by R a , R b and/or R c , said R a , R b and/or R c independently is selected from the group consisting of C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens Substituted C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, halogen.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-N＝，R 3、R 4和R 5中至少一个不是氢时，R 1选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环，R 1为无取代或被R d、R e和/或R f取代，所述R d、R e和R f各自独立地选自C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is - N=, when at least one of R 3 , R 4 and R 5 is not hydrogen, R 1 is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, pyrazole ring, imidazole ring, R 1 is unsubstituted or substituted by R d , Re and/or R f , each of said R d , Re and R f is independently selected from C 1 -C 6 alkyl, by 1-5 identical or different Halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy substituted with 1-5 identical or different halogens, C 1 -C 6 alkoxy, hydroxy, halogen, cyano, carboxyl.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-N＝，R 3、R 4和R 5中至少一个不是氢时，R 2为-NR 7R 8，所述R 7选自氢、C 1-C 6烷基、或C 3-C 6环烷基，所述R 8选自氢、C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个羟基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、(被1-5个相同或不同的卤素取代的C 1-C 6烷氧基)-(C 1-C 6亚烷基)-、C 3-C 6环烷基、被1-3个C 3-C 6环烷基取代的C 1-C 6烷基、被1-5个相同或不同的3-8元杂环基取代的C 1-C 6烷基，其中R 8无取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is - N=, when at least one of R 3 , R 4 and R 5 is not hydrogen, R 2 is -NR 7 R 8 , and said R 7 is selected from hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 ring Alkyl, said R 8 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 alkyl substituted with 1-5 hydroxy C 6 alkyl, C 1 -C 6 alkyl substituted by 1-3 identical or different C 1 -C 6 alkoxy, (C 1 -C 6 substituted by 1-5 identical or different halogen alkoxy)-(C 1 -C 6 alkylene)-, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by 1-3 C 3 -C 6 cycloalkyl, by 1-5 C 1 -C 6 alkyl substituted by the same or different 3-8-membered heterocyclyl groups, wherein R 8 is unsubstituted or substituted by R j , R k and/or RL , the R j , R k and RL are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, halogen, cyano, carboxyl.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-N＝，R 3、R 4和R 5中至少一个不是氢时，R 2为-NR 7R 8，所述R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基未被取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is - N=, when at least one of R 3 , R 4 and R 5 is not hydrogen, R 2 is -NR 7 R 8 , said R 7 and R 8 together with the N atom to which they are commonly attached form a 4-6 membered heterocycloalkane base, the 4-6 membered heterocycloalkyl is unsubstituted or substituted by R j , R k and/or RL , each of which is independently selected from C 1 -C 6 alkanes group, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl.
根据本发明的某些实施例，式I所示化合物中，W是-C(R 3)＝，X是-N＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 3、R 5和R 6中至少一个不是氢。 According to certain embodiments of the present invention, in the compound represented by formula I, W is -C(R 3 )=, X is -N=, Y is -C(R 5 )=, Z is -C(R 6 ) =, at least one of R 3 , R 5 and R 6 is not hydrogen.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-N＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 3、R 5和R 6中至少一个不是氢时，R 3选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -N=, Y is -C(R 5 )=, Z is -C(R 6 ) )=, when at least one of R 3 , R 5 and R 6 is not hydrogen, R 3 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C substituted by 1-5 identical or different halogens 6 alkyl, cyano.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-N＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 3、R 5和R 6中至少一个不是氢时，R 5选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、C 3-C 6环烷基、氰基、氨基，R 5未被取代或被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自C 1-C 3烷基、C 3-C 6环烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷氧基、C 1-C 3烷氧基、羟 基、卤素。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -N=, Y is -C(R 5 )=, Z is -C(R 6 ) )=, when at least one of R 3 , R 5 and R 6 is not hydrogen, R 5 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C substituted by 1-5 identical or different halogens 6 alkyl, C 3 -C 6 cycloalkyl, cyano, amino, R 5 is unsubstituted or substituted by R a , R b and/or R c , said R a , R b and/or R c independently is selected from the group consisting of C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens Substituted C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, halogen.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-N＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 3、R 5和R 6中至少一个不是氢时，R 6选自氢、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -N=, Y is -C(R 5 )=, Z is -C(R 6 ) )=, when at least one of R 3 , R 5 and R 6 is not hydrogen, R 6 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, Halogen, C1 - C6 alkyl substituted with 1-5 identical or different halogens, cyano.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-N＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 3、R 5和R 6中至少一个不是氢时，R 1选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环，R 1为无取代或被R d、R e和/或R f取代，所述R d、R e和R f各自独立地选自C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -N=, Y is -C(R 5 )=, Z is -C(R 6 ) )=, when at least one of R 3 , R 5 and R 6 is not hydrogen, R 1 is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, pyrazole ring, imidazole ring, R 1 is unsubstituted or substituted by R d , Re and/or R f , each of said R d , Re and R f is independently selected from C 1 -C 6 alkyl, by 1-5 identical or different Halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy substituted with 1-5 identical or different halogens, C 1 -C 6 alkoxy, hydroxy, halogen, cyano, carboxyl.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-N＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 3、R 5和R 6中至少一个不是氢时，R 2为-NR 7R 8，所述R 7选自氢、C 1-C 6烷基、或C 3-C 6环烷基，所述R 8选自氢、C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个羟基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、(被1-5个相同或不同的卤素取代的C 1-C 6烷氧基)-(C 1-C 6亚烷基)-、C 3-C 6环烷基、被1-3个C 3-C 6环烷基取代的C 1-C 6烷基、被1-5个相同或不同的3-8元杂环基取代的C 1-C 6烷基，其中R 8无取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -N=, Y is -C(R 5 )=, Z is -C(R 6 ) )=, when at least one of R 3 , R 5 and R 6 is not hydrogen, R 2 is -NR 7 R 8 , and said R 7 is selected from hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 ring Alkyl, said R 8 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 alkyl substituted with 1-5 hydroxy C 6 alkyl, C 1 -C 6 alkyl substituted by 1-3 identical or different C 1 -C 6 alkoxy, (C 1 -C 6 substituted by 1-5 identical or different halogen alkoxy)-(C 1 -C 6 alkylene)-, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by 1-3 C 3 -C 6 cycloalkyl, by 1-5 C 1 -C 6 alkyl substituted by the same or different 3-8-membered heterocyclyl groups, wherein R 8 is unsubstituted or substituted by R j , R k and/or RL , the R j , R k and RL are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, halogen, cyano, carboxyl.
根据本发明的某些实施例，式I所示化合物中，当W是-C(R 3)＝，X是-N＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 3、R 5和R 6中至少一个不是氢时，R 2为-NR 7R 8，所述R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基未被取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 According to certain embodiments of the present invention, in the compound represented by formula I, when W is -C(R 3 )=, X is -N=, Y is -C(R 5 )=, Z is -C(R 6 ) )=, when at least one of R 3 , R 5 and R 6 is not hydrogen, R 2 is -NR 7 R 8 , said R 7 , R 8 together with the N atom to which they are connected together form a 4-6 membered heterocycloalkane base, the 4-6 membered heterocycloalkyl is unsubstituted or substituted by R j , R k and/or RL , each of which is independently selected from C 1 -C 6 alkanes group, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl.
根据本发明的某些实施例，式I所示化合物中，R 3、R 4、R 5和R 6各自独立地选自氢、卤素、甲基、乙基、丙基、异丙基、环丙基、被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、被1-3个卤素取代的环丙基；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯；R 1为苯基或吡啶基；所述苯基或吡啶基被1或2个选自下列的取代基取代：卤素、羟基、氰基、C 1-C 6烷基、-O-C 1-C 6烷基；当取代基为多个时，所述取代基相同或不同；较佳地，所述苯基或吡啶基被1或2个选自下列的取代基取代：卤素、羟基、氰基、C 1-C 3烷基、-O-C 1-C 3烷基；R 5选自：卤素、C 1-C 6烷基、3-6元环烷基；所述C 1-C 6烷基任选地被卤素取代；较佳地，R 5选自：卤素、C 1-C 3烷基、C 1-C 3卤代烷基、环丙基；较佳地，所述卤素为F或Cl；较佳地，R 5选自：-F、-Cl、-CH 3、-CF 2、-CF 3、环丙基。 According to certain embodiments of the present invention, in the compound represented by formula I, R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, cyclic propyl, methyl substituted with 1-3 halo, ethyl substituted with 1-3 halo, propyl substituted with 1-3 halo, isopropyl substituted with 1-3 halo, 1-3 halo substituted -3 halogen-substituted cyclopropyl; the halogen is selected from fluorine, chlorine, bromine, iodine, preferably, the halogen is selected from fluorine, chlorine; R 1 is phenyl or pyridyl; the phenyl or Pyridyl is substituted with 1 or 2 substituents selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl; when there are multiple substituents, the substitution The groups are the same or different; preferably, the phenyl or pyridyl is substituted by 1 or 2 substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1 -C 3 alkyl, -OC 1 -C 3 alkyl; R 5 is selected from: halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl; the C 1 -C 6 alkyl is optionally substituted by halogen; preferably, R 5 is selected from : halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyclopropyl; preferably, the halogen is F or Cl; preferably, R 5 is selected from: -F, -Cl, -CH 3 , -CF 2 , -CF 3 , cyclopropyl.
根据本发明的某些实施例，式I所示化合物中，R 1选自被1个、2个或更多个卤素取代的下列基团：C 6-8芳基或5-8元杂芳基；较佳地，R 1选自被1个或2个氟或氯取代的下列基团：苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吡咯基、吡唑基、咪唑基；较佳地，R 1选自被1个或2个氟取代的下列基团：苯基或吡啶基； According to certain embodiments of the present invention, in the compound represented by formula I, R 1 is selected from the following groups substituted by 1, 2 or more halogens: C 6-8 aryl or 5-8 membered heteroaryl Preferably, R 1 is selected from the following groups substituted with 1 or 2 fluorine or chlorine: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazole group; preferably, R 1 is selected from the following groups substituted by 1 or 2 fluorines: phenyl or pyridyl;
根据本发明的某些实施例，R 2为-NR 7R 8，所述R 7选自氢、C 1-C 6烷基、或C 3-C 6环烷基；所述R 8选自被R j取代的C 3-C 12环烷基；较佳地，R 2为-NR 7R 8，所述R 7选自氢，所述R 8选自被R j取代的C 3-C 6环烷基；所述R j选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 According to certain embodiments of the present invention, R 2 is -NR 7 R 8 , and R 7 is selected from hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl; and R 8 is selected from C 3 -C 12 cycloalkyl substituted by R j ; preferably, R 2 is -NR 7 R 8 , the R 7 is selected from hydrogen, and the R 8 is selected from C 3 -C substituted by R j 6 cycloalkyl; the R j is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl.
根据本发明的某些实施例，式I所示化合物中，当R 3、R 4、R 5和R 6各自独立地选自氢、卤素、甲基、乙基、丙基、异丙基、环丙基、被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、被1-3个卤素取代的环丙基时， 所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯；R 1选自
Figure PCTCN2022087589-appb-000008
Figure PCTCN2022087589-appb-000009
According to certain embodiments of the present invention, in the compound represented by formula I, when R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, Cyclopropyl, methyl substituted with 1-3 halogens, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens, When 1-3 halogen-substituted cyclopropyl groups are used, the halogen is selected from fluorine, chlorine, bromine and iodine, preferably, the halogen is selected from fluorine and chlorine; R 1 is selected from
Figure PCTCN2022087589-appb-000008
Figure PCTCN2022087589-appb-000009
根据本发明的某些实施例，式I所示化合物中，当R 3、R 4、R 5和R 6各自独立地选自氢、卤素、甲基、乙基、丙基、异丙基、环丙基、被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、被1-3个卤素取代的环丙基时，所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯；R 1选自
Figure PCTCN2022087589-appb-000010
Figure PCTCN2022087589-appb-000011
According to certain embodiments of the present invention, in the compound represented by formula I, when R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, Cyclopropyl, methyl substituted with 1-3 halogens, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens, When 1-3 halogen-substituted cyclopropyl groups are used, the halogen is selected from fluorine, chlorine, bromine, and iodine, preferably, the halogen is selected from fluorine and chlorine; R 1 is selected from
Figure PCTCN2022087589-appb-000010
Figure PCTCN2022087589-appb-000011
根据本发明的某些实施例，式I所示化合物中，当R 3、R 4、R 5和R 6各自独立地选自氢、卤素、甲基、乙基、丙基、异丙基、环丙基、被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、被1-3个卤素取代的环丙基时，所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯；R 2选自
Figure PCTCN2022087589-appb-000012
Figure PCTCN2022087589-appb-000013
According to certain embodiments of the present invention, in the compound represented by formula I, when R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, Cyclopropyl, methyl substituted with 1-3 halogens, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens, In the case of 1-3 halogen-substituted cyclopropyl groups, the halogen is selected from fluorine, chlorine, bromine, and iodine, preferably, the halogen is selected from fluorine and chlorine; R 2 is selected from
Figure PCTCN2022087589-appb-000012
Figure PCTCN2022087589-appb-000013
根据本发明的某些实施例，式I所示化合物中，当R 3、R 4、R 5和R 6各自独立地选自氢、卤素、甲基、乙基、丙基、异丙基、环丙基、被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、被1-3个卤素取代的环丙基时，所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯；R 2选自
Figure PCTCN2022087589-appb-000014
Figure PCTCN2022087589-appb-000015
According to certain embodiments of the present invention, in the compound represented by formula I, when R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, Cyclopropyl, methyl substituted with 1-3 halogens, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens, In the case of 1-3 halogen-substituted cyclopropyl groups, the halogen is selected from fluorine, chlorine, bromine, and iodine, preferably, the halogen is selected from fluorine and chlorine; R 2 is selected from
Figure PCTCN2022087589-appb-000014
Figure PCTCN2022087589-appb-000015
根据本发明的某些实施例，式I所示化合物中，R 2为-NHR 8，R 8选自被羟基取代的C 2-C 4烷基或被氰基取代的C 2-C 4烷基；未定义的基团如前任一方案所述。 According to certain embodiments of the present invention, in the compound represented by formula I, R 2 is -NHR 8 , and R 8 is selected from C 2 -C 4 alkyl substituted by hydroxy or C 2 -C 4 alkane substituted by cyano group groups; undefined groups are as described in any of the preceding schemes.
根据本发明的某些实施例，式I所示化合物中，R 2为-NHR 8，R 8选自C 3-C 10环烷基、C 6-C 10螺环烷基、桥连的C 5-C 10环烷基，所述R 8是未被取代的或者被R j取代，所述R j独立地选自-F、甲基、甲氧基、氰基；未定义的基团如前任一方案所述。 According to certain embodiments of the present invention, in the compound represented by formula I, R 2 is -NHR 8 , and R 8 is selected from C 3 -C 10 cycloalkyl, C 6 -C 10 spirocycloalkyl, bridged C 5 -C 10 cycloalkyl, the R 8 is unsubstituted or substituted by R j , the R j is independently selected from -F, methyl, methoxy, cyano; undefined groups such as as described in the previous scheme.
根据本发明的某些实施例，式I所示化合物中，R 2为-NHR 8，R 8选自环丙基、环丁基、
Figure PCTCN2022087589-appb-000016
所述R 8是未被取代的或者被R j取代，所述R j独立地选自-F、甲基、甲氧基、氰基；未定义的基团如前任一方案所述。 According to certain embodiments of the present invention, in the compound represented by formula I, R 2 is -NHR 8 , and R 8 is selected from cyclopropyl, cyclobutyl,
Figure PCTCN2022087589-appb-000016
The R8 is unsubstituted or substituted with Rj independently selected from -F, methyl, methoxy, cyano; undefined groups are as described in any of the preceding schemes.
根据本发明的某些实施例，式I所示化合物中，R 2为-NR 7R 8，R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基是未被取代的或者被R j取代；R j选自-F、氰基、-NH-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基；未定义的基团如前任一方案所述。 According to certain embodiments of the present invention, in the compound represented by formula I, R 2 is -NR 7 R 8 , and R 7 and R 8 together with the N atom to which they are connected together form a 4-6 membered heterocycloalkyl, and the said 4-6 membered heterocycloalkyl is unsubstituted or substituted by R j ; R j is selected from -F, cyano, -NH-(C 1 -C 6 alkyl), C 1 -C substituted by hydroxy 6Alkyl ; undefined groups are as described in any of the preceding schemes.
根据本发明的某些实施例，式I所示化合物中，R 2为-NR 7R 8，R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基同时被R j和R L取代；R j选自-F、氰基、-NH-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基；R L选自甲基、羟基；未定义的基团如前任一方案所述。 According to certain embodiments of the present invention, in the compound represented by formula I, R 2 is -NR 7 R 8 , and R 7 and R 8 together with the N atom to which they are connected together form a 4-6 membered heterocycloalkyl, and the said 4-6 membered heterocycloalkyl is simultaneously substituted by R j and RL ; R j is selected from -F, cyano, -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkane substituted by hydroxy group; R L is selected from methyl, hydroxyl; undefined groups are as described in any of the previous schemes.
根据本发明的某些实施例，式I所示化合物中，R 2为-NR 7R 8，R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基同时被R j、R k和R L取代；R j和R k各自独立地选自-F、氰基、-NH-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基；R L选自甲基、羟基；未定义的基团如前任一方案所述。 According to certain embodiments of the present invention, in the compound represented by formula I, R 2 is -NR 7 R 8 , and R 7 and R 8 together with the N atom to which they are connected together form a 4-6 membered heterocycloalkyl, and the said 4-6 membered heterocycloalkyl is simultaneously substituted by R j , R k and R L ; R j and R k are each independently selected from -F, cyano, -NH-(C 1 -C 6 alkyl), by Hydroxy-substituted C1 - C6 alkyl; R L is selected from methyl, hydroxyl; undefined groups are as described in any of the preceding schemes.
根据本发明的某些实施例，式I所示化合物中，R 2选自无取代的或被R j取代的以下基团：
Figure PCTCN2022087589-appb-000017
Figure PCTCN2022087589-appb-000018
其中R A1、R A2以及环A的部分环原子相连形成3-7元环烷基或3-7元杂环烷基，所述3-7元杂环烷基的1-3个环原子独立选自N、O和S；未定义的基团如前任一方案所述。 According to certain embodiments of the present invention, in the compound shown in formula I, R 2 is selected from the following groups unsubstituted or substituted by R j :
Figure PCTCN2022087589-appb-000017
Figure PCTCN2022087589-appb-000018
wherein R A1 , R A2 and some ring atoms of ring A are connected to form a 3-7-membered cycloalkyl or a 3-7-membered heterocycloalkyl, and 1-3 ring atoms of the 3-7-membered heterocycloalkyl are independent Selected from N, O and S; undefined groups are as described in any of the preceding schemes.
根据本发明的某些实施例，式I所示化合物中，R 2选自无取代的或被R j取代的以下基团：
Figure PCTCN2022087589-appb-000019
R j选自-F、氰基、-N-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基；未定义的基团如前任一方案所述。 According to certain embodiments of the present invention, in the compound shown in formula I, R 2 is selected from the following groups unsubstituted or substituted by R j :
Figure PCTCN2022087589-appb-000019
R j is selected from -F, cyano, -N-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted with hydroxy; undefined groups are as described in any of the preceding schemes.
根据本发明的某些实施例，式I所示化合物为式Ia所示化合物：According to certain embodiments of the present invention, the compound shown in formula I is the compound shown in formula Ia:
Figure PCTCN2022087589-appb-000020
Figure PCTCN2022087589-appb-000020
其中：R 5、R 8具有上文所述的定义；R 1a和R 1b各自独立地选自-H、-F。 wherein: R 5 , R 8 have the above-mentioned definitions; R 1a and R 1b are each independently selected from -H, -F.
根据本发明的某些实施例，在式Ia所示化合物中，R 5选自二氟甲基、三氟甲基；R 8选自被羟基取代的C 2-C 4烷基或被氰基取代的C 2-C 4烷基；R 1a和R 1b各自独立地选自-H、-F。 According to certain embodiments of the present invention, in the compound represented by formula Ia, R 5 is selected from difluoromethyl, trifluoromethyl; R 8 is selected from C 2 -C 4 alkyl substituted by hydroxyl or cyano group Substituted C2 - C4 alkyl; R 1a and R 1b are each independently selected from -H, -F.
根据本发明的某些实施例，R 5选自二氟甲基、三氟甲基；R 8选自C 3-C 10环烷基、C 6-C 10螺环烷基、桥连的C 5-C 10环烷基，所述R 8是未被取代的或者被R j取代，所述R j独立地选自-F、甲基、甲氧基、氰基；较佳地，R 8选自环丙基、环丁基、
Figure PCTCN2022087589-appb-000021
所述R 8是未被取代的或者被R j取代，所述R j独立地选自-F、甲基、甲氧基、氰基；R 1a和R 1b各自独立地选自-H、-F。 According to certain embodiments of the present invention, R 5 is selected from difluoromethyl, trifluoromethyl; R 8 is selected from C 3 -C 10 cycloalkyl, C 6 -C 10 spirocycloalkyl, bridged C 5 -C 10 cycloalkyl, the R 8 is unsubstituted or substituted by R j , the R j is independently selected from -F, methyl, methoxy, cyano; preferably, R 8 is selected from cyclopropyl, cyclobutyl,
Figure PCTCN2022087589-appb-000021
Said R 8 is unsubstituted or substituted by R j , and said R j is independently selected from -F, methyl, methoxy, cyano; R 1a and R 1b are each independently selected from -H, - F.
根据本发明的某些实施例，式I所示化合物为式Ic所示化合物：According to certain embodiments of the present invention, the compound shown in formula I is the compound shown in formula Ic:
Figure PCTCN2022087589-appb-000022
Figure PCTCN2022087589-appb-000022
其中：R 5、R 7、R 8具有上文所述的定义；R 1a和R 1b各自独立地选自-H、-F。 wherein: R 5 , R 7 , R 8 have the above-mentioned definitions; R 1a and R 1b are each independently selected from -H, -F.
根据本发明的某些实施例，在式Ic所示化合物中，R 5选自二氟甲基、三氟甲基；R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基是未被取代的或者被R j取代；R j选自-F、氰基、-NH-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基；R 1a和R 1b各自独立地选自-H、-F。 According to certain embodiments of the present invention, in the compound represented by formula Ic, R 5 is selected from difluoromethyl, trifluoromethyl; R 7 , R 8 together with the N atom they are connected to together form a 4-6-membered heterocyclic Cycloalkyl, the 4-6 membered heterocycloalkyl is unsubstituted or substituted by R j ; R j is selected from -F, cyano, -NH-(C 1 -C 6 alkyl), hydroxy Substituted C 1 -C 6 alkyl; R 1a and R 1b are each independently selected from -H, -F.
根据本发明的某些实施例，在式Ic所示化合物中，R 5选自二氟甲基、三氟甲基；R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基同时被R j和R L取代；R j选自-F、氰基、-NH-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基；R L选自甲基、羟基；R 1a和R 1b各自独立地选自-H、-F。 According to certain embodiments of the present invention, in the compound represented by formula Ic, R 5 is selected from difluoromethyl, trifluoromethyl; R 7 , R 8 together with the N atom they are connected to together form a 4-6-membered heterocyclic Cycloalkyl, the 4-6 membered heterocycloalkyl is substituted by both R j and R L ; R j is selected from -F, cyano, -NH-(C 1 -C 6 alkyl), hydroxy substituted C 1 -C 6 alkyl; R L is selected from methyl, hydroxyl; R 1a and R 1b are each independently selected from -H, -F.
根据本发明的某些实施例，在式Ic所示化合物中，R 5选自二氟甲基、三氟甲基；R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基同时被R j、R k和R L取代；R j和R k各自独立地选自-F、氰基、-NH-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基；R L选自甲基、羟基；R 1a和R 1b各自独立地选自-H、-F。 According to certain embodiments of the present invention, in the compound represented by formula Ic, R 5 is selected from difluoromethyl, trifluoromethyl; R 7 , R 8 together with the N atom they are connected to together form a 4-6-membered heterocyclic Cycloalkyl, the 4-6 membered heterocycloalkyl is simultaneously substituted with R j , R k and R L ; R j and R k are each independently selected from -F, cyano, -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted by hydroxyl; R L is selected from methyl, hydroxyl; R 1a and R 1b are each independently selected from -H, -F.
根据本发明的某些实施例，式I所示化合物为式If所示化合物：According to certain embodiments of the present invention, the compound represented by formula I is the compound represented by formula If:
Figure PCTCN2022087589-appb-000023
Figure PCTCN2022087589-appb-000023
其中：R 2、R 5具有上文所述的定义；R 1a和R 1b各自独立地选自-H、-F。 wherein: R 2 , R 5 have the above definitions; R 1a and R 1b are each independently selected from -H, -F.
根据本发明的某些实施例，在式If所示化合物中，R 5选自二氟甲基、三氟甲基；R 2选自无取代的或被R j取代的以下基团：
Figure PCTCN2022087589-appb-000024
Figure PCTCN2022087589-appb-000025
其中R A1、R A2以及环A的部分环原子相连形成3-7元环烷基或3-7元杂环烷基，所述3-7元杂环烷基的1-3个环原子独立选自N、O和S；R j选自-F、氰基、-N-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基；R 1a和R 1b各自独立地选自-H、-F。 According to certain embodiments of the present invention, in the compound represented by formula If, R 5 is selected from difluoromethyl, trifluoromethyl; R 2 is selected from the following groups unsubstituted or substituted by R j :
Figure PCTCN2022087589-appb-000024
Figure PCTCN2022087589-appb-000025
wherein R A1 , R A2 and some ring atoms of ring A are connected to form a 3-7-membered cycloalkyl or a 3-7-membered heterocycloalkyl, and 1-3 ring atoms of the 3-7-membered heterocycloalkyl are independent is selected from N, O and S; R j is selected from -F, cyano, -N-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted by hydroxy; R 1a and R 1b are each independently is selected from -H, -F.
根据本发明的某些实施例，在式If所示化合物中，R 5选自二氟甲基、三氟甲基；R 2选自无取代的或被R j取代的以下基团：
Figure PCTCN2022087589-appb-000026
R j选自-F、氰基、-N-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基；R 1a和R 1b各自独立地选自-H、-F。 According to certain embodiments of the present invention, in the compound represented by formula If, R 5 is selected from difluoromethyl, trifluoromethyl; R 2 is selected from the following groups unsubstituted or substituted by R j :
Figure PCTCN2022087589-appb-000026
R j is selected from -F, cyano, -N-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted by hydroxy; R 1a and R 1b are each independently selected from -H, -F .
根据本发明的某些实施例，式I所示化合物中，R 2选自
Figure PCTCN2022087589-appb-000027
Figure PCTCN2022087589-appb-000028
Figure PCTCN2022087589-appb-000029
Figure PCTCN2022087589-appb-000030
未定义的基团如前任一方案所述。 According to certain embodiments of the present invention, in the compound represented by formula I, R 2 is selected from
Figure PCTCN2022087589-appb-000027
Figure PCTCN2022087589-appb-000028
Figure PCTCN2022087589-appb-000029
Figure PCTCN2022087589-appb-000030
Undefined groups are as described in any of the previous schemes.
根据本发明的某些实施例，式I所示化合物具有如下式Im、In、Ip或Iq所示的结构：According to certain embodiments of the present invention, the compound shown in formula I has the structure shown in the following formula Im, In, Ip or Iq:
Figure PCTCN2022087589-appb-000031
Figure PCTCN2022087589-appb-000031
其中，R 1、R 2、R 3、R 4、R 5、R 6独立地具有上文所述的定义； wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 independently have the definitions set forth above;
较佳地，R 3、R 4、R 6为氢。 Preferably, R 3 , R 4 and R 6 are hydrogen.
根据本发明的某些实施例，所述式I化合物选自下列任一化合物，或其互变异构体、立体异构体、水合物、溶剂化物、药学可接受的盐或前药：According to certain embodiments of the present invention, the compound of formula I is selected from any of the following compounds, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:
Figure PCTCN2022087589-appb-000032
Figure PCTCN2022087589-appb-000032
Figure PCTCN2022087589-appb-000033
Figure PCTCN2022087589-appb-000033
Figure PCTCN2022087589-appb-000034
Figure PCTCN2022087589-appb-000034
Figure PCTCN2022087589-appb-000035
Figure PCTCN2022087589-appb-000035
Figure PCTCN2022087589-appb-000036
Figure PCTCN2022087589-appb-000036
Figure PCTCN2022087589-appb-000037
Figure PCTCN2022087589-appb-000037
Figure PCTCN2022087589-appb-000038
Figure PCTCN2022087589-appb-000038
Figure PCTCN2022087589-appb-000039
Figure PCTCN2022087589-appb-000039
Figure PCTCN2022087589-appb-000040
Figure PCTCN2022087589-appb-000040
Figure PCTCN2022087589-appb-000041
Figure PCTCN2022087589-appb-000041
Figure PCTCN2022087589-appb-000042
Figure PCTCN2022087589-appb-000042
Figure PCTCN2022087589-appb-000043
Figure PCTCN2022087589-appb-000043
根据本发明的某些实施例，所述式I化合物选自下列任一化合物，或其互变异构体、立体异构体、水合物、溶剂化物、药学可接受的盐或前药：According to certain embodiments of the present invention, the compound of formula I is selected from any of the following compounds, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:
Figure PCTCN2022087589-appb-000044
Figure PCTCN2022087589-appb-000044
Figure PCTCN2022087589-appb-000045
Figure PCTCN2022087589-appb-000045
Figure PCTCN2022087589-appb-000046
Figure PCTCN2022087589-appb-000046
Figure PCTCN2022087589-appb-000047
Figure PCTCN2022087589-appb-000047
Figure PCTCN2022087589-appb-000048
Figure PCTCN2022087589-appb-000048
Figure PCTCN2022087589-appb-000049
Figure PCTCN2022087589-appb-000049
Figure PCTCN2022087589-appb-000050
Figure PCTCN2022087589-appb-000050
Figure PCTCN2022087589-appb-000051
Figure PCTCN2022087589-appb-000051
Figure PCTCN2022087589-appb-000052
Figure PCTCN2022087589-appb-000052
Figure PCTCN2022087589-appb-000053
Figure PCTCN2022087589-appb-000053
在本发明的第二方面，本发明提供了如式M-1所示的中间体，用于制备如本发明第一方面所述的式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，所述中间体M-1具有结构：In the second aspect of the present invention, the present invention provides an intermediate represented by the formula M-1 for preparing the compound represented by the formula I or the tautomerism of the compound represented by the formula I as described in the first aspect of the present invention Conformer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, the intermediate M-1 has the structure:
Figure PCTCN2022087589-appb-000054
Figure PCTCN2022087589-appb-000054
其中，W、X、Y、Z、R 1的定义如本发明第一方面所述。 Wherein, the definitions of W, X, Y, Z, and R 1 are as described in the first aspect of the present invention.
本发明提供了如式M-2所示的中间体，用于制备如本发明第一方面所述的式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，所述中间体M-2具有结构：The present invention provides an intermediate represented by formula M-2 for preparing the compound represented by formula I or the tautomer, stereoisomer, A hydrate, solvate, pharmaceutically acceptable salt or prodrug, the intermediate M-2 has the structure:
Figure PCTCN2022087589-appb-000055
Figure PCTCN2022087589-appb-000055
其中，W、X、Y、Z、R 1的定义如本发明第一方面所述。 Wherein, the definitions of W, X, Y, Z, and R 1 are as described in the first aspect of the present invention.
本发明提供了如式M-3所示的中间体，用于制备如本发明第一方面所述的式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，所述中间体M-3具有结构：The present invention provides an intermediate represented by formula M-3 for preparing the compound represented by formula I as described in the first aspect of the present invention or the tautomer, stereoisomer, A hydrate, solvate, pharmaceutically acceptable salt or prodrug, the intermediate M-3 has the structure:
Figure PCTCN2022087589-appb-000056
Figure PCTCN2022087589-appb-000056
其中，W、X、Y、Z、R 1和R 2的定义如本发明第一方面所述。 Wherein, the definitions of W, X, Y, Z, R 1 and R 2 are as described in the first aspect of the present invention.
本发明提供了如式M-3所示的中间体，用于制备如本发明第一方面所述的式I所示化合物 或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，所述中间体M-3具有结构：The present invention provides an intermediate represented by formula M-3 for preparing the compound represented by formula I as described in the first aspect of the present invention or the tautomer, stereoisomer, A hydrate, solvate, pharmaceutically acceptable salt or prodrug, the intermediate M-3 has the structure:
Figure PCTCN2022087589-appb-000057
Figure PCTCN2022087589-appb-000057
其中，W、X、Y、Z、R 1的定义如本发明第一方面所述。 Wherein, the definitions of W, X, Y, Z, and R 1 are as described in the first aspect of the present invention.
根据本发明的某些实施例，所述中间体M-1选自下列任一化合物：According to certain embodiments of the present invention, the intermediate M-1 is selected from any of the following compounds:
Figure PCTCN2022087589-appb-000058
Figure PCTCN2022087589-appb-000058
Figure PCTCN2022087589-appb-000059
Figure PCTCN2022087589-appb-000059
根据本发明的某些实施例，所述中间体M-2选自下列任一化合物：According to certain embodiments of the present invention, the intermediate M-2 is selected from any of the following compounds:
Figure PCTCN2022087589-appb-000060
Figure PCTCN2022087589-appb-000060
根据本发明的某些实施例，所述中间体M-3选自下列任一化合物：According to certain embodiments of the present invention, the intermediate M-3 is selected from any of the following compounds:
Figure PCTCN2022087589-appb-000061
Figure PCTCN2022087589-appb-000061
Figure PCTCN2022087589-appb-000062
Figure PCTCN2022087589-appb-000062
根据本发明的某些实施例，所述中间体M-4选自下列任一化合物：According to certain embodiments of the present invention, the intermediate M-4 is selected from any of the following compounds:
Figure PCTCN2022087589-appb-000063
Figure PCTCN2022087589-appb-000063
在本发明的第三方面，本发明提供了一种制备如本发明第一方面所述的式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的方法，其包括步骤：In the third aspect of the present invention, the present invention provides a tautomer, stereoisomer, hydrate, A method for a solvate, pharmaceutically acceptable salt or prodrug, comprising the steps of:
(1)在酸性条件下，使中间体M-1水解得到中间体M-2，(1) under acidic conditions, the intermediate M-1 is hydrolyzed to obtain the intermediate M-2,
Figure PCTCN2022087589-appb-000064
和/或
Figure PCTCN2022087589-appb-000064
and / or
(2)在碱性条件下，使中间体M-2与
Figure PCTCN2022087589-appb-000065
接触得到中间体M-3，其中R 8具有上文所述的定义， (2) under alkaline condition, make intermediate M-2 and
Figure PCTCN2022087589-appb-000065
Contacting provides intermediate M- 3 , wherein R has the above-mentioned definition,
Figure PCTCN2022087589-appb-000066
和/或
Figure PCTCN2022087589-appb-000066
and / or
(3)在碘单质存在下，在碱性条件下使中间体M-3发生环化反应得到式I所示化合物，(3) in the presence of elemental iodine, under alkaline conditions, intermediate M-3 is cyclized to obtain the compound shown in formula I,
Figure PCTCN2022087589-appb-000067
Figure PCTCN2022087589-appb-000067
其中，W、X、Y、Z、R 1、R 2和R 8具有上文所述的定义。 wherein W, X, Y, Z, R 1 , R 2 and R 8 have the definitions set forth above.
根据本发明的某些实施例，步骤(1)中，所述酸性条件可以由无机酸和/或有机酸提供，如硫酸、醋酸。例如，在惰性气体氛围如氮气置换中，使M-1与硫酸和醋酸接触，然后将反应体系加热到25-90℃，搅拌反应，得到M-2。According to some embodiments of the present invention, in step (1), the acidic conditions may be provided by inorganic acids and/or organic acids, such as sulfuric acid and acetic acid. For example, in an inert gas atmosphere such as nitrogen replacement, M-1 is contacted with sulfuric acid and acetic acid, and then the reaction system is heated to 25-90°C, and the reaction is stirred to obtain M-2.
根据本发明的某些实施例，步骤(2)中，所述碱性条件可以由无机碱和/或有机碱提供，如碳酸钾、碳酸铯、碳酸钠、叔丁醇钾、叔丁醇钠等。例如，将M-2、
Figure PCTCN2022087589-appb-000068
与碳酸铯加入N,N-二甲基甲酰胺中，置换氮气，加热到25-75℃，搅拌反应得到M-3，其中R 8具有上文所述的定义。 According to some embodiments of the present invention, in step (2), the alkaline conditions can be provided by inorganic bases and/or organic bases, such as potassium carbonate, cesium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide Wait. For example, the M-2,
Figure PCTCN2022087589-appb-000068
Add cesium carbonate to N,N-dimethylformamide, replace nitrogen, heat to 25-75°C, and stir the reaction to obtain M-3, wherein R8 has the above-mentioned definition.
根据本发明的某些实施例，步骤(3)中，所述碱性条件可以由无机碱和/或有机碱提供，如碳酸铯、吡啶等。例如，将M-3溶解在四氢呋喃中，在低温(如0℃)下缓慢加入碘单质、吡啶，置换氮气，加热到20-50℃，搅拌反,0.5-2小时，得到式I所示化合物。According to some embodiments of the present invention, in step (3), the basic conditions may be provided by inorganic bases and/or organic bases, such as cesium carbonate, pyridine and the like. For example, dissolve M-3 in tetrahydrofuran, slowly add iodine and pyridine at low temperature (such as 0°C), replace nitrogen, heat to 20-50°C, stir for 0.5-2 hours, and obtain the compound shown in formula I .
根据本发明的某些实施例，当R 8含有羟基时，所述制备方法还包括选自下组的一种或多种步骤： According to certain embodiments of the present invention, when R 8 contains a hydroxyl group, the preparation method further comprises one or more steps selected from the group consisting of:
在所述步骤(2)之前还包括步骤(2-1)：通过羟基保护基保护羟基；和/或Before the step (2), it also includes a step (2-1): protecting the hydroxyl group by a hydroxyl protecting group; and/or
在所述步骤(3)之后还包括步骤(3-2)：脱去羟基保护基；Step (3-2) is also included after the step (3): removing the hydroxyl protecting group;
较佳地，所述羟基保护基选自含硅烷基的羟基保护基，如TBS、TMS等。Preferably, the hydroxyl protecting group is selected from silyl-containing hydroxyl protecting groups, such as TBS, TMS and the like.
另外，本发明还提供了一种制备如本发明第一方面所述的式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的方法，其包括步骤：In addition, the present invention also provides a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound of formula I or a tautomer, stereoisomer, hydrate, solvate, etc. A method of an acceptable salt or prodrug comprising the steps of:
(A)在碱性条件下，使中间体M-2与硫光气或硫羰基二咪唑接触得到中间体M-4，(A) under alkaline conditions, make intermediate M-2 contact with thiophosgene or thiocarbonyl diimidazole to obtain intermediate M-4,
Figure PCTCN2022087589-appb-000069
和/或
Figure PCTCN2022087589-appb-000069
and / or
(B)在碘单质存在下，在碱性条件下使M-4与R 2-H接触得到式I所示化合物， (B) in the presence of elemental iodine, under alkaline conditions, M-4 is contacted with R 2 -H to obtain the compound shown in formula I,
Figure PCTCN2022087589-appb-000070
Figure PCTCN2022087589-appb-000070
其中R 2具有上文所述的定义。 wherein R 2 has the definition set forth above.
根据本发明的某些实施例，步骤(A)中，所述碱性条件可以由有机碱提供，如乙醇钠、乙醇钾等。例如，在惰性气体氛围如氮气保护下，在低温如0℃条件下，使M-2与乙醇钠接触，搅拌反应后，缓慢加入硫光气，回流反应，得到M-4。According to some embodiments of the present invention, in step (A), the alkaline condition can be provided by an organic base, such as sodium ethoxide, potassium ethoxide and the like. For example, in an inert gas atmosphere such as nitrogen protection, at a low temperature such as 0 °C, M-2 is contacted with sodium ethoxide, after stirring the reaction, slowly adding thiophosgene, and refluxing to react to obtain M-4.
根据本发明的某些实施例，步骤(B)中，所述碱性条件可以由无机碱和/或有机碱提供，如碳酸铯、吡啶等。例如，将M-4、R 2-H和吡啶溶解到四氢呋喃中，置换氮气，降温至低温如0℃，将碘单质慢慢加入反应体系，加热搅拌，得到式I所示化合物。 According to some embodiments of the present invention, in step (B), the basic conditions may be provided by inorganic bases and/or organic bases, such as cesium carbonate, pyridine and the like. For example, M-4, R 2 -H and pyridine are dissolved in tetrahydrofuran, nitrogen is replaced, the temperature is lowered to a low temperature such as 0° C., elemental iodine is slowly added to the reaction system, heated and stirred to obtain the compound represented by formula I.
在本发明的第四方面，本发明提供了一种药物组合物，其包含治疗有效量的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药中的至少一种。In the fourth aspect of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmacy at least one of the above acceptable salts or prodrugs.
根据本发明的某些实施例，所述药物组合物还包括一种或多种药学上可接受的辅料。According to some embodiments of the present invention, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.
根据本发明的某些实施例，所述药物组合物还可以进一步含有一种或多种额外的治疗剂。According to certain embodiments of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.
在本发明的第五方面，本发明提供了式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或所述的药物组合物在制备药物中的用途，所述药物用于治疗或者预防MAT2A相关疾病，本发明还提供了本发明第一方面所述的任意化合物或本发明第四方面所述的药物组合物治疗或者预防MAT2A相关疾病的医药用途。In the fifth aspect of the present invention, the present invention provides the compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or said Use of the pharmaceutical composition in the preparation of a medicament for treating or preventing MAT2A-related diseases, the present invention also provides any compound described in the first aspect of the present invention or the pharmaceutical composition described in the fourth aspect of the present invention. Or medicinal use to prevent MAT2A-related diseases.
根据本发明的某些实施例，所述药物用于治疗或者预防癌症。According to certain embodiments of the present invention, the medicament is for treating or preventing cancer.
根据本发明的某些实施例，所述癌症是MTAP缺失的癌症。According to certain embodiments of the invention, the cancer is an MTAP-deficient cancer.
根据本发明的某些实施例，所述癌症选自间皮瘤、神经母细胞瘤、直肠癌、结肠癌、熟悉 的腺瘤性息肉病和遗传性非息肉性结直肠癌、食道癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、甲状腺乳头状癌、肾癌、肾实质癌、卵巢癌、子宫颈癌、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、前列腺癌、膀胱癌、睾丸癌、乳腺癌、泌尿癌、黑素瘤、脑瘤、淋巴瘤、头颈癌、急性淋巴白血病(ALL)、慢性淋巴白血病(CLL)、急性髓样白血病(AML)、慢性粒细胞白血病(CML)、肝细胞癌、胆囊癌、兄弟支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底肉瘤、畸胎瘤、视网膜母细胞瘤、脉络膜黑色素瘤、精原细胞瘤、横纹肌肉瘤、骨肉瘤、软骨肉瘤、肌瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤和浆细胞瘤。According to certain embodiments of the invention, the cancer is selected from the group consisting of mesothelioma, neuroblastoma, rectal cancer, colon cancer, familiar adenomatous polyposis and hereditary nonpolyposis colorectal cancer, esophageal cancer, lip Cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, intrauterine cancer Membranous cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary cancer, melanoma, brain tumor, lymphoma, head and neck cancer, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) ), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, gallbladder carcinoma, brother bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratoma, Retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, fibroids, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma.
本发明还提供一种预防或治疗MAT2A相关疾病的方法，包括给予患者预防或治疗有效量的式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药中的至少一种，或上述药物组合物。The present invention also provides a method for preventing or treating MAT2A-related diseases, comprising administering to a patient a preventive or therapeutically effective amount of the compound represented by formula (I), its tautomer, stereoisomer, hydrate and solvate , at least one of a pharmaceutically acceptable salt or prodrug, or the above-mentioned pharmaceutical composition.
根据本发明的某些实施例，所述患者哺乳动物，优选是人。According to certain embodiments of the present invention, the patient mammal, preferably a human.
本发明还提供式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药中的至少一种，或其药物组合物在治疗或预防MAT2A相关疾病中的应用。The present invention also provides at least one of the compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or a pharmaceutical combination thereof The application of the drug in the treatment or prevention of MAT2A-related diseases.
有益效果beneficial effect
根据本发明的实施例，本发明所述化合物和/或其组合物能够有效抑制MAT2A酶活性，对HCT116 MTAP-/-细胞增殖及细胞中SAM水平有很好的抑制作用，具有更好的药代动力学性质，副作用小，尤其是减少了胃肠道不良反应(例如恶心、呕吐、腹痛、腹泻、腹胀、食欲减退、消化不良等)。在制备治疗与MAT2A相关疾病的药物方面具有广阔的应用前景。 According to the embodiments of the present invention, the compounds and/or compositions thereof of the present invention can effectively inhibit the activity of MAT2A enzyme, have a good inhibitory effect on the proliferation of HCT116 MTAP-/- cells and the level of SAM in cells, and have better pharmacological effects. Kinetic properties, less side effects, especially reduced gastrointestinal adverse reactions (such as nausea, vomiting, abdominal pain, diarrhea, abdominal distension, loss of appetite, indigestion, etc.). It has broad application prospects in preparing medicines for treating MAT2A-related diseases.
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。Additional aspects and advantages of the present invention will be set forth, in part, from the following description, and in part will be apparent from the following description, or may be learned by practice of the invention.
术语定义与说明Definition and Explanation of Terms
除非另有说明，本申请说明书和权利要求书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。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。Unless otherwise stated, definitions of groups and terms set forth in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions set forth in tables, and definitions of specific compounds in the examples etc., can be arbitrarily combined and combined with each other. Such combinations, group definitions and compound structures after the combination should fall within the scope described in the specification of the present application.
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。Unless otherwise defined, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, publications cited throughout this document are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms in this document, the definitions in this chapter shall prevail.
除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/Vis光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本申请的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH 2O等同于OCH 2。 Unless otherwise stated, conventional methods within the skill in the art are employed, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy and pharmacological methods. Unless specific definitions are presented, the terms employed herein in the related descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in this application. The techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds. When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 .
本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“1～6的整数”应当理解为记载了0、1、2、3、4、5和6的每一个整数。当该数值范围被理解为“数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数以及该范围内的每一个小数。例如，“1～10的数”应当被理解为不仅记载了1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载 了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。The numerical range described in the specification and claims of the present application, when the numerical range is understood as an "integer", should be understood as describing the two endpoints of the range and each integer in the range. For example, "an integer of 1 to 6" should be understood as reciting each integer of 0, 1, 2, 3, 4, 5, and 6. When such a numerical range is read as a "number," it should be understood as reciting both endpoints of the range and each integer within the range and every decimal point within the range. For example, "a number from 1 to 10" should be understood as not only reciting each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also reciting at least that each integer is respectively associated with Sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
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 that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”或者“其药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable salts thereof" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。In addition to the pharmaceutically acceptable salts, other salts are also contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the present invention.
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。本发明使用的立体化学定义和惯例大体上按照S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994来定义。本发明化合物可含有不对称中心或手性中心，因此以不同的立体异构形式存在。所预期的是，本发明化合物的所有立体异构体形式，包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)和几何(或构象)异构体及它们的混合物，如外消旋混合物，均在本发明的范围之内。The term "stereoisomer" refers to isomers that result from different arrangements of atoms in a molecule in space. Stereochemical definitions and conventions used herein are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds”, defined by John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention are contemplated, including but not limited to diastereomers, enantiomers, and atropisomers and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。就给定的化学结构而言，除了这些立体异构体互为镜像外，这些立体异构体是相同的。具体的立体异构体也可称为对映异构体，并且所述异构体的混合物通常称作对映异构体的混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或方法中没有立体选择性或立体特异性时，可出现所述外消旋混合物或外消旋体。Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to designate the rotation of plane polarized light by the compound, where (–) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method Spin body.
依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。旋光性的I-或(S)-异构体可使用手性合成子或手性制剂制备，或使用常规技术拆分。如果此化合物含有一个双键，取代基可能为E或Z构型；如果此化合物中含有二取代的环烷基，环烷基的取代基可能为顺式或反式(cis-或trans-)构型。Depending on the choice of starting materials and methods, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, for example, as pure optical isomers, or as mixtures of isomers, such as racemic and non-isomeric isomers. A mixture of enantiomers, depending on the number of asymmetric carbon atoms. Optically active I- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be of E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may be cis or trans (cis- or trans-) structure.
当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。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，用楔形键和虚线键表示一个立体中心的绝对构型。When the bond to the chiral carbon in the formula of the present invention is depicted in line, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and Mixtures of both are included within the scope of this formula. A schematic representation of racemate or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise stated, wedge and dashed bonds are used to indicate the absolute configuration of a stereocenter.
含有不对称取代的碳原子的本发明化合物能够以旋光活性形式或外消旋形式分离。化合物的外消旋混合物的拆分可以通过本领域已知的许多方法中的任一种来进行。示例性方法包括使用手性拆分酸的分级重结晶，该手性拆分酸是旋光活性的成盐有机酸。用于分级重结晶方法的适合的拆分剂例如是旋光活性酸，例如酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸或各种旋光活性樟脑磺酸如β-樟脑磺酸的D和L形式。适合于分级结晶方法的其它的拆分剂包括立体异构纯形式的α-甲基-苄胺(例如，S和R形式或者非对映异构纯形式)、2-苯基甘氨醇、降麻黄碱、麻黄碱、N-甲基麻黄碱、环己基乙胺、1，2-二氨基环己烷等。外消旋混合物的拆分还可以通过在填充有旋光活性拆分剂(例如，二硝基苯甲酰基苯基甘氨酸)的柱子上洗脱来进行。可以采用高效液相色谱(HPLC)法也可以采用超临界流体色谱法(SFC)进行。具体方法的选择以及洗脱条件、色谱柱的选择可以由本领域技术人员根据化合物的结构以及试验结果选择。进一步的，还可以使用已知构型的光学纯的起始原料或试剂，通过立体有机合成，获得本发明所描述化合物的任何对映体或非对映体。Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids. Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as β- D and L forms of camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine in stereoisomerically pure form (eg, S and R forms or diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of the racemic mixture can also be performed by elution on a column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). Selection of specific methods, elution conditions, and selection of chromatographic columns can be selected by those skilled in the art according to the structures of compounds and test results. Further, any enantiomer or diastereomer of the compounds described in the present invention can also be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.
烯烃、C＝N双键等的许多几何异构体也可以存在于本文所述的化合物中，且所有这种稳定的异构体在本发明中均被考虑。当本文所描述化合物含有烯双键时，除非另外说明，否则，这种双键包括E和Z几何异构体。Many geometric isomers of olefins, C=N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers.
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。本发明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。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。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。本发明包含化合物的所有互变异构形式。The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form predominates; in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.
术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。The term "pharmaceutical composition" means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。The term "solvate" means that a compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。The term "prodrug" refers to a compound of the invention that can be converted under physiological conditions or by solvolysis to a biologically active compound. The prodrugs of the present invention are prepared by modifying functional groups in the compounds, which modifications can be removed by conventional procedures or in vivo to yield the parent compounds. Prodrugs include compounds formed by connecting a hydroxyl or amino group in the compounds of the present invention to any group. When the prodrugs of the compounds of the present invention are administered to mammalian individuals, the prodrugs are cleaved to form free hydroxyl, free the amino group.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of classes of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like.
术语“烷基”是指具有1至数个碳原子的直链饱和一价烃基或具有3至6个碳原子的支链的饱和单价烃基，例如甲基，乙基，丙基，2-丙基，丁基，戊基等。本领域技术人员将认识到，术语“烷基”可包括“亚烷基”基团。The term "alkyl" refers to a linear saturated monovalent hydrocarbon group having 1 to several carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propane base, butyl, pentyl, etc. Those skilled in the art will recognize that the term "alkyl" can include "alkylene" groups.
术语“C 1-C 10烷基”应理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、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1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2、3、4、5、6个碳原子(“C 1-C 6烷基”)，例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基，更特别地，所述基团具有1、2或3个碳原子(“C 1-C 3烷基”)，例如甲基、乙基、正丙基或异丙基。 The term "C 1 -C 10 alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, the group has 1, 2, 3, 4, 5, 6 carbon atoms (" C1 - C6 alkyl"), eg methyl, ethyl, propyl, butyl, isopropyl , isobutyl, sec-butyl, tert-butyl, more particularly, said groups having 1, 2 or 3 carbon atoms (" C1 -C3 alkyl"), eg methyl, ethyl, n- propyl or isopropyl.
术语“亚烷基”应理解为表示具有1-6个碳原子的直链饱和二价烃基或具有3-6个碳原子的支链饱和二价烃基，除非另有说明，例如亚甲基、亚乙基、亚丙基、1-甲基亚丙基、亚丁基等。The term "alkylene" should be understood to mean a straight-chain saturated divalent hydrocarbon radical having 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical having 3 to 6 carbon atoms, unless otherwise specified, such as methylene, Ethylene, propylene, 1-methylpropylene, butylene, etc.
术语“烯基”是指含双键的具有2至数个碳原子的直链一价烃基或具有丙烯基，丁烯基等含双键的具有3至数个碳原子的支链一价烃基。The term "alkenyl" refers to a straight-chain monovalent hydrocarbon group with 2 to several carbon atoms containing double bonds or a branched monovalent hydrocarbon group with 3 to several carbon atoms containing double bonds such as propenyl, butenyl, etc. .
术语“C 2-C 10烯基”应理解为表示具有2至10个碳原子的稀基，所述烯基符合上述定义。术语“C 2-C 6烯基”应理解为表示含有一个或多个碳-碳双键、具有2、3、4、5或6个碳原子的直链一价烃基或具有丙烯基、丁烯基等的双键的具有3至6个碳原子的支链一价烃基。 The term "C 2 -C 10 alkenyl" is understood to mean an alkenyl group having 2 to 10 carbon atoms, said alkenyl group being in accordance with the above definition. The term "C 2 -C 6 alkenyl" is understood to mean a straight-chain monovalent hydrocarbon group containing one or more carbon-carbon double bonds, having 2, 3, 4, 5 or 6 carbon atoms or a A branched monovalent hydrocarbon group having 3 to 6 carbon atoms of a double bond such as an alkenyl group.
术语“炔基”是指含三键的具有2至数个碳原子的直链一价烃基或含三个碳原子的支链一价烃基，例如乙炔基，丙炔基，丁炔基等。The term "alkynyl" refers to a straight chain monovalent hydrocarbon group having 2 to several carbon atoms or a branched monovalent hydrocarbon group containing three carbon atoms, such as ethynyl, propynyl, butynyl and the like, containing a triple bond.
术语“C 2-C 10炔基”应理解为表示具有2至10个碳原子的炔基，所述炔基符合上述定义。术语“C 2-C 6炔基”应理解为表示含有2-6个碳原子和至少一个碳碳三键的直链、支链或者环状烃基，例如乙炔基、丙炔基、丁炔基和3-甲基丁炔基等。 The term "C 2 -C 10 alkynyl" is understood to mean an alkynyl group having 2 to 10 carbon atoms, said alkynyl group being in accordance with the above definition. The term "C 2 -C 6 alkynyl" is to be understood as meaning a straight-chain, branched or cyclic hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl and 3-methylbutynyl, etc.
“烷氧基”是指-OR基团，其中R是如上定义的烷基，例如，甲氧基，乙氧基，丙氧基或异丙氧基等。"Alkoxy" refers to an -OR group where R is an alkyl group as defined above, eg, methoxy, ethoxy, propoxy or isopropoxy, and the like.
术语“C 1-C 10烷氧基”应理解为-O-(C 1-10烷基)，其中“C 1-10烷基”具有上述定义；术语“C 1-C 6烷氧基”应理解为-O-(C 1-6烷基)，其中“C 1-6烷基”具有上述定义。 The term "C 1 -C 10 alkoxy" should be understood as -O-(C 1-10 alkyl), wherein "C 1-10 alkyl" has the above definition; the term "C 1 -C 6 alkoxy" It should be understood as -O-(C 1-6 alkyl), wherein "C 1-6 alkyl" has the above definition.
术语“烷氧基烷基”是指被一个以上的烷氧基取代的烷基，所述烷基具有上述定义，例如2-甲氧基乙基，1-，2-或3–甲氧基丙基，2-乙氧基乙基等。The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, as defined above, such as 2-methoxyethyl, 1-, 2- or 3-methoxy propyl, 2-ethoxyethyl, etc.
术语“烷氧基烷氧基”是指-OR基团，其中R是如上定义的烷氧基烷基，例如甲氧基乙氧基，乙氧基丙氧基等。The term "alkoxyalkoxy" refers to the -OR group, wherein R is an alkoxyalkyl group as defined above, eg, methoxyethoxy, ethoxypropoxy, and the like.
术语“烷氧基烷基氨基”是指-NRR′基，其中R是氢或烷基，R′是烷氧基烷基，各自如上所定义，例如甲氧基乙基氨基，甲氧基丙基氨基等。The term "alkoxyalkylamino" refers to a -NRR' group, wherein R is hydrogen or alkyl, and R' is alkoxyalkyl, each as defined above, eg, methoxyethylamino, methoxypropyl amino, etc.
术语“烷基羰基”是指-C(O)R基团，其中R是本文所定义的烷基，例如甲基羰基，乙基羰基等。The term "alkylcarbonyl" refers to a -C(O)R group, wherein R is an alkyl group as defined herein, eg, methylcarbonyl, ethylcarbonyl, and the like.
术语“烷氧羰基”是指-C(O)OR基团，其中R是如上定义的烷基，例如甲氧羰基，乙氧羰基等。The term "alkoxycarbonyl" refers to a -C(O)OR group, wherein R is an alkyl group as defined above, eg, methoxycarbonyl, ethoxycarbonyl, and the like.
术语“烷氧基羧基烷基”是指被烷氧基羧基(例如甲基羧甲基，乙基羧乙基等)取代的如上定义的烷基。The term "alkoxycarboxyalkyl" refers to an alkyl group as defined above substituted with an alkoxycarboxy group (eg, methylcarboxymethyl, ethylcarboxyethyl, etc.).
术语“烷硫基”是指-SR基团，其中R是如上定义的烷基，例如甲硫基，乙硫基等。The term "alkylthio" refers to a -SR group wherein R is an alkyl group as defined above, eg, methylthio, ethylthio, and the like.
术语“烷基磺酰基”是指-SO 2R基团，其中R是如上定义的烷基，例如，甲基磺酰基，乙基磺酰基等。 The term "alkylsulfonyl" refers to a -SO2R group, wherein R is an alkyl group as defined above, eg, methylsulfonyl, ethylsulfonyl, and the like.
术语“烷基磺酰基烷基”是指-(亚烷基)-SO 2R基团，其中R是如上所定义的烷基，例如，甲基磺酰基乙基，乙基磺酰基甲基等。 The term "alkylsulfonylalkyl" refers to a -(alkylene) -SO2R group, where R is an alkyl group as defined above, eg, methylsulfonylethyl, ethylsulfonylmethyl, etc. .
术语“氨基”是指-NH 2。 The term "amino" refers to -NH2 .
术语“烷基氨基”是指-NHR基团，其中R是如上定义的烷基，例如甲基氨基，乙基氨基，丙基氨基或2-丙基氨基等。The term "alkylamino" refers to a -NHR group wherein R is an alkyl group as defined above, eg methylamino, ethylamino, propylamino or 2-propylamino and the like.
术语“氨基烷基”是指被-NR’R”取代的烷基，其中R’和R”独立地是氢、烷基、卤代烷基、羟基烷基、烷氧基、或烷基羰基，例如氨基甲基，氨基乙基，甲基氨基甲基等。The term "aminoalkyl" refers to an alkyl group substituted with -NR'R", wherein R' and R" are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, or alkylcarbonyl, such as Aminomethyl, aminoethyl, methylaminomethyl, etc.
术语“氨基烷氧基”是指-OR基团，其中R是如上定义的氨基烷基，例如氨基乙氧基，甲基氨基丙氧基，二甲基氨基乙氧基，二乙氨基丙氧基等。The term "aminoalkoxy" refers to the -OR group, wherein R is an aminoalkyl group as defined above, eg, aminoethoxy, methylaminopropoxy, dimethylaminoethoxy, diethylaminopropoxy Base et al.
术语“氨基烷基氨基”是指-NRR’基，其中R是氢或烷基，R’是氨基烷基，所述烷基、氨基烷基如上所定义，例如，氨基乙基氨基，甲基氨基丙基氨基，二甲基氨基乙基氨基，二乙基氨基丙基氨基等。The term "aminoalkylamino" refers to a group -NRR', wherein R is hydrogen or alkyl, and R' is aminoalkyl, wherein alkyl, aminoalkyl are as defined above, eg, aminoethylamino, methyl Aminopropylamino, dimethylaminoethylamino, diethylaminopropylamino, etc.
术语“氨基羰基”是指-CONH 2基团。 The term "aminocarbonyl" refers to the -CONH2 group.
术语“烷基氨基羰基”是指-CONHR基团，其中R是如上定义的烷基，例如甲基氨基羰基，乙基氨基羰基等。The term "alkylaminocarbonyl" refers to the group -CONHR wherein R is an alkyl group as defined above, eg, methylaminocarbonyl, ethylaminocarbonyl, and the like.
术语“氨基磺酰基”是指-SO 2NH 2基团。 The term "aminosulfonyl" refers to the -SO2NH2 group.
术语“氨基磺酰基烷基”是指-(亚烷基)SO 2NRR’基团，其中R为氢或烷基，R’为氢，烷基或环烷基，或R和R’与它们所连接的氮原子一起形成杂环基，如上文所定义，例如，甲基氨基磺酰基乙基，二甲基磺酰基乙基等。 The term "aminosulfonylalkyl" refers to a -(alkylene) SO2NRR ' group wherein R is hydrogen or alkyl, R' is hydrogen, alkyl or cycloalkyl, or R and R' are combined with them The attached nitrogen atoms together form a heterocyclyl group, as defined above, eg, methylaminosulfonylethyl, dimethylsulfonylethyl, and the like.
术语“烷基氨基磺酰基”是指-SO 2NHR基团，其中R是如上定义的烷基，例如，甲基氨基磺酰基，乙基氨基磺酰基等。 The term "alkylaminosulfonyl" refers to a -SO2NHR group where R is an alkyl group as defined above, eg, methylaminosulfonyl, ethylaminosulfonyl, and the like.
术语“氨基羰基烷基”是指-(亚烷基)-CONRR’基，其中R和R’独立地是氢，烷基，卤代烷 基，羟烷基或烷氧基烷基，各自如本文所定义，例如，氨基羰基乙基，甲基氨基羰基乙基，二甲基氨基羰基乙基等。The term "aminocarbonylalkyl" refers to a -(alkylene)-CONRR' group, wherein R and R' are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, each as described herein Definition, for example, aminocarbonylethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, etc.
术语“氨基磺酰基烷基”是指-(亚烷基)-SO 2NRR’基团，其中R和R’独立地是氢，烷基，卤代烷基，羟烷基或烷氧基烷基，各自如本文所定义，例如氨基磺酰基乙基，甲基氨基磺酰基乙基，二甲基氨基磺酰基乙基等。 The term "aminosulfonylalkyl" refers to a -(alkylene) -SO2NRR ' group wherein R and R' are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, Each is as defined herein, eg, aminosulfonylethyl, methylaminosulfonylethyl, dimethylaminosulfonylethyl, and the like.
术语“芳基”是指6至数个环原子的单价单环或双环芳族烃基。术语“C 6-C 10芳基”是指6至10个环原子的单价单环或双环芳族烃基，例如苯基或萘基。 The term "aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group of 6 to several ring atoms. The term "C 6 -C 10 aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 ring atoms, such as phenyl or naphthyl.
术语“芳烷基”是指-(亚烷基)-R基团，其中R是如上所定义的芳基，例如苄基，苯乙基等。The term "aralkyl" refers to a -(alkylene)-R group, wherein R is an aryl group as defined above, eg, benzyl, phenethyl, and the like.
术语“桥环烷基”是指饱和的单环5至7元烃基，其中两个不相邻的环原子通过(CRR’)n基团连接，其中n为1至3，并且每个R独立地为H或甲基(在本文中也称为桥接基团)。桥连的环烷基任选地被一个或两个独立地选自烷基，卤素，烷氧基，羟基或氰基的取代基取代。桥环烷基的示例包括但不限于双环[2.2.1]庚烷，双环[2.2.2]辛烷等The term "bridged cycloalkyl" refers to a saturated monocyclic 5- to 7-membered hydrocarbon group in which two non-adjacent ring atoms are joined by a (CRR')n group, where n is 1 to 3, and each R is independently Ground is H or methyl (also referred to herein as a bridging group). The bridged cycloalkyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy or cyano. Examples of bridged cycloalkyl include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like
术语“桥环烷基烷基”是指-(亚烷基)-R基团，其中R是如上定义的桥环烷基。示例包括但不限于双环[2.2.1]庚基甲基等。The term "bridged cycloalkylalkyl" refers to a -(alkylene)-R group, wherein R is bridged cycloalkyl as defined above. Examples include, but are not limited to, bicyclo[2.2.1]heptylmethyl and the like.
术语“桥连杂环基”是指具有5至8个环碳环原子的饱和单环，其中两个不相邻的环原子通过(CRR’)n基团连接，其中n为1至3，并且每个R独立地为H或甲基(在本文中也可称为“桥连”基团)，并且其中一个或两个环碳原子(包括桥连基团中的原子)被选自N，O或S(O)n的杂原子取代，其中n是0至2的整数。桥杂环基任选被一个或两个独立选自烷基，卤素，烷氧基，羟基或氰基的取代基取代。示例包括但不限于2-氮杂双环[2.2.2]辛烷，喹啉环，7-氧杂双环[2.2.l]庚烷等。The term "bridged heterocyclyl" refers to a saturated monocyclic ring having 5 to 8 ring carbon ring atoms, wherein two non-adjacent ring atoms are connected by a (CRR')n group, where n is 1 to 3, and each R is independently H or methyl (also referred to herein as a "bridging" group), and wherein one or two ring carbon atoms (including atoms in the bridging group) are selected from N , a heteroatom substitution of O or S(O)n, where n is an integer from 0 to 2. Bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy or cyano. Examples include, but are not limited to, 2-azabicyclo[2.2.2]octane, quinoline rings, 7-oxabicyclo[2.2.1]heptane, and the like.
术语“桥连的杂环基烷基”是指-(亚烷基)-R基团，其中R是如上定义的桥连的杂环基(包括特定的桥连的杂环基环)。The term "bridged heterocyclylalkyl" refers to a -(alkylene)-R group, wherein R is a bridged heterocyclyl group as defined above (including specific bridged heterocyclyl rings).
术语“环烷基”是指三至数个碳原子的单环一价烃基，其可以是饱和的或含有一个双键。环烷基可以是未取代的或被一个或两个独立地选自烷基，卤素，烷氧基，羟基或氰基的取代基取代。实例包括但不限于环丙基，环丁基，环戊基，环己基，1-氰基环丙-1-基，1-氰基甲基环丙-1-基，3-氟环己基等。当环烷基含有双键时，其在本文中可以称为环烯基。术语“C 3-C 6环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～6个碳原子，包括稠合或桥接的多环系统。如环丙基、环丁基、环戊基、环己基。 The term "cycloalkyl" refers to a monocyclic monovalent hydrocarbon group of three to several carbon atoms, which may be saturated or contain one double bond. Cycloalkyl groups may be unsubstituted or substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy or cyano. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocyclopropan-1-yl, 1-cyanomethylcyclopropan-1-yl, 3-fluorocyclohexyl, and the like . When a cycloalkyl group contains a double bond, it may be referred to herein as a cycloalkenyl group. The term "C3 - C6cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
术语“环烷基烷基”是指-(亚烷基)-R基团，其中R是如上定义的环烷基。实例包括但不限于环丙基甲基，环丁基甲基等。The term "cycloalkylalkyl" refers to a -(alkylene)-R group, wherein R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, and the like.
术语“环烷基烷氧基”是指-O-R基团，其中R是如上定义的环烷基烷基。实例包括但不限于环丙基甲氧基，环丁基甲氧基等。The term "cycloalkylalkoxy" refers to the group -O-R, wherein R is cycloalkylalkyl as defined above. Examples include, but are not limited to, cyclopropylmethoxy, cyclobutylmethoxy, and the like.
术语“环烷氧基烷基”是指-(亚烷基)-OR基团，其中R是如上定义的环烷基。实例包括但不限于环丙氧基甲基，环丙氧基乙基，环丁氧基乙基等。The term "cycloalkoxyalkyl" refers to a -(alkylene)-OR group, wherein R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxyethyl, and the like.
术语“环烷基磺酰基氨基”是指-NRSO 2-R’基团，其中R是氢或烷基，并且R’是环烷基，各自如上所定义。实例包括但不限于环丙基磺酰基氨基等。 The term "cycloalkylsulfonylamino" refers to the group -NRSO2 - R', wherein R is hydrogen or alkyl, and R' is cycloalkyl, each as defined above. Examples include, but are not limited to, cyclopropylsulfonylamino and the like.
术语“氰基烷基”是指被氰基例如氰基甲基，氰基乙基等取代的如上定义的烷基。The term "cyanoalkyl" refers to an alkyl group as defined above substituted with a cyano group such as cyanomethyl, cyanoethyl and the like.
术语“羧基”是指-COOH基团。The term "carboxy" refers to the -COOH group.
术语“羧基烷基”是指被羧基例如羧甲基，羧乙基等取代的如上定义的烷基。The term "carboxyalkyl" refers to an alkyl group as defined above substituted with a carboxyl group such as carboxymethyl, carboxyethyl and the like.
术语“氘代烷基”是指如上所定义的烷基，其中烷基链中的1-6个氢原子被氘原子取代。示例包括但不限于-CD3，-CH 2CHD 2等等。 The term "deuterated alkyl" refers to an alkyl group as defined above wherein 1-6 hydrogen atoms in the alkyl chain are replaced by deuterium atoms. Examples include, but are not limited to, -CD3 , -CH2CHD2 , and the like.
术语“二烷基氨基”是指-NRR’基团，其中R和R’是如上定义的烷基，例如二甲基氨基，甲基乙基氨基等。The term "dialkylamino" refers to a -NRR' group wherein R and R' are alkyl groups as defined above, eg, dimethylamino, methylethylamino, and the like.
术语“二烷基氨基羰基”是指-CONRR’基团，其中R和R’是如上定义的烷基，例如二甲基 氨基羰基，二乙基氨基羰基等。The term "dialkylaminocarbonyl" refers to a -CONRR' group wherein R and R' are alkyl groups as defined above, for example, dimethylaminocarbonyl, diethylaminocarbonyl, and the like.
术语“二烷基氨基磺酰基”是指-SO 2NRR’基团，其中R和R’是如上定义的烷基，例如二甲基氨基磺酰基，二乙基氨基磺酰基等。 The term "dialkylaminosulfonyl" refers to a -SO2NRR ' group, where R and R' are alkyl groups as defined above, eg, dimethylaminosulfonyl, diethylaminosulfonyl, and the like.
术语“稠合的环烷基”是指稠合至如本文所定义的苯基或五元或六元杂芳基环的三至六个碳原子的饱和一价烃基，并且任选地被一个，两个或三个独立选择的取代基取代烷基，卤素，烷氧基，卤代烷基，卤代烷氧基，羟基和氰基。实例包括但不限于四氢萘基，4,5,6,7-四氢-1H-吲哚基，4,5,6,7-四氢苯并恶唑基等。The term "fused cycloalkyl" refers to a saturated monovalent hydrocarbon group of three to six carbon atoms fused to a phenyl or five- or six-membered heteroaryl ring, as defined herein, and optionally surrounded by a , two or three independently selected substituents replace alkyl, halo, alkoxy, haloalkyl, haloalkoxy, hydroxy and cyano. Examples include, but are not limited to, tetrahydronaphthyl, 4,5,6,7-tetrahydro-lH-indolyl, 4,5,6,7-tetrahydrobenzoxazolyl, and the like.
术语“稠合的杂环基”是指与如本文定义的环烷基，苯基或五元或六元杂芳基环稠合的如本文定义的杂环基。稠合的杂环基任选地被一个或两个独立地选自烷基，卤素，烷氧基，羟基或氰基的取代基取代。示例包括但不限于4,5,6,7-四氢-1H-吡咯并[2,3-b]吡啶基，1,2,3,4-四氢喹啉基，3,4-二氢喹啉-2(1H)-等。The term "fused heterocyclyl" refers to a heterocyclyl, as defined herein, fused to a cycloalkyl, phenyl, or five- or six-membered heteroaryl ring, as defined herein. The fused heterocyclyl group is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy or cyano. Examples include, but are not limited to, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro Quinoline-2(1H)-etc.
术语“稠合的杂环基烷基”是指-(亚烷基)-R基团，其中R是如上定义的稠合杂环氧基(包括特定的稠合杂环基环)。The term "fused heterocyclylalkyl" refers to a -(alkylene)-R group, wherein R is a fused heterocyclyloxy group as defined above (including specific fused heterocyclyl rings).
术语“卤素”或“卤代基”是指氟，氯，溴或碘，优选氟或氯。The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
术语“卤代烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw，其中v＝1至3，w＝1至(2v+1))。卤代烷基的实例包括，但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。当烷基仅被氟取代时，在本申请中可以称为氟烷基。The term "haloalkyl" is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens (eg -CvFw, where v=1 to 3 and w=1 to (2v +1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. When an alkyl group is substituted only with fluorine, it may be referred to as a fluoroalkyl group in this application.
术语“卤代烷氧基”是指-OR基团，其中R是如上所定义的卤代烷基，例如，-OCF 3，-OCHF 2等等。当R是其中烷基仅被氟取代的卤代烷基时，在本申请中被称为氟烷氧基。 The term "haloalkoxy" refers to the -OR group, wherein R is a haloalkyl group as defined above, eg, -OCF3 , -OCHF2 , and the like. When R is a haloalkyl group in which the alkyl group is substituted only with fluorine, it is referred to in this application as fluoroalkoxy.
术语“卤代烷氧基烷基”是指各自被如上定义的卤代烷氧基取代的烷基，例如三氟甲氧基乙基等。The term "haloalkoxyalkyl" refers to alkyl groups each substituted with a haloalkoxy group as defined above, eg, trifluoromethoxyethyl and the like.
术语“杂亚烷基”是指具有两个至六个碳原子的线性饱和二价烃基或具有三个至六个碳原子的支链饱和二价烃基，其中一个碳原子被-O-，-NR-，-NR’CO-，-CONR’-，SO2NR’-或-NR’SCh-取代，除非另有说明，其中R和R’独立地为H或本文定义的烷基，例如-CH 2O-，-OCH 2-，-(CH 2) 2O-，-O(CH 2) 2-，-(CH 2) 2NH-，-NH(CH 2) 2-等。 The term "heteroalkylene" refers to a linear saturated divalent hydrocarbon radical having two to six carbon atoms or a branched saturated divalent hydrocarbon radical having three to six carbon atoms, one of which is replaced by -O-,- NR-, -NR'CO-, -CONR'-, SO2NR'- or -NR'SCh- substituted, unless otherwise specified, wherein R and R' are independently H or alkyl as defined herein, e.g. -CH O-, -OCH 2 -, -(CH 2 ) 2 O-, -O(CH 2 ) 2 -, -(CH 2 ) 2 NH-, -NH(CH 2 ) 2 - and the like.
术语“羟基烷基”是指被一个或两个羟基取代的具有一个或多个碳原子的直链一价烃基或具有三个或六个碳的支链一价烃基，条件是如果存在两个羟基，则它们不在同一碳原子上原子。代表性实例包括但不限于羟甲基，2-羟乙基，2-羟丙基，3-羟丙基，1-(羟甲基)-2-甲基丙基，2-羟丁基，3-羟丁基，4-羟丁基，2，3-二羟丙基，1-(羟甲基)-2-羟乙基，2,3-二羟丁基，3,4-二羟丁基和2-(羟甲基)-3-羟丙基，优选2-羟乙基，2,3-二羟丙基和1-(羟甲基)-2-羟乙基。The term "hydroxyalkyl" refers to a straight-chain monovalent hydrocarbon group of one or more carbon atoms or a branched-chain monovalent hydrocarbon group of three or six carbons substituted with one or two hydroxy groups, provided that if two are present hydroxyl, they are not atoms on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxy Butyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl.
术语“羟基烷氧基”是指-OR基团，其中R是如上定义的羟基烷基，例如，羟基乙氧基，羟基丙氧基等。The term "hydroxyalkoxy" refers to the -OR group where R is a hydroxyalkyl group as defined above, eg, hydroxyethoxy, hydroxypropoxy, and the like.
术语“羟基烷基氨基”是指-NRR’基团，其中R是氢或烷基，R’是羟烷基，各自如上所定义，例如，羟乙基氨基，羟丙基氨基等。The term "hydroxyalkylamino" refers to a -NRR' group wherein R is hydrogen or alkyl and R' is hydroxyalkyl, each as defined above, eg, hydroxyethylamino, hydroxypropylamino, and the like.
除非另有说明，否则“杂芳基”是指具有5至10个环原子的单价单环或双环芳族基团，其中一个或多个(在一个实施方案中为一个，两个或三个)环原子选自N，O，或S，其余的环原子是碳。杂芳基的非限制性实例包括吡啶基，哒嗪基，吡嗪基，嘧啶基，三嗪基，喹啉基，喹喔啉基，喹唑啉基，肉桂啉基，邻苯二甲酰基，苯并三嗪基，嘌呤基，苯并咪唑基，苯并吡唑基，异苯并三唑基，异苯并三唑基，苯并三唑啉基，异苯并三唑基，异苯并三唑基。Unless otherwise specified, "heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic group having 5 to 10 ring atoms, of which one or more (in one embodiment one, two or three ) ring atoms are selected from N, O, or S, and the remaining ring atoms are carbon. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnamyl, phthaloyl , benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, isobenzotriazolyl, isobenzotriazolyl, benzotriazolinyl, isobenzotriazolyl, iso Benzotriazolyl.
如本文所定义，术语“杂芳基”和“芳基”是互斥的。当杂芳基环含有5或6个环原子时，在本文中也称为5或6元杂芳基。As defined herein, the terms "heteroaryl" and "aryl" are mutually exclusive. When a heteroaryl ring contains 5 or 6 ring atoms, it is also referred to herein as a 5 or 6 membered heteroaryl.
术语“杂芳烷基”是指-(亚烷基)-R基团，其中R是如上定义的杂芳基(包括特定的环)。The term "heteroaralkyl" refers to a -(alkylene)-R group, wherein R is a heteroaryl group (including specified rings) as defined above.
术语“杂芳氧基”是指-OR，其中R是如上定义的杂芳基(包括特定的环)。The term "heteroaryloxy" refers to -OR, wherein R is a heteroaryl group (including specified rings) as defined above.
术语“杂芳烷氧基”是指-O-(亚烷基)-R基团，其中R是如上定义的杂芳基(包括特定的环)。The term "heteroaralkoxy" refers to the group -O-(alkylene)-R, wherein R is a heteroaryl group (including specified rings) as defined above.
术语“杂芳基羰基”是指-COR，其中R是如上定义的杂芳基(包括特定的环)。The term "heteroarylcarbonyl" refers to -COR, wherein R is a heteroaryl group (including specified rings) as defined above.
术语“杂芳基氨基”是指-NRR’，其中R是氢或烷基，R’是杂芳基(包括特定的环)，如上所定义。The term "heteroarylamino" refers to -NRR' wherein R is hydrogen or alkyl and R' is heteroaryl (including specified rings), as defined above.
术语“杂环基”是指4至8个环原子的饱和或不饱和单价单环基团，其中一个或两个环原子是选自N，O或S(O)n的杂原子，其中n是0至2的整数，剩余的环原子为C。另外，杂环基环中的一个或两个环碳原子可以任选地被-CO-基团取代。更具体地，术语杂环基包括但不限于氮杂环丁烷基，氧杂环丁烷基，吡咯烷基，哌啶基，2-氧代吡咯烷基，2-氧代哌啶基，吗啉代，哌嗪基，四氢吡喃基，硫代吗啉代等。当杂环基环是不饱和的时，它可以包含一个或两个环双键，条件是该环不是芳族的。当杂环基包含至少一个氮原子时，其在本文中可以称为杂环氨基。The term "heterocyclyl" refers to a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms, wherein one or two ring atoms are heteroatoms selected from N, O or S(O)n, wherein n is an integer from 0 to 2, and the remaining ring atoms are C. Additionally, one or two ring carbon atoms in the heterocyclyl ring can be optionally substituted with a -CO- group. More specifically, the term heterocyclyl includes, but is not limited to, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, Morpholino, piperazinyl, tetrahydropyranyl, thiomorpholino, etc. When the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, provided that the ring is not aromatic. When a heterocyclyl group contains at least one nitrogen atom, it may be referred to herein as a heterocyclylamino group.
术语“杂环基烷基”是指-(亚烷基)-R基团，其中R是如上定义的杂环基(包括特定的杂环基环)。例如，氧杂环丁烷基乙基，哌啶基乙基等。The term "heterocyclylalkyl" refers to a -(alkylene)-R group, wherein R is a heterocyclyl group as defined above (including specified heterocyclyl rings). For example, oxetanylethyl, piperidinylethyl and the like.
术语“杂环基氧基”是指-OR基团，其中R是如上定义的杂环基(包括特定的杂环基环)。The term "heterocyclyloxy" refers to the -OR group, wherein R is a heterocyclyl group as defined above (including specified heterocyclyl rings).
术语“杂环基烷氧基”是指-O-(亚烷基)-R基团，其中R是如上定义的杂环基(包括特定的杂环基环)。例如，氧杂环丁烷基乙氧基，哌啶基乙氧基等。The term "heterocyclylalkoxy" refers to the group -O-(alkylene)-R, wherein R is heterocyclyl as defined above (including specified heterocyclyl rings). For example, oxetanylethoxy, piperidinylethoxy, and the like.
术语“杂环基羰基”是指-COR，其中R是如上定义的杂环基(包括特定的环)。The term "heterocyclylcarbonyl" refers to -COR, wherein R is heterocyclyl (including specified rings) as defined above.
术语“杂环基氨基”是指-NRR’基团，其中R为氢或烷基，R’为杂环基(包括特定的杂环基环)，如上文所定义。The term "heterocyclylamino" refers to a -NRR' group wherein R is hydrogen or alkyl and R' is heterocyclyl (including specified heterocyclyl rings), as defined above.
术语“杂环基氧基烷基”是指-(亚烷基)-OR基团，其中R是如上定义的杂环基(包括特定的杂环基环)。例如，氧杂环丁烷基氧乙基，哌啶基氧乙基等。The term "heterocyclyloxyalkyl" refers to a -(alkylene)-OR group, wherein R is heterocyclyl as defined above (including specified heterocyclyl rings). For example, oxetanyloxyethyl, piperidinyloxyethyl and the like.
术语“杂环基氧基烷氧基”是指-O-(亚烷基)-R基团，其中R是如上定义的杂环基氧基(包括特定的杂环基环)。例如，氧杂环丁烷基氧基乙氧基，哌啶基氧基乙氧基等。The term "heterocyclyloxyalkoxy" refers to the group -O-(alkylene)-R, wherein R is heterocyclyloxy as defined above (including specified heterocyclyl rings). For example, oxetanyloxyethoxy, piperidinyloxyethoxy, and the like.
术语“杂环基氧基烷基氨基”是指-NR-(亚烷基)-R’基团，其中R为氢或烷基，并且R’为杂环基氧基(包括特定的杂环基环)，如上文所定义。例如，氧杂环丁烷基氧乙基氨基，哌啶基氧乙基氨基等。The term "heterocyclyloxyalkylamino" refers to the -NR-(alkylene)-R' group, wherein R is hydrogen or alkyl, and R' is heterocyclyloxy (including specified heterocycles) base ring), as defined above. For example, oxetanyloxyethylamino, piperidinyloxyethylamino, and the like.
双环情况下，术语“双环”“稠合”是指两个环经两个原子间的键连接在一起(例如，萘)，经一系列原子结合在一起形成一桥(例如，奎宁环)或单个原子在一起形成螺环化合物(例如，1,4-二氧杂-8-氮杂-螺[4.5]癸烷及N,3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-基)。In the case of a bicyclic ring, the term "bicyclic" and "fused" means that two rings are joined together by a bond between two atoms (eg, naphthalene), and are joined together by a series of atoms to form a bridge (eg, quinuclidine) or single atoms taken together to form spiro compounds (e.g., 1,4-dioxa-8-aza-spiro[4.5]decane and N,3,3-dimethyl-1,5-dioxaspiro [5.5]undecan-9-yl).
术语“3至6元杂环烷基”是指3至6个环原子的饱和单环基团，其中1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子；另外，杂环基环中的一个或两个环碳原子可以任选地被-CO-基团取代。The term "3 to 6 membered heterocycloalkyl" refers to a saturated monocyclic group of 3 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, The remainder are carbon atoms; in addition, one or two ring carbon atoms in the heterocyclyl ring may be optionally substituted with a -CO- group.
本文单独或组合使用的“氧代”是指＝O。"Oxo," as used herein, alone or in combination, refers to =0.
任选是指随后所述的事件可能发生或也可能不发生，且该表述包括所述事件发生的情况和它不发生的情况。例如，“任选取代的烷基”包括本文定义的“烷基”和“被取代的烷基”。Optional means that the subsequently described event may or may not occur, and that the expression includes instances where the event occurs and instances where it does not. For example, "optionally substituted alkyl" includes "alkyl" and "substituted alkyl" as defined herein.
“任选取代的芳基”是指任选被一个，两个或三个取代基取代的芳基，所述取代基独立地选自烷基，环烷基，羧基，烷氧基羰基，羟基，羟烷基，烷氧基，烷基磺酰基，氨基，烷基氨基，二烷基氨基，卤素，卤代烷基，卤代烷氧基，和氰基。"Optionally substituted aryl" refers to an aryl group optionally substituted with one, two or three substituents independently selected from alkyl, cycloalkyl, carboxyl, alkoxycarbonyl, hydroxy , hydroxyalkyl, alkoxy, alkylsulfonyl, amino, alkylamino, dialkylamino, halogen, haloalkyl, haloalkoxy, and cyano.
“任选取代的杂芳基”是指如上定义的杂芳基，其任选地被1、2或3个独立地选自烷基，烷基磺酰基，环烷基，羧基，烷氧基羰基，羟基，烷氧基，卤代，卤代烷基，卤代烷氧基，氨基，烷基氨基，二烷基氨基和氰基的取代基取代。"Optionally substituted heteroaryl" refers to a heteroaryl group as defined above, optionally with 1, 2 or 3 independently selected from the group consisting of alkyl, alkylsulfonyl, cycloalkyl, carboxy, alkoxy Substituent substitution of carbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino and cyano.
“任选取代的杂环基”是指如上定义的杂环基，其任选地被一个，两个或三个独立地选自烷基，烷基磺酰基，环烷基，羧基，烷氧基羰基，羟基，羟烷基，烷氧基，烷氧基烷基，氨基烷基，卤素，卤代烷基，卤代烷氧基的取代基取代和氰基，除非另有说明。"Optionally substituted heterocyclyl" refers to a heterocyclyl group as defined above, optionally with one, two or three independently selected from the group consisting of alkyl, alkylsulfonyl, cycloalkyl, carboxyl, alkoxy Substituents of oxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halogen, haloalkyl, haloalkoxy and cyano, unless otherwise stated.
“螺环烷基”是指具有6至10个环碳原子的饱和双环，其中所述环仅通过一个原子连接， 所述连接原子也称为螺原子，最通常为季碳(“螺碳”)。螺环烷基环任选地被一个或两个独立地选自烷基，卤素，烷氧基，羟基和氰基的取代基取代。代表性示例包括但不限于螺[3.3]庚烷，螺[3.4]辛烷，螺[3.5]壬烷，螺[4.4]壬烷(1：2：1：1)等。"Spirocycloalkyl" refers to a saturated bicyclic ring having 6 to 10 ring carbon atoms, wherein the rings are joined by only one atom, also known as a spiro atom, most commonly a quaternary carbon ("spirocarbon" ). The spirocycloalkyl ring is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy and cyano. Representative examples include, but are not limited to, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane (1:2:1:1), and the like.
“螺环烷基烷基”是指-(亚烷基)-R基团，其中R是如上定义的螺环烷基(包括特定的螺环烷基)。"Spirocycloalkylalkyl" refers to a -(alkylene)-R group, wherein R is a spirocycloalkyl group as defined above (including specific spirocycloalkyl groups).
“螺杂环基”是指具有6至10个环原子的饱和双环，其中一个，两个或三个环原子选自N，O或S(O)n，其中n是选自0至2的整数，其余的环原子为C，并且环仅通过一个原子连接，该连接原子也称为螺原子，最通常为季碳(“螺碳”)。螺杂环基任选地被一个或两个取代基取代实例包括但不限于，代表性实例包括但不限于：2,6-二氮杂螺[3.3]庚烷，2,6-二氮杂螺[3.4]辛烷，2-氮杂螺[3.4]辛烷，2-氮杂螺[3.5]-壬烷，2,7-二氮杂螺[4.4]壬烷等。"Spiroheterocyclyl" means a saturated bicyclic ring having 6 to 10 ring atoms, wherein one, two or three ring atoms are selected from N, O or S(O)n, where n is selected from 0 to 2 Integer, the remaining ring atoms are C, and the rings are connected by only one atom, also known as a spiro atom, most commonly a quaternary carbon ("spiro carbon"). Spiroheterocyclyl optionally substituted with one or two substituents Examples include, but are not limited to, representative examples include, but are not limited to: 2,6-diazaspiro[3.3]heptane, 2,6-diaza Spiro[3.4]octane, 2-azaspiro[3.4]octane, 2-azaspiro[3.5]-nonane, 2,7-diazaspiro[4.4]nonane, etc.
“螺杂环基烷基”是指-(亚烷基)-R基团，其中R是如上定义的螺杂环基(包括特定螺杂环基)。"Spiroheterocyclylalkyl" refers to a -(alkylene)-R group, wherein R is a spiroheterocyclyl group as defined above (including specific spiroheterocyclyl groups).
“磺酰基氨基”是指-NRSO 2R’基团，其中R是氢或烷基，并且R’是烷基，任选取代的芳基，任选取代的杂芳基或任选取代的杂环基，每个基团如本文所定义。 "Sulfonylamino" refers to a -NRSO2R ' group, wherein R is hydrogen or alkyl, and R' is alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heteroaryl Cyclic groups, each as defined herein.
“取代的环烷基”是指被一个，两个或三个取代基取代的具有三个至六个碳原子的饱和单环一价烃基，其中三个取代基中的两个独立地选自烷基，卤素，烷氧基，羟基，卤代烷基或卤代烷氧基和第三取代基是烷基，卤素，羟基烷基，卤代烷基，卤代烷氧基或氰基。实例包括但不限于3-羟基-3-三氟环丁基，2，2-二甲基-3-羟基环丁基等。"Substituted cycloalkyl" refers to a saturated monocyclic monovalent hydrocarbon group of three to six carbon atoms substituted with one, two or three substituents, wherein two of the three substituents are independently selected from Alkyl, halogen, alkoxy, hydroxy, haloalkyl or haloalkoxy and the third substituent is alkyl, halo, hydroxyalkyl, haloalkyl, haloalkoxy or cyano. Examples include, but are not limited to, 3-hydroxy-3-trifluorocyclobutyl, 2,2-dimethyl-3-hydroxycyclobutyl, and the like.
“取代的环烷基烷基”是指-(亚烷基)-取代的环烷基，每个术语在本文中定义。实例包括但不限于1-羟甲基环丙-1-基甲基等。"Substituted cycloalkylalkyl" refers to -(alkylene)-substituted cycloalkyl, as each term is defined herein. Examples include, but are not limited to, 1-hydroxymethylcyclopropan-1-ylmethyl and the like.
“脲基”是指-NHCONRR’基团，其中R和R’独立地是氢或烷基，如上文所定义，例如，-NHCONH甲基，-NHCON(CH 3) 2等。 "Ureido" refers to a -NHCONRR' group, wherein R and R' are independently hydrogen or alkyl, as defined above, eg, -NHCONHmethyl, -NHCON( CH3 ) 2 , and the like.
“硫脲烷基”是指-(亚烷基)-NHSO 2NRR’基团，其中R和R’独立地是氢或烷基，如上所定义。 "Thiouranyl" refers to a -(alkylene) -NHSO2NRR ' group, wherein R and R' are independently hydrogen or alkyl, as defined above.
术语“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.
术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。The term "therapeutically effective amount" refers to the amount of active compound or drug that a researcher, veterinarian, physician or other clinician is seeking to elicit a biological or medical response in a tissue, system, animal, individual or human, and includes one of the following or more of: (1) Prevention of disease: eg, prevention of disease, disorder or condition in individuals susceptible to a disease, disorder or condition but not yet experiencing or developing disease pathology or symptoms. (2) Inhibiting a disease: eg, inhibiting a disease, disorder or condition (ie preventing further progression of the pathology and/or condition) in an individual who is experiencing or developing the pathology or symptom of the disease, disorder or condition. (3) Alleviating disease: eg, alleviating a disease, disorder or condition (ie, reversing the pathology and/or symptoms) in an individual who is experiencing or experiencing the pathology or symptoms of the disease, disorder or condition.
具体实施方式Detailed ways
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the intended protection scope of the present invention.
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise stated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.
如无特别说明，本发明的化合物均是通过核磁共振(NMR)和/或质谱(MS)来确定。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)。 Unless otherwise specified, the compounds of the present invention are identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The units of NMR shifts are 10-6 (ppm). The solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
本发明的缩写定义如下：Abbreviations of the present invention are defined as follows:
试剂：Reagents:
DIPEA：也可写为DIEA，二异丙基乙胺，亦即N,N-二异丙基乙胺DIPEA: can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
DMF：N,N-二甲基甲酰胺DMF: N,N-Dimethylformamide
DMP：Dess-Martin氧化剂，又称戴斯-马丁氧化剂DMP: Dess-Martin oxidizer, also known as Dess-Martin oxidizer
DMSO：二甲基亚砜DMSO: Dimethyl Sulfoxide
THF：四氢呋喃THF: Tetrahydrofuran
TosMIC：对甲基苯磺酰甲基异腈TosMIC: p-Toluenesulfonylmethylisonitrile
EA：乙酸乙酯EA: Ethyl acetate
符号或单位：Symbol or unit:
EC 80：concentration for 80％of maximal effect，能引起80％最大效应的浓度 EC 80 : concentration for 80% of maximal effect, the concentration that can cause 80% of the maximal effect
IC 50：半数抑制浓度，指达到最大抑制效果一半时的浓度 IC 50 : half inhibitory concentration, refers to the concentration at which half of the maximum inhibitory effect is achieved
M：mol/L，摩尔浓度，如1M盐酸表示1mol/L盐酸溶液M: mol/L, molar concentration, such as 1M hydrochloric acid means 1mol/L hydrochloric acid solution
N：当量浓度，例如2N盐酸表示2mol/L盐酸溶液N: equivalent concentration, for example, 2N hydrochloric acid means 2mol/L hydrochloric acid solution
RT：保留时间RT: retention time
试验方法：experiment method:
LC-MS：液质联用色谱LC-MS: Liquid chromatography-mass spectrometry
SFC：超临界流体色谱SFC: Supercritical Fluid Chromatography
TLC：薄层色谱TLC: Thin Layer Chromatography
酸性制备方法A：Welch，Ultimate C 18柱，10μm，21.2mm×250mm。流动相A为1‰的三氟醋酸纯水溶液，流动相B为乙腈溶液。梯度条件：0～3分钟，流动相A保持90％，3～18分钟梯度洗脱，由90％变为5％，18～22分钟保持5％。 Acid Preparation Method A: Welch, Ultimate C 18 column, 10 μm, 21.2 mm x 250 mm. Mobile phase A is 1‰ trifluoroacetic acid pure aqueous solution, and mobile phase B is acetonitrile solution. Gradient conditions: 0 to 3 minutes, mobile phase A maintained at 90%, 3 to 18 minutes for gradient elution, from 90% to 5%, and 18 to 22 minutes to maintain 5%.
实施例1：目标化合物I-1的制备Example 1: Preparation of target compound I-1
4-(2-氯苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-1)4-(2-Chlorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (target compound I-1)
Figure PCTCN2022087589-appb-000071
Figure PCTCN2022087589-appb-000071
目标化合物I-1的合成路线如下所示：The synthetic route of the target compound I-1 is as follows:
Figure PCTCN2022087589-appb-000072
Figure PCTCN2022087589-appb-000072
第一步：2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈)(I-1C)的合成The first step: Synthesis of 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile)(I-1C)
Figure PCTCN2022087589-appb-000073
Figure PCTCN2022087589-appb-000073
在室温下，将2-(2-氯苯基)乙腈(1.20g,7.92mmol)，氢氧化钾(444mg,7.92mmol)和2-溴-4-(三氟甲基)吡啶(1.79g,7.92mmol)溶解在四氢呋喃(12mL)中，充分搅拌，在66℃反应12小时。反应结束后加水(20mL)淬灭，用乙酸乙酯(45mL)萃取，然后用饱和食盐水(20mL*2)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩得到粗品黄色油状产物2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈)(I-1C)(2.45g，粗品)，直接用于下一步。At room temperature, 2-(2-chlorophenyl)acetonitrile (1.20 g, 7.92 mmol), potassium hydroxide (444 mg, 7.92 mmol) and 2-bromo-4-(trifluoromethyl)pyridine (1.79 g, 7.92 mmol) was dissolved in tetrahydrofuran (12 mL), stirred well, and reacted at 66° C. for 12 hours. After the reaction was completed, water (20 mL) was added to quench, extracted with ethyl acetate (45 mL), then washed with saturated brine (20 mL*2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude yellow oily product 2- (2-Chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile)(I-1C) (2.45 g, crude) was used directly in the next step.
1H NMR(400MHz,DMSO_d 6):δ8.90(d,1H),7.77-7.87(m,2H),7.62(dd,1H),7.53-7.57(m,1H),7.42-7.50(m,2H),6.36(s,1H). 1 H NMR (400MHz, DMSO_d 6 ): δ 8.90 (d, 1H), 7.77-7.87 (m, 2H), 7.62 (dd, 1H), 7.53-7.57 (m, 1H), 7.42-7.50 (m, 2H), 6.36(s, 1H).
第二步：2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-1D)的合成The second step: Synthesis of 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-1D)
Figure PCTCN2022087589-appb-000074
Figure PCTCN2022087589-appb-000074
把2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈)(I-1C)(2.45g,8.26mmol)和硫酸(11.0mg,112.5mmol)加入醋酸(18mL)中，置换氮气，加热到90℃，搅拌2小时。将反应液降温至室温，倒入水(20mL)中，用乙酸乙酯(100mL*3)萃取，合并有机相，然后用饱和食盐水(50mL*2)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩得到黄色固体2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-1D)(800mg，产率30.6％)。Combine 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile) (I-1C) (2.45 g, 8.26 mmol) and sulfuric acid (11.0 mg, 112.5 mmol) ) was added to acetic acid (18 mL), replaced with nitrogen, heated to 90°C, and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (20 mL), extracted with ethyl acetate (100 mL*3), the organic phases were combined, washed with saturated brine (50 mL*2), and the organic phase was dried over anhydrous sodium sulfate , filtered and concentrated to give 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-1D) (800 mg, 30.6% yield) as a yellow solid.
LC-MS,M/Z(ESI):315.0[M+H] + LC-MS, M/Z(ESI): 315.0[M+H] +
第三步：2-(2-氯苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-1E)的合成The third step: 2-(2-chlorophenyl)-N-(methylaminothioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-1E) Synthesis
Figure PCTCN2022087589-appb-000075
Figure PCTCN2022087589-appb-000075
把2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(500mg,1.59mmol)和异硫氰酸根甲烷(174.3mg,2.38mmol)，碳酸铯(1.04g,3.18mmol)加入N,N-二甲基甲酰胺(5mL)中，置换氮气，加热到75℃，搅拌2小时。将反应液降温至室温，倒入水(20mL)中，用乙酸乙酯(50mL*3)萃取，合并有机相，然后用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝100:0-2:1)得到得到黑褐色固体2-(2-氯苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-1E)(300mg，产率48.7％)。Combine 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (500 mg, 1.59 mmol) and isothiocyanatomethane (174.3 mg, 2.38 mmol), Cesium carbonate (1.04 g, 3.18 mmol) was added to N,N-dimethylformamide (5 mL), nitrogen was replaced, and the mixture was heated to 75° C. and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (20 mL), extracted with ethyl acetate (50 mL*3), the organic phases were combined, washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered, Concentrate to obtain the crude product, which is separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=100:0-2:1) to obtain a dark brown solid 2-(2-chlorophenyl)-N-(methyl) Carboxamoyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-1E) (300 mg, 48.7% yield).
LC-MS,M/Z(ESI):388.0[M+H] + LC-MS, M/Z(ESI): 388.0[M+H] +
1H NMR(400MHz,DMSO_d 6):δ11.70(s,1H),10.40(d,1H),8.87(d,1H),7.72-7.79(m,1H),7.47-7.55(m,2H),7.33-7.37(m,2H),7.05(d,1H),5.99(s,1H),3.00(d,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ11.70(s,1H), 10.40(d,1H), 8.87(d,1H), 7.72-7.79(m,1H), 7.47-7.55(m,2H) ,7.33-7.37(m,2H),7.05(d,1H),5.99(s,1H),3.00(d,3H).
第四步：4-(2-氯苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-1)的合成The fourth step: 4-(2-chlorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I- 1) Synthesis
Figure PCTCN2022087589-appb-000076
Figure PCTCN2022087589-appb-000076
把2-(2-氯苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(300mg,773.6μmol)溶解在四氢呋喃(1mL)中，在0℃下缓慢加入碘单质(589.0mg,2.32mmol)，吡啶(183.6mg,2.32mmol)，置换氮气，加热到25℃搅拌反应2小时。加入水(20mL)，用乙酸乙酯(100mL*3)萃取，合并有机相，用饱和食盐水(90mL*2)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。然后通过高效液相色谱仪进行分离，分离方法为(柱子：Waters Xbridge 150*25mm*5μm；溶剂：A＝水+10mM碳酸氢铵，B＝乙腈；梯度：24％-54％，9分钟)，得到黄色固体4-(2-氯苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-1)(77.8mg，产率28.1％)。Dissolve 2-(2-chlorophenyl)-N-(methylcarbamoyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (300 mg, 773.6 μmol) in In tetrahydrofuran (1 mL), elemental iodine (589.0 mg, 2.32 mmol) and pyridine (183.6 mg, 2.32 mmol) were slowly added at 0° C., nitrogen was replaced, and the reaction was heated to 25° C. and stirred for 2 hours. Water (20 mL) was added, extracted with ethyl acetate (100 mL*3), the organic phases were combined, washed with saturated brine (90 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Then it was separated by high performance liquid chromatography, and the separation method was (column: Waters Xbridge 150*25mm*5μm; solvent: A=water+10mM ammonium bicarbonate, B=acetonitrile; gradient: 24%-54%, 9 minutes) , 4-(2-chlorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I- 1) (77.8 mg, 28.1% yield).
LC-MS,M/Z(ESI):354.0[M+H] + LC-MS, M/Z(ESI): 354.0[M+H] +
1H NMR(400MHz,DMSO-d 6):δ8.13-8.25(m,2H),7.53-7.61(m,1H),7.38-7.47(m,2H),7.26-7.34(m,1H),6.71(dd,1H),6.60(s,1H),2.90(d,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ 8.13-8.25 (m, 2H), 7.53-7.61 (m, 1H), 7.38-7.47 (m, 2H), 7.26-7.34 (m, 1H), 6.71(dd, 1H), 6.60(s, 1H), 2.90(d, 3H).
实施例2：目标化合物I-2的制备Example 2: Preparation of target compound I-2
4-(2-氯苯基)-6-甲基-1-(甲基氨基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-2)4-(2-Chlorophenyl)-6-methyl-1-(methylamino)-3H-pyrido[1,2-c]pyrimidin-3-one (target compound I-2)
Figure PCTCN2022087589-appb-000077
Figure PCTCN2022087589-appb-000077
目标化合物I-2的合成路线如下所示：The synthetic route of the target compound I-2 is as follows:
Figure PCTCN2022087589-appb-000078
Figure PCTCN2022087589-appb-000078
第一步：2-(2-氯苯基)-2-(4-甲基吡啶-2-基)乙腈(I-2B)的合成The first step: Synthesis of 2-(2-chlorophenyl)-2-(4-methylpyridin-2-yl)acetonitrile (I-2B)
Figure PCTCN2022087589-appb-000079
Figure PCTCN2022087589-appb-000079
把2-(2-氯苯基)乙腈(2.00g,13.2mmol)和2-溴-4-甲基吡啶(2.72g,15.8mmol)溶解在二甲基亚砜(20mL)中，分批加入氢氧化钾(2.22g,39.6mmol)，再缓慢升温至100℃反应12小时。反应结束后降至室温，加水(50mL)淬灭，用乙酸乙酯(30mL*3)萃取，合并有机相，然后用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品棕黑色固体2-(2-氯苯基)-2-(4-甲基吡啶-2-基)乙腈(I-2B)(3.12g，产率97.5％)。2-(2-Chlorophenyl)acetonitrile (2.00 g, 13.2 mmol) and 2-bromo-4-methylpyridine (2.72 g, 15.8 mmol) were dissolved in dimethylsulfoxide (20 mL) and added in portions Potassium hydroxide (2.22 g, 39.6 mmol) was slowly heated to 100° C. and reacted for 12 hours. After the reaction was completed, it was cooled to room temperature, quenched by adding water (50 mL), extracted with ethyl acetate (30 mL*3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product 2-(2-Chlorophenyl)-2-(4-methylpyridin-2-yl)acetonitrile (I-2B) as a brown-black solid (3.12 g, 97.5% yield).
LC-MS,M/Z(ESI):243.0[M+H] + LC-MS, M/Z(ESI): 243.0[M+H] +
第二步：2-(2-氯苯基)-2-(4-甲基吡啶-2-基)乙酰胺(I-2C)的合成The second step: the synthesis of 2-(2-chlorophenyl)-2-(4-methylpyridin-2-yl)acetamide (I-2C)
Figure PCTCN2022087589-appb-000080
Figure PCTCN2022087589-appb-000080
把2-(2-氯苯基)-2-(4-甲基吡啶-2-基)乙腈(3.00g,12.4mmol)溶于醋酸(30mL)中，降温至0℃，缓慢加入浓硫酸(10ml)，再加热到80℃，搅拌反应2小时。将反应液降至室温，分批倒入冰水(100mL)中淬灭，用乙酸乙酯(100mL*3)萃取，然后用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品，粗品经反相Flash分离(0.1％盐酸)纯化，得到黄色固体2-(2-氯苯基)-2-(4-甲基吡啶-2-基)乙酰胺(I-2C)(1.62g，产率50.3％)。2-(2-Chlorophenyl)-2-(4-methylpyridin-2-yl)acetonitrile (3.00 g, 12.4 mmol) was dissolved in acetic acid (30 mL), cooled to 0 °C, and concentrated sulfuric acid ( 10ml), then heated to 80°C and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into ice water (100 mL) in batches to quench, extracted with ethyl acetate (100 mL*3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated The crude product was obtained, which was purified by reverse phase flash separation (0.1% hydrochloric acid) to give 2-(2-chlorophenyl)-2-(4-methylpyridin-2-yl)acetamide (I-2C) ( 1.62 g, 50.3% yield).
LC-MS,M/Z(ESI):261.0[M+H] + LC-MS, M/Z(ESI): 261.0[M+H] +
第三步：2-(2-氯苯基)-N-(甲基氨基硫代甲酰基)-2-(4-甲基吡啶-2-基)乙酰胺(I-2D)的合成The third step: synthesis of 2-(2-chlorophenyl)-N-(methylaminothioformyl)-2-(4-methylpyridin-2-yl)acetamide (I-2D)
Figure PCTCN2022087589-appb-000081
Figure PCTCN2022087589-appb-000081
把2-(2-氯苯基)-2-(4-甲基吡啶-2-基)乙酰胺(0.50g,1.92mmol)，异硫氰酸根甲烷(0.21g,2.88mmol)和碳酸铯(1.25g，3.84mmol)加入N,N-二甲基甲酰胺(10mL)中，加热到75℃ 反应2小时。将反应液降至室温，加水(30mL)淬灭，用乙酸乙酯(30mL*3)萃取，然后用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到棕色固体2-(2-氯苯基)-N-(甲基氨基硫代甲酰基)-2-(4-甲基吡啶-2-基)乙酰胺(I-2D)(483.2mg，产率75.3％)。Combine 2-(2-chlorophenyl)-2-(4-methylpyridin-2-yl)acetamide (0.50 g, 1.92 mmol), isothiocyanatomethane (0.21 g, 2.88 mmol) and cesium carbonate ( 1.25 g, 3.84 mmol) was added to N,N-dimethylformamide (10 mL), heated to 75° C. and reacted for 2 hours. The reaction solution was cooled to room temperature, quenched by adding water (30 mL), extracted with ethyl acetate (30 mL*3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown solid 2-( 2-Chlorophenyl)-N-(methylcarbamoyl)-2-(4-methylpyridin-2-yl)acetamide (I-2D) (483.2 mg, 75.3% yield).
LC-MS,M/Z(ESI):334.2[M+H] + LC-MS, M/Z(ESI): 334.2[M+H] +
第四步：4-(2-氯苯基)-6-甲基-1-(甲基氨基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-2)The fourth step: 4-(2-chlorophenyl)-6-methyl-1-(methylamino)-3H-pyrido[1,2-c]pyrimidin-3-one (target compound I-2)
Figure PCTCN2022087589-appb-000082
Figure PCTCN2022087589-appb-000082
把2-(2-氯苯基)-N-(甲基氨基硫代甲酰基)-2-(4-甲基吡啶-2-基)乙酰胺(0.40g,1.92mmol)、碘单质(0.912g,3.59mmol)和吡啶(0.284g，3.59mmol)加入四氢呋喃(10mL)中，加热到25℃反应2小时。加水(30mL)淬灭，用乙酸乙酯(30mL*3)萃取，合并有机相，然后用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得粗品，然后通过高效液相色谱仪进行分离，分离方法为(柱子：Waters Xbridge 150*25mm*5μm；溶剂：A＝水+0.05％体积氨水(30％)，B＝乙腈；梯度：16％-46％，9分钟)，得到黄色固体4-(2-氯苯基)-6-甲基-1-(甲基氨基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-2)(92.9mg，产率25.8％)。2-(2-Chlorophenyl)-N-(methylaminothioformyl)-2-(4-methylpyridin-2-yl)acetamide (0.40 g, 1.92 mmol), iodine (0.912 g, 3.59 mmol) and pyridine (0.284 g, 3.59 mmol) were added to tetrahydrofuran (10 mL), heated to 25° C. to react for 2 hours. Add water (30mL) to quench, extract with ethyl acetate (30mL*3), combine the organic phases, then wash with saturated brine (30mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product, which is then subjected to high performance liquid chromatography The separation method is (column: Waters Xbridge 150*25mm*5μm; solvent: A=water+0.05% volume ammonia (30%), B=acetonitrile; gradient: 16%-46%, 9 minutes), get 4-(2-Chlorophenyl)-6-methyl-1-(methylamino)-3H-pyrido[1,2-c]pyrimidin-3-one (I-2) (92.9 mg, yield 25.8%).
1H NMR(400MHz,DMSO-d 6):δ7.91(d,1H),7.80(s,1H),7.49-7.57(m,1H),7.38(dd,2H),7.20-7.25(m,1H),6.42(d,1H),6.16(s,1H),2.88(d,3H),2.04(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.91 (d, 1H), 7.80 (s, 1H), 7.49-7.57 (m, 1H), 7.38 (dd, 2H), 7.20-7.25 (m, 1H), 6.42(d, 1H), 6.16(s, 1H), 2.88(d, 3H), 2.04(s, 3H).
LC-MS,M/Z(ESI):300.2[M+H] + LC-MS, M/Z(ESI): 300.2[M+H] +
实施例3：目标化合物I-3的制备Example 3: Preparation of target compound I-3
6-氯-4-(2-氯苯基)-1-(甲基氨基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-3)6-Chloro-4-(2-chlorophenyl)-1-(methylamino)-3H-pyrido[1,2-c]pyrimidin-3-one (I-3)
Figure PCTCN2022087589-appb-000083
Figure PCTCN2022087589-appb-000083
化合物I-3的合成路线参考I-2的合成方法，得到6-氯-4-(2-氯苯基)-1-(甲基氨基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-3)The synthetic route of compound I-3 refers to the synthetic method of I-2 to obtain 6-chloro-4-(2-chlorophenyl)-1-(methylamino)-3H-pyrido[1,2-c]pyrimidine -3-keto (I-3)
LC-MS,M/Z(ESI):320.0[M+H] + LC-MS, M/Z(ESI): 320.0[M+H] +
实施例4：目标化合物I-4的制备Example 4: Preparation of target compound I-4
4-(2-氯苯基)-6-环丙基-1-(甲基氨基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-4)4-(2-Chlorophenyl)-6-cyclopropyl-1-(methylamino)-3H-pyrido[1,2-c]pyrimidin-3-one (I-4)
Figure PCTCN2022087589-appb-000084
Figure PCTCN2022087589-appb-000084
目标化合物I-4的合成路线如下所示：The synthetic route of the target compound I-4 is as follows:
Figure PCTCN2022087589-appb-000085
Figure PCTCN2022087589-appb-000085
第一步：2-(2-氯苯基)-2-(4-环丙基-2-吡啶基)乙腈(I-4B)的合成The first step: Synthesis of 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetonitrile (I-4B)
Figure PCTCN2022087589-appb-000086
Figure PCTCN2022087589-appb-000086
在室温下，将2-(2-氯苯基)乙腈(1.25g,8.24mmol)，氢氧化钾(693mg,12.3mmol)和2-溴-4-环丙基-吡啶(1.60g,8.08mmol)溶解在二甲基亚砜(16mL)中，充分搅拌，在70℃反应10小时。反应结束后加乙酸乙酯(40mL)，用饱和食盐水(150mL)洗涤，然后水相用乙酸乙酯(150mL)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-3:1)得到黄色油状产物2-(2-氯苯基)-2-(4-环丙基-2-吡啶基)乙腈(I-4B)(700mg，产率31.6％)。At room temperature, 2-(2-chlorophenyl)acetonitrile (1.25 g, 8.24 mmol), potassium hydroxide (693 mg, 12.3 mmol) and 2-bromo-4-cyclopropyl-pyridine (1.60 g, 8.08 mmol) were combined ) was dissolved in dimethyl sulfoxide (16 mL), stirred well, and reacted at 70° C. for 10 hours. After the reaction was completed, ethyl acetate (40 mL) was added, washed with saturated brine (150 mL), and then the aqueous phase was extracted with ethyl acetate (150 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Column separation and purification (petroleum ether:ethyl acetate (V/V)=10:1-3:1) to obtain 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridine as a yellow oily product) yl)acetonitrile (I-4B) (700 mg, 31.6% yield).
LC-MS,M/Z(ESI):269.1[M+H] + LC-MS, M/Z(ESI): 269.1[M+H] +
第二步：2-(2-氯苯基)-2-(4-环丙基-2-吡啶基)乙酰胺(I-4C)的合成The second step: Synthesis of 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetamide (I-4C)
Figure PCTCN2022087589-appb-000087
Figure PCTCN2022087589-appb-000087
把2-(2-氯苯基)-2-(4-环丙基-2-吡啶基)乙腈(I-4B)(700mg,2.60mmol)、硫酸(7.66g,78.1mmol)、加入醋酸(10mL)中，置换氮气，加热到90℃，搅拌2小时。将反应液降温 至室温，倒入冰水(50mL)中，用饱和氢氧化钠溶液(30mL)调节pH至9左右，用乙酸乙酯(150mL)萃取，合并有机相，然后用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1-0:1)得到黄色油状化合物2-(2-氯苯基)-2-(4-环丙基-2-吡啶基)乙酰胺(I-4C)(380mg，产率50.9％)。2-(2-Chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetonitrile (I-4B) (700mg, 2.60mmol), sulfuric acid (7.66g, 78.1mmol), acetic acid ( 10 mL), replaced with nitrogen, heated to 90°C, and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into ice water (50 mL), adjusted to pH about 9 with saturated sodium hydroxide solution (30 mL), extracted with ethyl acetate (150 mL), combined with the organic phases, and then washed with saturated brine ( 50 mL) was washed, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product, which was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=3:1-0:1) to obtain yellow oily compound 2-(2 -Chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetamide (I-4C) (380 mg, 50.9% yield).
LC-MS,M/Z(ESI):287.1[M+H] + LC-MS, M/Z(ESI): 287.1[M+H] +
第三步：2-(2-氯苯基)-2-(4-环丙基-2-吡啶基)-N-(甲基氨基硫代甲酰基)乙酰胺((I-4D)的合成The third step: synthesis of 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)-N-(methylaminothioformyl)acetamide ((I-4D)
Figure PCTCN2022087589-appb-000088
Figure PCTCN2022087589-appb-000088
把2-(2-氯苯基)-2-(4-环丙基-2-吡啶基)乙酰胺(380mg,1.33mmol)和异硫氰酸根甲烷(145mg,1.99mmol)，碳酸铯(853mg,2.65mmol)加入N,N-二甲基甲酰胺(5mL)中，置换氮气，加热到75℃，搅拌2小时。将反应液降温至室温，倒入水(30mL)中，用乙酸乙酯(90mL)萃取，合并有机相，然后用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-3:1)得到得到黄色油状化合物2-(2-氯苯基)-2-(4-环丙基-2-吡啶基)-N-(甲基氨基硫代甲酰基)乙酰胺(I-4D)(160mg，产率33.6％)。Combine 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetamide (380 mg, 1.33 mmol) and isothiocyanatomethane (145 mg, 1.99 mmol), cesium carbonate (853 mg) , 2.65 mmol) was added to N,N-dimethylformamide (5 mL), replaced with nitrogen, heated to 75° C., and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (30 mL), extracted with ethyl acetate (90 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-3:1) to obtain a yellow oily compound 2-(2-chlorophenyl)-2-(4-cyclopropyl- 2-Pyridinyl)-N-(methylaminothiol)acetamide (I-4D) (160 mg, 33.6% yield).
LC-MS,M/Z(ESI):360.2[M+H] + LC-MS, M/Z(ESI): 360.2[M+H] +
第四步：4-(2-氯苯基)-6-环丙基-1-(甲基氨基)吡啶并[1,2-c]嘧啶-3-酮(I-4)的合成The fourth step: Synthesis of 4-(2-chlorophenyl)-6-cyclopropyl-1-(methylamino)pyrido[1,2-c]pyrimidin-3-one (I-4)
Figure PCTCN2022087589-appb-000089
Figure PCTCN2022087589-appb-000089
把2-(2-氯苯基)-2-(4-环丙基-2-吡啶基)-N-(甲基氨基硫代甲酰基)乙酰胺(I-4D)(160mg,444μmol)溶解在四氢呋喃(5mL)中，在0℃下缓慢加入碘单质(169mg,666μmol)，吡啶(52.7mg,666μmol)，置换氮气，20℃搅拌反应2小时。加入水(20mL)，加入饱和亚硫酸钠溶液(20mL)，然后用乙酸乙酯(60mL)萃取，用饱和食盐水(20mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品用硅胶柱分离纯化(乙酸乙酯:甲醇(V/V)＝1:0-10:1)得到黄色固体化合物4-(2-氯苯基)-6-环丙基-1-(甲基氨基)吡啶并[1,2-c]嘧啶-3-酮(I-4)(40.0mg，产率26.3％)。Dissolve 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)-N-(methylaminothioyl)acetamide (I-4D) (160 mg, 444 μmol) In tetrahydrofuran (5 mL), elemental iodine (169 mg, 666 μmol) and pyridine (52.7 mg, 666 μmol) were slowly added at 0° C., nitrogen was replaced, and the reaction was stirred at 20° C. for 2 hours. Water (20 mL) was added, saturated sodium sulfite solution (20 mL) was added, then extracted with ethyl acetate (60 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (ethyl acetate:methanol (V/V)=1:0-10:1) to obtain a yellow solid compound 4-(2-chlorophenyl)-6-cyclopropyl-1-(methyl) ylamino)pyrido[1,2-c]pyrimidin-3-one (I-4) (40.0 mg, 26.3% yield).
1H NMR(400MHz,DMSO_d 6):δ7.90(d,1H),7.80(br d,1H),7.51-7.57(m,1H),7.35-7.42(m,2H),7.21-7.27(m,1H),6.17(s,2H),2.87(d,3H),1.23(s,1H),0.88-0.95(m,2H),0.68-0.76(m,2H).LC-MS,M/Z(ESI):326.1[M+H] + 1 H NMR (400MHz, DMSO_d 6 ): δ7.90(d,1H), 7.80(br d,1H), 7.51-7.57(m,1H), 7.35-7.42(m,2H), 7.21-7.27(m ,1H),6.17(s,2H),2.87(d,3H),1.23(s,1H),0.88-0.95(m,2H),0.68-0.76(m,2H).LC-MS,M/Z (ESI):326.1[M+H] +
实施例5：目标化合物I-5的制备Example 5: Preparation of target compound I-5
1-(甲基氨基)-4-(邻甲苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-5)1-(Methylamino)-4-(o-tolyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-5)
Figure PCTCN2022087589-appb-000090
Figure PCTCN2022087589-appb-000090
目标化合物I-5的合成路线如下所示：The synthetic route of the target compound I-5 is as follows:
Figure PCTCN2022087589-appb-000091
Figure PCTCN2022087589-appb-000091
第一步：2-(邻甲苯基)-2-[4-(三氟甲基)-2-吡啶基]乙腈(I-5B)的合成The first step: Synthesis of 2-(o-tolyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetonitrile (I-5B)
Figure PCTCN2022087589-appb-000092
Figure PCTCN2022087589-appb-000092
在室温下，将2-(2-甲基苯基)乙腈(2.19g,16.7mmol)，氢氧化钾(1.34g,23.9mmol)和2-溴-4-三氟甲基-吡啶(3.60g,15.9mmol)溶解在二甲基亚砜(20mL)中，充分搅拌，在70℃反应3小时。反应结束后加水(100mL)，用乙酸乙酯(300mL)萃取，然后有机相用饱和食盐水(100mL)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝20:1-3:1)得到黄色固体产物2-(邻甲苯基)-2-[4-(三氟甲基)-2-吡啶基]乙腈(I-5B)(7.35g，产率82.9％)。At room temperature, 2-(2-methylphenyl)acetonitrile (2.19 g, 16.7 mmol), potassium hydroxide (1.34 g, 23.9 mmol) and 2-bromo-4-trifluoromethyl-pyridine (3.60 g) were combined , 15.9 mmol) was dissolved in dimethyl sulfoxide (20 mL), stirred well, and reacted at 70° C. for 3 hours. After the reaction, water (100 mL) was added, extracted with ethyl acetate (300 mL), the organic phase was washed with saturated brine (100 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated and purified with a silica gel column ( Petroleum ether:ethyl acetate (V/V)=20:1-3:1) to obtain a yellow solid product 2-(o-tolyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetonitrile (I-5B) (7.35 g, 82.9% yield).
1H NMR(400MHz,DMSO_d 6):δ8.92(d,1H),7.79-7.84(m,1H),7.70(s,1H),7.35-7.41(m,1H),7.23-7.31(m,3H),6.19(s,1H),2.31(s,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.92(d,1H), 7.79-7.84(m,1H), 7.70(s,1H), 7.35-7.41(m,1H), 7.23-7.31(m, 3H), 6.19(s, 1H), 2.31(s, 3H).
LC-MS,M/Z(ESI):277.1[M+H] + LC-MS, M/Z(ESI): 277.1[M+H] +
第二步：2-(邻甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-5C)的合成The second step: Synthesis of 2-(o-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-5C)
Figure PCTCN2022087589-appb-000093
Figure PCTCN2022087589-appb-000093
在0℃下，将2-(邻甲苯基)-2-[4-(三氟甲基)-2-吡啶基]乙腈(I-5B)(7.34g,26.3mmol)缓慢加入到硫酸(64.6g,659mmol,35.2mL)中，置换氮气，加热到30℃，搅拌2小时。将反应液倒入冰水(100mL)中，用饱和氢氧化钠溶液(100mL)调节pH至9左右，用乙酸乙酯(600mL)萃取，然后用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到 得到白色固体化合物2-(邻甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-5C)(5.45g，产率68.1％)。2-(o-Tolyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetonitrile (I-5B) (7.34 g, 26.3 mmol) was slowly added to sulfuric acid (64.6 mmol) at 0 °C g, 659 mmol, 35.2 mL), replaced with nitrogen, heated to 30°C, and stirred for 2 hours. The reaction solution was poured into ice water (100 mL), adjusted to pH about 9 with saturated sodium hydroxide solution (100 mL), extracted with ethyl acetate (600 mL), washed with saturated brine (200 mL), and washed with anhydrous sodium sulfate. Dry, filter and concentrate to give a white solid compound 2-(o-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-5C) (5.45g, 68.1% yield) ).
1H NMR(400MHz,DMSO_d 6):δ8.80(d,1H),7.77(br s,1H),7.65(d,1H),7.40(s,1H),7.37(br d,1H),7.26(br s,1H),7.17-7.23(m,3H),5.40(s,1H),2.21(s,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ 8.80(d, 1H), 7.77(br s, 1H), 7.65(d, 1H), 7.40(s, 1H), 7.37(br d, 1H), 7.26 (br s,1H),7.17-7.23(m,3H),5.40(s,1H),2.21(s,3H).
LC-MS,M/Z(ESI):295.1[M+H] + LC-MS, M/Z(ESI): 295.1[M+H] +
第三步：N-(甲基氨基硫代甲酰基)-2-(邻甲苯基)-2-[4-(三氟甲基)-2-吡啶基]乙酰胺(I-5D)的合成The third step: synthesis of N-(methylaminothioformyl)-2-(o-tolyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetamide (I-5D)
Figure PCTCN2022087589-appb-000094
Figure PCTCN2022087589-appb-000094
把2-(邻甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(4.12g,13.5mmol)和异硫氰酸根甲烷(1.49g,20.3mmol)，碳酸铯(13.2g,40.7mmol)加入N,N-二甲基甲酰胺(40mL)中，置换氮气，加热到75℃，搅拌2小时。将反应液降温至室温，倒入水(30mL)中，用乙酸乙酯(90mL)萃取，然后用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-3:1)得到得到棕色固体化合物N-(甲基氨基硫代甲酰基)-2-(邻甲苯基)-2-[4-(三氟甲基)-2-吡啶基]乙酰胺(I-5D)(3.96g，产率77.8％)。Combine 2-(o-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (4.12 g, 13.5 mmol) and isothiocyanatomethane (1.49 g, 20.3 mmol), carbonic acid Cesium (13.2 g, 40.7 mmol) was added to N,N-dimethylformamide (40 mL), nitrogen was replaced, and the mixture was heated to 75° C. and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (30 mL), extracted with ethyl acetate (90 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product, which was separated by silica gel column Purification (petroleum ether:ethyl acetate (V/V)=10:1-3:1) to obtain a brown solid compound N-(methylaminothioformyl)-2-(o-tolyl)-2-[ 4-(Trifluoromethyl)-2-pyridyl]acetamide (I-5D) (3.96 g, 77.8% yield).
LC-MS,M/Z(ESI):368.1[M+H] + LC-MS, M/Z(ESI): 368.1[M+H] +
第四步：1-(甲基氨基)-4-(邻甲苯基)-6-(三氟甲基)吡啶并[1,2-c]嘧啶-3-酮(I-5)的合成The fourth step: synthesis of 1-(methylamino)-4-(o-tolyl)-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one (I-5)
Figure PCTCN2022087589-appb-000095
Figure PCTCN2022087589-appb-000095
把N-(甲基氨基硫代甲酰基)-2-(邻甲苯基)-2-[4-(三氟甲基)-2-吡啶基]乙酰胺(3.96g,10.5mmol)溶解在四氢呋喃(40mL)中，在0℃下缓慢加入碘单质(8.05g,31.7mmol)，吡啶(10.3g,31.7mmol)，置换氮气，加热到20℃搅拌反应2小时。加入水(50mL)，加入饱和亚硫酸钠溶液(100mL)，然后用乙酸乙酯(300mL)萃取，用饱和食盐水(100mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。粗品在25℃用二氯甲烷(5mL)溶解后加石油醚(30mL)打浆搅拌0.5小时，过滤得到黄色固体化合物1-(甲基氨基)-4-(邻甲苯基)-6-(三氟甲基)吡啶并[1,2-c]嘧啶-3-酮(I-5)(2.00g，产率56.7％)。Dissolve N-(methylaminothioformyl)-2-(o-tolyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetamide (3.96 g, 10.5 mmol) in tetrahydrofuran (40 mL), iodine (8.05 g, 31.7 mmol) and pyridine (10.3 g, 31.7 mmol) were slowly added at 0 °C, nitrogen was replaced, and the reaction was heated to 20 °C and stirred for 2 hours. Water (50 mL) was added, saturated sodium sulfite solution (100 mL) was added, then extracted with ethyl acetate (300 mL), the organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The crude product was dissolved in dichloromethane (5 mL) at 25°C, then added with petroleum ether (30 mL), beating and stirring for 0.5 hours, and filtered to obtain a yellow solid compound 1-(methylamino)-4-(o-tolyl)-6-(trifluoro Methyl)pyrido[1,2-c]pyrimidin-3-one (I-5) (2.00 g, 56.7% yield).
1H NMR(400MHz,DMSO_d 6):δ8.04(br d,1H),7.92-8.01(m,1H),7.28-7.32(m,2H),7.22-7.27(m,1H),7.06(d,1H),6.66(br d,1H),6.62(s,1H),2.90(s,3H),2.04(s,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.04(br d, 1H), 7.92-8.01(m, 1H), 7.28-7.32(m, 2H), 7.22-7.27(m, 1H), 7.06(d ,1H),6.66(br d,1H),6.62(s,1H),2.90(s,3H),2.04(s,3H).
LC-MS,M/Z(ESI):334.1[M+H] + LC-MS, M/Z(ESI): 334.1[M+H] +
实施例6：目标化合物I-6的制备Example 6: Preparation of target compound I-6
4-(2-氯苯基)-1-(环丙基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-6)4-(2-Chlorophenyl)-1-(cyclopropylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-6)
Figure PCTCN2022087589-appb-000096
Figure PCTCN2022087589-appb-000096
目标化合物I-6的合成路线如下所示：The synthetic route of the target compound I-6 is as follows:
Figure PCTCN2022087589-appb-000097
Figure PCTCN2022087589-appb-000097
第一步：2-(2-氯苯基)-N-(环丙基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-6B)的合成The first step: 2-(2-chlorophenyl)-N-(cyclopropylaminothioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-6B )Synthesis
Figure PCTCN2022087589-appb-000098
Figure PCTCN2022087589-appb-000098
把2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(350mg,1.11mmol)和异硫氰基环丙烷(165mg,1.67mmol)，碳酸铯(724mg,2.22mmol)加入N,N-二甲基甲酰胺(2.50mL)中，置换氮气，加热到75℃，搅拌2小时。将反应液降至室温，倒入水(10.0mL)中，用乙酸乙酯(15.0mL)萃取，合并有机相，然后用饱和食盐水(15.0mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝100:0-2:1)得到黑褐色固体2-(2-氯苯基)-N-(环丙基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-6B)(320mg，产率69.5％)。Combine 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (350 mg, 1.11 mmol) and isothiocyanocyclopropane (165 mg, 1.67 mmol), Cesium carbonate (724 mg, 2.22 mmol) was added to N,N-dimethylformamide (2.50 mL), nitrogen was replaced, and the mixture was heated to 75° C. and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (10.0 mL), extracted with ethyl acetate (15.0 mL), the organic phases were combined, washed with saturated brine (15.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated The crude product was obtained, which was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=100:0-2:1) to obtain 2-(2-chlorophenyl)-N-(cyclopropylamino) as a dark brown solid Thioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-6B) (320 mg, 69.5% yield).
1H NMR(400MHz,DMSO_d 6):δ11.79(s,1H),10.38(d,1H),8.87(d,1H),7.76(d,1H),7.47-7.53(m,2H),7.32-7.37(m,2H),7.07(d,1H),5.99(s,1H),3.12-3.16(m,1H),0.76-0.82(m,2H),0.65-0.68(m,2H). 1 H NMR (400MHz, DMSO_d 6 ): δ 11.79(s, 1H), 10.38(d, 1H), 8.87(d, 1H), 7.76(d, 1H), 7.47-7.53(m, 2H), 7.32 -7.37(m, 2H), 7.07(d, 1H), 5.99(s, 1H), 3.12-3.16(m, 1H), 0.76-0.82(m, 2H), 0.65-0.68(m, 2H).
第二步：4-(2-氯苯基)-1-(环丙基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-6)的合成The second step: 4-(2-chlorophenyl)-1-(cyclopropylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I -6) Synthesis
Figure PCTCN2022087589-appb-000099
Figure PCTCN2022087589-appb-000099
把2-(2-氯苯基)-N-(环丙基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-6B)(320mg,773μmol)溶解在四氢呋喃(1.00mL)中，在0℃下缓慢加入碘单质(588mg,2.32mmol)，吡啶(183mg,2.32mmol)，置换氮气，加热到25℃搅拌反应2小时。加入水(10.0mL)，用乙酸乙酯(10.0mL)萃取，合并有机相，用饱和食盐水(10.0mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。然后通过高效液相色谱仪进行分离，分离方法为(柱子：Waters Xbridge 150*25mm*5μm；溶剂：A＝水+10mM碳酸氢铵，B＝乙腈；梯度：24％-54％，9分钟)，得到黄色固体4-(2-氯苯基)-1-(环丙基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-6)(54.1mg，产率17.9％)。2-(2-Chlorophenyl)-N-(cyclopropylaminothiocarbonyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-6B) (320 mg , 773 μmol) was dissolved in tetrahydrofuran (1.00 mL), and iodine (588 mg, 2.32 mmol) and pyridine (183 mg, 2.32 mmol) were slowly added at 0° C., nitrogen was replaced, and the reaction was heated to 25° C. and stirred for 2 hours. Water (10.0 mL) was added, extracted with ethyl acetate (10.0 mL), the organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Then it was separated by high performance liquid chromatography, and the separation method was (column: Waters Xbridge 150*25mm*5μm; solvent: A=water+10mM ammonium bicarbonate, B=acetonitrile; gradient: 24%-54%, 9 minutes) , 4-(2-chlorophenyl)-1-(cyclopropylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I -6) (54.1 mg, 17.9% yield).
1H NMR(400MHz,DMSO_d 6):δ8.28-8.32(m,2H),7.57-7.59(m,1H),7.42-7.44(m,2H),7.32(d,1H),6.59-6.66(m,2H),2.87(s,1H),0.68-0.80(m,4H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.28-8.32(m, 2H), 7.57-7.59(m, 1H), 7.42-7.44(m, 2H), 7.32(d, 1H), 6.59-6.66( m,2H),2.87(s,1H),0.68-0.80(m,4H).
LC-MS,M/Z(ESI):380.1[M+H] + LC-MS, M/Z(ESI): 380.1[M+H] +
实施例7：目标化合物I-7的制备Example 7: Preparation of target compound I-7
4-(2-氯苯基)-1-((1-羟基丙烷-2-基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-7)4-(2-Chlorophenyl)-1-((1-hydroxypropan-2-yl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3- Ketone (I-7)
Figure PCTCN2022087589-appb-000100
Figure PCTCN2022087589-appb-000100
化合物I-7可参考I-60或I-61的合成方法得到。Compound I-7 can be obtained by referring to the synthetic method of I-60 or I-61.
LC-MS,M/Z(ESI):398.1[M+H] + LC-MS, M/Z(ESI): 398.1[M+H] +
实施例8：目标化合物I-8的制备Example 8: Preparation of target compound I-8
4-(2-氯苯基)-1-((2-羟丙基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-8)4-(2-Chlorophenyl)-1-((2-hydroxypropyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I -8)
Figure PCTCN2022087589-appb-000101
Figure PCTCN2022087589-appb-000101
化合物I-8可参考I-60或I-61的合成方法得到。Compound I-8 can be obtained by referring to the synthetic method of I-60 or I-61.
LC-MS,M/Z(ESI):398.1[M+H] + LC-MS, M/Z(ESI): 398.1[M+H] +
实施例9：目标化合物I-9的制备Example 9: Preparation of target compound I-9
4-(2-氯苯基)-1-(3-羟基吡咯烷-1-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-9)4-(2-Chlorophenyl)-1-(3-hydroxypyrrolidin-1-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one ( I-9)
Figure PCTCN2022087589-appb-000102
Figure PCTCN2022087589-appb-000102
化合物I-9可参考I-70或I-71的合成方法得到。Compound I-9 can be obtained by referring to the synthetic method of I-70 or I-71.
LC-MS,M/Z(ESI):410.1[M+H] + LC-MS, M/Z(ESI): 410.1[M+H] +
实施例10：目标化合物I-10的制备Example 10: Preparation of target compound I-10
1-(甲基氨基)-4-(2-甲基吡啶-3-基)-6-(三氟甲基)-3H-吡啶基[1,2-c]嘧啶-3-酮(I-10)1-(Methylamino)-4-(2-methylpyridin-3-yl)-6-(trifluoromethyl)-3H-pyridyl[1,2-c]pyrimidin-3-one (I- 10)
Figure PCTCN2022087589-appb-000103
Figure PCTCN2022087589-appb-000103
目标化合物I-10的合成路线如下所示：The synthetic route of the target compound I-10 is as follows:
Figure PCTCN2022087589-appb-000104
Figure PCTCN2022087589-appb-000104
第一步：2-(2-甲基吡啶-3-基)乙腈(I-10B)的合成The first step: the synthesis of 2-(2-methylpyridin-3-yl)acetonitrile (I-10B)
Figure PCTCN2022087589-appb-000105
Figure PCTCN2022087589-appb-000105
在氮气保护下，于-60℃向叔丁醇钾(10.0g,89.1mmol)的乙二醇二甲醚(100mL)溶液中加入对甲基苯磺酰甲基异腈(9.50g,48.7mmol)，反应在-60℃搅拌1小时，然后加入2-甲基吡啶-3-甲醛(I-10A)(5.00g,41.3mmol)，反应接着在-60℃搅拌1小时，最后加入甲醇(100mL)，反应在80℃搅拌4小时。反应完成后，将反应混合物减压浓缩，残留物用硅胶 柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:1)得到黄色固体化合物2-(2-甲基吡啶-3-基)乙腈(I-10B)(6.00g,45.4mmol,产率55.0％)。Under nitrogen protection, to a solution of potassium tert-butoxide (10.0 g, 89.1 mmol) in ethylene glycol dimethyl ether (100 mL) was added p-toluenesulfonylmethylisonitrile (9.50 g, 48.7 mmol) at -60°C ), the reaction was stirred at -60 °C for 1 hour, then 2-methylpyridine-3-carbaldehyde (I-10A) (5.00 g, 41.3 mmol) was added, the reaction was then stirred at -60 °C for 1 hour, and finally methanol (100 mL) was added. ) and the reaction was stirred at 80°C for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-1:1) to obtain a yellow solid compound 2-(2-methyl) Pyridin-3-yl)acetonitrile (I-10B) (6.00 g, 45.4 mmol, 55.0% yield).
1H NMR(400MHz,DMSO_d 6):δ8.44(br d,1H),7.64(d,1H),7.15(dd,1H),3.67(s,2H),2.53(s,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.44(br d,1H), 7.64(d,1H), 7.15(dd,1H), 3.67(s,2H), 2.53(s,3H).
LC-MS,M/Z(ESI):133.0[M+H] + LC-MS, M/Z(ESI): 133.0[M+H] +
第二步：2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-10C)的合成The second step: Synthesis of 2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-10C)
Figure PCTCN2022087589-appb-000106
Figure PCTCN2022087589-appb-000106
在氮气保护下，向2-(2-甲基吡啶-3-基)乙腈(I-10B)(6.00g,45.4mmol)的二甲基亚砜(50.0mL)溶液中加入2-溴-4-(三氟甲基)吡啶(10.5g,46.5mmol)和氢氧化钾(7.64g,136mmol)，反应在90℃搅拌10小时。反应完成后，将反应混合物用水(150mL)稀释，然后用乙酸乙酯(100mL*3)萃取，合并有机层，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-1:1)得到黄色固体化合物2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-10C)(10.0g,36.1mmol,产率79.5％)。To a solution of 2-(2-methylpyridin-3-yl)acetonitrile (I-10B) (6.00 g, 45.4 mmol) in dimethylsulfoxide (50.0 mL) was added 2-bromo-4 under nitrogen protection - (trifluoromethyl)pyridine (10.5 g, 46.5 mmol) and potassium hydroxide (7.64 g, 136 mmol), the reaction was stirred at 90°C for 10 hours. After the completion of the reaction, the reaction mixture was diluted with water (150 mL), then extracted with ethyl acetate (100 mL*3), the organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-1:1) to obtain a yellow solid compound 2-(2-methylpyridin-3-yl)-2-(4-( Trifluoromethyl)pyridin-2-yl)acetonitrile (I-10C) (10.0 g, 36.1 mmol, 79.5% yield).
LC-MS,M/Z(ESI):278.2[M+H] + LC-MS, M/Z(ESI): 278.2[M+H] +
第三步：2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-10D)的合成The third step: Synthesis of 2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-10D)
Figure PCTCN2022087589-appb-000107
Figure PCTCN2022087589-appb-000107
向硫酸(40.0mL)中加入2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-10C)(14.0g,50.5mmol)，反应在25℃搅拌5小时。反应完成后，将反应液在0℃下慢慢加入到氢氧化钠水溶液(5.00M,400mL)中，然后用乙酸乙酯(300mL*3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，得到黄色固体2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-10D)(15.0g)，直接用于下一步。To sulfuric acid (40.0 mL) was added 2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-10C) (14.0 g, 50.5 mmol) and the reaction was stirred at 25°C for 5 hours. After the reaction was completed, the reaction solution was slowly added to an aqueous sodium hydroxide solution (5.00M, 400mL) at 0°C, then extracted with ethyl acetate (300mL*3), the organic layers were combined, dried over anhydrous sodium sulfate, and filtered. , concentrated to give 2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-10D) (15.0 g) as a yellow solid, which was directly for the next step.
第四步：N-(甲基氨基硫代甲酰基)-2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-10E)的合成The fourth step: N-(methylaminothioformyl)-2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide ( Synthesis of I-10E)
Figure PCTCN2022087589-appb-000108
Figure PCTCN2022087589-appb-000108
向2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-10D)(5.00g,16.9mmol)的N,N-二甲基甲酰胺(50.0mL)溶液中加入碳酸铯(8.28g,25.4mmol)和甲基异硫氰酸酯(1.36g,18.6mmol)，反应在30℃搅拌10小时。反应完成后，将反应混合物用水(200mL)稀释，然后用乙酸乙酯(100mL*3)萃取，合并有机层，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:1)得到黄色固体化合物N-(甲基氨基硫代甲酰基)-2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺 (I-10E)(6.00g,16.3mmol,产率96.2％)。To 2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-10D) (5.00 g, 16.9 mmol) in N,N - Cesium carbonate (8.28 g, 25.4 mmol) and methyl isothiocyanate (1.36 g, 18.6 mmol) were added to the dimethylformamide (50.0 mL) solution, and the reaction was stirred at 30° C. for 10 hours. After the completion of the reaction, the reaction mixture was diluted with water (200 mL), then extracted with ethyl acetate (100 mL*3), the organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-1:1) to obtain a yellow solid compound N-(methylaminothioformyl)-2-(2-methylpyridine) -3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-10E) (6.00 g, 16.3 mmol, 96.2% yield).
1H NMR(400MHz,DMSO_d 6):δ11.68(s,1H),10.40(br d,1H),8.85(d,1H),8.40(dd,1H),7.70-7.77(m,1H),7.55(s,1H),7.49(dd,1H),7.25(dd,1H),5.82(s,1H)3.01(d,3H),2.44(s,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ 11.68(s, 1H), 10.40(br d, 1H), 8.85(d, 1H), 8.40(dd, 1H), 7.70-7.77(m, 1H), 7.55(s, 1H), 7.49(dd, 1H), 7.25(dd, 1H), 5.82(s, 1H), 3.01(d, 3H), 2.44(s, 3H).
LC-MS,M/Z(ESI):369.2[M+H] + LC-MS, M/Z(ESI): 369.2[M+H] +
第五步：1-(甲基氨基)-4-(2-甲基吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-10)的合成The fifth step: 1-(methylamino)-4-(2-methylpyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3- Synthesis of Ketone (I-10)
Figure PCTCN2022087589-appb-000109
Figure PCTCN2022087589-appb-000109
向N-(甲基氨基硫代甲酰基)-2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-10E)(5.00g,13.6mmol)的四氢呋喃(50.0mL)溶液中加入碘单质(10.3g,40.7mmol)和吡啶(3.22g,40.7mmol)，反应在25℃搅拌10小时。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(200mL)稀释，然后用乙酸乙酯(100mL*3)萃取，合并有机层，用饱和亚硫酸钠水溶液(200mL*3)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:1-二氯甲烷:甲醇(V/V)＝10:1)，然后再用高效液相色谱仪分离纯化，分离方法为(柱子：Waters Xbridge BEH C18 250*50mm*10μm；溶剂：A＝水+0.05体积％氨水(99.0％)，B＝乙腈；梯度：15％-45％，20分钟)，得到黄色固体化合物1-(甲基氨基)-4-(2-甲基吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-10)(649mg,1.93mmol,产率14.2％)。To N-(methylaminothioformyl)-2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-10E ) (5.00 g, 13.6 mmol) in tetrahydrofuran (50.0 mL) solution was added iodine (10.3 g, 40.7 mmol) and pyridine (3.22 g, 40.7 mmol), and the reaction was stirred at 25° C. for 10 hours. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium sulfite solution (200 mL), then extracted with ethyl acetate (100 mL*3), the organic layers were combined, washed with saturated aqueous sodium sulfite solution (200 mL*3), dried over anhydrous sodium sulfate, and filtered. , concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:1-dichloromethane:methanol (V/V)=10:1), and then by high performance liquid chromatography Instrument separation and purification, the separation method is (column: Waters Xbridge BEH C18 250*50mm*10μm; solvent: A=water+0.05% by volume ammonia water (99.0%), B=acetonitrile; gradient: 15%-45%, 20 minutes) , the yellow solid compound 1-(methylamino)-4-(2-methylpyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 - Ketone (I-10) (649 mg, 1.93 mmol, 14.2% yield).
1H NMR(400MHz,DMSO_d 6):δ8.46(dd,1H),7.99-8.15(m,2H),7.49(dd,1H),7.28(dd,1H),6.72(dd,1H),6.64(s,1H),2.90(d,3H),2.24(s,3H). 1 H NMR (400 MHz, DMSO_d 6 ): δ 8.46 (dd, 1H), 7.99-8.15 (m, 2H), 7.49 (dd, 1H), 7.28 (dd, 1H), 6.72 (dd, 1H), 6.64 (s, 1H), 2.90(d, 3H), 2.24(s, 3H).
LC-MS,M/Z(ESI):335.1[M+H] + LC-MS, M/Z(ESI): 335.1[M+H] +
实施例11：目标化合物I-11的制备Example 11: Preparation of target compound I-11
4-(3-氯吡啶-2-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶基[1,2-c]嘧啶-3-酮(I-11)4-(3-Chloropyridin-2-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyridyl[1,2-c]pyrimidin-3-one (I-11 )
Figure PCTCN2022087589-appb-000110
Figure PCTCN2022087589-appb-000110
目标化合物I-11的合成路线如下所示：The synthetic route of the target compound I-11 is as follows:
Figure PCTCN2022087589-appb-000111
Figure PCTCN2022087589-appb-000111
第一步：2-(3-氯-2-吡啶-2-基)-2-[4-(三氟甲基)-2-吡啶基]乙腈(I-11B)的合成The first step: Synthesis of 2-(3-chloro-2-pyridin-2-yl)-2-[4-(trifluoromethyl)-2-pyridyl]acetonitrile (I-11B)
Figure PCTCN2022087589-appb-000112
Figure PCTCN2022087589-appb-000112
在室温下，将2-(3-氯-2-吡啶-2-基)乙腈(4.50g,29.4mmol)，氢氧化钾(2.48g,44.2mmol)和2-溴-4-三氟甲基-吡啶(6.67g,29.4mmol)溶解在四氢呋喃(20mL)中，充分搅拌，在70℃反应10小时。反应结束后加水(50mL)，用乙酸乙酯(90mL)萃取，然后有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:1)得到棕色固体产物2-(3-氯-2-吡啶-2-基)-2-[4-(三氟甲基)-2-吡啶-2-基]乙腈(I-11B)(7.65g，产率82.4％)。2-(3-Chloro-2-pyridin-2-yl)acetonitrile (4.50 g, 29.4 mmol), potassium hydroxide (2.48 g, 44.2 mmol) and 2-bromo-4-trifluoromethyl were mixed at room temperature -Pyridine (6.67 g, 29.4 mmol) was dissolved in tetrahydrofuran (20 mL), stirred well, and reacted at 70°C for 10 hours. After the reaction, water (50 mL) was added, extracted with ethyl acetate (90 mL), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated and purified with a silica gel column (petroleum ether: Ethyl acetate (V/V)=5:1-1:1) to obtain a brown solid product 2-(3-chloro-2-pyridin-2-yl)-2-[4-(trifluoromethyl)-2 -Pyridin-2-yl]acetonitrile (I-11B) (7.65 g, 82.4% yield).
LC-MS,M/Z(ESI):298.1[M+H] + LC-MS, M/Z(ESI): 298.1[M+H] +
第二步：2-(3-氯吡啶-2-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-11C)的合成The second step: Synthesis of 2-(3-chloropyridin-2-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-11C)
Figure PCTCN2022087589-appb-000113
Figure PCTCN2022087589-appb-000113
把2-(3-氯-2-吡啶-2-基)-2-[4-(三氟甲基)-2-吡啶-2-基]乙腈(I-11B)(2.00g,6.72mmol)溶于硫酸(37.1g,380mmol,20.0mL)中，置换氮气，加热到30℃，搅拌2小时。将反应液倒入冰水(50mL)中，用饱和碳酸钠溶液(30mL)调节pH至9左右，用乙酸乙酯(150mL)萃取，然后用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0-1:1)得到灰色固体化合物2-(3-氯吡啶-2-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-11C)(2.00g，产率85.1％)。2-(3-Chloro-2-pyridin-2-yl)-2-[4-(trifluoromethyl)-2-pyridin-2-yl]acetonitrile (I-11B) (2.00 g, 6.72 mmol) It was dissolved in sulfuric acid (37.1 g, 380 mmol, 20.0 mL), replaced with nitrogen, heated to 30° C., and stirred for 2 hours. The reaction solution was poured into ice water (50 mL), the pH was adjusted to about 9 with saturated sodium carbonate solution (30 mL), extracted with ethyl acetate (150 mL), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. , filtered, concentrated, separated and purified with silica gel column (petroleum ether:ethyl acetate (V/V)=1:0-1:1) to obtain a gray solid compound 2-(3-chloropyridin-2-yl)-2- (4-(Trifluoromethyl)pyridin-2-yl)acetamide (I-11C) (2.00 g, 85.1% yield).
LC-MS,M/Z(ESI):316.1[M+H] + LC-MS, M/Z(ESI): 316.1[M+H] +
第三步：2-(3-氯-2-吡啶-2-基)-N-(甲基氨基硫代甲酰基)-2-[4-(三氟甲基)-2-吡啶-2-基]乙酰胺(I-11D)的合成The third step: 2-(3-chloro-2-pyridin-2-yl)-N-(methylaminothioformyl)-2-[4-(trifluoromethyl)-2-pyridine-2- Synthesis of Acetamide (I-11D)
Figure PCTCN2022087589-appb-000114
Figure PCTCN2022087589-appb-000114
把2-(3-氯吡啶-2-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-11C)(2.00g,6.34mmol)和异硫氰酸根甲烷(694mg,9.50mmol,649μL)，碳酸铯(4.13g,12.6mmol)加入N,N-二甲基甲酰胺(20mL)中，置换氮气，加热到75℃，搅拌2小时。将反应液降温至室温，倒入水(30mL)中，用乙酸乙酯(90mL)萃取，合并有机相，然后用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:1)得到棕色油状化合物2-(3-氯-2-吡啶-2-基)-N-(甲基氨基硫代甲酰基)-2-[4-(三氟甲基)-2-吡啶-2-基]乙酰胺(I-11D)(800mg，产率32.5％)。Combine 2-(3-chloropyridin-2-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-11C) (2.00 g, 6.34 mmol) and isothiocyanate Methane (694 mg, 9.50 mmol, 649 μL) and cesium carbonate (4.13 g, 12.6 mmol) were added to N,N-dimethylformamide (20 mL), nitrogen was replaced, heated to 75° C. and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (30 mL), extracted with ethyl acetate (90 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-1:1) to obtain a brown oily compound 2-(3-chloro-2-pyridin-2-yl)-N-(methyl) (I-11D) (800 mg, 32.5% yield).
LC-MS,M/Z(ESI):389.1[M+H] + LC-MS, M/Z(ESI): 389.1[M+H] +
第四步：4-(3-氯吡啶-2-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶基[1,2-c]嘧啶-3-酮(目标化合物I-11)的合成The fourth step: 4-(3-chloropyridin-2-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyridyl[1,2-c]pyrimidin-3-one Synthesis of (Target Compound I-11)
Figure PCTCN2022087589-appb-000115
Figure PCTCN2022087589-appb-000115
把2-(3-氯-2-吡啶-2-基)-N-(甲基氨基硫代甲酰基)-2-[4-(三氟甲基)-2-吡啶-2-基]乙酰胺(400mg,1.03mmol)溶解在四氢呋喃(5mL)中，在0℃下缓慢加入碘单质(522mg,2.06)，碳酸铯(1.01g,3.09mmol)，置换氮气，加热到20℃搅拌反应2小时。加入水(20mL)，加入饱和亚硫酸钠溶液(10mL)，然后用乙酸乙酯(60mL)萃取，用饱和食盐水(30mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。然后通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge C18 150*50mm*10μm；溶剂：A＝水+碳酸氢铵(0.05％)，B＝乙腈；梯度：14％-44％，11分钟)，冻干得到黄色固体化合物4-(3-氯吡啶-2-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶基[1,2-c]嘧啶-3-酮(I-11)(40mg，产率10.9％)。2-(3-Chloro-2-pyridin-2-yl)-N-(methylcarbamoyl)-2-[4-(trifluoromethyl)-2-pyridin-2-yl]ethyl The amide (400 mg, 1.03 mmol) was dissolved in tetrahydrofuran (5 mL), and iodine (522 mg, 2.06) and cesium carbonate (1.01 g, 3.09 mmol) were slowly added at 0 °C, and the nitrogen was replaced, and the reaction was heated to 20 °C and stirred for 2 hours. . Water (20 mL) was added, saturated sodium sulfite solution (10 mL) was added, then extracted with ethyl acetate (60 mL), the organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated to obtain a crude product. Then it was separated by reversed-phase high performance liquid chromatography, and the separation method was (column: Waters Xbridge C18 150*50mm*10μm; solvent: A=water+ammonium bicarbonate (0.05%), B=acetonitrile; gradient: 14%- 44%, 11 minutes), lyophilized to give a yellow solid compound 4-(3-chloropyridin-2-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyridinyl[1, 2-c]pyrimidin-3-one (I-11) (40 mg, 10.9% yield).
1H NMR(400MHz,DMSO_d 6):δ8.62(d,1H),8.12-8.14(m,2H),8.04(d,1H),7.46-7.49(m,1H),6.76-6.79(m,2H),2.92(d,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.62(d,1H), 8.12-8.14(m,2H), 8.04(d,1H), 7.46-7.49(m,1H), 6.76-6.79(m, 2H), 2.92(d, 3H).
LC-MS,M/Z(ESI):355.1[M+H] + LC-MS, M/Z(ESI): 355.1[M+H] +
实施例12：目标化合物I-12的制备Example 12: Preparation of target compound I-12
(S)-4-(2-氯苯基)-1-((1-羟基丙烷-2-基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-12)(S)-4-(2-Chlorophenyl)-1-((1-hydroxypropan-2-yl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c] Pyrimidine-3-one (I-12)
Figure PCTCN2022087589-appb-000116
Figure PCTCN2022087589-appb-000116
化合物I-12可参考I-60或I-61的合成方法得到。Compound I-12 can be obtained by referring to the synthetic method of I-60 or I-61.
LC-MS,M/Z(ESI):398.1[M+H] + LC-MS, M/Z(ESI): 398.1[M+H] +
实施例13：目标化合物I-13的制备Example 13: Preparation of target compound I-13
(R)-4-(2-氯苯基)-1-((1-羟基丙烷-2-基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-13)(R)-4-(2-Chlorophenyl)-1-((1-hydroxypropan-2-yl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c] Pyrimidine-3-one (I-13)
Figure PCTCN2022087589-appb-000117
Figure PCTCN2022087589-appb-000117
化合物I-13可参考I-60或I-61的合成方法得到。Compound I-13 can be obtained by referring to the synthetic method of I-60 or I-61.
LC-MS,M/Z(ESI):398.1[M+H] + LC-MS, M/Z(ESI): 398.1[M+H] +
实施例14：目标化合物I-14的制备Example 14: Preparation of target compound I-14
4-(2-氯苯基)-1-(((1-羟基环丙基)甲基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-14)4-(2-Chlorophenyl)-1-(((1-hydroxycyclopropyl)methyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine- 3-keto (I-14)
Figure PCTCN2022087589-appb-000118
Figure PCTCN2022087589-appb-000118
目标化合物I-14的合成路线如下所示：The synthetic route of the target compound I-14 is as follows:
Figure PCTCN2022087589-appb-000119
Figure PCTCN2022087589-appb-000119
第一步：2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-14B)的合成The first step: Synthesis of 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-14B)
Figure PCTCN2022087589-appb-000120
Figure PCTCN2022087589-appb-000120
将邻氯苯乙腈(50.0g,329.8mmol)和氢氧化钾(27.8g,494.8mmol)溶解在二甲基亚砜(500mL)中，再将2-溴-4-(三氟甲基)吡啶(74.5g,329.8mmol)加到反应液中，75℃反应10小时。将反应液倒入水(500mL)中，然后用乙酸乙酯(1200mL)萃取，用饱和食盐水(300mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品，用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-5:1)得到棕色油状化合物2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-14B)(71.0g，产率72.6％)。o-Chlorophenylacetonitrile (50.0 g, 329.8 mmol) and potassium hydroxide (27.8 g, 494.8 mmol) were dissolved in dimethyl sulfoxide (500 mL), followed by 2-bromo-4-(trifluoromethyl)pyridine (74.5 g, 329.8 mmol) was added to the reaction solution and reacted at 75°C for 10 hours. The reaction solution was poured into water (500 mL), then extracted with ethyl acetate (1200 mL), the organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated and purified by silica gel column chromatography (Petroleum ether:ethyl acetate (V/V)=50:1-5:1) to obtain a brown oily compound 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridine-2- yl)acetonitrile (I-14B) (71.0 g, 72.6% yield).
1H NMR(400MHz,CDCl 3):δ8.83(d,1H),7.64-7.71(m,1H),7.49-7.57(m,2H),7.46(br d,1H),7.33-7.43(m,2H),5.87(s,1H). 1 H NMR (400MHz, CDCl 3 ): δ8.83(d,1H), 7.64-7.71(m,1H), 7.49-7.57(m,2H), 7.46(br d,1H), 7.33-7.43(m ,2H),5.87(s,1H).
LC-MS,M/Z(ESI):297.1[M+H] + LC-MS, M/Z(ESI): 297.1[M+H] +
第二步：2-(2-氯苯基)-2-(4-(三氟甲基)-2-吡啶基)乙酰胺(I-14C)的合成The second step: Synthesis of 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)-2-pyridyl)acetamide (I-14C)
Figure PCTCN2022087589-appb-000121
Figure PCTCN2022087589-appb-000121
将2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-14B)(50.0g,168.5mmol)溶解在浓硫酸(250mL)中，70℃反应2小时。将反应液倒入冰水(300mL)中，用饱和氢氧化钠溶液调节pH至9左右，然后用乙酸乙酯(1200mL)萃取，用饱和食盐水(300mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品，粗品用石油醚打浆纯化得到白色固体化合物2-(2-氯苯 基)-2-(4-(三氟甲基)-2-吡啶基)乙酰胺(I-14C)(46.0g，产率86.7％)。2-(2-Chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-14B) (50.0 g, 168.5 mmol) was dissolved in concentrated sulfuric acid (250 mL), The reaction was carried out at 70°C for 2 hours. The reaction solution was poured into ice water (300 mL), the pH was adjusted to about 9 with saturated sodium hydroxide solution, then extracted with ethyl acetate (1200 mL), the organic phase was washed with saturated brine (300 mL), and dried over anhydrous sodium sulfate. , concentrated to obtain the crude product, the crude product was purified by beating with petroleum ether to obtain a white solid compound 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)-2-pyridyl)acetamide (I-14C) ( 46.0 g, 86.7% yield).
LC-MS,M/Z(ESI):315.0[M+H] + LC-MS, M/Z(ESI): 315.0[M+H] +
第三步：(1-(叔-丁基(二甲基)甲硅烷基)氧代环丙基)甲胺(14D-2)The third step: (1-(tert-butyl(dimethyl)silyl)oxocyclopropyl)methanamine (14D-2)
Figure PCTCN2022087589-appb-000122
Figure PCTCN2022087589-appb-000122
将1-(氨基甲基)环丙醇(5.00g,57.4mmol)和三乙胺(11.6g,114.8mmol,16.0mL)溶解在二氯甲烷(50.0mL)中，氮气保护下0℃加叔丁基二甲基氯硅烷(13.0g,86.1mmol,10.6mL)，然后在40℃下搅拌反应10小时。将反应液浓缩得到粗品，将水(200mL)倒入反应液中，然后用二氯甲烷(600mL)萃取，用饱和食盐水(200mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-10:1)得到黄色油状化合物(1-(叔-丁基(二甲基)甲硅烷基)氧代环丙基)甲胺(14D-2)(13.8g，产率59.6％)。Dissolve 1-(aminomethyl)cyclopropanol (5.00 g, 57.4 mmol) and triethylamine (11.6 g, 114.8 mmol, 16.0 mL) in dichloromethane (50.0 mL), add tert. Butyldimethylsilyl chloride (13.0 g, 86.1 mmol, 10.6 mL), then the reaction was stirred at 40°C for 10 hours. The reaction solution was concentrated to obtain the crude product, water (200 mL) was poured into the reaction solution, then extracted with dichloromethane (600 mL), the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-10:1) to obtain yellow oily compound (1-(tert-butyl(dimethyl)silyl)oxo Cyclopropyl)methylamine (14D-2) (13.8 g, 59.6% yield).
1H NMR(400MHz,DMSO-d 6):δ3.45(s,2H),0.84-0.88(m,9H),0.37(s,4H),0.03(s,6H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 3.45 (s, 2H), 0.84-0.88 (m, 9H), 0.37 (s, 4H), 0.03 (s, 6H).
第四步：叔-丁基-(1-(异硫氰基甲基)环丙氧基)-二甲基-硅烷(I-14D)的合成The fourth step: synthesis of tert-butyl-(1-(isothiocyanatomethyl) cyclopropoxy)-dimethyl-silane (I-14D)
Figure PCTCN2022087589-appb-000123
Figure PCTCN2022087589-appb-000123
将(1-(叔-丁基(二甲基)甲硅烷基)氧代环丙基)甲胺(1.5g,7.45mmol)(14D-2)和碳酸铯(6.07g,18.6mmol)溶解在二氯甲烷(15mL)中，在氮气保护下加入硫光气(1.03g,8.94mmol,685uL)，25℃反应2小时。把反应液过滤，有机相浓缩得到黄色固体化合物叔-丁基-(1-(异硫氰基甲基)环丙氧基)-二甲基-硅烷(I-14D)(1.50g，产率82.7％)，直接用于下一步。(1-(tert-Butyl(dimethyl)silyl)oxocyclopropyl)methanamine (1.5 g, 7.45 mmol) (14D-2) and cesium carbonate (6.07 g, 18.6 mmol) were dissolved in Thiophosgene (1.03 g, 8.94 mmol, 685 uL) was added to dichloromethane (15 mL) under nitrogen protection, and the reaction was carried out at 25° C. for 2 hours. The reaction solution was filtered, and the organic phase was concentrated to obtain a yellow solid compound tert-butyl-(1-(isothiocyanomethyl)cyclopropoxy)-dimethyl-silane (I-14D) (1.50 g, yield 82.7%), which was directly used in the next step.
第五步：：N-(((1-((叔丁基二甲基甲硅烷基)氧代)环丙基)甲基)氨基硫代甲酰基)-2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-14E)的合成The fifth step: N-(((1-((tert-butyldimethylsilyl)oxo)cyclopropyl)methyl)aminothioformyl)-2-(2-chlorophenyl) - Synthesis of 2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-14E)
Figure PCTCN2022087589-appb-000124
Figure PCTCN2022087589-appb-000124
将叔丁基-(1-(异硫氰酸甲基)环丙氧基)二甲基硅烷(1.50g,6.16mmol)(I-14D)和碳酸铯(3.11g,9.54mmol)溶解在N,N-二加基甲酰胺(10mL)中，加2-(2-氯苯基)-2-(4-(三氟甲基)-2-吡啶基)乙酰胺(1.5g,4.77mmol)，25℃反应2小时。把水(50mL)加到反应液中，然后用乙酸乙酯(120mL)萃取，用饱和食盐水(40mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0-20:1)得到棕色固体化合物N-(((1-((叔丁基二甲基甲硅烷基)氧代)环丙基)甲基)氨基硫代甲酰基)-2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-14E)(423mg，产率14.6％)。tert-Butyl-(1-(isothiocyanatomethyl)cyclopropoxy)dimethylsilane (1.50 g, 6.16 mmol) (I-14D) and cesium carbonate (3.11 g, 9.54 mmol) were dissolved in N , N-diaddition formamide (10 mL), add 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)-2-pyridyl)acetamide (1.5 g, 4.77 mmol) , 25 ℃ reaction for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (120 mL), the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:0-20:1) to obtain a brown solid compound N-(((1-((tert-butyldimethylsilyl) Oxo)cyclopropyl)methyl)carbamoyl)-2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-14E ) (423 mg, 14.6% yield).
1H NMR(400MHz,DMSO-d 6):δ11.78(s,1H),10.67(s,1H),8.85(d,1H),7.76(d,1H),7.52(m,1H),7.48(s,1H),7.35-7.39(m,1H),7.35(d,1H),7.33(m,1H),6.00(s,1H),3.87(d,1H),3.75(d,1H),0.85-0.90(m,4H),0.82(s,9H),-0.01(s,6H). 1 H NMR (400MHz, DMSO-d 6 ): δ 11.78(s,1H), 10.67(s,1H), 8.85(d,1H), 7.76(d,1H), 7.52(m,1H), 7.48 (s,1H),7.35-7.39(m,1H),7.35(d,1H),7.33(m,1H),6.00(s,1H),3.87(d,1H),3.75(d,1H), 0.85-0.90(m,4H),0.82(s,9H),-0.01(s,6H).
LC-MS,M/Z(ESI):558.2[M+H] + LC-MS, M/Z(ESI): 558.2[M+H] +
第六步：1-(((1-((叔丁基二甲基甲硅烷基)氧代)环丙基)甲基)氨基)-4-(2-氯苯基)-6-(三氟甲基)吡啶并[1,2-c]嘧啶-3-酮(I-14F)的合成The sixth step: 1-(((1-((tert-butyldimethylsilyl)oxo)cyclopropyl)methyl)amino)-4-(2-chlorophenyl)-6-(tri Synthesis of Fluoromethyl)pyrido[1,2-c]pyrimidin-3-one (I-14F)
Figure PCTCN2022087589-appb-000125
Figure PCTCN2022087589-appb-000125
将N-(((1-((叔丁基二甲基甲硅烷基)氧代)环丙基)甲基)氨基硫代甲酰基)-2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(400mg,656μmol)溶解在四氢呋喃(10mL)中，加碘(333mg,1.31mmol)和碳酸铯(428mg,1.31mmol)，25℃反应2小时。把水(10mL)加到反应液中，加入饱和亚硫酸钠溶液(10mL)，然后用乙酸乙酯(90mL)萃取，用饱和食盐水(30mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge C18 150*50mm*10μm；溶剂：A＝水+碳酸氢铵(0.05％)，B＝乙腈；梯度：54％-84％，11分钟)，得到棕色固体化合物1-(((1-((叔丁基二甲基甲硅烷基)氧代)环丙基)甲基)氨基)-4-(2-氯苯基)-6-(三氟甲基)吡啶并[1,2-c]嘧啶-3-酮(I-14D)(100mg，产率29.1％)。N-(((1-((tert-butyldimethylsilyl)oxo)cyclopropyl)methyl)carbamoyl)-2-(2-chlorophenyl)-2-( 4-(Trifluoromethyl)pyridin-2-yl)acetamide (400mg, 656μmol) was dissolved in tetrahydrofuran (10mL), iodine (333mg, 1.31mmol) and cesium carbonate (428mg, 1.31mmol) were added, and the reaction was carried out at 25°C 2 hours. Water (10 mL) was added to the reaction solution, saturated sodium sulfite solution (10 mL) was added, then extracted with ethyl acetate (90 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by reversed-phase high performance liquid chromatography, and the separation method was (column: Waters Xbridge C18 150*50mm*10μm; solvent: A=water+ammonium bicarbonate (0.05%), B=acetonitrile; gradient: 54%- 84%, 11 min) to give a brown solid compound 1-(((1-((tert-butyldimethylsilyl)oxo)cyclopropyl)methyl)amino)-4-(2-chlorobenzene yl)-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one (I-14D) (100 mg, 29.1% yield).
LC-MS,M/Z(ESI):524.2[M+H] + LC-MS, M/Z(ESI): 524.2[M+H] +
第七步：4-(2-氯苯基)-1-(((1-羟基环丙基)甲基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-14)Step 7: 4-(2-Chlorophenyl)-1-(((1-hydroxycyclopropyl)methyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2- c] Pyrimidine-3-one (target compound I-14)
Figure PCTCN2022087589-appb-000126
Figure PCTCN2022087589-appb-000126
将1-(((1-((叔丁基二甲基甲硅烷基)氧代)环丙基)甲基)氨基)-4-(2-氯苯基)-6-(三氟甲基)吡啶并[1,2-c]嘧啶-3-酮(I-14E)(50.0mg,95.4μmol)溶解在甲醇(3.00mL)中，加入樟脑磺酸(71.7mg,286.2μmol)，25℃反应0.5小时。在反应液中加入饱和碳酸氢钠溶液(20mL)调节pH至7，然后用乙酸乙酯(45.0mL)萃取，用饱和食盐水(20mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。然后通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150*25mm*5μm；溶剂：A＝水+碳酸氢铵(0.05％)，B＝乙腈；梯度：32％-62％，8分钟)，得到黄色固体化合物4-(2-氯苯基)-1-(((1-羟基环丙基)甲基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-14)(25.0mg，产率31.7％)。1-(((1-((tert-butyldimethylsilyl)oxo)cyclopropyl)methyl)amino)-4-(2-chlorophenyl)-6-(trifluoromethyl) ) pyrido[1,2-c]pyrimidin-3-one (I-14E) (50.0 mg, 95.4 μmol) was dissolved in methanol (3.00 mL), and camphorsulfonic acid (71.7 mg, 286.2 μmol) was added at 25° C. The reaction was carried out for 0.5 hours. Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution to adjust pH to 7, then extracted with ethyl acetate (45.0 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Then it was separated by reversed-phase high performance liquid chromatography, and the separation method was (column: Waters Xbridge 150*25mm*5μm; solvent: A=water+ammonium bicarbonate (0.05%), B=acetonitrile; gradient: 32%-62 %, 8 minutes) to give a yellow solid compound 4-(2-chlorophenyl)-1-(((1-hydroxycyclopropyl)methyl)amino)-6-(trifluoromethyl)-3H-pyridine and [1,2-c]pyrimidin-3-one (I-14) (25.0 mg, 31.7% yield).
1H NMR(400MHz,DMSO-d 6):δ8.25-8.34(m,1H),8.18-8.24(m,1H),7.56-7.58(m,1H),7.41-7.45(m,2H),7.29-7.33(m,1H),6.66-6.72(m,1H),6.58(s,1H),3.62-3.69(m,1H),3.54-3.68(m,2H),0.83(s,4H). 1 H NMR (400MHz, DMSO-d 6 ): δ 8.25-8.34(m,1H), 8.18-8.24(m,1H), 7.56-7.58(m,1H), 7.41-7.45(m,2H), 7.29-7.33(m, 1H), 6.66-6.72(m, 1H), 6.58(s, 1H), 3.62-3.69(m, 1H), 3.54-3.68(m, 2H), 0.83(s, 4H).
LC-MS,M/Z(ESI):410.1[M+H] + LC-MS, M/Z(ESI): 410.1[M+H] +
实施例15：目标化合物I-15的制备Example 15: Preparation of target compound I-15
5-(2-氯苯基)-8-(甲基氨基)-3-(三氟甲基)-6H-嘧啶并[1,6-b]哒嗪-6-酮(I-15)5-(2-Chlorophenyl)-8-(methylamino)-3-(trifluoromethyl)-6H-pyrimido[1,6-b]pyridazin-6-one (I-15)
Figure PCTCN2022087589-appb-000127
Figure PCTCN2022087589-appb-000127
目标化合物I-15的合成路线如下所示：The synthetic route of the target compound I-15 is as follows:
Figure PCTCN2022087589-appb-000128
Figure PCTCN2022087589-appb-000128
第一步：2-(2-氯苯基)-2-(5-(三氟甲基)哒嗪-3-基)乙腈(I-15B)的合成The first step: Synthesis of 2-(2-chlorophenyl)-2-(5-(trifluoromethyl)pyridazin-3-yl)acetonitrile (I-15B)
Figure PCTCN2022087589-appb-000129
Figure PCTCN2022087589-appb-000129
向邻氯苯乙腈(I-15A)(850.0mg,5.61mmol)的二甲基亚砜(3.00mL)溶液中加入3-氯-5-(三氟甲基)哒嗪(1.02g,5.61mmol)和氢氧化钾(629mg,11.2mmol)，反应在90℃搅拌10小时。反应完成后，将反应混合物用水(20.0mL)稀释，然后用乙酸乙酯(20.0mL*3)萃取，合并有机层，用饱和食盐水(20.0mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-10:1)得到棕色油状物2-(2-氯苯基)-2-(5-(三氟甲基)哒嗪-3-基)乙腈(I-15B)(900.0mg,3.02mmol,产率53.9％)。To a solution of o-chlorophenylacetonitrile (I-15A) (850.0 mg, 5.61 mmol) in dimethyl sulfoxide (3.00 mL) was added 3-chloro-5-(trifluoromethyl)pyridazine (1.02 g, 5.61 mmol) ) and potassium hydroxide (629 mg, 11.2 mmol) and the reaction was stirred at 90°C for 10 hours. After the completion of the reaction, the reaction mixture was diluted with water (20.0 mL), then extracted with ethyl acetate (20.0 mL*3), the organic layers were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated , the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-10:1) to obtain 2-(2-chlorophenyl)-2-(5-(tris) as a brown oil Fluoromethyl)pyridazin-3-yl)acetonitrile (I-15B) (900.0 mg, 3.02 mmol, 53.9% yield).
LC-MS,M/Z(ESI):298.0[M+H] + LC-MS, M/Z(ESI): 298.0[M+H] +
第二步：2-(2-氯苯基)-2-(5-(三氟甲基)哒嗪-3-基)乙酰胺(I-15C)的合成The second step: Synthesis of 2-(2-chlorophenyl)-2-(5-(trifluoromethyl)pyridazin-3-yl)acetamide (I-15C)
Figure PCTCN2022087589-appb-000130
Figure PCTCN2022087589-appb-000130
向浓硫酸(8.00mL)中加入2-(2-氯苯基)-2-(5-(三氟甲基)哒嗪-3-基)乙腈(I-15B)(900mg,3.02mmol)，反应在25℃搅拌6小时。反应完成后，将反应液在0℃下慢慢加入到氢氧化钠水溶液(4.00M,80.0mL)中，然后用乙酸乙酯(20.0mL*3)萃取，合并有机层，无水硫酸 钠干燥，过滤，浓缩，得到黄色固体2-(2-氯苯基)-2-(5-(三氟甲基)哒嗪-3-基)乙酰胺(I-15C)(900.0mg,2.85mmol,产率94.3％)，直接用于下一步。To concentrated sulfuric acid (8.00 mL) was added 2-(2-chlorophenyl)-2-(5-(trifluoromethyl)pyridazin-3-yl)acetonitrile (I-15B) (900 mg, 3.02 mmol), The reaction was stirred at 25°C for 6 hours. After the completion of the reaction, the reaction solution was slowly added to an aqueous sodium hydroxide solution (4.00M, 80.0 mL) at 0°C, then extracted with ethyl acetate (20.0 mL*3), the organic layers were combined and dried over anhydrous sodium sulfate , filtered and concentrated to give yellow solid 2-(2-chlorophenyl)-2-(5-(trifluoromethyl)pyridazin-3-yl)acetamide (I-15C) (900.0 mg, 2.85 mmol, yield 94.3%), used directly in the next step.
LC-MS,M/Z(ESI):316.1[M+H] + LC-MS, M/Z(ESI): 316.1[M+H] +
第三步：2-(2-氯苯基)-N-(甲基氨基硫代甲酰基)-2-(5-(三氟甲基)哒嗪-3-基)乙酰胺(I-15D)的合成The third step: 2-(2-chlorophenyl)-N-(methylaminothioformyl)-2-(5-(trifluoromethyl)pyridazin-3-yl)acetamide (I-15D )Synthesis
Figure PCTCN2022087589-appb-000131
Figure PCTCN2022087589-appb-000131
向2-(2-氯苯基)-2-(5-(三氟甲基)哒嗪-3-基)乙酰胺(I-15C)(450.0mg,1.43mmol)的N,N-二甲基甲酰胺(5.00mL)溶液中加入甲基异硫氰酸酯(156mg,2.14mmol)和碳酸铯(697mg,2.14mmol)，反应在室温搅拌10小时。反应完成后，将反应混合物用水(30.0mL)稀释，然后用乙酸乙酯(20.0mL*3)萃取，合并有机层，用饱和食盐水(30.0mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-10:1)得到黄色固体化合物2-(2-氯苯基)-N-(甲基氨基硫代甲酰基)-2-(5-(三氟甲基)哒嗪-3-基)乙酰胺(I-15D)(160mg,412μmol,产率28.9％)。To 2-(2-chlorophenyl)-2-(5-(trifluoromethyl)pyridazin-3-yl)acetamide (I-15C) (450.0 mg, 1.43 mmol) in N,N-dimethyl Methyl isothiocyanate (156 mg, 2.14 mmol) and cesium carbonate (697 mg, 2.14 mmol) were added to the methylformamide (5.00 mL) solution, and the reaction was stirred at room temperature for 10 hours. After the reaction was completed, the reaction mixture was diluted with water (30.0 mL), then extracted with ethyl acetate (20.0 mL*3), the organic layers were combined, washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated , the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-10:1) to obtain a yellow solid compound 2-(2-chlorophenyl)-N-(methylaminothio) formyl)-2-(5-(trifluoromethyl)pyridazin-3-yl)acetamide (I-15D) (160 mg, 412 μmol, 28.9% yield).
LC-MS,M/Z(ESI):389.0[M+H] + LC-MS, M/Z(ESI): 389.0[M+H] +
第四步：5-(2-氯苯基)-8-(甲基氨基)-3-(三氟甲基)-6H-嘧啶并[1,6-b]哒嗪-6-酮(I-15)的合成The fourth step: 5-(2-chlorophenyl)-8-(methylamino)-3-(trifluoromethyl)-6H-pyrimido[1,6-b]pyridazin-6-one (I -15) synthesis
Figure PCTCN2022087589-appb-000132
Figure PCTCN2022087589-appb-000132
向2-(2-氯苯基)-N-(甲基氨基硫代甲酰基)-2-(5-(三氟甲基)哒嗪-3-基)乙酰胺(I-15D)(160.0mg,412μmol)的四氢呋喃(3.00mL)溶液中加入碘单质(313.0mg,1.23mmol)和吡啶(97.7mg,1.23mmol)，反应在25℃搅拌10小时。反应完成后，将反应混合物用水(10.0mL)稀释，然后用乙酸乙酯(10.0mL*3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，残留物用层析板分离纯化(乙酸乙酯:甲醇(V/V)＝10:1)，得到黄色固体化合物5-(2-氯苯基)-8-(甲基氨基)-3-(三氟甲基)-6H-嘧啶并[1,6-b]哒嗪-6-酮(I-15)(5.20mg,14.5μmol,3.53％产率)。To 2-(2-chlorophenyl)-N-(methylcarbamoyl)-2-(5-(trifluoromethyl)pyridazin-3-yl)acetamide (I-15D) (160.0 mg, 412 μmol) in tetrahydrofuran (3.00 mL) was added elemental iodine (313.0 mg, 1.23 mmol) and pyridine (97.7 mg, 1.23 mmol), and the reaction was stirred at 25° C. for 10 hours. After the reaction was completed, the reaction mixture was diluted with water (10.0 mL), then extracted with ethyl acetate (10.0 mL*3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by chromatography ( Ethyl acetate:methanol (V/V)=10:1) to give a yellow solid compound 5-(2-chlorophenyl)-8-(methylamino)-3-(trifluoromethyl)-6H-pyrimidine [1,6-b]pyridazin-6-one (I-15) (5.20 mg, 14.5 μmol, 3.53% yield).
1H NMR(400MHz,DMSO_d 6):δ8.43(d,1H),8.15(br d,1H),7.53-7.62(m,1H),7.38-7.50(m,2H),7.28-7.35(m,1H),7.11(s,1H),2.90(d,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.43(d,1H), 8.15(br d,1H), 7.53-7.62(m,1H), 7.38-7.50(m,2H), 7.28-7.35(m ,1H),7.11(s,1H),2.90(d,3H).
LC-MS,M/Z(ESI):355.1[M+H] + LC-MS, M/Z(ESI): 355.1[M+H] +
实施例16：目标化合物I-16的制备Example 16: Preparation of target compound I-16
5-(2-氯苯基)-3-甲基-8-(甲基氨基)-6H-嘧啶并[1,6-b]哒嗪-6-酮(I-16)5-(2-Chlorophenyl)-3-methyl-8-(methylamino)-6H-pyrimido[1,6-b]pyridazin-6-one (I-16)
Figure PCTCN2022087589-appb-000133
Figure PCTCN2022087589-appb-000133
化合物I-16的合成路线参考I-15的合成方法，得到5-(2-氯苯基)-3-甲基-8-(甲基氨基)-6H-嘧啶并[1,6-b]哒嗪-6-酮(I-16)。The synthetic route of compound I-16 refers to the synthetic method of I-15 to obtain 5-(2-chlorophenyl)-3-methyl-8-(methylamino)-6H-pyrimido[1,6-b] Pyridazin-6-one (I-16).
LC-MS,M/Z(ESI):301.1[M+H] + LC-MS, M/Z(ESI): 301.1[M+H] +
实施例17：目标化合物I-17的制备Example 17: Preparation of target compound I-17
3-氯-5-(2-氯苯基)-8-(甲基氨基)-6H-嘧啶并[1,6-b]哒嗪-6-酮(I-17)3-Chloro-5-(2-chlorophenyl)-8-(methylamino)-6H-pyrimido[1,6-b]pyridazin-6-one (I-17)
Figure PCTCN2022087589-appb-000134
Figure PCTCN2022087589-appb-000134
化合物I-17的合成路线参考I-15的合成方法，得到3-氯-5-(2-氯苯基)-8-(甲基氨基)-6H-嘧啶并[1,6-b]哒嗪-6-酮(I-17)。The synthetic route of compound I-17 refers to the synthetic method of I-15 to obtain 3-chloro-5-(2-chlorophenyl)-8-(methylamino)-6H-pyrimido[1,6-b]pyridin Azin-6-one (I-17).
LC-MS,M/Z(ESI):321.0[M+H] + LC-MS, M/Z(ESI): 321.0[M+H] +
实施例18：目标化合物I-18的制备Example 18: Preparation of target compound I-18
5-(2-氯苯基)-3-环丙基-8-(甲氨基)-6H-嘧啶[1,6-b]哒嗪-6-酮(I-18)5-(2-Chlorophenyl)-3-cyclopropyl-8-(methylamino)-6H-pyrimidine[1,6-b]pyridazin-6-one (I-18)
Figure PCTCN2022087589-appb-000135
Figure PCTCN2022087589-appb-000135
化合物I-18的合成路线参考I-15的合成方法，得到5-(2-氯苯基)-3-环丙基-8-(甲氨基)-6H-嘧啶[1,6-b]哒嗪-6-酮(I-18)。The synthetic route of compound I-18 refers to the synthetic method of I-15 to obtain 5-(2-chlorophenyl)-3-cyclopropyl-8-(methylamino)-6H-pyrimidine[1,6-b]pyridin Azin-6-one (I-18).
LC-MS,M/Z(ESI):327.1[M+H] + LC-MS, M/Z(ESI): 327.1[M+H] +
实施例19：目标化合物I-19的制备Example 19: Preparation of target compound I-19
5-(2-氯苯基)-8-(环丙基氨基)-3-(三氟甲基)-6H-嘧啶[1,6-b]哒嗪-6-酮(I-19)5-(2-Chlorophenyl)-8-(cyclopropylamino)-3-(trifluoromethyl)-6H-pyrimidin[1,6-b]pyridazin-6-one (I-19)
Figure PCTCN2022087589-appb-000136
Figure PCTCN2022087589-appb-000136
化合物I-19的合成路线参考I-15的合成方法，得到5-(2-氯苯基)-8-(环丙基氨基)-3-(三氟甲基)-6H-嘧啶[1,6-b]哒嗪-6-酮(I-19)。The synthetic route of compound I-19 refers to the synthetic method of I-15 to obtain 5-(2-chlorophenyl)-8-(cyclopropylamino)-3-(trifluoromethyl)-6H-pyrimidine[1, 6-b]pyridazin-6-one (I-19).
LC-MS,M/Z(ESI):381.1[M+H] + LC-MS, M/Z(ESI): 381.1[M+H] +
实施例20：目标化合物I-20的制备Example 20: Preparation of target compound I-20
5-(2-氯苯基)-8-(3-羟基吡咯烷-1-基)-3-(三氟甲基)-6H-嘧啶基[1,6-b]哒嗪-6-酮(I-20)5-(2-Chlorophenyl)-8-(3-hydroxypyrrolidin-1-yl)-3-(trifluoromethyl)-6H-pyrimidinyl[1,6-b]pyridazin-6-one (I-20)
Figure PCTCN2022087589-appb-000137
Figure PCTCN2022087589-appb-000137
化合物I-20的合成路线参考I-15的合成方法，得到5-(2-氯苯基)-8-(3-羟基吡咯烷-1-基)-3-(三氟甲基)-6H-嘧啶基[1,6-b]哒嗪-6-酮(I-20)。The synthetic route of compound I-20 refers to the synthetic method of I-15 to obtain 5-(2-chlorophenyl)-8-(3-hydroxypyrrolidin-1-yl)-3-(trifluoromethyl)-6H - Pyrimidyl[1,6-b]pyridazin-6-one (I-20).
LC-MS,M/Z(ESI):411.1[M+H] + LC-MS, M/Z(ESI): 411.1[M+H] +
实施例21：目标化合物I-21的制备Example 21: Preparation of target compound I-21
9-(2-氯苯基)-6-(甲基氨基)-2-(三氟甲基)-8H-嘧啶[1,6-a]嘧啶-8-酮(I-21)9-(2-Chlorophenyl)-6-(methylamino)-2-(trifluoromethyl)-8H-pyrimidin[1,6-a]pyrimidin-8-one (I-21)
Figure PCTCN2022087589-appb-000138
Figure PCTCN2022087589-appb-000138
化合物I-21的合成路线参考I-2的合成方法，得到9-(2-氯苯基)-6-(甲基氨基)-2-(三氟甲基)-8H-嘧啶[1,6-a]嘧啶-8-酮(I-21)。The synthetic route of compound I-21 refers to the synthetic method of I-2 to obtain 9-(2-chlorophenyl)-6-(methylamino)-2-(trifluoromethyl)-8H-pyrimidine[1,6 -a]pyrimidin-8-one (I-21).
LC-MS,M/Z(ESI):355.1[M+H] + LC-MS, M/Z(ESI): 355.1[M+H] +
实施例22：目标化合物I-22的制备Example 22: Preparation of target compound I-22
4-(2-氯苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-嘧啶[1,6-c]嘧啶-3-酮(I-22)4-(2-Chlorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrimidin[1,6-c]pyrimidin-3-one (I-22)
Figure PCTCN2022087589-appb-000139
Figure PCTCN2022087589-appb-000139
化合物I-22的合成路线参考I-2的合成方法，得到4-(2-氯苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-嘧啶[1,6-c]嘧啶-3-酮(I-22)。The synthetic route of compound I-22 refers to the synthetic method of I-2 to obtain 4-(2-chlorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrimidine[1,6 -c]pyrimidin-3-one (I-22).
LC-MS,M/Z(ESI):355.1[M+H] + LC-MS, M/Z(ESI): 355.1[M+H] +
实施例23：目标化合物I-23的制备Example 23: Preparation of target compound I-23
4-(2-甲氧基吡啶-3-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-23)4-(2-Methoxypyridin-3-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I -twenty three)
Figure PCTCN2022087589-appb-000140
Figure PCTCN2022087589-appb-000140
目标化合物I-23的合成路线如下所示：The synthetic route of the target compound I-23 is as follows:
Figure PCTCN2022087589-appb-000141
Figure PCTCN2022087589-appb-000141
第一步：2-甲氧基吡啶-3-甲醛(I-23B)的合成The first step: the synthesis of 2-methoxypyridine-3-carbaldehyde (I-23B)
Figure PCTCN2022087589-appb-000142
Figure PCTCN2022087589-appb-000142
在室温下，将(2-甲氧基吡啶-3-基)甲醇(15.0g,108mmol)溶解到二氯甲烷(200mL)中，氮气保护下在0～10℃中分批加入戴斯-马丁氧化剂(54.9g，129mmol)，加完后25℃下反应2小时，反应液在0～10℃氮气保护下用饱和的硫代硫酸钠(500mL)淬灭，用二氯甲烷(200mL*2)萃取，合并有机相，用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝300:1-30:1)得到无色油状化合物2-甲氧基吡啶-3-甲醛(I-23B)(12.0g，产率81.2％)。At room temperature, (2-methoxypyridin-3-yl)methanol (15.0 g, 108 mmol) was dissolved in dichloromethane (200 mL), and Dess-Martin was added in portions at 0 to 10 °C under nitrogen protection. Oxidant (54.9g, 129mmol) was added and reacted at 25°C for 2 hours. The reaction solution was quenched with saturated sodium thiosulfate (500mL) under nitrogen protection at 0～10°C, and then diluted with dichloromethane (200mL*2). Extracted, combined the organic phases, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=300:1- 30:1) to give 2-methoxypyridine-3-carbaldehyde (I-23B) (12.0 g, 81.2% yield) as a colorless oily compound.
LC-MS,M/Z(ESI):138.2[M+H] + LC-MS, M/Z(ESI): 138.2[M+H] +
第二步：2-(2-甲氧基吡啶-3-基)乙腈(I-23C)的合成The second step: the synthesis of 2-(2-methoxypyridin-3-yl)acetonitrile (I-23C)
Figure PCTCN2022087589-appb-000143
Figure PCTCN2022087589-appb-000143
在室温下，将对甲基苯磺酰甲基异腈(6.26g，32.1mmol)溶解到乙二醇二甲醚(50mL)中，氮气保护下在-78～-65℃分批加入叔丁醇钾(6.55g，58.3mmol)，加完后-78～-65℃下反应1小时，然后在-78～-65℃下滴加2-甲氧基吡啶-3-甲醛(I-23B)(4.00g，29.2mmol)，加完后在-78～-65℃下反应0.5小时，然后加入甲醇(50mL)80℃下反应0.5小时。反应液0～25℃下用乙酸(200mL，2.0M)淬灭，用乙酸乙酯(100mL*2)萃取，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝300:1-30:1)得到黄色油状化合物(2-(2-甲氧基吡啶-3-基)乙腈(I-23C)(2.69g，产率67.1％)。At room temperature, p-toluenesulfonylmethylisonitrile (6.26 g, 32.1 mmol) was dissolved in ethylene glycol dimethyl ether (50 mL), and tert-butyl was added in portions at -78 to -65 °C under nitrogen protection. Potassium alkoxide (6.55g, 58.3mmol), react at -78～-65℃ for 1 hour after adding, then add 2-methoxypyridine-3-carbaldehyde (I-23B) dropwise at -78～-65℃ (4.00 g, 29.2 mmol), react at -78～-65°C for 0.5 hours after the addition, and then add methanol (50 mL) and react at 80°C for 0.5 hours. The reaction solution was quenched with acetic acid (200 mL, 2.0 M) at 0~25 °C, extracted with ethyl acetate (100 mL*2), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated The crude product was obtained, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=300:1-30:1) to obtain a yellow oily compound (2-(2-methoxypyridin-3-yl)) Acetonitrile (I-23C) (2.69 g, 67.1% yield).
LC-MS,M/Z(ESI):149.2[M+H] + LC-MS, M/Z(ESI): 149.2[M+H] +
第三步：2-(2-甲氧基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-23D)的合成The third step: Synthesis of 2-(2-methoxypyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-23D)
Figure PCTCN2022087589-appb-000144
Figure PCTCN2022087589-appb-000144
在室温下，将2-(2-甲氧基吡啶-3-基)乙腈(I-23C)(2.87g，1.94mmol)加入到1-甲基-2-吡咯烷酮(70mL)中，氮气保护下加入2-溴-4-(三氟甲基)吡啶(4.82g，21.3mmol)，加完后90℃下搅拌反应8小时，将反应液加入到水(300mL)中淬灭，用乙酸乙酯(100mL*2)萃取，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-10:1)得到黄色油状化合物2-(2-甲氧基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-23D)(4.40g，产率77.5％)。2-(2-Methoxypyridin-3-yl)acetonitrile (I-23C) (2.87 g, 1.94 mmol) was added to 1-methyl-2-pyrrolidone (70 mL) at room temperature under nitrogen 2-Bromo-4-(trifluoromethyl)pyridine (4.82 g, 21.3 mmol) was added, and the reaction was stirred at 90° C. for 8 hours after the addition, and the reaction solution was added to water (300 mL) to quench, and ethyl acetate was used for quenching. (100mL*2) extraction, the organic phases were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V) =50:1-10:1) to obtain a yellow oily compound 2-(2-methoxypyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-23D ) (4.40 g, 77.5% yield).
LC-MS,M/Z(ESI):294.1[M+H] + LC-MS, M/Z(ESI): 294.1[M+H] +
第四步：2-(2-甲氧基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-23E)The fourth step: 2-(2-methoxypyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-23E)
Figure PCTCN2022087589-appb-000145
Figure PCTCN2022087589-appb-000145
在室温下，氮气保护下将2-(2-甲氧基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-23D)(3.00g,10.2mmol)加入到浓硫酸(30mL)中，25℃下搅拌反应5小时，反应液0～10℃下加入到饱和的碳酸氢钠溶液(400mL)中，用乙酸乙酯(50mL*2)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-3:1)得到黄色固体化合物(2-(2-甲氧基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-23E)(1.10g,产率34.5％)。2-(2-Methoxypyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-23D) (3.00 g, 10.2 mmol) was added to concentrated sulfuric acid (30 mL), stirred at 25 °C for 5 hours, the reaction solution was added to saturated sodium bicarbonate solution (400 mL) at 0 to 10 °C, and extracted with ethyl acetate (50 mL*2). , the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-3 : 1) yellow solid compound (2-(2-methoxypyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-23E) (1.10g) was obtained , the yield is 34.5%).
LC-MS,/Z(ESI):312.2[M+H] + LC-MS, /Z(ESI): 312.2[M+H] +
第五步：2-(2-甲氧基吡啶-3-基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-23F)的合成The fifth step: 2-(2-methoxypyridin-3-yl)-N-(methylaminothioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide Synthesis of (I-23F)
Figure PCTCN2022087589-appb-000146
Figure PCTCN2022087589-appb-000146
氮气保护下，将(2-(2-甲氧基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-23E)(100.0mg，321.0μmol)和甲基异硫氰酸酯(23.5mg,321.0μmol)，碳酸铯(209.2mg,642μmol)加入到四氢呋喃(2mL)中，加完后60℃下搅拌反应2小时，反应液过滤，浓缩得到粗品，粗品通过薄层色谱纯化(石油醚：乙酸乙酯＝2:1)得到黄色固体2-(2-甲氧基吡啶-3-基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-23F)(20.0mg,产率16.2％)。Under nitrogen protection, (2-(2-methoxypyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-23E) (100.0 mg, 321.0 μmol) and methyl isothiocyanate (23.5 mg, 321.0 μmol), cesium carbonate (209.2 mg, 642 μmol) were added to tetrahydrofuran (2 mL), and the reaction was stirred at 60 °C for 2 hours after the addition, and the reaction solution was filtered and concentrated. The crude product was obtained, and the crude product was purified by thin layer chromatography (petroleum ether:ethyl acetate=2:1) to obtain 2-(2-methoxypyridin-3-yl)-N-(methylaminothiocarbonyl) as a yellow solid -2-(4-(Trifluoromethyl)pyridin-2-yl)acetamide (I-23F) (20.0 mg, 16.2% yield).
LC-MS,M/Z(ESI):385.1[M+H] + LC-MS, M/Z(ESI): 385.1[M+H] +
第六步：4-(2-甲氧基吡啶-3-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-23)Step 6: 4-(2-Methoxypyridin-3-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 - Ketone (I-23)
Figure PCTCN2022087589-appb-000147
Figure PCTCN2022087589-appb-000147
在氮气保护下，将2-(2-甲氧基吡啶-3-基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-23F)(20.0mg,52.0μmol)，碘(39.6mg,156μmol)和吡啶(12.4mg,156.0μmol)加入到四氢呋喃(1mL)中，加完后25℃下搅拌反应6小时，反应液浓缩得到粗品。然后粗品经反相制备(柱子:Phenomenex Synergi C 18 100*25mm*4μm；溶剂：A＝水+0.1体积％三氟乙酸(99％)，B＝乙腈；梯度：29％-49％，7分钟)得到目标化合物4-(2-甲氧基吡啶-3-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-23)(6.61mg，产率35.3％)。 Under nitrogen protection, 2-(2-methoxypyridin-3-yl)-N-(methylaminothiocarbonyl)-2-(4-(trifluoromethyl)pyridin-2-yl) Acetamide (I-23F) (20.0 mg, 52.0 μmol), iodine (39.6 mg, 156 μmol) and pyridine (12.4 mg, 156.0 μmol) were added to tetrahydrofuran (1 mL), and the reaction was stirred at 25° C. for 6 hours after the addition. The reaction solution was concentrated to obtain crude product. The crude product was then prepared by reverse phase (column: Phenomenex Synergi C 18 100*25mm*4μm; solvent: A=water+0.1 vol% trifluoroacetic acid (99%), B=acetonitrile; gradient: 29%-49%, 7 minutes ) to obtain the target compound 4-(2-methoxypyridin-3-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 - Ketone (I-23) (6.61 mg, 35.3% yield).
1H NMR(400MHz,CDCl 3):δ8.74(d,1H),8.28(d,1H),7.60(d,1H),7.11(s,1H),7.04(q, 1H),6.82(d,1H),3.86(s,3H),3.03(s,3H). 1 H NMR (400 MHz, CDCl 3 ): δ 8.74(d, 1H), 8.28(d, 1H), 7.60(d, 1H), 7.11(s, 1H), 7.04(q, 1H), 6.82(d ,1H),3.86(s,3H),3.03(s,3H).
LC-MS,M/Z(ESI):351.2[M+H] + LC-MS, M/Z(ESI): 351.2[M+H] +
实施例24：目标化合物I-24的制备Example 24: Preparation of target compound I-24
4-(2-氯吡啶-3-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-24)4-(2-Chloropyridin-3-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-24 )
Figure PCTCN2022087589-appb-000148
Figure PCTCN2022087589-appb-000148
目标化合物I-24的合成路线如下所示：The synthetic route of the target compound I-24 is as follows:
Figure PCTCN2022087589-appb-000149
Figure PCTCN2022087589-appb-000149
第一步：4-(2-羟基吡啶-3-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-23A)的合成The first step: 4-(2-hydroxypyridin-3-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one Synthesis of (I-23A)
Figure PCTCN2022087589-appb-000150
Figure PCTCN2022087589-appb-000150
在室温下，将4-(2-甲氧基吡啶-3-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-23)(200.0mg,571.0μmol)加入到浓盐酸(20mL)中，氮气保护下在75℃反应8小时，反应液浓缩得到粗品。粗品用高效液相色谱仪分离纯化，分离方法为(柱子:Phenomenex Synergi C 18 150*40mm*15μm；溶剂：A＝水+0.1体积％三氟乙酸(99％)，B＝乙腈；梯度：2％-32％，10分钟)制备得到黄色固体化合物4-(2-羟基吡啶-3-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-24A)(60.0mg，产率31.3％)。 At room temperature, 4-(2-methoxypyridin-3-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine- 3-keto (I-23) (200.0 mg, 571.0 μmol) was added to concentrated hydrochloric acid (20 mL), reacted at 75° C. for 8 hours under nitrogen protection, and the reaction solution was concentrated to obtain the crude product. The crude product was separated and purified by high performance liquid chromatography, and the separation method was (column: Phenomenex Synergi C 18 150*40mm*15μm; solvent: A=water+0.1 vol% trifluoroacetic acid (99%), B=acetonitrile; gradient: 2 %-32%, 10 minutes) to prepare a yellow solid compound 4-(2-hydroxypyridin-3-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1, 2-c]pyrimidin-3-one (I-24A) (60.0 mg, 31.3% yield).
LC-MS,M/Z(ESI):337.1[M+H] + LC-MS, M/Z(ESI): 337.1[M+H] +
第二步：4-(2-氯吡啶-3-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-24)Step 2: 4-(2-Chloropyridin-3-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-24)
Figure PCTCN2022087589-appb-000151
Figure PCTCN2022087589-appb-000151
在氮气保护下，将4-(2-羟基吡啶-3-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3- 酮(I-24A)(50.0mg,149.0μmol)溶于乙腈(1mL)中，氮气保护下20～25℃下加入三氯氧磷(27.4mg,178.0μmol)加完后25℃下搅拌反应6小时，反应液加入0～10℃加入到饱和碳酸氢钠溶液(10mL)中，二氯甲烷(30.0mL*3)萃取，无水硫酸钠干燥，过滤浓缩得到粗品。粗品用高效液相色谱仪分离纯化，分离方法为(柱子:Phenomenex Synergi C18 100*25mm*4μm；溶剂：A＝水+0.1体积％三氟乙酸(99％)，B＝乙腈；梯度：29％-49％B，7分钟)得到目标化合物4-(2-氯吡啶-3-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-24)(24.5mg，产率43.1％)。Under nitrogen protection, 4-(2-hydroxypyridin-3-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 - Ketone (I-24A) (50.0mg, 149.0μmol) was dissolved in acetonitrile (1mL), phosphorus oxychloride (27.4mg, 178.0μmol) was added under nitrogen protection at 20～25℃, and the reaction was stirred at 25℃ After 6 hours, the reaction solution was added to saturated sodium bicarbonate solution (10 mL) at 0-10 °C, extracted with dichloromethane (30.0 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was separated and purified by high performance liquid chromatography, and the separation method was (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A=water+0.1% by volume trifluoroacetic acid (99%), B=acetonitrile; gradient: 29% -49%B, 7 min) to give the target compound 4-(2-chloropyridin-3-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2- c] Pyrimidine-3-one (I-24) (24.5 mg, 43.1% yield).
1H NMR(400MHz,CDCl 3):δ8.98-9.00(m,1H),8.55(d,1H),7.61-7.77(m,1H),7.46-7.49(m,1H),7.10(s,1H),7.03(s,1H),3.09(s,3H). 1 H NMR (400 MHz, CDCl 3 ): δ 8.98-9.00 (m, 1H), 8.55 (d, 1H), 7.61-7.77 (m, 1H), 7.46-7.49 (m, 1H), 7.10 (s, 1H), 7.03(s, 1H), 3.09(s, 3H).
LC-MS,M/Z(ESI):355.1[M+H] + LC-MS, M/Z(ESI): 355.1[M+H] +
实施例25：目标化合物I-25的制备Example 25: Preparation of target compound I-25
4-(2,6-二甲基苯基)-1-(甲基氨基)-6-(三氟甲基)-3H–吡啶并[1,2-c]嘧啶-3-酮(I-25)4-(2,6-Dimethylphenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I- 25)
Figure PCTCN2022087589-appb-000152
Figure PCTCN2022087589-appb-000152
目标化合物I-25的合成路线如下所示：The synthetic route of the target compound I-25 is as follows:
Figure PCTCN2022087589-appb-000153
Figure PCTCN2022087589-appb-000153
第一步：2-(2,6-二甲基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-25B)的合成The first step: Synthesis of 2-(2,6-dimethylphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-25B)
Figure PCTCN2022087589-appb-000154
Figure PCTCN2022087589-appb-000154
将2-溴-4-(三氟甲基)吡啶(0.64g,4.42mmol),2-(2,6-二甲基苯基)乙腈(1.0g,4.42mmol)溶解在四氢呋喃(10mL)中，置换氮气，然后慢慢滴加叔丁醇钾的四氢呋喃溶液(6.64mL,6.64mmol,1M)室温下反应3h。用饱和的氯化铵溶液(20mL)淬灭反应，乙酸乙酯(20mL)萃取两次，分离干燥有机相，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝5/1)得到2-(2,6-二甲基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-25B)(1.1g，产率85％)。2-Bromo-4-(trifluoromethyl)pyridine (0.64 g, 4.42 mmol), 2-(2,6-dimethylphenyl)acetonitrile (1.0 g, 4.42 mmol) were dissolved in tetrahydrofuran (10 mL) , nitrogen was replaced, and then a solution of potassium tert-butoxide in tetrahydrofuran (6.64 mL, 6.64 mmol, 1 M) was slowly added dropwise to react at room temperature for 3 h. The reaction was quenched with saturated ammonium chloride solution (20 mL), extracted twice with ethyl acetate (20 mL), the organic phase was separated and dried, and the crude product was obtained by spin drying. The crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=5/ 1) 2-(2,6-dimethylphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-25B) (1.1 g, 85% yield) was obtained.
LC-MS,M/Z(ESI):291.1[M+H] + LC-MS, M/Z(ESI): 291.1[M+H] +
第二步：2-(2,6-二甲基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-25C)的合成The second step: Synthesis of 2-(2,6-dimethylphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-25C)
Figure PCTCN2022087589-appb-000155
Figure PCTCN2022087589-appb-000155
把2-(2,6-二甲基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-25B)(0.8g,2.76mmol)溶到浓硫酸(5mL)中，置换空气，室温搅拌14h。把反应液缓慢倒入冰水(50mL)中，然后乙酸乙酯(20mL)萃取两次，有机相合并再用饱和碳酸氢钠溶液(100mL)洗一次，分离干燥有机相，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝30/1)得到2-(2,6-二甲基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-25C)(0.6g,产率70.5％)。Dissolve 2-(2,6-dimethylphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-25B) (0.8 g, 2.76 mmol) in concentrated sulfuric acid ( 5mL), replace the air, and stir at room temperature for 14h. The reaction solution was slowly poured into ice water (50 mL), then extracted twice with ethyl acetate (20 mL), the organic phases were combined and washed once with saturated sodium bicarbonate solution (100 mL), the organic phase was separated and dried, and spin-dried to obtain the crude product, The crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=30/1) to obtain 2-(2,6-dimethylphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl) Acetamide (I-25C) (0.6 g, 70.5% yield).
LC-MS,M/Z(ESI):309.1[M+H] + LC-MS, M/Z(ESI): 309.1[M+H] +
第三步：2-(2,6-二甲基苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-25D)的合成The third step: 2-(2,6-dimethylphenyl)-N-(methylaminothioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide ( I-25D) synthesis
Figure PCTCN2022087589-appb-000156
Figure PCTCN2022087589-appb-000156
将2-(2,6-二甲基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-25C)(500mg,1.62mmol)和碳酸铯(1.05g,3.24mmol)溶到N,N-二甲基甲酰胺(5mL)中，置换氮气，缓慢加入异硫氰酸甲酯(119mg,1.622mmol)，在室温下搅拌6h。食盐水(20mL)淬灭反应，乙酸乙酯(20mL)萃取两次，分离干燥有机相，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1)得到2-(2,6-二甲基苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-25D)(450mg,产率72.6％)。2-(2,6-Dimethylphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-25C) (500 mg, 1.62 mmol) and cesium carbonate (1.05 g, 3.24 mmol) was dissolved in N,N-dimethylformamide (5 mL), nitrogen was replaced, methyl isothiocyanate (119 mg, 1.622 mmol) was slowly added, and the mixture was stirred at room temperature for 6 h. The reaction was quenched with brine (20 mL), extracted twice with ethyl acetate (20 mL), the organic phase was separated and dried, and the crude product was obtained by spin drying. The crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to obtain 2- (2,6-Dimethylphenyl)-N-(methylcarbamoyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-25D) (450 mg , the yield is 72.6%).
LC-MS,M/Z(ESI):382.1[M+H] + LC-MS, M/Z(ESI): 382.1[M+H] +
第四步：4-(2,6-二甲基苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-25)的合成Step 4: 4-(2,6-Dimethylphenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3- Synthesis of Ketone (I-25)
Figure PCTCN2022087589-appb-000157
Figure PCTCN2022087589-appb-000157
将2-(2,6-二甲基苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(120mg，0.32mmol)和吡啶(74.7mg，0.944mmol)溶到四氢呋喃(10mL)中，置换氮气，降温到0℃，将碘单质(240mg,0.944mmol)慢慢加入反应液。在室温下搅拌14h。用饱和的硫代硫酸钠溶液(100mL)淬灭反应，乙酸乙酯(10mL)萃取3次，有机相合并旋干，得到粗品，粗品用乙酸乙酯重结晶得到4-(2,6-二甲基苯基)-1-(甲氨基)-6-(三氟甲基)-3H-吡啶[1,2-c]嘧啶-3-酮(I-25)(17mg,产率16％)。2-(2,6-Dimethylphenyl)-N-(methylcarbamoyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (120 mg, 0.32 mmol) and pyridine (74.7 mg, 0.944 mmol) were dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, the temperature was lowered to 0 °C, and elemental iodine (240 mg, 0.944 mmol) was slowly added to the reaction solution. Stir at room temperature for 14h. The reaction was quenched with saturated sodium thiosulfate solution (100 mL), extracted 3 times with ethyl acetate (10 mL), and the organic phases were combined and spun to dry to obtain a crude product, which was recrystallized from ethyl acetate to obtain 4-(2,6-bismuth) Methylphenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyridin[1,2-c]pyrimidin-3-one (I-25) (17 mg, 16% yield) .
1H NMR(400MHz,DMSO-d 6)δ8.05(d,J＝7.8Hz,1H),7.96(s,1H),7.19-7.13(m,1H),7.10(d,J＝7.4Hz,2H),6.65(dd,J＝7.8,1.8Hz,1H),6.38(s,1H),2.89(s,3H),1.94(s,6H). 1 H NMR (400MHz, DMSO-d 6 )δ8.05(d,J=7.8Hz,1H),7.96(s,1H),7.19-7.13(m,1H),7.10(d,J=7.4Hz, 2H), 6.65(dd, J=7.8, 1.8Hz, 1H), 6.38(s, 1H), 2.89(s, 3H), 1.94(s, 6H).
LC-MS,M/Z(ESI):348.1[M+H] + LC-MS, M/Z(ESI): 348.1[M+H] +
实施例26：目标化合物I-26的制备Example 26: Preparation of target compound I-26
1-(甲氨基)-4-(对甲苯基)-6-(三氟甲基)-3H-吡啶[1,2-c]嘧啶-3-酮(I-26)1-(Methylamino)-4-(p-tolyl)-6-(trifluoromethyl)-3H-pyridin[1,2-c]pyrimidin-3-one (I-26)
Figure PCTCN2022087589-appb-000158
Figure PCTCN2022087589-appb-000158
目标化合物I-26的合成路线如下所示：The synthetic route of the target compound I-26 is shown below:
Figure PCTCN2022087589-appb-000159
Figure PCTCN2022087589-appb-000159
第一步：2-(对甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-26B)的合成The first step: Synthesis of 2-(p-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-26B)
Figure PCTCN2022087589-appb-000160
Figure PCTCN2022087589-appb-000160
将2-溴-4-(三氟甲基)吡啶(0.58g,4.42mmol)，对甲基苯乙腈(1.0g,4.42mmol)溶解在四氢呋喃(10mL)中，置换氮气，然后慢慢滴加叔丁醇钾的四氢呋喃溶液(5.31mL，5.31mmol，1M)室温下反应3h。用饱和的氯化铵溶液(20mL)淬灭反应，乙酸乙酯(20mL)萃取两次，分离干燥有机相，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝50/1)得到2-(对甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-26B)(1.1g，产率90％)。2-Bromo-4-(trifluoromethyl)pyridine (0.58 g, 4.42 mmol), p-tolyl acetonitrile (1.0 g, 4.42 mmol) were dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, and then slowly added dropwise A solution of potassium tert-butoxide in tetrahydrofuran (5.31 mL, 5.31 mmol, 1 M) was reacted at room temperature for 3 h. The reaction was quenched with saturated ammonium chloride solution (20 mL), extracted twice with ethyl acetate (20 mL), the organic phase was separated and dried, and the crude product was obtained by spin drying. The crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=50/ 1) 2-(p-Tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-26B) (1.1 g, 90% yield) was obtained.
LC-MS,M/Z(ESI):277.1[M+H] + LC-MS, M/Z(ESI): 277.1[M+H] +
第二步：2-(对甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-26C)的合成The second step: Synthesis of 2-(p-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-26C)
Figure PCTCN2022087589-appb-000161
Figure PCTCN2022087589-appb-000161
把2-(对甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-26B)(0.5g，1.8mmol)溶到浓硫酸(5mL)中，置换空气，室温搅拌14h。把反应液缓慢倒入冰水(50mL)中，然后乙酸乙酯(20mL)萃取两次，有机相合并再用饱和碳酸氢钠溶液(100mL)洗一次，分离干燥有机相，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1)得到2-(对甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-26C)(0.3g,产率56.2％)。Dissolve 2-(p-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-26B) (0.5 g, 1.8 mmol) in concentrated sulfuric acid (5 mL) and replace air , stirred at room temperature for 14h. The reaction solution was slowly poured into ice water (50 mL), then extracted twice with ethyl acetate (20 mL), the organic phases were combined and washed once with saturated sodium bicarbonate solution (100 mL), the organic phase was separated and dried, and spin-dried to obtain the crude product, The crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to obtain 2-(p-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-26C ) (0.3 g, 56.2% yield).
LC-MS,M/Z(ESI):295.1[M+H] + LC-MS, M/Z(ESI): 295.1[M+H] +
第三步：N-(甲基氨基硫代甲酰基)-2-(对甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-26D)的合成The third step: synthesis of N-(methylaminothioformyl)-2-(p-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-26D)
Figure PCTCN2022087589-appb-000162
Figure PCTCN2022087589-appb-000162
将2-(对甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-26C)(1.0g,3.4mmol)和碳酸铯(2.21g,6.8mmol)溶到N,N-二甲基甲酰胺(5mL)中，置换氮气，降温到0℃，慢慢滴加异硫氰酸甲酯(0.248g，3.4mmol)，在室温下搅拌14h。食盐水(20mL)淬灭反应，乙酸乙酯(20mL)萃取两次，分离干燥有机相，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1)得到N-(甲基氨基硫代甲酰基)-2-(对甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-26D)(762mg,产率58.8％)。Combine 2-(p-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-26C) (1.0 g, 3.4 mmol) and cesium carbonate (2.21 g, 6.8 mmol) It was dissolved in N,N-dimethylformamide (5 mL), nitrogen was replaced, the temperature was lowered to 0 °C, methyl isothiocyanate (0.248 g, 3.4 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 14 h. The reaction was quenched with brine (20 mL), extracted twice with ethyl acetate (20 mL), the organic phase was separated and dried, and spin-dried to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to obtain N- (Methylcarbamoyl)-2-(p-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-26D) (762 mg, 58.8% yield) .
LC-MS,M/Z(ESI):368.1[M+H] + LC-MS, M/Z(ESI): 368.1[M+H] +
第四步：1-(甲氨基)-4-(对甲苯基)-6-(三氟甲基)-3H-吡啶[1,2-c]嘧啶-3-酮(I-26)的合成The fourth step: Synthesis of 1-(methylamino)-4-(p-tolyl)-6-(trifluoromethyl)-3H-pyridine[1,2-c]pyrimidin-3-one (I-26)
Figure PCTCN2022087589-appb-000163
Figure PCTCN2022087589-appb-000163
将N-(甲基氨基硫代甲酰基)-2-(对甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-26D)(762mg，2.072mmol)和吡啶(492mg,6.22mmol)溶到四氢呋喃(10mL)中，置换氮气，降温到0℃，将碘单质(1.5g,6.22mmol)慢慢加入反应液。在室温下搅拌14h。用饱和的硫代硫酸钠(100mL)淬灭反应，乙酸乙酯(100mL)萃取3次，有机相合并旋干，得到粗品，粗品用乙酸乙酯重结晶得到1-(甲氨基)-4-(对甲苯基)-6-(三氟甲基)-3H-吡啶[1,2-c]嘧啶-3-酮(I-26)(71mg,产率10％)。N-(methylcarbamoyl)-2-(p-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-26D) (762 mg, 2.072 mmol ) and pyridine (492 mg, 6.22 mmol) were dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, the temperature was lowered to 0 °C, and elemental iodine (1.5 g, 6.22 mmol) was slowly added to the reaction solution. Stir at room temperature for 14h. The reaction was quenched with saturated sodium thiosulfate (100 mL), extracted three times with ethyl acetate (100 mL), and the organic phases were combined and spun dry to obtain a crude product, which was recrystallized from ethyl acetate to obtain 1-(methylamino)-4- (p-Tolyl)-6-(trifluoromethyl)-3H-pyridin[1,2-c]pyrimidin-3-one (I-26) (71 mg, 10% yield).
1H NMR(400MHz,DMSO-d 6)δ7.97(d,J＝7.6Hz,1H),7.92(s,1H),7.22(d,J＝7.9Hz,2H),7.13(d,J＝7.9Hz,2H),6.97(s,1H),6.61(d,J＝7.3Hz,1H),2.86(s,3H),2.33(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.97 (d, J=7.6 Hz, 1H), 7.92 (s, 1H), 7.22 (d, J=7.9 Hz, 2H), 7.13 (d, J= 7.9Hz, 2H), 6.97(s, 1H), 6.61(d, J=7.3Hz, 1H), 2.86(s, 3H), 2.33(s, 3H).
LC-MS,M/Z(ESI):334.1[M+H] + LC-MS, M/Z(ESI): 334.1[M+H] +
实施例27：目标化合物I-27的制备Example 27: Preparation of target compound I-27
1-(甲基氨基)-4-(间甲苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-27)1-(Methylamino)-4-(m-tolyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-27)
Figure PCTCN2022087589-appb-000164
Figure PCTCN2022087589-appb-000164
目标化合物I-27的合成路线如下所示：The synthetic route of the target compound I-27 is shown below:
Figure PCTCN2022087589-appb-000165
Figure PCTCN2022087589-appb-000165
第一步:2-(间甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-27B)的合成The first step: the synthesis of 2-(m-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-27B)
Figure PCTCN2022087589-appb-000166
Figure PCTCN2022087589-appb-000166
将2-溴-4-(三氟甲基)吡啶(1g,4.42mmol)，间甲苯乙腈(0.58g,4.42mmol)溶解在四氢呋喃(10mL)中，置换氮气，反应降温至0℃,然后慢慢滴加叔丁醇钾的四氢呋喃溶液(4.87mL，4.87mmol，1M)，反应升至室温下反应3h。用饱和的氯化铵溶液(20mL)淬灭反应，乙酸乙酯(20mL*2)萃取两次，合并有机相，用无水硫酸钠干燥，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝5/1)得到2-(间甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-27B)(0.8g，产率65％)。2-Bromo-4-(trifluoromethyl)pyridine (1 g, 4.42 mmol), m-toluene acetonitrile (0.58 g, 4.42 mmol) were dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, the reaction was cooled to 0 ° C, and then slowly A solution of potassium tert-butoxide in tetrahydrofuran (4.87 mL, 4.87 mmol, 1 M) was slowly added dropwise, and the reaction was warmed to room temperature for 3 h. The reaction was quenched with saturated ammonium chloride solution (20 mL), extracted twice with ethyl acetate (20 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was separated and purified by silica gel column (petroleum ether/ethyl acetate=5/1) to give 2-(m-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-27B) (0.8 g, 65% yield) ).
LC-MS,M/Z(ESI):277.1[M+H] + LC-MS, M/Z(ESI): 277.1[M+H] +
第二步:2-(间甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-27C)的合成Step 2: Synthesis of 2-(m-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-27C)
Figure PCTCN2022087589-appb-000167
Figure PCTCN2022087589-appb-000167
把2-(间甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-27B)(0.8g，2.9mmol)溶到浓硫酸(5mL)中，置换氮气，室温搅拌14h。把反应液缓慢倒入冰水(30mL)中，然后乙酸乙酯(20mL*2)萃取两次，有机相合并再用饱和碳酸氢钠溶液(50mL)洗涤，合并有机相，用无水硫酸钠干燥，旋干得到2-(间甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-27C)(0.85g,产率100％)。Dissolve 2-(m-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-27B) (0.8 g, 2.9 mmol) in concentrated sulfuric acid (5 mL), replacing nitrogen , stirred at room temperature for 14h. The reaction solution was slowly poured into ice water (30 mL), then extracted twice with ethyl acetate (20 mL*2), the organic phases were combined and washed with saturated sodium bicarbonate solution (50 mL), the organic phases were combined, and anhydrous sodium sulfate was used for washing. Dry and spin dry to give 2-(m-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-27C) (0.85 g, 100% yield).
LC-MS,M/Z(ESI):295.1[M+H] +。 LC-MS, M/Z (ESI): 295.1 [M+H] + .
第三步：N-(甲基氨基硫代甲酰基)-2-(间甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-27D)的合成The third step: synthesis of N-(methylaminothioformyl)-2-(m-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-27D)
Figure PCTCN2022087589-appb-000168
Figure PCTCN2022087589-appb-000168
将2-(间甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-27C)(400mg，1.36mmol)和碳酸铯(886mg，2.72mmol)溶到N,N-二甲基甲酰胺(4mL)中，置换氮气，缓慢加入异硫氰酸甲酯(149mg，2.0mmol)，在室温下搅拌6h。加水(20mL)淬灭反应，乙酸乙酯(20mL*2)萃取两次，合并有机相，并用食盐水洗涤(20mL*3)，有机相用无水硫酸钠干燥，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1)得到N-(甲基氨基硫代甲酰基)-2-(间甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-27D)(330mg,产率66％)。2-(m-Tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-27C) (400 mg, 1.36 mmol) and cesium carbonate (886 mg, 2.72 mmol) were dissolved in In N,N-dimethylformamide (4 mL), nitrogen was replaced, methyl isothiocyanate (149 mg, 2.0 mmol) was slowly added, and the mixture was stirred at room temperature for 6 h. Water (20 mL) was added to quench the reaction, extracted twice with ethyl acetate (20 mL*2), the organic phases were combined and washed with brine (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was passed through Silica gel column separation and purification (petroleum ether/ethyl acetate=10/1) to obtain N-(methylaminothioformyl)-2-(m-tolyl)-2-(4-(trifluoromethyl)pyridine- 2-yl)acetamide (I-27D) (330 mg, 66% yield).
LC-MS,M/Z(ESI):368.1[M+H] +。 LC-MS, M/Z (ESI): 368.1 [M+H] + .
第四步：1-(甲基氨基)-4-(间甲苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-27)的合成The fourth step: 1-(methylamino)-4-(m-tolyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-27) Synthesis
Figure PCTCN2022087589-appb-000169
Figure PCTCN2022087589-appb-000169
将N-(甲基氨基硫代甲酰基)-2-(间甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-27D)(330mg，0.90mmol)和吡啶(213mg，2.69mmol)溶到四氢呋喃(10mL)中，置换氮气，降温到0℃，将碘单质(684mg，2.69mmol)慢慢加入反应液。在室温下搅拌14h。用饱和的硫代硫酸钠(50mL)淬灭反应，乙酸乙酯(50mL*2)萃取，合并有机相，用无水硫酸钠干燥，旋干得到粗品，粗品用乙酸乙酯重结晶得到1-(甲基氨基)-4-(间甲苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-27)(110mg,产率37％)。N-(methylcarbamoyl)-2-(m-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-27D) (330 mg, 0.90 mmol ) and pyridine (213 mg, 2.69 mmol) were dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, the temperature was lowered to 0°C, and elemental iodine (684 mg, 2.69 mmol) was slowly added to the reaction solution. Stir at room temperature for 14h. The reaction was quenched with saturated sodium thiosulfate (50 mL), extracted with ethyl acetate (50 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was recrystallized from ethyl acetate to obtain 1- (Methylamino)-4-(m-tolyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-27) (110 mg, yield 37 %).
1H NMR(400MHz,dmso)δ7.96(d,J＝7.7Hz,1H),7.45–7.18(m,1H),7.15(d,J＝8.0Hz,1H),7.05(s,1H),7.00(d,J＝7.1Hz,1H),6.94(s,1H),6.61(d,J＝6.5Hz,1H),2.86(s,3H),2.30(s,3H). 1 H NMR(400MHz,dmso)δ7.96(d,J=7.7Hz,1H),7.45-7.18(m,1H),7.15(d,J=8.0Hz,1H),7.05(s,1H), 7.00(d, J=7.1Hz, 1H), 6.94(s, 1H), 6.61(d, J=6.5Hz, 1H), 2.86(s, 3H), 2.30(s, 3H).
LC-MS,M/Z(ESI):334.1[M+H] +。 LC-MS, M/Z (ESI): 334.1 [M+H] + .
实施例28：目标化合物I-28的制备Example 28: Preparation of target compound I-28
1-(乙基氨基)-4-(间甲苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-28)1-(Ethylamino)-4-(m-tolyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-28)
Figure PCTCN2022087589-appb-000170
Figure PCTCN2022087589-appb-000170
目标化合物I-28的合成路线如下所示：The synthetic route of the target compound I-28 is as follows:
Figure PCTCN2022087589-appb-000171
Figure PCTCN2022087589-appb-000171
第一步：N-(乙基氨基硫代甲酰基)-2-(间甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-28A)的合成The first step: Synthesis of N-(ethylaminothioformyl)-2-(m-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-28A)
Figure PCTCN2022087589-appb-000172
Figure PCTCN2022087589-appb-000172
将2-(间甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-27C)(500mg，1.7mmol)和碳酸铯(1.1g，3.4mmol)溶到N,N-二甲基甲酰胺(5mL)中，置换氮气，缓慢加入异硫氰酸乙酯(222mg，2.6mmol)，在室温下搅拌6h。加水(20mL)淬灭反应，乙酸乙酯(20mL*2)萃取两次，合并有机相，并用食盐水洗涤(20mL*3)，有机相用无水硫酸钠干燥，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1)得到N-(乙基氨基硫代甲酰基)-2-(间甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-28A)(380mg，产率59％)。Dissolve 2-(m-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-27C) (500 mg, 1.7 mmol) and cesium carbonate (1.1 g, 3.4 mmol) In N,N-dimethylformamide (5 mL), nitrogen was replaced, ethyl isothiocyanate (222 mg, 2.6 mmol) was slowly added, and the mixture was stirred at room temperature for 6 h. Water (20 mL) was added to quench the reaction, extracted twice with ethyl acetate (20 mL*2), the organic phases were combined and washed with brine (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was passed through Silica gel column separation and purification (petroleum ether/ethyl acetate=10/1) to obtain N-(ethylaminothioformyl)-2-(m-tolyl)-2-(4-(trifluoromethyl)pyridine- 2-yl)acetamide (I-28A) (380 mg, 59% yield).
LC-MS,M/Z(ESI):382.1[M+H] + LC-MS, M/Z(ESI): 382.1[M+H] +
第二步：1-(乙基氨基)-4-(间甲苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-28)的合成The second step: 1-(ethylamino)-4-(m-tolyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-28) Synthesis
Figure PCTCN2022087589-appb-000173
Figure PCTCN2022087589-appb-000173
将N-(乙基氨基硫代甲酰基)-2-(间甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-28A)(380mg，1.0mmol)和吡啶(236mg，2.99mmol)溶到四氢呋喃(10mL)中，置换氮气，降温到0℃，将碘单质(759mg，2.99mmol)慢慢加入反应液。在室温下搅拌14h。用饱和的硫代硫酸钠(50mL)淬灭反应，乙酸乙酯(50mL*2)萃取，合并有机相，用无水硫酸钠干燥，旋干得到粗品，粗品用乙酸乙酯重结晶得到1-(乙基氨基)-4-(间甲苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-28)(97mg,产率28％)。N-(ethylaminothiocarbonyl)-2-(m-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-28A) (380 mg, 1.0 mmol ) and pyridine (236 mg, 2.99 mmol) were dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, the temperature was lowered to 0°C, and elemental iodine (759 mg, 2.99 mmol) was slowly added to the reaction solution. Stir at room temperature for 14h. The reaction was quenched with saturated sodium thiosulfate (50 mL), extracted with ethyl acetate (50 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was recrystallized from ethyl acetate to obtain 1- (Ethylamino)-4-(m-tolyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-28) (97 mg, yield 28 %).
1H NMR(400MHz,DMSO-d6)δ8.03(d,J＝7.9Hz,1H),7.90–7.85(m,1H),7.30(t,J＝7.6Hz,1H),7.15(d,J＝7.6Hz,1H),7.08–6.98(m,2H),6.94(d,J＝2.0Hz,1H),6.61(dd,J＝7.9,2.1Hz,1H),3.45–3.36(m,2H),2.31(s,3H),1.18(t,J＝7.2Hz,3H). 1 H NMR(400MHz,DMSO-d6)δ8.03(d,J=7.9Hz,1H),7.90-7.85(m,1H),7.30(t,J=7.6Hz,1H),7.15(d,J = 7.6Hz, 1H), 7.08–6.98 (m, 2H), 6.94 (d, J=2.0Hz, 1H), 6.61 (dd, J=7.9, 2.1Hz, 1H), 3.45–3.36 (m, 2H) ,2.31(s,3H),1.18(t,J=7.2Hz,3H).
LC-MS,M/Z(ESI):348.1[M+H] + LC-MS, M/Z(ESI): 348.1[M+H] +
实施例29：目标化合物I-29的制备Example 29: Preparation of target compound I-29
4-(3-氯苯基)-1-(甲氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-29)4-(3-Chlorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-29)
Figure PCTCN2022087589-appb-000174
Figure PCTCN2022087589-appb-000174
目标化合物I-29的合成路线如下所示：The synthetic route of the target compound I-29 is as follows:
Figure PCTCN2022087589-appb-000175
Figure PCTCN2022087589-appb-000175
第一步：2-(3-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-29B)的合成The first step: Synthesis of 2-(3-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-29B)
Figure PCTCN2022087589-appb-000176
Figure PCTCN2022087589-appb-000176
将2-溴-4-(三氟甲基)吡啶(1.49g,6.6mmol)，间氯苯乙腈(1.0g,6.6mmol)溶解在四氢呋喃(10mL)中，置换氮气，然后慢慢滴加叔丁醇钾四氢呋喃溶液(7.26mL,7.26mmol,1M)室温下反应3h。用饱和的氯化铵溶液(20mL)淬灭反应，乙酸乙酯(20mL)萃取两次，分离干燥有机相，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1)得到2-(3-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-29B)(1.4g，产率73.7％)。2-Bromo-4-(trifluoromethyl)pyridine (1.49 g, 6.6 mmol), m-chlorobenzeneacetonitrile (1.0 g, 6.6 mmol) were dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, and then tert. Potassium butoxide in tetrahydrofuran (7.26 mL, 7.26 mmol, 1 M) was reacted at room temperature for 3 h. The reaction was quenched with saturated ammonium chloride solution (20 mL), extracted twice with ethyl acetate (20 mL), the organic phase was separated and dried, and the crude product was obtained by spin drying. The crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=10/ 1) 2-(3-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-29B) (1.4 g, 73.7% yield) was obtained.
LC-MS,M/Z(ESI):297.1[M+H] + LC-MS, M/Z(ESI): 297.1[M+H] +
第二步：2-(3-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-29C)的合成The second step: Synthesis of 2-(3-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-29C)
Figure PCTCN2022087589-appb-000177
Figure PCTCN2022087589-appb-000177
把2-(3-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-29B)(1.6g,5.39mmol)溶到浓硫酸(8mL)中，置换氮气，室温搅拌14h。把反应液缓慢倒入冰水(50mL)中，然后乙酸乙酯(20mL)萃取两次，有机相合并再用饱和碳酸氢钠溶液(100mL)洗一次，分离干燥有机相，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1)得到2-(3-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-29C)(1.2g,产率70.7％)。2-(3-Chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-29B) (1.6 g, 5.39 mmol) was dissolved in concentrated sulfuric acid (8 mL), The nitrogen was replaced, and the mixture was stirred at room temperature for 14 h. The reaction solution was slowly poured into ice water (50 mL), then extracted twice with ethyl acetate (20 mL), the organic phases were combined and washed once with saturated sodium bicarbonate solution (100 mL), the organic phase was separated and dried, and spin-dried to obtain the crude product, The crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to obtain 2-(3-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I -29C) (1.2 g, 70.7% yield).
LC-MS,M/Z(ESI):315.1[M+H] + LC-MS, M/Z(ESI): 315.1[M+H] +
第三步：2-(甲基氨基硫代甲酰基)-2-(3-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-29D)的合成The third step: 2-(methylaminothioformyl)-2-(3-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-29D) Synthesis
Figure PCTCN2022087589-appb-000178
Figure PCTCN2022087589-appb-000178
将2-(3-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-29C)(50mg,0.159mmol)和碳酸铯(104mg，0.318mmol)溶到N，N-二甲基甲酰胺(5mL)中，置换氮气，降温到0℃，慢慢滴加异硫氰酸甲酯(17.43mg，0.238mmol)，在室温下搅拌14h。食盐水(20mL)淬灭反应，乙酸乙酯(20mL)萃取两次，分离干燥有机相，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1)得到2-(甲基氨基硫代甲酰基)-2-(3-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-29D)(30mg,产率48.7％)。Combine 2-(3-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-29C) (50 mg, 0.159 mmol) and cesium carbonate (104 mg, 0.318 mmol) It was dissolved in N,N-dimethylformamide (5 mL), nitrogen was replaced, the temperature was lowered to 0°C, methyl isothiocyanate (17.43 mg, 0.238 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 14 h. The reaction was quenched with brine (20 mL), extracted twice with ethyl acetate (20 mL), the organic phase was separated and dried, and the crude product was obtained by spin drying. The crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to obtain 2- (Methylcarbamoyl)-2-(3-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-29D) (30 mg, yield 48.7 %).
LC-MS,M/Z(ESI):388.1[M+H] + LC-MS, M/Z(ESI): 388.1[M+H] +
第四步：4-(3-氯苯基)-1-(甲氨基)-6-(三氟甲基)-3H-吡啶[1,2-c]嘧啶-3-酮(I-29)的合成The fourth step: 4-(3-Chlorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyridin[1,2-c]pyrimidin-3-one (I-29) Synthesis
Figure PCTCN2022087589-appb-000179
Figure PCTCN2022087589-appb-000179
将2-(甲基氨基硫代甲酰基)-2-(3-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-29D)(50mg，0.129mmol)和吡啶(31mg，0.39mmol)溶到四氢呋喃(10mL)中，置换氮气，降温到0℃，将碘单质(98mg，0.39mmol)慢慢加入反应液。在室温下搅拌14h。用饱和的硫代硫酸钠(100mL)淬灭反应，乙酸乙酯(100mL)萃取3次，有机相合并旋干，得到粗品，粗品用乙酸乙酯重结晶得到4-(3-氯苯基)-1-(甲氨基)-6-(三氟甲基)-3H-吡啶[1,2-c]嘧啶-3-酮(I-29)(12mg,产率26％)。2-(Methylaminothiocarbonyl)-2-(3-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-29D) (50 mg, 0.129 mmol) and pyridine (31 mg, 0.39 mmol) were dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, the temperature was lowered to 0°C, and elemental iodine (98 mg, 0.39 mmol) was slowly added to the reaction solution. Stir at room temperature for 14h. The reaction was quenched with saturated sodium thiosulfate (100 mL), extracted three times with ethyl acetate (100 mL), the organic phases were combined and spun dry to obtain a crude product, which was recrystallized from ethyl acetate to obtain 4-(3-chlorophenyl) -1-(Methylamino)-6-(trifluoromethyl)-3H-pyridin[1,2-c]pyrimidin-3-one (I-29) (12 mg, 26% yield).
1H NMR(400MHz,DMSO-d 6)δ8.01(d,J＝7.9Hz,2H),7.48–7.43(m,1H),7.43–7.38(m,1H),7.33(t,J＝1.7Hz,1H),7.23–7.19(m,1H),6.95(s,1H),6.68(dd,J＝7.8,2.0Hz,1H),2.87(d,J＝3.6Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.01 (d, J=7.9 Hz, 2H), 7.48-7.43 (m, 1H), 7.43-7.38 (m, 1H), 7.33 (t, J=1.7 Hz, 1H), 7.23–7.19 (m, 1H), 6.95 (s, 1H), 6.68 (dd, J=7.8, 2.0Hz, 1H), 2.87 (d, J=3.6Hz, 3H).
LC-MS,M/Z(ESI):354.1[M+H] + LC-MS, M/Z(ESI): 354.1[M+H] +
实施例30：目标化合物I-30的制备Example 30: Preparation of target compound I-30
3-(1-(甲基氨基)-3-氧杂-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-4-基)苯甲腈(目标化合物I-30)3-(1-(methylamino)-3-oxa-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-4-yl)benzonitrile (target compound I- 30)
Figure PCTCN2022087589-appb-000180
Figure PCTCN2022087589-appb-000180
目标化合物I-30的合成路线如下所示：The synthetic route of the target compound I-30 is as follows:
Figure PCTCN2022087589-appb-000181
Figure PCTCN2022087589-appb-000181
第一步：2-(3-溴苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-30B)的合成The first step: Synthesis of 2-(3-bromophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-30B)
Figure PCTCN2022087589-appb-000182
Figure PCTCN2022087589-appb-000182
在氮气保护下，向2-(3-溴苯基)乙腈(5.00g,25.5mmol)的二甲基亚砜(50.0mL)溶液中加入2-溴-4-(三氟甲基)吡啶(5.76g,25.5mmol)和氢氧化钾(2.15g,38.3mmol)，反应在90℃搅拌10h。反应完成后，将反应混合物用水(200mL)稀释，然后用乙酸乙酯(100mL*3)萃取，合并有机层，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至10:1)得到黄色固体化合物2-(3-溴苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-30B)(6.00g,17.6mmol,69.0％产率)。To a solution of 2-(3-bromophenyl)acetonitrile (5.00 g, 25.5 mmol) in dimethyl sulfoxide (50.0 mL) was added 2-bromo-4-(trifluoromethyl)pyridine ( 5.76 g, 25.5 mmol) and potassium hydroxide (2.15 g, 38.3 mmol), the reaction was stirred at 90 °C for 10 h. After the completion of the reaction, the reaction mixture was diluted with water (200 mL), then extracted with ethyl acetate (100 mL*3), the organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=50:1 to 10:1) gave a yellow solid compound 2-(3-bromophenyl)-2-(4-(trifluoromethyl) )pyridin-2-yl)acetonitrile (I-30B) (6.00 g, 17.6 mmol, 69.0% yield).
1H NMR(400MHz,DMSO_d 6):δ8.91(d,1H),7.96(s,1H),7.77-7.86(m,1H),7.73(t,1H),7.48-7.63(m,2H),7.34-7.45(m,1H),6.12(s,1H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.91(d,1H), 7.96(s,1H), 7.77-7.86(m,1H), 7.73(t,1H), 7.48-7.63(m,2H) ,7.34-7.45(m,1H),6.12(s,1H).
LC-MS,M/Z(ESI):341.0[M+H] + LC-MS, M/Z(ESI): 341.0[M+H] +
第二步：2-(3-溴苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-30C)的合成The second step: the synthesis of 2-(3-bromophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-30C)
Figure PCTCN2022087589-appb-000183
Figure PCTCN2022087589-appb-000183
向硫酸(8.00mL)中加入2-(3-溴苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-30B)(2.00g,5.86mmol)，反应在25℃搅拌10h。反应完成后，将反应液在0℃下慢慢加入到氢氧化钠水溶液(4.00M,80.0mL)中，然后用乙酸乙酯(50.0mL*3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，得到黄色固体2-(3-溴苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-30C)(2.00g,5.57mmol,产率95.0％)，直接用于下一步。To sulfuric acid (8.00 mL) was added 2-(3-bromophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-30B) (2.00 g, 5.86 mmol) to react Stir at 25°C for 10h. After the reaction was completed, the reaction solution was slowly added to an aqueous sodium hydroxide solution (4.00M, 80.0 mL) at 0°C, then extracted with ethyl acetate (50.0 mL*3), the organic layers were combined and dried over anhydrous sodium sulfate , filtered, and concentrated to give a yellow solid 2-(3-bromophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-30C) (2.00 g, 5.57 mmol, yielded rate 95.0%), used directly in the next step.
第三步：2-(3-溴苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-30D)的合成The third step: 2-(3-bromophenyl)-N-(methylaminothioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-30D) Synthesis
Figure PCTCN2022087589-appb-000184
Figure PCTCN2022087589-appb-000184
向2-(3-溴苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-30C)(1.00g,2.78mmol)的N,N-二甲基甲酰胺(20.0mL)溶液中加入碳酸铯(1.36g,4.18mmol)和甲基异硫氰酸酯(305mg,4.18mmo)，反应在75℃搅拌10h。反应完成后，将反应混合物用水(100mL)稀释，然后用乙酸乙酯(80.0mL*3)萃取，合并有机层，用饱和食盐水(80.0mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至10:1)得到棕色油状化合物2-(3-溴苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-30D)(750mg,1.74mmol,62.3％产率)。N,N-Dimethyl to 2-(3-bromophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-30C) (1.00 g, 2.78 mmol) Cesium carbonate (1.36 g, 4.18 mmol) and methyl isothiocyanate (305 mg, 4.18 mmol) were added to the formamide (20.0 mL) solution, and the reaction was stirred at 75° C. for 10 h. After the reaction was completed, the reaction mixture was diluted with water (100 mL), then extracted with ethyl acetate (80.0 mL*3), the organic layers were combined, washed with saturated brine (80.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated, The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=50:1 to 10:1) to obtain 2-(3-bromophenyl)-N-(methylaminothio) as a brown oily compound Formyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-30D) (750 mg, 1.74 mmol, 62.3% yield).
第四步：4-(3-溴苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-30E)的合成The fourth step: 4-(3-bromophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I- 30E) synthesis
Figure PCTCN2022087589-appb-000185
Figure PCTCN2022087589-appb-000185
向2-(3-溴苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-30D)(700mg,1.62mmol)的四氢呋喃(1.00mL)溶液中加入碘单质(1.23g,4.86mmol)和吡啶(384mg,4.86mmol)，反应在25℃搅拌10h。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(10.0mL)稀释，然后用乙酸乙酯(50.0mL*3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，残留物用乙酸乙酯(10.0mL)打浆，得到黄色固体化合物4-(3-溴苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-30E)(200mg,产率31.0％)。To 2-(3-bromophenyl)-N-(methylcarbamoyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-30D) (700 mg, To a solution of 1.62 mmol) in tetrahydrofuran (1.00 mL), elemental iodine (1.23 g, 4.86 mmol) and pyridine (384 mg, 4.86 mmol) were added, and the reaction was stirred at 25° C. for 10 h. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium sulfite solution (10.0 mL), then extracted with ethyl acetate (50.0 mL*3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was washed with ethyl acetate (10.0 mL) was beaten to give a yellow solid compound 4-(3-bromophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine- 3-keto (I-30E) (200 mg, 31.0% yield).
LC-MS,M/Z(ESI):398.0[M+H] + LC-MS, M/Z(ESI): 398.0[M+H] +
第五步：3-(1-(甲基氨基)-3-氧杂-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-4-基)苯甲腈(I-30)的合成The fifth step: 3-(1-(methylamino)-3-oxa-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-4-yl)benzonitrile ( Synthesis of I-30)
Figure PCTCN2022087589-appb-000186
Figure PCTCN2022087589-appb-000186
在氮气保护下，向4-(3-溴苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-30E)(180mg,452μmol)，三(二亚苄基丙酮)二钯(20.7mg,22.6μmol)，1,1-双(二苯基膦基)二茂铁(12.5mg,22.6μmol)的N,N-二甲基甲酰胺(2.00mL)溶液中加入氰化锌(70.0mg,596μmol)，反应在120℃搅拌10h。反应完成后，将反应混合物过滤，滤液用水(10.0mL)稀释，然后用乙酸乙酯(30.0mL*3)萃取，合并有机层，用饱和亚硫酸钠水溶液(20.0mL*3)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用乙酸乙酯(10.0mL)打浆，得到黄色固体化合物3-(1-(甲基氨基)-3-氧杂-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-4-基)苯甲腈(I-30)(84.0mg,244μmol,54.0％产率)。Under nitrogen protection, 4-(3-bromophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one ( I-30E) (180 mg, 452 μmol), tris(dibenzylideneacetone)dipalladium (20.7 mg, 22.6 μmol), 1,1-bis(diphenylphosphino)ferrocene (12.5 mg, 22.6 μmol) Zinc cyanide (70.0 mg, 596 μmol) was added to the solution of N,N-dimethylformamide (2.00 mL), and the reaction was stirred at 120 °C for 10 h. After the reaction was completed, the reaction mixture was filtered, the filtrate was diluted with water (10.0 mL), then extracted with ethyl acetate (30.0 mL*3), the organic layers were combined, washed with saturated aqueous sodium sulfite solution (20.0 mL*3), and anhydrous sodium sulfate Dry, filter, concentrate, and the residue is slurried with ethyl acetate (10.0 mL) to give yellow solid compound 3-(1-(methylamino)-3-oxa-6-(trifluoromethyl)-3H-pyridine [1,2-c]pyrimidin-4-yl)benzonitrile (I-30) (84.0 mg, 244 μmol, 54.0% yield).
1H NMR(400MHz,DMSO_d 6):δ8.30(br s,1H),8.20(br d,1H),7.80-7.87(m,1H),7.76(s,1H),7.61-7.68(m,2H),6.95(s,1H),6.71(dd,1H),2.89(s,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.30(br s, 1H), 8.20(br d, 1H), 7.80-7.87(m, 1H), 7.76(s, 1H), 7.61-7.68(m, 2H), 6.95(s, 1H), 6.71(dd, 1H), 2.89(s, 3H).
LC-MS,M/Z(ESI):345.2[M+H] + LC-MS, M/Z(ESI): 345.2[M+H] +
实施例31：目标化合物I-31的制备Example 31: Preparation of target compound I-31
4-(3-氟苯基)-1-(甲氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-31)4-(3-Fluorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-31)
Figure PCTCN2022087589-appb-000187
Figure PCTCN2022087589-appb-000187
目标化合物I-31的合成路线如下所示：The synthetic route of the target compound I-31 is as follows:
Figure PCTCN2022087589-appb-000188
Figure PCTCN2022087589-appb-000188
第一步：2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-31B)的合成The first step: Synthesis of 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-31B)
Figure PCTCN2022087589-appb-000189
Figure PCTCN2022087589-appb-000189
将2-溴-4-(三氟甲基)吡啶(1.67g,7.4mmol)，间氟苯乙腈(1.0g,7.4mmol)溶解在四氢呋喃(10mL)中，置换氮气，然后慢慢滴加叔丁醇钾的四氢呋喃溶液(8.14mL，8.14mmol，1M)室温下反应3h。用饱和的氯化铵溶液(20mL)淬灭反应，乙酸乙酯(20mL)萃取两次，分离干燥有机相，旋干得到粗品，粗品用硅胶柱分离纯化(石油醚/乙酸乙酯＝50/1)得到2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-31B)(1.1g，产率53％)。2-Bromo-4-(trifluoromethyl)pyridine (1.67 g, 7.4 mmol), m-fluorobenzeneacetonitrile (1.0 g, 7.4 mmol) were dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, and then tert. A solution of potassium butoxide in tetrahydrofuran (8.14 mL, 8.14 mmol, 1 M) was reacted at room temperature for 3 h. The reaction was quenched with saturated ammonium chloride solution (20 mL), extracted twice with ethyl acetate (20 mL), the organic phase was separated and dried, and the crude product was obtained by spin drying. The crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=50/ 1) 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-31B) (1.1 g, 53% yield) was obtained.
LC-MS,M/Z(ESI):281.2[M+H] + LC-MS, M/Z(ESI): 281.2[M+H] +
第二步：2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-31C)的合成The second step: Synthesis of 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-31C)
Figure PCTCN2022087589-appb-000190
Figure PCTCN2022087589-appb-000190
把2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-31B)(0.8g，2.85mmol)溶到浓硫酸(8mL)中，置换氮气，室温搅拌14h。把反应液缓慢倒入冰水(50mL)中，然后乙酸乙酯(20mL)萃取两次，有机相合并再用饱和碳酸氢钠溶液(100mL)洗一次，分离干燥有机相，旋干得到粗品，粗品过柱(石油醚/乙酸乙酯＝3/1)得到2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺 (I-31C)(0.6g,产率70.8％)。2-(3-Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-31B) (0.8 g, 2.85 mmol) was dissolved in concentrated sulfuric acid (8 mL), The nitrogen was replaced, and the mixture was stirred at room temperature for 14 h. The reaction solution was slowly poured into ice water (50 mL), then extracted twice with ethyl acetate (20 mL), the organic phases were combined and washed once with saturated sodium bicarbonate solution (100 mL), the organic phase was separated and dried, and spin-dried to obtain the crude product, The crude product was passed through column (petroleum ether/ethyl acetate=3/1) to obtain 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-31C) (0.6 g, 70.8% yield).
LC-MS,M/Z(ESI):299.1[M+H] + LC-MS, M/Z(ESI): 299.1[M+H] +
第三步：2-(3-氟苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-31D)的合成The third step: 2-(3-Fluorophenyl)-N-(methylaminothioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-31D) Synthesis
Figure PCTCN2022087589-appb-000191
Figure PCTCN2022087589-appb-000191
将2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-31C)(100mg,0.335mmol)和碳酸铯(218mg，0.671mmol)溶到N,N-二甲基甲酰胺(5mL)中，置换氮气，降温到0℃，慢慢滴加异硫氰酸甲酯(24.52mg，0.335mmol)，在室温下搅拌6h。食盐水(20mL)淬灭反应，乙酸乙酯(20mL)萃取两次，分离干燥有机相，旋干得到粗品，粗品用硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1)得到2-(3-氟苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-31D)(100mg,产率80.0％)。Combine 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-31C) (100 mg, 0.335 mmol) and cesium carbonate (218 mg, 0.671 mmol) It was dissolved in N,N-dimethylformamide (5 mL), nitrogen was replaced, the temperature was lowered to 0°C, methyl isothiocyanate (24.52 mg, 0.335 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 6 h. The reaction was quenched with brine (20 mL), extracted twice with ethyl acetate (20 mL), the organic phase was separated and dried, spin-dried to obtain a crude product, and the crude product was separated and purified with a silica gel column (petroleum ether/ethyl acetate=10/1) to obtain 2- (3-Fluorophenyl)-N-(methylaminothioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-31D) (100 mg, yield 80.0 %).
LC-MS,M/Z(ESI):371.4[M+H] + LC-MS, M/Z(ESI): 371.4[M+H] +
第四步：1-(甲氨基)-4-(3-氟苯基)-6-(三氟甲基)-3H-吡啶[1,2-c]嘧啶-3-酮(I-31)的合成The fourth step: 1-(methylamino)-4-(3-fluorophenyl)-6-(trifluoromethyl)-3H-pyridin[1,2-c]pyrimidin-3-one (I-31) Synthesis
Figure PCTCN2022087589-appb-000192
Figure PCTCN2022087589-appb-000192
将2-(3-氟苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-31D)(50mg，0.135mmol)和吡啶(32mg，0.40mmol)溶到四氢呋喃(10mL)中，置换氮气，降温到0℃，将碘单质(103mg，0.40mmol)慢慢加入反应液。在室温下搅拌14h。用饱和的硫代硫酸钠溶液(100mL)淬灭反应，乙酸乙酯(100mL)萃取3次，有机相合并旋干，得到粗品，粗品用乙酸乙酯重结晶得到4-(3-氟苯基)-1-(甲氨基)-6-(三氟甲基)-3H-吡啶[1,2-c]嘧啶-3-酮(I-31)(7mg,产率16％)。2-(3-Fluorophenyl)-N-(methylcarbamoyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-31D) (50 mg, 0.135 mmol) and pyridine (32 mg, 0.40 mmol) were dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, the temperature was lowered to 0 °C, and elemental iodine (103 mg, 0.40 mmol) was slowly added to the reaction solution. Stir at room temperature for 14h. The reaction was quenched with saturated sodium thiosulfate solution (100 mL), extracted three times with ethyl acetate (100 mL), the organic phases were combined and spun dry to obtain a crude product, which was recrystallized from ethyl acetate to obtain 4-(3-fluorophenyl) )-1-(methylamino)-6-(trifluoromethyl)-3H-pyridin[1,2-c]pyrimidin-3-one (1-31) (7 mg, 16% yield).
1H NMR(400MHz,DMSO-d 6)δ8.01(d,J＝7.9Hz,2H),7.50–7.42(m,1H),7.22–7.15(m,1H),7.14–7.05(m,2H),6.97(s,1H),6.68(dd,J＝7.8,1.9Hz,1H),2.87(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.01 (d, J=7.9 Hz, 2H), 7.50-7.42 (m, 1H), 7.22-7.15 (m, 1H), 7.14-7.05 (m, 2H) ), 6.97(s, 1H), 6.68(dd, J=7.8, 1.9Hz, 1H), 2.87(s, 3H).
LC-MS,M/Z(ESI):338.1[M+H] + LC-MS, M/Z(ESI): 338.1[M+H] +
实施例32：目标化合物I-32的制备Example 32: Preparation of target compound I-32
1-(乙基氨基)-4-(3-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-32)1-(Ethylamino)-4-(3-fluorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-32)
Figure PCTCN2022087589-appb-000193
Figure PCTCN2022087589-appb-000193
目标化合物I-32的合成路线如下所示：The synthetic route of the target compound I-32 is as follows:
Figure PCTCN2022087589-appb-000194
Figure PCTCN2022087589-appb-000194
第一步:N-(乙基氨基硫代甲酰基)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-32A)的合成The first step: N-(ethylaminothioformyl)-2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-32A) Synthesis
Figure PCTCN2022087589-appb-000195
Figure PCTCN2022087589-appb-000195
将2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-31C)(500mg，1.68mmol)和碳酸铯(1.09g，3.35mmol)溶到N，N-二甲基甲酰胺(10mL)中，置换氮气，慢慢滴加异硫氰酸乙酯(0.22g，2.51mmol)，在室温下搅拌14h。食盐水(20mL)淬灭反应，乙酸乙酯(20mL)萃取两次，分离干燥有机相，旋干得到粗品，粗品用硅胶柱分离纯化(石油醚/乙酸乙酯＝20/1)得到N-(乙基氨基硫代甲酰基)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-32A)(345mg,产率53.4％)。Combine 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-31C) (500 mg, 1.68 mmol) and cesium carbonate (1.09 g, 3.35 mmol) ) was dissolved in N,N-dimethylformamide (10 mL), nitrogen was replaced, ethyl isothiocyanate (0.22 g, 2.51 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 14 h. The reaction was quenched with brine (20 mL), extracted twice with ethyl acetate (20 mL), the organic phase was separated and dried, spin-dried to obtain the crude product, and the crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=20/1) to obtain N- (Ethylcarbamoyl)-2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-32A) (345 mg, yield 53.4 %).
LC-MS,M/Z(ESI):386.1[M+H] + LC-MS, M/Z(ESI): 386.1[M+H] +
第二步：1-(乙基氨基)-4-(3-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-32)的合成The second step: 1-(ethylamino)-4-(3-fluorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I- 32) Synthesis
Figure PCTCN2022087589-appb-000196
Figure PCTCN2022087589-appb-000196
将N-(乙基氨基硫代甲酰基)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-32A)(300mg，0.78mmol)和吡啶(185mg，2.34mmol)溶到四氢呋喃(10mL)中，置换氮气，降温到0℃，将碘单质(593mg，2.34mmol)慢慢加入反应液。在室温下搅拌14h。用饱和的硫代硫酸钠溶液 (100mL)淬灭反应，乙酸乙酯(100mL)萃取3次，有机相合并旋干，得到粗品，粗品用乙酸乙酯重结晶得到1-(乙基氨基)-4-(3-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-32)(150mg,产率54.9％)。N-(ethylaminothiocarbonyl)-2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-32A) (300 mg, 0.78 mmol) and pyridine (185 mg, 2.34 mmol) were dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, the temperature was lowered to 0 °C, and elemental iodine (593 mg, 2.34 mmol) was slowly added to the reaction solution. Stir at room temperature for 14h. The reaction was quenched with saturated sodium thiosulfate solution (100 mL), extracted 3 times with ethyl acetate (100 mL), and the organic phases were combined and spin-dried to obtain a crude product, which was recrystallized from ethyl acetate to obtain 1-(ethylamino)- 4-(3-Fluorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (1-32) (150 mg, 54.9% yield).
1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.39(d,J＝7.7Hz,1H),7.50–7.41(m,1H),7.23–7.05(m,3H),6.95(s,1H),6.62(d,J＝7.8Hz,1H),3.45–3.34(m,2H),1.18(t,J＝7.1Hz,3H). 1 H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.39(d,J=7.7Hz,1H),7.50-7.41(m,1H),7.23-7.05(m,3H),6.95 (s, 1H), 6.62 (d, J=7.8Hz, 1H), 3.45–3.34 (m, 2H), 1.18 (t, J=7.1Hz, 3H).
LC-MS,M/Z(ESI):352.3[M+H] + LC-MS, M/Z(ESI): 352.3[M+H] +
实施例33：目标化合物I-33的制备Example 33: Preparation of target compound I-33
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000197
Figure PCTCN2022087589-appb-000197
第一步：2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈的合成The first step: Synthesis of 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile
Figure PCTCN2022087589-appb-000198
Figure PCTCN2022087589-appb-000198
在室温下，将3-氟苯乙腈(3.00g,22.2mmol)，2-溴-4-(三氟甲基)吡啶(5.02g,22.2mmol)和氢氧化钾(2.49g,44.4mmol)加入到1-甲基-2-吡咯烷酮(60.0mL)中，氮气保护下在90℃反应8小时。反应完成后，反应液加入到饱和的碳酸氢钠水溶液(600mL)，然后用乙酸乙酯(100mL*2)萃取，合并有机层相，用饱和食盐水(50.0mL*2)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝200:1至6:1)得到黄色固体化合物2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(5.50g，产率88.4％)。At room temperature, 3-fluorophenylacetonitrile (3.00 g, 22.2 mmol), 2-bromo-4-(trifluoromethyl)pyridine (5.02 g, 22.2 mmol) and potassium hydroxide (2.49 g, 44.4 mmol) were added into 1-methyl-2-pyrrolidone (60.0 mL), and react at 90° C. for 8 hours under nitrogen protection. After the completion of the reaction, the reaction solution was added to saturated aqueous sodium bicarbonate solution (600 mL), then extracted with ethyl acetate (100 mL*2), the organic layers were combined, and the organic phase was washed with saturated brine (50.0 mL*2). Dry over sodium sulfate, filter, and concentrate to obtain crude product. The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=200:1 to 6:1) to obtain a yellow solid compound 2-(3-fluorophenyl)-2-(4-(trifluoro) Methyl)pyridin-2-yl)acetonitrile (5.50 g, 88.4% yield).
LC-MS,M/Z(ESI):281.2[M+H] + LC-MS, M/Z(ESI): 281.2[M+H] +
第二步：2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The second step: synthesis of 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
Figure PCTCN2022087589-appb-000199
Figure PCTCN2022087589-appb-000199
在室温下，将2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(5.40g,19.3mmol)加入到浓硫酸(50.0mL)中，氮气保护下在25℃反应1小时。反应完成后，反应液0～25℃下加入到饱和的碳酸氢钠水溶液(500mL)中，然后用乙酸乙酯(200mL*2)萃取，合并有机层相，用饱和食盐水(50.0mL*2)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品2-(3-氟苯 基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(5.20g，粗品)。2-(3-Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (5.40 g, 19.3 mmol) was added to concentrated sulfuric acid (50.0 mL) at room temperature, The reaction was carried out at 25°C for 1 hour under nitrogen protection. After the completion of the reaction, the reaction solution was added to saturated aqueous sodium bicarbonate solution (500 mL) at 0-25°C, then extracted with ethyl acetate (200 mL*2), the organic layers were combined, and saturated brine (50.0 mL*2) was used for extraction. ) washed the organic phase, dried over anhydrous sodium sulfate, filtered and concentrated to give crude 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (5.20 g, crude product ).
LC-MS,M/Z(ESI):299.1[M+H] + LC-MS, M/Z(ESI): 299.1[M+H] +
第三步：N-((2,2-二氟乙基)氨基硫代甲酰基)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The third step: N-((2,2-difluoroethyl)carbamoyl)-2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl ) Synthesis of acetamide
Figure PCTCN2022087589-appb-000200
Figure PCTCN2022087589-appb-000200
在室温下，将2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(200mg,671μmol)，1,1-二氟-2-异硫氰基乙烷(165mg,1.34mmol)和碳酸铯(437mg,1.34mmol)加入到N,N-二甲基甲酰胺(5.00mL)中，氮气保护下在25℃反应12小时。反应完成后，反应液过滤，浓缩，得到粗品化合物N-((2,2-二氟乙基)氨基硫代甲酰基)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(200mg，粗品)。直接用于下一步。At room temperature, 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (200 mg, 671 μmol), 1,1-difluoro-2-iso Thiocyanoethane (165 mg, 1.34 mmol) and cesium carbonate (437 mg, 1.34 mmol) were added to N,N-dimethylformamide (5.00 mL) and reacted at 25° C. for 12 hours under nitrogen protection. After completion of the reaction, the reaction solution was filtered and concentrated to obtain the crude compound N-((2,2-difluoroethyl)carbamoyl)-2-(3-fluorophenyl)-2-(4-(trifluorophenyl)- Fluoromethyl)pyridin-2-yl)acetamide (200 mg, crude). used directly in the next step.
LC-MS,M/Z(ESI):422.1[M+H] + LC-MS, M/Z(ESI): 422.1[M+H] +
第四步：1-((2,2-二氟乙基)氨基)-4-(3-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-33)的合成The fourth step: 1-((2,2-difluoroethyl)amino)-4-(3-fluorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c] Synthesis of Pyrimidine-3-one (I-33)
Figure PCTCN2022087589-appb-000201
Figure PCTCN2022087589-appb-000201
在氮气保护下，将N-((2,2-二氟乙基)氨基硫代甲酰基)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(100mg,237μmol)，碘单质(181mg,712μmol)和吡啶(93.9mg,1.19mmol)加入到四氢呋喃(3.00mL)中，氮气保护下25℃反应8小时。反应完成后，反应液过滤，浓缩得到粗品。残留物用高效液相色谱仪分离纯化，分离方法为(柱子：Phenomenex Synergi C18 150*25mm*5um；溶剂：A＝水+0.1体积％氨水(30％)，B＝乙腈；梯度：26％-56％，8分钟)，得到目标化合物1-((2,2-二氟乙基)氨基)-4-(3-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-33)(3.02mg，产率3.22％)。Under nitrogen protection, N-((2,2-difluoroethyl)carbamoyl)-2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridine-2 -yl)acetamide (100 mg, 237 μmol), elemental iodine (181 mg, 712 μmol) and pyridine (93.9 mg, 1.19 mmol) were added to tetrahydrofuran (3.00 mL) and reacted at 25° C. for 8 hours under nitrogen protection. After completion of the reaction, the reaction solution was filtered and concentrated to obtain the crude product. The residue was separated and purified by high performance liquid chromatography, and the separation method was (column: Phenomenex Synergi C18 150*25mm*5um; solvent: A=water+0.1 vol% ammonia water (30%), B=acetonitrile; gradient: 26%- 56%, 8 min) to give the target compound 1-((2,2-difluoroethyl)amino)-4-(3-fluorophenyl)-6-(trifluoromethyl)-3H-pyrido[ 1,2-c]pyrimidin-3-one (I-33) (3.02 mg, 3.22% yield).
1H NMR(400MHz,CD 3OD)δ8.10(d,1H),7.48-7.52(m,1H),7.11-7.17(m,4H),6.75(d,1H),6.06-6.35(m,1H),3.92(t,2H). 1 H NMR (400MHz, CD 3 OD) δ8.10(d,1H), 7.48-7.52(m,1H), 7.11-7.17(m,4H), 6.75(d,1H), 6.06-6.35(m, 1H), 3.92(t, 2H).
LC-MS,M/Z(ESI):388.1[M+H] + LC-MS, M/Z(ESI): 388.1[M+H] +
实施例34：目标化合物I-34的制备Example 34: Preparation of target compound I-34
4-(2-氟苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-34)4-(2-Fluorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-34)
Figure PCTCN2022087589-appb-000202
Figure PCTCN2022087589-appb-000202
目标化合物I-34的合成路线如下所示：The synthetic route of the target compound I-34 is as follows:
Figure PCTCN2022087589-appb-000203
Figure PCTCN2022087589-appb-000203
第一步:2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-34B)的合成The first step: the synthesis of 2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-34B)
Figure PCTCN2022087589-appb-000204
Figure PCTCN2022087589-appb-000204
将2-溴-4-(三氟甲基)吡啶(1g,4.42mmol),2-(2-氟苯基)乙腈(0.60g,4.42mmol)溶解在四氢呋喃(10mL)中，置换氮气，反应降温至0℃,然后慢慢滴加叔丁醇钾的四氢呋喃溶液(5.3mL，5.3mmol，1M)，反应升至室温下反应3h。用饱和的氯化铵溶液(20mL)淬灭反应，乙酸乙酯(20mL*2)萃取两次，合并有机相，用无水硫酸钠干燥，旋干得到粗品，粗品过硅胶柱(石油醚/乙酸乙酯＝50/1)得到2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-34B)(0.92g，产率：73％)。Dissolve 2-bromo-4-(trifluoromethyl)pyridine (1 g, 4.42 mmol), 2-(2-fluorophenyl)acetonitrile (0.60 g, 4.42 mmol) in tetrahydrofuran (10 mL), replace nitrogen, and react The temperature was lowered to 0°C, and then a solution of potassium tert-butoxide in tetrahydrofuran (5.3 mL, 5.3 mmol, 1 M) was slowly added dropwise, and the reaction was raised to room temperature for 3 h. The reaction was quenched with saturated ammonium chloride solution (20 mL), extracted twice with ethyl acetate (20 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was passed through a silica gel column (petroleum ether/ Ethyl acetate = 50/1) to give 2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-34B) (0.92 g, yield: 73 %).
LC-MS,M/Z(ESI):281.0[M+H] + LC-MS, M/Z(ESI): 281.0[M+H] +
第二步:2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-34C)的合成Step 2: Synthesis of 2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-34C)
Figure PCTCN2022087589-appb-000205
Figure PCTCN2022087589-appb-000205
把2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-34B)(0.92g，3.35mmol)溶到浓硫酸(5mL)中，置换氮气，室温搅拌14h。把反应液缓慢倒入冰水(50mL)中，然后乙酸乙酯(20mL*2)萃取两次，有机相合并再用饱和碳酸氢钠溶液(100mL)洗涤，合并有机相，用无水硫酸钠干燥，旋干得到2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-34C)(0.98g,产率100％)。2-(2-Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-34B) (0.92 g, 3.35 mmol) was dissolved in concentrated sulfuric acid (5 mL), The nitrogen was replaced, and the mixture was stirred at room temperature for 14 h. The reaction solution was slowly poured into ice water (50 mL), then extracted twice with ethyl acetate (20 mL*2), the organic phases were combined and washed with saturated sodium bicarbonate solution (100 mL), the organic phases were combined, and anhydrous sodium sulfate was used for washing. Dry and spin dry to give 2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-34C) (0.98 g, 100% yield).
LC-MS,M/Z(ESI):299.1[M+H] + LC-MS, M/Z(ESI): 299.1[M+H] +
第三步：2-(2-氟苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-34D)的合成The third step: 2-(2-Fluorophenyl)-N-(methylaminothioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-34D) Synthesis
Figure PCTCN2022087589-appb-000206
Figure PCTCN2022087589-appb-000206
将2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-34C)(400mg，1.34mmol)和碳酸铯(874mg，2.68mmol)溶到N,N-二甲基甲酰胺(4mL)中，置换氮气，慢慢滴加异硫氰酸甲酯(147mg，2.0mmol)，在室温下搅拌6h。加水(20mL)淬灭反应，乙酸乙酯(20mL*2)萃取两次，合并有机相，并用卤水洗涤(20mL*3)，有机相用无水硫酸钠干燥，旋干得到粗品，粗品过硅胶柱(石油醚/乙酸乙酯＝10/1)得到2-(2-氟苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-34D)(350mg,产率70％)。Combine 2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-34C) (400 mg, 1.34 mmol) and cesium carbonate (874 mg, 2.68 mmol) It was dissolved in N,N-dimethylformamide (4 mL), nitrogen was replaced, methyl isothiocyanate (147 mg, 2.0 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 6 h. Add water (20mL) to quench the reaction, extract twice with ethyl acetate (20mL*2), combine the organic phases and wash with brine (20mL*3), dry the organic phase with anhydrous sodium sulfate, spin dry to obtain the crude product, which is passed through silica gel Column (petroleum ether/ethyl acetate = 10/1) to give 2-(2-fluorophenyl)-N-(methylaminothioformyl)-2-(4-(trifluoromethyl)pyridine-2 -yl)acetamide (I-34D) (350 mg, 70% yield).
LC-MS,M/Z(ESI):372.0[M+H] + LC-MS, M/Z(ESI): 372.0[M+H] +
第四步：4-(2-氟苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-34)的合成The fourth step: 4-(2-fluorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I- 34) Synthesis
Figure PCTCN2022087589-appb-000207
Figure PCTCN2022087589-appb-000207
将2-(2-氟苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-34D)(200mg，0.54mmol)和吡啶(128mg，1.62mmol)溶到四氢呋喃(10mL)中，置换氮气，降温到0℃，将碘单质(410mg，1.62mmol)慢慢加入反应液。在室温下搅拌14h。用饱和的硫代硫酸钠溶液(50mL)淬灭反应，乙酸乙酯(50mL*3)萃取，合并有机相，用无水硫酸钠干燥，旋干得到粗品，粗品用乙酸乙酯重结晶得到4-(2-氟苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-34)(40mg,产率22％)。2-(2-Fluorophenyl)-N-(methylcarbamoyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-34D) (200 mg, 0.54 mmol) and pyridine (128 mg, 1.62 mmol) were dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, the temperature was lowered to 0°C, and elemental iodine (410 mg, 1.62 mmol) was slowly added to the reaction solution. Stir at room temperature for 14h. The reaction was quenched with saturated sodium thiosulfate solution (50 mL), extracted with ethyl acetate (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was recrystallized with ethyl acetate to obtain 4 -(2-Fluorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-34) (40 mg, yield 22%).
超临界色谱(SFC)条件：Supercritical chromatography (SFC) conditions:
色谱柱：Chiralcel OD-3 50×4.6mm I.D.,3μm；流动相：流动相A为CO 2，流动相B为甲醇(0.05％二乙胺)；梯度洗脱条件：0～1.8min，5％～40％B(v/v)；1.8min～2.7min，40％B(v/v)；2.7min～3min，40％～5％B(v/v)；流速：3mL/min；检测器：PDA；柱温：35℃；背压：100Bar； Chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3μm; mobile phase: mobile phase A is CO 2 , mobile phase B is methanol (0.05% diethylamine); gradient elution conditions: 0～1.8min, 5% ~40%B(v/v); 1.8min~2.7min, 40%B(v/v); 2.7min~3min, 40%~5%B(v/v); flow rate: 3mL/min; detector : PDA; column temperature: 35℃; back pressure: 100Bar;
保留时间：1.32min。Retention time: 1.32min.
1H NMR(400MHz,dmso)δ8.09–8.01(m,2H),7.48–7.38(m,1H),7.34–7.21(m,3H),6.77(d,J＝2.6Hz,1H),6.69(dd,J＝7.8,2.1Hz,1H),2.87(d,J＝3.7Hz,3H). 1 H NMR(400MHz,dmso)δ8.09-8.01(m,2H),7.48-7.38(m,1H),7.34-7.21(m,3H),6.77(d,J=2.6Hz,1H),6.69 (dd,J=7.8,2.1Hz,1H),2.87(d,J=3.7Hz,3H).
LC-MS,M/Z(ESI):338.4[M+H] + LC-MS, M/Z(ESI): 338.4[M+H] +
实施例35：目标化合物I-35的制备Example 35: Preparation of target compound I-35
1-(乙胺基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶[1,2-c]嘧啶-3-酮(I-35)1-(Ethylamino)-4-(2-fluorophenyl)-6-(trifluoromethyl)-3H-pyridin[1,2-c]pyrimidin-3-one (I-35)
Figure PCTCN2022087589-appb-000208
Figure PCTCN2022087589-appb-000208
目标化合物I-35的合成路线如下所示：The synthetic route of the target compound I-35 is as follows:
Figure PCTCN2022087589-appb-000209
Figure PCTCN2022087589-appb-000209
第一步:N-(乙基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-35A)的合成The first step: the synthesis of N-(ethylaminothioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-35A)
Figure PCTCN2022087589-appb-000210
Figure PCTCN2022087589-appb-000210
将2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-34C)(500mg，1.68mmol)和碳酸铯(1.09g，3.35mmol)溶到N,N-二甲基甲酰胺(5mL)中，置换氮气，降温到0℃，慢慢滴加异硫氰酸乙酯(219mg，2.51mmol)，在室温下搅拌14h。食盐水(20mL)淬灭反应，乙酸乙酯(20mL*2)萃取两次，分离干燥有机相，旋干得到粗品，粗品通过硅胶柱分离纯化得到(石油醚/乙酸乙酯＝10/1)得到N-(乙基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-35A)(600mg,产率93％)。Combine 2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-34C) (500 mg, 1.68 mmol) and cesium carbonate (1.09 g, 3.35 mmol) ) was dissolved in N,N-dimethylformamide (5 mL), nitrogen was replaced, the temperature was lowered to 0°C, ethyl isothiocyanate (219 mg, 2.51 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 14 h. The reaction was quenched with brine (20 mL), extracted twice with ethyl acetate (20 mL*2), the organic phase was separated and dried, and the crude product was obtained by spin drying. The crude product was separated and purified by silica gel column to obtain (petroleum ether/ethyl acetate=10/1) This gave N-(ethylaminothiocarbonyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-35A) (600 mg, 93% yield).
LC-MS,M/Z(ESI):386.1[M+H] + LC-MS, M/Z(ESI): 386.1[M+H] +
第二步：1-(乙胺基)-4-(2-氟苯基)-6-(三氟甲基)-3氢-吡啶[1,2-c]嘧啶-3-酮(I-35)的合成The second step: 1-(ethylamino)-4-(2-fluorophenyl)-6-(trifluoromethyl)-3hydro-pyridine[1,2-c]pyrimidin-3-one (I- 35) Synthesis
Figure PCTCN2022087589-appb-000211
Figure PCTCN2022087589-appb-000211
将N-(乙基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-35A)(500mg，1.30mmol)和吡啶(308mg，3.89mmol)溶到四氢呋喃(10mL)中，置换氮气，降温到0℃，将碘单质(1.00g，3.89mmol)慢慢加入反应液。在室温下搅拌14h。用饱和的硫代硫酸钠(100mL)淬灭反应，乙酸乙酯(100mL*3)萃取3次，有机相合并旋干，得到粗品，粗品用乙酸乙酯重结 晶得到1-(乙胺基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶[1,2-c]嘧啶-3-酮(I-35)(50mg,产率11％)。Combine N-(ethylaminothioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-35A) (500 mg, 1.30 mmol) and pyridine (308 mg, 3.89 mmol) ) was dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, the temperature was lowered to 0°C, and elemental iodine (1.00 g, 3.89 mmol) was slowly added to the reaction solution. Stir at room temperature for 14h. The reaction was quenched with saturated sodium thiosulfate (100 mL), extracted 3 times with ethyl acetate (100 mL*3), the organic phases were combined and spin-dried to obtain a crude product, which was recrystallized from ethyl acetate to obtain 1-(ethylamino) -4-(2-Fluorophenyl)-6-(trifluoromethyl)-3H-pyridin[1,2-c]pyrimidin-3-one (I-35) (50 mg, 11% yield).
1H NMR(400MHz,DMSO-d 6)δ8.13(d,1H),8.00-7.98(m,1H),7.49-7.47(m,1H),7.29-7.27(m,3H),6.79(s,1H),6.72-6.70(m,1H)，3.44-3.41(m,2H),1.23-1.19(m,3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.13(d,1H), 8.00-7.98(m,1H), 7.49-7.47(m,1H), 7.29-7.27(m,3H), 6.79(s) ,1H),6.72-6.70(m,1H),3.44-3.41(m,2H),1.23-1.19(m,3H).
LC-MS,M/Z(ESI):352.3[M+H] +。 LC-MS, M/Z (ESI): 352.3 [M+H] + .
实施例36：目标化合物I-36的制备Example 36: Preparation of target compound I-36
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000212
Figure PCTCN2022087589-appb-000212
第一步：2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈的合成The first step: Synthesis of 2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile
Figure PCTCN2022087589-appb-000213
Figure PCTCN2022087589-appb-000213
在室温下，将2-氟苯乙腈(5.00g,37.0mmol)，2-溴-4-(三氟甲基)吡啶(8.36g,37.0mmol)和氢氧化钾(2.08g,37.0mmol)加入到N-甲基吡咯烷酮(80.0mL)中，氮气保护下在90℃反应15小时。反应完成后，反应液加入水(200mL)，然后用乙酸乙酯(100mL*2)萃取，合并有机层相，用饱和食盐水(50.0mL*2)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝200:1至6:1)得黄色固体化合物2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(7.90g，产率76.2％)。At room temperature, 2-fluorophenylacetonitrile (5.00 g, 37.0 mmol), 2-bromo-4-(trifluoromethyl)pyridine (8.36 g, 37.0 mmol) and potassium hydroxide (2.08 g, 37.0 mmol) were added into N-methylpyrrolidone (80.0 mL) and react at 90°C for 15 hours under nitrogen protection. After the completion of the reaction, water (200 mL) was added to the reaction solution, and then extracted with ethyl acetate (100 mL*2). The organic layers were combined, washed with saturated brine (50.0 mL*2), dried over anhydrous sodium sulfate, and filtered. , concentrated to obtain crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=200:1 to 6:1) to obtain yellow solid compound 2-(2-fluorophenyl)-2-(4-(trifluoromethyl) )pyridin-2-yl)acetonitrile (7.90 g, 76.2% yield).
LC-MS,M/Z(ESI):281.2(M+H) + LC-MS, M/Z (ESI): 281.2 (M+H) +
第二步：2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The second step: synthesis of 2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
Figure PCTCN2022087589-appb-000214
Figure PCTCN2022087589-appb-000214
在室温下，将2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(7.80g,27.8mmol)加入到浓 硫酸(20.0mL)中，氮气保护下在25℃反应1小时。反应完成后，反应液0～10℃下小心加入到饱和的碳酸氢钠水溶液(300mL)中，然后用乙酸乙酯(150mL*2)萃取，合并有机层相，用饱和食盐水(50.0mL*2)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝100:1至6:1)得到黄色固体化合物2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(5.40g，产率65.1％)。2-(2-Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (7.80 g, 27.8 mmol) was added to concentrated sulfuric acid (20.0 mL) at room temperature, The reaction was carried out at 25°C for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was carefully added to saturated aqueous sodium bicarbonate solution (300 mL) at 0-10 °C, then extracted with ethyl acetate (150 mL*2), the organic layers were combined, and saturated brine (50.0 mL*2) was used for extraction. 2) Wash the organic phase, dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=100:1 to 6:1) to obtain a yellow solid compound 2-(2-fluorophenyl)-2-(4-(trifluoromethyl) ) pyridin-2-yl)acetamide (5.40 g, 65.1% yield).
LC-MS,M/Z(ESI):299.1[M+H] + LC-MS, M/Z(ESI): 299.1[M+H] +
第三步：1,1-二氟-2-异硫氰基乙烷的合成The third step: synthesis of 1,1-difluoro-2-isothiocyanatoethane
Figure PCTCN2022087589-appb-000215
Figure PCTCN2022087589-appb-000215
在室温下，将2,2-二氟乙胺(300mg,3.70mmol)，三乙胺(1.50g,14.8mmol)加入到二氯甲烷(5mL)中，0～10℃下加入硫光气(425mg,3.70mmol)，加完后在25℃反应2小时，反应液过滤，浓缩得到粗品化合物1,1-二氟-2-异硫氰基乙烷(450mg，粗品)。直接用于下一步。At room temperature, 2,2-difluoroethylamine (300 mg, 3.70 mmol) and triethylamine (1.50 g, 14.8 mmol) were added to dichloromethane (5 mL), and thiophosgene ( 425 mg, 3.70 mmol), reacted at 25°C for 2 hours after the addition, the reaction solution was filtered and concentrated to obtain the crude compound 1,1-difluoro-2-isothiocyanatoethane (450 mg, crude). used directly in the next step.
第四步：N-((2,2-二氟乙基)氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The fourth step: N-((2,2-difluoroethyl)carbamoyl)-2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl ) Synthesis of acetamide
Figure PCTCN2022087589-appb-000216
Figure PCTCN2022087589-appb-000216
在室温下，将2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(500mg,1.68mmol)，1,1-二氟-2-异硫氰基乙烷(248mg,2.01mmol)和碳酸铯(2.18g,6.71mmol)加入到N,N-二甲基甲酰胺(10.0mL)中，氮气保护下在25℃反应8小时。反应完成后，反应液过滤浓缩得到粗品化合物N-((2,2-二氟乙基)氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(600mg，粗品)。直接用于下一步。At room temperature, 2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (500 mg, 1.68 mmol), 1,1-difluoro-2- Isothiocyanatoethane (248 mg, 2.01 mmol) and cesium carbonate (2.18 g, 6.71 mmol) were added to N,N-dimethylformamide (10.0 mL) and reacted at 25° C. for 8 hours under nitrogen protection. After the completion of the reaction, the reaction solution was filtered and concentrated to obtain the crude compound N-((2,2-difluoroethyl)carbamoyl)-2-(2-fluorophenyl)-2-(4-(trifluoromethyl) yl)pyridin-2-yl)acetamide (600 mg, crude). used directly in the next step.
LC-MS,M/Z(ESI):422.1(M+H) + LC-MS, M/Z (ESI): 422.1 (M+H) +
第五步：1-((2,2-二氟乙基)氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-36)的合成The fifth step: 1-((2,2-difluoroethyl)amino)-4-(2-fluorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c] Synthesis of Pyrimidine-3-one (I-36)
Figure PCTCN2022087589-appb-000217
Figure PCTCN2022087589-appb-000217
在氮气保护下，将N-((2,2-二氟乙基)氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(40.0mg,94.3μmol)，碘单质(72.3mg,285μmol)和吡啶(37.6mg,475μmol)加入到四氢呋喃(1.00mL)中，氮气保护下25℃下反应8小时，反应液过滤浓缩得到粗品，残留物用高效液相色谱仪分离纯化，分离方法为(柱子：Phenomenex Synergi C18 150*30mm*7um；溶剂：A＝水+0.1体积％三氟乙酸(99％)，B＝乙腈；梯度：40％-60％，7分钟)，得到目标化合物1-((2,2-二氟乙基)氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-36)(12.7mg，31.4％产率)。Under nitrogen protection, N-((2,2-difluoroethyl)carbamoyl)-2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridine-2 -yl)acetamide (40.0 mg, 94.3 μmol), iodine element (72.3 mg, 285 μmol) and pyridine (37.6 mg, 475 μmol) were added to tetrahydrofuran (1.00 mL), and reacted at 25°C for 8 hours under nitrogen protection, the reaction solution The crude product was obtained by filtration and concentration, and the residue was separated and purified by high performance liquid chromatography. The separation method was (column: Phenomenex Synergi C18 150*30mm*7um; solvent: A=water+0.1% by volume trifluoroacetic acid (99%), B= Acetonitrile; gradient: 40%-60%, 7 min) to give the title compound 1-((2,2-difluoroethyl)amino)-4-(2-fluorophenyl)-6-(trifluoromethyl) )-3H-pyrido[1,2-c]pyrimidin-3-one (1-36) (12.7 mg, 31.4% yield).
1H NMR(400MHz,CDCl 3)δ8.84-8.90(m,1H),7.47-7.49(m,1H),7.28-7.33(m,3H),7.24-7.20(t,1H),6.91-6.93(m,1H),5.87-6.16(m,1H),3.85-3.92(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 8.84-8.90 (m, 1H), 7.47-7.49 (m, 1H), 7.28-7.33 (m, 3H), 7.24-7.20 (t, 1H), 6.91-6.93 (m,1H),5.87-6.16(m,1H),3.85-3.92(m,2H).
。.
LC-MS,M/Z(ESI):388.1[M+H] + LC-MS, M/Z(ESI): 388.1[M+H] +
实施例37：目标化合物I-37的制备Example 37: Preparation of target compound I-37
4-(2,6-二氟苯基)-1-(甲氨基)-6-(三氟甲基)-3H-吡啶[1,2-c]嘧啶-3-酮(I-37)4-(2,6-Difluorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyridin[1,2-c]pyrimidin-3-one (I-37)
Figure PCTCN2022087589-appb-000218
Figure PCTCN2022087589-appb-000218
目标化合物I-37的合成路线如下所示：The synthetic route of the target compound I-37 is shown below:
Figure PCTCN2022087589-appb-000219
Figure PCTCN2022087589-appb-000219
第一步:2-(2,6-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-37B)的合成The first step: Synthesis of 2-(2,6-difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-37B)
Figure PCTCN2022087589-appb-000220
Figure PCTCN2022087589-appb-000220
将2-溴-4-(三氟甲基)吡啶(1g,4.42mmol),2-(2,6-二氟苯基)乙腈(0.75g,4.87mmol)溶解在四氢呋喃(10mL)中，置换氮气，然后慢慢滴加叔丁醇钾的四氢呋喃溶液(6.19mL，6.19mmol，1M)，室温下反应3h。用饱和的氯化铵溶液(20mL)淬灭反应，乙酸乙酯(20mL*2)萃取两次，分离干燥有机相，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1)得到2-(2,6-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-37B)(1.1g，产率83％)。2-Bromo-4-(trifluoromethyl)pyridine (1 g, 4.42 mmol), 2-(2,6-difluorophenyl)acetonitrile (0.75 g, 4.87 mmol) were dissolved in tetrahydrofuran (10 mL) and replaced nitrogen, and then slowly dropwise added potassium tert-butoxide in tetrahydrofuran solution (6.19 mL, 6.19 mmol, 1 M), and reacted at room temperature for 3 h. The reaction was quenched with saturated ammonium chloride solution (20 mL), extracted twice with ethyl acetate (20 mL*2), the organic phase was separated and dried, and the crude product was obtained by spin drying. The crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate= 10/1) to give 2-(2,6-difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-37B) (1.1 g, 83% yield) .
LC-MS,M/Z(ESI):299.0[M+H] + LC-MS, M/Z(ESI): 299.0[M+H] +
第二步:2-(2,6-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-37C)的合成Step 2: Synthesis of 2-(2,6-difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-37C)
Figure PCTCN2022087589-appb-000221
Figure PCTCN2022087589-appb-000221
把2-(2,6-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-37B)(1g，3.35mmol)溶到浓硫酸(5mL)中，置换氮气，室温搅拌14h。把反应液缓慢倒入冰水(50mL)中，然后乙酸乙酯(20mL*2)萃取两次，有机相合并再用饱和碳酸氢钠溶液(100mL)洗一次，分离干燥有机相，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1)得到2-(2,6-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-37C)(1g,产率94％)。2-(2,6-Difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-37B) (1 g, 3.35 mmol) was dissolved in concentrated sulfuric acid (5 mL) In the solution, nitrogen was replaced, and the mixture was stirred at room temperature for 14 h. The reaction solution was slowly poured into ice water (50mL), then extracted twice with ethyl acetate (20mL*2), the organic phases were combined and washed once with saturated sodium bicarbonate solution (100mL), the organic phase was separated and dried, and spin-dried to obtain The crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=10/1) to obtain 2-(2,6-difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl) ) acetamide (I-37C) (1 g, 94% yield).
LC-MS,M/Z(ESI):317.0[M+H] + LC-MS, M/Z(ESI): 317.0[M+H] +
第三步：2-(2,6-二氟苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-37D)的合成The third step: 2-(2,6-difluorophenyl)-N-(methylaminothioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I -37D) synthesis
Figure PCTCN2022087589-appb-000222
Figure PCTCN2022087589-appb-000222
将2-(2,6-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-37C)(600mg，1.90mmol)和碳酸铯(1.24g，3.79mmol)溶到N,N-二甲基甲酰胺(5mL)中，置换氮气，降温到0℃，慢慢滴加异硫氰酸甲酯(166mg，2.28mmol)，在室温下搅拌14h。食盐水(20mL)淬灭反应，乙酸乙酯(20mL*2)萃取两次，分离干燥有机相，旋干得到粗品，粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝20/1)得到2-(2,6-二氟苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-37D)(500mg,产率68％)。Combine 2-(2,6-difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-37C) (600 mg, 1.90 mmol) and cesium carbonate (1.24 g) , 3.79 mmol) was dissolved in N,N-dimethylformamide (5 mL), replaced with nitrogen, cooled to 0 °C, slowly added methyl isothiocyanate (166 mg, 2.28 mmol) dropwise, and stirred at room temperature for 14 h . The reaction was quenched with brine (20 mL), extracted twice with ethyl acetate (20 mL*2), the organic phase was separated and dried, and the crude product was obtained by spin drying. The crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate=20/1) to obtain 2-(2,6-Difluorophenyl)-N-(methylaminothiocarbonyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-37D)( 500 mg, 68% yield).
LC-MS,M/Z(ESI):390.0[M+H] + LC-MS, M/Z(ESI): 390.0[M+H] +
第四步：4-(2,6-二氟苯基)-1-(甲氨基)-6-(三氟甲基)-3H-吡啶[1,2-c]嘧啶-3-酮(I-37)的合成The fourth step: 4-(2,6-difluorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyridin[1,2-c]pyrimidin-3-one (I -37) synthesis
Figure PCTCN2022087589-appb-000223
Figure PCTCN2022087589-appb-000223
将2-(2,6-二氟苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-37D)(500mg，1.28mmol)和吡啶(406mg，5.14mmol)溶到四氢呋喃(10mL)中，置换氮气，降温到0℃，将碘单质(1.30g，5.14mmol)慢慢加入反应液。在室温下搅拌14h。用饱和的硫代硫酸钠溶液(100mL)淬灭反应，乙酸乙酯(100mL*3)萃取3次，有机相合并旋干，得到粗品，粗品用乙酸乙酯重结晶得到4-(2,6-二氟苯基)-1-(甲氨基)-6-(三氟甲基)-3H-吡啶[1,2-c]嘧啶-3-酮(I-37)(70mg,产率15％)。2-(2,6-Difluorophenyl)-N-(methylaminothiocarbonyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-37D) (500 mg, 1.28 mmol) and pyridine (406 mg, 5.14 mmol) were dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, the temperature was lowered to 0°C, and elemental iodine (1.30 g, 5.14 mmol) was slowly added to the reaction solution. Stir at room temperature for 14h. The reaction was quenched with saturated sodium thiosulfate solution (100 mL), extracted 3 times with ethyl acetate (100 mL*3), the organic phases were combined and spin-dried to obtain a crude product, which was recrystallized from ethyl acetate to obtain 4-(2,6 -Difluorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyridin[1,2-c]pyrimidin-3-one (I-37) (70 mg, 15% yield ).
1H NMR(400MHz,DMSO-d 6)δ8.13(d,2H),7.52–7.50(m,1H),7.22–7.18(m,2H),6.79– 6.77(m,2H)，2.90(s,3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.13(d,2H), 7.52-7.50(m,1H), 7.22-7.18(m,2H), 6.79- 6.77(m,2H), 2.90(s , 3H).
LC-MS,M/Z(ESI):356.4[M+H] + LC-MS, M/Z(ESI): 356.4[M+H] +
实施例38：目标化合物I-38的制备Example 38: Preparation of target compound I-38
4-(2-氯苯基)-1-(二甲氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-38)4-(2-Chlorophenyl)-1-(dimethylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (target compound I-38)
Figure PCTCN2022087589-appb-000224
Figure PCTCN2022087589-appb-000224
目标化合物I-38的合成路线如下所示：The synthetic route of the target compound I-38 is as follows:
Figure PCTCN2022087589-appb-000225
Figure PCTCN2022087589-appb-000225
氮气保护下，在0℃，向4-(2-氯苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-1)(100mg,283μmol)的四氢呋喃(2.00mL)溶液中加入钠氢(17.0mg,424μmol)，反应在25℃搅拌0.5小时，然后在0℃下，慢慢加入碘甲烷(44.1mg,311μmol)，反应在25℃搅拌10小时。反应完成后，将反应混合物用水(10.0mL)稀释，然后用乙酸乙酯(10.0mL*3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，残留物用层析板分离纯化(乙酸乙酯:甲醇(V/V)＝10:1)，得到黄色固体化合物4-(2-氯苯基)-1-(二甲氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-3)(59.3mg,产率55.1％)。Under nitrogen protection, at 0 °C, to 4-(2-chlorophenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 - To a solution of ketone (I-1) (100 mg, 283 μmol) in tetrahydrofuran (2.00 mL) was added sodium hydrogen (17.0 mg, 424 μmol), the reaction was stirred at 25 °C for 0.5 h, then at 0 °C, iodomethane ( 44.1 mg, 311 μmol), the reaction was stirred at 25°C for 10 hours. After the reaction was completed, the reaction mixture was diluted with water (10.0 mL), then extracted with ethyl acetate (10.0 mL*3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by chromatography ( Ethyl acetate:methanol (V/V)=10:1) to obtain a yellow solid compound 4-(2-chlorophenyl)-1-(dimethylamino)-6-(trifluoromethyl)-3H-pyridine and [1,2-c]pyrimidin-3-one (I-3) (59.3 mg, 55.1% yield).
1H NMR(400MHz,DMSO_d 6):δ7.99(d,1H),7.52-7.65(m,1H),7.39-7.50(m,2H),7.25-7.36(m,1H),6.68(s,1H),6.63(dd,1H),2.94(s,6H). 1 H NMR (400MHz, DMSO_d 6 ): δ7.99(d,1H), 7.52-7.65(m,1H), 7.39-7.50(m,2H), 7.25-7.36(m,1H), 6.68(s, 1H), 6.63(dd, 1H), 2.94(s, 6H).
LC-MS,M/Z(ESI):368.1[M+H] + LC-MS, M/Z(ESI): 368.1[M+H] +
实施例39：目标化合物I-39的制备Example 39: Preparation of target compound I-39
4-(2-氯苯基)-1-(乙胺基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-39)4-(2-Chlorophenyl)-1-(ethylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (target compound I-39)
Figure PCTCN2022087589-appb-000226
Figure PCTCN2022087589-appb-000226
目标化合物I-39的合成路线如下所示：The synthetic route of the target compound I-39 is shown below:
Figure PCTCN2022087589-appb-000227
Figure PCTCN2022087589-appb-000227
第一步：2-(2-氯苯基)-N-(乙基氨基硫代甲酰)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-39A)的合成The first step: 2-(2-chlorophenyl)-N-(ethylaminothiocarbonyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-39A) Synthesis
Figure PCTCN2022087589-appb-000228
Figure PCTCN2022087589-appb-000228
向2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-1D)(4.00g,12.7mmol)的N,N-二甲基甲酰胺(40.0mL)溶液中加入碳酸铯(6.21g,19.1mmol)和乙基异硫氰酸酯(1.11g,12.7mmol)，反应在70℃搅拌10小时。反应完成后，将反应混合物用水(200mL)稀释，然后用乙酸乙酯(100mL*3)萃取，合并有机层，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝20:1-5:1)得到黄色固体化合物2-(2-氯苯基)-N-(乙基氨基硫代甲酰)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-39A)(3.50g,8.71mmol,产率68.5％)。N,N-Dimethyl to 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-1D) (4.00 g, 12.7 mmol) Cesium carbonate (6.21 g, 19.1 mmol) and ethyl isothiocyanate (1.11 g, 12.7 mmol) were added to the formamide (40.0 mL) solution, and the reaction was stirred at 70° C. for 10 hours. After the completion of the reaction, the reaction mixture was diluted with water (200 mL), then extracted with ethyl acetate (100 mL*3), the organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=20:1-5:1) to obtain a yellow solid compound 2-(2-chlorophenyl)-N-(ethylaminothiocarbonyl) )-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-39A) (3.50 g, 8.71 mmol, 68.5% yield).
LC-MS,M/Z(ESI):402.1[M+H] + LC-MS, M/Z(ESI): 402.1[M+H] +
第二步：4-(2-氯苯基)-1-(乙胺基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-39)的合成The second step: 4-(2-chlorophenyl)-1-(ethylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I- 39) Synthesis
向2-(2-氯苯基)-N-(乙基氨基硫代甲酰)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-39A)(4.00g,9.95mmol)的四氢呋喃(50.0mL)溶液中加入碘单质(7.58g,29.9mmol)和吡啶(2.36g,29.9mmol)，反应在25℃搅拌10小时。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(200mL)稀释，然后用乙酸乙酯(200mL*3)萃取，合并有机层，用饱和亚硫酸钠水溶液(200mL*3)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用高效液相色谱仪分离纯化，分离方法为(柱子：Phenomenex luna C18 250*70mm,10μm；溶剂：A＝水+0.225体积％甲酸(99.0％)，B＝乙腈；梯度：35％-65％，20分钟)，得到黄色固体化合物4-(2-氯苯基)-1-(乙胺基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-39)(937mg,产率25.2％)。To 2-(2-chlorophenyl)-N-(ethylaminothiocarbonyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-39A) (4.00 g , 9.95 mmol) in tetrahydrofuran (50.0 mL) solution was added iodine (7.58 g, 29.9 mmol) and pyridine (2.36 g, 29.9 mmol), and the reaction was stirred at 25° C. for 10 hours. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium sulfite solution (200 mL), then extracted with ethyl acetate (200 mL*3), the organic layers were combined, washed with saturated aqueous sodium sulfite solution (200 mL*3), dried over anhydrous sodium sulfate, and filtered. , concentrated, and the residue was separated and purified by high performance liquid chromatography. The separation method was (column: Phenomenex luna C18 250*70mm, 10μm; solvent: A=water+0.225 vol% formic acid (99.0%), B=acetonitrile; gradient: 35%-65%, 20 minutes) to give yellow solid compound 4-(2-chlorophenyl)-1-(ethylamino)-6-(trifluoromethyl)-3H-pyrido[1,2- c] Pyrimidine-3-one (I-39) (937 mg, 25.2% yield).
1H NMR(400MHz,DMSO_d 6):δ8.19(br d,1H),8.03-8.14(m,1H),7.57-7.65(m,1H),7.41-7.46(m,2H),7.23-7.37(m,1H),6.78(br d,1H),6.63(br s,1H),3.45-3.55(m,2H),1.22(t,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ 8.19 (br d, 1H), 8.03-8.14 (m, 1H), 7.57-7.65 (m, 1H), 7.41-7.46 (m, 2H), 7.23-7.37 (m, 1H), 6.78(br d, 1H), 6.63(br s, 1H), 3.45-3.55(m, 2H), 1.22(t, 3H).
LC-MS,M/Z(ESI):368.0[M+H] + LC-MS, M/Z(ESI): 368.0[M+H] +
实施例40：目标化合物I-40的制备Example 40: Preparation of target compound I-40
1-氨基-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-40)1-Amino-4-(2-chlorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (target compound I-40)
Figure PCTCN2022087589-appb-000229
Figure PCTCN2022087589-appb-000229
目标化合物I-40的合成路线如下所示：The synthetic route of the target compound I-40 is as follows:
Figure PCTCN2022087589-appb-000230
Figure PCTCN2022087589-appb-000230
第一步：2-(2-氯苯基)-N-((4-甲氧苄基)氨基硫代甲酰)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-40A)的合成The first step: 2-(2-chlorophenyl)-N-((4-methoxybenzyl)aminothiol)-2-(4-(trifluoromethyl)pyridin-2-yl)ethyl Synthesis of Amide (I-40A)
Figure PCTCN2022087589-appb-000231
Figure PCTCN2022087589-appb-000231
向2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-1D)(2.50g,7.94mmol)的N,N-二甲基甲酰胺(20.0mL)溶液中加入碳酸铯(3.88g,11.9mmol)和4-甲氧基苄基异硫氰酸酯(2.14g,11.9mmol)，反应在75℃搅拌10小时。反应完成后，将反应混合物用水(100mL)稀释，然后用乙酸乙酯(80.0mL*3)萃取，合并有机层，用饱和食盐水(80.0mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至10:1)得到黄色油状物2-(2-氯苯基)-N-((4-甲氧苄基)氨基硫代甲酰)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-40A)(2.50g，粗品)，直接用于下一步。N,N-Dimethyl to 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-1D) (2.50 g, 7.94 mmol) To the formamide (20.0 mL) solution was added cesium carbonate (3.88 g, 11.9 mmol) and 4-methoxybenzyl isothiocyanate (2.14 g, 11.9 mmol), and the reaction was stirred at 75° C. for 10 hours. After the reaction was completed, the reaction mixture was diluted with water (100 mL), then extracted with ethyl acetate (80.0 mL*3), the organic layers were combined, washed with saturated brine (80.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated, The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=50:1 to 10:1) to obtain 2-(2-chlorophenyl)-N-((4-methoxyl) as a yellow oil Benzyl)carbamoyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-40A) (2.50 g, crude) was used directly in the next step.
第二步：4-(2-氯苯基)-1-((4-甲氧苄基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-40B)的合成Step 2: 4-(2-Chlorophenyl)-1-((4-methoxybenzyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine- Synthesis of 3-keto(I-40B)
Figure PCTCN2022087589-appb-000232
Figure PCTCN2022087589-appb-000232
向2-(2-氯苯基)-N-((4-甲氧苄基)氨基硫代甲酰)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-40A)(1.00g,2.02mmol)的四氢呋喃(20mL)溶液中加入碘单质(1.54g,6.06mmol)和吡啶(479mg,6.06mmol)，反应在25℃搅拌10小时。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(50.0mL)稀释，然后用乙酸乙酯(30.0mL*3)萃取，合并有机层，用饱和亚硫酸钠水溶液(30.0mL*3)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用乙酸乙酯(30.0mL)打浆，得到黄色固体化合物4-(2-氯苯基)-1-((4-甲氧苄基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-40B)(1.30g，粗品)，直接用于下一步。To 2-(2-chlorophenyl)-N-((4-methoxybenzyl)carbamoyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I Elemental iodine (1.54 g, 6.06 mmol) and pyridine (479 mg, 6.06 mmol) were added to a solution of -40A) (1.00 g, 2.02 mmol) in tetrahydrofuran (20 mL), and the reaction was stirred at 25° C. for 10 hours. After the completion of the reaction, the reaction mixture was diluted with saturated aqueous sodium sulfite solution (50.0 mL), then extracted with ethyl acetate (30.0 mL*3), the organic layers were combined, washed with saturated aqueous sodium sulfite solution (30.0 mL*3), and anhydrous sodium sulfate Dry, filter, concentrate, and the residue is slurried with ethyl acetate (30.0 mL) to give yellow solid compound 4-(2-chlorophenyl)-1-((4-methoxybenzyl)amino)-6-(tris Fluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-40B) (1.30 g, crude) was used directly in the next step.
1H NMR(400MHz,DMSO_d 6):δ8.52(br s,1H),8.21(br d,1H),7.50-7.60(m,2H),7.48(dd,1H),7.42(dt,2H),7.26-7.34(m,3H),6.73(br d,1H),6.60(br s,1H),4.56-4.68(m,2H),3.74(s,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ 8.52 (br s, 1H), 8.21 (br d, 1H), 7.50-7.60 (m, 2H), 7.48 (dd, 1H), 7.42 (dt, 2H) ,7.26-7.34(m,3H),6.73(br d,1H),6.60(br s,1H),4.56-4.68(m,2H),3.74(s,3H).
LC-MS,M/Z(ESI):460.3[M+H] + LC-MS, M/Z(ESI): 460.3[M+H] +
第三步：1-氨基-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-40)的合成The third step: Synthesis of 1-amino-4-(2-chlorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-40)
Figure PCTCN2022087589-appb-000233
Figure PCTCN2022087589-appb-000233
向三氟乙酸(10.0mL)溶液中加入4-(2-氯苯基)-1-((4-甲氧苄基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-40B)(200mg,435μmol)，反应在75℃搅拌10小时。反应完成后，将反应混合物减压浓缩，残留物用高效液相色谱仪分离纯化，分离方法为(色谱柱：3_Phenomenex Luna C18 75*30mm*3μm；溶剂：A＝水+0.225体积％盐酸(37.0％)，B＝乙腈；梯度：25％-45％，6.5分钟)，得到黄色固体化合物1-氨基-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-40)(41.1mg,113μmol,25.9％产率)。To a solution of trifluoroacetic acid (10.0 mL) was added 4-(2-chlorophenyl)-1-((4-methoxybenzyl)amino)-6-(trifluoromethyl)-3H-pyrido[1 ,2-c]pyrimidin-3-one (I-40B) (200 mg, 435 μmol), and the reaction was stirred at 75° C. for 10 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by high performance liquid chromatography. The separation method was (chromatographic column: 3_Phenomenex Luna C18 75*30mm*3 μm; solvent: A=water+0.225 vol% hydrochloric acid (37.0 %), B = acetonitrile; gradient: 25%-45%, 6.5 min) to give yellow solid compound 1-amino-4-(2-chlorophenyl)-6-(trifluoromethyl)-3H-pyrido [1,2-c]pyrimidin-3-one (I-40) (41.1 mg, 113 μmol, 25.9% yield).
1H NMR(400MHz,DMSO_d 6):δ8.53(br d,1H),7.58-7.68(m,1H),7.42-7.56(m,2H),7.30-7.41(m,1H),7.08-7.25(m,1H),6.87(s,1H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.53 (br d, 1H), 7.58-7.68 (m, 1H), 7.42-7.56 (m, 2H), 7.30-7.41 (m, 1H), 7.08-7.25 (m,1H),6.87(s,1H).
LC-MS,M/Z(ESI):340.0[M+H] + LC-MS, M/Z(ESI): 340.0[M+H] +
实施例41：目标化合物I-41的制备Example 41: Preparation of target compound I-41
4-(2-氯苯基)-1-[( 2H 3)甲基氨基]-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-41) 4-(2-Chlorophenyl)-1-[( 2 H 3 )methylamino]-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (target Compound I-41)
Figure PCTCN2022087589-appb-000234
Figure PCTCN2022087589-appb-000234
目标化合物I-41的合成路线如下所示：The synthetic route of the target compound I-41 is as follows:
Figure PCTCN2022087589-appb-000235
Figure PCTCN2022087589-appb-000235
第一步：异硫氰基( 2H 3)甲烷(3A)的合成 The first step: Synthesis of isothiocyanato ( 2 H 3 ) methane (3A)
Figure PCTCN2022087589-appb-000236
Figure PCTCN2022087589-appb-000236
向氘代甲胺盐酸盐(3A-1)(500mg,7.09mmol)的二氯甲烷(15.0mL)溶液中加入N,N-二异丙基乙胺(1.83g,14.2mmol)和碳酸铯(4.62g,14.2mmol)，然后将硫光气(978mg,8.51mmol)的二氯甲烷(10.0mL)溶液慢慢加入其中，反应在25℃搅拌10小时。反应完成后，将反应混合物减压浓缩，得到棕色油状化合物异硫氰基( 2H 3)甲烷(3A)(500mg，粗品)，直接用于下一步。 To a solution of deuterated methylamine hydrochloride (3A-1) (500 mg, 7.09 mmol) in dichloromethane (15.0 mL) was added N,N-diisopropylethylamine (1.83 g, 14.2 mmol) and cesium carbonate (4.62 g, 14.2 mmol), then a solution of thiophosgene (978 mg, 8.51 mmol) in dichloromethane (10.0 mL) was added slowly and the reaction was stirred at 25°C for 10 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give isothiocyano( 2 H 3 )methane (3A) (500 mg, crude) as a brown oily compound, which was used directly in the next step.
第二步：2-(2-氯苯基)-N-((甲基-d3)氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-41A)的合成Step 2: 2-(2-Chlorophenyl)-N-((methyl-d3)carbamoyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide ( Synthesis of I-41A)
Figure PCTCN2022087589-appb-000237
Figure PCTCN2022087589-appb-000237
向2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-1D)(1.00g,3.18mmol)的N,N-二甲基甲酰胺(15.0mL)溶液中加入碳酸铯(1.55g,4.77mmol)和异硫氰基( 2H 3)甲烷(363mg,4.77mmol)，反应在75℃搅拌10小时。反应完成后，将反应混合物用水(50.0mL)稀释，然后用乙酸乙酯(30.0mL*3)萃取，合并有机层，用饱和食盐水(30.0mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝20:1至10:1)得到黄色固体化合物2-(2-氯苯基)-N-((甲基-d3)氨基甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-41A)(200mg,产率16.1％)。 N,N-Dimethyl to 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-1D) (1.00 g, 3.18 mmol) To the formamide (15.0 mL) solution was added cesium carbonate (1.55 g, 4.77 mmol) and isothiocyanato( 2 H 3 )methane (363 mg, 4.77 mmol), and the reaction was stirred at 75° C. for 10 hours. After the completion of the reaction, the reaction mixture was diluted with water (50.0 mL), then extracted with ethyl acetate (30.0 mL*3), the organic layers were combined, washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated , the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=20:1 to 10:1) to obtain a yellow solid compound 2-(2-chlorophenyl)-N-((methyl- d3) Aminomethylcarbamoyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-41A) (200 mg, 16.1% yield).
第三步：4-(2-氯苯基)-1-[( 2H 3)甲基氨基]-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-41)的合成 The third step: 4-(2-chlorophenyl)-1-[( 2 H 3 )methylamino]-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 -Synthesis of ketone (I-41)
Figure PCTCN2022087589-appb-000238
Figure PCTCN2022087589-appb-000238
向2-(2-氯苯基)-N-((甲基-d3)氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-41A)(200mg,512μmol)的四氢呋喃(2.00mL)溶液中加入碘单质(390mg,1.54mmol)和吡啶(121mg,1.54mmol)，反应在30℃搅拌10小时。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(20.0mL)稀释，然后用乙酸乙酯(10.0mL*3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，残留物用乙酸乙酯(10.0mL)打浆，得到黄色固体化合物4-(2-氯苯基)-1-[( 2H 3)甲基氨基]-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-41)(59.7mg,167μmol,32.7％产率)。 To 2-(2-chlorophenyl)-N-((methyl-d3)carbamoyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-41A ) (200 mg, 512 μmol) in tetrahydrofuran (2.00 mL) was added iodine (390 mg, 1.54 mmol) and pyridine (121 mg, 1.54 mmol), and the reaction was stirred at 30° C. for 10 hours. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium sulfite solution (20.0 mL), then extracted with ethyl acetate (10.0 mL*3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was washed with ethyl acetate (10.0 mL) was beaten to obtain a yellow solid compound 4-(2-chlorophenyl)-1-[( 2 H 3 )methylamino]-6-(trifluoromethyl)-3H-pyrido[1,2 -c]pyrimidin-3-one (I-41) (59.7 mg, 167 μmol, 32.7% yield).
1H NMR(400MHz,DMSO_d 6):δ8.09(d,1H),8.03(s,1H),7.53-7.65(m,1H),7.37-7.48(m,2H),7.24-7.35(m,1H),6.72(br d,1H),6.60(s,1H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.09(d,1H), 8.03(s,1H), 7.53-7.65(m,1H), 7.37-7.48(m,2H), 7.24-7.35(m, 1H), 6.72(br d, 1H), 6.60(s, 1H).
LC-MS,M/Z(ESI):357.1[M+H] + LC-MS, M/Z(ESI): 357.1[M+H] +
实施例42：目标化合物I-42的制备Example 42: Preparation of target compound I-42
4-(2-氯苯基)-6-(二氟甲基)-1-(甲基氨基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-42)4-(2-Chlorophenyl)-6-(difluoromethyl)-1-(methylamino)-3H-pyrido[1,2-c]pyrimidin-3-one (target compound I-42)
Figure PCTCN2022087589-appb-000239
Figure PCTCN2022087589-appb-000239
目标化合物I-42的合成路线如下所示：The synthetic route of the target compound I-42 is as follows:
Figure PCTCN2022087589-appb-000240
Figure PCTCN2022087589-appb-000240
第一步：2-(2-氯苯基)-2-(4-(二氟甲基)吡啶-2-基)乙腈(I-42B)的合成The first step: Synthesis of 2-(2-chlorophenyl)-2-(4-(difluoromethyl)pyridin-2-yl)acetonitrile (I-42B)
Figure PCTCN2022087589-appb-000241
Figure PCTCN2022087589-appb-000241
在0℃下，向邻氯苄腈(I-42A)(400mg,2.64mmol)的N,N-二甲基甲酰胺(2.00mL)溶液中加入钠氢(115mg,2.88mmol)，反应在30℃搅拌1小时，然后加入2-溴-4-(二氟甲基)吡啶(400mg,1.92mmol)，反应在30℃搅拌10小时。反应完成后，将反应混合物用水(20.0mL)稀释，然后用乙酸乙酯(20.0mL*3)萃取，合并有机层，用饱和食盐水(20.0mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝20:1至10:1)得到黄色油状物2-(2-氯苯基)-2-(4-(二氟甲基)吡啶-2-基)乙腈(I-42B)(460mg,产率85.8％)。To a solution of o-chlorobenzonitrile (I-42A) (400 mg, 2.64 mmol) in N,N-dimethylformamide (2.00 mL) at 0 °C was added sodium hydrogen (115 mg, 2.88 mmol), and the reaction was carried out at 30 Stir at °C for 1 hour, then add 2-bromo-4-(difluoromethyl)pyridine (400 mg, 1.92 mmol) and stir the reaction at 30 °C for 10 hours. After the completion of the reaction, the reaction mixture was diluted with water (20.0 mL), then extracted with ethyl acetate (20.0 mL*3), the organic layers were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated , the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=20:1 to 10:1) to obtain 2-(2-chlorophenyl)-2-(4-(diol) as a yellow oil Fluoromethyl)pyridin-2-yl)acetonitrile (I-42B) (460 mg, 85.8% yield).
LC-MS,M/Z(ESI):279.1[M+H] + LC-MS, M/Z(ESI): 279.1[M+H] +
第二步：2-(2-氯苯基)-2-(4-(二氟甲基)吡啶-2-基)乙酰胺(I-42C)的合成The second step: Synthesis of 2-(2-chlorophenyl)-2-(4-(difluoromethyl)pyridin-2-yl)acetamide (I-42C)
Figure PCTCN2022087589-appb-000242
Figure PCTCN2022087589-appb-000242
向硫酸(2.00mL)中加入2-(2-氯苯基)-2-(4-(二氟甲基)吡啶-2-基)乙腈(I-42B)(450mg,1.61mmol)，反应在30℃搅拌10小时。反应完成后，将反应液在0℃下慢慢加入到氢氧化钠水溶液(5.00M,50.0mL)中，然后用乙酸乙酯(30.0mL*3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，得到黄色固体2-(2-氯苯基)-2-(4-(二氟甲基)吡啶-2-基)乙酰胺(I-42C)(450mg,产率93.9％)，直接用于下一步。To sulfuric acid (2.00 mL) was added 2-(2-chlorophenyl)-2-(4-(difluoromethyl)pyridin-2-yl)acetonitrile (I-42B) (450 mg, 1.61 mmol), the reaction was Stir at 30°C for 10 hours. After the reaction was completed, the reaction solution was slowly added to an aqueous sodium hydroxide solution (5.00M, 50.0mL) at 0°C, then extracted with ethyl acetate (30.0mL*3), the organic layers were combined and dried over anhydrous sodium sulfate , filtered and concentrated to give yellow solid 2-(2-chlorophenyl)-2-(4-(difluoromethyl)pyridin-2-yl)acetamide (I-42C) (450 mg, 93.9% yield) , used directly in the next step.
LC-MS,M/Z(ESI):297.2[M+H] + LC-MS, M/Z(ESI): 297.2[M+H] +
第三步：2-(2-氯苯基)-2-(4-(二氟甲基)吡啶-2-基)-N-(甲基氨基硫代甲酰)乙酰胺(I-42D)的合成The third step: 2-(2-chlorophenyl)-2-(4-(difluoromethyl)pyridin-2-yl)-N-(methylaminothioyl)acetamide (I-42D) Synthesis
Figure PCTCN2022087589-appb-000243
Figure PCTCN2022087589-appb-000243
向2-(2-氯苯基)-2-(4-(二氟甲基)吡啶-2-基)乙酰胺(I-42C)(400mg,1.35mmol)的N,N-二甲基甲酰胺(10.0mL)溶液中加入甲基异硫氰酸酯(108mg,1.48mmol)和碳酸铯(659mg,2.02mmol)，反应在50℃搅拌10小时。反应完成后，将反应混合物用水(20.0mL)稀释，然后用乙酸乙酯(10.0mL*3)萃取，合并有机层，用饱和食盐水(10.0mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝20:1至3:1)得到黄色固体化合物2-(2-氯苯基)-2-(4-(二氟甲基)吡啶-2-基)-N-(甲基氨基硫代甲酰)乙酰胺(I-42D)(400mg,产率80.2％)。To 2-(2-chlorophenyl)-2-(4-(difluoromethyl)pyridin-2-yl)acetamide (I-42C) (400 mg, 1.35 mmol) in N,N-dimethylmethane To the amide (10.0 mL) solution was added methyl isothiocyanate (108 mg, 1.48 mmol) and cesium carbonate (659 mg, 2.02 mmol), and the reaction was stirred at 50° C. for 10 hours. After the reaction was completed, the reaction mixture was diluted with water (20.0 mL), then extracted with ethyl acetate (10.0 mL*3), the organic layers were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated , the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=20:1 to 3:1) to obtain a yellow solid compound 2-(2-chlorophenyl)-2-(4-(diol) Fluoromethyl)pyridin-2-yl)-N-(methylaminothioyl)acetamide (I-42D) (400 mg, 80.2% yield).
LC-MS,M/Z(ESI):370.2[M+H] + LC-MS, M/Z(ESI): 370.2[M+H] +
第四步：4-(2-氯苯基)-6-(二氟甲基)-1-(甲基氨基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-42)的合成The fourth step: 4-(2-chlorophenyl)-6-(difluoromethyl)-1-(methylamino)-3H-pyrido[1,2-c]pyrimidin-3-one (I- 42) Synthesis
Figure PCTCN2022087589-appb-000244
Figure PCTCN2022087589-appb-000244
向2-(2-氯苯基)-2-(4-(二氟甲基)吡啶-2-基)-N-(甲基氨基硫代甲酰)乙酰胺(I-42D)(380mg,1.03mmol)的四氢呋喃(5.00mL)溶液中加入碘单质(782mg,3.08mmol)和吡啶(1.00g,3.08mmol)，反应在25℃搅拌10小时。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(50.0mL)稀释，然后用乙酸乙酯(30.0mL*3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，用饱和亚硫酸钠水溶液(30.0mL*3)洗涤，残留物用乙酸乙酯(10.0mL)打浆，得到黄色固体化合物4-(2-氯苯基)-6-(二氟甲基)-1-(甲基氨基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-42)(107mg,产率30.4％)。To 2-(2-chlorophenyl)-2-(4-(difluoromethyl)pyridin-2-yl)-N-(methylcarbamoyl)acetamide (I-42D) (380 mg, To a solution of 1.03 mmol) in tetrahydrofuran (5.00 mL), elemental iodine (782 mg, 3.08 mmol) and pyridine (1.00 g, 3.08 mmol) were added, and the reaction was stirred at 25° C. for 10 hours. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium sulfite (50.0 mL), then extracted with ethyl acetate (30.0 mL*3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and washed with saturated aqueous sodium sulfite (30.0 mL). mL*3) was washed, and the residue was slurried with ethyl acetate (10.0 mL) to obtain a yellow solid compound 4-(2-chlorophenyl)-6-(difluoromethyl)-1-(methylamino)-3H - Pyrido[1,2-c]pyrimidin-3-one (I-42) (107 mg, 30.4% yield).
1H NMR(400MHz,DMSO_d 6):δ8.04(d,1H),7.99(br s,1H),7.51-7.62(m,1H),7.35-7.47(m,2H),7.27(dd,1H),6.84(t,1H),6.63(br s,1H),6.59(br d,1H),2.89(s,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ 8.04 (d, 1H), 7.99 (br s, 1H), 7.51-7.62 (m, 1H), 7.35-7.47 (m, 2H), 7.27 (dd, 1H) ), 6.84(t, 1H), 6.63(br s, 1H), 6.59(br d, 1H), 2.89(s, 3H).
LC-MS,M/Z(ESI):336.2[M+H] + LC-MS, M/Z(ESI): 336.2[M+H] +
实施例43：目标化合物I-43的制备Example 43: Preparation of target compound I-43
6-(二氟甲基)-1-(乙基氨基)-4-(2-氟苯基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-43)6-(Difluoromethyl)-1-(ethylamino)-4-(2-fluorophenyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-43)
Figure PCTCN2022087589-appb-000245
Figure PCTCN2022087589-appb-000245
目标化合物I-43的合成路线如下所示：The synthetic route of the target compound I-43 is as follows:
Figure PCTCN2022087589-appb-000246
Figure PCTCN2022087589-appb-000246
第一步：2-溴-4-(二氟甲基)吡啶(3G)的合成The first step: the synthesis of 2-bromo-4-(difluoromethyl)pyridine (3G)
Figure PCTCN2022087589-appb-000247
Figure PCTCN2022087589-appb-000247
氮气保护下，在-70℃下，向2-溴吡啶-4-甲醛3G-1)(2.00g，10.8mmol,)的二氯甲烷(20.0mL)溶液中加入二乙氨基三氟化硫(5.20g,32.3mmol)，反应在20℃搅拌2小时。反应完成后，将反应混合物用饱和碳酸氢钠水溶液(50.0mL)淬灭，然后用二氯甲烷(30.0mL*3)萃取，合并有机层，干燥，过滤，浓缩得到黄色油状物2-溴-4-(二氟甲基)吡啶(3G)(2.00g,产率89.4％)。直接用于下一步。Under nitrogen protection, diethylaminosulfur trifluoride ( 5.20 g, 32.3 mmol), the reaction was stirred at 20°C for 2 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (50.0 mL), then extracted with dichloromethane (30.0 mL*3), the organic layers were combined, dried, filtered, and concentrated to give a yellow oil 2-bromo- 4-(Difluoromethyl)pyridine (3G) (2.00 g, 89.4% yield). used directly in the next step.
1H NMR(400MHz,DMSO_d 6)δ8.58(d,1H),7.86(s,1H),7.65(d,1H),7.09(t,1H). 1 H NMR (400MHz, DMSO_d 6 )δ8.58(d,1H),7.86(s,1H),7.65(d,1H),7.09(t,1H).
第二步：2-(4-(二氟甲基)吡啶-2-基)-2-(2-氟苯基)乙腈(I-43B)的合成The second step: Synthesis of 2-(4-(difluoromethyl)pyridin-2-yl)-2-(2-fluorophenyl)acetonitrile (I-43B)
Figure PCTCN2022087589-appb-000248
Figure PCTCN2022087589-appb-000248
氮气保护下，在0℃下，向2-(2-氟苯基)乙腈(I-43A)(900mg,6.66mmol)的N,N-二甲基甲酰胺(10.0mL)溶液中加入钠氢(400mg,9.99mmol,60％纯度)，反应在20℃搅拌1小时，然后加入2-溴-4-(二氟甲基)吡啶(3G)(1.00g,4.81mmol)，反应在20℃搅拌10小时。反应完成后，将反应混合物用水(50.0mL)稀释，然后用乙酸乙酯(20.0mL*3)萃取，合并有机层，干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至10:1)得到黄色油状物2-(4-(二氟甲基)吡啶-2-基)-2-(2-氟苯基)乙腈(I-43B)(300mg,1.14mmol,产率23.8％)。To a solution of 2-(2-fluorophenyl)acetonitrile (I-43A) (900 mg, 6.66 mmol) in N,N-dimethylformamide (10.0 mL) was added sodium hydrogen at 0°C under nitrogen protection (400 mg, 9.99 mmol, 60% purity), the reaction was stirred at 20°C for 1 hour, then 2-bromo-4-(difluoromethyl)pyridine (3G) (1.00 g, 4.81 mmol) was added and the reaction was stirred at 20°C 10 hours. After the completion of the reaction, the reaction mixture was diluted with water (50.0 mL), then extracted with ethyl acetate (20.0 mL*3), the organic layers were combined, dried, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate) Ester (V/V) = 50:1 to 10:1) to give 2-(4-(difluoromethyl)pyridin-2-yl)-2-(2-fluorophenyl)acetonitrile (I- 43B) (300 mg, 1.14 mmol, 23.8% yield).
1H NMR(400MHz,DMSO_d 6)δ8.69-8.84(m,1H),7.59(br s,2H),7.55(td,1H),7.43-7.51(m,1H),7.27-7.34(m,2H),6.98-7.27(m,1H),6.25(s,1H). 1 H NMR(400MHz, DMSO_d 6 )δ8.69-8.84(m,1H),7.59(br s,2H),7.55(td,1H),7.43-7.51(m,1H),7.27-7.34(m, 2H), 6.98-7.27(m, 1H), 6.25(s, 1H).
LC-MS,M/Z(ESI):263.0[M+H] + LC-MS, M/Z(ESI): 263.0[M+H] +
第三步：2-(4-(二氟甲基)吡啶-2-基)-2-(2-氟苯基)乙酰胺(I-43C)的合成The third step: Synthesis of 2-(4-(difluoromethyl)pyridin-2-yl)-2-(2-fluorophenyl)acetamide (I-43C)
Figure PCTCN2022087589-appb-000249
Figure PCTCN2022087589-appb-000249
向硫酸(3.00mL)中加入2-(4-(二氟甲基)吡啶-2-基)-2-(2-氟苯基)乙腈(I-43B)(300mg,1.14mmol)，反应在20℃搅拌10小时。反应完成后，将反应液在0℃下慢慢加入到氢氧化钠水溶液(4.00M，30.0mL)中，然后用乙酸乙酯(20.0mL*3)萃取，合并有机层，干燥，过滤，浓缩得到淡黄色固体2-(4-(二氟甲基)吡啶-2-基)-2-(2-氟苯基)乙酰胺(I-43C)(300mg,产率93.6％)。直接用于下一步。To sulfuric acid (3.00 mL) was added 2-(4-(difluoromethyl)pyridin-2-yl)-2-(2-fluorophenyl)acetonitrile (I-43B) (300 mg, 1.14 mmol), the reaction was Stir at 20°C for 10 hours. After the completion of the reaction, the reaction solution was slowly added to an aqueous sodium hydroxide solution (4.00M, 30.0 mL) at 0°C, then extracted with ethyl acetate (20.0 mL*3), the organic layers were combined, dried, filtered, and concentrated 2-(4-(Difluoromethyl)pyridin-2-yl)-2-(2-fluorophenyl)acetamide (I-43C) (300 mg, 93.6% yield) was obtained as a pale yellow solid. used directly in the next step.
LC-MS,M/Z(ESI):281.1[M+H] + LC-MS, M/Z(ESI): 281.1[M+H] +
第四步：2-(4-(二氟甲基)吡啶-2-基)-N-(乙基氨基硫代甲酰基)-2-(2-氟苯基)乙酰胺(I-43D)的合成The fourth step: 2-(4-(difluoromethyl)pyridin-2-yl)-N-(ethylaminothioformyl)-2-(2-fluorophenyl)acetamide (I-43D) Synthesis
Figure PCTCN2022087589-appb-000250
Figure PCTCN2022087589-appb-000250
氮气保护下，在0℃下，向2-(4-(二氟甲基)吡啶-2-基)-2-(2-氟苯基)乙酰胺(I-43C)(200mg,714μmol)的N,N-二甲基甲酰胺(5.00mL)溶液中加入钠氢(42.8mg,1.07mmol,60％纯度)，反应在0℃搅拌0.5小时，然后缓慢加入乙基异硫氰酸酯(93.3mg,1.07mmol)的N,N-二甲基甲酰胺(2.00mL)溶液，反应在15℃搅拌10小时。反应完成后，将反应混合物用水(20.0mL)稀释，然后盐酸水溶液(1.00M)调至pH＝3，再用乙酸乙酯(20.0mL*3)萃取，合并有机层，用稀盐酸(1.00M，20.0mL*3)洗涤，干燥，过滤，浓缩得到黄色油状化合物2-(4-(二氟甲基)吡啶-2-基)-N-(乙基氨基硫代甲酰基)-2-(2-氟苯基)乙酰胺(I-43D)(260mg)。直接用于下一步。To 2-(4-(difluoromethyl)pyridin-2-yl)-2-(2-fluorophenyl)acetamide (I-43C) (200 mg, 714 μmol) under nitrogen protection at 0 °C Sodium hydrogen (42.8 mg, 1.07 mmol, 60% purity) was added to the N,N-dimethylformamide (5.00 mL) solution, the reaction was stirred at 0 °C for 0.5 h, and then ethyl isothiocyanate (93.3 mg, 1.07 mmol) in N,N-dimethylformamide (2.00 mL) and the reaction was stirred at 15°C for 10 hours. After the completion of the reaction, the reaction mixture was diluted with water (20.0 mL), and then adjusted to pH=3 with aqueous hydrochloric acid (1.00 M), extracted with ethyl acetate (20.0 mL*3), and the organic layers were combined and diluted with dilute hydrochloric acid (1.00 M). , 20.0 mL*3), washed, dried, filtered and concentrated to give a yellow oily compound 2-(4-(difluoromethyl)pyridin-2-yl)-N-(ethylaminothioformyl)-2-( 2-Fluorophenyl)acetamide (I-43D) (260 mg). used directly in the next step.
LC-MS,M/Z(ESI):368.1[M+H] + LC-MS, M/Z(ESI): 368.1[M+H] +
第五步：6-(二氟甲基)-1-(乙胺基)-4-(2-氟苯基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-43)的合成The fifth step: 6-(difluoromethyl)-1-(ethylamino)-4-(2-fluorophenyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I- 43) Synthesis
Figure PCTCN2022087589-appb-000251
Figure PCTCN2022087589-appb-000251
向2-(4-(二氟甲基)吡啶-2-基)-N-(乙基氨基硫代甲酰基)-2-(2-氟苯基)乙酰胺(I-43D)(260mg,708μmol)的四氢呋喃(5.00mL)溶液中加入吡啶(168mg,2.12mmol)和碘单质(539mg, 2.12mmol)，反应在20℃搅拌10小时。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(15.0mL)稀释，然后用乙酸乙酯(20.0mL*3)萃取，合并有机层，用饱和亚硫酸钠水溶液(20.0mL*3)洗涤，干燥，过滤，浓缩，残留物用乙酸乙酯(5.00mL)打浆，得到黄色固体化合物6-(二氟甲基)-1-(乙胺基)-4-(2-氟苯基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-43)(52.1mg,产率21.9％)。To 2-(4-(difluoromethyl)pyridin-2-yl)-N-(ethylaminothiocarbonyl)-2-(2-fluorophenyl)acetamide (I-43D) (260 mg, Pyridine (168 mg, 2.12 mmol) and iodine (539 mg, 2.12 mmol) were added to a solution of 708 μmol) in tetrahydrofuran (5.00 mL), and the reaction was stirred at 20° C. for 10 hours. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium sulfite solution (15.0 mL), then extracted with ethyl acetate (20.0 mL*3), the organic layers were combined, washed with saturated aqueous sodium sulfite solution (20.0 mL*3), dried, filtered, Concentrated, the residue was slurried with ethyl acetate (5.00 mL) to give yellow solid compound 6-(difluoromethyl)-1-(ethylamino)-4-(2-fluorophenyl)-3H-pyrido[ 1,2-c]pyrimidin-3-one (I-43) (52.1 mg, 21.9% yield).
1H NMR(400MHz,DMSO_d 6)δ8.09(br d,1H),7.96(br s,1H),7.36-7.52(m,1H),7.20-7.35(m,3H),6.66-7.06(m,2H),6.59(d,1H),3.41(q,2H),1.21(t,3H). 1 H NMR (400MHz, DMSO_d 6 )δ8.09(br d,1H),7.96(br s,1H),7.36-7.52(m,1H),7.20-7.35(m,3H),6.66-7.06(m , 2H), 6.59(d, 1H), 3.41(q, 2H), 1.21(t, 3H).
LC-MS,M/Z(ESI):334.1[M+H] + LC-MS, M/Z(ESI): 334.1[M+H] +
实施例44：目标化合物I-44的制备Example 44: Preparation of target compound I-44
6-(二氟甲基)-4-(2-氟苯基)-1-(甲基氨基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-44)6-(Difluoromethyl)-4-(2-fluorophenyl)-1-(methylamino)-3H-pyrido[1,2-c]pyrimidin-3-one (I-44)
Figure PCTCN2022087589-appb-000252
Figure PCTCN2022087589-appb-000252
化合物I-的合成路线参考HW121135的合成方法。The synthetic route of compound I- refers to the synthetic method of HW121135.
LC-MS,M/Z(ESI):320.1[M+H] + LC-MS, M/Z(ESI): 320.1[M+H] +
实施例45：目标化合物I-45的制备Example 45: Preparation of target compound I-45
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000253
Figure PCTCN2022087589-appb-000253
第一步：2-氯-4-环丙基吡啶的合成The first step: the synthesis of 2-chloro-4-cyclopropylpyridine
Figure PCTCN2022087589-appb-000254
Figure PCTCN2022087589-appb-000254
在氮气保护下，向4-溴-2-氯吡啶(7.00g,36.4mmol)的1,4-二氧六环(50.0mL)和水(10.0mL)的溶液中加入环丙基硼酸(3.12g,36.4mmol)，碳酸钾(15.1g,109mmol)和1,1-双(二苯基膦)二茂铁氯化钯(1.33g,1.82mmol)，反应在90℃搅拌10小时。反应完成后，将反应液用水(40.0mL)稀释，然后用乙酸乙酯(40.0mL*3)萃取，合并有机相，无水硫酸钠干燥， 过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0至20:1)，得到无色油状化合物2-氯-4-环丙基吡啶(4.00g,26.0mmol,71.6％收率)。To a solution of 4-bromo-2-chloropyridine (7.00 g, 36.4 mmol) in 1,4-dioxane (50.0 mL) and water (10.0 mL) was added cyclopropylboronic acid (3.12 g) under nitrogen protection g, 36.4 mmol), potassium carbonate (15.1 g, 109 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (1.33 g, 1.82 mmol), and the reaction was stirred at 90°C for 10 hours. After the reaction was completed, the reaction solution was diluted with water (40.0 mL), then extracted with ethyl acetate (40.0 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:0 to 20:1) to give 2-chloro-4-cyclopropylpyridine (4.00 g, 26.0 mmol, 71.6% yield) as a colorless oily compound.
1H NMR(400MHz,DMSO_d 6)δ8.19(d,1H),7.23(d,1H),7.10(dd,1H),1.91-2.06(m,1H),1.05-1.12(m,2H),0.81-0.89(m,2H). 1 H NMR (400MHz, DMSO_d 6 )δ8.19(d,1H), 7.23(d,1H), 7.10(dd,1H), 1.91-2.06(m,1H), 1.05-1.12(m,2H), 0.81-0.89(m,2H).
LC-MS,M/Z(ESI):154.0[M+H] + LC-MS, M/Z(ESI): 154.0[M+H] +
第二步：2-(4-环丙基吡啶-2-基)-2-(2-氟苯基)乙腈的合成The second step: Synthesis of 2-(4-cyclopropylpyridin-2-yl)-2-(2-fluorophenyl)acetonitrile
Figure PCTCN2022087589-appb-000255
Figure PCTCN2022087589-appb-000255
在氮气保护下，向2-氯-4-环丙基吡啶(1.00g,6.51mmol)的二甲基亚砜(10.0mL)溶液中加入2-氟苯乙腈(950mg,7.03mmol,)和氢氧化钾(731mg,13.0mmol)，反应在90℃搅拌10小时。反应完成后，将反应混合物用水(30.0mL)稀释，然后用乙酸乙酯(20.0mL*3)萃取，合并有机相，用水(30.0mL*3)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至10:1)得到黄色油状化合物2-(4-环丙基吡啶-2-基)-2-(2-氟苯基)乙腈(600mg,2.38mmol,36.5％收率)。To a solution of 2-chloro-4-cyclopropylpyridine (1.00 g, 6.51 mmol) in dimethyl sulfoxide (10.0 mL) under nitrogen protection was added 2-fluorophenylacetonitrile (950 mg, 7.03 mmol,) and hydrogen Potassium oxide (731 mg, 13.0 mmol), the reaction was stirred at 90°C for 10 hours. After the reaction was completed, the reaction mixture was diluted with water (30.0 mL), then extracted with ethyl acetate (20.0 mL*3), the organic phases were combined, washed with water (30.0 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated, The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=50:1 to 10:1) to obtain the yellow oily compound 2-(4-cyclopropylpyridin-2-yl)-2-( 2-Fluorophenyl)acetonitrile (600 mg, 2.38 mmol, 36.5% yield).
1H NMR(400MHz,DMSO_d 6)δ8.36(d,1H),7.51(td,1H),7.44(tdd,1H),7.22-7.34(m,3H),7.03(dd,1H),5.99(s,1H),1.90-2.03(m,1H),1.00-1.13(m,2H),0.70-0.85(m,2H). 1 H NMR (400MHz, DMSO_d 6 )δ8.36(d,1H), 7.51(td,1H), 7.44(tdd,1H), 7.22-7.34(m,3H), 7.03(dd,1H), 5.99( s,1H),1.90-2.03(m,1H),1.00-1.13(m,2H),0.70-0.85(m,2H).
LC-MS,M/Z(ESI):253.2[M+H] + LC-MS, M/Z(ESI): 253.2[M+H] +
第三步：2-(4-环丙基吡啶-2-基)-2-(2-氟苯基)乙酰胺的合成The third step: synthesis of 2-(4-cyclopropylpyridin-2-yl)-2-(2-fluorophenyl)acetamide
Figure PCTCN2022087589-appb-000256
Figure PCTCN2022087589-appb-000256
向硫酸(3.00mL)和醋酸(6.00mL)中加入2-(4-环丙基吡啶-2-基)-2-(2-氟苯基)乙腈(550mg,2.18mmol)，反应在60℃搅拌10小时。反应完成后，将反应液在0℃下慢慢加入到氢氧化钠水溶液(4.00M,30.0mL)中，然后用乙酸乙酯(20.0mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到淡黄色固体2-(4-环丙基吡啶-2-基)-2-(2-氟苯基)乙酰胺(450mg,1.66mmol,76.4％收率)。直接用于下一步。To sulfuric acid (3.00 mL) and acetic acid (6.00 mL) was added 2-(4-cyclopropylpyridin-2-yl)-2-(2-fluorophenyl)acetonitrile (550 mg, 2.18 mmol), and the reaction was carried out at 60 °C Stir for 10 hours. After the reaction was completed, the reaction solution was slowly added to an aqueous sodium hydroxide solution (4.00M, 30.0mL) at 0°C, then extracted with ethyl acetate (20.0mL*3), the organic phases were combined and dried over anhydrous sodium sulfate , filtered and concentrated to give 2-(4-cyclopropylpyridin-2-yl)-2-(2-fluorophenyl)acetamide (450 mg, 1.66 mmol, 76.4% yield) as a pale yellow solid. used directly in the next step.
LC-MS,M/Z(ESI):271.2[M+H] + LC-MS, M/Z(ESI): 271.2[M+H] +
第四步：2-(4-环丙基吡啶-2-基)-2-(2-氟苯基)-N-(甲基氨基硫代甲酰)乙酰胺的合成The fourth step: the synthesis of 2-(4-cyclopropylpyridin-2-yl)-2-(2-fluorophenyl)-N-(methylaminothiocarbonyl)acetamide
Figure PCTCN2022087589-appb-000257
Figure PCTCN2022087589-appb-000257
向2-(4-环丙基吡啶-2-基)-2-(2-氟苯基)乙酰胺(1.00g,2.78mmol)的N,N-二甲基甲酰胺(5.00mL)溶液中加入碳酸铯(603mg,1.85mmol)和甲基异硫氰酸酯(101mg,1.39mmol)，反应在75℃搅拌10小时。反应完成后，将反应混合物用水(20.0mL)稀释，然后用乙酸乙酯(20.0mL*3)萃取，用水(20.0mL*3)洗涤，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至10:1)得到黄色油状化合物2-(4-环丙基吡啶-2-基)-2-(2-氟苯基)-N-(甲基氨基硫代甲酰)乙酰胺(170mg,495μmol,53.5％收率)。To a solution of 2-(4-cyclopropylpyridin-2-yl)-2-(2-fluorophenyl)acetamide (1.00 g, 2.78 mmol) in N,N-dimethylformamide (5.00 mL) Cesium carbonate (603 mg, 1.85 mmol) and methyl isothiocyanate (101 mg, 1.39 mmol) were added and the reaction was stirred at 75°C for 10 hours. After the reaction was completed, the reaction mixture was diluted with water (20.0 mL), then extracted with ethyl acetate (20.0 mL*3), washed with water (20.0 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=50:1 to 10:1) to obtain the yellow oily compound 2-(4-cyclopropylpyridin-2-yl)-2-( 2-Fluorophenyl)-N-(methylcarbamoyl)acetamide (170 mg, 495 μmol, 53.5% yield).
LC-MS,M/Z(ESI):344.1(M+H) + LC-MS, M/Z (ESI): 344.1 (M+H) +
第五步：6-环丙基-4-(2-氟苯基)-1-(甲基氨基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-45)的合成The fifth step: 6-cyclopropyl-4-(2-fluorophenyl)-1-(methylamino)-3H-pyrido[1,2-c]pyrimidin-3-one (I-45) synthesis
Figure PCTCN2022087589-appb-000258
Figure PCTCN2022087589-appb-000258
向2-(4-环丙基吡啶-2-基)-2-(2-氟苯基)-N-(甲基氨基硫代甲酰)乙酰胺(150mg,437μmol)的四氢呋喃(3.00mL)溶液中加入碘单质(333mg,1.31mmol)和吡啶(104mg,1.31mmol)，反应在30℃搅拌10小时。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(10.0mL)稀释，然后用乙酸乙酯(10.0mL*3)萃取，合并有机层，用饱和亚硫酸钠水溶液(10.0mL*3)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用乙酸乙酯(3.00mL)打浆，得到黄色固体化合物6-环丙基-4-(2-氟苯基)-1-(甲基氨基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-45)(15.0mg,45.3μmol,10.4％收率)。To 2-(4-cyclopropylpyridin-2-yl)-2-(2-fluorophenyl)-N-(methylaminothioyl)acetamide (150 mg, 437 μmol) in tetrahydrofuran (3.00 mL) Elemental iodine (333 mg, 1.31 mmol) and pyridine (104 mg, 1.31 mmol) were added to the solution, and the reaction was stirred at 30° C. for 10 hours. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium sulfite solution (10.0 mL), then extracted with ethyl acetate (10.0 mL*3), the organic layers were combined, washed with saturated aqueous sodium sulfite solution (10.0 mL*3), and anhydrous sodium sulfate Dry, filter, concentrate, and the residue is slurried with ethyl acetate (3.00 mL) to give yellow solid compound 6-cyclopropyl-4-(2-fluorophenyl)-1-(methylamino)-3H-pyrido [1,2-c]pyrimidin-3-one (I-45) (15.0 mg, 45.3 μmol, 10.4% yield).
1H NMR(400MHz,DMSO_d 6)δ7.91(d,1H),7.82(d,1H),7.34-7.45(m,1H),7.19-7.30(m,3H),6.36(s,1H)6.16(dd,1H),2.87(d,3H),1.69-1.83(m,1H),0.87-0.98(m,2H),0.66-0.77(m,2H). 1 H NMR (400MHz, DMSO_d 6 )δ7.91(d,1H), 7.82(d,1H), 7.34-7.45(m,1H), 7.19-7.30(m,3H), 6.36(s,1H)6.16 (dd,1H),2.87(d,3H),1.69-1.83(m,1H),0.87-0.98(m,2H),0.66-0.77(m,2H).
LC-MS,M/Z(ESI):310.1[M+H] + LC-MS, M/Z(ESI): 310.1[M+H] +
实施例46：目标化合物I-46的制备Example 46: Preparation of target compound I-46
1-(甲基氨基)-4-苯基-6-(三氟甲基)吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-46)1-(Methylamino)-4-phenyl-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one (target compound I-46)
Figure PCTCN2022087589-appb-000259
Figure PCTCN2022087589-appb-000259
目标化合物I-46的合成路线如下所示：The synthetic route of the target compound I-46 is as follows:
Figure PCTCN2022087589-appb-000260
Figure PCTCN2022087589-appb-000260
第一步：2-苯基-2-(4-(三氟甲基)-2-吡啶基)乙腈(I-46B)的合成The first step: Synthesis of 2-phenyl-2-(4-(trifluoromethyl)-2-pyridyl)acetonitrile (I-46B)
Figure PCTCN2022087589-appb-000261
Figure PCTCN2022087589-appb-000261
在室温下，将苯乙腈(3.00g,25.6mmol,2.97mL)，氢氧化钾(2.05g,36.6mmol)和2-溴-4-三氟甲基-吡啶(5.51g,24.3mmol)溶解在二甲基亚砜(20mL)中，充分搅拌，在70℃反应3小时。反应结束后加水(100mL)，用乙酸乙酯(300mL)萃取，然后有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0-20:1)得到黑棕色油状产物2-苯基-2-(4-(三氟甲基)-2-吡啶基)乙腈(I-46B)(5.54g，产率69.3％)。At room temperature, phenylacetonitrile (3.00 g, 25.6 mmol, 2.97 mL), potassium hydroxide (2.05 g, 36.6 mmol) and 2-bromo-4-trifluoromethyl-pyridine (5.51 g, 24.3 mmol) were dissolved in In dimethyl sulfoxide (20 mL), the mixture was stirred well and reacted at 70°C for 3 hours. After the reaction, water (100 mL) was added, extracted with ethyl acetate (300 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified with a silica gel column (petroleum ether: Ethyl acetate (V/V)=1:0-20:1) gave the product 2-phenyl-2-(4-(trifluoromethyl)-2-pyridyl)acetonitrile (I-46B) as a dark brown oily product (5.54 g, 69.3% yield).
LC-MS,M/Z(ESI):263.1[M+H] + LC-MS, M/Z(ESI): 263.1[M+H] +
第二步：2-苯基-2-(4-(三氟甲基)-2-吡啶基)乙酰胺(I-46C)的合成The second step: Synthesis of 2-phenyl-2-(4-(trifluoromethyl)-2-pyridyl)acetamide (I-46C)
Figure PCTCN2022087589-appb-000262
Figure PCTCN2022087589-appb-000262
把2-苯基-2-(4-(三氟甲基)-2-吡啶基)乙腈(I-46B)(5.50g,16.8mmol)缓慢加入到硫酸(41.1g,419mmol,22.3mL)中，置换氮气，加热到30℃，搅拌2小时。将反应液倒入冰水(100mL)中，用氢氧化钠溶液(100mL)调节pH至9左右，用乙酸乙酯(600mL)萃取，然后用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，浓缩，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0-1:1)得到灰色固体化合物2-苯基-2-(4-(三氟甲基)-2-吡啶基)乙酰胺(I-46C)(4.86g，产率98.6％)。2-Phenyl-2-(4-(trifluoromethyl)-2-pyridyl)acetonitrile (I-46B) (5.50 g, 16.8 mmol) was slowly added to sulfuric acid (41.1 g, 419 mmol, 22.3 mL) , replaced nitrogen, heated to 30 ° C, and stirred for 2 hours. The reaction solution was poured into ice water (100 mL), the pH was adjusted to about 9 with sodium hydroxide solution (100 mL), extracted with ethyl acetate (600 mL), washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. , filtered, concentrated, separated and purified with silica gel column (petroleum ether:ethyl acetate (V/V)=1:0-1:1) to obtain a gray solid compound 2-phenyl-2-(4-(trifluoromethyl) )-2-pyridyl)acetamide (I-46C) (4.86 g, 98.6% yield).
1H NMR(400MHz,DMSO_d 6):δ8.80(d,1H),7.82(s,1H),7.68(s,1H),7.65(d,1H),7.32-7.41(m,4H),7.23-7.31(m,2H),5.27(s,1H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.80(d,1H), 7.82(s,1H), 7.68(s,1H), 7.65(d,1H), 7.32-7.41(m,4H), 7.23 -7.31(m, 2H), 5.27(s, 1H).
LC-MS,M/Z(ESI):281.1[M+H] + LC-MS, M/Z(ESI): 281.1[M+H] +
第三步：N-(甲基氨基硫代甲酰)-2-苯基-2-(4-(三氟甲基)-2-吡啶基)乙酰胺(I-46D)的合成The third step: synthesis of N-(methylaminothioformyl)-2-phenyl-2-(4-(trifluoromethyl)-2-pyridyl)acetamide (I-46D)
Figure PCTCN2022087589-appb-000263
Figure PCTCN2022087589-appb-000263
把2-苯基-2-[4-(三氟甲基)-2-吡啶基]乙酰胺(I-46C)(500mg,1.70mmol)和异硫氰酸根甲烷(186mg,2.55mmol,174μL)，碳酸铯(1.66g,5.11mmol)加入N,N-二甲基甲酰胺(10mL)中，置换氮气，加热到75℃，搅拌2小时。将反应液降温至室温，倒入水(50mL)中，用乙酸乙酯(120mL)萃取，合并有机相，然后用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0-20:1)得到棕色油状化合物N-(甲基氨基硫代甲酰)-2-苯基-2-(4-(三氟甲基)-2-吡啶基)乙酰胺(I-46D)(380mg，产率60.8％)。Combine 2-phenyl-2-[4-(trifluoromethyl)-2-pyridyl]acetamide (I-46C) (500 mg, 1.70 mmol) and isothiocyanatomethane (186 mg, 2.55 mmol, 174 μL) , cesium carbonate (1.66g, 5.11mmol) was added to N,N-dimethylformamide (10mL), nitrogen was replaced, heated to 75°C, and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), extracted with ethyl acetate (120 mL), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=1:0-20:1) to obtain a brown oily compound N-(methylaminothiocarbonyl)-2-phenyl-2-( 4-(Trifluoromethyl)-2-pyridyl)acetamide (I-46D) (380 mg, 60.8% yield).
1H NMR(400MHz,DMSO_d 6):δ11.61(s,1H),10.42(d,1H),8.85(d,1H),7.72(d,1H),7.50(s,1H),7.34-7.43(m,5H),5.66(s,1H),3.00(d,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ 11.61(s,1H), 10.42(d,1H), 8.85(d,1H), 7.72(d,1H), 7.50(s,1H), 7.34-7.43 (m, 5H), 5.66(s, 1H), 3.00(d, 3H).
LC-MS,M/Z(ESI):354.1[M+H] + LC-MS, M/Z(ESI): 354.1[M+H] +
第四步：1-(甲基氨基)-4-苯基-6-(三氟甲基)吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-46)的合成The fourth step: synthesis of 1-(methylamino)-4-phenyl-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one (target compound I-46)
Figure PCTCN2022087589-appb-000264
Figure PCTCN2022087589-appb-000264
把N-(甲基氨基硫代甲酰)-2-苯基-2-(4-(三氟甲基)-2-吡啶基)乙酰胺(I-46D)(380mg,1.03mmol)溶解在四氢呋喃(10mL)中，在0℃下缓慢加入碘单质(787mg,3.10mmol)，吡啶(1.01g,3.10mmol)，置换氮气，加热到25℃搅拌反应2小时。加入水(20mL)，加入饱和亚硫酸钠溶液(10mL)，然后用乙酸乙酯(90mL)萃取，用饱和食盐水(30mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。粗品在25℃用石油醚(30mL)打浆搅拌0.5小时过滤得到黄色固体化合物1-(甲基氨基)-4-苯基-6-(三氟甲基)吡啶并[1,2-c]嘧啶-3-酮(I-46)(150mg，产率43.9％)。Dissolve N-(methylcarbamoyl)-2-phenyl-2-(4-(trifluoromethyl)-2-pyridyl)acetamide (I-46D) (380 mg, 1.03 mmol) in In tetrahydrofuran (10 mL), elemental iodine (787 mg, 3.10 mmol) and pyridine (1.01 g, 3.10 mmol) were slowly added at 0 °C, nitrogen was replaced, and the reaction was heated to 25 °C and stirred for 2 hours. Water (20 mL) was added, saturated sodium sulfite solution (10 mL) was added, then extracted with ethyl acetate (90 mL), the organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The crude product was slurried with petroleum ether (30 mL) at 25°C and stirred for 0.5 hours to obtain a yellow solid compound 1-(methylamino)-4-phenyl-6-(trifluoromethyl)pyrido[1,2-c]pyrimidine -3-One (I-46) (150 mg, 43.9% yield).
1H NMR(400MHz,DMSO_d 6):δ8.01(d,1H),7.97(s,1H),7.42-7.46(m,2H),7.33-7.39(m,1H),7.27(d,2H),6.97(s,1H),6.67(d,1H),2.89(d,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.01(d,1H), 7.97(s,1H), 7.42-7.46(m,2H), 7.33-7.39(m,1H), 7.27(d,2H) ,6.97(s,1H),6.67(d,1H),2.89(d,3H).
LC-MS,M/Z(ESI):320.1[M+H] + LC-MS, M/Z(ESI): 320.1[M+H] +
实施例47：目标化合物I-47的制备Example 47: Preparation of target compound I-47
1-((2,2-二氟乙基)氨基)-4-(邻甲苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-47)1-((2,2-Difluoroethyl)amino)-4-(o-tolyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one ( Target compound I-47)
Figure PCTCN2022087589-appb-000265
Figure PCTCN2022087589-appb-000265
目标化合物I-47的合成路线如下所示：The synthetic route of the target compound I-47 is shown below:
Figure PCTCN2022087589-appb-000266
Figure PCTCN2022087589-appb-000266
第一步：N-((2,2-二氟乙基)氨基硫代甲酰)-2-(邻甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-47A)的合成The first step: N-((2,2-difluoroethyl)carbamoyl)-2-(o-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)ethyl Synthesis of Amide (I-47A)
Figure PCTCN2022087589-appb-000267
Figure PCTCN2022087589-appb-000267
向2-(邻甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-5C)(300mg,1.02mmol)的N,N-二甲基甲酰胺(10.0mL)溶液中加入1,1-二氟-2-异硫氰基乙烷(3B)(700mg,5.69mmol)和碳酸铯(498mg,1.53mmol)，反应在75℃搅拌10小时。反应完成后，将反应混合物用水(50.0mL)稀释，然后用乙酸乙酯(30.0mL*3)萃取，合并有机层，用饱和食盐水(30.0mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝20:1至10:1)得到黄色固体化合物N-((2,2-二氟乙基)氨基硫代甲酰)-2-(邻甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-47A)(120mg，粗品)，直接用于下一步。To 2-(o-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-5C) (300 mg, 1.02 mmol) in N,N-dimethylformamide ( 1,1-Difluoro-2-isothiocyanatoethane (3B) (700 mg, 5.69 mmol) and cesium carbonate (498 mg, 1.53 mmol) were added to the solution in 10.0 mL), and the reaction was stirred at 75° C. for 10 hours. After the completion of the reaction, the reaction mixture was diluted with water (50.0 mL), then extracted with ethyl acetate (30.0 mL*3), the organic layers were combined, washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated , the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=20:1 to 10:1) to obtain a yellow solid compound N-((2,2-difluoroethyl)aminothiomethane Acyl)-2-(o-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-47A) (120 mg, crude) was used directly in the next step.
第二步：1-((2,2-二氟乙基)氨基)-4-(邻甲苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-47)的合成Step 2: 1-((2,2-Difluoroethyl)amino)-4-(o-tolyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine- Synthesis of 3-keto(I-47)
Figure PCTCN2022087589-appb-000268
Figure PCTCN2022087589-appb-000268
向N-((2,2-二氟乙基)氨基硫代甲酰)-2-(邻甲苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-47A)(100mg,240μmol)的四氢呋喃(3.00mL)溶液中加入碘单质(182mg,719μmol)和吡啶(56.9mg,719μmol)，反应在25℃搅拌8小时。反应完成后，将反应混合物用水(10.0mL)稀释，然后用乙酸乙酯(10.0mL*3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，残留物用高效液相色谱仪分离纯化两次，分离方法为(柱子：Welch Ultimate XB-SiOH 250*50*10μm；溶剂：A＝水+0.1体积％氨水(99.0％)，B＝乙腈；梯度：1％-30％，15分钟)和(色谱柱：Welch Ultimate XB-SiOH 250*50*10μm；溶剂：A＝水+0.05体积％甲酸(99.0％)，B＝乙腈；梯度：30％-60％，7分钟)，得到黄色固体化合物1-((2,2-二氟乙基)氨基)-4-(邻甲苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-47)(11.2mg,28.9μmol,12.1％产率)。To N-((2,2-difluoroethyl)carbamoyl)-2-(o-tolyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I Elemental iodine (182 mg, 719 μmol) and pyridine (56.9 mg, 719 μmol) were added to a solution of -47A) (100 mg, 240 μmol) in tetrahydrofuran (3.00 mL), and the reaction was stirred at 25° C. for 8 hours. After the completion of the reaction, the reaction mixture was diluted with water (10.0 mL), then extracted with ethyl acetate (10.0 mL*3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by high performance liquid chromatography Purified twice, the separation method is (column: Welch Ultimate XB-SiOH 250*50*10μm; solvent: A=water+0.1 vol% ammonia water (99.0%), B=acetonitrile; gradient: 1%-30%, 15 minutes ) and (column: Welch Ultimate XB-SiOH 250*50*10μm; solvent: A=water+0.05% by volume formic acid (99.0%), B=acetonitrile; gradient: 30%-60%, 7 minutes) to give yellow Solid compound 1-((2,2-difluoroethyl)amino)-4-(o-tolyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3- Ketone (I-47) (11.2 mg, 28.9 μmol, 12.1% yield).
1H NMR(400MHz,DMSO_d 6):δ8.44(br s,1H),8.03-8.31(m,1H),7.29-7.35(m,2H),7.22-7.28(m,1H),7.08(d,1H),6.68(br d,1H),6.55-6.64(m,1H),6.22(tt,1H),3.72-3.84(m,2H),2.06(s,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.44(br s, 1H), 8.03-8.31(m, 1H), 7.29-7.35(m, 2H), 7.22-7.28(m, 1H), 7.08(d ,1H),6.68(br d,1H),6.55-6.64(m,1H),6.22(tt,1H),3.72-3.84(m,2H),2.06(s,3H).
LC-MS,M/Z(ESI):384.0[M+H] + LC-MS, M/Z(ESI): 384.0[M+H] +
实施例48：目标化合物I-48的制备Example 48: Preparation of target compound I-48
4-(2-异丙基苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-48)4-(2-Isopropylphenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-48)
Figure PCTCN2022087589-appb-000269
Figure PCTCN2022087589-appb-000269
目标化合物I-48的合成路线如下所示：The synthetic route of the target compound I-48 is as follows:
Figure PCTCN2022087589-appb-000270
Figure PCTCN2022087589-appb-000270
第一步：2-异丙基苯甲醛(I-48B)的合成The first step: the synthesis of 2-isopropylbenzaldehyde (I-48B)
Figure PCTCN2022087589-appb-000271
Figure PCTCN2022087589-appb-000271
在室温下，将1-溴-2-异丙基苯(5g，25.1mmol)溶于50mL四氢呋喃中，氮气保护下在-78℃缓慢滴入正丁基锂(25.1mL,62.8mmol)，然后在-78℃继续反应1h。向-78℃的反应液中缓慢滴入N,N-二甲基甲酰胺(9.72mL,126mmol)，然后自然升温到25℃继续反应2h。反应液用饱和氯化铵溶液(200mL)淬灭，用乙酸乙酯(100mL*3)萃取，合并有机相，用饱和食盐水(100mL*2)洗涤，无水硫酸钠干燥，过滤浓缩得到黄色油状化合物2-异丙基苯甲醛(I-48B)(4.7g，粗品)。粗品直接用于下一步。At room temperature, 1-bromo-2-isopropylbenzene (5 g, 25.1 mmol) was dissolved in 50 mL of tetrahydrofuran, and n-butyllithium (25.1 mL, 62.8 mmol) was slowly added dropwise at -78 °C under nitrogen protection, and then The reaction was continued for 1 h at -78°C. N,N-dimethylformamide (9.72 mL, 126 mmol) was slowly added dropwise to the reaction solution at -78°C, and then the temperature was naturally raised to 25°C to continue the reaction for 2 h. The reaction solution was quenched with saturated ammonium chloride solution (200 mL), extracted with ethyl acetate (100 mL*3), the organic phases were combined, washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow Oily compound 2-isopropylbenzaldehyde (I-48B) (4.7 g, crude). The crude product was used directly in the next step.
第二步：2-(2-异丙基苯基)乙腈(I-48C)的合成The second step: the synthesis of 2-(2-isopropylphenyl)acetonitrile (I-48C)
Figure PCTCN2022087589-appb-000272
Figure PCTCN2022087589-appb-000272
将对甲苯磺酰甲基异氰(7.11g，36.4mmol)溶于四氢呋喃(20mL)中，在氮气保护下在-78℃缓慢滴入叔丁醇钾的四氢呋喃溶液(76mL,76mmol，1M)，并在-78℃下继续搅拌1h。缓慢滴入2-异丙基苯甲醛(I-48B)(4.5g，30.4mmol)的四氢呋喃(20mL)溶液，并在-78℃继续搅拌2h。向反应液中缓慢加入甲醇(40mL)，然后搅拌回流15h。将反应液缓慢倒入水(200mL)中，用乙酸乙酯(100mL*3)萃取，合并有机相，用饱和食盐水(100mL*2)洗涤，无水硫酸钠干燥，过滤浓缩得到黄色油状粗品。粗品经过硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0-1:3)得到黄色油状化合物2-(2-异丙基苯基)乙腈(I-48C)(1.8g,产率37.2％)。P-toluenesulfonylmethyl isocyanide (7.11 g, 36.4 mmol) was dissolved in tetrahydrofuran (20 mL), and a solution of potassium tert-butoxide in tetrahydrofuran (76 mL, 76 mmol, 1 M) was slowly added dropwise at -78 °C under nitrogen protection, And stirring was continued for 1 h at -78°C. A solution of 2-isopropylbenzaldehyde (I-48B) (4.5 g, 30.4 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise, and stirring was continued at -78 °C for 2 h. Methanol (40 mL) was slowly added to the reaction solution, followed by stirring and refluxing for 15 h. The reaction solution was slowly poured into water (200 mL), extracted with ethyl acetate (100 mL*3), the organic phases were combined, washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oily crude product . The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:0-1:3) to obtain a yellow oily compound 2-(2-isopropylphenyl)acetonitrile (I-48C) (1.8 g, 37.2% yield).
1H NMR(400MHz,CDCl 3)δ7.36-7.33(m,3H),7.24-7.17(m,1H),3.75(s,2H),3.12-3.01(m,1H),1.27(d,J＝6.8Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ 7.36-7.33(m, 3H), 7.24-7.17(m, 1H), 3.75(s, 2H), 3.12-3.01(m, 1H), 1.27(d, J =6.8Hz,6H).
第三步：2-(2-异丙基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-48D)的合成The third step: Synthesis of 2-(2-isopropylphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-48D)
Figure PCTCN2022087589-appb-000273
Figure PCTCN2022087589-appb-000273
在室温下，将2-(2-异丙基苯基)乙腈(I-48C)(800mg，5.02mmol)加入到四氢呋喃(10mL)中，氮气保护下0℃加入2-溴-4-(三氟甲基)吡啶(1g，4.42mmol)和叔丁醇钾的四氢呋喃溶液(8.37mL,8.37mmol，1M)，然后25℃搅拌18h。将反应液加入到水(100mL)中淬灭，用乙酸乙酯(50mL*2)萃取，合并有机相，用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-10:1)制备得到黄色油状化合物2-(2-异丙基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-48D)(1.0g，产率78％)。At room temperature, 2-(2-isopropylphenyl)acetonitrile (I-48C) (800 mg, 5.02 mmol) was added to tetrahydrofuran (10 mL), and 2-bromo-4-(tris) was added at 0°C under nitrogen protection. Fluoromethyl)pyridine (1 g, 4.42 mmol) and potassium tert-butoxide in tetrahydrofuran (8.37 mL, 8.37 mmol, 1 M), then stirred at 25 °C for 18 h. The reaction solution was added to water (100 mL) to quench, extracted with ethyl acetate (50 mL*2), the organic phases were combined, washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-10:1) to obtain a yellow oily compound 2-(2-isopropylphenyl)-2-(4- (Trifluoromethyl)pyridin-2-yl)acetonitrile (I-48D) (1.0 g, 78% yield).
LC-MS,M/Z(ESI):305.1[M+H] + LC-MS, M/Z(ESI): 305.1[M+H] +
第四步：2-(2-异丙基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-48E)的合成The fourth step: the synthesis of 2-(2-isopropylphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-48E)
Figure PCTCN2022087589-appb-000274
Figure PCTCN2022087589-appb-000274
在0℃下向2-(2-异丙基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(I-48D)(1.0g,3.29mmol)中缓慢加入浓硫酸(5mL)，25℃下搅拌反应18h，将反应液缓慢加入到冰水(100mL)中，并用碳酸氢钠将pH调至7～8，用乙酸乙酯(50mL*3)萃取，合并有机相，用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品，向粗品中加入甲基叔丁基醚(10mL)然后搅拌0.5h，过滤得到黄色固体产物2-(2-异丙基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-48E)(950mg,产率90％)。To 2-(2-isopropylphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (I-48D) (1.0 g, 3.29 mmol) was added slowly at 0 °C Concentrated sulfuric acid (5mL), stirred for 18h at 25°C, slowly added the reaction solution to ice water (100mL), adjusted the pH to 7-8 with sodium bicarbonate, extracted with ethyl acetate (50mL*3), combined The organic phase was washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, to the crude product was added methyl tert-butyl ether (10 mL) and stirred for 0.5 h, and filtered to obtain a yellow solid product 2- (2-Isopropylphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-48E) (950 mg, 90% yield).
LC-MS,M/Z(ESI):323.2[M+H] + LC-MS, M/Z(ESI): 323.2[M+H] +
第五步：2-(2-异丙基苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-48F)的合成The fifth step: 2-(2-isopropylphenyl)-N-(methylaminothioformyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I- 48F) synthesis
Figure PCTCN2022087589-appb-000275
Figure PCTCN2022087589-appb-000275
将2-(2-异丙基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-48E)(950mg，2.95mmol)和碳酸铯(1921mg,5.89mmol)溶于N,N-二甲基甲酰胺(10mL)中，在氮气保护下加入甲基异硫氰酸酯(259mg,3.54mmol)，在25℃下搅拌反应16h，将反应液倒入水(100mL)中，用乙酸乙酯(50mL*3)萃取，有机相合并，用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品，粗品硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-5:1)得到黄色固体2-(2-异丙基苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-48F)(530mg,产率45.5％)。Combine 2-(2-isopropylphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-48E) (950 mg, 2.95 mmol) and cesium carbonate (1921 mg, 5.89 mmol) was dissolved in N,N-dimethylformamide (10 mL), methyl isothiocyanate (259 mg, 3.54 mmol) was added under nitrogen protection, the reaction was stirred at 25 ° C for 16 h, the reaction solution was poured into In water (100mL), extract with ethyl acetate (50mL*3), combine the organic phases, wash with saturated brine (50mL*2), dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product, which is purified by silica gel column separation (petroleum Ether:ethyl acetate (V/V)=50:1-5:1) to give yellow solid 2-(2-isopropylphenyl)-N-(methylaminothiocarbonyl)-2-(4 -(Trifluoromethyl)pyridin-2-yl)acetamide (I-48F) (530 mg, 45.5% yield).
LC-MS,M/Z(ESI):396.1[M+H] + LC-MS, M/Z(ESI): 396.1[M+H] +
第六步：4-(2-异丙基苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-48)The sixth step: 4-(2-isopropylphenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one ( I-48)
Figure PCTCN2022087589-appb-000276
Figure PCTCN2022087589-appb-000276
在氮气保护下，将2-(2-异丙基苯基)-N-(甲基氨基硫代甲酰基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-48F)(530mg,1.34mmol)，碘(1021mg,4.02mmol)和吡啶(0.325mL,4.02mmol)加入到四氢呋喃(8mL)中，然后25℃下搅拌反应18h，反应液缓慢倒入水(100mL)中，用乙酸乙酯(30mL*3)，有机相合并用，饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品。然后粗品经反相制备(色谱柱:Phenomenex Synergi C 18 100*25mm*4μm；溶剂：A＝水+0.1体积％甲酸(99％)，B＝乙腈；梯度：5％-95％，7分钟)得到目标化合物4-(2-异丙基苯基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-48)(104mg，产率21.47％)。 Under nitrogen protection, 2-(2-isopropylphenyl)-N-(methylcarbamoyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide ( I-48F) (530 mg, 1.34 mmol), iodine (1021 mg, 4.02 mmol) and pyridine (0.325 mL, 4.02 mmol) were added to tetrahydrofuran (8 mL), and then the reaction was stirred at 25° C. for 18 h, and the reaction solution was slowly poured into water ( 100 mL) in ethyl acetate (30 mL*3), the organic phases were combined, washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was then prepared by reverse phase (column: Phenomenex Synergi C 18 100*25mm*4μm; solvent: A=water+0.1 vol% formic acid (99%), B=acetonitrile; gradient: 5%-95% in 7 min) The target compound 4-(2-isopropylphenyl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I -48) (104 mg, 21.47% yield).
1H NMR(400MHz,dmso)δ8.06(d,J＝7.7Hz,1H),8.00(s,1H),7.43(dd,J＝7.8,1.2Hz,1H),7.38(td,J＝7.6,1.2Hz,1H),7.24(td,J＝7.4,1.5Hz,1H),7.01(d,J＝7.3Hz,1H),6.65(d,J＝7.8Hz,1H),6.60(s,1H),2.91(s,3H),2.70(dt,J＝13.7,6.9Hz,1H),1.12(d,J＝6.8Hz,3H),0.99(d,J＝6.9Hz,3H). 1 H NMR (400MHz, dmso) δ 8.06 (d, J=7.7Hz, 1H), 8.00 (s, 1H), 7.43 (dd, J=7.8, 1.2Hz, 1H), 7.38 (td, J=7.6 ,1.2Hz,1H),7.24(td,J＝7.4,1.5Hz,1H),7.01(d,J＝7.3Hz,1H),6.65(d,J＝7.8Hz,1H),6.60(s,1H) ), 2.91(s, 3H), 2.70(dt, J=13.7, 6.9Hz, 1H), 1.12(d, J=6.8Hz, 3H), 0.99(d, J=6.9Hz, 3H).
LC-MS,M/Z(ESI):362.1[M+H] + LC-MS, M/Z(ESI): 362.1[M+H] +
实施例49：目标化合物I-49的制备Example 49: Preparation of target compound I-49
4-(2-氯苯基)-1-(2-甲磺酰乙胺基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-49)4-(2-Chlorophenyl)-1-(2-methanesulfonylethylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (target Compound I-49)
Figure PCTCN2022087589-appb-000277
Figure PCTCN2022087589-appb-000277
目标化合物I-49的合成路线如下所示：The synthetic route of the target compound I-49 is as follows:
Figure PCTCN2022087589-appb-000278
Figure PCTCN2022087589-appb-000278
第一步：(2-异硫氰酸乙基)(甲基)硫烷(I-49B)的合成The first step: the synthesis of (2-isothiocyanate ethyl) (methyl) sulfane (I-49B)
Figure PCTCN2022087589-appb-000279
Figure PCTCN2022087589-appb-000279
将2-甲基巯基乙胺(200mg,2.13mmol)和碳酸铯(2.08g,6.38mmol)溶解在二氯甲烷(8.00mL)中，在氮气保护下加入硫光气(489mg,4.26mmol,326uL)，25℃反应2小时。把反应液过滤，有机相浓缩得到棕色固体化合物(2-异硫氰酸乙基)(甲基)硫烷(I-49B)(250mg，粗品)。2-Methylmercaptoethylamine (200 mg, 2.13 mmol) and cesium carbonate (2.08 g, 6.38 mmol) were dissolved in dichloromethane (8.00 mL), and thiophosgene (489 mg, 4.26 mmol, 326 uL) was added under nitrogen protection ) at 25°C for 2 hours. The reaction solution was filtered, and the organic phase was concentrated to obtain a brown solid compound (2-isothiocyanatoethyl)(methyl)sulfane (I-49B) (250 mg, crude product).
第二步：2-(2-氯苯基)-N-(2-甲基巯基乙基氨基硫代甲酰)-2-(4-(三氟甲基)-2-吡啶-2-基)乙酰胺(I-49C)的合成The second step: 2-(2-chlorophenyl)-N-(2-methylmercaptoethylcarbamoyl)-2-(4-(trifluoromethyl)-2-pyridin-2-yl ) Synthesis of Acetamide (I-49C)
Figure PCTCN2022087589-appb-000280
Figure PCTCN2022087589-appb-000280
将(2-异硫氰酸根合乙基)(甲基)硫烷(I-49B)(250mg,1.88mmol)和碳酸铯(1.55g,4.77mmol)溶解在N,N-二甲基甲酰胺(8.00mL)中，加2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-1D)(500mg,1.59mmol)，75℃反应2小时。把水(50mL)加到反应液中，然后用乙酸乙酯(120mL)萃取，用饱和食盐水(40mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:1)得到棕色油状化合物2-(2-氯苯基)-N-(2-甲基巯基乙基氨基硫代甲酰)-2-(4-(三氟甲基)-2-吡啶基)乙酰胺(I-49C)(355mg， 产率49.4％)。(2-Isothiocyanatoethyl)(methyl)sulfane (I-49B) (250 mg, 1.88 mmol) and cesium carbonate (1.55 g, 4.77 mmol) were dissolved in N,N-dimethylformamide (8.00 mL), add 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-1D) (500 mg, 1.59 mmol), 75°C React for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (120 mL), the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-1:1) to obtain 2-(2-chlorophenyl)-N-(2-methylmercaptoethyl) as a brown oily compound (1-49C) (355 mg, 49.4% yield).
1H NMR(400MHz,DMSO-d 6):δ11.77(s,1H),10.65(m,1H),8.88(d,1H),7.73-7.78(m,1H),7.50-7.55(m,2H),7.36-7.39(m,2H),7.06(d,1H),6.01(s,1H),3.75(q,2H),2.72(t,2H),2.08(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ 11.77(s, 1H), 10.65(m, 1H), 8.88(d, 1H), 7.73-7.78(m, 1H), 7.50-7.55(m, 2H), 7.36-7.39(m, 2H), 7.06(d, 1H), 6.01(s, 1H), 3.75(q, 2H), 2.72(t, 2H), 2.08(s, 3H).
LC-MS,M/Z(ESI):448.0[M+H] + LC-MS, M/Z(ESI): 448.0[M+H] +
第三步：4-(2-氯苯基)-1-(2-甲基巯基乙胺基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-49D)的合成The third step: 4-(2-chlorophenyl)-1-(2-methylmercaptoethylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 -Synthesis of ketone (I-49D)
Figure PCTCN2022087589-appb-000281
Figure PCTCN2022087589-appb-000281
将2-(2-氯苯基)-N-(2-甲基巯基乙基氨基硫代甲酰)-2-[4-(三氟甲基)-2-吡啶基]乙酰胺(I-49C)(350mg,773μmol)溶解在四氢呋喃(10mL)中，加碘(589mg,2.32mmol)和碳酸铯(756mg,2.32mmol)，25℃反应2h。把水(20mL)加到反应液中，加入饱和亚硫酸钠溶液(30mL)，然后用乙酸乙酯(90mL)萃取，用饱和食盐水(30mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品在25℃用石油醚(30mL)打浆搅拌0.5小时过滤得到黄色固体化合物4-(2-氯苯基)-1-(2-甲基巯基乙胺基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-49D)(300mg，粗品)。2-(2-Chlorophenyl)-N-(2-methylmercaptoethylcarbamoyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetamide (I- 49C) (350 mg, 773 μmol) was dissolved in tetrahydrofuran (10 mL), iodine (589 mg, 2.32 mmol) and cesium carbonate (756 mg, 2.32 mmol) were added, and the reaction was carried out at 25° C. for 2 h. Water (20 mL) was added to the reaction solution, saturated sodium sulfite solution (30 mL) was added, then extracted with ethyl acetate (90 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was slurried with petroleum ether (30 mL) at 25°C and stirred for 0.5 hours to obtain a yellow solid compound 4-(2-chlorophenyl)-1-(2-methylmercaptoethylamino)-6-(trifluoromethyl) -3H-pyrido[1,2-c]pyrimidin-3-one (I-49D) (300 mg, crude).
LC-MS,M/Z(ESI):414.1[M+H] + LC-MS, M/Z(ESI): 414.1[M+H] +
第四步：4-(2-氯苯基)-1-(2-甲磺酰乙胺基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-49)的合成Step 4: 4-(2-Chlorophenyl)-1-(2-methanesulfonylethylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 -Synthesis of ketone (target compound I-49)
Figure PCTCN2022087589-appb-000282
Figure PCTCN2022087589-appb-000282
把4-(2-氯苯基)-1-(2-甲基巯基乙胺基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-49D)(150mg,362μmol)溶解在二氯甲烷(5.00mL)中，在10℃下加间氯过氧苯甲酸(156mg,772μmol,85％)，10℃搅拌反应0.5小时。加入水(20mL)，加入饱和亚硫酸钠溶液(20mL)搅拌0.5小时，饱和碳酸氢钠溶液(10mL)洗涤，然后用二氯甲烷(45mL)萃取，用饱和食盐水(20mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品在25℃用乙酸乙酯(10mL)打浆搅拌0.5小时过滤得到黄色固体化合物4-(2-氯苯基)-1-(2-甲磺酰乙胺基)-6-(三氟甲基)吡啶并[1,2-c]嘧啶-3-酮(I-49)(160mg，产率93.4％)。4-(2-Chlorophenyl)-1-(2-methylmercaptoethylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one ( I-49D) (150 mg, 362 μmol) was dissolved in dichloromethane (5.00 mL), m-chloroperoxybenzoic acid (156 mg, 772 μmol, 85%) was added at 10 °C, and the reaction was stirred at 10 °C for 0.5 hours. Water (20 mL) was added, saturated sodium sulfite solution (20 mL) was added, stirred for 0.5 hours, washed with saturated sodium bicarbonate solution (10 mL), then extracted with dichloromethane (45 mL), the organic phase was washed with saturated brine (20 mL), and anhydrous Dry over sodium sulfate and concentrate to give crude product. The crude product was slurried with ethyl acetate (10 mL) at 25°C and stirred for 0.5 hours to obtain a yellow solid compound 4-(2-chlorophenyl)-1-(2-methanesulfonylethylamino)-6-(trifluoromethyl) ) pyrido[1,2-c]pyrimidin-3-one (I-49) (160 mg, 93.4% yield).
1H NMR(400MHz,DMSO_d 6):δ8.62(d,1H),7.47-7.51(m,1H),7.30-7.34(m,2H),7.25-7.30(m,1H),7.21-7.23(m,1H),6.30(s,1H),6.15-6.17(m,1H),3.57-3.61(m,2H),3.25-3.27(m,2H),3.04(s,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.62(d,1H), 7.47-7.51(m,1H), 7.30-7.34(m,2H), 7.25-7.30(m,1H), 7.21-7.23( m, 1H), 6.30(s, 1H), 6.15-6.17(m, 1H), 3.57-3.61(m, 2H), 3.25-3.27(m, 2H), 3.04(s, 3H).
LC-MS,M/Z(ESI):446.1[M+H] + LC-MS, M/Z(ESI): 446.1[M+H] +
实施例50：目标化合物I-50的制备Example 50: Preparation of target compound I-50
4-(2-氯吡啶-3-基)-1-(乙胺基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-50)4-(2-Chloropyridin-3-yl)-1-(ethylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (target compound I -50)
Figure PCTCN2022087589-appb-000283
Figure PCTCN2022087589-appb-000283
目标化合物I-50的合成路线如下所示：The synthetic route of the target compound I-50 is as follows:
Figure PCTCN2022087589-appb-000284
Figure PCTCN2022087589-appb-000284
第一步：N-(乙基氨基硫代甲酰)-2-(2-甲氧基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-50A)的合成The first step: N-(ethylaminothiocarbonyl)-2-(2-methoxypyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide Synthesis of (I-50A)
Figure PCTCN2022087589-appb-000285
Figure PCTCN2022087589-appb-000285
向2-(2-甲氧基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-23E)(1.50g,4.82mmol)的N,N-二甲基甲酰胺(5.00mL)溶液中加入乙基异硫氰酸酯(504mg,5.78mmol)和碳酸铯(2.36g,7.23mmol)，反应在30℃搅拌10小时。反应完成后，将反应混合物用水(30.0mL)稀释，然后用乙酸乙酯(30.0mL*3)萃取，合并有机层，用饱和食盐水(30.0mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1至3:1)得到黄色固体化合物N-(乙基氨基硫代甲酰)-2-(2-甲氧基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-50A)(1.70g，产率88％)。To 2-(2-methoxypyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-23E) (1.50 g, 4.82 mmol) in N, Ethyl isothiocyanate (504 mg, 5.78 mmol) and cesium carbonate (2.36 g, 7.23 mmol) were added to the N-dimethylformamide (5.00 mL) solution, and the reaction was stirred at 30° C. for 10 hours. After the completion of the reaction, the reaction mixture was diluted with water (30.0 mL), then extracted with ethyl acetate (30.0 mL*3), the organic layers were combined, washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated , the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=10:1 to 3:1) to obtain a yellow solid compound N-(ethylaminothiocarbonyl)-2-(2- Methoxypyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-50A) (1.70 g, 88% yield).
LC-MS,M/Z(ESI):399.2[M+H] + LC-MS, M/Z(ESI): 399.2[M+H] +
第二步：1-(乙胺基)-4-(2-甲氧基吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-50B)的合成Step 2: 1-(Ethylamino)-4-(2-methoxypyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 -Synthesis of ketone (I-50B)
Figure PCTCN2022087589-appb-000286
Figure PCTCN2022087589-appb-000286
向N-(乙基氨基硫代甲酰)-2-(2-甲氧基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-50A)(1.50g,3.77mmol)的四氢呋喃(10.0mL)溶液中加入碘单质(2.87g,11.3mmol)和吡啶(893mg,11.3mmol)，反应在25℃搅拌10小时。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(50.0mL)稀释，然后用乙酸乙酯/甲醇(10/1，30.0mL*3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，用饱和亚硫酸钠水溶液(30.0mL)洗涤，残留物用甲醇(10.0mL)打浆，得到黄色固体化合物1-(乙胺基)-4-(2-甲氧基吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-50B)(500mg,产率33.3％)，直接用于下一步。To N-(ethylaminothiocarbonyl)-2-(2-methoxypyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I- To a solution of 50A) (1.50 g, 3.77 mmol) in tetrahydrofuran (10.0 mL) was added iodine (2.87 g, 11.3 mmol) and pyridine (893 mg, 11.3 mmol), and the reaction was stirred at 25° C. for 10 hours. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium sulfite solution (50.0 mL), then extracted with ethyl acetate/methanol (10/1, 30.0 mL*3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, Washed with saturated aqueous sodium sulfite solution (30.0 mL), the residue was slurried with methanol (10.0 mL) to give a yellow solid compound 1-(ethylamino)-4-(2-methoxypyridin-3-yl)-6-( Trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-50B) (500 mg, 33.3% yield) was used directly in the next step.
LC-MS,M/Z(ESI):365.0[M+H] + LC-MS, M/Z(ESI): 365.0[M+H] +
第三步：1-(乙胺基)-4-(2-羟基吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-50C)的合成The third step: 1-(Ethylamino)-4-(2-hydroxypyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one Synthesis of (I-50C)
Figure PCTCN2022087589-appb-000287
Figure PCTCN2022087589-appb-000287
向盐酸水溶液(6.00M，10.0mL)中加入1-(乙胺基)-4-(2-甲氧基吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-50B)(200mg,549μmol)，反应在80℃搅拌10小时。反应完成后，将反应混合物减压浓缩，得到黄色固体化合物1-(乙胺基)-4-(2-羟基吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-50C)(180mg，产率93.6％)，直接用于下一步。To aqueous hydrochloric acid (6.00 M, 10.0 mL) was added 1-(ethylamino)-4-(2-methoxypyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1 ,2-c]pyrimidin-3-one (I-50B) (200 mg, 549 μmol), and the reaction was stirred at 80° C. for 10 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a yellow solid compound 1-(ethylamino)-4-(2-hydroxypyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[ 1,2-c]pyrimidin-3-one (I-50C) (180 mg, 93.6% yield) was used directly in the next step.
LC-MS,M/Z(ESI):351.0[M+H] + LC-MS, M/Z(ESI): 351.0[M+H] +
第四步：4-(2-氯吡啶-3-基)-1-(乙胺基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-50)的合成The fourth step: 4-(2-chloropyridin-3-yl)-1-(ethylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one Synthesis of (I-50)
Figure PCTCN2022087589-appb-000288
Figure PCTCN2022087589-appb-000288
向1-(乙胺基)-4-(2-羟基吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-50C)(170mg,485μmol)的乙腈(10.0mL)溶液中加入三氯氧磷(112mg,728μmol)，反应在65℃搅 拌10小时。反应完成后，将反应混合物减压浓缩，残留物用高效液相色谱仪分离纯化，分离方法为(柱子：Phenomenex C18 75*30mm*3μm；溶剂：A＝水+0.05体积％甲酸(99.0％)，B＝乙腈；梯度：20％-50％，7分钟)，得到黄色固体化合物4-(2-氯吡啶-3-基)-1-(乙胺基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-50)(15.2mg,37.5μmol,7.73％产率)。To 1-(ethylamino)-4-(2-hydroxypyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I- To a solution of 50C) (170 mg, 485 μmol) in acetonitrile (10.0 mL) was added phosphorus oxychloride (112 mg, 728 μmol), and the reaction was stirred at 65° C. for 10 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by high performance liquid chromatography. The separation method was (column: Phenomenex C18 75*30mm*3μm; solvent: A=water+0.05% by volume formic acid (99.0%) , B=acetonitrile; gradient: 20%-50%, 7 min) to give yellow solid compound 4-(2-chloropyridin-3-yl)-1-(ethylamino)-6-(trifluoromethyl) -3H-pyrido[1,2-c]pyrimidin-3-one (I-50) (15.2 mg, 37.5 μmol, 7.73% yield).
1H NMR(400MHz,DMSO_d 6):δ8.44(dd,1H),8.19(br d,1H),8.04-8.15(m,1H),7.78(dd,1H),7.52(dd,1H),6.76(br d,1H),6.70(br s,1H),3.47-3.65(m,2H),1.21(t,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ 8.44 (dd, 1H), 8.19 (br d, 1H), 8.04-8.15 (m, 1H), 7.78 (dd, 1H), 7.52 (dd, 1H), 6.76(br d, 1H), 6.70(br s, 1H), 3.47-3.65(m, 2H), 1.21(t, 3H).
LC-MS,M/Z(ESI):369.1[M+H] + LC-MS, M/Z(ESI): 369.1[M+H] +
实施例51：目标化合物I-51的制备Example 51: Preparation of target compound I-51
4-(2-氯吡啶-3-基)-1-((2,2-二氟乙基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-51)4-(2-Chloropyridin-3-yl)-1-((2,2-difluoroethyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine -3-keto(I-51)
Figure PCTCN2022087589-appb-000289
Figure PCTCN2022087589-appb-000289
化合物I-51可参考I-24的合成方法得到。Compound I-51 can be obtained by referring to the synthetic method of I-24.
LC-MS,M/Z(ESI):405.0[M+H] + LC-MS, M/Z(ESI): 405.0[M+H] +
实施例52：目标化合物I-52的制备Example 52: Preparation of target compound I-52
1-(乙胺基)-4-(2-甲基吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-52)1-(Ethylamino)-4-(2-methylpyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (target compound I-52)
Figure PCTCN2022087589-appb-000290
Figure PCTCN2022087589-appb-000290
目标化合物I-52的合成路线如下所示：The synthetic route of the target compound I-52 is as follows:
Figure PCTCN2022087589-appb-000291
Figure PCTCN2022087589-appb-000291
第一步：N-(乙基氨基硫代甲酰)-2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-52A)的合成The first step: N-(ethylaminothioformyl)-2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide ( I-52A) synthesis
Figure PCTCN2022087589-appb-000292
Figure PCTCN2022087589-appb-000292
向2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-10D)(350mg,1.19mmol)的N,N-二甲基甲酰胺(5.00mL)溶液中加入碳酸铯(579mg,1.78mmol)和乙基异硫氰酸酯(110mg,1.26mmol)，反应在30℃搅拌10小时。反应完成后，将反应混合物用水(30.0mL)稀释，然后用乙酸乙酯(30.0mL*3)萃取，合并有机层，用饱和食盐水(30.0mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1至1:1)得到黄色油状物N-(乙基氨基硫代甲酰)-2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-52A)(410mg,产率90.5％)。To 2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-10D) (350 mg, 1.19 mmol) in N,N- Cesium carbonate (579 mg, 1.78 mmol) and ethyl isothiocyanate (110 mg, 1.26 mmol) were added to the dimethylformamide (5.00 mL) solution, and the reaction was stirred at 30° C. for 10 hours. After the completion of the reaction, the reaction mixture was diluted with water (30.0 mL), then extracted with ethyl acetate (30.0 mL*3), the organic layers were combined, washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated , the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=5:1 to 1:1) to obtain N-(ethylaminothiocarbonyl)-2-(2- Methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-52A) (410 mg, 90.5% yield).
LC-MS,M/Z(ESI):383.2[M+H] + LC-MS, M/Z(ESI): 383.2[M+H] +
第二步：1-(乙胺基)-4-(2-甲基吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-52)的合成Step 2: 1-(Ethylamino)-4-(2-methylpyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3- Synthesis of Ketone (I-52)
Figure PCTCN2022087589-appb-000293
Figure PCTCN2022087589-appb-000293
向N-(乙基氨基硫代甲酰)-2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-52A)(300mg,785μmol)的四氢呋喃(3.00mL)溶液中加入碘单质(597mg,2.35mmol)和吡啶(186mg,2.35mmol)，反应在25℃搅拌10小时。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(20.0mL)稀释，然后用乙酸乙酯(20.0mL*3)萃取，合并有机层，用饱和亚硫酸钠水溶液(20.0mL*3)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用乙酸乙酯(5.00mL)打浆，得到黄色固体化合物1-(乙胺基)-4-(2-甲基吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-52)(46.8mg,产率16.8％)。To N-(ethylaminothioyl)-2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-52A ) (300 mg, 785 μmol) in tetrahydrofuran (3.00 mL) was added iodine (597 mg, 2.35 mmol) and pyridine (186 mg, 2.35 mmol), and the reaction was stirred at 25° C. for 10 hours. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium sulfite solution (20.0 mL), then extracted with ethyl acetate (20.0 mL*3), the organic layers were combined, washed with saturated aqueous sodium sulfite solution (20.0 mL*3), and anhydrous sodium sulfate Dry, filter, concentrate, and the residue is slurried with ethyl acetate (5.00 mL) to give a yellow solid compound 1-(ethylamino)-4-(2-methylpyridin-3-yl)-6-(trifluoromethyl) yl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-52) (46.8 mg, 16.8% yield).
1H NMR(400MHz,DMSO_d 6):δ8.46(dd,1H),8.14(br d,1H),8.00(br s,1H),7.49(dd,1H),7.28(dd,1H),6.67-6.75(m,1H),6.62(s,1H),3.43(q,2H),2.24(s,3H),1.21(t,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ 8.46 (dd, 1H), 8.14 (br d, 1H), 8.00 (br s, 1H), 7.49 (dd, 1H), 7.28 (dd, 1H), 6.67 -6.75(m, 1H), 6.62(s, 1H), 3.43(q, 2H), 2.24(s, 3H), 1.21(t, 3H).
LC-MS,M/Z(ESI):349.2[M+H] + LC-MS, M/Z(ESI): 349.2[M+H] +
实施例53：目标化合物I-53的制备Example 53: Preparation of target compound I-53
1-((2,2-二氟乙基)氨基)-4-(2-甲基吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-53)1-((2,2-Difluoroethyl)amino)-4-(2-methylpyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c] Pyrimidine-3-one (target compound I-53)
Figure PCTCN2022087589-appb-000294
Figure PCTCN2022087589-appb-000294
目标化合物I-53的合成路线如下所示：The synthetic route of the target compound I-53 is as follows:
Figure PCTCN2022087589-appb-000295
Figure PCTCN2022087589-appb-000295
第一步：N-((2,2-二氟乙基)氨基硫代甲酰)-2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-53A)的合成The first step: N-((2,2-difluoroethyl)carbamoyl)-2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridine Synthesis of -2-yl)acetamide (I-53A)
Figure PCTCN2022087589-appb-000296
Figure PCTCN2022087589-appb-000296
向2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-10D)(600mg,2.03mmol)的N,N-二甲基甲酰胺(10.0mL)溶液中加入碳酸铯(993mg,3.05mmol)和1,1-二氟-2-异硫氰基乙烷(900mg,7.31mmol)，反应在25℃搅拌10小时。反应完成后，将反应混合物用水(50.0mL)稀释，然后用乙酸乙酯(30.0mL*3)萃取，合并有机层，用饱和食盐水(30.0mL)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝20:1至10:1)得到黄色油状物N-((2,2-二氟乙基)氨基硫代甲酰)-2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-53A)(300mg，粗品)，直接用于下一步。To 2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-10D) (600 mg, 2.03 mmol) in N,N- To the dimethylformamide (10.0 mL) solution was added cesium carbonate (993 mg, 3.05 mmol) and 1,1-difluoro-2-isothiocyanatoethane (900 mg, 7.31 mmol), and the reaction was stirred at 25°C for 10 hours . After the completion of the reaction, the reaction mixture was diluted with water (50.0 mL), then extracted with ethyl acetate (30.0 mL*3), the organic layers were combined, washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated , the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=20:1 to 10:1) to obtain N-((2,2-difluoroethyl)aminothiomethane as a yellow oil Acyl)-2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-53A) (300 mg, crude), used directly Next step.
LC-MS,M/Z(ESI):419.2[M+H] + LC-MS, M/Z(ESI): 419.2[M+H] +
第三步：1-((2,2-二氟乙基)氨基)-4-(2-甲基吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-53)的合成The third step: 1-((2,2-difluoroethyl)amino)-4-(2-methylpyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1, Synthesis of 2-c]pyrimidin-3-one (I-53)
Figure PCTCN2022087589-appb-000297
Figure PCTCN2022087589-appb-000297
向N-((2,2-二氟乙基)氨基硫代甲酰)-2-(2-甲基吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-53A)(300mg,717μmol)的四氢呋喃(5.00mL)溶液中加入碘单质(546mg,2.15mmol) 和吡啶(170mg,2.15mmol)，反应在25℃搅拌10小时。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(50.0mL)稀释，然后用乙酸乙酯(30.0mL*3)萃取，合并有机层，用饱和亚硫酸钠水溶液(30.0mL*3)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:1至二氯甲烷:甲醇(V/V)＝10:1)，然后再用高效液相色谱仪分离纯化，分离方法为(柱子：Waters Xbridge C18 150*25mm*5μm；溶剂：A＝水+0.05体积％氨水(99.0％)，B＝乙腈；梯度：13％-43％，9分钟)，得到黄色固体化合物1-((2,2-二氟乙基)氨基)-4-(2-甲基吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-53)(6.28mg,产率2.27％)。to N-((2,2-difluoroethyl)carbamoyl)-2-(2-methylpyridin-3-yl)-2-(4-(trifluoromethyl)pyridine-2- yl)acetamide (I-53A) (300 mg, 717 μmol) in tetrahydrofuran (5.00 mL) was added iodine (546 mg, 2.15 mmol) and pyridine (170 mg, 2.15 mmol), and the reaction was stirred at 25° C. for 10 hours. After the completion of the reaction, the reaction mixture was diluted with saturated aqueous sodium sulfite solution (50.0 mL), then extracted with ethyl acetate (30.0 mL*3), the organic layers were combined, washed with saturated aqueous sodium sulfite solution (30.0 mL*3), and anhydrous sodium sulfate Dry, filter, concentrate, and the residue is separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:1 to dichloromethane:methanol (V/V)=10:1), and then use high-efficiency Separation and purification by liquid chromatography, the separation method is (column: Waters Xbridge C18 150*25mm*5μm; solvent: A=water+0.05% by volume ammonia water (99.0%), B=acetonitrile; gradient: 13%-43%, 9 minutes) to give a yellow solid compound 1-((2,2-difluoroethyl)amino)-4-(2-methylpyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido [1,2-c]pyrimidin-3-one (1-53) (6.28 mg, 2.27% yield).
1H NMR(400MHz,DMSO_d 6):δ8.46(dd,1H),8.21-8.41(m,1H),7.50(dd,1H),7.28(dd,1H),6.67(br d,1H),6.59(s,1H),6.20(tt,1H),3.70-3.79(m,2H),2.26(s,3H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.46(dd,1H), 8.21-8.41(m,1H), 7.50(dd,1H), 7.28(dd,1H), 6.67(br d,1H), 6.59(s, 1H), 6.20(tt, 1H), 3.70-3.79(m, 2H), 2.26(s, 3H).
LC-MS,M/Z(ESI):385.2[M+H] + LC-MS, M/Z(ESI): 385.2[M+H] +
实施例54：目标化合物I-54的制备Example 54: Preparation of target compound I-54
1-(乙基氨基)-4-(2-氟吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-54)1-(Ethylamino)-4-(2-fluoropyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-54 )
Figure PCTCN2022087589-appb-000298
Figure PCTCN2022087589-appb-000298
化合物I-54可参考I-35的合成方法得到。Compound I-54 can be obtained by referring to the synthetic method of I-35.
LC-MS,M/Z(ESI):353.1[M+H] + LC-MS, M/Z(ESI): 353.1[M+H] +
实施例55：目标化合物I-55的制备Example 55: Preparation of target compound I-55
1-((2,2-二氟乙基)氨基)-4-(2-氟吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-55)1-((2,2-Difluoroethyl)amino)-4-(2-fluoropyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine -3-keto(I-55)
Figure PCTCN2022087589-appb-000299
Figure PCTCN2022087589-appb-000299
化合物I-55可参考I-35的合成方法得到。Compound I-55 can be obtained by referring to the synthetic method of I-35.
LC-MS,M/Z(ESI):389.1[M+H] + LC-MS, M/Z(ESI): 389.1[M+H] +
实施例56：目标化合物I-56的制备Example 56: Preparation of target compound I-56
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000300
Figure PCTCN2022087589-appb-000300
第一步：2-(6-氟吡啶-2-基)乙腈的合成The first step: the synthesis of 2-(6-fluoropyridin-2-yl)acetonitrile
Figure PCTCN2022087589-appb-000301
Figure PCTCN2022087589-appb-000301
在氮气保护下，于-78℃向正丁基锂(2.50M,34.8mL)的四氢呋喃(50.0mL)溶液中加入乙腈(3.90g,95.0mmol)，反应在-78℃搅拌1小时。然后加入2,6-二氟吡啶(5.00g,43.5mmol)，反应在-78℃搅拌2小时。反应完成后，将反应混合物用水(100mL)淬灭，然后用乙酸乙酯(100mL*3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0至50:1)，得到黄色油状化合物2-(6-氟吡啶-2-基)乙腈(1.00g,7.35mmol,16.9％收率)。To a solution of n-butyllithium (2.50 M, 34.8 mL) in tetrahydrofuran (50.0 mL) was added acetonitrile (3.90 g, 95.0 mmol) at -78 °C under nitrogen protection, and the reaction was stirred at -78 °C for 1 hour. 2,6-Difluoropyridine (5.00 g, 43.5 mmol) was then added and the reaction was stirred at -78°C for 2 hours. After the completion of the reaction, the reaction mixture was quenched with water (100 mL), then extracted with ethyl acetate (100 mL*3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a silica gel column (petroleum ether). : ethyl acetate (V/V)=1:0 to 50:1) to obtain a yellow oily compound 2-(6-fluoropyridin-2-yl)acetonitrile (1.00 g, 7.35 mmol, 16.9% yield).
1H NMR(400MHz,DMSO_d 6)δ7.93-8.12(m,1H),7.38(dd,1H),7.17(dd,1H),4.23(s,2H). 1 H NMR (400MHz, DMSO_d 6 ) δ 7.93-8.12 (m, 1H), 7.38 (dd, 1H), 7.17 (dd, 1H), 4.23 (s, 2H).
第二步：2-(6-氟吡啶-2-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈的合成The second step: Synthesis of 2-(6-fluoropyridin-2-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile
Figure PCTCN2022087589-appb-000302
Figure PCTCN2022087589-appb-000302
在氮气保护下，向醋酸钯(16.5mg,73.5μmol)的1,4二氧六环(2.00mL)溶液中加入4，6-双(二苯基膦)吩噁嗪(60.8mg,110μmol)，反应在45℃搅拌1小时。在氮气保护下，将以上反应混合液，慢慢加入到2-(6-氟吡啶-2-基)乙腈(100mg,735μmol)、2-溴-4-(三氟甲基)吡啶(249mg,1.10mmol)和叔丁醇钾(165mg,1.47mmol)的1,4-二氧六环(2.00mL)溶液中，反应在60℃搅拌10小时。反应完成后，将反应混合物用水(10.0mL)稀释，然后用乙酸乙酯(10.0mL*3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶板分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)，得到黄色油状化合物2-(6-氟吡啶-2-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(120mg,427μmol,58.1％收率)。To a solution of palladium acetate (16.5 mg, 73.5 μmol) in 1,4 dioxane (2.00 mL) was added 4,6-bis(diphenylphosphine)phenoxazine (60.8 mg, 110 μmol) under nitrogen protection , the reaction was stirred at 45 °C for 1 hour. Under nitrogen protection, the above reaction mixture was slowly added to 2-(6-fluoropyridin-2-yl)acetonitrile (100 mg, 735 μmol), 2-bromo-4-(trifluoromethyl)pyridine (249 mg, 1.10 mmol) and potassium tert-butoxide (165 mg, 1.47 mmol) in 1,4-dioxane (2.00 mL), the reaction was stirred at 60°C for 10 hours. After the completion of the reaction, the reaction mixture was diluted with water (10.0 mL), then extracted with ethyl acetate (10.0 mL*3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel plate (petroleum ether:ethyl acetate (V/V)=3:1) to give yellow oily compound 2-(6-fluoropyridin-2-yl)-2-(4-(trifluoromethyl)pyridin-2-yl) Acetonitrile (120 mg, 427 μmol, 58.1% yield).
1H NMR(400MHz,DMSO_d 6)δ14.03(br s,1H),8.23(t,1H),7.89-7.99(m,1H),7.32(s,1H),7.23(dd,1H),6.72-6.87(m,2H). 1 H NMR(400MHz, DMSO_d 6 )δ14.03(br s,1H),8.23(t,1H),7.89-7.99(m,1H),7.32(s,1H),7.23(dd,1H),6.72 -6.87(m,2H).
LC-MS,M/Z(ESI):282.0[M+H] + LC-MS, M/Z(ESI): 282.0[M+H] +
第三步：2-(6-氟吡啶-2-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The third step: synthesis of 2-(6-fluoropyridin-2-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
Figure PCTCN2022087589-appb-000303
Figure PCTCN2022087589-appb-000303
向硫酸(3.00mL)中加入2-(6-氟吡啶-2-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(100mg,356μmol)，反应在20℃搅拌10小时。反应完成后，将反应液在0℃下慢慢加入用氢氧化钠水溶液(4.00M,20.0mL)淬灭，然后用乙酸乙酯(20.0mL*3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，得到黄色固体化合物2-(6-氟吡啶-2-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(100mg,334μmol,94.0％收率)。直接用于下一步。To sulfuric acid (3.00 mL) was added 2-(6-fluoropyridin-2-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (100 mg, 356 μmol), and the reaction was stirred at 20°C 10 hours. After the completion of the reaction, the reaction solution was slowly added at 0 °C and quenched with aqueous sodium hydroxide solution (4.00M, 20.0 mL), then extracted with ethyl acetate (20.0 mL*3), the organic layers were combined, anhydrous sodium sulfate Dry, filter and concentrate to give yellow solid compound 2-(6-fluoropyridin-2-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (100 mg, 334 μmol, 94.0% yield). Rate). used directly in the next step.
1H NMR(400MHz,DMSO_d 6)δ8.80(d,1H),7.98(q,1H),7.76-7.89(m,2H),7.71(d,1H),7.30-7.44(m,2H),7.09(dd,1H),5.39(s,1H). 1 H NMR (400MHz, DMSO_d 6 )δ8.80(d,1H),7.98(q,1H),7.76-7.89(m,2H),7.71(d,1H),7.30-7.44(m,2H), 7.09(dd,1H),5.39(s,1H).
LC-MS,M/Z(ESI):300.1(M+H) + LC-MS, M/Z (ESI): 300.1 (M+H) +
第四步：2-(6-氟吡啶-2-基)-N-(甲基氨基硫代甲酰)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The fourth step: the synthesis of 2-(6-fluoropyridin-2-yl)-N-(methylaminothiocarbonyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
Figure PCTCN2022087589-appb-000304
Figure PCTCN2022087589-appb-000304
向2-(6-氟吡啶-2-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(50.0mg,167μmol)和1,1-二氟-2-异硫氰基乙烷(700mg,5.69mmol)的N,N-二甲基甲酰胺(1.00mL)溶液中加入碳酸铯(109mg,334μmol)和异硫氰酸甲酯(18.3mg,251μmol)，反应在30℃搅拌10小时。反应完成后，将反应混合物用水(10.0mL)稀释，然后用乙酸乙酯(10.0mL*3)萃取，合并有机层，用水(10.0mL*3)洗涤，无水硫酸钠干燥，过滤，浓缩，得到黄色油状化合物2-(6-氟吡啶-2-基)-N-(甲基氨基硫代甲酰)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(60.0mg)。直接用于下一步。To 2-(6-fluoropyridin-2-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (50.0 mg, 167 μmol) and 1,1-difluoro-2-iso To a solution of thiocyanoethane (700mg, 5.69mmol) in N,N-dimethylformamide (1.00mL) was added cesium carbonate (109mg, 334μmol) and methyl isothiocyanate (18.3mg, 251μmol), reacted Stir at 30°C for 10 hours. After the reaction was completed, the reaction mixture was diluted with water (10.0 mL), then extracted with ethyl acetate (10.0 mL*3), the organic layers were combined, washed with water (10.0 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated, The yellow oily compound 2-(6-fluoropyridin-2-yl)-N-(methylaminothioyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (60.0 mg). used directly in the next step.
LC-MS,M/Z(ESI):373.1(M+H) + LC-MS, M/Z (ESI): 373.1 (M+H) +
第五步4-(6-氟吡啶-2-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-56)的合成The fifth step 4-(6-fluoropyridin-2-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one ( 1-56) synthesis
Figure PCTCN2022087589-appb-000305
Figure PCTCN2022087589-appb-000305
向2-(6-氟吡啶-2-基)-N-(甲基氨基硫代甲酰)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(60.0mg,161μmol)的四氢呋喃(3.00mL)溶液中加入碘单质(123mg,483μmol)和吡啶(38.2mg,483μmol)，反应在20℃搅拌10小时。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(50.0mL)稀释，然后用乙酸乙酯(30.0mL*3)萃取，合并有机层，用饱和亚硫酸钠水溶液(30.0mL*3)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶板分离纯化(乙酸乙酯：甲醇(V/V)＝10:1)，得到黄色固体化合物4-(6-氟吡啶-2-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-56)(3.09mg,8.90μmol,5.52％收率)。To 2-(6-fluoropyridin-2-yl)-N-(methylcarbamoyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (60.0 mg, 161 μmol ) in tetrahydrofuran (3.00 mL) was added iodine (123 mg, 483 μmol) and pyridine (38.2 mg, 483 μmol), and the reaction was stirred at 20° C. for 10 hours. After the completion of the reaction, the reaction mixture was diluted with saturated aqueous sodium sulfite solution (50.0 mL), then extracted with ethyl acetate (30.0 mL*3), the organic layers were combined, washed with saturated aqueous sodium sulfite solution (30.0 mL*3), and anhydrous sodium sulfate Dry, filter, concentrate, and the residue is separated and purified by silica gel plate (ethyl acetate:methanol (V/V)=10:1) to obtain yellow solid compound 4-(6-fluoropyridin-2-yl)-1-( Methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-56) (3.09 mg, 8.90 μmol, 5.52% yield).
1H NMR(400MHz,DMSO_d 6)δ8.11-8.29(m,2H),8.03(q,1H),7.48-7.71(m,2H),7.11(dd,1H),6.79(dd,1H),2.90(s,3H). 1 H NMR (400MHz, DMSO_d 6 ) δ 8.11-8.29(m, 2H), 8.03(q, 1H), 7.48-7.71(m, 2H), 7.11(dd, 1H), 6.79(dd, 1H), 2.90(s,3H).
LC-MS,M/Z(ESI):339.1[M+H] + LC-MS, M/Z(ESI): 339.1[M+H] +
实施例57：目标化合物I-57的制备Example 57: Preparation of target compound I-57
4-(2-氟吡啶-4-基)-1-(甲基氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-57)4-(2-Fluoropyridin-4-yl)-1-(methylamino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-57 )
Figure PCTCN2022087589-appb-000306
Figure PCTCN2022087589-appb-000306
化合物I-57可参考I-31的合成方法得到。Compound I-57 can be obtained by referring to the synthetic method of I-31.
LC-MS,M/Z(ESI):339.1[M+H] + LC-MS, M/Z(ESI): 339.1[M+H] +
实施例58：目标化合物I-58的制备Example 58: Preparation of target compound I-58
4-(2-氯苯基)-1-(吡咯烷-1-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-58)4-(2-Chlorophenyl)-1-(pyrrolidin-1-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-58 )
Figure PCTCN2022087589-appb-000307
Figure PCTCN2022087589-appb-000307
目标化合物I-58的合成路线如下所示：The synthetic route of the target compound I-58 is as follows:
Figure PCTCN2022087589-appb-000308
Figure PCTCN2022087589-appb-000308
第一步：4-(2-氯苯基)-1-硫代-6-(三氟甲基)-1H-吡啶并[1,2-c]嘧啶-3(2H)-酮(I-58A)的合成The first step: 4-(2-chlorophenyl)-1-thio-6-(trifluoromethyl)-1H-pyrido[1,2-c]pyrimidin-3(2H)-one (I- 58A) synthesis
Figure PCTCN2022087589-appb-000309
Figure PCTCN2022087589-appb-000309
氮气保护下，向100mL三口烧瓶中加入钠(2.0g,87mmol)，同时加入无水乙醇(40mL)，待钠块全部溶解后，反应体系降至0℃。向三口瓶中加入2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-1D)(2.74g,8.71mmol)，搅拌30min后，缓慢加入硫光气(2.0g，17.41mmol)，回流条件下反应12h。反应降至室温，体系浓缩干，加入100mL乙酸乙酯，有机相用水洗(50 mL*2)，收集有机相，用无水硫酸钠干燥，旋干得到粗品，粗品硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1)得到4-(2-氯苯基)-1-硫代-6-(三氟甲基)-1H-吡啶并[1,2-c]嘧啶-3(2H)-酮(I-58A)(1.6g,产率52％)。Under nitrogen protection, sodium (2.0 g, 87 mmol) was added to a 100 mL three-necked flask, and anhydrous ethanol (40 mL) was added at the same time. After all the sodium lumps were dissolved, the reaction system was lowered to 0 °C. 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-1D) (2.74g, 8.71mmol) was added to the there-necked flask, and after stirring for 30min , slowly added thiophosgene (2.0 g, 17.41 mmol), and reacted under reflux conditions for 12 h. The reaction was cooled to room temperature, the system was concentrated to dryness, 100 mL of ethyl acetate was added, the organic phase was washed with water (50 mL*2), the organic phase was collected, dried with anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was separated and purified on a silica gel column (petroleum ether). /ethyl acetate=10/1) to give 4-(2-chlorophenyl)-1-thio-6-(trifluoromethyl)-1H-pyrido[1,2-c]pyrimidine-3(2H )-keto (I-58A) (1.6 g, 52% yield).
LC-MS,M/Z(ESI):357.0[M+H] +。 LC-MS, M/Z (ESI): 357.0 [M+H] + .
第二步：4-(2-氯苯基)-1-(吡咯烷-1-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-58)的合成Step 2: 4-(2-Chlorophenyl)-1-(pyrrolidin-1-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one Synthesis of (I-58)
Figure PCTCN2022087589-appb-000310
Figure PCTCN2022087589-appb-000310
将4-(2-氯苯基)-1-硫代-6-(三氟甲基)-1H-吡啶并[1,2-c]嘧啶-3(2H)-酮(I-58A)(300mg，0.84mmol)，吡咯烷(120mg,1.68mmol)和吡啶(133mg，1.68mmol)溶到四氢呋喃(3mL)中，置换氮气，降温到0℃，将碘单质(427mg，1.68mmol)慢慢加入反应液。在50℃下搅拌14h。用饱和的硫代硫酸钠(20mL)淬灭反应，乙酸乙酯(50mL*2)萃取，合并有机相，用无水硫酸钠干燥，旋干得到粗品，粗品用乙酸乙酯重结晶得到4-(2-氯苯基)-1-(吡咯烷-1-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-58)(39mg,产率12％)。4-(2-Chlorophenyl)-1-thio-6-(trifluoromethyl)-1H-pyrido[1,2-c]pyrimidin-3(2H)-one (I-58A) ( 300 mg, 0.84 mmol), pyrrolidine (120 mg, 1.68 mmol) and pyridine (133 mg, 1.68 mmol) were dissolved in tetrahydrofuran (3 mL), replaced with nitrogen, cooled to 0 °C, and iodine (427 mg, 1.68 mmol) was slowly added The reaction solution. Stir at 50°C for 14h. The reaction was quenched with saturated sodium thiosulfate (20 mL), extracted with ethyl acetate (50 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was recrystallized from ethyl acetate to obtain 4- (2-Chlorophenyl)-1-(pyrrolidin-1-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-58)( 39 mg, 12% yield).
1H NMR(400MHz,DMSO-d6)δ7.99(d,J＝7.5Hz,1H),7.60–7.51(m,1H),7.47–7.36(m,2H),7.32–7.24(m,1H),6.60(p,J＝1.5,1.1Hz,1H),6.52(dd,J＝7.8,2.1Hz,1H),3.54(q,J＝5.6Hz,4H),1.92–1.85(m,4H). 1 H NMR(400MHz, DMSO-d6)δ7.99(d,J=7.5Hz,1H),7.60-7.51(m,1H),7.47-7.36(m,2H),7.32-7.24(m,1H) ,6.60(p,J＝1.5,1.1Hz,1H),6.52(dd,J＝7.8,2.1Hz,1H),3.54(q,J＝5.6Hz,4H),1.92–1.85(m,4H).
LC-MS,M/Z(ESI):394.1[M+H] +。 LC-MS, M/Z (ESI): 394.1 [M+H] + .
实施例59：目标化合物I-59的制备Example 59: Preparation of target compound I-59
1-(氮杂环丁烷-1-基)-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-59)1-(azetidin-1-yl)-4-(2-chlorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one ( I-59)
Figure PCTCN2022087589-appb-000311
Figure PCTCN2022087589-appb-000311
目标化合物I-59的合成路线如下所示：The synthetic route of the target compound I-59 is shown below:
Figure PCTCN2022087589-appb-000312
Figure PCTCN2022087589-appb-000312
将4-(2-氯苯基)-1-硫代-6-(三氟甲基)-1H-吡啶并[1,2-c]嘧啶-3(2H)-酮(I-58A)(125mg，0.35mmol)，氮杂环丁烷(60mg,1.05mmol)和吡啶(83mg，1.05mmol)溶到四氢呋喃(1mL)中， 置换氮气，降温到0℃，将碘单质(178mg，0.7mmol)慢慢加入反应液。在50℃下搅拌14h。用饱和的硫代硫酸钠(10mL)淬灭反应，乙酸乙酯(50mL*2)萃取，合并有机相，用无水硫酸钠干燥，旋干得到粗品，粗品用乙酸乙酯重结晶得到1-(氮杂环丁烷-1-基)-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-59)(10mg,产率7.5％)。4-(2-Chlorophenyl)-1-thio-6-(trifluoromethyl)-1H-pyrido[1,2-c]pyrimidin-3(2H)-one (I-58A) ( 125 mg, 0.35 mmol), azetidine (60 mg, 1.05 mmol) and pyridine (83 mg, 1.05 mmol) were dissolved in tetrahydrofuran (1 mL), replaced with nitrogen, cooled to 0 °C, and iodine (178 mg, 0.7 mmol) Slowly add the reaction solution. Stir at 50°C for 14h. The reaction was quenched with saturated sodium thiosulfate (10 mL), extracted with ethyl acetate (50 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was recrystallized from ethyl acetate to obtain 1- (azetidin-1-yl)-4-(2-chlorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I- 59) (10 mg, 7.5% yield).
1H NMR(400MHz,DMSO-d6)δ7.85(dt,J＝7.8,0.9Hz,1H),7.61–7.52(m,1H),7.49–7.35(m,2H),7.33–7.23(m,1H),6.62(dq,J＝2.4,1.2Hz,1H),6.53(dd,J＝7.8,2.1Hz,1H),4.36–4.22(m,4H),2.31(p,J＝7.8Hz,2H). 1 H NMR (400MHz, DMSO-d6) δ7.85(dt, J=7.8, 0.9Hz, 1H), 7.61-7.52(m, 1H), 7.49-7.35(m, 2H), 7.33-7.23(m, 1H), 6.62 (dq, J=2.4, 1.2Hz, 1H), 6.53 (dd, J=7.8, 2.1Hz, 1H), 4.36–4.22 (m, 4H), 2.31 (p, J=7.8Hz, 2H) ).
LC-MS,M/Z(ESI):380.1[M+H] +。 LC-MS, M/Z (ESI): 380.1 [M+H] + .
实施例60：目标化合物I-60的制备Example 60: Preparation of target compound I-60
4-(2-氯苯基)-1-(((2S)-2-羟基丙基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-60)4-(2-Chlorophenyl)-1-(((2S)-2-hydroxypropyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 - Ketone (target compound I-60)
Figure PCTCN2022087589-appb-000313
Figure PCTCN2022087589-appb-000313
目标化合物I-60的合成路线如下所示：The synthetic route of the target compound I-60 is as follows:
Figure PCTCN2022087589-appb-000314
Figure PCTCN2022087589-appb-000314
第一步：(S)-2-((叔丁基二甲基甲硅烷基)氧代)丙烷-1-胺(3C-2)的合成The first step: Synthesis of (S)-2-((tert-butyldimethylsilyl)oxo)propane-1-amine (3C-2)
Figure PCTCN2022087589-appb-000315
Figure PCTCN2022087589-appb-000315
将(S)-1-氨基丙烷-2-醇(5.00g,66.6mmol)和三乙胺(13.5g,133.1mmol)溶解在二氯甲烷(50.0mL)中，氮气保护下0℃加叔丁基二甲基氯硅烷(15.1g,99.8mmol)，然后在40℃下搅拌反应10小时。将反应液浓缩得到粗品，将水(300mL)倒入反应液中，然后用二氯甲烷(600mL)萃取，用饱和食盐水(200mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。 粗品用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)＝50:1-10:1)得到黄色油状化合物(S)-2-((叔-丁基二甲基甲硅烷基)氧代)丙烷-1-胺(3C-2)(12.1g，产率96.0％)。(S)-1-aminopropan-2-ol (5.00 g, 66.6 mmol) and triethylamine (13.5 g, 133.1 mmol) were dissolved in dichloromethane (50.0 mL), and tert-butyl was added at 0°C under nitrogen protection dimethylchlorosilane (15.1 g, 99.8 mmol), then the reaction was stirred at 40°C for 10 hours. The reaction solution was concentrated to obtain the crude product, water (300 mL) was poured into the reaction solution, then extracted with dichloromethane (600 mL), the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol (V/V)=50:1-10:1) to obtain yellow oily compound (S)-2-((tert-butyldimethylsilyl)oxygen substituted)propan-1-amine (3C-2) (12.1 g, 96.0% yield).
1H NMR(400MHz,DMSO-d 6):δ3.65-3.74(m,1H),2.45(d,2H),1.05(d,3H),0.86(s,9H),0.04(s,6H). 1 H NMR (400MHz, DMSO-d 6 ): δ3.65-3.74(m, 1H), 2.45(d, 2H), 1.05(d, 3H), 0.86(s, 9H), 0.04(s, 6H) .
第二步：叔丁基-((1S)-2-异硫氰基-1-甲基-乙氧基)-二甲基-硅烷(3C)的合成The second step: synthesis of tert-butyl-((1S)-2-isothiocyano-1-methyl-ethoxy)-dimethyl-silane (3C)
Figure PCTCN2022087589-appb-000316
Figure PCTCN2022087589-appb-000316
将(S)-2-((叔-丁基二甲基甲硅烷基)氧代)丙烷-1-胺(1.50g,7.92mmol)和碳酸铯(6.45g,19.8mmol)溶解在二氯甲烷(15mL)中，在氮气保护下加入硫光气(1.09g,9.51mmol,728.6μL)，25℃反应2小时。把反应液过滤，有机相浓缩得到黄色固体化合物叔-丁基-((1S)-2-异硫氰基-1-甲基-乙氧基)-二甲基-硅烷(3C)(1.50g，产率81.8％)。(S)-2-((tert-butyldimethylsilyl)oxo)propan-1-amine (1.50 g, 7.92 mmol) and cesium carbonate (6.45 g, 19.8 mmol) were dissolved in dichloromethane (15 mL), thiophosgene (1.09 g, 9.51 mmol, 728.6 μL) was added under nitrogen protection, and the reaction was carried out at 25° C. for 2 hours. The reaction solution was filtered, and the organic phase was concentrated to obtain a yellow solid compound tert-butyl-((1S)-2-isothiocyano-1-methyl-ethoxy)-dimethyl-silane (3C) (1.50 g) , the yield is 81.8%).
第三步：N-(((S)-2-((叔丁基(二甲基)甲硅烷基)氧代)丙基)氨基硫代甲酰基)-2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-60A)的合成The third step: N-(((S)-2-((tert-butyl(dimethyl)silyl)oxo)propyl)aminothioformyl)-2-(2-chlorophenyl) - Synthesis of 2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-60A)
Figure PCTCN2022087589-appb-000317
Figure PCTCN2022087589-appb-000317
将叔丁基-((1S)-2-异硫氰基-1-甲基-乙氧基)-二甲基硅烷(3C)(1.50g,6.48mmol)和碳酸铯(3.11g,9.54mmol)溶解在N,N-二甲基甲酰胺(10mL)中，加2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-1D)(1.50g,4.77mmol)，75℃反应2小时。把水(50mL)加到反应液中，然后用乙酸乙酯(120mL)萃取，用饱和食盐水(40mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0-20:1)得到棕色固体化合物N-(((S)-2-((叔丁基(二甲基)甲硅烷基)氧代)丙基)氨基硫代甲酰基]-2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-60A)(1.70g，产率65.3％)。Combine tert-butyl-((1S)-2-isothiocyano-1-methyl-ethoxy)-dimethylsilane (3C) (1.50 g, 6.48 mmol) and cesium carbonate (3.11 g, 9.54 mmol) ) was dissolved in N,N-dimethylformamide (10 mL), 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I- 1D) (1.50 g, 4.77 mmol), reacted at 75°C for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (120 mL), the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:0-20:1) to obtain a brown solid compound N-(((S)-2-((tert-butyl(dimethyl) )silyl)oxo)propyl)aminothiocarbonyl]-2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I- 60A) (1.70 g, 65.3% yield).
1H NMR(400MHz,DMSO-d 6):δ11.80(d,1H),10.64-10.66(m,1H),8.84-8.88(m,1H),7.76(d,1H),7.48-7.54(m,2H),7.31-7.40(m,2H),7.05-7.10(m,1H),6.01(s,1H),4.08-4.16(m,1H),3.61-3.69(m,1H),3.38-3.46(m,1H),1.09(d,3H),0.80(d,9H),-0.03-0.02(m,6H). 1 H NMR (400MHz, DMSO-d 6 ): δ 11.80(d,1H), 10.64-10.66(m,1H), 8.84-8.88(m,1H), 7.76(d,1H), 7.48-7.54( m, 2H), 7.31-7.40(m, 2H), 7.05-7.10(m, 1H), 6.01(s, 1H), 4.08-4.16(m, 1H), 3.61-3.69(m, 1H), 3.38- 3.46(m,1H),1.09(d,3H),0.80(d,9H),-0.03-0.02(m,6H).
LC-MS,M/Z(ESI):546.2[M+H] + LC-MS, M/Z(ESI): 546.2[M+H] +
第四步：1-(((2S)-2-(叔丁基(二甲基)甲硅烷基)氧代丙基)氨基)-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-60B)的合成The fourth step: 1-(((2S)-2-(tert-butyl(dimethyl)silyl)oxopropyl)amino)-4-(2-chlorophenyl)-6-(trifluoro) Synthesis of methyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-60B)
Figure PCTCN2022087589-appb-000318
Figure PCTCN2022087589-appb-000318
将N-(((S)-2-((叔丁基(二甲基)甲硅烷基)氧代)丙基)氨基硫代甲酰基)-2-(2-氯苯基)-2-(4-(三 氟甲基)吡啶-2-基)乙酰胺(I-60A)(1.70g,3.11mmol)溶解在四氢呋喃(20mL)中，加碘(1.58g,6.23mmol)和碳酸铯(1.01g,3.11mmol)，25℃反应2小时。把水(20mL)加到反应液中，加入饱和亚硫酸钠溶液(20mL)，然后用乙酸乙酯(90mL)萃取，用饱和食盐水(30mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品通过正相高效液相色谱法进行分离，分离方法为(柱子：Welch Ultimate XB-CN 250*50*10μm；溶剂：A＝己烷，B＝乙醇+甲酸(0.1％)；梯度：1％-30％，15分钟)，得到棕色油状化合物1-(((2S)-2-(叔丁基(二甲基)甲硅烷基)氧代丙基)氨基)-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-60B)(1.40g，产率86.1％)。N-(((S)-2-((tert-butyl(dimethyl)silyl)oxo)propyl)aminothiocarbonyl)-2-(2-chlorophenyl)-2- (4-(Trifluoromethyl)pyridin-2-yl)acetamide (I-60A) (1.70 g, 3.11 mmol) was dissolved in tetrahydrofuran (20 mL), iodine (1.58 g, 6.23 mmol) and cesium carbonate ( 1.01 g, 3.11 mmol), react at 25°C for 2 hours. Water (20 mL) was added to the reaction solution, saturated sodium sulfite solution (20 mL) was added, then extracted with ethyl acetate (90 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by normal phase high performance liquid chromatography, and the separation method was (column: Welch Ultimate XB-CN 250*50*10 μm; solvent: A=hexane, B=ethanol+formic acid (0.1%); gradient: 1% -30%, 15 min) to give 1-(((2S)-2-(tert-butyl(dimethyl)silyl)oxopropyl)amino)-4-(2-chlorobenzene as a brown oily compound yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-60B) (1.40 g, 86.1% yield).
LC-MS,M/Z(ESI):512.2[M+H] + LC-MS, M/Z(ESI): 512.2[M+H] +
第五步：4-(2-氯苯基)-1-(((2S)-2-羟基丙基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-60)Step 5: 4-(2-Chlorophenyl)-1-(((2S)-2-hydroxypropyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c ] Pyrimidine-3-one (target compound I-60)
Figure PCTCN2022087589-appb-000319
Figure PCTCN2022087589-appb-000319
将1-(((2S)-2-(叔丁基(二甲基)甲硅烷基)氧代丙基)氨基)-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-60B)(300mg,585.9μmol)溶解在二氧六环(10.0mL)中，加入氯化氢-二氧六环溶液(4M,292.9μL)，25℃反应1小时。在反应液中加入饱和碳酸氢钠溶液(20mL)调节pH至9，然后用乙酸乙酯(45.0mL)萃取，用饱和食盐水(20mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。然后通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150*25mm*5μm；溶剂：A＝水+碳酸氢铵(0.05％)，B＝乙腈；梯度：28％-58％，10分钟)，得到黄色固体化合物4-(2-氯苯基)-1-(((2S)-2-羟基丙基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-60)(40mg，产率16.6％)。1-(((2S)-2-(tert-butyl(dimethyl)silyl)oxopropyl)amino)-4-(2-chlorophenyl)-6-(trifluoromethyl) -3H-pyrido[1,2-c]pyrimidin-3-one (I-60B) (300 mg, 585.9 μmol) was dissolved in dioxane (10.0 mL), and a solution of hydrogen chloride-dioxane (4M) was added , 292.9 μL), and reacted at 25°C for 1 hour. Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution to adjust pH to 9, then extracted with ethyl acetate (45.0 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Then it was separated by reversed-phase high performance liquid chromatography, and the separation method was (column: Waters Xbridge 150*25mm*5μm; solvent: A=water+ammonium bicarbonate (0.05%), B=acetonitrile; gradient: 28%-58 %, 10 minutes) to give a yellow solid compound 4-(2-chlorophenyl)-1-(((2S)-2-hydroxypropyl)amino)-6-(trifluoromethyl)-3H-pyrido [1,2-c]pyrimidin-3-one (I-60) (40 mg, 16.6% yield).
1H NMR(400MHz,DMSO-d 6):δ8.19-8.25(m,1H),8.01-8.08(m,1H),7.56-7.60(m,1H),7.41-7.44(m,2H),7.28-7.32(m,1H),6.73(d,1H),6.59(s,1H),4.8-4.90(m,1H),3.93-3.95(m,1H),3.37-3.38(m,1H),1.23(s,1H),1.11(d,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ 8.19-8.25 (m, 1H), 8.01-8.08 (m, 1H), 7.56-7.60 (m, 1H), 7.41-7.44 (m, 2H), 7.28-7.32(m, 1H), 6.73(d, 1H), 6.59(s, 1H), 4.8-4.90(m, 1H), 3.93-3.95(m, 1H), 3.37-3.38(m, 1H), 1.23(s, 1H), 1.11(d, 3H).
LC-MS,M/Z(ESI):398.1[M+H] + LC-MS, M/Z(ESI): 398.1[M+H] +
实施例61：目标化合物I-61的制备Example 61: Preparation of target compound I-61
4-(2-氯苯基)-1-(((2R)-2-羟基丙基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-61)4-(2-Chlorophenyl)-1-(((2R)-2-hydroxypropyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 - Ketone (target compound I-61)
Figure PCTCN2022087589-appb-000320
Figure PCTCN2022087589-appb-000320
目标化合物I-61的合成路线如下所示：The synthetic route of the target compound I-61 is as follows:
Figure PCTCN2022087589-appb-000321
Figure PCTCN2022087589-appb-000321
第一步：(R)-2-((叔丁基二甲基甲硅烷基)氧代)丙烷-1-胺(3D-2)的合成The first step: Synthesis of (R)-2-((tert-butyldimethylsilyl)oxo)propane-1-amine (3D-2)
Figure PCTCN2022087589-appb-000322
Figure PCTCN2022087589-appb-000322
将(R)-1-氨基丙烷-2-醇(5.00g,66.5mmol)和三乙胺(13.4g,133mmol)溶解在二氯甲烷(50.0mL)中，氮气保护下0℃加叔丁基二甲基氯硅烷(15.1g,99.8mmol)，然后在40℃下搅拌反应10小时。将反应液浓缩得到粗品，将水(200mL)倒入反应液中，然后用二氯甲烷(600mL)萃取，用饱和食盐水(200mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。粗品用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)＝50:1-10:1)得到黄色油状化合物(R)-2-((叔丁基二甲基甲硅烷基)氧代)丙烷-1-胺(3D-2)(10.5g，产率79.3％)。(R)-1-aminopropan-2-ol (5.00 g, 66.5 mmol) and triethylamine (13.4 g, 133 mmol) were dissolved in dichloromethane (50.0 mL), and tert-butyl was added at 0°C under nitrogen protection Dimethylchlorosilane (15.1 g, 99.8 mmol) and the reaction was stirred at 40°C for 10 hours. The reaction solution was concentrated to obtain the crude product, water (200 mL) was poured into the reaction solution, then extracted with dichloromethane (600 mL), the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol (V/V)=50:1-10:1) to obtain yellow oily compound (R)-2-((tert-butyldimethylsilyl)oxo ) propan-1-amine (3D-2) (10.5 g, 79.3% yield).
1H NMR(400MHz,DMSO-d 6):δ3.63-3.71(m,1H),2.44(d,1H),2.42(s,1H),1.04(d,3H),0.84-0.87(m,9H),0.04(s,6H). 1 H NMR (400MHz, DMSO-d 6 ): δ3.63-3.71(m,1H), 2.44(d,1H), 2.42(s,1H), 1.04(d,3H), 0.84-0.87(m, 9H),0.04(s,6H).
第二步：叔-丁基-((1R)-2-异硫氰基-1-甲基-乙氧基)-二甲基-硅烷(3D)的合成Step 2: Synthesis of tert-butyl-((1R)-2-isothiocyanato-1-methyl-ethoxy)-dimethyl-silane (3D)
Figure PCTCN2022087589-appb-000323
Figure PCTCN2022087589-appb-000323
将(R)-2-((叔-丁基二甲基甲硅烷基)氧代)丙烷-1-胺(1.50g,7.92mmol)和碳酸铯(7.74g,23.7mmol)溶解在二氯甲烷(15mL)中，在氮气保护下加入硫光气(1.82g,15.8mmol,1.21mL)，25℃反应2小时。把反应液过滤，有机相浓缩得到黄色固体化合物叔-丁基-((1R)-2-异硫氰基-1-甲基-乙氧基)-二甲基-硅烷(3D)(1.50g，产率81.83％)。(R)-2-((tert-butyldimethylsilyl)oxo)propan-1-amine (1.50 g, 7.92 mmol) and cesium carbonate (7.74 g, 23.7 mmol) were dissolved in dichloromethane (15 mL), thiophosgene (1.82 g, 15.8 mmol, 1.21 mL) was added under nitrogen protection, and the reaction was carried out at 25° C. for 2 hours. The reaction solution was filtered, and the organic phase was concentrated to obtain a yellow solid compound tert-butyl-((1R)-2-isothiocyano-1-methyl-ethoxy)-dimethyl-silane (3D) (1.50 g , the yield is 81.83%).
第三步：N-(((2R)-2-(叔-丁基(二甲基)甲硅烷基)氧代丙基)氨基硫代甲酰基)-2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-61A)的合成The third step: N-(((2R)-2-(tert-butyl(dimethyl)silyl)oxopropyl)aminothioformyl)-2-(2-chlorophenyl)- Synthesis of 2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-61A)
Figure PCTCN2022087589-appb-000324
Figure PCTCN2022087589-appb-000324
将叔-丁基-((1R)-2-异硫氰基-1-甲基-乙氧基)-二甲基-硅烷(3D)(1.50g,6.48mmol)和碳酸铯(4.66g,14.3mmol)溶解在N,N-二甲基甲酰胺(20mL)中，加2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-1D)(1.5g,4.77mmol)，75℃反应2小时。把水(50mL)加到反应液中，然后用乙酸乙酯(120mL)萃取，用饱和食盐水(40mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0-20:1)得到棕色固体化合物N-(((2R)-2-(叔-丁基(二甲基)甲硅烷基)氧代丙基)氨基硫代甲酰基)-2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-61A)(1.83g，产率73.9％)。tert-Butyl-((1R)-2-isothiocyano-1-methyl-ethoxy)-dimethyl-silane (3D) (1.50 g, 6.48 mmol) and cesium carbonate (4.66 g, 14.3 mmol) was dissolved in N,N-dimethylformamide (20 mL), and 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide ( I-1D) (1.5 g, 4.77 mmol), reacted at 75°C for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (120 mL), the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:0-20:1) to obtain a brown solid compound N-(((2R)-2-(tert-butyl(dimethyl) )silyl)oxopropyl)aminothioformyl)-2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-61A ) (1.83 g, 73.9% yield).
1H NMR(400MHz,DMSO-d 6):δ11.81(br d,1H),10.66(br s,1H),8.86(br m,1H),7.76(br d,1H),7.48-7.55(m,2H),7.31-7.38(m,2H),7.07(m,1H),6.01(d,1H),4.07-4.18(m,1H),3.60-3.70(m,1H),3.38-3.47(m,1H),1.09(d,3H),0.80(s,9H),-0.04-0.02(m,6H). 1 H NMR (400MHz, DMSO-d 6 ): δ 11.81 (br d, 1H), 10.66 (br s, 1H), 8.86 (br m, 1H), 7.76 (br d, 1H), 7.48-7.55 ( m, 2H), 7.31-7.38(m, 2H), 7.07(m, 1H), 6.01(d, 1H), 4.07-4.18(m, 1H), 3.60-3.70(m, 1H), 3.38-3.47( m,1H),1.09(d,3H),0.80(s,9H),-0.04-0.02(m,6H).
LC-MS,M/Z(ESI):546.2[M+H] + LC-MS, M/Z(ESI): 546.2[M+H] +
第四步：1-(((2R)-2-(叔丁基(二甲基)甲硅烷基)氧代丙基)氨基)-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-61B)的合成The fourth step: 1-(((2R)-2-(tert-butyl(dimethyl)silyl)oxopropyl)amino)-4-(2-chlorophenyl)-6-(trifluoro) Synthesis of methyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-61B)
Figure PCTCN2022087589-appb-000325
Figure PCTCN2022087589-appb-000325
将N-(((2R)-2-(叔-丁基(二甲基)甲硅烷基)氧代丙基)氨基硫代甲酰基)-2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-61A)(1.83g,2.48mmol)溶解在四氢呋喃(20mL)中，加碘(1.89g,7.43mmol)和碳酸铯(2.42g,7.43mmol)，25℃反应2小时。把水(20mL)加到反应液中，加入饱和亚硫酸钠溶液(20mL)，然后用乙酸乙酯(90mL)萃取，用饱和食盐水(30mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:2)得到黄色固体化合物1-(((2R)-2-(叔丁基(二甲基)甲硅烷基)氧代丙基)氨基)-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-61B)(850mg，产率65.9％)。N-(((2R)-2-(tert-butyl(dimethyl)silyl)oxopropyl)carbamoyl)-2-(2-chlorophenyl)-2-( 4-(Trifluoromethyl)pyridin-2-yl)acetamide (I-61A) (1.83 g, 2.48 mmol) was dissolved in tetrahydrofuran (20 mL), iodine (1.89 g, 7.43 mmol) and cesium carbonate (2.42 mmol) were added g, 7.43 mmol), reacted at 25°C for 2 hours. Water (20 mL) was added to the reaction solution, saturated sodium sulfite solution (20 mL) was added, then extracted with ethyl acetate (90 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-1:2) to obtain yellow solid compound 1-(((2R)-2-(tert-butyl(dimethyl)) Silyl)oxopropyl)amino)-4-(2-chlorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I- 61B) (850 mg, 65.9% yield).
1H NMR(400MHz,DMSO-d 6):δ8.17(m,1H),8.10(m,1H),7.57(br m,1H),7.40-7.44(m,2H),7.26-7.31(m,1H),6.72-6.78(m,1H),6.60(s,1H),4.11-4.26(m,1H),3.36-3.40(m,1H),3.28(br d,1H),1.15(m,3H),0.82(d,9H),-0.05-0.03(m,6H). 1 H NMR (400MHz, DMSO-d 6 ): δ 8.17 (m, 1H), 8.10 (m, 1H), 7.57 (br m, 1H), 7.40-7.44 (m, 2H), 7.26-7.31 (m ,1H),6.72-6.78(m,1H),6.60(s,1H),4.11-4.26(m,1H),3.36-3.40(m,1H),3.28(br d,1H),1.15(m, 3H),0.82(d,9H),-0.05-0.03(m,6H).
LC-MS,M/Z(ESI):512.3[M+H] + LC-MS, M/Z(ESI): 512.3[M+H] +
第五步：4-(2-氯苯基)-1-(((2R)-2-羟基丙基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-61)Step 5: 4-(2-Chlorophenyl)-1-(((2R)-2-hydroxypropyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c ]pyrimidin-3-one (target compound I-61)
Figure PCTCN2022087589-appb-000326
Figure PCTCN2022087589-appb-000326
将1-(((2R)-2-(叔-丁基(二甲基)甲硅烷基)氧代丙基)氨基)-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-61B)(200mg,382μmol)溶解在甲醇(15.0mL)中，加入樟脑磺酸(287mg,1.15mmol)，25℃反应0.5小时。在反应液中加入饱和碳酸氢钠溶液(6.00mL)调节pH至7，然后用乙酸乙酯(90.0mL)萃取，用饱和食盐水(40mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。然后通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150*25mm*5μm；溶剂：A＝水+碳酸氢铵(0.05％)，B＝乙腈；梯度：26％-56％，10分钟)，冻干得到黄色固体化合物4-(2-氯苯基)-1-[[(2R)-2-羟基丙基]氨基]-6-(三氟甲基)吡啶并[1,2-c]嘧啶-3-酮(I-61)(60mg，产率39.3％)。1-(((2R)-2-(tert-butyl(dimethyl)silyl)oxopropyl)amino)-4-(2-chlorophenyl)-6-(trifluoromethyl) )-3H-pyrido[1,2-c]pyrimidin-3-one (I-61B) (200 mg, 382 μmol) was dissolved in methanol (15.0 mL), camphorsulfonic acid (287 mg, 1.15 mmol) was added, 25°C The reaction was carried out for 0.5 hours. Saturated sodium bicarbonate solution (6.00 mL) was added to the reaction solution to adjust the pH to 7, then extracted with ethyl acetate (90.0 mL), the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product . Then it was separated by reversed-phase high performance liquid chromatography, and the separation method was (column: Waters Xbridge 150*25mm*5μm; solvent: A=water+ammonium bicarbonate (0.05%), B=acetonitrile; gradient: 26%-56 %, 10 minutes), lyophilized to give a yellow solid compound 4-(2-chlorophenyl)-1-[[(2R)-2-hydroxypropyl]amino]-6-(trifluoromethyl)pyrido[ 1,2-c]pyrimidin-3-one (I-61) (60 mg, 39.3% yield).
1H NMR(400MHz,DMSO-d 6):δ8.16-8.33(m,1H),7.92-8.14(m,1H),7.54-7.61(m,1H),7.38-7.47(m,2H),7.27-7.34(m,1H),6.72(br d,1H),6.58(s,1H),4.88(br d,1H),3.85-4.03(m,1H),3.17-3.30(m,2H),1.11(d,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ 8.16-8.33 (m, 1H), 7.92-8.14 (m, 1H), 7.54-7.61 (m, 1H), 7.38-7.47 (m, 2H), 7.27-7.34(m, 1H), 6.72(br d, 1H), 6.58(s, 1H), 4.88(br d, 1H), 3.85-4.03(m, 1H), 3.17-3.30(m, 2H), 1.11(d,3H).
LC-MS,M/Z(ESI):398.1[M+H] + LC-MS, M/Z(ESI): 398.1[M+H] +
实施例62：目标化合物I-62的制备Example 62: Preparation of target compound I-62
4-(2-氯苯基)-1-(((1S,3S)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-62)4-(2-Chlorophenyl)-1-(((1S,3S)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c] Pyrimidine-3-one (target compound I-62)
Figure PCTCN2022087589-appb-000327
Figure PCTCN2022087589-appb-000327
目标化合物I-62的合成路线如下所示：The synthetic route of the target compound I-62 is as follows:
Figure PCTCN2022087589-appb-000328
Figure PCTCN2022087589-appb-000328
第一步：(1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁胺(3E-2)的合成The first step: Synthesis of (1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutylamine (3E-2)
Figure PCTCN2022087589-appb-000329
Figure PCTCN2022087589-appb-000329
将(1S,3S)-3-氨基环丁醇盐酸盐(5.00g,40.5mmol)和三乙胺(12.3g,121mmol,9.92mL)溶解在二氯甲烷(100mL)中，氮气保护下0℃加叔丁基二甲基氯硅烷(12.2g,80.9mmol)，然后在40℃下搅拌反应10小时。将反应液浓缩得到粗品，将水(200mL)倒入反应液中，然后用二氯甲烷(600mL)萃取，用饱和食盐水(200mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)＝50:1-20:1)得到黄色油状化合物(1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁胺(3E-2)(6.00g，产率73.6％)。(1S,3S)-3-aminocyclobutanol hydrochloride (5.00 g, 40.5 mmol) and triethylamine (12.3 g, 121 mmol, 9.92 mL) were dissolved in dichloromethane (100 mL) under nitrogen protection at 0 tert-Butyldimethylsilyl chloride (12.2 g, 80.9 mmol) was added at °C and the reaction was stirred at 40 °C for 10 hours. The reaction solution was concentrated to obtain the crude product, water (200 mL) was poured into the reaction solution, then extracted with dichloromethane (600 mL), the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol (V/V)=50:1-20:1) to obtain yellow oily compound (1S,3S)-3-((tert-butyldimethylsilyl) oxo)cyclobutylamine (3E-2) (6.00 g, 73.6% yield).
1H NMR(400MHz,CDCl 3):δ3.87(m,1H),2.84-2.95(m,1H),2.59-2.68(m,2H),1.64(d,1H),1.61-1.68(m,3H),0.87(s,9H),0.03(s,6H). 1 H NMR (400 MHz, CDCl 3 ): δ 3.87 (m, 1H), 2.84-2.95 (m, 1H), 2.59-2.68 (m, 2H), 1.64 (d, 1H), 1.61-1.68 (m, 3H), 0.87(s, 9H), 0.03(s, 6H).
第二步：叔丁基((1S,3S)-3-异硫氰基环丁氧基)二甲基硅烷(3E)的合成Step 2: Synthesis of tert-butyl((1S,3S)-3-isothiocyanocyclobutoxy)dimethylsilane (3E)
Figure PCTCN2022087589-appb-000330
Figure PCTCN2022087589-appb-000330
将(1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁胺(3E-2)(1.50g,7.45mmol)和碳酸铯(7.28g,22.4mmol)溶解在二氯甲烷(15mL)中，在氮气保护下加入硫光气(1.71g,14.9mmol,1.14mL)，25℃反应2小时。把反应液过滤，有机相浓缩得到黄色固体化合物叔丁基((1S,3S)-3-异硫氰基环丁氧基)二甲基硅烷(3E)(1.50g，产率82.7％)。(1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutylamine (3E-2) (1.50 g, 7.45 mmol) and cesium carbonate (7.28 g, 22.4 mmol) were dissolved In dichloromethane (15 mL), under nitrogen protection, thiophosgene (1.71 g, 14.9 mmol, 1.14 mL) was added, and the reaction was carried out at 25° C. for 2 hours. The reaction solution was filtered, and the organic phase was concentrated to obtain a yellow solid compound tert-butyl((1S,3S)-3-isothiocyanocyclobutoxy)dimethylsilane (3E) (1.50 g, yield 82.7%).
第三步：N-(((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-62A)的合成The third step: N-(((1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(2-chlorophenyl) )-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-62A)
Figure PCTCN2022087589-appb-000331
Figure PCTCN2022087589-appb-000331
将叔丁基((1S,3S)-3-异硫氰基环丁氧基)二甲基硅烷(3E)(1.50g,6.16mmol)和碳酸铯(4.66g,14.3mmol)溶解在N,N-二甲基甲酰胺(15mL)中，加2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-1D)(1.50g,4.77mmol)，75℃反应2小时。把水(50mL)加到反应液中，然后用乙酸乙酯(120mL)萃取，用饱和食盐水(40mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0-20:1)得到棕色油状化合物N-(((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-62A)(1.66g，产率59.3％)。Tert-butyl((1S,3S)-3-isothiocyanocyclobutoxy)dimethylsilane (3E) (1.50 g, 6.16 mmol) and cesium carbonate (4.66 g, 14.3 mmol) were dissolved in N, To N-dimethylformamide (15 mL) was added 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-1D) (1.50 g , 4.77mmol), 75 ℃ of reaction 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (120 mL), the organic phase was washed with saturated brine (40 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:0-20:1) to obtain a brown oily compound N-(((1S,3S)-3-((tert-butyldimethylformaldehyde) Silyl)oxo)cyclobutyl)carbamoyl)-2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I -62A) (1.66 g, 59.3% yield).
1H NMR(400MHz,DMSO-d 6):δ11.77(s,1H),10.55(d,1H),8.88(d,1H),7.76(d,1H),7.48-7.55(m,2H),7.31-7.41(m,2H),7.09(m,1H),5.99(s,1H),4.00-4.14(m,2H),2.66-2.76(m,2H),1.79-1.91(m,2H),0.84(s,9H),0.01(s,6H). 1 H NMR (400MHz, DMSO-d 6 ): δ 11.77(s, 1H), 10.55(d, 1H), 8.88(d, 1H), 7.76(d, 1H), 7.48-7.55(m, 2H) ,7.31-7.41(m,2H),7.09(m,1H),5.99(s,1H),4.00-4.14(m,2H),2.66-2.76(m,2H),1.79-1.91(m,2H) ,0.84(s,9H),0.01(s,6H).
LC-MS,M/Z(ESI):558.3[M+H] + LC-MS, M/Z(ESI): 558.3[M+H] +
第四步：1-(((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-62B)的合成The fourth step: 1-(((1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)amino)-4-(2-chlorophenyl)-6- Synthesis of (trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-62B)
Figure PCTCN2022087589-appb-000332
Figure PCTCN2022087589-appb-000332
将N-(((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-62A)(1.66g,2.63mmol)溶解在四氢呋喃(20mL)中，加碘(2.01g,7.90mmol)和碳酸铯(2.57g,7.90mmol)，25℃反应2小时。把水(20mL)加到反应液中，加入饱和亚硫酸钠溶液(20mL)，然后用乙酸乙酯(90mL)萃取，用饱和食盐水(30mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品在25℃石油醚(30mL)中打浆0.5小时，过滤得到棕色固体化合物1-(((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-62B)(1.04g，产率70.3％)。N-(((1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(2-chlorophenyl)-2 -(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-62A) (1.66 g, 2.63 mmol) was dissolved in tetrahydrofuran (20 mL), iodine (2.01 g, 7.90 mmol) and cesium carbonate were added (2.57 g, 7.90 mmol), reacted at 25°C for 2 hours. Water (20 mL) was added to the reaction solution, saturated sodium sulfite solution (20 mL) was added, then extracted with ethyl acetate (90 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was slurried in petroleum ether (30 mL) at 25°C for 0.5 hours, and filtered to obtain a brown solid compound 1-(((1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl) Amino)-4-(2-chlorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-62B) (1.04 g, yield 70.3 %).
1H NMR(400MHz,DMSO-d 6):δ8.23(br d,1H),7.97-8.15(m,1H),7.53-7.61(m,1H),7.38-7.46(m,2H),7.25-7.33(m,1H),6.72(br d,1H),6.58(br s,1H),4.03-4.14(m,1H),3.92-4.03(m,1H),2.64-2.77(m,2H),1.94-2.10(m,2H),0.88(s,9H),0.05(s,6H). 1 H NMR (400MHz, DMSO-d 6 ): δ 8.23(br d, 1H), 7.97-8.15(m, 1H), 7.53-7.61(m, 1H), 7.38-7.46(m, 2H), 7.25 -7.33(m,1H),6.72(br d,1H),6.58(br s,1H),4.03-4.14(m,1H),3.92-4.03(m,1H),2.64-2.77(m,2H) ,1.94-2.10(m,2H),0.88(s,9H),0.05(s,6H).
LC-MS,M/Z(ESI):524.0[M+H] + LC-MS, M/Z(ESI): 524.0[M+H] +
第五步：4-(2-氯苯基)-1-(((1S,3S)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-62)The fifth step: 4-(2-chlorophenyl)-1-(((1S,3S)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[1, 2-c]pyrimidin-3-one (target compound I-62)
Figure PCTCN2022087589-appb-000333
Figure PCTCN2022087589-appb-000333
将1-(((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(51.2mg,90.5μmol)溶解在甲醇(5.00mL)中，加入樟脑磺酸(45.3mg,181μmol)，25℃反应0.5小时。在反应液中加入水(10mL)饱和碳酸氢钠溶液(3mL)调节pH至7，然后用乙酸乙酯(45.0mL)萃取，用饱和食盐水(20mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。然后通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150*25mm*5μm；溶剂：A＝水+碳酸氢铵(0.05％)，B＝乙腈；梯度：27％-57％，9分钟)，得到黄色固体化合物4-(2-氯苯基)-1-(((1S,3S)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-62)(25mg，产率65.6％)。1-(((1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)amino)-4-(2-chlorophenyl)-6-(trifluoro) Methyl)-3H-pyrido[1,2-c]pyrimidin-3-one (51.2 mg, 90.5 μmol) was dissolved in methanol (5.00 mL), camphorsulfonic acid (45.3 mg, 181 μmol) was added, and the reaction was carried out at 25°C 0.5 hours. To the reaction solution was added water (10 mL) saturated sodium bicarbonate solution (3 mL) to adjust the pH to 7, then extracted with ethyl acetate (45.0 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, Concentration gave crude product. Then it was separated by reversed-phase high performance liquid chromatography, and the separation method was (column: Waters Xbridge 150*25mm*5μm; solvent: A=water+ammonium bicarbonate (0.05%), B=acetonitrile; gradient: 27%-57 %, 9 minutes) to give a yellow solid compound 4-(2-chlorophenyl)-1-(((1S,3S)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H - Pyrido[1,2-c]pyrimidin-3-one (I-62) (25 mg, 65.6% yield).
1H NMR(400MHz,DMSO-d 6):δ8.23(br d,1H),7.97-8.11(m,1H),7.53-7.63(m,1H),7.37-7.47(m,2H),7.25-7.33(m,1H),6.72(m,1H),6.58(s,1H),5.17(d,1H),3.83-3.99(m,2H),2.62-2.68(m,2H),1.87-2.01(m,2H). 1 H NMR (400MHz, DMSO-d 6 ): δ 8.23(br d, 1H), 7.97-8.11(m, 1H), 7.53-7.63(m, 1H), 7.37-7.47(m, 2H), 7.25 -7.33(m,1H),6.72(m,1H),6.58(s,1H),5.17(d,1H),3.83-3.99(m,2H),2.62-2.68(m,2H),1.87-2.01 (m,2H).
LC-MS,M/Z(ESI):410.1[M+H] + LC-MS, M/Z(ESI): 410.1[M+H] +
实施例63：目标化合物I-63的制备Example 63: Preparation of target compound I-63
4-(2-氯苯基)-1-(((1R,3R)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-63)4-(2-Chlorophenyl)-1-(((1R,3R)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c] Pyrimidine-3-one (target compound I-63)
Figure PCTCN2022087589-appb-000334
Figure PCTCN2022087589-appb-000334
目标化合物I-63的合成路线如下所示：The synthetic route of the target compound I-63 is as follows:
Figure PCTCN2022087589-appb-000335
Figure PCTCN2022087589-appb-000335
第一步：(1R,3R)-3-((叔丁基二甲基甲硅烷基)氧代)环丁胺(3F-2)的合成The first step: Synthesis of (1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutylamine (3F-2)
Figure PCTCN2022087589-appb-000336
Figure PCTCN2022087589-appb-000336
将(1R,3R)-3-氨基环丁醇盐酸盐(5.00g,40.5mmol)和三乙胺(12.3g,121mmol,9.92mL)溶解在二氯甲烷(100mL)中，氮气保护下0℃加叔丁基二甲基氯硅烷(12.2g,80.9mmol)，然后在40℃下搅拌反应10小时。将反应液浓缩得到粗品，将水(200mL)倒入反应液中，然后用二氯甲烷(600mL)萃取，用饱和食盐水(200mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)＝50:1-20:1)得到黄色油状化合物(1R,3R)-3-((叔丁基二甲基甲硅烷基)氧代)环丁胺(3F-2)(5.20g，产率63.8％)。(1R,3R)-3-aminocyclobutanol hydrochloride (5.00 g, 40.5 mmol) and triethylamine (12.3 g, 121 mmol, 9.92 mL) were dissolved in dichloromethane (100 mL) under nitrogen protection at 0 tert-Butyldimethylsilyl chloride (12.2 g, 80.9 mmol) was added at °C and the reaction was stirred at 40 °C for 10 hours. The reaction solution was concentrated to obtain the crude product, water (200 mL) was poured into the reaction solution, then extracted with dichloromethane (600 mL), the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol (V/V)=50:1-20:1) to obtain yellow oily compound (1R,3R)-3-((tert-butyldimethylsilyl) oxo)cyclobutylamine (3F-2) (5.20 g, 63.8% yield).
1H NMR(400MHz,CDCl 3)δ4.49(m,1H),3.42(m,1H),1.95-2.02(m,2H),1.87-1.94(m,2H),0.84(s,9H),0.00(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ 4.49(m, 1H), 3.42(m, 1H), 1.95-2.02(m, 2H), 1.87-1.94(m, 2H), 0.84(s, 9H), 0.00(s,6H).
第二步：(1R,3R)-3-(叔丁基异硫氰基环丁氧基)二甲基硅烷(3F)的合成The second step: Synthesis of (1R,3R)-3-(tert-butylisothiocyanocyclobutoxy)dimethylsilane (3F)
Figure PCTCN2022087589-appb-000337
Figure PCTCN2022087589-appb-000337
将(1R,3R)-3-((叔丁基二甲基甲硅烷基)氧代)环丁胺(3F-2)(1.50g,7.45mmol)和碳酸铯(7.28g,22.4mmol)溶解在二氯甲烷(15mL)中，在氮气保护下加入硫光气(1.71g,14.9mmol,1.14mL)，25℃反应2小时。把反应液过滤，有机相浓缩得到黄色固体化合物(1R,3R)-3-(叔丁基异硫氰基环丁氧基)二甲基硅烷(3F)(1.50g，产率82.7％)。(1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutylamine (3F-2) (1.50 g, 7.45 mmol) and cesium carbonate (7.28 g, 22.4 mmol) were dissolved In dichloromethane (15 mL), under nitrogen protection, thiophosgene (1.71 g, 14.9 mmol, 1.14 mL) was added, and the reaction was carried out at 25° C. for 2 hours. The reaction solution was filtered, and the organic phase was concentrated to obtain a yellow solid compound (1R,3R)-3-(tert-butylisothiocyanocyclobutoxy)dimethylsilane (3F) (1.50 g, yield 82.7%).
第三步：N-(((1R,3R)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-63A)的合成The third step: N-(((1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(2-chlorobenzene Synthesis of yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-63A)
Figure PCTCN2022087589-appb-000338
Figure PCTCN2022087589-appb-000338
将(1R,3R)-3-(叔丁基异硫氰基环丁氧基)二甲基硅烷(3F)(1.50g,6.16mmol)和碳酸铯(4.66g,14.3mmol)溶解在N,N-二甲基甲酰胺(15mL)中，加2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-1D)(1.50g,4.77mmol)，75℃反应2小时。把水(50mL)加到反应液中，然后用乙酸乙酯(120mL)萃取，用饱和食盐水(40mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0-20:1)得到棕色油状化合物N-(((1R,3R)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-63A)(1.51g，产率50.1％)。(1R,3R)-3-(tert-butylisothiocyanocyclobutoxy)dimethylsilane (3F) (1.50 g, 6.16 mmol) and cesium carbonate (4.66 g, 14.3 mmol) were dissolved in N,N- In dimethylformamide (15 mL), 2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-1D) (1.50 g, 4.77 g) was added mmol), and reacted at 75°C for 2 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (120 mL), the organic phase was washed with saturated brine (40 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:0-20:1) to obtain the brown oily compound N-(((1R,3R)-3-((tert-butyldimethylformaldehyde) Silyl)oxo)cyclobutyl)carbamoyl)-2-(2-chlorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (I -63A) (1.51 g, 50.1% yield).
1H NMR(400MHz,DMSO-d 6):δ11.79(s,1H),10.61(br d,1H),8.88(d,1H),7.76(br d,1H),7.47-7.58(m,2H),7.36(m,2H),7.09(m,1H),6.00(s,1H),4.49-4.57(m,1H),4.45(m,1H),2.32(br d,2H),2.20-2.28(m,2H),0.84(s,9H),0.01(s,6H). 1 H NMR (400MHz, DMSO-d 6 ): δ 11.79(s, 1H), 10.61(br d, 1H), 8.88(d, 1H), 7.76(br d, 1H), 7.47-7.58(m, 2H), 7.36(m, 2H), 7.09(m, 1H), 6.00(s, 1H), 4.49-4.57(m, 1H), 4.45(m, 1H), 2.32(br d, 2H), 2.20- 2.28(m, 2H), 0.84(s, 9H), 0.01(s, 6H).
LC-MS,M/Z(ESI):558.3[M+H] + LC-MS, M/Z(ESI): 558.3[M+H] +
第四步：1-(((1R,3R)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-63B)的合成The fourth step: 1-(((1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)amino)-4-(2-chlorophenyl)-6- Synthesis of (trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-63B)
Figure PCTCN2022087589-appb-000339
Figure PCTCN2022087589-appb-000339
将N-(((1R,3R)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氯苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(I-63A)(2.64g,4.12mmol)溶解在四氢呋喃(40mL)中，加碘(3.14g,12.3mmol)和碳酸铯(4.02g,12.3mmol)，25℃反应2小时。把水(20mL)加到反应液中，加入饱和亚硫酸钠溶液(20mL)，然后用乙酸乙酯(90mL)萃取，用饱和食盐水(30mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。粗品在25℃石油醚(30mL)中打浆0.5小时，过滤得到棕色固体化合物1-(((1R,3R)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-63B)(1.95g，产率89.5％)。N-(((1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(2-chlorophenyl)-2 -(4-(trifluoromethyl)pyridin-2-yl)acetamide (I-63A) (2.64 g, 4.12 mmol) was dissolved in tetrahydrofuran (40 mL), iodine (3.14 g, 12.3 mmol) and cesium carbonate were added (4.02 g, 12.3 mmol), reacted at 25°C for 2 hours. Water (20 mL) was added to the reaction solution, saturated sodium sulfite solution (20 mL) was added, followed by extraction with ethyl acetate (90 mL), the organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The crude product was slurried in petroleum ether (30 mL) at 25°C for 0.5 hours, and filtered to obtain a brown solid compound 1-(((1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl) Amino)-4-(2-chlorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-63B) (1.95 g, 89.5 yield) %).
1H NMR(400MHz,DMSO-d 6):δ8.30(br d,1H),7.82-8.22(m,1H),7.54-7.61(m,1H),7.41-7.46(m,2H),7.30(m,1H),6.71(br d,1H),6.58(s,1H),4.51-4.59(m,1H),4.36(br s,1H),2.41(br d,2H),2.21-2.29(m,2H),0.88(s,9H),0.05(s,6H). 1 H NMR (400MHz, DMSO-d 6 ): δ 8.30 (br d, 1H), 7.82-8.22 (m, 1H), 7.54-7.61 (m, 1H), 7.41-7.46 (m, 2H), 7.30 (m,1H),6.71(br d,1H),6.58(s,1H),4.51-4.59(m,1H),4.36(br s,1H),2.41(br d,2H),2.21-2.29( m,2H),0.88(s,9H),0.05(s,6H).
LC-MS,M/Z(ESI):524.2[M+H] + LC-MS, M/Z(ESI): 524.2[M+H] +
第五步：目标化合物4-(2-氯苯基)-1-(((1R,3R)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(目标化合物I-63)The fifth step: target compound 4-(2-chlorophenyl)-1-(((1R,3R)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[ 1,2-c]pyrimidin-3-one (target compound I-63)
Figure PCTCN2022087589-appb-000340
Figure PCTCN2022087589-appb-000340
将1-(((1R,3R)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(2-氯苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(200mg,378μmol)溶解在甲醇(15.0mL)中，加入樟脑磺酸(378mg,1.51mmol)，25℃反应0.5小时。在反应液中加入水(20mL)饱和碳酸氢钠溶液(20mL)调节pH至7，然后用乙酸乙酯(90.0mL)萃取，用饱和食盐水(40mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。粗品在25℃石油醚(30mL)中打浆0.5小时，过滤得到黄色固体化合物4-(2-氯苯基)-1-(((1R,3R)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-63)(215mg，产率69.2％)。1-(((1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)amino)-4-(2-chlorophenyl)-6-(trifluoro) Methyl)-3H-pyrido[1,2-c]pyrimidin-3-one (200 mg, 378 μmol) was dissolved in methanol (15.0 mL), camphorsulfonic acid (378 mg, 1.51 mmol) was added, and the reaction was carried out at 25°C for 0.5 hours . To the reaction solution was added water (20 mL) saturated sodium bicarbonate solution (20 mL) to adjust the pH to 7, then extracted with ethyl acetate (90.0 mL), the organic phase was washed with saturated brine (40 mL), dried over sodium sulfate, and concentrated to obtain Crude. The crude product was slurried in petroleum ether (30 mL) at 25°C for 0.5 hours, and filtered to obtain a yellow solid compound 4-(2-chlorophenyl)-1-(((1R,3R)-3-hydroxycyclobutyl)amino)-6 -(Trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-63) (215 mg, 69.2% yield).
1H NMR(400MHz,DMSO-d 6):δ8.56(d,1H),8.36-8.52(m,1H),7.56(d,1H),7.42(s,2H),7.30(d,1H),6.66(d,1H),6.57(s,1H),5.11(d,1H),4.45(s,1H),4.35(d,1H),2.43(d,2H),2.20(s,2H). 1 H NMR (400MHz, DMSO-d 6 ): δ8.56(d,1H), 8.36-8.52(m,1H), 7.56(d,1H), 7.42(s,2H), 7.30(d,1H) ,6.66(d,1H),6.57(s,1H),5.11(d,1H),4.45(s,1H),4.35(d,1H),2.43(d,2H),2.20(s,2H).
LC-MS,M/Z(ESI):410.1[M+H] + LC-MS, M/Z(ESI): 410.1[M+H] +
实施例64：目标化合物I-64的制备Example 64: Preparation of target compound I-64
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000341
Figure PCTCN2022087589-appb-000341
第一步：(1R,2R)-2-((叔丁基二甲基甲硅烷基)氧代)环丁烷-1-胺的合成The first step: Synthesis of (1R,2R)-2-((tert-butyldimethylsilyl)oxo)cyclobutane-1-amine
Figure PCTCN2022087589-appb-000342
Figure PCTCN2022087589-appb-000342
将(1R,2R)-2-氨基环丁烷-1-醇盐酸盐(900mg,7.28mmol)，和三乙胺(1.88g,18.6mmol,2.59mL)溶解在二氯甲烷(30.0mL)中，氮气保护下0℃加叔丁基二甲基氯硅烷(2.20g,14.5mmol)，然后在40℃下搅拌反应10小时。将反应液浓缩得到粗品，将水(30.0mL)倒入反应液中，然后用二氯甲烷(90.0mL)萃取，用饱和食盐水(30.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)＝1:0-20:1)得到黄色油状化合物(1R,2R)-2-((叔丁基二甲基甲硅烷基)氧代)环丁烷-1-胺(822mg，产率56.1％)。(1R,2R)-2-aminocyclobutan-1-ol hydrochloride (900 mg, 7.28 mmol), and triethylamine (1.88 g, 18.6 mmol, 2.59 mL) were dissolved in dichloromethane (30.0 mL) In the solution, tert-butyldimethylsilyl chloride (2.20 g, 14.5 mmol) was added at 0°C under nitrogen protection, and then the reaction was stirred at 40°C for 10 hours. The reaction solution was concentrated to obtain the crude product, water (30.0 mL) was poured into the reaction solution, then extracted with dichloromethane (90.0 mL), the organic phase was washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, Concentration gave crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol (V/V)=1:0-20:1) to obtain yellow oily compound (1R,2R)-2-((tert-butyldimethylsilyl) oxo)cyclobutan-1-amine (822 mg, 56.1% yield).
1H NMR(400MHz,DMSO_d 6)δ3.66(m,1H),2.78-3.00(m,1H),1.75-1.97(m,4H),0.86(s, 9H),0.04(d,6H). 1 H NMR (400MHz, DMSO_d 6 )δ3.66(m,1H),2.78-3.00(m,1H),1.75-1.97(m,4H),0.86(s,9H),0.04(d,6H).
第二步：叔-丁基((1R,2R)-2-异硫氰基环丁氧基)二甲基硅烷的合成The second step: synthesis of tert-butyl((1R,2R)-2-isothiocyanocyclobutoxy)dimethylsilane
Figure PCTCN2022087589-appb-000343
Figure PCTCN2022087589-appb-000343
将(1R,2R)-2-((叔丁基二甲基甲硅烷基)氧代)环丁烷-1-胺(200mg,993μmol)和碳酸铯(970mg,2.98mmol)溶解在二氯甲烷(10.0mL)中，在氮气保护下加入硫光气(228mg,1.99mmol,152uL)，25℃反应2小时。把反应液过滤，有机相浓缩得到黄色固体化合物叔丁基((1R,2R)-2-异硫氰基环丁氧基)二甲基硅烷(3)(240mg，粗产物)，直接用于下一步。(1R,2R)-2-((tert-butyldimethylsilyl)oxo)cyclobutan-1-amine (200 mg, 993 μmol) and cesium carbonate (970 mg, 2.98 mmol) were dissolved in dichloromethane (10.0 mL), thiophosgene (228 mg, 1.99 mmol, 152 uL) was added under nitrogen protection, and the reaction was carried out at 25° C. for 2 hours. The reaction solution was filtered, and the organic phase was concentrated to obtain a yellow solid compound tert-butyl((1R,2R)-2-isothiocyanocyclobutoxy)dimethylsilane (3) (240 mg, crude product), which was directly used for Next step.
第三步：N-(((1R,2R)-2-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The third step: N-(((1R,2R)-2-((tert-butyldimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(2-fluorophenyl) )-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
Figure PCTCN2022087589-appb-000344
Figure PCTCN2022087589-appb-000344
将叔丁基((1R,2R)-2-异硫氰基环丁氧基)二甲基硅烷(240mg,804μmol)和碳酸铯(262mg,804μmol)溶解在N,N-二甲基甲酰胺(15.0mL)中，加2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(240mg,985μmol)，25℃反应2小时。把水(20.0mL)加到反应液中，然后用乙酸乙酯(90.0mL)萃取，用饱和食盐水(30.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0-20:1)得到黄色油状化合物N-(((1R,2R)-2-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(330mg，产率54.1％)。Dissolve tert-butyl((1R,2R)-2-isothiocyanocyclobutoxy)dimethylsilane (240 mg, 804 μmol) and cesium carbonate (262 mg, 804 μmol) in N,N-dimethylformamide (15.0 mL), 2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (240 mg, 985 μmol) was added, and the mixture was reacted at 25° C. for 2 hours. Water (20.0 mL) was added to the reaction solution, followed by extraction with ethyl acetate (90.0 mL), the organic phase was washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:0-20:1) to obtain a yellow oily compound N-(((1R,2R)-2-((tert-butyldimethylformaldehyde) Silyl)oxo)cyclobutyl)carbamoyl)-2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (330mg , yield 54.1%).
LC-MS,M/Z(ESI):542.2[M+H] + LC-MS, M/Z(ESI): 542.2[M+H] +
第四步：1-(((1R,2R)-2-((叔丁基二甲基甲硅烷基)氧基)环丁基)氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮的合成The fourth step: 1-(((1R,2R)-2-((tert-butyldimethylsilyl)oxy)cyclobutyl)amino)-4-(2-fluorophenyl)-6- Synthesis of (trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one
Figure PCTCN2022087589-appb-000345
Figure PCTCN2022087589-appb-000345
将N-(((1R,2R)-2-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(300mg,395μmol)溶解在四氢呋喃(15.0mL)中，加碘(251mg,989μmol)和吡啶(93.9mg,1.19mmol,95.8μL)，25℃反应2小时。反应液中，加入饱和亚硫酸钠溶液(30.0mL)，然后用乙酸乙酯(90mL)萃取，用饱和食盐水(30mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150*25mm*5um；溶剂：A＝水+0.1体积％碳酸氢氨(30％)，B＝乙腈；梯度：62％-92％，8.5分钟)，得到黄色固体化合物1-(((1R,2R)-2-((叔丁基二甲基甲硅烷基)氧基)环丁基)氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(150mg，产率37.8％)。N-(((1R,2R)-2-((tert-butyldimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(2-fluorophenyl)-2 -(4-(Trifluoromethyl)pyridin-2-yl)acetamide (300 mg, 395 μmol) was dissolved in tetrahydrofuran (15.0 mL), iodine (251 mg, 989 μmol) and pyridine (93.9 mg, 1.19 mmol, 95.8 μL) were added ) at 25°C for 2 hours. To the reaction solution, saturated sodium sulfite solution (30.0 mL) was added, then extracted with ethyl acetate (90 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by reversed-phase high performance liquid chromatography, and the separation method was (column: Waters Xbridge 150*25mm*5um; solvent: A=water+0.1 vol% ammonium bicarbonate (30%), B=acetonitrile; gradient: 62 %-92%, 8.5 minutes) to give yellow solid compound 1-(((1R,2R)-2-((tert-butyldimethylsilyl)oxy)cyclobutyl)amino)-4-( 2-Fluorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (150 mg, 37.8% yield).
LC-MS,M/Z(ESI):508.2[M+H] + LC-MS, M/Z(ESI): 508.2[M+H] +
第五步：4-(2-氟苯基)-1-(((1R,2R)-2-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶 -3-酮(化合物I-64)The fifth step: 4-(2-Fluorophenyl)-1-(((1R,2R)-2-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[1, 2-c]pyrimidin-3-one (Compound I-64)
Figure PCTCN2022087589-appb-000346
Figure PCTCN2022087589-appb-000346
将1-(((1R,2R)-2-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(2-氟苯基)-6-(三氟甲基)-4,4a-二氢-3H-吡啶并[1,2-c]嘧啶-3-酮(140mg,139μmol)溶解在甲醇(15.0mL)中，加入樟脑磺酸(97.2mg,418μmol)，25℃反0.5小时。在反应液中加入水(30mL)，然后用乙酸乙酯(90.0mL)萃取，用饱和食盐水(30.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品首先用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)＝1:0-10:1)，然后通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150*25mm*5um；溶剂：A＝水+0.05体积％碳酸氢氨(99％)，B＝乙腈；梯度：27％-57％，8分钟)，得到黄色固体化合物4-(2-氟苯基)-1-(((1R,2R)-2-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-64)(30.0mg，产率54.0％)。1-(((1R,2R)-2-((tert-butyldimethylsilyl)oxo)cyclobutyl)amino)-4-(2-fluorophenyl)-6-(tri Fluoromethyl)-4,4a-dihydro-3H-pyrido[1,2-c]pyrimidin-3-one (140 mg, 139 μmol) was dissolved in methanol (15.0 mL), camphorsulfonic acid (97.2 mg, 418 μmol) at 25°C for 0.5 hours. Water (30 mL) was added to the reaction solution, followed by extraction with ethyl acetate (90.0 mL), the organic phase was washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was first separated and purified by silica gel column (dichloromethane: methanol (V/V)=1:0-10:1), and then separated by reversed-phase high performance liquid chromatography. The separation method was (column: Waters Xbridge 150* 25mm*5um; solvent: A = water + 0.05 vol% ammonium bicarbonate (99%), B = acetonitrile; gradient: 27%-57%, 8 minutes) to give yellow solid compound 4-(2-fluorophenyl) -1-(((1R,2R)-2-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-64 ) (30.0 mg, 54.0% yield).
1H NMR(400MHz,DMSO_d 6)δ8.20(s,1H),8.19(s,1H),7.43-7.48(m,1H),7.26-7.33(m,3H),6.79(s,1H),6.72-6.77(m,1H),5.38(d,1H),4.20-4.28(m,1H),4.05-4.13(m,1H),2.00-2.08(m,2H),1.44-1.56(m,1H),1.31-1.41(m,1H). 1 H NMR (400MHz, DMSO_d 6 )δ8.20(s,1H), 8.19(s,1H), 7.43-7.48(m,1H), 7.26-7.33(m,3H), 6.79(s,1H), 6.72-6.77(m,1H), 5.38(d,1H), 4.20-4.28(m,1H), 4.05-4.13(m,1H), 2.00-2.08(m,2H), 1.44-1.56(m,1H) ),1.31-1.41(m,1H).
LC-MS,M/Z(ESI):394.1[M+H] + LC-MS, M/Z(ESI): 394.1[M+H] +
实施例65：目标化合物I-65的制备Example 65: Preparation of target compound I-65
4-(2-氟苯基)-1-(((1R,2S)-2-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-65)4-(2-Fluorophenyl)-1-(((1R,2S)-2-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c] Pyrimidine-3-one (I-65)
Figure PCTCN2022087589-appb-000347
Figure PCTCN2022087589-appb-000347
化合物I-65的合成参考I-62的合成方法得到。The synthesis of compound I-65 was obtained with reference to the synthesis method of I-62.
LC-MS,M/Z(ESI):394.1[M+H] + LC-MS, M/Z(ESI): 394.1[M+H] +
实施例66：目标化合物I-66的制备Example 66: Preparation of target compound I-66
4-(2-氯苯基)-1-(((1R,2R)-2-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-66)4-(2-Chlorophenyl)-1-(((1R,2R)-2-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c] Pyrimidine-3-one (I-66)
Figure PCTCN2022087589-appb-000348
Figure PCTCN2022087589-appb-000348
化合物I-66的合成参考I-62的合成方法得到。The synthesis of compound I-66 was obtained with reference to the synthesis method of I-62.
LC-MS,M/Z(ESI):410.1[M+H] + LC-MS, M/Z(ESI): 410.1[M+H] +
实施例67：目标化合物I-67的制备Example 67: Preparation of target compound I-67
4-(2-氯苯基)-1-(((1R,2S)-2-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-67)4-(2-Chlorophenyl)-1-(((1R,2S)-2-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c] Pyrimidine-3-one (I-67)
Figure PCTCN2022087589-appb-000349
Figure PCTCN2022087589-appb-000349
化合物I-67的合成参考I-62的合成方法得到。The synthesis of compound I-67 was obtained with reference to the synthesis method of I-62.
LC-MS,M/Z(ESI):410.1[M+H] + LC-MS, M/Z(ESI): 410.1[M+H] +
实施例68：目标化合物I-68的制备Example 68: Preparation of target compound I-68
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000350
Figure PCTCN2022087589-appb-000350
第一步：2-((叔丁基二甲基甲硅烷基)氧基)-2-甲基丙-1-胺的合成The first step: synthesis of 2-((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-amine
Figure PCTCN2022087589-appb-000351
Figure PCTCN2022087589-appb-000351
在室温下,将1-氨基-2-甲基丙-2-醇(2g,22.44mmol)溶于无水DCM(30mL)中,冷却到0℃加入叔丁基二甲基氯硅烷(TBSCl,4.1g,26.9mmol),然后加入咪唑(1.83g,26.9mmol)和4- 二甲氨基吡啶(DMAP,0.27g,2.24mmol),室温搅拌5小时,反应完成后过柱得无色油状化合物2-((叔丁基二甲基甲硅烷基)氧基)-2-甲基丙-1-胺(3.58g，产率78％)。At room temperature, 1-amino-2-methylpropan-2-ol (2 g, 22.44 mmol) was dissolved in dry DCM (30 mL), cooled to 0 °C, and tert-butyldimethylsilyl chloride (TBSCl, 4.1g, 26.9mmol), then add imidazole (1.83g, 26.9mmol) and 4-dimethylaminopyridine (DMAP, 0.27g, 2.24mmol), stir at room temperature for 5 hours, after the reaction is completed, pass through the column to obtain colorless oily compound 2 -((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-amine (3.58 g, 78% yield).
第二步：叔丁基((1-异硫氰酸根-2-甲基丙-2-基)氧基)二甲基硅烷的合成The second step: the synthesis of tert-butyl ((1-isothiocyanato-2-methylpropan-2-yl)oxy)dimethylsilane
Figure PCTCN2022087589-appb-000352
Figure PCTCN2022087589-appb-000352
在室温下,将化合物2-((叔丁基二甲基甲硅烷基)氧基)-2-甲基丙-1-胺(2g,9.83mmol)溶于无水DCM(20mL)中,然后加入TEA(1.99g,19.7mmol)和硫光气(1.36g,11.8mmol),室温搅拌5小时,反应完成后浓缩旋蒸得无色油状化合物叔丁基((1-异硫氰酸根-2-甲基丙-2-基)氧基)二甲基硅烷(2.5g粗品，产率100％)，直接用于下一步。Compound 2-((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-amine (2 g, 9.83 mmol) was dissolved in dry DCM (20 mL) at room temperature, then Add TEA (1.99g, 19.7mmol) and thiophosgene (1.36g, 11.8mmol), stir at room temperature for 5 hours, after the reaction is completed, it is concentrated and rotary evaporated to obtain a colorless oily compound tert-butyl ((1-isothiocyanato-2 -Methylpropan-2-yl)oxy)dimethylsilane (2.5 g crude, 100% yield) was used directly in the next step.
第三步：N-((2-((叔丁基二甲基甲硅烷基)氧基)-2-甲基丙基)氨基甲硫基)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The third step: N-((2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)aminomethylthio)-2-(2-fluorophenyl)-2 Synthesis of -(4-(trifluoromethyl)pyridin-2-yl)acetamide
Figure PCTCN2022087589-appb-000353
Figure PCTCN2022087589-appb-000353
将2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(300mg,1.01mmol)和碳酸铯(721mg，2.2mmol)溶到N，N-二甲基甲酰胺(5mL)中，置换空气，降温到0℃，慢慢滴加叔丁基((1-异硫氰酸根-2-甲基丙-2-基)氧基)二甲基硅烷(2.01mg，0.49mmol)，在室温下搅拌14h。食盐水(20mL)淬灭反应，乙酸乙酯(20mL)萃取两次，分离干燥有机相，旋干得到粗品，粗品过柱(石油醚/乙酸乙酯＝20/1)得到2-(3-氟苯基)-N-(甲硫酰胺)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(350mg,产率63.0％)。2-(3-Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (300 mg, 1.01 mmol) and cesium carbonate (721 mg, 2.2 mmol) were dissolved in N,N - in dimethylformamide (5 mL), replace the air, cool down to 0 °C, and slowly add tert-butyl ((1-isothiocyanato-2-methylpropan-2-yl)oxy) dimethyl Silane (2.01 mg, 0.49 mmol), stirred at room temperature for 14 h. The reaction was quenched with brine (20 mL), extracted twice with ethyl acetate (20 mL), the organic phase was separated and dried, spin-dried to obtain the crude product, and the crude product was passed through a column (petroleum ether/ethyl acetate=20/1) to obtain 2-(3- Fluorophenyl)-N-(methylthioamide)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (350 mg, 63.0% yield).
LC-MS,M/Z(ESI):544.2[M+H] +。 LC-MS, M/Z (ESI): 544.2 [M+H] + .
第四步：1-((2-((叔丁基二甲基硅基)氧基)-2-甲基丙基)氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮的合成The fourth step: 1-((2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)amino)-4-(2-fluorophenyl)-6-(trifluoro Synthesis of methyl)-3H-pyrido[1,2-c]pyrimidin-3-one
Figure PCTCN2022087589-appb-000354
Figure PCTCN2022087589-appb-000354
将2-(3-氟苯基)-氮-(甲硫酰胺)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(200mg，0.37mmol)和吡啶(87mg，1.1mmol)溶到四氢呋喃(10mL)中，置换氮气，降温到0℃，将碘单质(280mg，1.1mmol)慢慢加入反应液。在室温下搅拌14h。用饱和的硫代硫酸钠(10mL)淬灭反应，乙酸乙酯(10mL)萃取3次，有机相合并旋干，得到粗品，粗品用乙酸乙酯重结晶得到1-((2-((叔丁基二甲基硅基)氧基)-2-甲基丙基)氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(150mg,产率80％)。Combine 2-(3-fluorophenyl)-nitrogen-(methionamide)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (200 mg, 0.37 mmol) and pyridine (87 mg, 1.1 mmol) was dissolved in tetrahydrofuran (10 mL), nitrogen was replaced, the temperature was lowered to 0 °C, and elemental iodine (280 mg, 1.1 mmol) was slowly added to the reaction solution. Stir at room temperature for 14h. The reaction was quenched with saturated sodium thiosulfate (10 mL), extracted three times with ethyl acetate (10 mL), and the organic phases were combined and spun to dry to obtain a crude product, which was recrystallized from ethyl acetate to obtain 1-((2-((tert. Butyldimethylsilyl)oxy)-2-methylpropyl)amino)-4-(2-fluorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2- c] Pyrimidine-3-one (150 mg, 80% yield).
LC-MS,M/Z(ESI):510.1[M+H] +。 LC-MS, M/Z (ESI): 510.1 [M+H] + .
第五步:4-(2-氟苯基)-1-((2-羟基-2-甲基丙基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-68)的合成Step 5: 4-(2-Fluorophenyl)-1-((2-hydroxy-2-methylpropyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2- Synthesis of c]pyrimidin-3-one (I-68)
Figure PCTCN2022087589-appb-000355
Figure PCTCN2022087589-appb-000355
将1-((2-((叔丁基二甲基硅基)氧)-2-甲基丙烷)氨基)-4-(2-氟苯基)-6-(三氟甲基)-3氢-吡啶并[1,2-c]嘧啶-3-酮(100mg,0.19mmol)溶解到2mL甲醇中，然后加入樟脑磺酸(228mg,0.98mmol),在30℃下搅拌14h。反应液经酸性制备方法A制备得目标化合物浅黄色固体4-(2-氟苯)-1-((2-羟基-2-甲基丙基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-68)(6mg,产率8％)。1-((2-((tert-butyldimethylsilyl)oxy)-2-methylpropane)amino)-4-(2-fluorophenyl)-6-(trifluoromethyl)-3 Hydrogen-pyrido[1,2-c]pyrimidin-3-one (100 mg, 0.19 mmol) was dissolved in 2 mL of methanol, then camphorsulfonic acid (228 mg, 0.98 mmol) was added, and the mixture was stirred at 30° C. for 14 h. The reaction solution was prepared by acidic preparation method A to obtain the target compound as a pale yellow solid 4-(2-fluorobenzene)-1-((2-hydroxy-2-methylpropyl)amino)-6-(trifluoromethyl)- 3H-pyrido[1,2-c]pyrimidin-3-one (1-68) (6 mg, 8% yield).
1H NMR(400MHz,DMSO-d 6)δ8.28(s,1H),7.79(s,1H),7.45-7.43(m,1H),7.32-7.26(m,3H),6.77-6.68(m,2H),4.75(s,1H)，3.40(m,2H),1.16(s,6H). 1 H NMR (400MHz, DMSO-d 6 )δ8.28(s,1H), 7.79(s,1H), 7.45-7.43(m,1H), 7.32-7.26(m,3H), 6.77-6.68(m , 2H), 4.75(s, 1H), 3.40(m, 2H), 1.16(s, 6H).
LC-MS,M/Z(ESI):396.1[M+H] + LC-MS, M/Z(ESI): 396.1[M+H] +
实施例69：目标化合物I-69的制备Example 69: Preparation of target compound I-69
4-(2-氯苯基)-1-((2-羟基-2-甲基丙基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-69)4-(2-Chlorophenyl)-1-((2-hydroxy-2-methylpropyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine- 3-keto (I-69)
Figure PCTCN2022087589-appb-000356
Figure PCTCN2022087589-appb-000356
化合物I-69的合成参考I-68的合成方法得到。The synthesis of compound I-69 was obtained with reference to the synthesis method of I-68.
LC-MS,M/Z(ESI):412.1[M+H] + LC-MS, M/Z(ESI): 412.1[M+H] +
实施例70：目标化合物I-70的制备Example 70: Preparation of target compound I-70
(R)-4-(2-氯苯基)-1-(3-羟基吡咯烷-1-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-70)(R)-4-(2-Chlorophenyl)-1-(3-hydroxypyrrolidin-1-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine- 3-keto (I-70)
Figure PCTCN2022087589-appb-000357
Figure PCTCN2022087589-appb-000357
目标化合物I-70的合成路线如下所示：The synthetic route of the target compound I-70 is as follows:
Figure PCTCN2022087589-appb-000358
Figure PCTCN2022087589-appb-000358
将4-(2-氯苯基)-1-硫代-6-(三氟甲基)-1H-吡啶并[1,2-c]嘧啶-3(2H)-酮(I-58A)(300mg，0.84mmol)，(R)-吡咯烷-3-醇(366mg,4.2mmol)和吡啶(333mg，4.2mmol)溶到四氢呋喃(3mL)中，置换氮气，降温到0℃，将碘单质(427mg，1.68mmol)慢慢加入反应液。在50℃下搅拌14h。用饱和的硫代硫酸钠(20mL)淬灭反应，乙酸乙酯(50mL*2)萃取，合并有机相，用无水硫酸钠干燥，旋干得到粗品，粗品用乙酸乙酯重结晶得到(R)-4-(2-氯苯基)-1-(3-羟基吡咯烷-1-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-70)(34mg,产率10％)。4-(2-Chlorophenyl)-1-thio-6-(trifluoromethyl)-1H-pyrido[1,2-c]pyrimidin-3(2H)-one (I-58A) ( 300 mg, 0.84 mmol), (R)-pyrrolidin-3-ol (366 mg, 4.2 mmol) and pyridine (333 mg, 4.2 mmol) were dissolved in tetrahydrofuran (3 mL), replaced with nitrogen, cooled to 0 °C, and iodine ( 427 mg, 1.68 mmol) was slowly added to the reaction solution. Stir at 50°C for 14h. The reaction was quenched with saturated sodium thiosulfate (20 mL), extracted with ethyl acetate (50 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was recrystallized from ethyl acetate to obtain (R )-4-(2-chlorophenyl)-1-(3-hydroxypyrrolidin-1-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3- Ketone (I-70) (34 mg, 10% yield).
1H NMR(400MHz,dmso)δ8.09–7.85(m,1H),7.74–7.48(m,1H),7.48–7.36(m,2H),7.29(dd,J＝5.9,3.3Hz,1H),6.61(d,J＝16.9Hz,1H),6.55–6.43(m,1H),4.35(s,1H),3.93–3.67(m,2H),3.56–3.44(m,1H),3.35–3.00(m,2H),1.94(dd,J＝27.7,19.4Hz,1H),2.02–1.76(m,1H). 1 H NMR(400MHz,dmso)δ8.09-7.85(m,1H),7.74-7.48(m,1H),7.48-7.36(m,2H),7.29(dd,J=5.9,3.3Hz,1H) ,6.61(d,J＝16.9Hz,1H),6.55-6.43(m,1H),4.35(s,1H),3.93-3.67(m,2H),3.56-3.44(m,1H),3.35-3.00 (m, 2H), 1.94 (dd, J=27.7, 19.4Hz, 1H), 2.02–1.76 (m, 1H).
LC-MS,M/Z(ESI):410.1[M+H] +。 LC-MS, M/Z (ESI): 410.1 [M+H] + .
实施例71：目标化合物I-71的制备Example 71: Preparation of target compound I-71
(S)-4-(2-氯苯基)-1-(3-羟基吡咯烷-1-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-71)(S)-4-(2-Chlorophenyl)-1-(3-hydroxypyrrolidin-1-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine- 3-keto (I-71)
Figure PCTCN2022087589-appb-000359
Figure PCTCN2022087589-appb-000359
目标化合物I-71的合成路线如下所示：The synthetic route of the target compound I-71 is as follows:
Figure PCTCN2022087589-appb-000360
Figure PCTCN2022087589-appb-000360
将4-(2-氯苯基)-1-硫代-6-(三氟甲基)-1H-吡啶并[1,2-c]嘧啶-3(2H)-酮(I-58A)(300mg，0.56 mmol)，(S)-吡咯烷-3-醇(244mg,2.8mmol)和吡啶(222mg，2.8mmol)溶到四氢呋喃(2mL)中，置换氮气，降温到0℃，将碘单质(285mg，1.12mmol)慢慢加入反应液。在50℃下搅拌14h。用饱和的硫代硫酸钠(20mL)淬灭反应，乙酸乙酯(50mL*2)萃取，合并有机相，用无水硫酸钠干燥，旋干得到粗品，粗品用乙酸乙酯重结晶得到(S)-4-(2-氯苯基)-1-(3-羟基吡咯烷-1-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-71)(34mg,产率10％)。4-(2-Chlorophenyl)-1-thio-6-(trifluoromethyl)-1H-pyrido[1,2-c]pyrimidin-3(2H)-one (I-58A) ( 300 mg, 0.56 mmol), (S)-pyrrolidin-3-ol (244 mg, 2.8 mmol) and pyridine (222 mg, 2.8 mmol) were dissolved in tetrahydrofuran (2 mL), replaced with nitrogen, cooled to 0 °C, and iodine ( 285 mg, 1.12 mmol) was slowly added to the reaction solution. Stir at 50°C for 14h. The reaction was quenched with saturated sodium thiosulfate (20 mL), extracted with ethyl acetate (50 mL*2), the organic phases were combined, dried with anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was recrystallized with ethyl acetate to obtain (S )-4-(2-chlorophenyl)-1-(3-hydroxypyrrolidin-1-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3- Ketone (I-71) (34 mg, 10% yield).
1H NMR(400MHz,DMSO-d6)δ7.98(t,J＝6.8Hz,1H),7.60–7.53(m,1H),7.46–7.36(m,2H),7.30–7.27(m,1H),6.61(d,J＝16.8Hz,1H),6.52(dt,J＝7.8,2.5Hz,1H),4.35(s,1H),3.85–3.72(m,2H),3.54–3.45(m,1H),3.30–3.20(m,2H),2.08–1.69(m,2H). 1 H NMR(400MHz, DMSO-d6)δ7.98(t,J=6.8Hz,1H),7.60-7.53(m,1H),7.46-7.36(m,2H),7.30-7.27(m,1H) ,6.61(d,J＝16.8Hz,1H),6.52(dt,J＝7.8,2.5Hz,1H),4.35(s,1H),3.85-3.72(m,2H),3.54-3.45(m,1H) ), 3.30–3.20 (m, 2H), 2.08–1.69 (m, 2H).
LC-MS,M/Z(ESI):410.1[M+H] +。 LC-MS, M/Z (ESI): 410.1 [M+H] + .
实施例72：目标化合物I-72的制备Example 72: Preparation of target compound I-72
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000361
Figure PCTCN2022087589-appb-000361
第一步：叔-丁基((1S,3S)-3-异硫氰基环丁氧基)二甲基硅烷的合成The first step: Synthesis of tert-butyl((1S,3S)-3-isothiocyanocyclobutoxy)dimethylsilane
Figure PCTCN2022087589-appb-000362
Figure PCTCN2022087589-appb-000362
将(1S,3S)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁烷-1-胺(1.80g,8.94mmol)和碳酸铯(8.74g,26.8mmol)溶解在二氯甲烷(30.0mL)中，在氮气保护下加入硫光气(2.06g,17.8mmol,1.37mL)，25℃反应2小时。反应完成后，把反应液过滤，有机相浓缩得到黄色固体化合物叔-丁基((1S,3S)-3-异硫氰基环丁氧基)二甲基硅烷(2.00g，粗产物)。直接用于下一步。(1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutan-1-amine (1.80 g, 8.94 mmol) and cesium carbonate (8.74 g, 26.8 mmol) were dissolved In dichloromethane (30.0 mL), under nitrogen protection, thiophosgene (2.06 g, 17.8 mmol, 1.37 mL) was added, and the reaction was carried out at 25° C. for 2 hours. After the reaction was completed, the reaction solution was filtered, and the organic phase was concentrated to obtain a yellow solid compound tert-butyl((1S,3S)-3-isothiocyanocyclobutoxy)dimethylsilane (2.00 g, crude product). used directly in the next step.
第二步：N-(((1S,3S)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The second step: N-(((1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(3-fluorobenzene Synthesis of yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
Figure PCTCN2022087589-appb-000363
Figure PCTCN2022087589-appb-000363
将2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(1.50g,5.03mmol)和碳酸铯(4.92g,15.1mmol)溶解在N,N-二甲基甲酰胺(30.0mL)中，加入叔-丁基((1S,3S)-3-异硫氰基环丁氧基)二甲基硅烷(2.00g,8.22mmol)，25℃反应2小时。反应完成后，把水(50.0mL)加到反应液中，然后用乙酸乙酯(120mL)萃取，用饱和食盐水(40.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至5:1)得到棕色油状化合物N-(((1S,3S)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(1.60g，产率54.4％)。2-(3-Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (1.50 g, 5.03 mmol) and cesium carbonate (4.92 g, 15.1 mmol) were dissolved in N , N-dimethylformamide (30.0 mL) was added tert-butyl((1S,3S)-3-isothiocyanocyclobutoxy)dimethylsilane (2.00 g, 8.22 mmol), 25 °C for 2 hours. After the reaction was completed, water (50.0 mL) was added to the reaction solution, then extracted with ethyl acetate (120 mL), the organic phase was washed with saturated brine (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=50:1 to 5:1) to obtain a brown oily compound N-(((1S,3S)-3-((tert-butyl Dimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (1.60 g, 54.4% yield).
LC-MS,M/Z(ESI):542.2[M+H] + LC-MS, M/Z(ESI): 542.2[M+H] +
第三步：1-(((1S,3S)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(3-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮的合成The third step: 1-(((1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)amino)-4-(3-fluorophenyl)-6 Synthesis of -(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one
Figure PCTCN2022087589-appb-000364
Figure PCTCN2022087589-appb-000364
将N-(((1S,3S)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(1.60g,2.74mmol)溶解在四氢呋喃(30.0mL)中，加碘(1.74g,6.85mmol)和碳酸铯(1.78g,5.48mmol)，25℃反应2小时。反应完成后，将反应液加入饱和亚硫酸钠溶液(50.0mL)中，然后用乙酸乙酯(150mL)萃取，用饱和食盐水(50.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0至1:1)，得到黄色油状化合物1-(((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(3-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(1.00g，产率72.0％)。N-(((1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(3-fluorophenyl)- 2-(4-(Trifluoromethyl)pyridin-2-yl)acetamide (1.60 g, 2.74 mmol) was dissolved in tetrahydrofuran (30.0 mL), iodine (1.74 g, 6.85 mmol) and cesium carbonate (1.78 g) were added , 5.48mmol), 25 ℃ of reaction 2 hours. After the reaction was completed, the reaction solution was added to saturated sodium sulfite solution (50.0 mL), then extracted with ethyl acetate (150 mL), the organic phase was washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product . The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:0 to 1:1) to obtain a yellow oily compound 1-(((1S,3S)-3-((tert-butyl Dimethylsilyl)oxo)cyclobutyl)amino)-4-(3-fluorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 - Ketone (1.00 g, 72.0% yield).
LC-MS,M/Z(ESI):508.2[M+H] + LC-MS, M/Z(ESI): 508.2[M+H] +
第四步：目标化合物4-(3-氟苯基)-1-(((1S,3S)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(化合物I-72)The fourth step: target compound 4-(3-fluorophenyl)-1-(((1S,3S)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[ 1,2-c]pyrimidin-3-one (Compound I-72)
Figure PCTCN2022087589-appb-000365
Figure PCTCN2022087589-appb-000365
将1-(((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(3-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(700mg,1.38mmol)溶解在甲醇(50.0mL)中，加入樟脑磺酸(1.28g,5.52mmol)，25℃反应0.5小时。反应完成后，在反应液中加入水(50.0mL)， 然后用乙酸乙酯(150mL)萃取，用饱和食盐水(50.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到黄色固体化合物4-(3-氟苯基)-1-(((1S,3S)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-72)(560mg，产率99.8％)。1-(((1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)amino)-4-(3-fluorophenyl)-6-(trifluorophenyl) Methyl)-3H-pyrido[1,2-c]pyrimidin-3-one (700mg, 1.38mmol) was dissolved in methanol (50.0mL), camphorsulfonic acid (1.28g, 5.52mmol) was added, and the reaction was carried out at 25°C 0.5 hours. After the reaction was completed, water (50.0 mL) was added to the reaction solution, then extracted with ethyl acetate (150 mL), the organic phase was washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid compound 4-(3-Fluorophenyl)-1-(((1S,3S)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c] Pyrimidine-3-one (I-72) (560 mg, 99.8% yield).
1H NMR(400MHz,DMSO-d 6)δ8.17(br d,1H),8.00(br d,1H),7.47(m,1H),7.17-7.22(m,1H),7.09-7.15(m,2H),6.97(s,1H),6.70(br d,1H),5.15(br d,1H),3.87-3.94(m,2H),2.64(br d,2H),1.94(br d,2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.17(br d,1H),8.00(br d,1H),7.47(m,1H),7.17-7.22(m,1H),7.09-7.15(m ,2H),6.97(s,1H),6.70(br d,1H),5.15(br d,1H),3.87-3.94(m,2H),2.64(br d,2H),1.94(br d,2H) ).
LC-MS,M/Z(ESI):394.1[M+H] + LC-MS, M/Z(ESI): 394.1[M+H] +
实施例73：目标化合物I-73的制备Example 73: Preparation of target compound I-73
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000366
Figure PCTCN2022087589-appb-000366
第一步：叔丁基((1S,3S)-3-异硫氰基环丁氧基)二甲基硅烷的合成The first step: synthesis of tert-butyl((1S,3S)-3-isothiocyanocyclobutoxy)dimethylsilane
Figure PCTCN2022087589-appb-000367
Figure PCTCN2022087589-appb-000367
将(1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁烷-1-胺(500mg,2.48mmol)和碳酸铯(2.43g,7.45mmol)溶解在二氯甲烷(10.0mL)中，在氮气保护下加入硫光气(570mg,4.97mmol,380uL)，25℃反应2小时。反应完成后，把反应液过滤，有机相浓缩得到黄色固体化合物叔-丁基((1S,3S)-3-异硫氰基环丁氧基)二甲基硅烷(600mg，粗产物)。直接用于下一步。(1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutan-1-amine (500 mg, 2.48 mmol) and cesium carbonate (2.43 g, 7.45 mmol) were dissolved in bismuth Thiophosgene (570 mg, 4.97 mmol, 380 uL) was added to methyl chloride (10.0 mL) under nitrogen protection, and the reaction was carried out at 25° C. for 2 hours. After the reaction was completed, the reaction solution was filtered, and the organic phase was concentrated to obtain a yellow solid compound tert-butyl((1S,3S)-3-isothiocyanatocyclobutoxy)dimethylsilane (600 mg, crude product). used directly in the next step.
第二步：N-(((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The second step: N-(((1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(2-fluorophenyl) )-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
Figure PCTCN2022087589-appb-000368
Figure PCTCN2022087589-appb-000368
将2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(672mg,2.26mmol)和碳酸铯(4.92g, 15.1mmol)溶解在N,N-二甲基甲酰胺(15.0mL)中，加入叔丁基((1S,3S)-3-异硫氰基环丁氧基)二甲基硅烷(500mg,2.05mmol)，75℃反应2小时。反应完成后，把水(50.0mL)加到反应液中，然后用乙酸乙酯(120mL)萃取，用饱和食盐水(40.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0至20:1)得到棕色油状化合物N-(((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(315mg，产率24.5％)。2-(2-Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (672 mg, 2.26 mmol) and cesium carbonate (4.92 g, 15.1 mmol) were dissolved in N, In N-dimethylformamide (15.0 mL), tert-butyl((1S,3S)-3-isothiocyanocyclobutoxy)dimethylsilane (500 mg, 2.05 mmol) was added, and the reaction was carried out at 75°C for 2 Hour. After the reaction was completed, water (50.0 mL) was added to the reaction solution, then extracted with ethyl acetate (120 mL), the organic phase was washed with saturated brine (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 1:0 to 20:1) to obtain a brown oily compound N-(((1S,3S)-3-((tert-butyldimethylformaldehyde) Silyl)oxo)cyclobutyl)carbamoyl)-2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (315mg , yield 24.5%).
LC-MS,M/Z(ESI):542.2(M+H) + LC-MS, M/Z (ESI): 542.2 (M+H) +
第三步：1-(((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮的合成The third step: 1-(((1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)amino)-4-(2-fluorophenyl)-6- Synthesis of (trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one
Figure PCTCN2022087589-appb-000369
Figure PCTCN2022087589-appb-000369
将N-(((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(310mg,495μmol)溶解在四氢呋喃(10.0mL)中，加碘(376mg,1.49mmol)和碳酸铯(483mg,1.49mmol)，25℃反应2小时。反应完成后，向反应液中加入饱和亚硫酸钠溶液(20.0mL)，然后用乙酸乙酯(90.0mL)萃取，用饱和食盐水(30.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1至0:1)，得到黄色固体化合物1-(((1s,3s)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(305mg，产率96.1％)。N-(((1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(2-fluorophenyl)-2 -(4-(trifluoromethyl)pyridin-2-yl)acetamide (310 mg, 495 μmol) was dissolved in tetrahydrofuran (10.0 mL), iodine (376 mg, 1.49 mmol) and cesium carbonate (483 mg, 1.49 mmol) were added, The reaction was carried out at 25°C for 2 hours. After the reaction was completed, saturated sodium sulfite solution (20.0 mL) was added to the reaction solution, then extracted with ethyl acetate (90.0 mL), the organic phase was washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Crude. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=3:1 to 0:1) to obtain a yellow solid compound 1-(((1s,3s)-3-((tert-butyl Dimethylsilyl)oxo)cyclobutyl)amino)-4-(2-fluorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 - Ketone (305 mg, 96.1% yield).
LC-MS,M/Z(ESI):508.2[M+H] + LC-MS, M/Z(ESI): 508.2[M+H] +
第四步：4-(2-氟苯基)-1-(((1S,3S)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(化合物I-73)The fourth step: 4-(2-Fluorophenyl)-1-(((1S,3S)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[1, 2-c]pyrimidin-3-one (Compound I-73)
Figure PCTCN2022087589-appb-000370
Figure PCTCN2022087589-appb-000370
将1-(((1S,3S)-3-((叔丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(300mg,468μmol)溶解在甲醇(10.0mL)中，加入樟脑磺酸(468mg,1.87mmol)，25℃反应0.5小时。反应完成后，在反应液中加入水(10.0mL)，饱和碳酸氢钠溶液(5.00mL)调节pH至7，然后用乙酸乙酯(45.0mL)萃取，用饱和食盐水(20.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用硅胶柱分离纯化(乙酸乙酯:甲醇(V/V)＝1:0至10:1)，得到黄色固体化合物4-(2-氟苯基)-1-(((1S,3S)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-73)(110mg，产率59.3％)。1-(((1S,3S)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)amino)-4-(2-fluorophenyl)-6-(trifluorophenyl) Methyl)-3H-pyrido[1,2-c]pyrimidin-3-one (300 mg, 468 μmol) was dissolved in methanol (10.0 mL), camphorsulfonic acid (468 mg, 1.87 mmol) was added, and the reaction was carried out at 25°C for 0.5 hours . After the reaction was completed, water (10.0 mL) was added to the reaction solution, and saturated sodium bicarbonate solution (5.00 mL) was used to adjust the pH to 7, then extracted with ethyl acetate (45.0 mL), and the organic matter was washed with saturated brine (20.0 mL). The phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was separated and purified by silica gel column (ethyl acetate:methanol (V/V)=1:0 to 10:1) to obtain yellow solid compound 4-(2-fluorophenyl)-1-(((1S,3S) -3-Hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-73) (110 mg, 59.3% yield).
1H NMR(400MHz,DMSO-d 6)δ8.21(d,1H),8.04(br d,1H),7.40-7.49(m,1H),7.24-7.34(m,3H),6.78(s,1H),6.71(m,1H),5.19(d,1H),3.82-3.99(m,2H),2.59-2.73(m,2H),1.88-2.02(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.21(d,1H), 8.04(br d,1H), 7.40-7.49(m,1H), 7.24-7.34(m,3H), 6.78(s, 1H), 6.71(m, 1H), 5.19(d, 1H), 3.82-3.99(m, 2H), 2.59-2.73(m, 2H), 1.88-2.02(m, 2H).
LC-MS,M/Z(ESI):394.1[M+H] + LC-MS, M/Z(ESI): 394.1[M+H] +
实施例74-78：目标化合物I-74～I-78的制备Examples 74-78: Preparation of target compounds I-74 to I-78
Figure PCTCN2022087589-appb-000371
Figure PCTCN2022087589-appb-000371
Figure PCTCN2022087589-appb-000372
Figure PCTCN2022087589-appb-000372
实施例79：化合物I-79的制备Example 79: Preparation of Compound 1-79
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000373
Figure PCTCN2022087589-appb-000373
第一步：4-(溴甲基)-2-氟吡啶的合成The first step: the synthesis of 4-(bromomethyl)-2-fluoropyridine
氮气保护下，向2-氟-4-甲基吡啶(20.0g,180mmol)的四氯化碳(200mL)溶液中加入N-溴代丁二酰亚胺(38.4g,216mmol)和偶氮二异丁腈(3.55g,21.6mmol)，反应在85℃搅拌12小时。反应完成后，将反应混合物过滤，滤液旋干，残留物用反相flash制备纯化(溶剂：A＝水+0.1体积％三氟乙酸(99.0％)，B＝乙腈)，得到黄色油状物4-(溴甲基)-2-氟吡啶(9.00g,46.6mmol,29.5％收率)。Under nitrogen protection, to a solution of 2-fluoro-4-methylpyridine (20.0 g, 180 mmol) in carbon tetrachloride (200 mL) was added N-bromosuccinimide (38.4 g, 216 mmol) and azodicarbonate Isobutyronitrile (3.55 g, 21.6 mmol), the reaction was stirred at 85°C for 12 hours. After the completion of the reaction, the reaction mixture was filtered, the filtrate was spin-dried, and the residue was purified by reverse-phase flash preparation (solvent: A=water+0.1 vol% trifluoroacetic acid (99.0%), B=acetonitrile) to give a yellow oil 4- (Bromomethyl)-2-fluoropyridine (9.00 g, 46.6 mmol, 29.5% yield).
1H NMR(400MHz,CDCl 3)δ8.18(d,1H),7.19(d,1H),6.94(s,1H),4.38(s,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.18(d,1H), 7.19(d,1H), 6.94(s,1H), 4.38(s,2H).
LC-MS,M/Z(ESI):189.9[M+H] + LC-MS, M/Z(ESI): 189.9[M+H] +
第二步：2-(2-氟吡啶-4-基)乙腈的合成The second step: the synthesis of 2-(2-fluoropyridin-4-yl)acetonitrile
氮气保护下，向4-(溴甲基)-2-氟吡啶(1.00g,5.18mmol)和醋酸钾(1.02g,10.4mmol)的乙腈(20.0mL)溶液中加入三甲基氰硅烷(514mg,5.18mmol)，反应在30℃搅拌12小时。反应完成后，将反应混合物过滤，滤液旋干，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝20:1至5:1)得到无色油状物2-(2-氟吡啶-4-基)乙腈(370mg,2.69mmol,52.1％收率)。To a solution of 4-(bromomethyl)-2-fluoropyridine (1.00 g, 5.18 mmol) and potassium acetate (1.02 g, 10.4 mmol) in acetonitrile (20.0 mL) was added trimethylsilane (514 mg) under nitrogen , 5.18 mmol), and the reaction was stirred at 30 °C for 12 h. After the completion of the reaction, the reaction mixture was filtered, the filtrate was spin-dried, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=20:1 to 5:1) to obtain 2-(2) as a colorless oil. -Fluoropyridin-4-yl)acetonitrile (370 mg, 2.69 mmol, 52.1% yield).
LC-MS,M/Z(ESI):137.0[M+H] + LC-MS, M/Z(ESI): 137.0[M+H] +
第三步：2-(2-氟吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈的合成The third step: Synthesis of 2-(2-fluoropyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile
在氮气保护下，向醋酸钯(57.2mg,255μmol)的1,4-二氧六环(10.0mL)溶液中加入4，6-双(二苯基膦)吩噁嗪(211mg,382μmol)，反应在45℃搅拌1小时。在氮气保护下，将以上反应混合液，慢慢加入到2-(2-氟吡啶-4-基)乙腈(350mg,2.55mmol)、2-溴-4-(三氟甲基)吡啶(864mg,3.82mmol)和叔丁醇钾(572mg,5.10mmol)的1,4-二氧六环(10.0mL)溶液中，置换氮气三次，反应在氮气氛围下，在60℃搅拌11小时。反应完成后，将反应混合物用水(50.0mL)稀释，然后用乙酸乙酯(30.0mL*3)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1至3:1)，得到黄色油状化合物2-(2-氟吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(200mg,688μmol,27.0％收率)。To a solution of palladium acetate (57.2 mg, 255 μmol) in 1,4-dioxane (10.0 mL) was added 4,6-bis(diphenylphosphine)phenoxazine (211 mg, 382 μmol) under nitrogen protection, The reaction was stirred at 45°C for 1 hour. Under nitrogen protection, the above reaction mixture was slowly added to 2-(2-fluoropyridin-4-yl)acetonitrile (350 mg, 2.55 mmol), 2-bromo-4-(trifluoromethyl)pyridine (864 mg) , 3.82 mmol) and potassium tert-butoxide (572 mg, 5.10 mmol) in 1,4-dioxane (10.0 mL), nitrogen was replaced three times, and the reaction was stirred at 60 °C for 11 hours under nitrogen atmosphere. After the reaction was completed, the reaction mixture was diluted with water (50.0 mL), then extracted with ethyl acetate (30.0 mL*3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a silica gel column (petroleum ether:ethyl acetate (V/V)=10:1 to 3:1) to give yellow oily compound 2-(2-fluoropyridin-4-yl)-2-(4-(trifluoromethyl)pyridine- 2-yl)acetonitrile (200 mg, 688 μmol, 27.0% yield).
LC-MS,M/Z(ESI):282.0(M+H) + LC-MS, M/Z (ESI): 282.0 (M+H) +
第四步：2-(2-氟吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The fourth step: the synthesis of 2-(2-fluoropyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
向硫酸(2.00mL)中加入2-(2-氟吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(200mg,688μmol)，反应在25℃搅拌12小时。反应完成后，将反应液倒入冰水(30.0mL)，然后用饱和碳酸氢钠水溶液调至pH＝8，然后用乙酸乙酯(30.0mL*2)萃取，合并有机层，用盐水(100mL)洗涤，干燥，得到黄色油状物2-(2-氟吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(200mg,668μmol,97.1％收率)。直接用于下一步。To sulfuric acid (2.00 mL) was added 2-(2-fluoropyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (200 mg, 688 μmol), and the reaction was stirred at 25°C 12 hours. After the completion of the reaction, the reaction solution was poured into ice water (30.0 mL), and then adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (30.0 mL*2), the organic layers were combined, and brine (100 mL) was used for extraction. ) and dried to give 2-(2-fluoropyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (200 mg, 668 μmol, 97.1% yield) as a yellow oil ). used directly in the next step.
LC-MS,M/Z(ESI):300.0(M+H) + LC-MS, M/Z (ESI): 300.0 (M+H) +
第五步：N-(环丙基氨基硫代甲酰)-2-(2-氟吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The fifth step: N-(cyclopropylaminothioformyl)-2-(2-fluoropyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide synthesis
氮气保护下，在-20℃下，向2-(2-氟吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(180mg,602μmol)的N,N-二甲基甲酰胺(5.00mL)溶液中加入碳酸铯(588mg,1.80mmol)和环丙基异硫氰酸酯(89.5mg,902μmol)，反应在25℃搅拌12小时。反应完成后，将反应混合物用乙酸乙酯(50.0mL)稀释，然后用盐水(50.0mL*3)洗涤，无水硫酸钠干燥，过滤，浓缩，得到黄色油状化合物N-(环丙基氨基硫代甲酰)-2-(2-氟吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(100mg)。直接用于下一步。Under nitrogen at -20°C, a solution of 2-(2-fluoropyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (180 mg, 602 μmol) in N , N-dimethylformamide (5.00 mL) solution was added cesium carbonate (588 mg, 1.80 mmol) and cyclopropyl isothiocyanate (89.5 mg, 902 μmol), and the reaction was stirred at 25° C. for 12 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (50.0 mL), then washed with brine (50.0 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oily compound N-(cyclopropylamino sulfur Formyl)-2-(2-fluoropyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (100 mg). used directly in the next step.
LC-MS,M/Z(ESI):399.1[M+H] + LC-MS, M/Z(ESI): 399.1[M+H] +
第六步：1-(环丙基氨基)-4-(2-氟吡啶-4-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-79)的合成Step 6: 1-(Cyclopropylamino)-4-(2-fluoropyridin-4-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3- Synthesis of Ketone (I-79)
Figure PCTCN2022087589-appb-000374
Figure PCTCN2022087589-appb-000374
在0℃下，向N-(环丙基氨基硫代甲酰)-2-(2-氟吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(100mg,251μmol)的四氢呋喃(3.00mL)溶液中加入吡啶(59.6mg,753μmol)和碘单质(191mg,753μmol)，反应在25℃搅拌10分钟。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(20.0mL)稀释，然后用乙酸乙酯(20.0mL*2)萃取，合并有机层，无水硫酸钠干燥，过滤，浓缩，残留物用高效液相色谱仪分离纯化，分离方法为(柱子：ACSWH-GX-K Phenomenex C18 75*30mm*3um；溶剂：A＝水+0.225体积％甲酸(99.0％)，B＝乙腈；梯度：22％-52％，7分钟)，得到黄色固体化合物1-(环丙基氨基)-4-(2-氟吡啶-4-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-79)(1.99mg,5.24μmol,2.09％收率)。To N-(cyclopropylaminothiocarbonyl)-2-(2-fluoropyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)ethyl at 0 °C Pyridine (59.6 mg, 753 μmol) and iodine (191 mg, 753 μmol) were added to a solution of amide (100 mg, 251 μmol) in tetrahydrofuran (3.00 mL), and the reaction was stirred at 25° C. for 10 minutes. After the completion of the reaction, the reaction mixture was diluted with saturated aqueous sodium sulfite solution (20.0 mL), then extracted with ethyl acetate (20.0 mL*2), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to high-performance liquid Chromatography separation and purification, the separation method is (column: ACSWH-GX-K Phenomenex C18 75*30mm*3um; solvent: A=water+0.225 volume% formic acid (99.0%), B=acetonitrile; gradient: 22%-52% , 7 minutes) to give a yellow solid compound 1-(cyclopropylamino)-4-(2-fluoropyridin-4-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c ]pyrimidin-3-one (I-79) (1.99 mg, 5.24 μmol, 2.09% yield).
1H NMR(400MHz,MeOD)δ8.53(d,1H),8.39(d,1H),7.54(s,1H),7.38(d,1H),7.32(dd,1H),7.21(s,1H),3.09-3.14(m,1H),0.96-1.04(m,2H),0.81-0.89(m,2H). 1 H NMR (400MHz, MeOD)δ8.53(d,1H), 8.39(d,1H), 7.54(s,1H), 7.38(d,1H), 7.32(dd,1H), 7.21(s,1H) ),3.09-3.14(m,1H),0.96-1.04(m,2H),0.81-0.89(m,2H).
LC-MS,M/Z(ESI):365.0[M+H] + LC-MS, M/Z(ESI): 365.0[M+H] +
实施例80：化合物I-80的制备Example 80: Preparation of Compound 1-80
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000375
Figure PCTCN2022087589-appb-000375
第一步：3-(溴甲基)-2-氟吡啶的合成The first step: the synthesis of 3-(bromomethyl)-2-fluoropyridine
在室温下，将2-氟-3-甲基吡啶(10.0g,90.0mmol)，N-溴代丁二酰亚胺(16.0g,90.0mmol)和过氧化苯甲酰(1.09g,4.50mmol)加入到乙腈(150mL)中，氮气保护下在70℃反应12小时。反应完成后，反应液过滤浓缩得到粗品。残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝200:1至30:1)得到黄色固体化合物3-(溴甲基)-2-氟吡啶(10.0g，产率58.5％)。At room temperature, 2-fluoro-3-methylpyridine (10.0 g, 90.0 mmol), N-bromosuccinimide (16.0 g, 90.0 mmol) and benzoyl peroxide (1.09 g, 4.50 mmol) were combined ) was added to acetonitrile (150 mL) and reacted at 70°C for 12 hours under nitrogen protection. After the completion of the reaction, the reaction solution was filtered and concentrated to obtain the crude product. The residue was separated and purified with silica gel column (petroleum ether:ethyl acetate (V/V)=200:1 to 30:1) to obtain a yellow solid compound 3-(bromomethyl)-2-fluoropyridine (10.0 g, yield 58.5%).
LC-MS,M/Z(ESI):190.1[M+H] + LC-MS, M/Z(ESI): 190.1[M+H] +
第二步：2-(2-氟吡啶-3-基)乙腈的合成The second step: the synthesis of 2-(2-fluoropyridin-3-yl)acetonitrile
在室温下，将3-(溴甲基)-2-氟吡啶(4.00g,21.1mmol)，三甲基氰硅烷(2.09g,21.1mmol)和碳酸钾(5.82g,42.1mmol)加入到乙腈(40.0mL)中，氮气保护下在30℃反应8小时。反应完成后，反应液过滤浓缩得到粗品，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝200:1至20:1)，得到黄色固体化合物2-(2-氟吡啶-3-基)乙腈(2.20g，产率61.4％)。3-(Bromomethyl)-2-fluoropyridine (4.00 g, 21.1 mmol), trimethylsilyl cyanide (2.09 g, 21.1 mmol) and potassium carbonate (5.82 g, 42.1 mmol) were added to acetonitrile at room temperature (40.0 mL), reacted at 30°C for 8 hours under nitrogen protection. After the completion of the reaction, the reaction solution was filtered and concentrated to obtain the crude product, and the residue was separated and purified with a silica gel column (petroleum ether:ethyl acetate (V/V)=200:1 to 20:1) to obtain a yellow solid compound 2-(2-fluoro). Pyridin-3-yl)acetonitrile (2.20 g, 61.4% yield).
LC-MS,M/Z(ESI):137.0[M+H] + LC-MS, M/Z(ESI): 137.0[M+H] +
第三步：2-(2-氟吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈的合成The third step: Synthesis of 2-(2-fluoropyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile
在室温下，将4，6-双(二苯基膦)吩噁嗪(911mg,1.65mmol)和醋酸钯(247mg,1.10mmol)加入到1,4-二氧六环(20.0mL)中氮气保护下45℃反应1小时，再将反应液加入到2-溴-4-(三氟甲基)吡啶(3.74g,16.5mmol)，2-(2-氟吡啶-3-基)乙腈(1.50g,11.0mmol)，叔丁醇钾(2.47g,22.0mmol)和1,4-二氧六环(20.0mL)的混合溶液中，置换氮气三次，并在氮气保护下在 60℃反应10小时。反应完成后，反应液浓缩得到粗品，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝200:1至20:1)，得到黄色液体化合物2-(2-氟吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(2.20g，产率62.8％)。4,6-Bis(diphenylphosphino)phenoxazine (911 mg, 1.65 mmol) and palladium acetate (247 mg, 1.10 mmol) were added to 1,4-dioxane (20.0 mL) under nitrogen at room temperature The reaction was carried out at 45°C for 1 hour under protection, and then the reaction solution was added to 2-bromo-4-(trifluoromethyl)pyridine (3.74g, 16.5mmol), 2-(2-fluoropyridin-3-yl)acetonitrile (1.50 g) g, 11.0 mmol), potassium tert-butoxide (2.47 g, 22.0 mmol) and 1,4-dioxane (20.0 mL) in a mixed solution, replaced nitrogen three times, and reacted at 60 °C for 10 hours under nitrogen protection . After the reaction was completed, the reaction solution was concentrated to obtain a crude product, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=200:1 to 20:1) to obtain a yellow liquid compound 2-(2-fluoropyridine) -3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (2.20 g, 62.8% yield).
LC-MS,M/Z(ESI):282.1[M+H] + LC-MS, M/Z(ESI): 282.1[M+H] +
第四步：2-(2-氟吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The fourth step: the synthesis of 2-(2-fluoropyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
在室温下，将2-(2-氟吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(2.10g,7.47mmol)缓慢加入到浓硫酸(25.0mL)中，氮气保护下在25℃反应10小时。反应完成后，反应液0～25℃下加入到饱和的碳酸氢钠水溶液(200mL)中，然后用二氯甲烷(40.0mL*2)萃取，合并有机层相，用饱和食盐水(20.0mL*2)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到2-(2-氟吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(1.20g，粗品)。At room temperature, 2-(2-fluoropyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (2.10 g, 7.47 mmol) was slowly added to concentrated sulfuric acid (25.0 mL), reacted at 25 °C for 10 hours under nitrogen protection. After the completion of the reaction, the reaction solution was added to saturated aqueous sodium bicarbonate solution (200 mL) at 0-25 °C, then extracted with dichloromethane (40.0 mL*2), the organic layers were combined, and saturated brine (20.0 mL*2) was used for extraction. 2) Wash the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 2-(2-fluoropyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (1.20 g, crude product).
LC-MS,M/Z(ESI):300.1[M+H] + LC-MS, M/Z(ESI): 300.1[M+H] +
第五步：N-(环丙基氨基硫代甲酰)-2-(2-氟吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The fifth step: N-(cyclopropylaminothioformyl)-2-(2-fluoropyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide synthesis
在室温下，将2-(2-氟吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(300mg,1.00mmol)，环丙基异硫氰酸酯(149mg,1.50mmol)和碳酸铯(653mg,2.01mmol)加入到N，N-二甲基甲酰胺(4.00mL)中，氮气保护下在25℃反应10小时。反应完成后，反应液25℃下加入水(40.0mL)中，然后用乙酸乙酯(20.0mL*3)萃取，合并有机层相，用饱和食盐水(10.0mL*2)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到N-(环丙基氨基硫代甲酰)-2-(2-氟吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(400mg，粗品)。At room temperature, 2-(2-fluoropyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (300 mg, 1.00 mmol), cyclopropyl isothiocyanate The acid ester (149 mg, 1.50 mmol) and cesium carbonate (653 mg, 2.01 mmol) were added to N,N-dimethylformamide (4.00 mL) and reacted at 25° C. for 10 hours under nitrogen protection. After the completion of the reaction, the reaction solution was added to water (40.0 mL) at 25°C, then extracted with ethyl acetate (20.0 mL*3), the organic layers were combined, and the organic phase was washed with saturated brine (10.0 mL*2). dried over sodium sulfate, filtered, and concentrated to give N-(cyclopropylaminothiocarbonyl)-2-(2-fluoropyridin-3-yl)-2-(4-(trifluoromethyl)pyridine-2- yl)acetamide (400 mg, crude).
LC-MS,M/Z(ESI):399.0[M+H] + LC-MS, M/Z(ESI): 399.0[M+H] +
第六步：1-(环丙基氨基)-4-(2-氟吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-80)的合成Step 6: 1-(Cyclopropylamino)-4-(2-fluoropyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3- Synthesis of Ketone (I-80)
Figure PCTCN2022087589-appb-000376
Figure PCTCN2022087589-appb-000376
在氮气保护下，将N-(环丙基氨基硫代甲酰)-2-(2-氟吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(300mg,753μmol)，碘(573mg,2.26mmol)和吡啶(298mg,3.77mmol)加入到四氢呋喃(3.00mL)中，氮气保护下25℃下反应8小时。反应完成后，反应液过滤，浓缩得到粗品。残留物用高效液相色谱仪分离纯化，分离方法为(柱子：Phenomenex Synergi C18 150*50mm*10um；溶剂：A＝水+0.1体积％碳酸氢氨(99％)，B＝乙腈；梯度：19％-49％，10分钟)，得到目标化合物1-(环丙基氨基)-4-(2-氟吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-80)(98.0mg，产率35.0％)。Under nitrogen protection, N-(cyclopropylaminothiocarbonyl)-2-(2-fluoropyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)ethyl Amide (300 mg, 753 μmol), iodine (573 mg, 2.26 mmol) and pyridine (298 mg, 3.77 mmol) were added to tetrahydrofuran (3.00 mL) and reacted at 25° C. for 8 hours under nitrogen protection. After completion of the reaction, the reaction solution was filtered and concentrated to obtain the crude product. The residue was separated and purified by high performance liquid chromatography, and the separation method was (column: Phenomenex Synergi C18 150*50mm*10um; solvent: A=water+0.1 vol% ammonium bicarbonate (99%), B=acetonitrile; gradient: 19 %-49%, 10 minutes) to give the target compound 1-(cyclopropylamino)-4-(2-fluoropyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1, 2-c]pyrimidin-3-one (I-80) (98.0 mg, 35.0% yield).
1H NMR(400MHz,CD 3OD)δ8.29(d,1H),8.10(d,1H),7.93-7.98(m,1H),7.46(t,1H),7.02(s,1H),6.77(d,1H),2.96-3.00(m,1H),0.85-0.90(m,2H),0.71-0.74(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.29(d, 1H), 8.10(d, 1H), 7.93-7.98(m, 1H), 7.46(t, 1H), 7.02(s, 1H), 6.77 (d,1H),2.96-3.00(m,1H),0.85-0.90(m,2H),0.71-0.74(m,2H).
LC-MS,M/Z(ESI):365.0[M+H] + LC-MS, M/Z(ESI): 365.0[M+H] +
实施例81：化合物I-81的制备Example 81: Preparation of Compound 1-81
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000377
Figure PCTCN2022087589-appb-000377
在氮气保护下，将1-(乙胺基)-4-(2-氟-3-甲氧苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(200mg,524μmol)加入到溴化氢(5.00mL,30％的乙酸溶液)中，氮气保护下55℃下反应16小时。反应完成后，反应液过滤，浓缩得到粗品。残留物用高效液相色谱仪分离纯化，分离方法为(柱子：Phenomenex Synergi C18 150*25mm*5um；溶剂：A＝水+0.1体积％三氟乙酸(99％)，B＝乙腈；梯度：29％-59％，9分钟)，得到目标化合物1-(乙胺基)-4-(2-氟-3-羟基苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-81)(75.6mg，38.7％产率)。Under nitrogen protection, 1-(ethylamino)-4-(2-fluoro-3-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine -3-one (200 mg, 524 μmol) was added to hydrogen bromide (5.00 mL, 30% acetic acid solution), and the reaction was carried out at 55° C. for 16 hours under nitrogen protection. After completion of the reaction, the reaction solution was filtered and concentrated to obtain the crude product. The residue was separated and purified by high performance liquid chromatography, and the separation method was (column: Phenomenex Synergi C18 150*25mm*5um; solvent: A=water+0.1% by volume trifluoroacetic acid (99%), B=acetonitrile; gradient: 29 %-59%, 9 minutes) to give the target compound 1-(ethylamino)-4-(2-fluoro-3-hydroxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1, 2-c]pyrimidin-3-one (I-81) (75.6 mg, 38.7% yield).
1H NMR(400MHz,CD 3OD)δ8.42(d,1H),7.35(s,1H),7.07-7.19(m,3H),6.78-6.80(m,1H),3.72(q,2H),1.38(t,3H). 1 H NMR (400MHz, CD 3 OD) δ 8.42(d, 1H), 7.35(s, 1H), 7.07-7.19(m, 3H), 6.78-6.80(m, 1H), 3.72(q, 2H) ,1.38(t,3H).
LC-MS,M/Z(ESI):368.2[M+H] + LC-MS, M/Z(ESI): 368.2[M+H] +
实施例82：化合物I-82的制备Example 82: Preparation of Compound 1-82
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000378
Figure PCTCN2022087589-appb-000378
第一步：2-(2-氟-3-甲氧苯基)乙腈的合成The first step: the synthesis of 2-(2-fluoro-3-methoxyphenyl)acetonitrile
在室温下，叔丁醇钾(8.01g,71.4mmol)加入到乙二醇二甲醚(70.0mL)中，-78～-60℃℃下加入对甲基苯磺酰甲基异腈(7.60g,38.9mmol)，加完后-78～-60℃搅拌下反应0.5小时，然后在-78～-60℃下加入2-氟-3-甲氧基苯甲醛(5.00g,32.4mmol)，加完后在-78～-60℃反应 1小时，然后加入甲醇(70.0mL)，80℃反应0.5小时。反应完成后，25℃下向反应液中加入乙酸(30.0mL)，过滤浓缩得到粗品。残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝200:1至20:1)得到白色固体化合物2-(2-氟-3-甲氧苯基)乙腈(4.20g，产率78.4％)。At room temperature, potassium tert-butoxide (8.01 g, 71.4 mmol) was added to ethylene glycol dimethyl ether (70.0 mL), and p-methylbenzenesulfonylmethylisonitrile (7.60 °C) was added at -78 to -60 °C. g, 38.9mmol), after the addition, the reaction was carried out at -78～-60°C for 0.5 hours under stirring, and then 2-fluoro-3-methoxybenzaldehyde (5.00g, 32.4mmol) was added at -78～-60°C, After the addition, the reaction was carried out at -78 to -60°C for 1 hour, then methanol (70.0 mL) was added, and the reaction was carried out at 80°C for 0.5 hour. After the reaction was completed, acetic acid (30.0 mL) was added to the reaction solution at 25°C, and the crude product was obtained by filtration and concentration. The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=200:1 to 20:1) to obtain a white solid compound 2-(2-fluoro-3-methoxyphenyl)acetonitrile (4.20 g) , yield 78.4%).
第二步：2-(2-氟-3-甲氧苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈的合成The second step: the synthesis of 2-(2-fluoro-3-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile
在室温下，将2-(2-氟-3-甲氧苯基)乙腈(4.10g,24.8mmol)，2-溴-4-(三氟甲基)吡啶(5.61g,24.8mmol)和氢氧化钾(2.79g,49.7mmol)加入到N-甲基吡咯烷酮(40mL)中，氮气保护下在90℃反应12小时。反应完成后，反应液加入到饱和的碳酸氢钠水溶液(300mL)，然后用乙酸乙酯(50.0mL*2)萃取，合并有机层相，用饱和食盐水(30.0mL*2)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝200:1至15:1)，得到黄色固体化合物2-(2-氟-3-甲氧苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(4.10g，产率53.2％)。At room temperature, 2-(2-fluoro-3-methoxyphenyl)acetonitrile (4.10 g, 24.8 mmol), 2-bromo-4-(trifluoromethyl)pyridine (5.61 g, 24.8 mmol) and hydrogen Potassium oxide (2.79 g, 49.7 mmol) was added to N-methylpyrrolidone (40 mL), and the reaction was carried out at 90° C. for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was added to saturated aqueous sodium bicarbonate solution (300 mL), then extracted with ethyl acetate (50.0 mL*2), the organic layers were combined, and the organic phase was washed with saturated brine (30.0 mL*2), Dry over anhydrous sodium sulfate, filter, and concentrate to obtain crude product. The residue was separated and purified with a silica gel column (petroleum ether:ethyl acetate (V/V)=200:1 to 15:1) to obtain a yellow solid compound 2-(2-fluoro-3-methoxyphenyl)-2- (4-(Trifluoromethyl)pyridin-2-yl)acetonitrile (4.10 g, 53.2% yield).
LC-MS,M/Z(ESI):311.1[M+H] + LC-MS, M/Z(ESI): 311.1[M+H] +
第三步：2-(2-氟-3-甲氧苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The third step: synthesis of 2-(2-fluoro-3-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
在室温下，将2-(2-氟-3-甲氧苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(2.00g,6.45mmol)加入到浓硫酸(20.0mL)中，氮气保护下在25℃反应3小时。反应完成后，反应液0～10℃下加入到饱和的碳酸氢钠水溶液(300mL)中，然后用二氯甲烷(100mL*2)萃取，合并有机相，用饱和食盐水(30.0mL*2)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品2-(2-氟-3-甲氧苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(1.10g，粗品)。2-(2-Fluoro-3-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (2.00 g, 6.45 mmol) was added to concentrated sulfuric acid ( 20.0 mL), reacted at 25°C for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was added to saturated aqueous sodium bicarbonate solution (300 mL) at 0-10 °C, then extracted with dichloromethane (100 mL*2), the organic phases were combined, and saturated brine (30.0 mL*2) was used for extraction. The organic phase was washed, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 2-(2-fluoro-3-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide ( 1.10 g, crude).
LC-MS,M/Z(ESI):329.1[M+H] + LC-MS, M/Z(ESI): 329.1[M+H] +
第四步：N-(乙基氨基甲硫基)-2-(2-氟-3-甲氧基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The fourth step: N-(ethylaminomethylthio)-2-(2-fluoro-3-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide Synthesis
在室温下，将2-(2-氟-3-甲氧苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(1.10g,3.35mmol)，乙基异硫氰酸酯(350mg,4.02mmol)和碳酸铯(2.18g,6.70mmol)加入到N，N-二甲基甲酰胺(10mL)中，氮气保护下在25℃反应12小时。反应完成后，反应液25℃下加入水(100mL)中，然后用乙酸乙酯(40mL*3)萃取，合并有机层相，用饱和食盐水(20mL*2)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到黄色固体化合物N-(乙基氨基甲硫基)-2-(2-氟-3-甲氧基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(1.30g，粗品)。2-(2-Fluoro-3-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (1.10 g, 3.35 mmol), ethyliso Thiocyanate (350 mg, 4.02 mmol) and cesium carbonate (2.18 g, 6.70 mmol) were added to N,N-dimethylformamide (10 mL) and reacted at 25° C. for 12 hours under nitrogen protection. After the completion of the reaction, the reaction solution was added to water (100 mL) at 25°C, then extracted with ethyl acetate (40 mL*3), the organic layers were combined, the organic phase was washed with saturated brine (20 mL*2), and anhydrous sodium sulfate Dry, filter and concentrate to give a yellow solid compound N-(ethylaminomethylthio)-2-(2-fluoro-3-methoxyphenyl)-2-(4-(trifluoromethyl)pyridine-2 -yl)acetamide (1.30 g, crude).
LC-MS,M/Z(ESI):416.2[M+H] + LC-MS, M/Z(ESI): 416.2[M+H] +
第五步：1-(乙胺基)-4-(2-氟-3-甲氧苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-82)的合成Step 5: 1-(Ethylamino)-4-(2-fluoro-3-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 -Synthesis of ketone (I-82)
Figure PCTCN2022087589-appb-000379
Figure PCTCN2022087589-appb-000379
在氮气保护下，将N-(乙基氨基甲硫基)-2-(2-氟-3-甲氧基苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(5)(100mg,241μmol)，碘单质(183mg,722μmol)和碳酸铯(298mg,963μmol)加入到四氢呋喃(2.00mL)中，氮气保护下25℃下反应4小时。反应完成后，反应液过滤，浓缩得到粗品，残留物用高效液相色谱仪分离纯化，分离方法为(柱子：Phenomenex Synergi C18  150*50mm*10um；溶剂：A＝水+0.1体积％碳酸氢氨(99％)，B＝乙腈；梯度：23％-53％，10分钟)，得到目标化合物1-(乙胺基)-4-(2-氟-3-甲氧苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-82)(19.9mg，产率21.4％)。Under nitrogen protection, N-(ethylaminomethylthio)-2-(2-fluoro-3-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl) Acetamide (5) (100 mg, 241 μmol), iodine element (183 mg, 722 μmol) and cesium carbonate (298 mg, 963 μmol) were added to tetrahydrofuran (2.00 mL) and reacted at 25° C. for 4 hours under nitrogen protection. After the reaction is completed, the reaction solution is filtered, concentrated to obtain the crude product, and the residue is separated and purified by high performance liquid chromatography, and the separation method is (column: Phenomenex Synergi C18 150*50mm*10um; Solvent: A=water+0.1 volume % ammonium bicarbonate (99%), B=acetonitrile; gradient: 23%-53%, 10 min) to give the title compound 1-(ethylamino)-4-(2-fluoro-3-methoxyphenyl)-6-( Trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-82) (19.9 mg, 21.4% yield).
1H NMR(400MHz,CD 3OD)δ8.10(d,1H),7.18-7.22(m,2H),7.01(s,1H),6.85-6.86(m,1H),6.69-6.72(m,1H),3.92(s,3H),3.61(q,2H),1.32(t,3H). 1 H NMR (400MHz, CD 3 OD) δ 8.10 (d, 1H), 7.18-7.22 (m, 2H), 7.01 (s, 1H), 6.85-6.86 (m, 1H), 6.69-6.72 (m, 1H), 3.92(s, 3H), 3.61(q, 2H), 1.32(t, 3H).
LC-MS,M/Z(ESI):382.2[M+H] + LC-MS, M/Z(ESI): 382.2[M+H] +
实施例83：化合物I-83的制备Example 83: Preparation of Compound 1-83
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000380
Figure PCTCN2022087589-appb-000380
第一步：N-(环丙基氨基硫代甲酰)-2-(4-(二氟甲基)吡啶-2-基)-2-(2-氟苯基)乙酰胺的合成The first step: the synthesis of N-(cyclopropylaminothio)-2-(4-(difluoromethyl)pyridin-2-yl)-2-(2-fluorophenyl)acetamide
氮气保护下，在-20℃下，向异硫氰基环丙烷(531mg,5.35mmol)的N,N-二甲基甲酰胺(10.0mL)溶液中加入2-(4-(二氟甲基)吡啶-2-基)-2-(2-氟苯基)乙酰胺(300mg,1.07mmol)和碳酸铯(523mg,1.61mmol)，反应在25℃搅拌12小时。反应完成后，将反应混合物用乙酸乙酯(50.0mL)稀释，然后饱和食盐水(50.0mL*3)洗涤，干燥，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至5:1)，得到黄色油状化合物N-(环丙基氨基硫代甲酰)-2-(4-(二氟甲基)吡啶-2-基)-2-(2-氟苯基)乙酰胺(400mg,1.05mmol,98.5％收率)。Under nitrogen protection, to a solution of isothiocyanocyclopropane (531 mg, 5.35 mmol) in N,N-dimethylformamide (10.0 mL) was added 2-(4-(difluoromethyl) at -20 °C )pyridin-2-yl)-2-(2-fluorophenyl)acetamide (300 mg, 1.07 mmol) and cesium carbonate (523 mg, 1.61 mmol) and the reaction was stirred at 25°C for 12 hours. After the completion of the reaction, the reaction mixture was diluted with ethyl acetate (50.0 mL), then washed with saturated brine (50.0 mL*3), dried, and the residue was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) =50:1 to 5:1) to give a yellow oily compound N-(cyclopropylaminothiocarbonyl)-2-(4-(difluoromethyl)pyridin-2-yl)-2-(2- Fluorophenyl)acetamide (400 mg, 1.05 mmol, 98.5% yield).
LC-MS,M/Z(ESI):380.1[M+H] + LC-MS, M/Z(ESI): 380.1[M+H] +
第二步：1-(环丙基氨基)-6-(二氟甲基)-4-(2-氟苯基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-83)的合成The second step: 1-(cyclopropylamino)-6-(difluoromethyl)-4-(2-fluorophenyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I -83) synthesis
Figure PCTCN2022087589-appb-000381
Figure PCTCN2022087589-appb-000381
氮气保护下，在0℃下，向N-(环丙基氨基硫代甲酰)-2-(4-(二氟甲基)吡啶-2-基)-2-(2-氟苯基)乙酰胺(300mg,791μmol)的四氢呋喃(3.00mL)溶液中加入吡啶(188mg,2.37mmol)和碘单质(602mg,2.37mmol)，反应在20℃搅拌10小时。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(10.0mL)稀释，然后用乙酸乙酯(10.0mL*3)萃取，合并有机层，用饱和亚硫酸钠水溶液(10.0mL*3)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用高效液相色谱仪分离纯化，分离方法为(柱子：Phenomenex luna C18 150*25mm*10um；溶剂：A＝水+0.225体积％甲酸(99.0％)，B＝乙腈；梯度：20％-50％，10分钟)，得到黄色固体化合物1-(环丙基氨基)-6-(二氟甲基)-4-(2-氟苯基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-83)(95.2mg,271μmol,34.3％收率)。Under nitrogen protection, at 0 °C, to N-(cyclopropylaminothiocarbonyl)-2-(4-(difluoromethyl)pyridin-2-yl)-2-(2-fluorophenyl) Pyridine (188 mg, 2.37 mmol) and iodine (602 mg, 2.37 mmol) were added to a solution of acetamide (300 mg, 791 μmol) in tetrahydrofuran (3.00 mL), and the reaction was stirred at 20° C. for 10 hours. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium sulfite solution (10.0 mL), then extracted with ethyl acetate (10.0 mL*3), the organic layers were combined, washed with saturated aqueous sodium sulfite solution (10.0 mL*3), and anhydrous sodium sulfate Dry, filter, concentrate, and the residue is separated and purified by high performance liquid chromatography. The separation method is (column: Phenomenex luna C18 150*25mm*10um; solvent: A=water+0.225 vol% formic acid (99.0%), B=acetonitrile ; Gradient: 20%-50%, 10 min) to give yellow solid compound 1-(cyclopropylamino)-6-(difluoromethyl)-4-(2-fluorophenyl)-3H-pyrido[ 1,2-c]pyrimidin-3-one (I-83) (95.2 mg, 271 μmol, 34.3% yield).
1H NMR(400MHz,DMSO_d 6)δ7.90-8.10(m,1H),7.39-7.50(m,1H),7.21-7.37(m,3H),6.37-7.07(m,3H),2.85(s,1H),0.49-0.77(m,4H). 1 H NMR(400MHz, DMSO_d 6 )δ7.90-8.10(m,1H),7.39-7.50(m,1H),7.21-7.37(m,3H),6.37-7.07(m,3H),2.85(s ,1H),0.49-0.77(m,4H).
LC-MS,M/Z(ESI):346.2[M+H] + LC-MS, M/Z(ESI): 346.2[M+H] +
实施例84：化合物I-84制备Example 84: Preparation of Compound 1-84
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000382
Figure PCTCN2022087589-appb-000382
第一步：(2-甲基吡啶-4-基)甲醇的合成The first step: the synthesis of (2-methylpyridin-4-yl) methanol
氮气保护下，在0～10℃向2-甲基吡啶-4-甲醛(3.00g,24.8mmol)的乙醇(30.0mL)溶液中加入硼氢化钠(1.95g,51.5mmol)，反应在25℃搅拌1小时。反应完成后，在氮气保护下，将反应液于0～5℃用稀盐酸(1.00M,40.0mL)淬灭，然后用氢氧化钠将pH调至大于9，然后用二氯甲烷(40.0mL*3)萃取，合并有机层，用盐水(20.0mL*2)洗涤，无水硫酸钠干燥，过滤，浓缩得到白色固体(2-甲基吡啶-4-基)甲醇(2.00g)。直接用于下一步。Under nitrogen protection, sodium borohydride (1.95 g, 51.5 mmol) was added to a solution of 2-methylpyridine-4-carbaldehyde (3.00 g, 24.8 mmol) in ethanol (30.0 mL) at 0 to 10 °C, and the reaction was carried out at 25 °C. Stir for 1 hour. After the completion of the reaction, under nitrogen protection, the reaction solution was quenched with dilute hydrochloric acid (1.00M, 40.0mL) at 0~5°C, then the pH was adjusted to greater than 9 with sodium hydroxide, and then dichloromethane (40.0mL) was used. *3) Extraction, the organic layers were combined, washed with brine (20.0 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to give (2-methylpyridin-4-yl)methanol (2.00 g) as a white solid. used directly in the next step.
LC-MS,M/Z(ESI):124.3[M+H] + LC-MS, M/Z(ESI): 124.3[M+H] +
第二步：4-(氯甲基)-2-甲基吡啶的合成The second step: the synthesis of 4-(chloromethyl)-2-methylpyridine
向(2-甲基吡啶-4-基)甲醇(2.00g,16.2mmol)的二氯甲烷(45.0mL)溶液中加入二氯亚砜(24.6g,207mmol)，反应在25℃搅拌12小时。反应完成后，将反应混合物旋干，然后加入二氯甲烷(100mL)，用饱和碳酸氢钠水溶液(50.0mL*2)洗涤，无水硫酸钠干燥，过滤，得到黄色油状物4-(氯甲基)-2-甲基吡啶(2.20g,15.5mmol,95.7％收率)。直接用于下一步。To a solution of (2-methylpyridin-4-yl)methanol (2.00 g, 16.2 mmol) in dichloromethane (45.0 mL) was added thionyl chloride (24.6 g, 207 mmol) and the reaction was stirred at 25°C for 12 hours. After the reaction was completed, the reaction mixture was spin-dried, then dichloromethane (100 mL) was added, washed with saturated aqueous sodium bicarbonate solution (50.0 mL*2), dried over anhydrous sodium sulfate, and filtered to obtain 4-(chloromethane) as a yellow oil. yl)-2-methylpyridine (2.20 g, 15.5 mmol, 95.7% yield). used directly in the next step.
第三步：2-(2-甲基吡啶-4-基)乙腈的合成The third step: the synthesis of 2-(2-methylpyridin-4-yl)acetonitrile
在0℃下，向氰化钠(1.52g,31.0mmol)的二甲基亚砜(20.0mL)溶液中，加入4-(氯甲基)-2-甲基吡啶(2.20g,15.5mmol)的二甲基亚砜(15.0mL)溶液中，反应在25℃搅拌3小时。反应完成后，将反应混合物用饱和碳酸氢钠水溶液(50.0mL)稀释，然后用乙酸乙酯(30.0mL*2)萃取，合并有机层，用盐水(50.0mL*3)洗涤，无水硫酸钠干燥，过滤，得到黄色油状物2-(2-甲基吡啶-4-基)乙腈(1.50g,9.81mmol,63.1％收率)。直接用于下一步。To a solution of sodium cyanide (1.52 g, 31.0 mmol) in dimethyl sulfoxide (20.0 mL) at 0 °C was added 4-(chloromethyl)-2-methylpyridine (2.20 g, 15.5 mmol) in dimethyl sulfoxide (15.0 mL), the reaction was stirred at 25 °C for 3 h. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (50.0 mL), then extracted with ethyl acetate (30.0 mL*2), the organic layers were combined, washed with brine (50.0 mL*3), and anhydrous sodium sulfate Drying and filtering gave 2-(2-methylpyridin-4-yl)acetonitrile (1.50 g, 9.81 mmol, 63.1% yield) as a yellow oil. used directly in the next step.
LC-MS,M/Z(ESI):133.1[M+H] + LC-MS, M/Z(ESI): 133.1[M+H] +
第四步：2-(2-甲基吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈的合成The fourth step: the synthesis of 2-(2-methylpyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile
向2-(2-甲基吡啶-4-基)乙腈(1.50g,9.81mmol)和2-溴-4-(三氟甲基)吡啶(2.66g,11.8mmol) 的二甲基亚砜(10.0mL)溶液中加入氢氧化钾(1.65g,29.4mmol)，反应在氮气保护下于90℃搅拌12小时。反应完成后，将反应混合物用水(100mL)稀释，然后用乙酸乙酯(80.0mL*2)萃取，合并有机层，用水(100mL*3)洗涤，无水硫酸钠干燥，过滤，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1至0:1)，得到黄色固体化合物2-(2-甲基吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(1.90g,5.79mmol,收率59.1％)。To 2-(2-methylpyridin-4-yl)acetonitrile (1.50 g, 9.81 mmol) and 2-bromo-4-(trifluoromethyl)pyridine (2.66 g, 11.8 mmol) in dimethylsulfoxide ( 10.0 mL) solution was added potassium hydroxide (1.65 g, 29.4 mmol), and the reaction was stirred at 90° C. for 12 hours under nitrogen protection. After the reaction was completed, the reaction mixture was diluted with water (100 mL), then extracted with ethyl acetate (80.0 mL*2), the organic layers were combined, washed with water (100 mL*3), dried over anhydrous sodium sulfate, filtered, and the residue was washed with silica gel Column separation and purification (petroleum ether:ethyl acetate (V/V)=10:1 to 0:1) to obtain a yellow solid compound 2-(2-methylpyridin-4-yl)-2-(4-(tris) Fluoromethyl)pyridin-2-yl)acetonitrile (1.90 g, 5.79 mmol, 59.1% yield).
LC-MS,M/Z(ESI):278.1[M+H] + LC-MS, M/Z(ESI): 278.1[M+H] +
第五步：2-(2-甲基吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The fifth step: the synthesis of 2-(2-methylpyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
向硫酸(3.00mL)中加入2-(2-甲基吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(900mg,2.74mmol)，反应在25℃搅拌12小时。反应完成后，将反应液倒入冰水(50.0mL)，然后用饱和碳酸氢钠水溶液调至pH＝9，然后用乙酸乙酯(50.0mL*2)萃取，合并有机层，用盐水(100mL)洗涤，无水硫酸钠干燥，过滤，得到棕色油状物2-(2-甲基吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(800mg,2.49mmol,90.8％收率)。直接用于下一步。To sulfuric acid (3.00 mL) was added 2-(2-methylpyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (900 mg, 2.74 mmol), and the reaction was carried out at 25 °C was stirred for 12 hours. After the reaction was completed, the reaction solution was poured into ice water (50.0 mL), and then adjusted to pH=9 with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (50.0 mL*2), the organic layers were combined, and brine (100 mL) ), dried over anhydrous sodium sulfate, and filtered to give 2-(2-methylpyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (800 mg) as a brown oil. , 2.49 mmol, 90.8% yield). used directly in the next step.
LC-MS,M/Z(ESI):296.0[M+H] + LC-MS, M/Z(ESI): 296.0[M+H] +
第六步：N-(环丙基氨基硫代甲酰)-2-(2-甲基吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The sixth step: N-(cyclopropylaminothiocarbonyl)-2-(2-methylpyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide Synthesis
氮气保护下，在-20℃下，向2-(2-甲基吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(300mg,833μmol)的N,N-二甲基甲酰胺(10.0mL)溶液中加入碳酸铯(814mg,2.50mmol)和环丙基异硫氰酸酯(124mg,1.25mmol)，反应在25℃搅拌12小时。反应完成后，将反应混合物用乙酸乙酯(50.0mL)稀释，然后用盐水(50.0mL*3)洗涤，无水硫酸钠干燥，过滤，得到红色油状化合物N-(环丙基氨基硫代甲酰)-2-(2-甲基吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(400mg)。直接用于下一步。Under nitrogen protection, at -20 °C, a solution of 2-(2-methylpyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (300 mg, 833 μmol) was added. Cesium carbonate (814 mg, 2.50 mmol) and cyclopropyl isothiocyanate (124 mg, 1.25 mmol) were added to the N,N-dimethylformamide (10.0 mL) solution, and the reaction was stirred at 25° C. for 12 hours. After the completion of the reaction, the reaction mixture was diluted with ethyl acetate (50.0 mL), then washed with brine (50.0 mL*3), dried over anhydrous sodium sulfate, and filtered to obtain a red oily compound N-(cyclopropylaminothiomethane) Acyl)-2-(2-methylpyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (400 mg). used directly in the next step.
LC-MS,M/Z(ESI):395.1[M+H] + LC-MS, M/Z(ESI): 395.1[M+H] +
第七步：1-(环丙基氨基)-4-(2-甲基吡啶-4-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-84)的合成Step 7: 1-(Cyclopropylamino)-4-(2-methylpyridin-4-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 -Synthesis of ketone (I-84)
Figure PCTCN2022087589-appb-000383
Figure PCTCN2022087589-appb-000383
在0℃下，向N-(环丙基氨基硫代甲酰)-2-(2-甲基吡啶-4-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(100mg,253.54μmol)的四氢呋喃(3.00mL)溶液中加入吡啶(60.2mg,761μmol)和碘单质(193mg,761μmol)，反应在25℃搅拌12小时。反应完成后，将反应混合物用饱和亚硫酸钠水溶液(20.0mL)稀释，然后用乙酸乙酯(20.0mL*2)萃取，合并有机层，无水硫酸钠干燥，过滤，残留物用高效液相色谱仪分离纯化，分离方法为(柱子：YMC Triart C18 150*25mm*5um；溶剂：A＝水+0.225体积％甲酸(99.0％)，B＝乙腈；梯度：3％-33％，10分钟)，得到黄色固体化合物1-(环丙基氨基)-4-(2-甲基吡啶-4-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-84)(8.46mg,23.5μmol,9.26％收率)。To N-(cyclopropylaminothiocarbonyl)-2-(2-methylpyridin-4-yl)-2-(4-(trifluoromethyl)pyridin-2-yl) at 0 °C Pyridine (60.2 mg, 761 μmol) and iodine (193 mg, 761 μmol) were added to a solution of acetamide (100 mg, 253.54 μmol) in tetrahydrofuran (3.00 mL), and the reaction was stirred at 25° C. for 12 hours. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium sulfite solution (20.0 mL), then extracted with ethyl acetate (20.0 mL*2), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the residue was subjected to high performance liquid chromatography. Separation and purification, the separation method is (column: YMC Triart C18 150*25mm*5um; solvent: A=water+0.225 vol% formic acid (99.0%), B=acetonitrile; gradient: 3%-33%, 10 minutes) to obtain Yellow solid compound 1-(cyclopropylamino)-4-(2-methylpyridin-4-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3- Ketone (I-84) (8.46 mg, 23.5 μmol, 9.26% yield).
1H NMR(400MHz,CD 3OD)δ8.51(d,1H),8.06(d,1H),7.33(s,1H),7.24(d,1H),7.17(s,1H),6.72(dd,1H),2.95-2.99(m,1H),2.60(s,3H),0.84-0.92(m,2H),0.70-0.74(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.51(d,1H), 8.06(d,1H), 7.33(s,1H), 7.24(d,1H), 7.17(s,1H), 6.72(dd ,1H),2.95-2.99(m,1H),2.60(s,3H),0.84-0.92(m,2H),0.70-0.74(m,2H).
LC-MS,M/Z(ESI):361.1(M+H) + LC-MS, M/Z (ESI): 361.1 (M+H) +
实施例85：化合物I-85的制备Example 85: Preparation of Compound 1-85
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000384
Figure PCTCN2022087589-appb-000384
第一步：叔-丁基((1R,3R)-3-异硫氰基环丁氧基)二甲基硅烷的合成The first step: Synthesis of tert-butyl((1R,3R)-3-isothiocyanocyclobutoxy)dimethylsilane
将(1R,3R)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁烷-1-胺(250mg,1.24mmol)和碳酸铯(1.21g,3.72mmol)溶解在二氯甲烷(10.0mL)中，在氮气保护下加入硫光气(285mg,2.48mmol,190μL)，25℃反应2小时。反应完成后，把反应液过滤，有机相浓缩得到黄色固体化合物叔-丁基((1R,3R)-3-异硫氰基环丁氧基)二甲基硅烷(300mg，粗产物)。直接用于下一步。(1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutan-1-amine (250 mg, 1.24 mmol) and cesium carbonate (1.21 g, 3.72 mmol) were dissolved in Thiophosgene (285 mg, 2.48 mmol, 190 μL) was added to dichloromethane (10.0 mL) under nitrogen protection, and the reaction was carried out at 25° C. for 2 hours. After the reaction was completed, the reaction solution was filtered, and the organic phase was concentrated to obtain a yellow solid compound tert-butyl((1R,3R)-3-isothiocyanocyclobutoxy)dimethylsilane (300 mg, crude product). used directly in the next step.
第二步：N-(((1R,3R)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The second step: N-(((1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(2-fluorobenzene Synthesis of yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
将2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(250mg,838μmol)和碳酸铯(819mg,2.51mmol)溶解在N,N-二甲基甲酰胺(15.0mL)中，加叔-丁基((1R,3R)-3-异硫氰基环丁氧基)二甲基硅烷(300mg,1.23mmol)，75℃反应2小时。反应完成后，把水(50.0mL)加到反应液中，然后用乙酸乙酯(120mL)萃取，用饱和食盐水(40.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0至20:1)得到棕色油状化合物N-(((1R,3R)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(300mg，产率33.0％)。2-(2-Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (250 mg, 838 μmol) and cesium carbonate (819 mg, 2.51 mmol) were dissolved in N,N- In dimethylformamide (15.0 mL), tert-butyl((1R,3R)-3-isothiocyanocyclobutoxy)dimethylsilane (300 mg, 1.23 mmol) was added, and the reaction was carried out at 75°C for 2 hours. . After the reaction was completed, water (50.0 mL) was added to the reaction solution, then extracted with ethyl acetate (120 mL), the organic phase was washed with saturated brine (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:0 to 20:1) to obtain the brown oily compound N-(((1R,3R)-3-((tert-butyl Dimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (300 mg, 33.0% yield).
LC-MS,M/Z(ESI):542.2[M+H] + LC-MS, M/Z(ESI): 542.2[M+H] +
第三步：1-(((1R,3R)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮的合成The third step: 1-(((1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)amino)-4-(2-fluorophenyl)-6 Synthesis of -(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one
将N-(((1R,3R)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(290mg,267μmol)溶解在四氢呋喃(10.0mL)中，加碘(135mg,535μmol)和碳酸铯(218mg,669μmol)，25℃反应2小时。反应完成后，向反 应液中加入饱和亚硫酸钠溶液(20.0mL)，然后用乙酸乙酯(90.0mL)萃取，用饱和食盐水(30.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到得到黄色油状化合物1-(((1R,3R)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(155mg，粗品)。直接用于下一步。N-(((1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(2-fluorophenyl)- 2-(4-(Trifluoromethyl)pyridin-2-yl)acetamide (290 mg, 267 μmol) was dissolved in tetrahydrofuran (10.0 mL), iodine (135 mg, 535 μmol) and cesium carbonate (218 mg, 669 μmol) were added, 25 °C for 2 hours. After the reaction was completed, saturated sodium sulfite solution (20.0 mL) was added to the reaction solution, then extracted with ethyl acetate (90.0 mL), the organic phase was washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain The compound 1-(((1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)amino)-4-(2-fluorophenyl)-6 was obtained as a yellow oil -(Trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (155 mg, crude). used directly in the next step.
LC-MS,M/Z(ESI):508.2[M+H] + LC-MS, M/Z(ESI): 508.2[M+H] +
第四步：4-(2-氟苯基)-1-(((1S,3R)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(化合物I-85)The fourth step: 4-(2-Fluorophenyl)-1-(((1S,3R)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[1, 2-c]pyrimidin-3-one (Compound I-85)
Figure PCTCN2022087589-appb-000385
Figure PCTCN2022087589-appb-000385
将1-(((1S,3R)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(150mg,295μmol)溶解在甲醇(10.0mL)中，加入樟脑磺酸(274mg,1.18mmol)，25℃反应0.5小时。反应完成后，在反应液中加入水(30.0mL)，然后用乙酸乙酯(90.0mL)萃取，用饱和食盐水(30.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150*25mm*5um；溶剂：A＝水+碳酸氢铵(0.05％)，B＝乙腈；梯度：25％-55％，8分钟)，得到黄色固体化合物4-(2-氟苯基)-1-(((1S,3R)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-85)(30.0mg，产率30.3％)。1-(((1S,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)amino)-4-(2-fluorophenyl)-6-(tri Fluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (150 mg, 295 μmol) was dissolved in methanol (10.0 mL), camphorsulfonic acid (274 mg, 1.18 mmol) was added, and the reaction was carried out at 25°C for 0.5 Hour. After the reaction was completed, water (30.0 mL) was added to the reaction solution, followed by extraction with ethyl acetate (90.0 mL), the organic phase was washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by reversed-phase high performance liquid chromatography, and the separation method was (column: Waters Xbridge 150*25mm*5um; solvent: A=water+ammonium bicarbonate (0.05%), B=acetonitrile; gradient: 25%-55 %, 8 minutes) to give a yellow solid compound 4-(2-fluorophenyl)-1-(((1S,3R)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H - Pyrido[1,2-c]pyrimidin-3-one (I-85) (30.0 mg, 30.3% yield).
1H NMR(400MHz,DMSO-d 6)δ8.24(br d,1H),7.97-8.07(m,1H),7.42-7.47(m,1H),7.29-7.32(m,2H),7.27(s,1H),6.78(s,1H),6.73(m,1H),5.09(d,1H),4.43(br d,1H),4.30-4.36(m,1H),2.35(br d,2H),2.23(br m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.24(br d,1H),7.97-8.07(m,1H),7.42-7.47(m,1H),7.29-7.32(m,2H),7.27( s,1H),6.78(s,1H),6.73(m,1H),5.09(d,1H),4.43(br d,1H),4.30-4.36(m,1H),2.35(br d,2H) ,2.23(br m,2H).
LC-MS,M/Z(ESI):394.1(M+H) + LC-MS, M/Z (ESI): 394.1 (M+H) +
实施例86：化合物I-86的制备Example 86: Preparation of Compound 1-86
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000386
Figure PCTCN2022087589-appb-000386
第一步：N-(((1S,3R)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The first step: N-(((1S,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(3-fluorobenzene Synthesis of yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
将2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(250mg,838μmol)和碳酸铯(819mg,2.51mmol)溶解在N,N-二甲基甲酰胺(15.0mL)中，加叔-丁基((1R,3R)-3-异硫氰基环丁氧基)二甲基硅烷(300mg,1.23mmol,)，25℃反应2小时。反应完成后，把水(50.0mL)加到反应液中，然后用乙酸乙酯(120mL)萃取，用饱和食盐水(40.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至5:1)得到棕色油状化合物N-(((1R,3R)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(105mg，产率20.1％)。2-(3-Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (250 mg, 838 μmol) and cesium carbonate (819 mg, 2.51 mmol) were dissolved in N,N- In dimethylformamide (15.0 mL), tert-butyl((1R,3R)-3-isothiocyanocyclobutoxy)dimethylsilane (300 mg, 1.23 mmol,) was added, and the reaction was carried out at 25°C for 2 Hour. After the reaction was completed, water (50.0 mL) was added to the reaction solution, then extracted with ethyl acetate (120 mL), the organic phase was washed with saturated brine (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=50:1 to 5:1) to obtain a brown oily compound N-(((1R,3R)-3-((tert-butyl Dimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (105 mg, 20.1% yield).
LC-MS,M/Z(ESI):542.2[M+H] + LC-MS, M/Z(ESI): 542.2[M+H] +
第三步：1-(((1R,3R)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(3-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮的合成The third step: 1-(((1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)amino)-4-(3-fluorophenyl)-6 Synthesis of -(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one
将N-(((1R,3R)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基硫代甲酰)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(100mg,160μmol)溶解在四氢呋喃(5.00mL)中，加碘(81.3mg,320μmol)和碳酸铯(130mg,400μmol)，25℃反应2小时。反应完成后，向反应液中加入饱和亚硫酸钠溶液(20.0mL)，然后用乙酸乙酯(90.0mL)萃取，用饱和食盐水(30.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0至1:1)，得到黄色油状化合物1-(((1R,3R)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(3-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(105mg,粗品)。N-(((1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)carbamoyl)-2-(3-fluorophenyl)- 2-(4-(Trifluoromethyl)pyridin-2-yl)acetamide (100 mg, 160 μmol) was dissolved in tetrahydrofuran (5.00 mL), iodine (81.3 mg, 320 μmol) and cesium carbonate (130 mg, 400 μmol) were added, The reaction was carried out at 25°C for 2 hours. After the reaction was completed, saturated sodium sulfite solution (20.0 mL) was added to the reaction solution, then extracted with ethyl acetate (90.0 mL), the organic phase was washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Crude. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:0 to 1:1) to obtain a yellow oily compound 1-(((1R,3R)-3-((tert-butyl (yldimethylsilyl)oxo)cyclobutyl)amino)-4-(3-fluorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine- 3-keto (105 mg, crude).
LC-MS,M/Z(ESI):508.2(M+H) + LC-MS, M/Z (ESI): 508.2 (M+H) +
第四步：4-(3-氟苯基)-1-(((1R,3R)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(化合物I-86)The fourth step: 4-(3-Fluorophenyl)-1-(((1R,3R)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[1, 2-c]pyrimidin-3-one (Compound I-86)
Figure PCTCN2022087589-appb-000387
Figure PCTCN2022087589-appb-000387
将1-(((1R,3R)-3-((叔-丁基二甲基甲硅烷基)氧代)环丁基)氨基)-4-(3-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(100mg,197μmol)溶解在甲醇(50.0mL)中，加入樟脑磺酸(183mg,788μmol)，25℃反应0.5小时。反应完成后，在反应液中加入水(30.0mL)，然后用乙酸乙酯(90.0mL)萃取，用饱和食盐水(30.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150*25mm*5um；溶剂：A＝水+碳酸氢铵(0.05％)，B＝乙腈；梯度：28％-58％，8分钟)，得到黄色固体化合物4-(3-氟苯基)-1-(((1R,3R)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-86)(60.0mg，产率75.0％)。1-(((1R,3R)-3-((tert-butyldimethylsilyl)oxo)cyclobutyl)amino)-4-(3-fluorophenyl)-6-(tri Fluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (100 mg, 197 μmol) was dissolved in methanol (50.0 mL), camphorsulfonic acid (183 mg, 788 μmol) was added, and the reaction was carried out at 25°C for 0.5 hours . After the reaction was completed, water (30.0 mL) was added to the reaction solution, followed by extraction with ethyl acetate (90.0 mL), the organic phase was washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by reversed-phase high performance liquid chromatography, and the separation method was (column: Waters Xbridge 150*25mm*5um; solvent: A=water+ammonium bicarbonate (0.05%), B=acetonitrile; gradient: 28%-58 %, 8 minutes) to give a yellow solid compound 4-(3-fluorophenyl)-1-(((1R,3R)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H - Pyrido[1,2-c]pyrimidin-3-one (I-86) (60.0 mg, 75.0% yield).
1H NMR(400MHz,DMSO-d 6)δ8.18(br d,1H),7.96(br d,1H),7.44-7.51(m,1H),7.17-7.23(m,1H),7.10-7.16(m,2H),6.98(s,1H),6.70(m,1H),5.08(d,1H),4.38-4.47(m,1H),4.29-4.37(m,1H),2.32(br d,2H),2.19-2.24(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.18(br d,1H),7.96(br d,1H),7.44-7.51(m,1H),7.17-7.23(m,1H),7.10-7.16 (m, 2H), 6.98(s, 1H), 6.70(m, 1H), 5.08(d, 1H), 4.38-4.47(m, 1H), 4.29-4.37(m, 1H), 2.32(br d, 2H), 2.19-2.24(m, 2H).
LC-MS,M/Z(ESI):394.1[M+H] + LC-MS, M/Z(ESI): 394.1[M+H] +
实施例87：化合物I-87的制备Example 87: Preparation of Compound 1-87
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000388
Figure PCTCN2022087589-appb-000388
第一步：异硫氰基环丙烷的合成The first step: the synthesis of isothiocyanocyclopropane
将环丙胺(500mg,8.76mmol,606uL)和碳酸铯(5.71g,17.5mmol)溶解在二氯甲烷(20.0mL)中，在氮气保护下加入硫光气(2.01g,17.5mmol,1.34mL)，25℃反应2小时。反应完成后，把反应液过滤，有机相浓缩得到黄色固体化合物异硫氰基环丙烷(500mg，粗产物)。直接用于下一步。Cyclopropylamine (500 mg, 8.76 mmol, 606 uL) and cesium carbonate (5.71 g, 17.5 mmol) were dissolved in dichloromethane (20.0 mL), and thiophosgene (2.01 g, 17.5 mmol, 1.34 mL) was added under nitrogen protection , 25 ℃ reaction for 2 hours. After the reaction was completed, the reaction solution was filtered, and the organic phase was concentrated to obtain a yellow solid compound isothiocyanocyclopropane (500 mg, crude product). used directly in the next step.
第二步：N-(环丙基氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The second step: the synthesis of N-(cyclopropylaminothiocarbonyl)-2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
将2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(500mg,1.68mmol)和碳酸铯(1.64g,5.03mmol)溶解在N,N-二甲基甲酰胺(20.0mL)中，加异硫氰基环丙烷(500mg,5.04mmol)，75℃反应2小时。反应完成后，把水(50.0mL)加到反应液中，然后用乙酸乙酯(120mL)萃取，用饱和食盐水(40.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至10:1)得到黄色油状化合物N-(环丙基氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(320mg，产率47.4％)。2-(2-Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (500 mg, 1.68 mmol) and cesium carbonate (1.64 g, 5.03 mmol) were dissolved in N, To N-dimethylformamide (20.0 mL), isothiocyanocyclopropane (500 mg, 5.04 mmol) was added, and the mixture was reacted at 75° C. for 2 hours. After the reaction was completed, water (50.0 mL) was added to the reaction solution, then extracted with ethyl acetate (120 mL), the organic phase was washed with saturated brine (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=50:1 to 10:1) to obtain the yellow oily compound N-(cyclopropylaminothiocarbonyl)-2-(2-fluoro) Phenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (320 mg, 47.4% yield).
LC-MS,M/Z(ESI):398.2[M+H] + LC-MS, M/Z(ESI): 398.2[M+H] +
第三步：1-(环丙基氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(化合物I-87)The third step: 1-(cyclopropylamino)-4-(2-fluorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (compound I-87)
Figure PCTCN2022087589-appb-000389
Figure PCTCN2022087589-appb-000389
将N-(环丙基氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(100mg,248μmol)溶解在四氢呋喃(10.0mL)中，加碘(189mg,745μmol,)和吡啶(58.9mg,745μmol,60.1uL)，25℃反应2小时。反应完成后，向反应液中加入饱和亚硫酸钠溶液(20.0mL)，然后用乙酸乙酯(60.0mL)萃取，用饱和食盐水(20.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用硅胶板分离纯化(二氯甲烷:甲醇(V/V)＝10:1)，得到黄色油状化合物1-(环丙基氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-87)(90.0mg，产率95.6％)。N-(Cyclopropylcarbamoyl)-2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (100 mg, 248 μmol) was dissolved in In tetrahydrofuran (10.0 mL), iodine (189 mg, 745 μmol,) and pyridine (58.9 mg, 745 μmol, 60.1 uL) were added, and the mixture was reacted at 25° C. for 2 hours. After the reaction was completed, saturated sodium sulfite solution (20.0 mL) was added to the reaction solution, then extracted with ethyl acetate (60.0 mL), the organic phase was washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain Crude. The crude product was separated and purified by silica gel plate (dichloromethane:methanol (V/V)=10:1) to obtain the yellow oily compound 1-(cyclopropylamino)-4-(2-fluorophenyl)-6-(tri Fluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-87) (90.0 mg, 95.6% yield).
1H NMR(400MHz,DMSO-d 6)δ8.27(br d,1H),7.42-7.49(m,1H),7.23-7.41(m,4H),6.79(br s,1H),6.59-6.74(m,1H),3.07-3.20(m,1H),1.23(br s,2H),0.72-0.77(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.27(br d,1H),7.42-7.49(m,1H),7.23-7.41(m,4H),6.79(br s,1H),6.59-6.74 (m,1H),3.07-3.20(m,1H),1.23(br s,2H),0.72-0.77(m,2H).
LC-MS,M/Z(ESI):364.2[M+H] + LC-MS, M/Z(ESI): 364.2[M+H] +
实施例88：化合物I-88的制备Example 88: Preparation of Compound 1-88
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000390
Figure PCTCN2022087589-appb-000390
第一步：(1S,3S)-3-((叔丁氧羰基)氨基)-1-甲基环丁基苯甲酸酯的合成The first step: Synthesis of (1S,3S)-3-((tert-butoxycarbonyl)amino)-1-methylcyclobutylbenzoate
将((1S,3S)-3-羟基-3-甲基环丁基)氨基甲酸叔丁酯(3g,15mmol)溶解在二氯甲烷(30mL)中，降温到0℃，然后在搅拌状态下加入三乙胺(7.54g,75mmol),4-二甲氨基吡啶(182mg,1.5mmol)和苯甲酰氯(5.24g,37.3mmol).恢复至室温反应过夜，直接浓缩拌样过柱(石油醚/乙酸乙酯＝10/1)得到白色固体(1S,3S)-3-((叔丁氧羰基)氨基)-1-甲基环丁基苯甲酸酯(3g，产率66％)。Dissolve tert-butyl ((1S,3S)-3-hydroxy-3-methylcyclobutyl)carbamate (3 g, 15 mmol) in dichloromethane (30 mL), cool down to 0 °C, and stir under stirring Add triethylamine (7.54g, 75mmol), 4-dimethylaminopyridine (182mg, 1.5mmol) and benzoyl chloride (5.24g, 37.3mmol). Return to room temperature and react overnight, directly concentrate the sample and pass through column (petroleum ether) /ethyl acetate=10/1) to give (1S,3S)-3-((tert-butoxycarbonyl)amino)-1-methylcyclobutylbenzoate (3 g, 66% yield) as a white solid.
第二步：(1S,3S)-3-氨基-1-甲基环丁基苯甲酸酯的合成Step 2: Synthesis of (1S,3S)-3-amino-1-methylcyclobutylbenzoate
将(1S,3S)-3-((叔丁氧羰基)氨基)-1-甲基环丁基苯甲酸酯(500mg，1.64mmol)溶解在5mL二氯甲烷中，加入三氟乙酸(161mg，1.64mmol)，室温下反应1h，直接浓缩得到粗品(1S,3S)-3-氨基-1-甲基环丁基苯甲酸酯(340mg，产率100％)，该粗品直接用于下一步反应。(1S,3S)-3-((tert-butoxycarbonyl)amino)-1-methylcyclobutylbenzoate (500 mg, 1.64 mmol) was dissolved in 5 mL of dichloromethane, trifluoroacetic acid (161 mg) was added , 1.64 mmol), reacted at room temperature for 1 h, and concentrated directly to obtain the crude product (1S,3S)-3-amino-1-methylcyclobutylbenzoate (340 mg, yield 100%), which was directly used in the next one-step reaction.
第三步：(1S,3S)-3-异硫氰酸基-1-甲基环丁基苯甲酸酯的合成The third step: the synthesis of (1S,3S)-3-isothiocyanato-1-methylcyclobutylbenzoate
将(1S,3S)-3-氨基-1-甲基环丁基苯甲酸酯(340mg，1.66mmol)溶解在10mL四氢呋喃和2.3mL三乙胺中，然后降温到0℃.置换空气后，将硫光气(476mg，4.14mmol)加入，反应液搅拌30min.直接浓缩拌样过柱(石油醚/乙酸乙酯＝50/1)得到白色固体(1S,3S)-3-异硫氰酸基-1-甲基环丁基苯甲酸酯(100mg，产率24％)。(1S,3S)-3-amino-1-methylcyclobutylbenzoate (340 mg, 1.66 mmol) was dissolved in 10 mL of tetrahydrofuran and 2.3 mL of triethylamine, and then cooled to 0 °C. After replacing the air, Thiophosgene (476 mg, 4.14 mmol) was added, and the reaction solution was stirred for 30 min. The mixture was directly concentrated and passed through a column (petroleum ether/ethyl acetate=50/1) to obtain a white solid (1S,3S)-3-isothiocyanate yl-1-methylcyclobutylbenzoate (100 mg, 24% yield).
第四步：(1S,3S)-3-(3-(2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰基)硫脲)-1-甲基环丁基苯甲酸酯的合成Fourth step: (1S,3S)-3-(3-(2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetyl)thiourea)- Synthesis of 1-Methylcyclobutylbenzoate
将(1S,3S)-3-异硫氰酸基-1-甲基环丁基苯甲酸酯(100mg，0.4mmol)溶解在四氢呋喃(1 mL)中，分批加入钠氢(20mg，0.5mmol，60％)，降温到0℃，把2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(100mg，0.34mmol)加进去，自然恢复至室温，反应0.5h。反应液用水淬灭，然后用乙酸乙酯(20mL)萃取，有机相浓缩，拌样过柱(石油醚/乙酸乙酯＝10/1)得到(1S,3S)-3-(3-(2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰基)硫脲)-1-甲基环丁基苯甲酸酯(100mg，收率70％)(1S,3S)-3-isothiocyanato-1-methylcyclobutylbenzoate (100 mg, 0.4 mmol) was dissolved in tetrahydrofuran (1 mL) and sodium hydrogen (20 mg, 0.5 mmol, 60%), cooled to 0 °C, added 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (100 mg, 0.34 mmol), It was naturally returned to room temperature and reacted for 0.5h. The reaction solution was quenched with water, then extracted with ethyl acetate (20 mL), the organic phase was concentrated, and the sample was mixed and passed through a column (petroleum ether/ethyl acetate=10/1) to obtain (1S,3S)-3-(3-(2). -(3-Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetyl)thiourea)-1-methylcyclobutylbenzoate (100 mg, yield 70 %)
LC-MS,M/Z(ESI):546.20[M+H] +。 LC-MS, M/Z (ESI): 546.20 [M+H] + .
第五步：(1S,3S)-3-((4-(3-氟苯基)-3-氧代-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-1-基)氨基)-1-甲基环丁基苯甲酸酯的合成The fifth step: (1S,3S)-3-((4-(3-fluorophenyl)-3-oxo-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine Synthesis of -1-yl)amino)-1-methylcyclobutylbenzoate
将(1S,3S)-3-(3-(2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰基)硫脲)-1-甲基环丁基苯甲酸酯(100mg，0.18mmol)溶到10mL四氢呋喃中，氮气保护下，加入吡啶(0.05mL，0.55mmol)，然后降温到0℃，加入碘单质(140mg，0.55mmol)，然后恢复室温搅拌2h。用饱和的硫代硫酸钠淬灭反应，乙酸乙酯(20mL)萃取，有机相浓缩，拌样过柱(石油醚/乙酸乙酯＝3/1)得到(1S,3S)-3-((4-(3-氟苯基)-3-氧代-6-(三氟甲基)-3氢-吡啶并[1,2-c]嘧啶-1-基)氨基)-1-甲基环丁基苯甲酸酯(50mg，收率53％)。(1S,3S)-3-(3-(2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetyl)thiourea)-1-methyl Cyclobutylbenzoate (100 mg, 0.18 mmol) was dissolved in 10 mL of tetrahydrofuran, and under nitrogen protection, pyridine (0.05 mL, 0.55 mmol) was added, then the temperature was lowered to 0 °C, and iodine (140 mg, 0.55 mmol) was added, Then return to room temperature and stir for 2h. The reaction was quenched with saturated sodium thiosulfate, extracted with ethyl acetate (20 mL), the organic phase was concentrated, and the sample was mixed and passed through a column (petroleum ether/ethyl acetate=3/1) to obtain (1S,3S)-3-(( 4-(3-Fluorophenyl)-3-oxo-6-(trifluoromethyl)-3hydro-pyrido[1,2-c]pyrimidin-1-yl)amino)-1-methyl ring Butyl benzoate (50 mg, 53% yield).
LC-MS,M/Z(ESI):512.20[M+H] + LC-MS, M/Z(ESI): 512.20[M+H] +
第六步：4-(3-氟苯基)-1-(((1S,3S)-3-羟基-3-甲基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-88)的合成Step 6: 4-(3-Fluorophenyl)-1-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-6-(trifluoromethyl)-3H- Synthesis of Pyrido[1,2-c]pyrimidin-3-one (I-88)
Figure PCTCN2022087589-appb-000391
Figure PCTCN2022087589-appb-000391
室温下将原料(1S,3S)-3-((4-(3-氟苯基)-3-氧代-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-1-基)氨基)-1-甲基环丁基苯甲酸酯(50mg，0.1mmol)加入到四氢呋喃(3mL)和水(0.8mL)，甲醇(0.8mL)中，加入氢氧化锂(10mg,0.5mmol)，加热至40℃，搅拌16h。冷却至室温，将反应液浓缩，经酸性制备方法A制备得目标化合物白色固体4-(3-氟苯基)-1-(((1S,3S)-3-羟基-3-甲基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-88)(10mg,产率25％)。The starting material (1S,3S)-3-((4-(3-fluorophenyl)-3-oxo-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine was prepared at room temperature -1-yl)amino)-1-methylcyclobutylbenzoate (50 mg, 0.1 mmol) was added to tetrahydrofuran (3 mL) and water (0.8 mL), methanol (0.8 mL), and lithium hydroxide ( 10 mg, 0.5 mmol), heated to 40 °C and stirred for 16 h. Cooled to room temperature, the reaction solution was concentrated, and the target compound was prepared by the acidic preparation method A to obtain the target compound as a white solid 4-(3-fluorophenyl)-1-(((1S,3S)-3-hydroxy-3-methylcyclobutane yl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-88) (10 mg, 25% yield).
1H NMR(400MHz,DMSO-d 6)δ8.20(d,1H),8.09(s,1H),7.46(m,1H),7.18-7.11(m,3H),6.96(s,1H),6.67(d,1H)，5.05(s,1H),3.99-3.97(m,1H)，2.40-2.37(m,2H)，2.35-2.13(m,2H)，1.28-1.22(m,3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.20(d,1H), 8.09(s,1H), 7.46(m,1H), 7.18-7.11(m,3H), 6.96(s,1H), 6.67(d,1H), 5.05(s,1H), 3.99-3.97(m,1H), 2.40-2.37(m,2H), 2.35-2.13(m,2H), 1.28-1.22(m,3H).
LC-MS,M/Z(ESI):408.20[M+H] + LC-MS, M/Z(ESI): 408.20[M+H] +
实施例89：化合物I-89的制备Example 89: Preparation of Compound 1-89
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000392
Figure PCTCN2022087589-appb-000392
第一步：2-(2,3-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈的合成The first step: Synthesis of 2-(2,3-difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile
在室温下，将2-(2，3-二氟苯基)乙腈(1.626g，10.62mmol)加入到四氢呋喃(20mL)中，氮气保护下0℃加入2-溴-4-(三氟甲基)吡啶(2g，8.85mmol)和叔丁醇钾的四氢呋喃溶液(17.7mL,17.7mmol，1M)，然后25℃搅拌18h。将反应液加入到水(100mL)中淬灭，用乙酸乙酯(50mL*2)萃取，合并有机相，用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品，粗品经过柱层析分离纯化(石油醚/乙酸乙酯(V/V)＝50/1-10/1)得到黄色固体产物2-(2，3-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(2.3g，产率87％)。2-(2,3-Difluorophenyl)acetonitrile (1.626 g, 10.62 mmol) was added to tetrahydrofuran (20 mL) at room temperature, and 2-bromo-4-(trifluoromethyl) was added at 0°C under nitrogen protection ) pyridine (2 g, 8.85 mmol) and a solution of potassium tert-butoxide in tetrahydrofuran (17.7 mL, 17.7 mmol, 1 M), then stirred at 25 °C for 18 h. The reaction solution was added to water (100 mL) to quench, extracted with ethyl acetate (50 mL*2), the organic phases were combined, washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, The crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate (V/V)=50/1-10/1) to obtain a yellow solid product 2-(2,3-difluorophenyl)-2-(4- (Trifluoromethyl)pyridin-2-yl)acetonitrile (2.3 g, 87% yield).
LC-MS,M/Z(ESI):299.1[M+H] + LC-MS, M/Z(ESI): 299.1[M+H] +
第二步：2-(2,3-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The second step: Synthesis of 2-(2,3-difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
在0℃下向2-(2，3-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙腈(2.3g,7.71mmol)中缓慢加入浓硫酸(10mL)，25℃下搅拌反应18小时，将反应液缓慢加入到水(100mL)中，并用碳酸氢钠将pH调至7～8，用乙酸乙酯(50mL*3)萃取，合并有机相，用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤浓缩得到白色固体产物2-(2，3-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(2.2g,产率90％)。To 2-(2,3-difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (2.3 g, 7.71 mmol) was slowly added concentrated sulfuric acid (10 mL) at 0°C ), the reaction was stirred at 25°C for 18 hours, the reaction solution was slowly added to water (100 mL), the pH was adjusted to 7-8 with sodium bicarbonate, extracted with ethyl acetate (50 mL*3), the organic phases were combined, and the Washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a white solid product 2-(2,3-difluorophenyl)-2-(4-(trifluoromethyl)pyridine-2- yl)acetamide (2.2 g, 90% yield).
LC-MS,M/Z(ESI):317.3[M+H] + LC-MS, M/Z(ESI): 317.3[M+H] +
第三步：(1S,3S)-3-(3-(2-(2,3-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰基)硫脲基)环丁基苯甲酸酯的合成The third step: (1S,3S)-3-(3-(2-(2,3-difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetyl)thio Synthesis of Urea) Cyclobutyl Benzoate
向2-(2,3-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(500mg,1.58mmol)和(1S,3S)-3-异硫氰酸环丁基苯甲酸酯(553mg，2.37mmol)的N,N-二甲基乙酰胺(5mL)溶液中缓慢加入氢化钠(158mg，3.95mmol)，并在25℃搅拌18h。将反应液缓慢加入水(100mL)中，并用乙酸乙酯(30mL*3)萃取。有机层用饱和食盐水(20mL*2)洗涤，用无水硫酸钠干燥，过滤并浓缩得到粗产物。粗产物经柱层析纯化(石油醚/乙酸乙酯(V/V)＝1/0-1/3)得到黄色固体产物(1S,3S)-3-(3-(2-(2,3-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰基)硫脲基)环丁基苯甲酸酯(280mg，产率32.2％)。To 2-(2,3-difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (500 mg, 1.58 mmol) and (1S,3S)-3-isothio Sodium hydride (158 mg, 3.95 mmol) was slowly added to a solution of cyclobutyl cyanate (553 mg, 2.37 mmol) in N,N-dimethylacetamide (5 mL) and stirred at 25° C. for 18 h. The reaction solution was slowly added to water (100 mL), and extracted with ethyl acetate (30 mL*3). The organic layer was washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V)=1/0-1/3) to obtain the yellow solid product (1S,3S)-3-(3-(2-(2,3) -Difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetyl)thioureido)cyclobutylbenzoate (280 mg, 32.2% yield).
LC-MS,M/Z(ESI):550.1[M+H] + LC-MS, M/Z(ESI): 550.1[M+H] +
第四步：(1S,3S)-3-((4-(2,3-二氟苯基)-3-氧代-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-1-基)氨基)苯甲酸环丁酯的合成The fourth step: (1S,3S)-3-((4-(2,3-difluorophenyl)-3-oxo-6-(trifluoromethyl)-3H-pyrido[1,2- Synthesis of c]pyrimidin-1-yl)amino)cyclobutyl benzoate
向(1S,3S)-3-(3-(2-(2,3-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰基)硫脲基)环丁基苯甲酸酯(280mg,0.51mmol)的四氢呋喃(5mL)溶液中加入碘(388mg，1.53mmol)和吡啶(121mg，1.53 mmol)，然后在25℃搅拌5小时。将反应液加入饱和硫代硫酸钠溶液(20mL)中并用乙酸乙酯(10mL*3)萃取。有机层用饱和食盐水(5mL*2)洗涤，用无水硫酸钠干燥，过滤并浓缩得到粗产物。粗产物经柱层析纯化(二氯甲烷/甲醇(V/V)＝1/0-10/1)得到黄色固体产物(1S,3S)-3-((4-(2,3-二氟苯基)-3-氧代-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-1-基)氨基)苯甲酸环丁酯(90mg，产率34.3％)。To (1S,3S)-3-(3-(2-(2,3-difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetyl)thioureido) To a solution of cyclobutylbenzoate (280 mg, 0.51 mmol) in tetrahydrofuran (5 mL) was added iodine (388 mg, 1.53 mmol) and pyridine (121 mg, 1.53 mmol), followed by stirring at 25°C for 5 hours. The reaction solution was added to saturated sodium thiosulfate solution (20 mL) and extracted with ethyl acetate (10 mL*3). The organic layer was washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (dichloromethane/methanol (V/V)=1/0-10/1) to obtain (1S,3S)-3-((4-(2,3-difluoro) as a yellow solid product Phenyl)-3-oxo-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-1-yl)amino)benzoic acid cyclobutyl ester (90 mg, 34.3% yield) .
LC-MS,M/Z(ESI):516.3[M+H] + LC-MS, M/Z(ESI): 516.3[M+H] +
第五步：4-(2,3-二氟苯基)-1-(((1S,3S)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-89)的合成The fifth step: 4-(2,3-difluorophenyl)-1-(((1S,3S)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido Synthesis of [1,2-c]pyrimidin-3-one (I-89)
Figure PCTCN2022087589-appb-000393
Figure PCTCN2022087589-appb-000393
向(1S,3S)-3-((4-(2,3-二氟苯基)-3-氧代-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-1-基)氨基)苯甲酸环丁酯(90mg，0.175mmol)的四氢呋喃(3mL)、甲醇(1mL)和水(1mL)溶液中加入氢氧化锂(20.9mg，0.873mmol)，然后在50℃搅拌18小时。向反应液中加入水(100mL)，并用1N的盐酸水溶液调节pH＝6～7。用乙酸乙酯(20mL*3)萃取，有机层用饱和食盐水(20mL*2)洗涤，用无水硫酸钠干燥，过滤并浓缩得到粗产物。粗产物经反相制备纯化(柱子:Phenomenex Synergi C18 100*25mm*4um；溶剂：A＝水+0.1体积％甲酸(99％)，B＝乙腈；梯度：5％-95％，7分钟)得到黄色固体产物4-(2,3-二氟苯基)-1-(((1S,3S)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-89)(17.7mg,产率24.64％)。To (1S,3S)-3-((4-(2,3-difluorophenyl)-3-oxo-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine To a solution of cyclobutyl-1-yl)amino)benzoate (90 mg, 0.175 mmol) in tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide (20.9 mg, 0.873 mmol), followed by addition of lithium hydroxide (20.9 mg, 0.873 mmol) at 50 °C was stirred for 18 hours. Water (100 mL) was added to the reaction solution, and pH=6-7 was adjusted with 1N aqueous hydrochloric acid. Extracted with ethyl acetate (20 mL*3), the organic layer was washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by reverse phase preparation (column: Phenomenex Synergi C18 100*25mm*4um; solvent: A=water+0.1 vol% formic acid (99%), B=acetonitrile; gradient: 5%-95%, 7 min) to give Yellow solid product 4-(2,3-difluorophenyl)-1-(((1S,3S)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[ 1,2-c]pyrimidin-3-one (I-89) (17.7 mg, 24.64% yield).
1H NMR(400MHz,dmso)δ8.23(d,J＝7.8Hz,1H),8.07(d,J＝5.9Hz,1H),7.54-7.36(m,1H),7.27(dd,J＝12.7,7.6Hz,1H),7.11(t,J＝6.9Hz,1H),6.87(s,1H),6.74(dd,J＝7.8,1.9Hz,1H),5.17(d,J＝5.5Hz,1H),3.99-3.81(m,2H),2.64(dt,J＝10.8,6.7Hz,2H),1.94(dd,J＝19.3,9.1Hz,2H)。1H NMR(400MHz,dmso)δ8.23(d,J=7.8Hz,1H),8.07(d,J=5.9Hz,1H),7.54-7.36(m,1H),7.27(dd,J=12.7, 7.6Hz, 1H), 7.11 (t, J=6.9Hz, 1H), 6.87 (s, 1H), 6.74 (dd, J=7.8, 1.9Hz, 1H), 5.17 (d, J=5.5Hz, 1H) , 3.99-3.81 (m, 2H), 2.64 (dt, J=10.8, 6.7Hz, 2H), 1.94 (dd, J=19.3, 9.1Hz, 2H).
LC-MS,M/Z(ESI):412.0[M+H] + LC-MS, M/Z(ESI): 412.0[M+H] +
实施例90：化合物I-90的制备Example 90: Preparation of Compound 1-90
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000394
Figure PCTCN2022087589-appb-000394
第一步：4-(3-氟苯基)-1-硫代-6-(三氟甲基)-1H-吡啶并[1,2-c]嘧啶-3(2H)-酮的合成The first step: Synthesis of 4-(3-fluorophenyl)-1-thio-6-(trifluoromethyl)-1H-pyrido[1,2-c]pyrimidin-3(2H)-one
在0℃向2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(5g,16.77mmol)的乙醇(100mL)溶液中加入乙醇钠(11.41g,168mmol)和硫光气(3.86g,33.5mmol)，然后在80℃搅拌18小时。向反应液中加入水(500mL)并通过乙酸乙酯(200mL*3)萃取。有机层用饱和食盐水 (200mL*2)洗涤，用无水硫酸钠干燥，过滤并浓缩得到粗产物。粗产物经柱层析纯化(石油醚/乙酸乙酯(V/V)＝1/0-1/1)得到黄色固体产物4-(3-氟苯基)-1-硫代-6-(三氟甲基)-1H-吡啶并[1,2-c]嘧啶-3(2H)-酮(500mg,8.76％产率)。To a solution of 2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (5 g, 16.77 mmol) in ethanol (100 mL) at 0°C was added sodium ethoxide ( 11.41 g, 168 mmol) and thiophosgene (3.86 g, 33.5 mmol), then stirred at 80°C for 18 hours. Water (500 mL) was added to the reaction solution and extracted with ethyl acetate (200 mL*3). The organic layer was washed with saturated brine (200 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) = 1/0-1/1) to obtain a yellow solid product 4-(3-fluorophenyl)-1-thio-6-( Trifluoromethyl)-1H-pyrido[1,2-c]pyrimidin-3(2H)-one (500 mg, 8.76% yield).
LC-MS,M/Z(ESI):341.2[M+H]+LC-MS, M/Z(ESI): 341.2[M+H]+
第二步：4-(3-氟苯基)-1-(吡咯烷-1-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-90)的合成Step 2: 4-(3-Fluorophenyl)-1-(pyrrolidin-1-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one Synthesis of (I-90)
Figure PCTCN2022087589-appb-000395
Figure PCTCN2022087589-appb-000395
向4-(3-氟苯基)-1-硫代-6-(三氟甲基)-1H-吡啶并[1,2-c]嘧啶-3(2H)-酮(200mg，0.588mmol)的四氢呋喃(2mL)溶液中加入四氢吡咯(209mg，2.94mmol)和吡啶(232mg，2.94mmol)，然后向反应液中缓慢加入碘(448mg，1.763mmol)，反应液在25℃下反应18h。将反应液倒入水(10mL)中，用乙酸乙酯(5mL*3)萃取。有机相用饱和食盐水(5mL*2)洗涤，用无水硫酸钠干燥，过滤，旋干得到粗品。粗品经过反相制备(柱子:Phenomenex Synergi C18 100*25mm*4um；溶剂：A＝水+0.1体积％甲酸(99％)，B＝乙腈；梯度：5％-95％，7分钟)得到黄色固体产物4-(3-氟苯基)-1-(吡咯烷-1-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-90)(19.3mg，产率8.7％)。To 4-(3-fluorophenyl)-1-thio-6-(trifluoromethyl)-1H-pyrido[1,2-c]pyrimidin-3(2H)-one (200 mg, 0.588 mmol) To the solution of tetrahydrofuran (2 mL) was added tetrahydropyrrole (209 mg, 2.94 mmol) and pyridine (232 mg, 2.94 mmol), then iodine (448 mg, 1.763 mmol) was slowly added to the reaction solution, and the reaction solution was reacted at 25 °C for 18 h. The reaction solution was poured into water (10 mL), and extracted with ethyl acetate (5 mL*3). The organic phase was washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was prepared by reverse phase (column: Phenomenex Synergi C18 100*25mm*4um; solvent: A=water+0.1 vol% formic acid (99%), B=acetonitrile; gradient: 5%-95%, 7 minutes) to give a yellow solid Product 4-(3-Fluorophenyl)-1-(pyrrolidin-1-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I- 90) (19.3 mg, 8.7% yield).
1H NMR(400MHz,cdcl3)δ7.95(d,J＝7.7Hz,1H),7.55-7.40(m,1H),7.26-7.10(m,3H),7.02(s,1H),6.51(dd,J＝7.8,2.0Hz,1H),3.53(t,J＝6.5Hz,4H),1.89(t,J＝6.4Hz,4H). 1 H NMR(400MHz,cdcl3)δ7.95(d,J=7.7Hz,1H),7.55-7.40(m,1H),7.26-7.10(m,3H),7.02(s,1H),6.51(dd , J=7.8, 2.0Hz, 1H), 3.53 (t, J=6.5Hz, 4H), 1.89 (t, J=6.4Hz, 4H).
实施例91：化合物I-91的制备Example 91: Preparation of Compound 1-91
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000396
Figure PCTCN2022087589-appb-000396
第一步：4-(2-氟苯基)-1-硫代-6-(三氟甲基)-1H-吡啶并[1,2-c]嘧啶-3(2H)-酮的合成The first step: Synthesis of 4-(2-fluorophenyl)-1-thio-6-(trifluoromethyl)-1H-pyrido[1,2-c]pyrimidin-3(2H)-one
在0℃向2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(5g,16.77mmol)的乙醇(100mL)溶液中加入乙醇钠(11.41g,168mmol)和硫光气(3.86g,33.5mmol)，然后在80℃搅拌18小时。向反应液中加入水(500mL)并通过乙酸乙酯(200mL*3)萃取。有机层用饱和食盐水(200mL*2)洗涤，用无水硫酸钠干燥，过滤并浓缩得到粗产物。粗产物经柱层析纯化(石油醚/乙酸乙酯(V/V)＝1/0-1/1)得到黄色固体产物4-(2-氟苯基)-1-硫代-6-(三氟甲基)-1H-吡啶并[1,2-c]嘧啶-3(2H)-酮(500mg,8.76％产率)。To a solution of 2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (5 g, 16.77 mmol) in ethanol (100 mL) at 0°C was added sodium ethoxide ( 11.41 g, 168 mmol) and thiophosgene (3.86 g, 33.5 mmol), then stirred at 80°C for 18 hours. Water (500 mL) was added to the reaction solution and extracted with ethyl acetate (200 mL*3). The organic layer was washed with saturated brine (200 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) = 1/0-1/1) to obtain a yellow solid product 4-(2-fluorophenyl)-1-thio-6-( Trifluoromethyl)-1H-pyrido[1,2-c]pyrimidin-3(2H)-one (500 mg, 8.76% yield).
LC-MS,M/Z(ESI):341.2[M+H] + LC-MS, M/Z(ESI): 341.2[M+H] +
第二步：4-(2-氟苯基)-1-(吡咯烷-1-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-91)的合 成Step 2: 4-(2-Fluorophenyl)-1-(pyrrolidin-1-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one Synthesis of (I-91)
Figure PCTCN2022087589-appb-000397
Figure PCTCN2022087589-appb-000397
向4-(2-氟苯基)-1-硫代-6-(三氟甲基)-1H-吡啶并[1,2-c]嘧啶-3(2H)-酮(250mg，0.735mmol)的四氢呋喃(2mL)溶液中加入四氢吡咯(261mg，3.67mmol)和吡啶(291mg，3.67mmol)，然后向反应液中缓慢加入碘(559mg，2.204mmol)，反应液在25℃下反应18h。将反应液倒入水(10mL)中，用乙酸乙酯(5mL*3)萃取。有机相用饱和食盐水(5mL*2)洗涤，用无水硫酸钠干燥，过滤，旋干得到粗品。粗品经过反相制备(柱子:Phenomenex Synergi C18 100*25mm*4um；溶剂：A＝水+0.1体积％甲酸(99％)，B＝乙腈；梯度：5％-95％，7分钟)得到黄色固体产物4-(2-氟苯基)-1-(吡咯烷-1-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-91)(74.4mg，产率26.8％)。To 4-(2-fluorophenyl)-1-thio-6-(trifluoromethyl)-1H-pyrido[1,2-c]pyrimidin-3(2H)-one (250 mg, 0.735 mmol) To the solution of tetrahydrofuran (2 mL) was added tetrahydropyrrole (261 mg, 3.67 mmol) and pyridine (291 mg, 3.67 mmol), then iodine (559 mg, 2.204 mmol) was slowly added to the reaction solution, and the reaction solution was reacted at 25 °C for 18 h. The reaction solution was poured into water (10 mL), and extracted with ethyl acetate (5 mL*3). The organic phase was washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was prepared by reverse phase (column: Phenomenex Synergi C18 100*25mm*4um; solvent: A=water+0.1 vol% formic acid (99%), B=acetonitrile; gradient: 5%-95%, 7 minutes) to give a yellow solid Product 4-(2-Fluorophenyl)-1-(pyrrolidin-1-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I- 91) (74.4 mg, 26.8% yield).
1H NMR(400MHz,dmso)δ7.99(d,J＝7.7Hz,1H),7.52-7.40(m,1H),7.36-7.23(m,3H),6.81(s,1H),6.53(dd,J＝7.8,2.0Hz,1H),3.55(d,J＝3.3Hz,4H),1.90(s,4H). 1 H NMR(400MHz,dmso)δ7.99(d,J=7.7Hz,1H),7.52-7.40(m,1H),7.36-7.23(m,3H),6.81(s,1H),6.53(dd , J=7.8, 2.0Hz, 1H), 3.55(d, J=3.3Hz, 4H), 1.90(s, 4H).
LC-MS,M/Z(ESI):378.1[M+H] + LC-MS, M/Z(ESI): 378.1[M+H] +
实施例92：化合物I-92的制备Example 92: Preparation of Compound 1-92
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000398
Figure PCTCN2022087589-appb-000398
第一步：N-(环丙基氨基硫代甲酰)-2-(2-氟-3-甲氧苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The first step: N-(cyclopropylaminothiocarbonyl)-2-(2-fluoro-3-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)ethyl amide synthesis
在室温下，将2-(2-氟-3-甲氧苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(600mg,1.83mmol)，环丙基异硫氰酸酯(217mg,2.19mmol)和碳酸铯(596mg,1.83mmol)加入到N，N-二甲基甲酰胺(5.00mL)中，氮气保护下在25℃反应8小时。反应完成后，反应液25℃下加入水(90.0mL)中，然后用乙酸乙酯(30.0mL*2)萃取，合并有机层相，用饱和食盐水(20.0mL*2)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到黄色固体化合物N-(环丙基氨基硫代甲酰)-2-(2-氟-3-甲氧苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(750mg，粗品)。直接用于下一步。At room temperature, 2-(2-fluoro-3-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (600 mg, 1.83 mmol), cyclopropyliso Thiocyanate (217 mg, 2.19 mmol) and cesium carbonate (596 mg, 1.83 mmol) were added to N,N-dimethylformamide (5.00 mL) and reacted at 25° C. for 8 hours under nitrogen protection. After the reaction was completed, the reaction solution was added to water (90.0 mL) at 25°C, then extracted with ethyl acetate (30.0 mL*2), the organic layers were combined, and the organic phase was washed with saturated brine (20.0 mL*2). Dry over sodium sulfate, filter, and concentrate to obtain a yellow solid compound N-(cyclopropylaminothiocarbonyl)-2-(2-fluoro-3-methoxyphenyl)-2-(4-(trifluoromethyl) ) pyridin-2-yl)acetamide (750 mg, crude). used directly in the next step.
LC-MS,M/Z(ESI):428.0(M+H) + LC-MS, M/Z (ESI): 428.0 (M+H) +
第二步：1-(环丙基氨基)-4-(2-氟-3-甲氧苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮的合成Step 2: 1-(Cyclopropylamino)-4-(2-fluoro-3-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine- Synthesis of 3-keto
在氮气保护下，将N-(环丙基氨基硫代甲酰)-2-(2-氟-3-甲氧苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(750mg,1.75mmol)，碘单质(1.34g,5.26mmol)和吡啶(694mg,8.77mmol)加入到四氢呋喃(8.00mL)中，氮气保护下25℃下反应8小时。反应完成后，反应液过滤浓缩得到粗品，残留物用高效液相色谱仪分离纯化，分离方法为(柱子：Phenomenex Synergi C18 150*50mm*10um；溶剂：A＝水+0.1体积％碳酸氢氨(99％)，B＝乙腈；梯度：27％-57％，10分钟)，得到目标化合物1-(环丙基氨基)-4-(2-氟-3-甲氧苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(120mg，17.4％产率)。Under nitrogen protection, N-(cyclopropylaminothiocarbonyl)-2-(2-fluoro-3-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl ) acetamide (750 mg, 1.75 mmol), iodine element (1.34 g, 5.26 mmol) and pyridine (694 mg, 8.77 mmol) were added to tetrahydrofuran (8.00 mL) and reacted at 25° C. for 8 hours under nitrogen protection. After the reaction is completed, the reaction solution is filtered and concentrated to obtain the crude product, and the residue is separated and purified by high performance liquid chromatography, and the separation method is (column: Phenomenex Synergi C18 150*50mm*10um; Solvent: A=water+0.1 volume % ammonium bicarbonate ( 99%), B=acetonitrile; gradient: 27%-57%, 10 min) to give the title compound 1-(cyclopropylamino)-4-(2-fluoro-3-methoxyphenyl)-6-( Trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (120 mg, 17.4% yield).
LC-MS,M/Z(ESI):394.0[M+H] + LC-MS, M/Z(ESI): 394.0[M+H] +
第三步：1-(环丙基氨基)-4-(2-氟-3-羟基苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-92)的制备The third step: 1-(Cyclopropylamino)-4-(2-fluoro-3-hydroxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 - Preparation of ketone (I-92)
Figure PCTCN2022087589-appb-000399
Figure PCTCN2022087589-appb-000399
在氮气保护下，将1-(环丙基氨基)-4-(2-氟-3-甲氧苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(120mg,305μmol)加入到二氯甲烷(5.00mL)中，氮气保护下-78～-70℃下加入三溴化硼(764mg,3.05mmol)，加完后0℃下反应2小时。反应完成后，反应液0～5℃氮气保护下加入到饱和的碳酸氢钠水溶液(20.0mL)中，然后用二氯甲烷(40.0mL*3)萃取，合并有机层相，用饱和食盐水(20.0mL*2)洗涤有机相，无水硫酸钠干燥，过滤，浓缩，残留物用高效液相色谱仪分离纯化，分离方法为(柱子：Phenomenex Synergi C18 75*30mm*3um；溶剂：A＝水+0.1体积％三氟乙酸(99％)，B＝乙腈；梯度：26％-46％，9分钟)，得到目标化合物1-(环丙基氨基)-4-(2-氟-3-羟基苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-92)(75.1mg，62.9％产率)。Under nitrogen protection, 1-(cyclopropylamino)-4-(2-fluoro-3-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c] Pyrimidine-3-one (120 mg, 305 μmol) was added to dichloromethane (5.00 mL), and boron tribromide (764 mg, 3.05 mmol) was added at -78 to -70 °C under nitrogen protection, and reacted at 0 °C after the addition was complete. 2 hours. After the completion of the reaction, the reaction solution was added to saturated aqueous sodium bicarbonate solution (20.0 mL) under nitrogen protection at 0-5 °C, then extracted with dichloromethane (40.0 mL*3), the organic layers were combined, and saturated brine ( 20.0mL*2) organic phase was washed, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by high performance liquid chromatography. The separation method was (column: Phenomenex Synergi C18 75*30mm*3um; solvent: A=water + 0.1 vol% trifluoroacetic acid (99%), B=acetonitrile; gradient: 26%-46%, 9 min) to give the title compound 1-(cyclopropylamino)-4-(2-fluoro-3-hydroxyl Phenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-92) (75.1 mg, 62.9% yield).
1H NMR(400MHz,CD 3OD)δ8.39-8.37(d,1H),7.33(s,1H),7.33-7.07(m,3H),6.79-6.78(m,1H),3.10-3.06(m,1H),0.97-0.95(m,2H).0.83-0.80(m,2H). 1 H NMR (400MHz, CD 3 OD) δ8.39-8.37(d,1H), 7.33(s,1H), 7.33-7.07(m,3H), 6.79-6.78(m,1H), 3.10-3.06( m,1H),0.97-0.95(m,2H).0.83-0.80(m,2H).
LC-MS,M/Z(ESI):380.1[M+H] + LC-MS, M/Z(ESI): 380.1[M+H] +
实施例93：化合物I-93的制备Example 93: Preparation of Compound 1-93
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000400
Figure PCTCN2022087589-appb-000400
将4-(3-氟苯基)-1-(((1R,3R)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮 (50.0mg,124μmol)溶解在甲醇(2.00mL)中，加入氧化银(57.5mg,248μmol)和碘甲烷(17.6mg,124μmol,7.73μL)，25℃反应4小时。在反应液中加入水(1.00mL)，用饱和氯化铵溶液(5.00mL)淬灭，然后用乙酸乙酯(15.0mL)萃取，用饱和食盐水(5.00mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。然后通过反相高效液相色谱法进行分离，分离方法为(柱子：3_Phenomenex Luna C18 75*30mm*3um；溶剂：A＝水+0.05体积％三氟乙酸(99％)，B＝乙腈；梯度：33％-53％，9分钟)，得到黄色固体化合物4-(3-氟苯基)-1-(((1R,3R)-3-甲氧基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-93)(20.0mg，产率36.9％)。4-(3-Fluorophenyl)-1-(((1R,3R)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[1,2-c ] Pyrimidine-3-one (50.0 mg, 124 μmol) was dissolved in methanol (2.00 mL), silver oxide (57.5 mg, 248 μmol) and methyl iodide (17.6 mg, 124 μmol, 7.73 μL) were added, and the mixture was reacted at 25° C. for 4 hours. Water (1.00 mL) was added to the reaction solution, quenched with saturated ammonium chloride solution (5.00 mL), extracted with ethyl acetate (15.0 mL), the organic phase was washed with saturated brine (5.00 mL), and anhydrous sulfuric acid Dry over sodium, filter, and concentrate to give crude product. Then it was separated by reversed-phase high performance liquid chromatography, and the separation method was (column: 3_Phenomenex Luna C18 75*30mm*3um; solvent: A=water+0.05% by volume trifluoroacetic acid (99%), B=acetonitrile; gradient: 33%-53%, 9 minutes) to give a yellow solid compound 4-(3-fluorophenyl)-1-(((1R,3R)-3-methoxycyclobutyl)amino)-6-(tris Fluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-93) (20.0 mg, 36.9% yield).
1H NMR(400MHz,DMSO_d 6)δ8.00(d,1H),7.47-7.55(m,1H),7.12-7.27(m,4H),7.11(s,1H),6.71(m,1H),4.24(m,2H),2.82(s,3H),2.32-2.38(m,2H),2.10-2.17(m,2H). 1 H NMR (400MHz, DMSO_d 6 )δ8.00(d,1H), 7.47-7.55(m,1H), 7.12-7.27(m,4H), 7.11(s,1H), 6.71(m,1H), 4.24(m, 2H), 2.82(s, 3H), 2.32-2.38(m, 2H), 2.10-2.17(m, 2H).
LC-MS,M/Z(ESI):408.1[M+H] + LC-MS, M/Z(ESI): 408.1[M+H] +
实施例94：化合物I-94的制备Example 94: Preparation of Compound 1-94
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000401
Figure PCTCN2022087589-appb-000401
第一步：异硫氰基环丁烷的合成The first step: the synthesis of isothiocyanocyclobutane
将环丁胺(300mg,4.22mmol,361μL)和碳酸铯(4.12g,12.6mmol)溶解在二氯甲烷(15.0mL)中，在氮气保护下加入硫光气(970mg,8.44mmol,646μL)，25℃反应2小时。反应完成后，把反应液过滤，有机相浓缩得到黄色固体化合物异硫氰基环丁烷(400mg，粗产物)。直接用于下一步。Cyclobutylamine (300 mg, 4.22 mmol, 361 μL) and cesium carbonate (4.12 g, 12.6 mmol) were dissolved in dichloromethane (15.0 mL), and thiophosgene (970 mg, 8.44 mmol, 646 μL) was added under nitrogen protection, The reaction was carried out at 25°C for 2 hours. After the reaction was completed, the reaction solution was filtered, and the organic phase was concentrated to obtain a yellow solid compound isothiocyanocyclobutane (400 mg, crude product). used directly in the next step.
第二步：N-(环丁基氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The second step: the synthesis of N-(cyclobutylaminothiol)-2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
将2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(300mg,1.01mmol)和碳酸铯(983mg,3.02mmol)溶解在N,N-二甲基甲酰胺(15.0mL)中，加异硫氰基环丁烷(400mg,3.53mmol)，25℃反应2小时。反应完成后，把水(50.0mL)加到反应液中，然后用乙酸乙酯(120mL)萃取，用饱和食盐水(40.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用快速硅胶色谱柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至5:1)得到棕色油状化合物N-(环丁基氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(270mg，产率67.7％)。2-(2-Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (300 mg, 1.01 mmol) and cesium carbonate (983 mg, 3.02 mmol) were dissolved in N,N -In dimethylformamide (15.0 mL), isothiocyanocyclobutane (400 mg, 3.53 mmol) was added, and the reaction was carried out at 25° C. for 2 hours. After the reaction was completed, water (50.0 mL) was added to the reaction solution, then extracted with ethyl acetate (120 mL), the organic phase was washed with saturated brine (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was separated and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=50:1 to 5:1) to obtain the brown oily compound N-(cyclobutylcarbamoyl)-2-(2 -Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (270 mg, 67.7% yield).
LC-MS,M/Z(ESI):412.2[M+H] + LC-MS, M/Z(ESI): 412.2[M+H] +
第三步：目标化合物1-(环丁基氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(化合物I-94)The third step: target compound 1-(cyclobutylamino)-4-(2-fluorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (Compound I-94)
Figure PCTCN2022087589-appb-000402
Figure PCTCN2022087589-appb-000402
将N-(环丁基氨基硫代甲酰)-2-(2-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(120mg,275μmol)溶解在四氢呋喃(15.0mL)中，加碘(209mg,826μmol,)和吡啶(65.4mg,826μmol,66.7μL)，25℃反应2小时。反应完成后，向反应液中加入饱和亚硫酸钠溶液(20.0mL)，然后用乙酸乙酯(60.0mL)萃取，用饱和食盐水(20.0mL)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用硅胶板分离纯化(二氯甲烷:甲醇(V/V)＝10:1)，得到黄色固体化合物1-(环丁基氨基)-4-(2-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-94)(60.0mg，产率62.0％)。N-(Cyclobutylcarbamoyl)-2-(2-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (120 mg, 275 μmol) was dissolved in In tetrahydrofuran (15.0 mL), iodine (209 mg, 826 μmol,) and pyridine (65.4 mg, 826 μmol, 66.7 μL) were added, and the mixture was reacted at 25° C. for 2 hours. After the reaction was completed, saturated sodium sulfite solution (20.0 mL) was added to the reaction solution, then extracted with ethyl acetate (60.0 mL), the organic phase was washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain Crude. The crude product was separated and purified by silica gel plate (dichloromethane:methanol (V/V)=10:1) to obtain a yellow solid compound 1-(cyclobutylamino)-4-(2-fluorophenyl)-6-(tris Fluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I-94) (60.0 mg, 62.0% yield).
1H NMR(400MHz,DMSO-d 6)δ8.21(br d,1H),8.08(br d,1H),7.42-7.48(m,1H),7.25-7.32(m,3H),6.78(br s,1H),6.73(m,1H),4.38-4.47(m,1H),2.31(m,2H),2.10(br m,2H),1.68-1.77(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.21(br d,1H),8.08(br d,1H),7.42-7.48(m,1H),7.25-7.32(m,3H),6.78(br s,1H),6.73(m,1H),4.38-4.47(m,1H),2.31(m,2H),2.10(br m,2H),1.68-1.77(m,2H).
LC-MS,M/Z(ESI):378.2[M+H] + LC-MS, M/Z(ESI): 378.2[M+H] +
实施例95：化合物I-95的制备Example 95: Preparation of Compound 1-95
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000403
Figure PCTCN2022087589-appb-000403
第一步：(1R,3R)-3-((叔丁氧基羰基)氨基)环丁基苯甲酸酯的合成The first step: Synthesis of (1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutylbenzoate
向((1R,3R)-3-羟基环丁基)氨基甲酸叔丁酯(1g,5.34mmol)的二氯甲烷(10mL)溶液中加入三乙胺(3.72mL，26.7mmol)和4-二甲氨基吡啶(0.652g,5.34mmol)，然后在0℃向反应液 中逐滴加入苯甲酰氯(1.25mL,13.35mmol)，并在25℃搅拌18h。向反应液中加入水(100mL)并用二氯甲烷(20mL*3)萃取。有机层用饱和食盐水(20mL*2)洗涤，用无水硫酸钠干燥，过滤并浓缩得到粗产物。粗产物经柱色谱纯化(石油醚/乙酸乙酯(V/V)＝1/0-1/1)得到无色油状产物(1R，3R)-3-((叔丁氧基羰基)氨基)环丁基苯甲酸酯(1.2g，产率77％)。To a solution of tert-butyl ((1R,3R)-3-hydroxycyclobutyl)carbamate (1 g, 5.34 mmol) in dichloromethane (10 mL) was added triethylamine (3.72 mL, 26.7 mmol) and 4-dichloromethane (3.72 mL, 26.7 mmol) Methylaminopyridine (0.652 g, 5.34 mmol), then benzoyl chloride (1.25 mL, 13.35 mmol) was added dropwise to the reaction solution at 0 °C, and stirred at 25 °C for 18 h. Water (100 mL) was added to the reaction solution, followed by extraction with dichloromethane (20 mL*3). The organic layer was washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V)=1/0-1/1) to give the product (1R,3R)-3-((tert-butoxycarbonyl)amino) as a colorless oily product Cyclobutylbenzoate (1.2 g, 77% yield).
LC-MS,M/Z(ESI):292.3[M+H] + LC-MS, M/Z(ESI): 292.3[M+H] +
第二步：(1R,3R)-3-氨基环丁基苯甲酸酯的合成The second step: the synthesis of (1R,3R)-3-aminocyclobutylbenzoate
向(1R,3R)-3-((叔丁氧基羰基)氨基)环丁基苯甲酸酯(1.2g,4.12mmol)的二氯甲烷(5mL)溶液中加入三氟乙酸(5mL)，并在25℃下搅拌2小时。将反应液浓缩得到黄色油状产物(1R,3R)-3-氨基环丁基苯甲酸酯(700mg，产率89％，三氟乙酸盐)。产物直接用于下一步反应。To a solution of (1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutylbenzoate (1.2 g, 4.12 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL), and stirred at 25°C for 2 hours. The reaction solution was concentrated to give (1R,3R)-3-aminocyclobutylbenzoate (700 mg, 89% yield, trifluoroacetate) as a yellow oily product. The product was directly used in the next reaction.
LC-MS,M/Z(ESI):192.2[M+H] + LC-MS, M/Z(ESI): 192.2[M+H] +
第三步：(1R,3R)-3-异硫氰酸环丁基苯甲酸酯的合成The third step: the synthesis of (1R,3R)-3-isothiocyanate cyclobutyl benzoate
向(1R,3R)-3-氨基环丁基苯甲酸酯(700mg，3.66mmol)的四氢呋喃(10mL)溶液中加入三乙胺(2.55mL，18.3mmol)，然后在0℃向反应液中滴加硫光气(0.7mL，9.15mmol)，并在25℃搅拌2小时。浓缩反应液得到粗产物。粗产物通过柱层析纯化(石油醚/乙酸乙酯(V/V)＝1/0-3/1)得到黄色油状产物(1R,3R)-3-异硫氰酸环丁基苯甲酸酯(700mg,产率82％)。To a solution of (1R,3R)-3-aminocyclobutylbenzoate (700 mg, 3.66 mmol) in tetrahydrofuran (10 mL) was added triethylamine (2.55 mL, 18.3 mmol), and then added to the reaction solution at 0°C Thiophosgene (0.7 mL, 9.15 mmol) was added dropwise and stirred at 25°C for 2 hours. The reaction solution was concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V)=1/0-3/1) to give (1R,3R)-3-isothiocyanatocyclobutylbenzoic acid as a yellow oily product ester (700 mg, 82% yield).
第四步：(1R,3R)-3-(3-(2-(2,3-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰基)硫脲基)环丁基苯甲酸酯的合成The fourth step: (1R,3R)-3-(3-(2-(2,3-difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetyl)thio Synthesis of Urea) Cyclobutyl Benzoate
向2-(2,3-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(633mg,2mmol)和(1R,3R)-3-异硫氰酸环苯甲酸丁酯(700mg，3mmol)的N,N-二甲基乙酰胺(5mL)溶液中缓慢加入氢化钠(120mg，5mmol)，并在25℃搅拌18h。将反应液缓慢加入水(100mL)中，并用乙酸乙酯(30mL*3)萃取。有机层用饱和食盐水(20mL*2)洗涤，用无水硫酸钠干燥，过滤并浓缩得到粗产物。粗产物经柱层析纯化(石油醚/乙酸乙酯(V/V)＝1/0-1/3)得到黄色固体产物(1R,3R)-3-(3-(2-(2,3-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰基)硫脲基)环丁基苯甲酸酯(700mg，产率63.7％)。To 2-(2,3-difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (633 mg, 2 mmol) and (1R,3R)-3-isothiocyanate Sodium hydride (120 mg, 5 mmol) was slowly added to a solution of butyl cyclobenzoate (700 mg, 3 mmol) in N,N-dimethylacetamide (5 mL) and stirred at 25° C. for 18 h. The reaction solution was slowly added to water (100 mL), and extracted with ethyl acetate (30 mL*3). The organic layer was washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V)=1/0-1/3) to obtain the yellow solid product (1R,3R)-3-(3-(2-(2,3) -Difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetyl)thioureido)cyclobutylbenzoate (700 mg, 63.7% yield).
LC-MS,M/Z(ESI):550.1[M+H]+LC-MS, M/Z(ESI): 550.1[M+H]+
第五步：(1R,3R)-3-((4-(2,3-二氟苯基)-3-氧代-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-1-基)氨基)苯甲酸环丁酯的合成The fifth step: (1R,3R)-3-((4-(2,3-difluorophenyl)-3-oxo-6-(trifluoromethyl)-3H-pyrido[1,2- Synthesis of c]pyrimidin-1-yl)amino)cyclobutyl benzoate
向(1R,3R)-3-(3-(2-(2,3-二氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰基)硫脲基)环丁基苯甲酸酯(700mg,1.274mmol)的四氢呋喃(10mL)溶液中加入碘(970mg，3.82mmol)和吡啶(302mg，3.82mmol)，然后在25℃搅拌18小时。将反应液加入饱和硫代硫酸钠溶液(20mL)中并用乙酸乙酯(10mL*3)萃取。有机层用饱和食盐水(5mL*2)洗涤，用无水硫酸钠干燥，过滤并浓缩得到粗产物。粗产物经柱层析纯化(二氯甲烷/甲醇(V/V)＝1/0-10/1)得到黄色固体产物(1R,3R)-3-((4-(2,3-二氟苯基)-3-氧代-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-1-基)氨基)苯甲酸环丁酯(120mg，产率18.28％)。To (1R,3R)-3-(3-(2-(2,3-difluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetyl)thioureido) To a solution of cyclobutylbenzoate (700 mg, 1.274 mmol) in tetrahydrofuran (10 mL) were added iodine (970 mg, 3.82 mmol) and pyridine (302 mg, 3.82 mmol), followed by stirring at 25°C for 18 hours. The reaction solution was added to saturated sodium thiosulfate solution (20 mL) and extracted with ethyl acetate (10 mL*3). The organic layer was washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (dichloromethane/methanol (V/V)=1/0-10/1) to give the product (1R,3R)-3-((4-(2,3-difluoro) as a yellow solid Phenyl)-3-oxo-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-1-yl)amino)benzoic acid cyclobutyl ester (120 mg, 18.28% yield) .
LC-MS,M/Z(ESI):516.3[M+H] + LC-MS, M/Z(ESI): 516.3[M+H] +
第六步：4-(2,3-二氟苯基)-1-(((1R,3R)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-95)的合成Step 6: 4-(2,3-Difluorophenyl)-1-(((1R,3R)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido Synthesis of [1,2-c]pyrimidin-3-one (I-95)
Figure PCTCN2022087589-appb-000404
Figure PCTCN2022087589-appb-000404
向(1R,3R)-3-((4-(2,3-二氟苯基)-3-氧代-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-1-基)氨基)苯甲酸环丁酯(120mg，0.233mmol)的四氢呋喃(6mL)、甲醇(2mL)和水(2mL)溶液中加入氢氧化锂(27.9mg，1.164mmol)，然后在50℃搅拌18小时。向反应液中加入水(100mL)，并用1N的盐酸水溶液调节pH＝6～7。用乙酸乙酯(20mL*3)萃取，有机层用饱和食盐水(20mL*2)洗涤，用无水硫酸钠干燥，过滤并浓缩得到粗产物。粗产物经反相制备纯化(柱子:Phenomenex Synergi C18 100*25mm*4um；溶剂：A＝水+0.1体积％甲酸(99％)，B＝乙腈；梯度：5％-95％，7分钟)得到黄色固体产物4-(2,3-二氟苯基)-1-(((1R,3R)-3-羟基环丁基)氨基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-95)(24.4mg,产率25.5％)。To (1R,3R)-3-((4-(2,3-difluorophenyl)-3-oxo-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine To a solution of cyclobutyl-1-yl)amino)benzoate (120 mg, 0.233 mmol) in tetrahydrofuran (6 mL), methanol (2 mL) and water (2 mL) was added lithium hydroxide (27.9 mg, 1.164 mmol), followed by addition of lithium hydroxide (27.9 mg, 1.164 mmol) at 50 °C was stirred for 18 hours. Water (100 mL) was added to the reaction solution, and pH=6-7 was adjusted with 1N aqueous hydrochloric acid. Extracted with ethyl acetate (20 mL*3), the organic layer was washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by reverse phase preparation (column: Phenomenex Synergi C18 100*25mm*4um; solvent: A=water+0.1 vol% formic acid (99%), B=acetonitrile; gradient: 5%-95%, 7 min) to give Yellow solid product 4-(2,3-difluorophenyl)-1-(((1R,3R)-3-hydroxycyclobutyl)amino)-6-(trifluoromethyl)-3H-pyrido[ 1,2-c]pyrimidin-3-one (I-95) (24.4 mg, 25.5% yield).
1H NMR(400MHz,dmso)δ8.25(d,J＝7.8Hz,1H),8.02(s,1H),7.45(dd,J＝17.9,8.8Hz,1H),7.27(dd,J＝13.3,8.0Hz,1H),7.12(t,J＝6.9Hz,1H),6.88(s,1H),6.75(d,J＝7.8Hz,1H),5.08(d,J＝5.3Hz,1H),4.48-4.29(m,2H),2.34(dt,J＝12.1,6.1Hz,2H),2.22(ddd,J＝12.5,8.0,4.3Hz,2H)。1H NMR(400MHz,dmso)δ8.25(d,J=7.8Hz,1H),8.02(s,1H),7.45(dd,J=17.9,8.8Hz,1H),7.27(dd,J=13.3, 8.0Hz, 1H), 7.12(t, J＝6.9Hz, 1H), 6.88(s, 1H), 6.75(d, J＝7.8Hz, 1H), 5.08(d, J＝5.3Hz, 1H), 4.48 -4.29 (m, 2H), 2.34 (dt, J=12.1, 6.1 Hz, 2H), 2.22 (ddd, J=12.5, 8.0, 4.3 Hz, 2H).
LC-MS,M/Z(ESI):412.2[M+H] + LC-MS, M/Z(ESI): 412.2[M+H] +
实施例96：化合物I-96的制备Example 96: Preparation of Compound 1-96
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000405
Figure PCTCN2022087589-appb-000405
第一步：N-(环丙基氨基硫代甲酰)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The first step: Synthesis of N-(cyclopropylaminothioformyl)-2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide
在室温下，将2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(300mg,1.01mmol)，环丙基异硫氰酸酯(149mg,1.51mmol)和碳酸铯(655mg,2.01mmol)加入到N，N-二甲基甲酰胺(3.00mL)中，氮气保护下在25℃反应8小时。反应完成后，反应液25℃下加入水(30.0mL)中，然后用乙酸乙酯(20.0mL*2)萃取，合并有机层相，用饱和食盐水(10.0mL*2)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到黄色固体化合物N-(环丙基氨基硫代甲酰)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(300mg，粗品)。直接用于下一步。2-(3-Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (300 mg, 1.01 mmol), cyclopropyl isothiocyanate ( 149 mg, 1.51 mmol) and cesium carbonate (655 mg, 2.01 mmol) were added to N,N-dimethylformamide (3.00 mL) and reacted at 25°C for 8 hours under nitrogen protection. After the reaction was completed, the reaction solution was added to water (30.0 mL) at 25°C, then extracted with ethyl acetate (20.0 mL*2), the organic layers were combined, and the organic phase was washed with saturated brine (10.0 mL*2). Dry over sodium sulfate, filter, and concentrate to obtain a yellow solid compound N-(cyclopropylaminothioyl)-2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridine-2- yl)acetamide (300 mg, crude). used directly in the next step.
LC-MS,M/Z(ESI):398.2[M+H] + LC-MS, M/Z(ESI): 398.2[M+H] +
第二步：1-(环丙基氨基)-4-(3-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-96)的合成The second step: 1-(cyclopropylamino)-4-(3-fluorophenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (I -96) synthesis
Figure PCTCN2022087589-appb-000406
Figure PCTCN2022087589-appb-000406
在氮气保护下，将N-(环丙基氨基硫代甲酰)-2-(3-氟苯基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(300mg,755μmol)，碘单质(575mg,2.26mmol)和吡啶(298mg,3.77mmol)加入到四氢呋喃(3.00mL)中，氮气保护下35℃下反应6小时。反应完成后，反应液过滤浓缩得到粗品，残留物用高效液相色谱仪分离纯化，分离方法为(柱子：Phenomenex Synergi C18 150*50mm*10um；溶剂：A＝水+0.1体积％碳酸氢氨(99％)，B＝乙腈；梯度：29％-59％，10分钟)，得到目标化合物1-(环丙基氨基)-4-(3-氟苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-96)(29.6mg，10.5％产率)。Under nitrogen protection, N-(cyclopropylaminothiocarbonyl)-2-(3-fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (300 mg , 755 μmol), elemental iodine (575 mg, 2.26 mmol) and pyridine (298 mg, 3.77 mmol) were added to tetrahydrofuran (3.00 mL) and reacted at 35° C. for 6 hours under nitrogen protection. After the reaction is completed, the reaction solution is filtered and concentrated to obtain the crude product, and the residue is separated and purified by high performance liquid chromatography, and the separation method is (column: Phenomenex Synergi C18 150*50mm*10um; Solvent: A=water+0.1 volume % ammonium bicarbonate ( 99%), B=acetonitrile; gradient: 29%-59%, 10 min) to give the title compound 1-(cyclopropylamino)-4-(3-fluorophenyl)-6-(trifluoromethyl) -3H-pyrido[1,2-c]pyrimidin-3-one (1-96) (29.6 mg, 10.5% yield).
1H NMR(400MHz,CD 3OD)δ8.03-8.01(d,1H),7.52-7.47(m,1H),7.21-7.11(m,4H),6.79-6.66(d,1H),2.98-2.95(m,1H),0.91-0.862(m,2H).0.70(s,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.03-8.01 (d, 1H), 7.52-7.47 (m, 1H), 7.21-7.11 (m, 4H), 6.79-6.66 (d, 1H), 2.98- 2.95(m,1H),0.91-0.862(m,2H).0.70(s,2H).
LC-MS,M/Z(ESI):364.0[M+H] + LC-MS, M/Z(ESI): 364.0[M+H] +
实施例97：化合物I-97的制备Example 97: Preparation of Compound 1-97
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022087589-appb-000407
Figure PCTCN2022087589-appb-000407
第一步：N-(环丁基氨基硫代甲酰)-2-(2-氟吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺的合成The first step: N-(cyclobutylaminothioformyl)-2-(2-fluoropyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide synthesis
在室温下，将2-(2-氟吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(300mg,1.00mmol)，异硫氰基环丁烷(113mg,1.00mmol)和碳酸铯(653mg,1.83mmol)加入到N，N-二甲基甲酰胺(5.00mL)中，氮气保护下在25℃反应12小时。反应完成后，反应液25℃下加入水(50.0mL)中，然后用乙酸乙酯(20.0mL*3)萃取，合并有机层相，用饱和食盐水(10.0mL*2)洗涤有机相，无水硫酸钠干燥，过滤，浓缩得到黄色固体化合物N-(环丁基氨基硫代甲酰)-2-(2-氟吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(300mg，粗品)。直接用于下一步。At room temperature, 2-(2-fluoropyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (300 mg, 1.00 mmol), isothiocyanatocyclobutyl Alkane (113 mg, 1.00 mmol) and cesium carbonate (653 mg, 1.83 mmol) were added to N,N-dimethylformamide (5.00 mL) and reacted at 25° C. for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was added to water (50.0 mL) at 25°C, then extracted with ethyl acetate (20.0 mL*3), the organic layers were combined, and the organic phase was washed with saturated brine (10.0 mL*2). dried over sodium sulfate, filtered, and concentrated to give a yellow solid compound N-(cyclobutylaminothioyl)-2-(2-fluoropyridin-3-yl)-2-(4-(trifluoromethyl)pyridine) -2-yl)acetamide (300 mg, crude). used directly in the next step.
LC-MS,M/Z(ESI):413.2[M+H] + LC-MS, M/Z(ESI): 413.2[M+H] +
第三步：1-(环丁基氨基)-4-(2-氟吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-97)的合成The third step: 1-(cyclobutylamino)-4-(2-fluoropyridin-3-yl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3- Synthesis of Ketone (I-97)
Figure PCTCN2022087589-appb-000408
Figure PCTCN2022087589-appb-000408
在氮气保护下，将N-(环丁基氨基硫代甲酰)-2-(2-氟吡啶-3-基)-2-(4-(三氟甲基)吡啶-2-基)乙酰胺(300mg,727μmol)，碘单质(554mg,2.18mmol)和吡啶(230mg,2.91mmol)加入到四氢呋喃(4.00mL)中，氮气保护下25℃下反应8小时。反应完成后，反应液过滤，浓缩得到粗品，残留物用高效液相色谱仪分离纯化，分离方法为(柱子：Phenomenex Synergi C18 150*25mm*5um；溶剂：A＝水+0.1体积％碳酸氢氨(99％)，B＝乙腈；梯度：26％-56％，8分钟)，得到目标化合物1-(环丁基氨基)-4-(2-氟吡啶-3-基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-97)(21.7mg，7.42％产率)。Under nitrogen protection, N-(cyclobutylcarbamoyl)-2-(2-fluoropyridin-3-yl)-2-(4-(trifluoromethyl)pyridin-2-yl)ethyl Amide (300 mg, 727 μmol), iodine element (554 mg, 2.18 mmol) and pyridine (230 mg, 2.91 mmol) were added to tetrahydrofuran (4.00 mL) and reacted at 25° C. for 8 hours under nitrogen protection. After the reaction is completed, the reaction solution is filtered, concentrated to obtain the crude product, and the residue is separated and purified by high performance liquid chromatography, and the separation method is (column: Phenomenex Synergi C18 150*25mm*5um; Solvent: A=water+0.1 volume % ammonium bicarbonate (99%), B=acetonitrile; gradient: 26%-56%, 8 min) to give the title compound 1-(cyclobutylamino)-4-(2-fluoropyridin-3-yl)-6-(tris Fluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (1-97) (21.7 mg, 7.42% yield).
1H NMR(400MHz,CD 3OD)δ8.28-8.27(d,1H),8.24-8.22(d,1H),7.96-7.91(m,1H)7.46-7.44(m,1H),7.00(s,1H),6.78-6.75(m,1H),4.64-4.58(m,1H),2.49-2.46(m,2H),2.17-2.12(m,2H),1.85-1.80(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.28-8.27(d, 1H), 8.24-8.22(d, 1H), 7.96-7.91(m, 1H) 7.46-7.44(m, 1H), 7.00(s ,1H),6.78-6.75(m,1H),4.64-4.58(m,1H),2.49-2.46(m,2H),2.17-2.12(m,2H),1.85-1.80(m,2H).
LC-MS,M/Z(ESI):379.2(M+H) + LC-MS, M/Z (ESI): 379.2 (M+H) +
实施例98：化合物I-98的制备Example 98: Preparation of Compound 1-98
Figure PCTCN2022087589-appb-000409
Figure PCTCN2022087589-appb-000409
化合物1-(环丙基氨基)-4-(2,4-二氟-3-羟基苯基)-6-(三氟甲基)-3H-吡啶并[1,2-c]嘧啶-3-酮(I-98)的制备参考化合物I-92的制备方法得到。Compound 1-(Cyclopropylamino)-4-(2,4-difluoro-3-hydroxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-3 -The preparation of ketone (I-98) was obtained with reference to the preparation method of compound I-92.
1H NMR(400m Hz,CD 3OD)δ8.39-8.37(d,1H),7.33(s,1H),7.43-7.25(m,2H),6.79-6.78(m,1H),3.10-3.06(m,1H),0.97-0.95(m,2H).0.83-0.80(m,2H). 1 H NMR (400m Hz, CD 3 OD) δ 8.39-8.37(d, 1H), 7.33(s, 1H), 7.43-7.25(m, 2H), 6.79-6.78(m, 1H), 3.10-3.06 (m,1H),0.97-0.95(m,2H).0.83-0.80(m,2H).
LC-MS,M/Z(ESI):398.1(M+H) + LC-MS, M/Z (ESI): 398.1 (M+H) +
实施例99：下列化合物的制备参考以上化合物的制备方法得到。Example 99: The preparation of the following compounds was obtained with reference to the preparation methods of the above compounds.
Figure PCTCN2022087589-appb-000410
Figure PCTCN2022087589-appb-000410
Figure PCTCN2022087589-appb-000411
Figure PCTCN2022087589-appb-000411
Figure PCTCN2022087589-appb-000412
Figure PCTCN2022087589-appb-000412
Figure PCTCN2022087589-appb-000413
Figure PCTCN2022087589-appb-000413
Figure PCTCN2022087589-appb-000414
Figure PCTCN2022087589-appb-000414
Figure PCTCN2022087589-appb-000415
Figure PCTCN2022087589-appb-000415
Figure PCTCN2022087589-appb-000416
Figure PCTCN2022087589-appb-000416
Figure PCTCN2022087589-appb-000417
Figure PCTCN2022087589-appb-000417
Figure PCTCN2022087589-appb-000418
Figure PCTCN2022087589-appb-000418
Figure PCTCN2022087589-appb-000419
Figure PCTCN2022087589-appb-000419
Figure PCTCN2022087589-appb-000420
Figure PCTCN2022087589-appb-000420
Figure PCTCN2022087589-appb-000421
Figure PCTCN2022087589-appb-000421
Figure PCTCN2022087589-appb-000422
Figure PCTCN2022087589-appb-000422
Figure PCTCN2022087589-appb-000423
Figure PCTCN2022087589-appb-000423
Figure PCTCN2022087589-appb-000424
Figure PCTCN2022087589-appb-000424
Figure PCTCN2022087589-appb-000425
Figure PCTCN2022087589-appb-000425
Figure PCTCN2022087589-appb-000426
Figure PCTCN2022087589-appb-000426
Figure PCTCN2022087589-appb-000427
Figure PCTCN2022087589-appb-000427
Figure PCTCN2022087589-appb-000428
Figure PCTCN2022087589-appb-000428
Figure PCTCN2022087589-appb-000429
Figure PCTCN2022087589-appb-000429
Figure PCTCN2022087589-appb-000430
Figure PCTCN2022087589-appb-000430
Figure PCTCN2022087589-appb-000431
Figure PCTCN2022087589-appb-000431
Figure PCTCN2022087589-appb-000432
Figure PCTCN2022087589-appb-000432
Figure PCTCN2022087589-appb-000433
Figure PCTCN2022087589-appb-000433
Figure PCTCN2022087589-appb-000434
Figure PCTCN2022087589-appb-000434
Figure PCTCN2022087589-appb-000435
Figure PCTCN2022087589-appb-000435
Figure PCTCN2022087589-appb-000436
Figure PCTCN2022087589-appb-000436
Figure PCTCN2022087589-appb-000437
Figure PCTCN2022087589-appb-000437
Figure PCTCN2022087589-appb-000438
Figure PCTCN2022087589-appb-000438
Figure PCTCN2022087589-appb-000439
Figure PCTCN2022087589-appb-000439
Figure PCTCN2022087589-appb-000440
Figure PCTCN2022087589-appb-000440
Figure PCTCN2022087589-appb-000441
Figure PCTCN2022087589-appb-000441
Figure PCTCN2022087589-appb-000442
Figure PCTCN2022087589-appb-000442
Figure PCTCN2022087589-appb-000443
Figure PCTCN2022087589-appb-000443
Figure PCTCN2022087589-appb-000444
Figure PCTCN2022087589-appb-000444
Figure PCTCN2022087589-appb-000445
Figure PCTCN2022087589-appb-000445
Figure PCTCN2022087589-appb-000446
Figure PCTCN2022087589-appb-000446
Figure PCTCN2022087589-appb-000447
Figure PCTCN2022087589-appb-000447
Figure PCTCN2022087589-appb-000448
Figure PCTCN2022087589-appb-000448
Figure PCTCN2022087589-appb-000449
Figure PCTCN2022087589-appb-000449
Figure PCTCN2022087589-appb-000450
Figure PCTCN2022087589-appb-000450
Figure PCTCN2022087589-appb-000451
Figure PCTCN2022087589-appb-000451
Figure PCTCN2022087589-appb-000452
Figure PCTCN2022087589-appb-000452
Figure PCTCN2022087589-appb-000453
Figure PCTCN2022087589-appb-000453
Figure PCTCN2022087589-appb-000454
Figure PCTCN2022087589-appb-000454
生物学活性剂相关性质测试例Test examples of properties related to biologically active agents
测试例1：MAT2A酶活性抑制试验Test Example 1: MAT2A Enzyme Activity Inhibition Test
采用BPS Bioscience MAT2A抑制剂筛选试剂盒，检测化合物对MAT2A酶活性抑制的IC 50，首先用DMSO溶解待测化合物，所有化合物在DMSO稀释至起始浓度1mM，3倍稀释，10个浓度梯度。用Echo 550向反应板(784075,Greiner)每孔转移200nL稀释好的化合物，用封板膜封板，1000g离心1分钟，DMSO终浓度为1％。用1X的酶反应缓冲液配制准备2X MAT2A酶液，向384-反应板(Corning3702)中每孔加入10μL 2X MAT2A酶液，用封板膜封板，1000g离心60秒，室温孵育10分钟。用1X MAT2A激酶反应缓冲液配制2X L-Methionine和ATP混合液，向384-反应板中每孔加入10μL 2X L-Methionine和ATP混合液，用封板膜封住板，总反应体系为20μL。1000g离心60秒，室温孵育60分钟。每孔加入20μL检测缓冲液Colorimetric Detection Reagent，1000g离心30秒，室温反应15分钟。用Envision 2104读630nm的荧光信号，通过如下公式计算抑制率： BPS Bioscience MAT2A Inhibitor Screening Kit was used to detect the IC 50 of compounds inhibiting MAT2A enzymatic activity. First, the compounds to be tested were dissolved in DMSO, and all compounds were diluted in DMSO to an initial concentration of 1 mM, 3-fold dilution, and 10 concentration gradients. Transfer 200 nL of the diluted compound to each well of the reaction plate (784075, Greiner) with an Echo 550, seal the plate with a sealing film, centrifuge at 1000 g for 1 minute, and the final concentration of DMSO is 1%. Prepare 2X MAT2A enzyme solution with 1X enzyme reaction buffer, add 10 μL of 2X MAT2A enzyme solution to each well of a 384-reaction plate (Corning3702), seal the plate with a sealing film, centrifuge at 1000g for 60 seconds, and incubate at room temperature for 10 minutes. Prepare 2X L-Methionine and ATP mixture with 1X MAT2A kinase reaction buffer, add 10 μL of 2X L-Methionine and ATP mixture to each well of the 384-reaction plate, seal the plate with a sealing film, and the total reaction system is 20 μL. Centrifuge at 1000g for 60 seconds and incubate at room temperature for 60 minutes. Add 20 μL of detection buffer Colorimetric Detection Reagent to each well, centrifuge at 1000 g for 30 seconds, and react at room temperature for 15 minutes. The fluorescence signal at 630 nm was read with Envision 2104, and the inhibition rate was calculated by the following formula:
％inhibition＝100-(Signal cmpd-Signal Ave_PC)/(Signal Ave_VC-Signal Ave_PC)×100. %inhibition=100-(Signal cmpd-Signal Ave_PC )/(Signal Ave_VC -Signal Ave_PC ) ×100.
注：Signal  Ave_PC:反应板中的阳性对照孔的荧光信号；Signal  Ave_VC:反应板中的阴性对照孔的荧光信号。 Note: Signal Ave_PC : the fluorescent signal of the positive control well in the reaction plate; Signal Ave_VC : the fluorescent signal of the negative control well in the reaction plate.
利用以下非线性拟合公式来得到化合物的IC 50(半数抑制浓度)： The IC50 ( 50% inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope)) Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
注：X:化合物浓度log值；Y:Inhibition％Note: X: log value of compound concentration; Y: Inhibition%
按照上述实验方法测定本发明化合物对MAT2A酶活性抑制效果，结果如下表1所示：According to the above-mentioned experimental method, the inhibitory effect of the compound of the present invention on MAT2A enzyme activity was determined, and the results are shown in Table 1 below:
表1测试化合物对MAT2A酶活性抑制结果Table 1 Inhibition results of test compounds on MAT2A enzyme activity
测试化合物test compound IC 50(nM) IC50 (nM)
I-1I-1 49.349.3
I-2I-2 142.8142.8
I-4I-4 52.5852.58
I-5I-5 25.1725.17
I-6I-6 53.1553.15
I-10I-10 67.0567.05
I-11I-11 334.3334.3
I-14I-14 341.4341.4
I-23I-23 114.5114.5
I-24I-24 69.4669.46
I-25I-25 56.3956.39
I-26I-26 346.9346.9
I-27I-27 59.7759.77
I-28I-28 55.3455.34
I-29I-29 107.5107.5
I-30I-30 198.8198.8
I-31I-31 39.7239.72
I-32I-32 140140
I-34I-34 45.1045.10
I-35I-35 11.6111.61
I-36I-36 118.5118.5
I-37I-37 65.1965.19
I-38I-38 186.8186.8
I-39I-39 20.3020.30
I-40I-40 23.9423.94
I-41I-41 55.7955.79
I-42I-42 48.8348.83
I-46I-46 45.7145.71
I-47I-47 71.3271.32
I-50I-50 40.0440.04
I-52I-52 53.0253.02
I-53I-53 62.0262.02
I-58I-58 148.6148.6
I-59I-59 200.2200.2
I-60I-60 118.6118.6
I-62I-62 67.6267.62
I-63I-63 129.3129.3
I-70I-70 385.9385.9
I-73I-73 77.3777.37
I-80I-80 40.1940.19
I-81I-81 22.2922.29
I-83I-83 81.7881.78
I-85I-85 92.292.2
I-86I-86 45.5745.57
I-87I-87 59.559.5
I-88I-88 241.0241.0
I-89I-89 77.8077.80
I-90I-90 151.7151.7
I-91I-91 531.1531.1
I-92I-92 30.6030.60
I-94I-94 62.262.2
I-95I-95 46.2446.24
I-96I-96 46.0846.08
I-97I-97 17.8717.87
I-98I-98 18.2318.23
实验结果表明，本发明化合物对MAT2A酶具有很好的抑制活性。The experimental results show that the compounds of the present invention have good inhibitory activity on MAT2A enzyme.
测试例2：化合物对HCT116 MTAP-/-细胞增殖的影响 Test Example 2: Effects of Compounds on the Proliferation of HCT116 MTAP-/- Cells
按照下述实验方法测定对照化合物和本发明化合物对HCT116 MTAP-/-细胞增殖的影响。 The effects of control compounds and compounds of the present invention on the proliferation of HCT116 MTAP-/- cells were determined according to the following experimental methods.
HCT116 MTAP-/-细胞培养于MCCOYS 5A培养基中，加10％FBS和1％Penicillin-Streptomycin，置于37℃、5％CO 2条件下培养。细胞常规培养至细胞饱和度为80％-90％， 收取细胞。用相应的培养基重悬，配制成合适密度的细胞悬液。将稀释好的化合物用Echo 550转移150nL至384细胞培养板；将细胞种到384细胞培养板中，400/孔，30uL。化合物的终浓度上限起始浓度为20μM，按照4倍的梯度稀释，共10个浓度，对照化合物AGI-24512起始浓度为30μM，按照3倍的梯度稀释，共10个浓度。将培养板放置细胞培养箱，37℃，5％CO 2环境中培养5天。将细胞待测板放置室温平衡30分钟，每孔加30μL CTG试剂(CelltiterGlo试剂盒)，室温避光放置30分钟后用Envision仪器读取化学发光信号值。通过检测发光值计算化合物对HCT116 MTAP-/-细胞增殖的抑制活性IC 50。 HCT116 MTAP-/- cells were cultured in MCCOYS 5A medium, 10% FBS and 1% Penicillin-Streptomycin were added, and cultured at 37°C and 5% CO 2 . The cells were routinely cultured until the cell saturation was 80%-90%, and the cells were harvested. Resuspend in the corresponding medium to prepare a cell suspension of appropriate density. Transfer 150nL of diluted compounds to 384 cell culture plate with Echo 550; seed the cells into 384 cell culture plate, 400/well, 30uL. The initial concentration of the upper limit of the final concentration of the compound was 20 μM, which was diluted according to 4-fold gradient, with a total of 10 concentrations, and the starting concentration of the control compound AGI-24512 was 30 μM, which was diluted according to 3-fold gradient, with a total of 10 concentrations. Place the culture plate in a cell culture incubator at 37°C in a 5% CO 2 environment for 5 days. The plate to be tested was placed at room temperature for 30 minutes to equilibrate, 30 μL of CTG reagent (CelltiterGlo kit) was added to each well, and the chemiluminescence signal value was read with an Envision instrument after being placed in the dark at room temperature for 30 minutes. The inhibitory activity IC 50 of the compound on HCT116 MTAP-/- cell proliferation was calculated by detecting the luminescence value.
表2测试化合物对HCT116 MTAP-/-细胞增殖的抑制结果 Table 2 Inhibitory results of test compounds on the proliferation of HCT116 MTAP-/- cells
测试化合物test compound IC50(nM)IC50(nM)
I-1I-1 173173
I-2I-2 316.50316.50
I-4I-4 115115
I-5I-5 1919
I-6I-6 149149
I-10I-10 373373
I-24I-24 455455
I-27I-27 403403
I-31I-31 176176
I-34I-34 604604
I-35I-35 295295
I-39I-39 7575
I-40I-40 3535
I-41I-41 100100
I-43I-43 637637
I-47I-47 4646
I-50I-50 678678
I-52I-52 680680
I-53I-53 673673
I-58I-58 325325
I-62I-62 441441
I-80I-80 273273
I-81I-81 402402
I-86I-86 756756
I-87I-87 756756
I-88I-88 901901
I-89I-89 649649
I-92I-92 6161
I-94I-94 431431
I-95I-95 864864
I-96I-96 8989
I-97I-97 469469
I-98I-98 5151
实验结果显示，本发明化合物对HCT116 MTAP-/-细胞增殖有很好的抑制作用。 The experimental results show that the compounds of the present invention have a good inhibitory effect on the proliferation of HCT116 MTAP-/- cells.
测试例3：化合物对HCT116 MTAP-/-细胞中SAM水平作用 Test Example 3: Effects of Compounds on SAM Levels in HCT116 MTAP-/- Cells
按照下述实验方法测定对照化合物和本发明化合物对HCT116 MTAP-/-细胞中SAM水平作用。 The effects of control compounds and compounds of the present invention on SAM levels in HCT116 MTAP-/- cells were determined according to the following experimental methods.
HCT116 MTAP-/-细胞培养于MCCOYS 5A培养基中，加10％FBS和1％Penicillin-Streptomycin，置于37℃、5％CO 2条件下培养。细胞常规培养至细胞饱和度为80％-90％，收取细胞。用相应的培养基重悬，配制成合适密度的细胞悬液，接种在96孔培养皿中24小时后，用待测化合物与细胞在37℃、5％CO 2条件下共同孵育4小时。对化合物处理后细胞中SAM水平进行检测：将细胞在碳酸铵缓冲液(75mM，pH7.4)中轻轻洗涤一次，置于干冰上，并 用代谢物提取缓冲液(含有50ng/ml氘化d3SAM的80％冷甲醇和20％乙酸)裂解。在4℃、3200rpm离心30分钟后，收集上清液并储存在-80℃直至通过LC/MS分析SAM的水平。 HCT116 MTAP-/- cells were cultured in MCCOYS 5A medium, 10% FBS and 1% Penicillin-Streptomycin were added, and cultured at 37°C and 5% CO 2 . The cells were routinely cultured until the cell saturation was 80%-90%, and the cells were harvested. The cells were resuspended in the corresponding medium to prepare a cell suspension of appropriate density, inoculated in a 96-well culture dish for 24 hours, and incubated with the test compound and cells at 37°C and 5% CO 2 for 4 hours. Detection of SAM levels in cells after compound treatment: cells were gently washed once in ammonium carbonate buffer (75 mM, pH 7.4), placed on dry ice, and washed with metabolite extraction buffer (containing 50 ng/ml deuterated d3SAM). 80% cold methanol and 20% acetic acid) cleavage. After centrifugation at 3200 rpm for 30 min at 4°C, the supernatant was collected and stored at -80°C until the level of SAM was analyzed by LC/MS.
实验结果显示，化合物对HCT116 MTAP-/-细胞中SAM水平有明显的抑制作用。 The experimental results showed that the compounds had obvious inhibitory effect on the SAM level in HCT116 MTAP-/- cells.
测试例4：小鼠药代动力学Test Example 4: Mouse Pharmacokinetics
按照下述实验方法测定对照化合物和本发明化合物的小鼠药代动力学性质。The mouse pharmacokinetic properties of the control compounds and the compounds of the present invention were determined according to the following experimental methods.
采用雄性CD-1小鼠3只，剂量为10mg/kg，给药途径为灌胃，溶媒为5％DMSO+5％NMP+10％Solutol+80％(20％HP-β-CD)，禁食过夜，采血时间点为给药前和在给药后15、30分钟以及1、2、4、6、8、24小时。血液样品6800g 2-8℃离心6分钟，收集血浆，于-80℃保存。取各时间点血浆20μL加入400μL含10ng/mL内标的甲醇，涡旋混匀后2-8℃18000g离心7分钟。取200μL转移至96孔进样板中，进行LC-MS/MS定量分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。Three male CD-1 mice were used at a dose of 10 mg/kg. The route of administration was gavage. The vehicle was 5% DMSO + 5% NMP + 10% Solutol + 80% (20% HP-β-CD). After eating overnight, blood collection time points were before administration and at 15, 30 minutes and 1, 2, 4, 6, 8, and 24 hours after administration. The blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, and the plasma was collected and stored at -80°C. Take 20 μL of plasma at each time point, add 400 μL methanol containing 10 ng/mL internal standard, vortex and mix, and centrifuge at 18000g at 2-8°C for 7 minutes. Transfer 200 μL to a 96-well injection plate for quantitative analysis by LC-MS/MS. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.
表4小鼠灌胃给药的主要药代动力学参数(均值)The main pharmacokinetic parameters of table 4 mice administered by gavage (mean value)
化合物compound C max(ng/mL) Cmax (ng/mL) T max(h) Tmax (h) AUC (0-t)(h·ng/mL) AUC (0-t) (h ng/mL) T 1/2(h) T 1/2 (h)
I-1I-1 1566815668 0.830.83 8167581675 3.53.5
I-4I-4 1528215282 0.420.42 8702387023 2.692.69
I-31I-31 83508350 0.830.83 9275392753 5.065.06
I-34I-34 3.683.68 2.002.00 1429314293 132828132828
I-35I-35 76237623 1.171.17 5459754597 3.003.00
I-39I-39 31043104 1.501.50 2315723157 3.903.90
I-42I-42 1972319723 0.580.58 6089060890 2.292.29
I-43I-43 61256125 0.500.50 2648626486 3.673.67
I-47I-47 71077107 0.670.67 3119631196 2.702.70
I-80I-80 1623516235 0.670.67 3400934009 3.33.3
I-87I-87 51975197 1.171.17 3257132571 3.53.5
实验结果表明，本发明化合物在小鼠体内表现出优良的药代动力学性质。The experimental results show that the compounds of the present invention exhibit excellent pharmacokinetic properties in mice.
测试例5：大鼠药代动力学Test Example 5: Rat Pharmacokinetics
按照下述实验方法测定对照化合物和本发明化合物的大鼠药代动力学性质。The rat pharmacokinetic properties of the control compounds and the compounds of the present invention were determined according to the following experimental methods.
采用雄性SD大鼠3只，剂量为10mg/kg，给药途径为灌胃，溶媒为5％DMSO+5％NMP+10％Solutol+80％(40％HB-CD)，禁食过夜，采血时间点为给药前和在给药后15、30分钟以及1、2、4、6、8、24小时。血液样品6800g 2-8℃离心6分钟，收集血浆，于-80℃保存。取各时间点血浆20μL加入400μL含10ng/mL内标的甲醇，涡旋混匀后2-8℃18000g离心7分钟。取200μL转移至96孔进样板中，进行LC-MS/MS定量分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。Three male SD rats were used, the dose was 10 mg/kg, the route of administration was gavage, the vehicle was 5% DMSO + 5% NMP + 10% Solutol + 80% (40% HB-CD), fasted overnight, and blood was collected. Time points were pre-dose and at 15, 30 minutes and 1, 2, 4, 6, 8, 24 hours post-dose. The blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, and the plasma was collected and stored at -80°C. Take 20 μL of plasma at each time point, add 400 μL methanol containing 10 ng/mL internal standard, vortex and mix, and centrifuge at 18000g at 2-8°C for 7 minutes. Transfer 200 μL to a 96-well injection plate for quantitative analysis by LC-MS/MS. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.
表5大鼠灌胃给药的主要药代动力学参数(均值)The main pharmacokinetic parameters (mean value) of table 5 rats administered by gavage
化合物compound C max(ng/mL) Cmax (ng/mL) T max(h) Tmax (h) AUC (0-t)(h·ng/mL) AUC (0-t) (h ng/mL) T 1/2(h) T 1/2 (h)
I-1I-1 52185218 33 3190531905 3.023.02
I-4I-4 27402740 2.672.67 1983419834 3.013.01
I-5I-5 30413041 3.333.33 3860638606 4.294.29
I-31I-31 25352535 4.004.00 2845728457 5.905.90
I-34I-34 50475047 4.004.00 4839848398 5.795.79
I-35I-35 13311331 4.674.67 1376113761 4.864.86
I-39I-39 945945 6.006.00 1497214972 NANA
I-40I-40 27962796 4.674.67 3188131881 4.224.22
实验结果表明，本发明化合物在大鼠体内表现出优良的药代动力学性质。The experimental results show that the compounds of the present invention exhibit excellent pharmacokinetic properties in rats.
测试例6：犬药代动力学Test Example 6: Canine Pharmacokinetics
采用雄性比格犬3只，剂量为3mg/kg，给药途径为灌胃，溶媒为5％DMSO+5％Solutol+90％Saline，禁食过夜，采血时间点为给药前和在给药后15、30分钟以及1、2、4、6、8、24小时。血液样品6800g 2-8℃离心6分钟，收集血浆，于-80℃保存。取各时间点血浆40μL加入400μL含100ng/mL内标的甲醇，涡旋混匀后2-8℃18000g离心7分钟。取400μL转移至96孔进样板中，进行LC-MS/MS定量分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。Three male beagle dogs were used, the dose was 3 mg/kg, the route of administration was gavage, the vehicle was 5% DMSO+5% Solutol+90% Saline, fasted overnight, and the blood collection time points were before and after administration. After 15, 30 minutes and 1, 2, 4, 6, 8, 24 hours. The blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, and the plasma was collected and stored at -80°C. Take 40 μL of plasma at each time point, add 400 μL methanol containing 100 ng/mL internal standard, vortex and mix, and then centrifuge at 18000g at 2-8°C for 7 minutes. Transfer 400 μL to a 96-well injection plate for quantitative analysis by LC-MS/MS. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.
表6大鼠灌胃给药的主要药代动力学参数(均值)The main pharmacokinetic parameters of table 6 rats administered by gavage (mean value)
化合物compound T 1/2(h) T 1/2 (h) T max(h) Tmax (h) C max(ng/mL) Cmax (ng/mL) AUC (0-t)(h·ng/mL) AUC (0-t) (h ng/mL)
I-35I-35 4.144.14 3.003.00 459459 33103310
I-72I-72 5.745.74 2.002.00 874874 50705070
实验同时表明，化合物I-72有效改善了胃肠道副作用，在给药24h后未见胃肠道不良反应。The experiment also showed that the compound I-72 effectively improved the side effects of the gastrointestinal tract, and no gastrointestinal adverse reactions were seen 24 hours after administration.
测试例7：荷瘤HCT116 MTAP-/-小鼠模型抑制实验 Test Example 7: Tumor-bearing HCT116 MTAP-/- Mouse Model Inhibition Experiment
HCT116 MTAP-/-细胞培养于MCCOYS 5A培养基中，加10％FBS和1％Penicillin-Streptomycin，置于37℃、5％CO 2条件下培养。收集对数生长期细胞，重悬于MCCOYS5A基础培养基中，调整细胞浓度至10 6个/mL。在无菌条件下，接种0.1mL细胞悬液至小鼠右侧背部皮下，接种量为10 5个细胞/0.1mL/鼠。当肿瘤达到200-300mm 3时，小鼠被随机分为对照组和不同剂量的给药组，每天给药一次，连续给药4周。每周用卡尺测量2次肿瘤体积，采用公式0.5*W*W*L计算肿瘤体积(TV)，计算结果以平均和标准误差(SEM)表示。 HCT116 MTAP-/- cells were cultured in MCCOYS 5A medium, 10% FBS and 1% Penicillin-Streptomycin were added, and cultured at 37°C and 5% CO 2 . The cells in logarithmic growth phase were collected, resuspended in MCCOYS5A basal medium, and the cell concentration was adjusted to 10 6 cells/mL. Under sterile conditions, inoculate 0.1 mL of the cell suspension subcutaneously on the right back of the mouse at an inoculation amount of 10 5 cells/0.1 mL/mouse. When the tumor reached 200-300 mm3 , the mice were randomly divided into a control group and an administration group with different doses, which were administered once a day for 4 consecutive weeks. The tumor volume was measured twice a week with a caliper, and the tumor volume (TV) was calculated using the formula 0.5*W*W*L, and the calculated results were expressed as mean and standard error (SEM).
相对肿瘤体积(relative tumor volume，RTV)计算公式为：V t/V 0，其中V 0为分组时的肿瘤体积，V t为每一次测量时的肿瘤体积。 The calculation formula of relative tumor volume (RTV) is: V t /V 0 , where V 0 is the tumor volume at the time of grouping, and V t is the tumor volume at each measurement.
相对肿瘤增值率％T/CRTV计算公式为：TRTV/CRTV 100％，其中TRTV为治疗组RTV，CRTV为阴性对照组RTV。The relative tumor proliferation rate %T/CRTV was calculated as: TRTV/CRTV 100%, where TRTV was the RTV of the treatment group, and CRTV was the RTV of the negative control group.
抑瘤率％TGI TW计算公式为：(TW C-TW T)/TW C*100％，TW C为阴性对照组平均肿瘤重量，TW T为治疗组平均肿瘤重量。 The tumor inhibition rate %TGI TW was calculated as: (TW C -TW T )/TW C *100%, where TW C was the average tumor weight of the negative control group, and T T was the average tumor weight of the treatment group.
动物体重变化％BW C计算公式为：(BW t-BW 0)/BW 0*100％，其中BW t为每次测量时动物体重，BW 0为分组时动物体重。 The calculation formula of animal body weight change % BW C is: (BW t -BW 0 )/BW 0 *100%, where BW t is the animal body weight at each measurement, and BW 0 is the animal body weight at the time of grouping.
以上对本发明技术方案的实施方式进行了示例性的说明。应当理解，本发明的保护范围不拘囿于上述实施方式。凡在本发明的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。The embodiments of the technical solutions of the present invention have been exemplarily described above. It should be understood that the protection scope of the present invention is not limited to the above-mentioned embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention shall be included within the protection scope of the claims of the present application.

Claims (35)

  1. 一种化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：A compound, which is a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound shown in formula I or a compound shown in formula I:
    Figure PCTCN2022087589-appb-100001
    Figure PCTCN2022087589-appb-100001
    其中，in,
    W是-C(R 3)＝或-N＝；X是-C(R 4)＝或-N＝；Y是-C(R 5)＝；Z是-C(R 6)＝或-N＝；其中： W is -C(R 3 )= or -N=; X is -C(R 4 )= or -N=; Y is -C(R 5 )=; Z is -C(R 6 )= or -N =; where:
    R 3选自氢、烷基、烯基、炔基、烷氧基、烷基磺酰基、卤素、卤代烷基、卤代烷氧基、环烷基、环烷基烷氧基、氰基、氨基、烷基氨基、二烷基氨基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、羟基烷基、羟基烷氧基、羟基烷基氨基、烷氧基烷基、烷氧基烷氧基、烷氧基烷基氨基、氨基烷基、氨基烷氧基、氨基烷基氨基、杂芳基、杂芳氧基、杂芳烷氧基、杂芳基氨基、杂环烷基、杂环基氧基、杂环基氨基、杂环基烷氧基、杂环基氧基烷氧基和杂环基氧基烷基氨基，R 3本身或作为另一个基团的一部分是未被取代的或者被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自烷基、环烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤素、氰基、烷氧基羰基、羟烷基、烷氧基烷基和氨基烷基； R is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkoxy, cyano, amino, alkane amino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxy Oxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkoxy, heteroarylamino, heterocycloalkyl, heterocyclyloxy , heterocyclylamino, heterocyclylalkoxy, heterocyclyloxyalkoxy, and heterocyclyloxyalkylamino, R is unsubstituted by itself or as part of another group or is replaced by R a , R b and/ or R c substituted independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano group, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl and aminoalkyl;
    R 5选自氢、烷基、烯基、炔基、烷氧基、烷基磺酰基、卤素、卤代烷基、卤代烷氧基、环烷基、氰基、氨基、烷基氨基、二烷基氨基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、羟基烷基、羟基烷氧基、羟基烷基氨基、烷氧基烷基、烷氧基烷氧基、烷氧基烷基氨基、氨基烷基、氨基烷氧基、氨基烷基氨基、杂芳基、杂芳氧基、杂芳基氨基、杂环基、杂环基氧基、杂环基氨基、杂环基氧基烷氧基，R 5本身或作为另一个基团的一部分是未被取代的或者被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自烷基、环烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤素、氰基、羟烷基、烷氧基烷基和氨基烷基； R 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino , alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxy Alkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyl Oxyalkoxy , R is unsubstituted by itself or as part of another group or is substituted by Ra , Rb and/ or Rc independently selected from the group consisting of alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl and aminoalkyl;
    R 4和R 6各自独立地选自氢、烷基、烯基、炔基、烷氧基、烷硫基、烷基磺酰基、卤素、卤代烷基、卤代烷氧基、环烷基、氰基、氨基、烷基氨基、二烷基氨基、氨基羰基、烷基氨基羰基或二烷基氨基羰基； R4 and R6 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl;
    条件是：(i)W、X和Z中最多一个可以为-N＝，并且(ii)R 3、R 4、R 5和R 6中至少一个不是氢； Provided that: (i) at most one of W, X, and Z may be -N=, and (ii ) at least one of R3 , R4, R5 , and R6 is not hydrogen ;
    R 1选自环烷基、桥连的环烷基、稠合的环烷基、螺环烷基、芳基、杂芳基、杂环基、桥连杂环基、稠合杂环基或螺杂环基，其中芳基、杂芳基或杂环基无取代或被R d、R e和/或R f取代； R 1 is selected from cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl or spiroheterocyclyl, wherein aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with Rd , Re and/or Rf ;
    R 2为-NR 7R 8，其中： R 2 is -NR 7 R 8 , where:
    R 7选自氢、烷基、氘代烷基和环烷基； R is selected from hydrogen, alkyl, deuterated alkyl and cycloalkyl;
    R 8选自氢、烷基、氘代烷基、卤代烷基、羟基烷基、烷氧基烷基、卤代烷氧基烷基、氨基烷基、氨基磺酰基烷基、硫脲基烷基、烷基磺酰基、烷基磺酰基烷基、氰基烷基、烷基羰基、烷氧基羰基、烷基氨基羰基、二烷基氨基羰基、氨基羰基烷基、环烷基、环烷基烷基、取代的环烷基、取代的环烷基烷基、环烷氧基烷基、桥连的环烷基、桥连的环烷基环烷基、稠合的环烷基、螺环烷基，螺环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂芳基羰基、杂环基、杂环基烷基、杂环基羰基、杂环基氧基烷基、稠合的杂环基、稠合的杂环基烷基、桥连的杂环基、桥连的杂环基烷基、螺杂环基和螺杂环基烷基；所述R 8是未被取代的 或者被R j、R k和/或R L取代； R 8 is selected from hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl, thioureidoalkyl, alkane Sulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl , substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylcycloalkyl, fused cycloalkyl, spirocycloalkyl , spirocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxy alkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl; the R 8 is unsubstituted or substituted with R j , R k and/or RL ;
    或者R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述杂环烷基是未被取代的或者被R j、R k和/或R L取代； or R 7 , R 8 together with the N atom to which they are commonly attached form a 4-6 membered heterocycloalkyl which is unsubstituted or substituted with R j , R k and/or RL ;
    或者R 7、R 8与它们共同连接的N原子一起形成6-12元螺杂环基、6-12元桥连的杂环基、6-12元杂并环烷基，所述6-12元螺杂环基、6-12元桥连的杂环基和6-12元杂并环烷基是未被取代的或者被R j、R k和/或R L取代，所述6-12元螺杂环基、6-12元桥连的杂环基和6-12元杂并环烷基的1-5个环原子独立选自N、O和S； Or R 7 , R 8 together with the N atom to which they are connected together form a 6-12-membered spiro heterocyclyl, a 6-12-membered bridged heterocyclyl, a 6-12-membered heterocycloalkyl, and the 6-12 membered heterocyclyl Member spiroheterocyclyl, 6-12 membered bridged heterocyclyl and 6-12 membered heterocycloalkyl are unsubstituted or substituted by R j , R k and/or RL , the 6-12 1-5 ring atoms of membered spiroheterocyclyl, 6-12 membered bridged heterocyclyl and 6-12 membered heterocycloalkyl are independently selected from N, O and S;
    R d、R e、R j和R k各自独立地选自烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、烷基磺酰基、卤素、氰基、羧基、烷氧基羰基、羟烷基、烷氧基烷基、氨基烷基、氨基磺酰基、烷基氨基磺酰基、二烷基氨基磺酰基、磺酰基氨基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、杂环羰基和脲基； R d , Re , R j and R k are each independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxy Alkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocycle carbonyl and urea groups;
    R f和R L各自独立地选自烷基、环烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤素、氨基、烷基氨基、环烷基磺酰基氨基、氰基、氰基烷基、烷氧基羰基烷基、羧烷基、氨基羰基烷基和-X c-R 9，其中X c选自键、亚烷基和杂亚烷基，R 9选自任选被取代的芳基、任选被取代的杂芳基和任选被取代的杂环基。 Rf and RL are each independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino, alkylamino, cycloalkylsulfonylamino, cyano, cyano Alkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl and -Xc-R9, wherein Xc is selected from bond, alkylene and heteroalkylene, and R9 is selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.
  2. 如权利要求1所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：The compound of claim 1, which is a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound represented by the formula I or the compound represented by the formula I:
    Figure PCTCN2022087589-appb-100002
    Figure PCTCN2022087589-appb-100002
    其中，W、X、Y、Z、R 1的定义如权利要求1所述； Wherein, the definitions of W, X, Y, Z, R 1 are as described in claim 1;
    R 2为-NR 7R 8，其中： R 2 is -NR 7 R 8 , where:
    R 7选自氢、烷基、氘代烷基或环烷基； R is selected from hydrogen, alkyl, deuterated alkyl or cycloalkyl;
    R 8选自氢、烷基、氘代烷基、卤代烷基、羟基烷基、烷氧基烷基、卤代烷氧基烷基、氨基烷基、氨基磺酰基烷基、硫脲基烷基、烷基磺酰基、烷基磺酰基烷基、氰基烷基、烷基羰基、烷氧基羰基、烷基氨基羰基、二烷基氨基羰基、氨基羰基烷基、环烷基、环烷基烷基、取代的环烷基、取代的环烷基烷基、环烷氧基烷基、桥连的环烷基、桥连的环烷基环烷基、稠合的环烷基、螺环烷基，螺环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂芳基羰基、杂环基、杂环基烷基、杂环基羰基、杂环基氧基烷基、稠合的杂环基、稠合的杂环基烷基、桥连的杂环基、桥连的杂环基烷基、螺杂环基和螺杂环基烷基；所述R 8是未被取代的或者被R j、R k和/或R L取代； R 8 is selected from hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl, thioureidoalkyl, alkane Sulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl , substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylcycloalkyl, fused cycloalkyl, spirocycloalkyl , spirocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxy alkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl; the R 8 is unsubstituted or substituted with R j , R k and/or RL ;
    或者R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述杂环烷基是未被取代的或者被R j、R k和/或R L取代； or R 7 , R 8 together with the N atom to which they are commonly attached form a 4-6 membered heterocycloalkyl which is unsubstituted or substituted with R j , R k and/or RL ;
    R j、R k和R L的定义如权利要求1所述。 The definitions of R j , R k and RL are as described in claim 1 .
  3. 如权利要求1或2所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中：R 2为-NR 7R 8，并且R 7和R 8不同时为氢。 The compound according to claim 1 or 2, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or pro-form of the compound represented by formula I drug, wherein: R 2 is -NR 7 R 8 , and R 7 and R 8 are not both hydrogen.
  4. 如权利要求1-3任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中：The compound according to any one of claims 1-3, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I A salt or prodrug, wherein:
    W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝； W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 )=;
    或者，W是-N＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝； Alternatively, W is -N=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 )=;
    或者，W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-N＝； Alternatively, W is -C( R3 )=, X is -C(R4 ) =, Y is -C(R5 ) =, Z is -N=;
    或者，W是-C(R 3)＝，X是-N＝，Y是-C(R 5)＝，Z是-C(R 6)＝。 Alternatively, W is -C(R 3 )=, X is -N=, Y is -C(R 5 )=, and Z is -C(R 6 )=.
  5. 如权利要求1-4任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，具有结构Im、In、Ip或IqThe compound according to any one of claims 1-4, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I Salts or prodrugs, having the structure Im, In, Ip or Iq
    Figure PCTCN2022087589-appb-100003
    Figure PCTCN2022087589-appb-100003
    其中，R 1、R 2、R 3、R 4、R 5、R 6的定义如权利要求1中所述； Wherein, the definitions of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as described in claim 1;
    较佳地，R 3、R 4、R 6为氢。 Preferably, R 3 , R 4 and R 6 are hydrogen.
  6. 如权利要求1-5任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 1为苯基或吡啶基；所述苯基或吡啶基被1或2个选自下列的取代基取代：卤素、羟基、氰基、C 1-C 6烷基、-O-C 1-C 6烷基；当取代基为多个时，所述取代基相同或不同； The compound according to any one of claims 1-5, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I Salt or prodrug, characterized in that R 1 is phenyl or pyridyl; the phenyl or pyridyl is substituted by 1 or 2 substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, -OC 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
    较佳地，所述苯基或吡啶基被1或2个选自下列的取代基取代：卤素、羟基、氰基、C 1-C 3烷基、-O-C 1-C 3烷基； Preferably, the phenyl or pyridyl is substituted by 1 or 2 substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1 -C 3 alkyl, -OC 1 -C 3 alkyl;
    较佳地，所述卤素为F或Cl；Preferably, the halogen is F or Cl;
    较佳地，R 1选自被1个或2个氟取代的下列基团：苯基或吡啶基。 Preferably, R 1 is selected from the following groups substituted with 1 or 2 fluorines: phenyl or pyridyl.
  7. 如权利要求1-6任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 5选自：卤素、C 1-C 6烷基、3-6元环烷基；所述C 1-C 6烷基任选地被卤素取代； The compound according to any one of claims 1-6, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I A salt or prodrug, characterized in that R 5 is selected from: halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl; the C 1 -C 6 alkyl is optionally substituted by halogen;
    较佳地，R 5选自：卤素、C 1-C 3烷基、C 1-C 3卤代烷基、环丙基； Preferably, R 5 is selected from: halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyclopropyl;
    较佳地，所述卤素为F或Cl；Preferably, the halogen is F or Cl;
    较佳地，R 5选自：-F、-Cl、-CH 3、-CF 2、-CF 3、环丙基。 Preferably, R 5 is selected from: -F, -Cl, -CH 3 , -CF 2 , -CF 3 , cyclopropyl.
  8. 如权利要求1-7任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中R 2为-NR 7R 8，当R 7、R 8与它们共同连接的N原子一起形成6-12元螺杂环基、6-12元桥连的杂环基、6-12元杂并环烷基时，所述R 2为：
    Figure PCTCN2022087589-appb-100004
    其中环A为4-6元杂环烷基，R A1、R A2以及环A的部分环原子相连形成3-7元环烷基或3-7元杂环烷基，所述3-7元杂环烷基的1-3个环原子独立选自N、O和S，所述R 2是未被取代的或者被R j、R k和/或R L取代。     The compound according to any one of claims 1-7, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I Salts or prodrugs, wherein R 2 is -NR 7 R 8 , when R 7 and R 8 together with the N atom to which they are attached together form a 6-12-membered spiro heterocyclyl, a 6-12-membered bridged heterocyclyl, When 6-12 membered heterocycloalkyl, the R 2 is:
    Figure PCTCN2022087589-appb-100004
    wherein Ring A is a 4-6 membered heterocycloalkyl, and R A1 , R A2 and some ring atoms of Ring A are connected to form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, and the 3-7 membered 1-3 ring atoms of heterocycloalkyl are independently selected from N, O and S , and R2 is unsubstituted or substituted with Rj , Rk and/or RL .
  9. 如权利要求5所述的的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中R 2选自无取代的或被R j、R k和/或R L取代的以下基团：
    Figure PCTCN2022087589-appb-100005
    Figure PCTCN2022087589-appb-100006
    其中R A1、R A2以及环A的部分环原子相连形成3-7元环烷基或3-7元杂环烷基，所述3-7元杂环烷基的1-3个环原子独立选自N、O和S；     The compound of claim 5, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula I , wherein R 2 is selected from the following groups unsubstituted or substituted by R j , R k and/or RL :
    Figure PCTCN2022087589-appb-100005
    Figure PCTCN2022087589-appb-100006
    wherein R A1 , R A2 and some ring atoms of ring A are connected to form a 3-7-membered cycloalkyl or a 3-7-membered heterocycloalkyl, and 1-3 ring atoms of the 3-7-membered heterocycloalkyl are independent selected from N, O and S;
    优选地，R 2选自无取代的或被R j、R k和/或R L取代的以下基团：
    Figure PCTCN2022087589-appb-100007
    Figure PCTCN2022087589-appb-100008
    Preferably, R 2 is selected from the following groups unsubstituted or substituted by R j , R k and/or RL :
    Figure PCTCN2022087589-appb-100007
    Figure PCTCN2022087589-appb-100008
  10. 如权利要求1-9任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中：The compound according to any one of claims 1-9, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I A salt or prodrug, wherein:
    R 3选自氢、C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 1-C 10烷氧基、C 1-C 10烷基磺酰基、卤素、被1-5个相同或不同的卤素取代的C 1-C 10烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷氧基、C 3-C 10环烷基、氰基、氨基、(C 1-C 10烷基)-NH-、N(C 1-C 10烷基) 2-、氨基羰基、(C 1-C 10烷基)-NH-C(O)-、N(C 1-C 10烷基) 2-C(O)-、被1-5个羟基取代的C 1-C 10烷基、被1-5个羟基取代的C 1-C 10烷氧基、(被1-5个羟基取代的C 1-C 10烷基)-NH-、被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷基、被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷氧基、(被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷基)-NH-、被1-5个氨基取代的C 1-C 10烷基、被1-5个氨基取代的C 1-C 10烷氧基、(被1-5个氨基取代的C 1-C 10烷基)-NH-，R 3本身或作为另一个基团的一部分是未被取代的或者被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自烷基、环烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤素、氰基、烷氧基羰基、羟烷基、烷氧基烷基和氨基烷基； R 3 is selected from hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylsulfonyl, halogen , C 1 -C 10 alkyl substituted by 1-5 identical or different halogens, C 1 -C 10 alkoxy substituted by 1-5 identical or different halogens, C 3 -C 10 cycloalkyl , cyano, amino, (C 1 -C 10 alkyl)-NH-, N(C 1 -C 10 alkyl) 2 -, aminocarbonyl, (C 1 -C 10 alkyl)-NH-C(O )-, N(C 1 -C 10 alkyl) 2 -C(O)-, C 1 -C 10 alkyl substituted with 1-5 hydroxy groups, C 1 -C 10 substituted with 1-5 hydroxy groups Alkoxy, (C 1 -C 10 alkyl substituted with 1-5 hydroxyl groups)-NH-, C 1 -C 10 alkane substituted with 1-5 identical or different C 1 -C 10 alkoxy groups base, C 1 -C 10 alkoxy substituted by 1-5 identical or different C 1 -C 10 alkoxy , (substituted by 1-5 identical or different C 1 -C 10 alkoxy C 1 -C 10 alkyl)-NH-, C 1 -C 10 alkyl substituted by 1-5 amino groups, C 1 -C 10 alkoxy substituted by 1-5 amino groups, (substituted by 1-5 amino-substituted C 1 -C 10 alkyl)-NH-, R is unsubstituted by itself or as part of another group or is substituted by R a , R b and/or R c , said R a , R b and/or R c are independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkane groups and aminoalkyl groups;
    R 5选自氢、C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 1-C 10烷氧基、C 1-C 10烷基磺酰基、卤素、被1-5个相同或不同的卤素取代的C 1-C 10烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷氧基、C 3-C 10环烷基、氰基、氨基、(C 1-C 10烷基)-NH-、N(C 1-C 10烷基) 2-、(C 1-C 10烷氧基)-C(O)-、氨基羰基、(C 1-C 10烷基)-氨基羰基、(C 1-C 10烷基) 2-氨基羰基、被1-5个羟基取代的C 1-C 10烷基、被1-5个羟基取代的C 1-C 10烷氧基、(被1-5个羟基取代的C 1-C 10烷基)-NH-、被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷基、被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷氧基、(被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷基)-NH-、被1-5个氨基取代的C 1-C 10烷基、被1-5个氨基取代的C 1-C 10烷氧基、(被1-5个氨基取代的C 1-C 10烷基)-NH-，R 5本身或作为另一个基团的一部分是未被取代的或者被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自烷基、环烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤素、氰基、羟烷基、烷氧基烷基和氨基烷基； R 5 is selected from hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylsulfonyl, halogen , C 1 -C 10 alkyl substituted by 1-5 identical or different halogens, C 1 -C 10 alkoxy substituted by 1-5 identical or different halogens, C 3 -C 10 cycloalkyl , cyano, amino, (C 1 -C 10 alkyl)-NH-, N(C 1 -C 10 alkyl) 2 -, (C 1 -C 10 alkoxy)-C(O)-, amino Carbonyl, (C 1 -C 10 alkyl)-aminocarbonyl, (C 1 -C 10 alkyl) 2 -aminocarbonyl, C 1 -C 10 alkyl substituted by 1-5 hydroxy, substituted by 1-5 Hydroxy-substituted C 1 -C 10 alkoxy, (C 1 -C 10 alkyl substituted with 1-5 hydroxy)-NH-, C 1 -C 10 alkoxy substituted with 1-5 identical or different Substituted C 1 -C 10 alkyl, C 1 -C 10 alkoxy substituted by 1-5 identical or different C 1 -C 10 alkoxy , (by 1-5 identical or different C 1 -C 10 alkoxy substituted C 1 -C 10 alkyl) -NH-, C 1 -C 10 alkyl substituted with 1-5 amino groups, C 1 -C 10 alkane substituted with 1-5 amino groups oxy, (C 1 -C 10 alkyl substituted with 1-5 amino groups)-NH-, R 5 is unsubstituted by itself or as part of another group or is replaced by R a , R b and/or Substituted with R c , the R a , R b and/or R c are independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkane oxyalkyl and aminoalkyl;
    R 4和R 6各自独立地选自氢、C 1-C 10烷基、C 2-C 10烯基、C 2-C 10炔基、C 1-C 10烷氧基、C 1-C 10烷硫基、C 1-C 10烷基磺酰基、卤素、被1-5个相同或不同的卤素取代的C 1-C 10烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷氧基、C 3-C 10环烷基、氰基、氨基、(C 1-C 10烷基)-NH-、N(C 1-C 10烷基) 2-、氨基羰基、(C 1-C 10烷基)-氨基羰基、(C 1-C 10烷基) 2-氨基羰基； R 4 and R 6 are each independently selected from hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 1 -C 10 Alkylthio, C 1 -C 10 alkylsulfonyl, halogen, C 1 -C 10 alkyl substituted with 1-5 identical or different halogens, C 1 substituted with 1-5 identical or different halogens -C 10 alkoxy, C 3 -C 10 cycloalkyl, cyano, amino, (C 1 -C 10 alkyl)-NH-, N(C 1 -C 10 alkyl) 2 -, aminocarbonyl, (C 1 -C 10 alkyl)-aminocarbonyl, (C 1 -C 10 alkyl) 2 -aminocarbonyl;
    条件是：(i)W、X和Z中最多一个可以为-N＝，并且(ii)R 3、R 4、R 5和R 6中至少一 个不是氢； Provided that: (i) at most one of W, X, and Z may be -N=, and (ii ) at least one of R3 , R4, R5 , and R6 is not hydrogen ;
    R 1选自C 6-C 10芳基、5-10元杂芳基、3-10元杂环基、5-10元桥连杂环基、5-10元稠合杂环基或5-10元螺杂环基，其中C 5-C 10芳基、5-10元杂芳基或3-10元杂环基无取代或被R d、R e和/或R f取代； R 1 is selected from C 6 -C 10 aryl, 5-10-membered heteroaryl, 3-10-membered heterocyclyl, 5-10-membered bridged heterocyclyl, 5-10-membered fused heterocyclyl or 5- 10-membered spiro heterocyclyl, wherein C 5 -C 10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl is unsubstituted or substituted by R d , Re and/or R f ;
    R 2为-NR 7R 8，其中： R 2 is -NR 7 R 8 , where:
    R 7选自氢、C 1-C 10烷基、氘代C 1-C 10烷基或C 3-C 10环烷基； R 7 is selected from hydrogen, C 1 -C 10 alkyl, deuterated C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl;
    R 8选自氢、C 1-C 10烷基、氘代C 1-C 10烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷基、被1-5个羟基取代的C 1-C 10烷基、被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷基、(被1-5个相同或不同的卤素取代的C 1-C 10烷氧基)-(C 1-C 10亚烷基)-、被1-5个氨基取代的C 1-C 10烷基、被1-5个氨基磺酰基取代的C 1-C 10烷基、被1-5个硫脲基取代的C 1-C 10烷基、C 1-C 10烷基磺酰基、(C 1-C 10烷基磺酰基)-(C 1-C 10亚烷基)-、被1-5个氰基取代的C 1-C 10烷基、(C 1-C 10烷基)-C(O)-、(C 1-C 10烷氧基)-C(O)-、(C 1-C 10烷基)-NH-C(O)-、N(C 1-C 10烷基) 2-C(O)-、被氨基羰基取代的C 1-C 10烷基、C 3-C 10环烷基、被1-3个C 3-C 10环烷基取代的C 1-C 10烷基、被1-3个C 3-C 10环烷氧基取代的C 1-C 10烷基、桥连的C 5-C 10环烷基、被桥连的C 5-C 10环烷基取代的C 3-C 10环烷基、稠合的C 5-C 10环烷基、C 6-C 10螺环烷基、被C 6-C 10螺环烷基取代的C 1-C 10烷基、C 5-C 10芳基、被1-5个相同或不同的C 5-C 10芳基取代的C 1-C 10烷基、5-10元杂芳基、被1-5个相同或不同的5-10元杂芳基取代的C 1-C 10烷基、(5-10元杂芳基)-C(O)-、3-10元杂环基、被1-5个相同或不同的3-10元杂环基取代的C 1-C 10烷基、(3-10元杂环基)-C(O)-、(3-10元杂环基)-O-(C 1-C 10亚烷基)-、5-10元稠合杂环基、被1-5个相同或不同的5-10元稠合杂环基取代的C 1-C 10烷基、5-10元桥连杂环基、被1-5个相同或不同的5-10元桥连杂环基取代的C 1-C 10烷基、5-10元螺杂环基、被1-5个相同或不同的5-10元螺杂环基取代的C 1-C 10烷基；所述R 8无取代或被R j、R k和/或R L取代； R 8 is selected from hydrogen, C 1 -C 10 alkyl, deuterated C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted with 1-5 identical or different halogens, 1-5 hydroxyl groups Substituted C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted by 1-5 identical or different C 1 -C 10 alkoxy, (substituted by 1-5 identical or different halogen C 1 -C 10 alkoxy)-(C 1 -C 10 alkylene)-, C 1 -C 10 alkyl substituted with 1-5 amino groups, C 1 substituted with 1-5 aminosulfonyl groups -C 10 alkyl, C 1 -C 10 alkyl substituted with 1-5 thiourea groups, C 1 -C 10 alkylsulfonyl, (C 1 -C 10 alkylsulfonyl)-(C 1 - C 10 alkylene)-, C 1 -C 10 alkyl substituted with 1-5 cyano groups, (C 1 -C 10 alkyl)-C(O)-, (C 1 -C 10 alkoxy )-C(O)-, (C 1 -C 10 alkyl)-NH-C(O)-, N(C 1 -C 10 alkyl) 2 -C(O)-, C substituted with aminocarbonyl 1 - C10 alkyl, C3 - C10 cycloalkyl, C1 - C10 alkyl substituted by 1-3 C3 - C10 cycloalkyl, 1-3 C3- C10 ring Alkoxy substituted C 1 -C 10 alkyl, bridged C 5 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl substituted by bridged C 5 -C 10 cycloalkyl, fused C 5 -C 10 cycloalkyl, C 6 -C 10 spiro cycloalkyl, C 1 -C 10 alkyl substituted by C 6 -C 10 spiro cycloalkyl, C 5 -C 10 aryl, 1 -C 1 -C 10 alkyl substituted with 5 identical or different C 5 -C 10 aryl groups, 5-10 membered heteroaryl, substituted by 1-5 identical or different 5-10 membered heteroaryl groups C 1 -C 10 alkyl, (5-10 membered heteroaryl)-C(O)-, 3-10 membered heterocyclyl, substituted by 1-5 same or different 3-10 membered heterocyclyl C 1 -C 10 alkyl, (3-10 membered heterocyclyl)-C(O)-, (3-10 membered heterocyclyl)-O-(C 1 -C 10 alkylene)-, 5- 10-membered fused heterocyclic group, C 1 -C 10 alkyl substituted by 1-5 identical or different 5-10-membered fused heterocyclic groups, 5-10-membered bridged heterocyclic group, 1-5 C 1 -C 10 alkyl substituted by the same or different 5-10 membered bridged heterocyclyl, 5-10 membered spiroheterocyclyl, 5-10 membered spiroheterocyclyl substituted by 1-5 same or different 5-10 membered heterocyclyl Substituted C 1 -C 10 alkyl; said R 8 is unsubstituted or substituted with R j , R k and/or RL ;
    或者R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基是未被取代的或者被R j、R k和/或R L取代； Alternatively R 7 , R 8 together with the N atom to which they are commonly attached form a 4-6 membered heterocycloalkyl group which is unsubstituted or is replaced by R j , R k and/or R L replaced;
    R d、R e、R j和R k各自独立地选自C 1-C 10烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷氧基、C 1-C 10烷氧基、羟基、C 1-C 10烷基磺酰基、卤素、氰基、羧基、(C 1-C 10烷氧基)-C(O)-、被1-5个羟基取代的C 1-C 10烷基、被1-5个相同或不同的C 1-C 10烷氧基取代的C 1-C 10烷基、被1-5个氨基取代的C 1-C 10烷基、氨基磺酰基、(C 1-C 10烷基)-NH-S(O) 2-、N(C 1-C 10烷基) 2-S(O) 2-、磺酰基氨基、氨基羰基、(C 1-C 10烷基)-NH-C(O)-、N(C 1-C 10烷基) 2-C(O)-、(3-10元杂环基)-C(O)-和脲基； R d , R e , R j and R k are each independently selected from C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted with 1-5 identical or different halogens, identical with 1-5 or different halogen substituted C 1 -C 10 alkoxy, C 1 -C 10 alkoxy, hydroxyl, C 1 -C 10 alkylsulfonyl, halogen, cyano, carboxyl, (C 1 -C 10 alkane oxy)-C(O)-, C 1 -C 10 alkyl substituted with 1-5 hydroxyl groups, C 1 -C 10 substituted with 1-5 identical or different C 1 -C 10 alkoxy groups Alkyl, C 1 -C 10 alkyl substituted with 1-5 amino groups, aminosulfonyl, (C 1 -C 10 alkyl)-NH-S(O) 2 -, N(C 1 -C 10 alkane base) 2 -S(O) 2 -, sulfonylamino, aminocarbonyl, (C 1 -C 10 alkyl)-NH-C(O)-, N(C 1 -C 10 alkyl) 2 -C( O)-, (3-10 membered heterocyclyl)-C(O)- and ureido;
    R f和R L各自独立地选自C 1-C 10烷基、C 5-C 10环烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷基、被1-5个相同或不同的卤素取代的C 1-C 10烷氧基、C 1-C 10烷氧基、羟基、卤素、氨基、(C 1-C 10烷基)-NH-、(C 3-C 10环烷基)-S(O) 2-NH-、氰基、被1-5个氰基取代的C 1-C 10烷基、被1-5个相同或不同的C 1-C 10烷氧基羰基取代的C 1-C 10烷基、被羧基取代的C 1-C 10烷基、被氨基羰基取代的C 1-C 10烷基、-X c-R 9，其中X c选自键、C 1-C 5亚烷基和C 1-C 5杂亚烷基，R 9选自任选被取代的C 5-C 10芳基、任选被取代的5-10元杂芳基和任选被取代的5-10元杂环基。 R f and RL are each independently selected from C 1 -C 10 alkyl, C 5 -C 10 cycloalkyl, C 1 -C 10 alkyl substituted with 1-5 identical or different halogens, C 1 -C 10 alkyl substituted with 1- 5 identical or different halogen-substituted C 1 -C 10 alkoxy, C 1 -C 10 alkoxy, hydroxy, halogen, amino, (C 1 -C 10 alkyl)-NH-, (C 3 - C 10 cycloalkyl)-S(O) 2 -NH-, cyano, C 1 -C 10 alkyl substituted with 1-5 cyano groups, C 1 -C 10 with 1-5 identical or different C 1 -C 10 alkyl substituted by alkoxycarbonyl, C 1 -C 10 alkyl substituted by carboxyl, C 1 -C 10 alkyl substituted by aminocarbonyl, -X c -R 9 , wherein X c is selected from Self-bond, C 1 -C 5 alkylene and C 1 -C 5 heteroalkylene, R 9 is selected from optionally substituted C 5 -C 10 aryl, optionally substituted 5-10 membered heteroaryl and optionally substituted 5-10 membered heterocyclyl.
  11. 如权利要求1-10任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中：The compound according to any one of claims 1-10, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I A salt or prodrug, wherein:
    R 3选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、氰基、氨基、(C 1-C 6烷基)-NH-、N(C 1-C 6烷基) 2-、被1-3个羟基取代的C 1-C 6烷基、被1-3个氨基取代的C 1-C 6烷基、被1-3个氨基取代的C 1-C 6烷氧基、(被1-3个氨基取代的C 1-C 6烷基)-NH-，R 3本身或作为另一个基团的一部分是未被取代的或者被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自C 1-C 3烷基、C 3-C 6环烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷氧基、C 1-C 3烷氧基、羟基、卤素、氰基； R 3 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogen, 1-5 identical or different Halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy substituted with 1-5 identical or different halogens, cyano, amino, (C 1 -C 6 alkyl)-NH-, N(C 1 -C 6 alkyl) 2 -, C 1 -C 6 alkyl substituted with 1-3 hydroxy groups, C 1 -C 6 alkyl substituted with 1-3 amino groups, C 1 -C 6 alkyl substituted with 1-3 amino groups Amino-substituted C1 -C6alkoxy, ( C1 - C6alkyl substituted with 1-3 amino groups)-NH-, R3 by itself or as part of another group is unsubstituted or Substituted by Ra, Rb and / or Rc independently selected from C1 - C3 alkyl, C3 - C6 cycloalkyl, 1-5 C 1 -C 3 alkyl substituted by the same or different halogen, C 1 -C 3 alkoxy substituted by 1-5 same or different halogen, C 1 -C 3 alkoxy, hydroxyl, halogen, cyano group;
    R 5选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6烷基磺酰基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 3-C 6环烷基、氰基、氨基、(C 1-C 6烷基)-NH-、N(C 1-C 6烷基) 2-、(C 1-C 6烷氧基)-C(O)-、氨基羰基、(C 1-C 6烷基)-氨基羰基、(C 1-C 6烷基) 2-氨基羰基、被1-3个羟基取代的C 1-C 6烷基、被1-3个羟基取代的C 1-C 6烷氧基、(被1-3个羟基取代的C 1-C 6烷基)-NH-、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷氧基、(被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基)-NH-、被1-3个氨基取代的C 1-C 6烷基、被1-3个氨基取代的C 1-C 6烷氧基、(被1-3个氨基取代的C 1-C 6烷基)-NH-，R 5本身或作为另一个基团的一部分是未被取代的或者被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自C 1-C 3烷基、C 3-C 6环烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷氧基、C 1-C 3烷氧基、羟基、卤素、氰基、被1-2个羟基取代的C 1-C 3烷基、被1-3个相同或不同的C 1-C 3烷氧基取代的C 1-C 3烷基和被1-2个氨基取代的C 1-C 3烷基； R 5 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfonyl, halogen , C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 alkoxy substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl , cyano, amino, (C 1 -C 6 alkyl)-NH-, N(C 1 -C 6 alkyl) 2 -, (C 1 -C 6 alkoxy)-C(O)-, amino Carbonyl, (C 1 -C 6 alkyl)-aminocarbonyl, (C 1 -C 6 alkyl) 2 -aminocarbonyl, C 1 -C 6 alkyl substituted by 1-3 hydroxy, substituted by 1-3 Hydroxy-substituted C 1 -C 6 alkoxy, (C 1 -C 6 alkyl substituted with 1-3 hydroxy)-NH-, C 1 -C 6 alkoxy substituted with 1-3 same or different Substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy substituted by 1-3 identical or different C 1 -C 6 alkoxy , (by 1-3 identical or different C 1 -C 6 alkoxy substituted C 1 -C 6 alkyl) -NH-, C 1 -C 6 alkyl substituted with 1-3 amino groups, C 1 -C 6 alkane substituted with 1-3 amino groups Oxygen, (C 1 -C 6 alkyl substituted with 1-3 amino groups)-NH-, R 5 is unsubstituted by itself or as part of another group or is unsubstituted by R a , R b and/or R c substituted, said R a , R b and/or R c independently selected from C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C substituted with 1-5 identical or different halogens 1 - C3 alkyl, C1 - C3 alkoxy substituted by 1-5 identical or different halogens, C1 - C3 alkoxy, hydroxy, halogen, cyano, substituted by 1-2 hydroxy Substituted C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted with 1-3 identical or different C 1 -C 3 alkoxy and C 1 -C 3 substituted with 1-2 amino groups alkyl;
    R 4和R 6各自独立地选自氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 6烷基磺酰基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 3-C 6环烷基、氰基、氨基、(C 1-C 6烷基)-NH-、N(C 1-C 6烷基) 2-、氨基羰基、(C 1-C 6烷基)-氨基羰基、(C 1-C 6烷基) 2-氨基羰基； R 4 and R 6 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 alkylsulfonyl, halogen, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 substituted with 1-5 identical or different halogens -C 6 alkoxy, C 3 -C 6 cycloalkyl, cyano, amino, (C 1 -C 6 alkyl)-NH-, N(C 1 -C 6 alkyl) 2 -, aminocarbonyl, (C 1 -C 6 alkyl)-aminocarbonyl, (C 1 -C 6 alkyl) 2 -aminocarbonyl;
    条件是：(i)W、X和Z中最多一个可以为-N＝，并且(ii)R 3、R 4、R 5和R 6中至少一个不是氢； Provided that: (i) at most one of W, X, and Z may be -N=, and (ii ) at least one of R3 , R4, R5 , and R6 is not hydrogen ;
    R 1选自C 6-C 10芳基、5-10元杂芳基，其中C 6-C 10芳基、或5-10元杂芳基无取代或被R d、R e和/或R f取代； R 1 is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, wherein C 6 -C 10 aryl, or 5-10 membered heteroaryl is unsubstituted or replaced by R d , Re and/or R f replace;
    R 2为-NR 7R 8，其中： R 2 is -NR 7 R 8 , where:
    R 7选自氢、C 1-C 6烷基、氘代C 1-C 6烷基或C 3-C 6环烷基； R 7 is selected from hydrogen, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
    R 8选自氢、C 1-C 6烷基、氘代C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个羟基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、(被1-5个相同或不同的卤素取代的C 1-C 6烷氧基)-(C 1-C 6亚烷基)-、被1-3个氨基取代的C 1-C 6烷基、被1-3个氨基磺酰基取代的C 1-C 6烷基、被1-3个硫脲基取代的C 1-C 6烷基、C 1-C 6烷基磺酰基、(C 1-C 6烷基磺酰基)-(C 1-C 6亚烷基)-、被1-5个氰基取代的C 1-C 6烷基、(C 1-C 6烷基)-C(O)-、(C 1-C 6烷氧基)-C(O)-、(C 1-C 6烷基)-NH-C(O)-、N(C 1-C 6烷基) 2-C(O)-、被氨基羰基取代的C 1-C 6烷基、C 3-C 6环烷基、被1-3个C 3-C 6环烷基取代的C 1-C 6烷基、被1-3个C 3-C 6环烷氧基取代的C 1-C 6烷基、C 6-C 10螺环烷基、被C 6-C 10螺环烷基取代的C 1-C 6烷基、C 6-C 8芳基、被1-3个相同或不同的C 6-C 8芳基取代的C 1-C 6烷基、5-8元杂芳基、被1-3个相同或不同的5-8元杂芳基取代的C 1-C 6烷基、(5-8元杂芳基)-C(O)-、3-8元杂环基、被1-5个相同或不同的3-8元杂环基取代的C 1-C 6烷基、(3-8元杂环基)-C(O)-、(3-8元杂环基)-O-(C 1-C 6亚烷基)-、5-10元稠合杂环基、被1-3个相同或不同的5-10元稠合杂环基取代的C 1-C 6烷基、5-10元桥连杂环基、被1-3个相同或不同的5-10元桥连杂环基取代的C 1-C 6烷基、5-10元螺杂环基、被1-3个相同或不同的5-10元螺杂环基取代的C 1-C 6烷基；所述R 8无取代或被R j、R k和/或R L取代； R 8 is selected from hydrogen, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, 1-5 hydroxyl groups Substituted C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by 1-3 identical or different C 1 -C 6 alkoxy, (substituted by 1-5 identical or different halogen C 1 -C 6 alkoxy)-(C 1 -C 6 alkylene)-, C 1 -C 6 alkyl substituted with 1-3 amino groups, C 1 substituted with 1-3 aminosulfonyl groups -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-3 thiourea groups, C 1 -C 6 alkylsulfonyl, (C 1 -C 6 alkylsulfonyl)-(C 1 - C 6 alkylene)-, C 1 -C 6 alkyl substituted with 1-5 cyano groups, (C 1 -C 6 alkyl)-C(O)-, (C 1 -C 6 alkoxy )-C(O)-, (C 1 -C 6 alkyl)-NH-C(O)-, N(C 1 -C 6 alkyl) 2 -C(O)-, C substituted with aminocarbonyl 1 - C6 alkyl, C3 - C6 cycloalkyl, C1 - C6 alkyl substituted by 1-3 C3- C6 cycloalkyl, 1-3 C3- C6 ring Alkoxy-substituted C 1 -C 6 alkyl, C 6 -C 10 spirocycloalkyl, C 1 -C 6 alkyl substituted by C 6 -C 10 spirocycloalkyl, C 6 -C 8 aryl , C 1 -C 6 alkyl substituted by 1-3 identical or different C 6 -C 8 aryl groups, 5-8-membered heteroaryl, 5-8-membered heteroaryl substituted by 1-3 identical or different C 6 -C 8 aryl groups C 1 -C 6 alkyl substituted by 1-5-membered heteroaryl, (5-8 membered heteroaryl)-C(O)-, 3-8 membered heterocyclyl, 3-8 membered heterocycle by 1-5 same or different group-substituted C 1 -C 6 alkyl, (3-8 membered heterocyclyl)-C(O)-, (3-8 membered heterocyclyl)-O-(C 1 -C 6 alkylene)- , 5-10-membered fused heterocyclic group, C 1 -C 6 alkyl substituted by 1-3 identical or different 5-10-membered fused heterocyclic groups, 5-10-membered bridged heterocyclic group, C 1 -C 6 alkyl substituted with 1-3 identical or different 5-10-membered bridged heterocyclyls, 5-10-membered spiro heterocyclyl, 5-10-membered spiro substituted by 1-3 identical or different 5-10-membered heterocyclyl groups Heterocyclyl-substituted C 1 -C 6 alkyl; the R 8 is unsubstituted or substituted with R j , R k and/or RL ;
    或者R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基未被取代的或者被R j、R k和/或R L取代； Or R 7 , R 8 together with the N atom to which they are commonly attached form a 4-6 membered heterocycloalkyl group which is unsubstituted or is replaced by R j , R k and/or R L replace;
    R d、R e、R j和R k各自独立地选自C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 1-C 6烷氧基、羟基、C 1-C 6烷基磺酰基、卤素、氰基、羧基、(C 1-C 6烷氧基)-C(O)-、被1-3个羟基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、被1-3个氨基取代的C 1-C 6烷基、氨基磺酰基、(C 1-C 6烷基)-NH-S(O) 2-、N(C 1-C 6烷基) 2-S(O) 2-、磺酰基氨基、氨基羰基、(C 1-C 6烷基)-NH-C(O)-、 N(C 1-C 6烷基) 2-C(O)-、(3-10元杂环基)-C(O)-和脲基； R d , Re , R j and R k are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, identical with 1-5 halogens or different halogen substituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, hydroxyl, C 1 -C 6 alkylsulfonyl, halogen, cyano, carboxyl, (C 1 -C 6 alkane oxy)-C(O)-, C 1 -C 6 alkyl substituted with 1-3 hydroxy, C 1 -C 6 substituted with 1-3 identical or different C 1 -C 6 alkoxy Alkyl, C 1 -C 6 alkyl substituted with 1-3 amino groups, aminosulfonyl, (C 1 -C 6 alkyl)-NH-S(O) 2 -, N(C 1 -C 6 alkane base) 2 -S(O) 2 -, sulfonylamino, aminocarbonyl, (C 1 -C 6 alkyl)-NH-C(O)-, N(C 1 -C 6 alkyl) 2 -C( O)-, (3-10 membered heterocyclyl)-C(O)- and ureido;
    R f和R L各自独立地选自C 1-C 6烷基、C 5-C 10环烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 1-C 6烷氧基、羟基、卤素、氨基、(C 1-C 6烷基)-NH-、(C 3-C 8环烷基)-S(O) 2-NH-、氰基、被1-3个氰基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基羰基取代的C 1-C 6烷基、被羧基取代的C 1-C 6烷基、被氨基羰基取代的C 1-C 6烷基、-X c-R 9，其中X c选自键、C 1-C 5亚烷基和C 1-C 5杂亚烷基，R 9选自任选被取代的C 6-C 10芳基、任选被取代的5-10元杂芳基和任选被取代的5-10元杂环基。 R f and RL are each independently selected from C 1 -C 6 alkyl, C 5 -C 10 cycloalkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 alkyl substituted with 1- 5 identical or different halogen-substituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, hydroxy, halogen, amino, (C 1 -C 6 alkyl)-NH-, (C 3 - C 8 cycloalkyl)-S(O) 2 -NH-, cyano, C 1 -C 6 alkyl substituted with 1-3 cyano groups, C 1 -C 6 substituted with 1-3 identical or different C 1 -C 6 groups C 1 -C 6 alkyl substituted by alkoxycarbonyl, C 1 -C 6 alkyl substituted by carboxyl, C 1 -C 6 alkyl substituted by aminocarbonyl, -X c -R 9 , wherein X c is selected from Self-bond, C 1 -C 5 alkylene and C 1 -C 5 heteroalkylene, R 9 is selected from optionally substituted C 6 -C 10 aryl, optionally substituted 5-10 membered heteroaryl and optionally substituted 5-10 membered heterocyclyl.
  12. 如权利要求1-11任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中：The compound according to any one of claims 1-11, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I A salt or prodrug, wherein:
    W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 3、R 4、R 5和R 6中至少一个不是氢； W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 )=, R 3 , R 4 , R 5 and R at least one of the 6 is not hydrogen;
    和/或，R 3选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基； And/or, R 3 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, cyano;
    和/或，R 4选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基； And/or, R 4 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, cyano;
    和/或，R 5选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、C 3-C 6环烷基、氰基、氨基，R 5未被取代或被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自C 1-C 3烷基、C 3-C 6环烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷氧基、C 1-C 3烷氧基、羟基、卤素； And/or, R 5 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl, cyano radical, amino, R 5 is unsubstituted or substituted by R a , R b and/ or R c independently selected from C 1 -C 3 alkyl, C 3 - C 6 cycloalkyl, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens, C 1 -C 3 alkoxy substituted with 1-5 identical or different halogens, C 1 - C 3 alkoxy, hydroxyl, halogen;
    和/或，R 6选自氢、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基； And/or, R 6 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halogen, substituted by 1-5 identical or different halogens C 1 -C 6 alkyl, cyano;
    和/或，R 1选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环，R 1为无取代或被R d、R e和/或R f取代，所述R d、R e和R f各自独立地选自C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基； And/or, R 1 is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, pyrazole ring, imidazole ring, R 1 is unsubstituted or by R d , Re and/or Substituted with R f , said R d , Re and R f are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 alkyl substituted with 1-5 halo 5 identical or different halogen-substituted C 1 -C 6 alkoxy groups, C 1 -C 6 alkoxy groups, hydroxyl groups, halogen groups, cyano groups, carboxyl groups;
    和/或，R 2为-NR 7R 8，R 7选自氢、C 1-C 6烷基、C 3-C 6环烷基，R 8选自氢、C 1-C 6烷基、氘代C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个羟基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、(被1-5个相同或不同的卤素取代的C 1-C 6烷氧基)-(C 1-C 6亚烷基)-、C 3-C 6环烷基、被1-3个C 3-C 6环烷基取代的C 1-C 6烷基、被1-5个相同或不同的3-8元杂环基取代的C 1-C 6烷基、(C 1-C 6烷基磺酰基)-(C 1-C 6亚烷基)-；所述R 8无取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基； And/or, R 2 is -NR 7 R 8 , R 7 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, R 8 is selected from hydrogen, C 1 -C 6 alkyl, Deuterated C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 alkyl substituted with 1-5 hydroxy, C 1 -C 6 alkyl substituted with 1-3 C 1 -C 6 alkyl substituted with the same or different C 1 -C 6 alkoxy groups, (C 1 -C 6 alkoxy substituted with 1-5 identical or different halogens)-(C 1 - C 6 alkylene)-, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted with 1-3 C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different 3 -8-membered heterocyclyl-substituted C 1 -C 6 alkyl, (C 1 -C 6 alkylsulfonyl)-(C 1 -C 6 alkylene)-; the R 8 is unsubstituted or replaced by R j , R k and/or R L substituted, each of said R j , R k and R L is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl ;
    和/或，R 2为-NR 7R 8，所述R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基未被取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 And/or, R 2 is -NR 7 R 8 , and said R 7 , R 8 together with the N atom to which they are connected together form a 4-6 membered heterocycloalkyl, and the 4-6 membered heterocycloalkyl is not substituted or substituted with R j , R k and/or RL each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, halogen , cyano, carboxyl.
  13. 如权利要求1-12任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中：The compound according to any one of claims 1-12, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I A salt or prodrug, wherein:
    W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 3、R 4、R 5和R 6中至少一个不是氢； W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 )=, R 3 , R 4 , R 5 and R at least one of the 6 is not hydrogen;
    和/或，R 3选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基； And/or, R 3 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, cyano;
    和/或，R 4选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基； And/or, R 4 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, cyano;
    和/或，R 5选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、C 3-C 6环烷基、氰基、氨基，所述R 5是未被取代的或者被R a、R b和/或R c取代，所述R a、R b 和/或R c独立地选自C 1-C 3烷基、C 3-C 6环烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷氧基、C 1-C 3烷氧基、羟基、卤素； And/or, R 5 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl, cyano group, amino group, the R 5 is unsubstituted or substituted by R a , R b and/or R c independently selected from C 1 -C 3 alkyl , C 3 -C 6 cycloalkyl, C 1 -C 3 alkyl substituted by 1-5 identical or different halogens, C 1 -C 3 alkoxy substituted by 1-5 identical or different halogens , C 1 -C 3 alkoxy, hydroxyl, halogen;
    和/或，R 6选自氢、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基； And/or, R 6 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halogen, substituted by 1-5 identical or different halogens C 1 -C 6 alkyl, cyano;
    和/或，R 1选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环，R 1为无取代或被R d、R e和/或R f取代，所述R d、R e和R f各自独立地选自C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基； And/or, R 1 is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, pyrazole ring, imidazole ring, R 1 is unsubstituted or by R d , Re and/or Substituted with R f , said R d , Re and R f are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 alkyl substituted with 1-5 halo 5 identical or different halogen-substituted C 1 -C 6 alkoxy groups, C 1 -C 6 alkoxy groups, hydroxyl groups, halogen groups, cyano groups, carboxyl groups;
    和/或，R 2为-NR 7R 8，R 7选自氢、C 1-C 6烷基、C 3-C 6环烷基，R 8选自氢、C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个羟基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、(被1-5个相同或不同的卤素取代的C 1-C 6烷氧基)-(C 1-C 6亚烷基)-、C 3-C 6环烷基、被1-3个C 3-C 6环烷基取代的C 1-C 6烷基、被1-5个相同或不同的3-8元杂环基取代的C 1-C 6烷基；所述R 8无取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基； And/or, R 2 is -NR 7 R 8 , R 7 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, R 8 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 alkyl substituted with 1-5 hydroxy groups, C 1 -C 6 alkyl substituted with 1-3 identical or different halogens Alkoxy-substituted C 1 -C 6 alkyl, (C 1 -C 6 alkoxy substituted with 1-5 identical or different halogens)-(C 1 -C 6 alkylene)-, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted with 1-3 C 3 -C 6 cycloalkyl, C 1 substituted with 1-5 same or different 3-8 membered heterocyclyl -C 6 alkyl; said R 8 is unsubstituted or substituted with R j , R k and/or RL each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl;
    和/或，R 2为-NR 7R 8，所述R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基未被取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 And/or, R 2 is -NR 7 R 8 , and said R 7 , R 8 together with the N atom to which they are connected together form a 4-6 membered heterocycloalkyl, and the 4-6 membered heterocycloalkyl is not substituted or substituted with R j , R k and/or RL each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, halogen , cyano, carboxyl.
  14. 如权利要求1-13任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中：The compound according to any one of claims 1-13, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I A salt or prodrug, wherein:
    W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 3、R 4、R 5和R 6中至少一个不是氢；R 3、R 4、R 5和R 6各自独立地选自氢、卤素、甲基、乙基、丙基、异丙基、环丙基、被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、被1-3个卤素取代的环丙基；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯； W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 )=, R 3 , R 4 , R 5 and R At least one of 6 is not hydrogen; R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, by 1-3 halogens Substituted methyl, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens, cyclopropyl substituted with 1-3 halogens ; Described halogen is selected from fluorine, chlorine, bromine, iodine, preferably, described halogen is selected from fluorine, chlorine;
    和/或，R 1选自被R d取代的苯环、被R d取代的吡啶环，所述R d选自氰基、卤素、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯； And/or, R 1 is selected from benzene ring substituted by R d , pyridine ring substituted by R d , and R d is selected from cyano, halogen, methyl, ethyl, propyl, isopropyl, methoxy base, ethoxy, propoxy, isopropoxy, methyl substituted with 1-3 halogens, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, substituted with 1 -3 halogen-substituted isopropyl groups; the halogen is selected from fluorine, chlorine, bromine, and iodine, preferably, the halogen is selected from fluorine and chlorine;
    和/或，R 2为-NR 7R 8，所述R 7选自氢、甲基、乙基、丙基，所述R 8选自氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、被1-3个卤素取代的环丙基、被一个羟基取代的丙基、被一个羟基取代的异丙基、被一个羟基取代的正丁基、被一个羟基取代的异丁基、被一个羟基取代的叔丁基、被一个羟基取代的环丙基、被一个羟基取代的环丁基、(C 1-C 3烷基磺酰基)-(C 1-C 3亚烷基)-；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯； And/or, R 2 is -NR 7 R 8 , the R 7 is selected from hydrogen, methyl, ethyl, and propyl, and the R 8 is selected from hydrogen, methyl, ethyl, propyl, and isopropyl , n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, substituted with 1-3 halogens isopropyl, cyclopropyl substituted with 1-3 halogens, propyl substituted with one hydroxy, isopropyl substituted with one hydroxy, n-butyl substituted with one hydroxy, isobutyl substituted with one hydroxy group, tert-butyl substituted with one hydroxy, cyclopropyl substituted with one hydroxy, cyclobutyl substituted with one hydroxy, (C 1 -C 3 alkylsulfonyl)-(C 1 -C 3 alkylene )-; the halogen is selected from fluorine, chlorine, bromine, iodine, preferably, the halogen is selected from fluorine, chlorine;
    和/或，R 2为-NR 7R 8，所述R 7、R 8与它们共同连接的N原子一起形成4元、5元或6元杂环烷基，所述4元、5元或6元杂环烷基未被取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自甲基、乙基、丙基、羟基、卤素；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯。 And/or, R 2 is -NR 7 R 8 , said R 7 , R 8 together with the N atom to which they are connected together form a 4-membered, 5-membered or 6-membered heterocycloalkyl, said 4-membered, 5-membered or 6-membered heterocycloalkyl is unsubstituted or substituted with R j , R k and/or RL each independently selected from methyl, ethyl, propyl, hydroxy, halogen ; The halogen is selected from fluorine, chlorine, bromine and iodine, preferably, the halogen is selected from fluorine and chlorine.
  15. 如权利要求1-14任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中：The compound according to any one of claims 1-14, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I A salt or prodrug, wherein:
    W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 3、R 4、R 5和R 6中至少一个不是氢；R 3、R 4、R 5和R 6各自独立地选自氢、卤素、甲基、乙基、丙基、异丙基、环丙基、被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、被1-3个卤素取代的环丙基；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯； W is -C(R 3 )=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 )=, R 3 , R 4 , R 5 and R At least one of 6 is not hydrogen; R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, by 1-3 halogens Substituted methyl, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens, cyclopropyl substituted with 1-3 halogens ; Described halogen is selected from fluorine, chlorine, bromine, iodine, preferably, described halogen is selected from fluorine, chlorine;
    和/或，R 1选自被R d取代的苯环，所述R d选自氰基、卤素、甲基、乙基、丙基、异丙基、被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯； And/or, R 1 is selected from benzene ring substituted by R d selected from cyano, halogen, methyl, ethyl, propyl, isopropyl, methyl substituted by 1-3 halogens , ethyl substituted by 1-3 halogens, propyl substituted by 1-3 halogens, isopropyl substituted by 1-3 halogens; the halogens are selected from fluorine, chlorine, bromine, iodine, preferably Preferably, the halogen is selected from fluorine, chlorine;
    和/或，R 2为-NR 7R 8，所述R 7选自氢、甲基、乙基、丙基，所述R 8选自氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、被1-3个卤素取代的环丙基、被一个羟基取代的丙基、被一个羟基取代的异丙基、被一个羟基取代的正丁基、被一个羟基取代的异丁基、被一个羟基取代的叔丁基、被一个羟基取代的环丙基、被一个羟基取代的环丁基、甲基磺酰基乙基、甲基磺酰基甲基；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯。 And/or, R 2 is -NR 7 R 8 , the R 7 is selected from hydrogen, methyl, ethyl, and propyl, and the R 8 is selected from hydrogen, methyl, ethyl, propyl, and isopropyl , n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, ethyl substituted with 1-3 halogens, propyl substituted with 1-3 halogens, substituted with 1-3 halogens isopropyl, cyclopropyl substituted with 1-3 halogens, propyl substituted with one hydroxy, isopropyl substituted with one hydroxy, n-butyl substituted with one hydroxy, isobutyl substituted with one hydroxy group, tert-butyl substituted with one hydroxy, cyclopropyl substituted with one hydroxy, cyclobutyl substituted with one hydroxy, methylsulfonylethyl, methylsulfonylmethyl; the halogen is selected from fluorine, Chlorine, bromine, iodine, preferably, the halogen is selected from fluorine and chlorine.
  16. 如权利要求12所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中：The compound of claim 12, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula I, in:
    R 3、R 4和R 6为氢； R 3 , R 4 and R 6 are hydrogen;
    R 5为被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、环丙基；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯。 R 5 is methyl substituted by 1-3 halogens, ethyl substituted by 1-3 halogens, propyl substituted by 1-3 halogens, isopropyl substituted by 1-3 halogens, cyclopropyl base; the halogen is selected from fluorine, chlorine, bromine and iodine, preferably, the halogen is selected from fluorine and chlorine.
  17. 如权利要求1-16任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中：The compound according to any one of claims 1-16, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I A salt or prodrug, wherein:
    W是-N＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 4、R 5和R 6中至少一个不是氢； W is -N=, X is -C(R 4 )=, Y is -C(R 5 )=, Z is -C(R 6 )=, at least one of R 4 , R 5 and R 6 is not hydrogen;
    和/或，R 4选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基； And/or, R 4 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, cyano;
    和/或，R 5选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、C 3-C 6环烷基、氰基、氨基，R 5未被取代或被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自C 1-C 3烷基、C 3-C 6环烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷氧基、C 1-C 3烷氧基、羟基、卤素； And/or, R 5 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl, cyano radical, amino, R 5 is unsubstituted or substituted by R a , R b and/ or R c independently selected from C 1 -C 3 alkyl, C 3 - C 6 cycloalkyl, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens, C 1 -C 3 alkoxy substituted with 1-5 identical or different halogens, C 1 - C 3 alkoxy, hydroxyl, halogen;
    和/或，R 6选自氢、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基； And/or, R 6 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halogen, substituted by 1-5 identical or different halogens C 1 -C 6 alkyl, cyano;
    和/或，R 1选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环，所述R 1为无取代或被R d、R e和/或R f取代，所述R d、R e和R f各自独立地选自C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基； And/or, R 1 is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, and the R 1 is unsubstituted or by R d , Re and and/or R f substituted, said R d , Re and R f are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, 1-5 same or different halogen-substituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl;
    和/或，R 2为-NR 7R 8，R 7选自氢、C 1-C 6烷基、或C 3-C 6环烷基，R 8选自氢、C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个羟基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、(被1-5个相同或不同的卤素取代的C 1-C 6烷氧基)-(C 1-C 6亚烷基)-、C 3-C 6环烷基、被1-3个C 3-C 6环烷基取代的C 1-C 6烷基、被1-5个相同或不同的3-8元杂环基取代的C 1-C 6烷基；所述R 8无取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基； And/or, R 2 is -NR 7 R 8 , R 7 is selected from hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, R 8 is selected from hydrogen, C 1 -C 6 alkyl , C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 alkyl substituted by 1-5 hydroxyl groups, C 1 -C 6 alkyl substituted by 1-3 identical or different halogens 6 alkoxy substituted C 1 -C 6 alkyl, (C 1 -C 6 alkoxy substituted by 1-5 identical or different halogens)-(C 1 -C 6 alkylene)-, C 3 -C6cycloalkyl, C1 - C6alkyl substituted by 1-3 C3 - C6cycloalkyl , C1-5 same or different 3-8 membered heterocyclyl substituted 1 - C6 alkyl; said R 8 is unsubstituted or substituted by R j , R k and/or RL , each of said R j , R k and RL is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl;
    和/或，R 2为-NR 7R 8，所述R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基未被取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 And/or, R 2 is -NR 7 R 8 , and said R 7 , R 8 together with the N atom to which they are connected together form a 4-6 membered heterocycloalkyl, and the 4-6 membered heterocycloalkyl is not substituted or substituted with R j , R k and/or RL each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, halogen , cyano, carboxyl.
  18. 如权利要求1-17任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中：The compound according to any one of claims 1-17, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I A salt or prodrug, wherein:
    W是-C(R 3)＝，X是-C(R 4)＝，Y是-C(R 5)＝，Z是-N＝，R 3、R 4和R 5中至少一个不是氢； W is -C( R3 )=, X is -C(R4 ) =, Y is -C(R5 ) =, Z is -N=, at least one of R3 , R4 and R5 is not hydrogen;
    和/或，R 3选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基； And/or, R 3 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, cyano;
    和/或，R 4选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基； And/or, R 4 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, cyano;
    和/或，R 5选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、C 3-C 6环烷基、氰基、氨基，R 5未被取代或被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自C 1-C 3烷基、C 3-C 6环烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷氧基、C 1-C 3烷氧基、羟基、卤素； And/or, R 5 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl, cyano radical, amino, R 5 is unsubstituted or substituted by R a , R b and/ or R c independently selected from C 1 -C 3 alkyl, C 3 - C 6 cycloalkyl, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens, C 1 -C 3 alkoxy substituted with 1-5 identical or different halogens, C 1 - C 3 alkoxy, hydroxyl, halogen;
    和/或，R 1选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环，R 1为无取代或被R d、R e和/或R f取代，所述R d、R e和R f各自独立地选自C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基； And/or, R 1 is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, pyrazole ring, imidazole ring, R 1 is unsubstituted or by R d , Re and/or Substituted with R f , said R d , Re and R f are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, C 1 -C 6 alkyl substituted with 1-5 halo 5 identical or different halogen-substituted C 1 -C 6 alkoxy groups, C 1 -C 6 alkoxy groups, hydroxyl groups, halogen groups, cyano groups, carboxyl groups;
    和/或，R 2为-NR 7R 8，R 7选自氢、C 1-C 6烷基、或C 3-C 6环烷基，R 8选自氢、C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个羟基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、(被1-5个相同或不同的卤素取代的C 1-C 6烷氧基)-(C 1-C 6亚烷基)-、C 3-C 6环烷基、被1-3个C 3-C 6环烷基取代的C 1-C 6烷基、被1-5个相同或不同的3-8元杂环基取代的C 1-C 6烷基；所述R 8无取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基； And/or, R 2 is -NR 7 R 8 , R 7 is selected from hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, R 8 is selected from hydrogen, C 1 -C 6 alkyl , C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 alkyl substituted by 1-5 hydroxyl groups, C 1 -C 6 alkyl substituted by 1-3 identical or different halogens 6 alkoxy substituted C 1 -C 6 alkyl, (C 1 -C 6 alkoxy substituted by 1-5 identical or different halogens)-(C 1 -C 6 alkylene)-, C 3 -C6cycloalkyl, C1 - C6alkyl substituted by 1-3 C3 - C6cycloalkyl , C1-5 same or different 3-8 membered heterocyclyl substituted 1 - C6 alkyl; said R 8 is unsubstituted or substituted by R j , R k and/or RL , each of said R j , R k and RL is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl;
    和/或，R 2为-NR 7R 8，所述R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基未被取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 And/or, R 2 is -NR 7 R 8 , and said R 7 , R 8 together with the N atom to which they are connected together form a 4-6 membered heterocycloalkyl, and the 4-6 membered heterocycloalkyl is not substituted or substituted with R j , R k and/or RL each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, halogen , cyano, carboxyl.
  19. 如权利要求1-18任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中：The compound according to any one of claims 1-18, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I A salt or prodrug, wherein:
    W是-C(R 3)＝，X是-N＝，Y是-C(R 5)＝，Z是-C(R 6)＝，R 3、R 5和R 6中至少一个不是氢； W is -C(R 3 )=, X is -N=, Y is -C(R 5 )=, Z is -C(R 6 )=, at least one of R 3 , R 5 and R 6 is not hydrogen;
    和/或，R 3选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基； And/or, R 3 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, cyano;
    和/或，R 5选自氢、C 1-C 6烷基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、C 3-C 6环烷基、氰基、氨基，R 5未被取代或被R a、R b和/或R c取代，所述R a、R b和/或R c独立地选自C 1-C 3烷基、C 3-C 6环烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷基、被1-5个相同或不同的卤素取代的C 1-C 3烷氧基、C 1-C 3烷氧基、羟基、卤素； And/or, R 5 is selected from hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl, cyano radical, amino, R 5 is unsubstituted or substituted by R a , R b and/ or R c independently selected from C 1 -C 3 alkyl, C 3 - C 6 cycloalkyl, C 1 -C 3 alkyl substituted with 1-5 identical or different halogens, C 1 -C 3 alkoxy substituted with 1-5 identical or different halogens, C 1 - C 3 alkoxy, hydroxyl, halogen;
    和/或，R 6选自氢、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、卤素、被1-5个相同或不同的卤素取代的C 1-C 6烷基、氰基； And/or, R 6 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halogen, substituted by 1-5 identical or different halogens C 1 -C 6 alkyl, cyano;
    和/或，R 1选自苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、吡咯环、吡唑环、咪唑环，所述R 1为无取代或被R d、R e和/或R f取代，所述R d、R e和R f各自独立地选自C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷氧基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基； And/or, R 1 is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, and the R 1 is unsubstituted or by R d , Re and and/or R f substituted, said R d , Re and R f are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-5 identical or different halogens, 1-5 same or different halogen-substituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl;
    和/或，R 2为-NR 7R 8，R 7选自氢、C 1-C 6烷基、或C 3-C 6环烷基，R 8选自氢、C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个羟基取代的C 1-C 6烷基、被1-3个相同或不同的C 1-C 6烷氧基取代的C 1-C 6烷基、(被1-5个相同或不同的卤素取代的C 1-C 6烷氧基)-(C 1-C 6亚烷基)-、C 3-C 6环烷基、被1-3个C 3-C 6环烷基取代的C 1-C 6烷基、被1-5个相同或不同的3-8元杂环基取代的C 1-C 6烷基；所述R 8无取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基； And/or, R 2 is -NR 7 R 8 , R 7 is selected from hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, R 8 is selected from hydrogen, C 1 -C 6 alkyl , C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 1 -C 6 alkyl substituted by 1-5 hydroxyl groups, C 1 -C 6 alkyl substituted by 1-3 identical or different halogens 6 alkoxy substituted C 1 -C 6 alkyl, (C 1 -C 6 alkoxy substituted by 1-5 identical or different halogens)-(C 1 -C 6 alkylene)-, C 3 -C6cycloalkyl, C1 - C6alkyl substituted by 1-3 C3 - C6cycloalkyl , C1-5 same or different 3-8 membered heterocyclyl substituted 1 - C6 alkyl; said R 8 is unsubstituted or substituted by R j , R k and/or RL , each of said R j , R k and RL is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl;
    和/或，R 2为-NR 7R 8，所述R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基未被取代或被R j、R k和/或R L取代，所述R j、R k和R L各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基； And/or, R 2 is -NR 7 R 8 , and said R 7 , R 8 together with the N atom to which they are connected together form a 4-6 membered heterocycloalkyl, and the 4-6 membered heterocycloalkyl is not substituted or substituted with R j , R k and/or RL each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, halogen , cyano, carboxyl;
    较佳地，式I所示化合物中，R 1选自被1个、2个或更多个卤素取代的下列基团：C 6-8芳基或5-8元杂芳基；较佳地，R 1选自被1个或2个氟或氯取代的下列基团：苯基、吡啶基、 嘧啶基、吡嗪基、哒嗪基、吡咯基、吡唑基、咪唑基；较佳地，R 1选自被1个或2个氟取代的下列基团：苯基或吡啶基； Preferably, in the compound represented by formula I, R 1 is selected from the following groups substituted by 1, 2 or more halogens: C 6-8 aryl or 5-8 membered heteroaryl; preferably , R 1 is selected from the following groups substituted by 1 or 2 fluorine or chlorine: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl; preferably , R 1 is selected from the following groups substituted by 1 or 2 fluorines: phenyl or pyridyl;
    较佳地，R 2为-NR 7R 8，所述R 7选自氢、C 1-C 6烷基、或C 3-C 6环烷基；所述R 8选自被R j取代的C 3-C 12环烷基；较佳地，R 2为-NR 7R 8，所述R 7选自氢，所述R 8选自被R j取代的C 3-C 6环烷基，所述R j选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、卤素、氰基、羧基。 Preferably, R 2 is -NR 7 R 8 , and said R 7 is selected from hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl; said R 8 is selected from R j substituted C 3 -C 12 cycloalkyl; preferably, R 2 is -NR 7 R 8 , the R 7 is selected from hydrogen, and the R 8 is selected from C 3 -C 6 cycloalkyl substituted by R j , The R j is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, halogen, cyano, carboxyl.
  20. 如权利要求1-19任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中：The compound according to any one of claims 1-19, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I A salt or prodrug, wherein:
    R 3、R 4、R 5和R 6各自独立地选自氢、卤素、甲基、乙基、丙基、异丙基、环丙基、被1-3个卤素取代的甲基、被1-3个卤素取代的乙基、被1-3个卤素取代的丙基、被1-3个卤素取代的异丙基、被1-3个卤素取代的环丙基；所述卤素选自氟、氯、溴、碘，较佳地，所述卤素选自氟、氯； R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, methyl substituted with 1-3 halogens, 1 - ethyl substituted with 3 halogens, propyl substituted with 1-3 halogens, isopropyl substituted with 1-3 halogens, cyclopropyl substituted with 1-3 halogens; the halogens are selected from fluorine , chlorine, bromine, iodine, preferably, the halogen is selected from fluorine, chlorine;
    和/或，R 1选自
    Figure PCTCN2022087589-appb-100009
    Figure PCTCN2022087589-appb-100010
    and/or, R 1 is selected from
    Figure PCTCN2022087589-appb-100009
    Figure PCTCN2022087589-appb-100010
    和/或，R 2选自
    Figure PCTCN2022087589-appb-100011
    Figure PCTCN2022087589-appb-100012
    and/or, R 2 is selected from
    Figure PCTCN2022087589-appb-100011
    Figure PCTCN2022087589-appb-100012
  21. 如权利要求1-20任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 2选自下列任一一种方案， The compound according to any one of claims 1-20, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I Salt or prodrug, characterized in that R 2 is selected from any one of the following schemes,
    方案(一)：R 2为-NHR 8，R 8选自被羟基取代的C 2-C 4烷基或被氰基取代的C 2-C 4烷基；或 Scheme (1): R 2 is -NHR 8 , and R 8 is selected from C 2 -C 4 alkyl substituted by hydroxy or C 2 -C 4 alkyl substituted by cyano; or
    方案(二)：R 2为-NHR 8，R 8选自C 3-C 10环烷基、C 6-C 10螺环烷基、桥连的C 5-C 10环烷基，所述R 8是未被取代的或者被R j取代，所述R j独立地选自-F、甲基、甲氧基、氰基；较 佳地，R 8选自环丙基、环丁基、
    Figure PCTCN2022087589-appb-100013
    所述R 8是未被取代的或者被R j取代，所述R j独立地选自-F、甲基、甲氧基、氰基；或     Scheme (two): R 2 is -NHR 8 , R 8 is selected from C 3 -C 10 cycloalkyl, C 6 -C 10 spirocycloalkyl, bridged C 5 -C 10 cycloalkyl, and the R 8 is unsubstituted or substituted by R j independently selected from -F, methyl, methoxy, cyano; preferably, R is selected from cyclopropyl, cyclobutyl ,
    Figure PCTCN2022087589-appb-100013
    The R8 is unsubstituted or substituted with Rj independently selected from -F, methyl, methoxy, cyano; or
    方案(三)：R 2为-NR 7R 8，R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基是未被取代的或者被R j取代；R j选自-F、氰基、-NH-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基；或 Scheme (3): R 2 is -NR 7 R 8 , R 7 and R 8 together with the N atom to which they are connected together form a 4-6-membered heterocycloalkyl, and the 4-6-membered heterocycloalkyl is not substituted or substituted by R j ; R j is selected from -F, cyano, -NH-(C 1 -C 6 alkyl), hydroxy substituted C 1 -C 6 alkyl; or
    方案(四)：R 2为-NR 7R 8，R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基同时被R j和R L取代；R j选自-F、氰基、-NH-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基；R L选自甲基、羟基；或 Scheme (four): R 2 is -NR 7 R 8 , R 7 and R 8 together with the N atom they are connected to together form a 4-6-membered heterocycloalkyl, and the 4-6-membered heterocycloalkyl is simultaneously surrounded by R j and R L are substituted; R j is selected from -F, cyano, -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted by hydroxyl; R L is selected from methyl, hydroxyl; or
    方案(五)：R 2为-NR 7R 8，R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基同时被R j、R k和R L取代；R j和R k各自独立地选自-F、氰基、-NH-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基；R L选自甲基、羟基；或 Scheme (5): R 2 is -NR 7 R 8 , R 7 and R 8 together with the N atom to which they are connected together form a 4-6-membered heterocycloalkyl, and the 4-6-membered heterocycloalkyl is simultaneously surrounded by R j , R k and R L substituted; R j and R k are each independently selected from -F, cyano, -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted with hydroxy; R L is selected from methyl, hydroxyl; or
    方案(六)：R 2选自无取代的或被R j取代的以下基团：
    Figure PCTCN2022087589-appb-100014
    Figure PCTCN2022087589-appb-100015
    其中R A1、R A2以及环A的部分环原子相连形成3-7元环烷基或3-7元杂环烷基，所述3-7元杂环烷基的1-3个环原子独立选自N、O和S；     Scheme (VI): R 2 is selected from the following groups unsubstituted or substituted by R j :
    Figure PCTCN2022087589-appb-100014
    Figure PCTCN2022087589-appb-100015
    wherein R A1 , R A2 and some ring atoms of ring A are connected to form a 3-7-membered cycloalkyl or a 3-7-membered heterocycloalkyl, and 1-3 ring atoms of the 3-7-membered heterocycloalkyl are independent selected from N, O and S;
    优选地，R 2选自无取代的或被R j取代的以下基团：
    Figure PCTCN2022087589-appb-100016
    Preferably, R is selected from the following groups unsubstituted or substituted by R :
    Figure PCTCN2022087589-appb-100016
    R j选自-F、氰基、-N-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基。 R j is selected from -F, cyano, -N-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted with hydroxy.
  22. 如权利要求1-21任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述式I所示化合物具有结构IaThe compound according to any one of claims 1-21, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I Salt or prodrug, characterized in that the compound shown in the formula I has structure Ia
    Figure PCTCN2022087589-appb-100017
    Figure PCTCN2022087589-appb-100017
    其中：in:
    R 5选自二氟甲基、三氟甲基； R 5 is selected from difluoromethyl, trifluoromethyl;
    R 8选自被羟基取代的C 2-C 4烷基或被氰基取代的C 2-C 4烷基； R 8 is selected from C 2 -C 4 alkyl substituted by hydroxy or C 2 -C 4 alkyl substituted by cyano;
    R 1a和R 1b各自独立地选自-H、-F； R 1a and R 1b are each independently selected from -H, -F;
    或者所述式I所示化合物具有结构IbOr the compound represented by the formula I has structure Ib
    Figure PCTCN2022087589-appb-100018
    Figure PCTCN2022087589-appb-100018
    其中：in:
    R 5选自二氟甲基、三氟甲基； R 5 is selected from difluoromethyl, trifluoromethyl;
    R 8选自C 3-C 10环烷基、C 6-C 10螺环烷基、桥连的C 5-C 10环烷基，所述R 8是未被取代的或者被R j取代，所述R j独立地选自-F、甲基、甲氧基、氰基；较佳地，R 8选自环丙基、环丁基、
    Figure PCTCN2022087589-appb-100019
    所述R 8是未被取代的或者被R j取代，所述R j独立地选自-F、甲基、甲氧基、氰基；     R 8 is selected from C 3 -C 10 cycloalkyl, C 6 -C 10 spirocycloalkyl, bridged C 5 -C 10 cycloalkyl, said R 8 is unsubstituted or substituted by R j , Said R j is independently selected from -F, methyl, methoxy, cyano; preferably, R is selected from cyclopropyl, cyclobutyl ,
    Figure PCTCN2022087589-appb-100019
    The R 8 is unsubstituted or substituted with R j independently selected from -F, methyl, methoxy, cyano;
    R 1a和R 1b各自独立地选自-H、-F； R 1a and R 1b are each independently selected from -H, -F;
    或者所述式I所示化合物具有结构IcOr the compound shown in the formula I has structure Ic
    Figure PCTCN2022087589-appb-100020
    Figure PCTCN2022087589-appb-100020
    其中：in:
    R 5选自二氟甲基、三氟甲基； R 5 is selected from difluoromethyl, trifluoromethyl;
    R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基是未被取代的或者被R j取代； R 7 , R 8 together with the N atom to which they are attached together form a 4-6 membered heterocycloalkyl group, which is unsubstituted or substituted by R j ;
    R j选自-F、氰基、-NH-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基； R j is selected from -F, cyano, -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted with hydroxy;
    R 1a和R 1b各自独立地选自-H、-F； R 1a and R 1b are each independently selected from -H, -F;
    或者所述式I所示化合物具有结构IdOr the compound shown in the formula I has structure Id
    Figure PCTCN2022087589-appb-100021
    Figure PCTCN2022087589-appb-100021
    其中：in:
    R 5选自二氟甲基、三氟甲基； R 5 is selected from difluoromethyl, trifluoromethyl;
    R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基同时被R j和R L取代； R 7 , R 8 together with the N atom to which they are attached together form a 4-6 membered heterocycloalkyl group, which is substituted by R j and RL at the same time;
    R j选自-F、氰基、-NH-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基；R L选自甲基、羟基； R j is selected from -F, cyano, -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted by hydroxyl; R L is selected from methyl, hydroxyl;
    R 1a和R 1b各自独立地选自-H、-F； R 1a and R 1b are each independently selected from -H, -F;
    或者所述式I所示化合物具有结构IeOr the compound shown in the formula I has the structure Ie
    Figure PCTCN2022087589-appb-100022
    Figure PCTCN2022087589-appb-100022
    其中：in:
    R 5选自二氟甲基、三氟甲基； R 5 is selected from difluoromethyl, trifluoromethyl;
    R 7、R 8与它们共同连接的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基同时被R j、R k和R L取代； R 7 , R 8 together with the N atom to which they are attached together form a 4-6 membered heterocycloalkyl group substituted with R j , R k and RL at the same time;
    R j和R k各自独立地选自-F、氰基、-NH-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基； R j and R k are each independently selected from -F, cyano, -NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted with hydroxy;
    R L选自甲基、羟基； R L is selected from methyl, hydroxyl;
    R 1a和R 1b各自独立地选自-H、-F； R 1a and R 1b are each independently selected from -H, -F;
    或者所述式I所示化合物具有结构IfOr the compound represented by the formula I has the structure If
    Figure PCTCN2022087589-appb-100023
    Figure PCTCN2022087589-appb-100023
    其中：in:
    R 5选自二氟甲基、三氟甲基； R 5 is selected from difluoromethyl, trifluoromethyl;
    R 2选自无取代的或被R j取代的以下基团：
    Figure PCTCN2022087589-appb-100024
    Figure PCTCN2022087589-appb-100025
    其中R A1、R A2以及环A的部分环原子相连形成3-7元环烷基或3-7元杂环烷基，所述3-7元杂环烷基的1-3个环原子独立选自N、O和S；     R is selected from the following groups unsubstituted or substituted by R :
    Figure PCTCN2022087589-appb-100024
    Figure PCTCN2022087589-appb-100025
    wherein R A1 , R A2 and some ring atoms of ring A are connected to form a 3-7-membered cycloalkyl or a 3-7-membered heterocycloalkyl, and 1-3 ring atoms of the 3-7-membered heterocycloalkyl are independent selected from N, O and S;
    优选地，R 2选自无取代的或被R j取代的以下基团：
    Figure PCTCN2022087589-appb-100026
    Preferably, R is selected from the following groups unsubstituted or substituted by R :
    Figure PCTCN2022087589-appb-100026
    R j选自-F、氰基、-N-(C 1-C 6烷基)、被羟基取代的C 1-C 6烷基； R j is selected from -F, cyano, -N-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted by hydroxy;
    R 1a和R 1b各自独立地选自-H、-F。 R 1a and R 1b are each independently selected from -H, -F.
  23. 如权利要求1-22任一项所述的化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中：The compound according to any one of claims 1-22, which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula I A salt or prodrug, wherein:
    R 2选自
    Figure PCTCN2022087589-appb-100027
    Figure PCTCN2022087589-appb-100028
    R 2 is selected from
    Figure PCTCN2022087589-appb-100027
    Figure PCTCN2022087589-appb-100028
    Figure PCTCN2022087589-appb-100029
    Figure PCTCN2022087589-appb-100029
  24. 如权利要求1-23任一项所述的化合物，其为下列所示化合物或下列所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学可接受的盐或前药：The compound of any one of claims 1-23, which is a compound shown below or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or pro-form of the compound shown below medicine:
    Figure PCTCN2022087589-appb-100030
    Figure PCTCN2022087589-appb-100030
    Figure PCTCN2022087589-appb-100031
    Figure PCTCN2022087589-appb-100031
    Figure PCTCN2022087589-appb-100032
    Figure PCTCN2022087589-appb-100032
    Figure PCTCN2022087589-appb-100033
    Figure PCTCN2022087589-appb-100033
    Figure PCTCN2022087589-appb-100034
    Figure PCTCN2022087589-appb-100034
    Figure PCTCN2022087589-appb-100035
    Figure PCTCN2022087589-appb-100035
    Figure PCTCN2022087589-appb-100036
    Figure PCTCN2022087589-appb-100036
    Figure PCTCN2022087589-appb-100037
    Figure PCTCN2022087589-appb-100037
    Figure PCTCN2022087589-appb-100038
    Figure PCTCN2022087589-appb-100038
    Figure PCTCN2022087589-appb-100039
    Figure PCTCN2022087589-appb-100039
    Figure PCTCN2022087589-appb-100040
    Figure PCTCN2022087589-appb-100040
    Figure PCTCN2022087589-appb-100041
    Figure PCTCN2022087589-appb-100041
    Figure PCTCN2022087589-appb-100042
    Figure PCTCN2022087589-appb-100042
    Figure PCTCN2022087589-appb-100043
    Figure PCTCN2022087589-appb-100043
    Figure PCTCN2022087589-appb-100044
    Figure PCTCN2022087589-appb-100044
    Figure PCTCN2022087589-appb-100045
    Figure PCTCN2022087589-appb-100045
    Figure PCTCN2022087589-appb-100046
    Figure PCTCN2022087589-appb-100046
    Figure PCTCN2022087589-appb-100047
    Figure PCTCN2022087589-appb-100047
    Figure PCTCN2022087589-appb-100048
    Figure PCTCN2022087589-appb-100048
    Figure PCTCN2022087589-appb-100049
    Figure PCTCN2022087589-appb-100049
    Figure PCTCN2022087589-appb-100050
    Figure PCTCN2022087589-appb-100050
  25. 如下所示的中间体M-1、中间体M-2、中间体M-3或中间体M-4：Intermediate M-1, Intermediate M-2, Intermediate M-3 or Intermediate M-4 as shown below:
    Figure PCTCN2022087589-appb-100051
    Figure PCTCN2022087589-appb-100051
    其中，W、X、Y、Z、R 1和R 2具有如权利要求1-24任一项所述的定义。 wherein W, X, Y, Z, R 1 and R 2 are as defined in any one of claims 1-24.
  26. 如权利要求25所述的中间体M-1、中间体M-2或中间体M-3，其特征在于：Intermediate M-1, intermediate M-2 or intermediate M-3 as claimed in claim 25, characterized in that:
    M-1或M-2中，W、X、Y和Z具有如权利要求1或4所述的定义，R 1具有如权利要求12所述的定义； In M-1 or M-2, W, X, Y and Z have the definitions as claimed in claim 1 or 4, and R 1 has the definitions as claimed in claim 12;
    M-3中，W、X、Y和Z具有如权利要求1或12所述的定义，R 1和R 2具有如权利要求12所述的定义。 In M-3, W, X, Y and Z have the definitions as claimed in claim 1 or 12 , and R 1 and R 2 have the definitions as claimed in claim 12 .
  27. 如权利要求25或26所述的中间体M-1、M-2或M-3，其选自下列任一化合物：Intermediate M-1, M-2 or M-3 as claimed in claim 25 or 26, which is selected from any of the following compounds:
    Figure PCTCN2022087589-appb-100052
    Figure PCTCN2022087589-appb-100052
    Figure PCTCN2022087589-appb-100053
    Figure PCTCN2022087589-appb-100053
    Figure PCTCN2022087589-appb-100054
    Figure PCTCN2022087589-appb-100054
    Figure PCTCN2022087589-appb-100055
    Figure PCTCN2022087589-appb-100055
    Figure PCTCN2022087589-appb-100056
    Figure PCTCN2022087589-appb-100056
  28. 一种制备权利要求1-24任一项所述式I所示化合物的方法，其包括步骤：A method for preparing the compound shown in the formula I of any one of claims 1-24, comprising the steps:
    (1)在酸性条件下，使中间体M-1水解得到权利要求25所述的中间体M-2；和/或(1) under acidic conditions, the intermediate M-1 is hydrolyzed to obtain the intermediate M-2 according to claim 25; and/or
    (2)在碱性条件下，使中间体M-2与
    Figure PCTCN2022087589-appb-100057
    接触得到中间体M-3，其中R 8具有如权利要求1-24任一项所述的定义；和/或     (2) under alkaline condition, make intermediate M-2 and
    Figure PCTCN2022087589-appb-100057
    Contacting yields intermediate M- 3 , wherein R has the definition as claimed in any one of claims 1-24; and/or
    (3)在碘单质存在下，在碱性条件下使中间体M-3发生环化反应得到化合物I；(3) in the presence of elemental iodine, under alkaline conditions, intermediate M-3 is cyclized to obtain compound I;
    其中，M-1、M-2和M-3具有权利要求25所述的结构和定义。Wherein, M-1, M-2 and M-3 have the structure and definition described in claim 25.
  29. 如权利要求28所述的方法，当R 8含有羟基时， The method of claim 28, when R8 contains hydroxyl,
    在所述步骤(2)之前还包括步骤(2-1)：通过羟基保护基保护羟基；和/或Before the step (2), it also includes a step (2-1): protecting the hydroxyl group by a hydroxyl protecting group; and/or
    在所述步骤(3)之后还包括步骤(3-2)：脱去羟基保护基。After the step (3), a step (3-2) is also included: removing the hydroxyl protecting group.
  30. 一种制备权利要求1-24任一项所述式I所示化合物的方法，其包括步骤：A method for preparing the compound shown in the formula I of any one of claims 1-24, comprising the steps:
    (A)在碱性条件下，使中间体M-2与硫光气或硫羰基二咪唑接触得到中间体M-4；和/或(A) under alkaline conditions, make intermediate M-2 contact with thiophosgene or thiocarbonyldiimidazole to obtain intermediate M-4; and/or
    (B)在碘单质存在下，在碱性条件下使中间体M-4与R 2-H接触得到权利要求1所述的化合物I，其中R 2具有如权利要求1-24任一项所述的定义； (B) in the presence of elemental iodine, the intermediate M-4 is contacted with R 2 -H under basic conditions to obtain the compound I according to claim 1, wherein R 2 has the compound I as claimed in any one of claims 1-24. the definition stated;
    其中，M-2和M-4具有权利要求25所述的结构和定义。Wherein, M-2 and M-4 have the structure and definition described in claim 25.
  31. 一种药物组合物，其特征在于包含药学上可接受的赋形剂以及权利要求1～24任一项所述任意化合物。A pharmaceutical composition, characterized by comprising a pharmaceutically acceptable excipient and any compound described in any one of claims 1-24.
  32. 权利要求1～24任一项所述的化合物或者权利要求31所述的药物组合物在制备药物中的用途，所述药物用于治疗或者预防MAT2A相关疾病。Use of the compound according to any one of claims 1 to 24 or the pharmaceutical composition according to claim 31 in the preparation of a medicament for treating or preventing MAT2A-related diseases.
  33. 权利要求1～24任一项所述的化合物或者权利要求31所述的药物组合物在制备药物中的用途，所述药物用于治疗或者预防癌症。Use of the compound of any one of claims 1 to 24 or the pharmaceutical composition of claim 31 in the preparation of a medicament for treating or preventing cancer.
  34. 权利要求33所述的用途，其中所述癌症是MTAP缺失的癌症。34. The use of claim 33, wherein the cancer is an MTAP-deficient cancer.
  35. 权利要求33所述的用途，其中所述癌症选自间皮瘤、神经母细胞瘤、直肠癌、结肠癌、熟悉的腺瘤性息肉病和遗传性非息肉性结直肠癌、食道癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、甲状腺乳头状癌、肾癌、肾实质癌、卵巢癌、子宫颈癌、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、前列腺癌、膀胱癌、睾丸癌、乳腺癌、泌尿癌、黑素瘤、脑瘤、淋巴瘤、头颈癌、急性淋巴白血病(ALL)、慢性淋巴白血病(CLL)、急性髓样白血病(AML)、慢性粒细胞白血病(CML)、肝细胞癌、胆囊癌、兄弟支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底肉瘤、畸胎瘤、视网膜母细胞瘤、脉络膜黑色素瘤、精原细胞瘤、横纹肌肉瘤、骨肉瘤、软骨肉瘤、肌瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤和浆细胞瘤。The use of claim 33, wherein the cancer is selected from the group consisting of mesothelioma, neuroblastoma, rectal cancer, colon cancer, familiar adenomatous polyposis and hereditary nonpolyposis colorectal cancer, esophageal cancer, lip Cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, intrauterine cancer Membranous cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary cancer, melanoma, brain tumor, lymphoma, head and neck cancer, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) ), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, gallbladder carcinoma, brother bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratoma, Retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, fibroids, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma.
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