WO2023116761A1 - 嘧啶杂环化合物，其制法与医药上的用途 - Google Patents

嘧啶杂环化合物，其制法与医药上的用途 Download PDF

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WO2023116761A1
WO2023116761A1 PCT/CN2022/140669 CN2022140669W WO2023116761A1 WO 2023116761 A1 WO2023116761 A1 WO 2023116761A1 CN 2022140669 W CN2022140669 W CN 2022140669W WO 2023116761 A1 WO2023116761 A1 WO 2023116761A1
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alkyl
alkylene
ring
membered
compound
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French (fr)
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陆洪福
彭晶晶
丁晓
刘金鑫
刘颖涛
任峰
周福生
蒋涛
梁涛
兰炯
吕强
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英矽智能科技知识产权有限公司
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Priority to CN202280076515.2A priority Critical patent/CN118647607A/zh
Priority to KR1020247023947A priority patent/KR20240124992A/ko
Publication of WO2023116761A1 publication Critical patent/WO2023116761A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • 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
    • C07D471/22—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 systems contains four or more hetero rings
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/18—Bridged 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
    • C07D487/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • the present invention claims the priority of the Chinese patent application CN202111583828.0 with the application date of December 22, 2021, and the priority of the Chinese patent application CN202210098381.6 with the application date of January 27, 2022, and the application date of May 23, 2022.
  • the priority of the Chinese patent application CN202210562007.7 dated December 07, 2022 is the priority of the Chinese patent application CN202211568373.X. This application cites part or all of the above-mentioned Chinese patent applications.
  • the invention belongs to the field of medicine, and in particular relates to a pyrimidine heterocyclic compound, its preparation method and its application in medicine.
  • CDK7 Cyclin-dependent kinase/cyclin complexes were identified as conserved components of the RNA polymerase II transcription machinery. Twenty mammalian CDKs currently exist. Among mammalian CDKs, CDK7 has robust kinase activity, and only CDK7 has dual functions of regulating cell cycle progression and transcription. In the cytosol, CDK7 exists as a heterotrimeric complex and is thought to function as a CDK1/2/4/6-activating kinase (CAK), whereby CDK7 contributes to the conservation of CDK1/2/4/6 Phosphorylation of residues is required for full catalytic CDK activity and cell cycle progression.
  • CAK CDK1/2/4/6-activating kinase
  • CDK7 forms the kinase core of the RNA polymerase II transcription factor complex and is responsible for phosphorylating the C-terminal domain (CTD) of RNA polymerase II, a necessary step for the initiation of gene transcription.
  • CTD C-terminal domain
  • CDK7 may serve as a therapeutic target for the treatment of many diseases and syndromes.
  • CDK7 can interact with multiple transcription factors, cofactors, chromatin regulators and non-coding RNAs in the transcriptional regulatory region to regulate transcription. Mutations in these transcription factors, cofactors, chromatin regulators, or noncoding RNAs can lead to diseases such as cancer, autoimmune diseases, neurological disorders, developmental syndromes, diabetes, cardiovascular disease, and obesity.
  • Some of these transcription factors control RNA polymerase II-mediated transcription initiation and elongation, and when their expression or function is altered, they can produce aggressive tumor cells (e.g. caused by c-Myc) or some forms of autoimmunity Sexuality (e.g. caused by AIRE).
  • CDK7 kinase can promote the abnormal expression of some tumor-related transcription factors by regulating the overall transcription process, and promote tumor development by regulating the phosphorylation of key cell cycle kinases. More importantly, CDK7 more significantly regulates the expression of oncogenic transcription factors than other housekeeping genes in cancer cells. Inhibition of CDK7 can differentially affect the transcription of certain oncogenes and housekeeping genes, thus ensuring a therapeutic window. Transcription regulation and cell cycle regulation can be performed by regulating CDK7-mediated phosphorylation modification, which can be used to treat abnormal proliferation diseases including cancer. As a global regulator of transcription, CDK7 may also serve as a therapeutic target for the treatment of diseases such as inflammation, viral replication such as HIV, EBV, cancer and cardiac hypertrophy.
  • diseases such as inflammation, viral replication such as HIV, EBV, cancer and cardiac hypertrophy.
  • CDK7-selective inhibitors The high sequence and structural similarity of the kinase domains of CDK family members hampers the discovery of CDK7-selective inhibitors. Therefore, the development of selective CDK7 inhibitors is of great value for clinical application.
  • the first aspect of the present invention provides a compound represented by formula (A) or a pharmaceutically acceptable salt thereof;
  • Ring A is none; or Ring A is selected from the group consisting of 3 to 14 membered carbocycles, 3 to 14 membered heterocyclic rings, 5 to 12 membered heteroaryls, C 5-12 aryls; Ring A is unsubstituted or replaced by 1, 2, 3, 4 or 5 are substituted by groups selected from S1 group; the 3- to 14-membered heterocycle has 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; The 5 to 12 membered heteroaryl has 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
  • L 3 is none, C 1-6 alkylene, C 2-6 alkenylene or ring B (the structure is ); wherein, 1, 2, 3, 4 or 5 hydrogen atoms on the C 1-6 alkylene group can optionally be independently substituted by R 13 ; on the C 2-6 alkenylene group 1, 2, 3, 4 or 5 hydrogen atoms may optionally each be independently substituted by R 13 ;
  • Ring B is selected from the group consisting of 3 to 14 membered carbocycle, 3 to 14 membered heterocyclic ring, 5 to 12 membered heteroaryl, C 5-12 aryl; Ring B is unsubstituted or replaced by 1, 2, 3, 4 or 5 are substituted by groups selected from S1 group; the 3 to 14 membered heterocyclic ring has 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; the 5 to 12 membered Heteroaryl has 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
  • the 5-12 membered heteroaryl has 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; the C 5-12 aryl, 5-12 membered heteroaryl are each independently Unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from S1 group;
  • L2 is selected from the group consisting of:
  • Each R 10 is independently hydrogen, C 1-6 alkyl, deuterated C 1-6 alkyl, -3 to 7-membered carbocyclyl, -C(O)-C 1-6 alkyl, -C(O )-C 1-4 alkyl-C 1-6 alkoxy, -C (O)-3 to 7-membered carbocyclyl, -C 1-4 alkyl-hydroxyl, -C 1-4 alkyl-cyanide Base, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl -NHC (O)-C 1-6 alkyl, -C 1-4 alkyl - NHC (O) -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-NHC(O)-3 to 7-membered carbocyclyl or -C 1-4 alkyl-NRR';
  • Each 3 to 7 membered heterocyclic group independently has 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of the 3 to 7 membered carbocycles is independently unsubstituted or replaced by 1, Substituted by 2, 3, 4 or 5 groups selected from group S1;
  • Each 3- to 7-membered carbocyclic group is independently unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from group S1;
  • each R 11 is independently hydrogen, C 1-6 alkyl or deuterated C 1-6 alkyl;
  • Each R 12 is independently hydrogen, C 1-6 alkyl or deuterated C 1-6 alkyl;
  • Each R 13 is independently hydrogen, cyano, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -3 to 7-membered carbocyclyl, -C 0-6 alkylene-NRR', -C 1-6 alkylene-hydroxyl or -C 0-6 alkylene-cyano;
  • Each R 14 is independently hydrogen, cyano, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -3 to 7-membered carbocyclyl, -C 0-6 alkylene-NRR', -C 1-6 alkylene-hydroxyl or -C 0-6 alkylene-cyano;
  • each m1 is each independently 1, 2, 3, 4, 5 or 6;
  • Each m2 is independently 0 or 1;
  • Each m3 is independently 0 or 1;
  • each m4 is independently 1 or 2;
  • each m5 is independently 0, 1, 2, 3, 4, 5 or 6;
  • each m6 is independently 0, 1, 2, 3, 4, 5 or 6;
  • Each m7 is independently 1 or 2;
  • R 1 is hydrogen, halogen, cyano, C 1-6 alkyl or 3 to 14 membered carbocyclyl; said C 1-6 alkyl, 3 to 14 membered carbocyclyl are independently unsubstituted or replaced by 1 , 2, 3, 4 or 5 groups selected from the group substituted: oxo, hydroxyl, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl;
  • R 2 is hydrogen, halogen, cyano, C 1-6 alkyl or 3 to 14 membered carbocyclyl; said C 1-6 alkyl, 3 to 14 membered carbocyclyl are independently unsubstituted or replaced by 1 , 2, 3, 4 or 5 groups selected from the group substituted: oxo, hydroxyl, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl;
  • X 2 is N or C (R 3 );
  • X 1 is N or C (R 4 );
  • Y is N or C (R 4 );
  • Z is N or C (R 3 );
  • Each R is independently hydrogen, halogen, cyano, C 1-6 alkyl or halogenated C 1-6 alkyl;
  • Each R is independently hydrogen, halogen, hydroxy, cyano, -C 2-4 alkenylene-phenyl, -C 2-4 alkynylene-phenyl, -S(O)-OH, -S( O) 2 -OH, -S-(C 1-6 alkyl), C 1-6 alkyl, -OC 1-6 alkyl, -C 1-6 alkylene -OC 1-6 alkyl, - OC 1-6 alkylene-OC 1-6 alkylene, -C 0-6 alkylene-NRR', -C 0-6 alkylene-C(O)OH, -C 0-6 alkylene -C(O)-C 1-6 alkyl, -C 0-6 alkylene-C(O)-NRR', -C 0-6 alkylene-NR-C(O)-C 1-6 Alkyl, -C 0-6 alkylene-S(O) 2 -C 1-6 alkyl, -C 0-6
  • the groups of the S1 group include: oxo, halogen, hydroxyl, cyano, C 1-6 alkyl, -OC 1-6 alkyl, -C 1-6 alkylene-OC 1-6 alkyl, -OC 1-6alkylene -OC 1-6alkylene , -C 0-6alkylene -NRR', -C 0-6alkylene -C(O)OH, -C 0-6alkylene -C(O)-C 1-6 alkyl, -C 0-6 alkylene-C(O)-NRR', -C 0-6 alkylene-NR-C(O)-C 1- 6 alkyl, -C 0-6 alkylene-S(O) 2 -C 1-6 alkyl, -C 0-6 alkylene-S(O) 2 -NRR', -C 0-6 alkylene Alkyl-NR-S(O) 2 -C 1-6 alkyl, -C 0-6
  • R and R' are each independently hydrogen, C 1-6 alkyl or deuterated C 1-6 alkyl; or R and R' optionally form a 3 to 14-membered heterocyclic group together with the nitrogen atom connected to them or 5 to 12-membered heteroaryl; wherein, the heterocyclic group and the heteroaryl each independently contain 0, 1 or 2 heteroatoms selected from N, O, and S in addition to the existing nitrogen atom;
  • two hydrogen atoms on any same carbon atom on the C 0-6 alkylene group may also optionally be substituted by a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic spirocyclic ring at the same time ;
  • two hydrogen atoms on any same carbon atom on the C1-6 alkylene group may optionally be simultaneously substituted by a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic spirocyclic ring .
  • R is hydrogen, halogen, cyano, C 1-4 alkyl, or a 3- to 7-membered carbocyclyl; the C 1-4 alkyl, 3- to 7-membered carbocyclyl are independently Unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from the group consisting of oxo, hydroxyl, halogen, C 1-3 alkyl, halo C 1-3 alkyl.
  • R is hydrogen, halogen, cyano, C 1-4 alkyl (e.g. methyl), haloC 1-4 alkyl (e.g. trifluoromethyl), 3 to 7 membered carbocycle group or halogenated 3- to 7-membered carbocyclyl.
  • R 2 is hydrogen, halogen, cyano, C 1-4 alkyl, or 3 to 7 membered carbocyclyl; said C 1-4 alkyl, 3 to 7 membered carbocyclyl are independently Unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from the group consisting of oxo, hydroxyl, halogen, C 1-3 alkyl, halo C 1-3 alkyl.
  • R is hydrogen, halogen, cyano, C 1-4 alkyl (e.g. methyl), haloC 1-4 alkyl (e.g. trifluoromethyl), 3 to 7 membered carbocycle group or halogenated 3- to 7-membered carbocyclyl.
  • Xi is N.
  • X 1 is C(R 4 ); wherein, R 4 is hydrogen, halogen, hydroxyl, cyano, -C 2-4 alkenylene-phenyl, -C 2-4 alkynylene- Phenyl, -S(O)-OH, -S(O) 2 -OH, -S-(C 1-6 alkyl) or R 8 ; R 8 is C 1-6 alkyl, -OC 1-6 Alkyl, -C 1-6 alkylene -OC 1-6 alkyl, -OC 1-6 alkylene -OC 1-6 alkyl, -C 0-6 alkylene -NRR', -C 0 -6 alkylene-C(O)OH, -C 0-6 alkylene-C(O)-C 1-6 alkyl, -C 0-6 alkylene-C(O)-NRR', -C 0-6 alkylene-NR-C(O)-C 1-6 alkyl, -C 0-6 al
  • X 1 is C(R 4 ); wherein, R 4 is -C 0-6 alkylene-NRR', -C 0-6 alkylene-C(O)OH, -C 0 -6 alkylene-C(O)-C 1-6 alkyl, -C 0-6 alkylene-C(O)-NRR', -C 0-6 alkylene-NR-C(O) -C 1-6 alkyl, -C 0-6 alkylene-S(O) 2 -C 1-6 alkyl, -C 0-6 alkylene-S(O) 2 -NRR', -C 0-6 alkylene-NR-S(O) 2 -C 1-6 alkyl, -C 0-6 alkylene-NR-S(O) 2 -NRR', -C 0-6 alkylene-P(O)O-(C 1-6 alkyl) 2 ⁇ -C 0-6 alkylene-P(O)-(O)-(O
  • X 1 is C(R 4 ); wherein, R 4 is -C 0-6 alkylene-P(O)O-(C 1-6 alkyl) 2 , -C 0-6 Alkylene-P (O)-(C 1-6 alkyl) (OC 1-6 alkyl) or -C 0-6 alkylene-P (O)-(C 1-6 alkyl) 2 ; Wherein, the C 1-6 alkyl, C 0-6 alkylene are independently unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from S1 group; the group S1 group The group definition is the same as before.
  • X 1 is C(R 4 ); wherein, R 4 is -P(O)O-(C 1-6 alkyl) 2 , -P(O)-(C 1-6 alkyl )(OC 1-6 alkyl) or -P(O)-(C 1-6 alkyl) 2 ; wherein, the C 1-6 alkyl is independently unsubstituted or replaced by 1, 2, 3, 4 or 5 groups selected from group S1 are substituted; the groups in group S1 are as defined above.
  • X 1 is C(R 4 ); wherein R 4 is hydrogen, halo, or cyano.
  • X 1 is C(R 4 ); wherein, R 4 is -P(O)O-(CH 3 ) 2 , -P(O)-(CH 3 )(O-CH 3 ) or -P(O)-(CH 3 ) 2 .
  • X 2 is C(R 3 ); R 3 is hydrogen.
  • Y is C( R4 ); R4 is hydrogen.
  • Z is C( R3 ); R3 is hydrogen.
  • two hydrogen atoms on the carbon atom on -CH 2 - are replaced by a cyclopropyl ring spiro ring, which means that two hydrogen atoms on the carbon atom on -CH 2 - are replaced by a divalent form of ethyl (i.e. ethylene After substitution, the ethylene group and the carbon atom jointly form a cyclopropyl group. and so on.
  • the compound of formula (A) is a compound of formula (I-A);
  • X 1 , Y, Z, X 2 , R 1 , R 2 , L 1 , L 2 , ring A and ring B are the same as above;
  • the compound of formula (A) is a compound of formula (I-B);
  • each of X 1 , Y, Z , X 2 , R 1 , R 2 , L 1 , L 2 , ring A, R 13 , and R 14 is as defined above; m0 is 1, 2, 3, 4, 5 or 6;
  • the compound of formula (A) is a compound of formula (A1);
  • X 1 , Y, Z, X 2 , R 1 , R 2 , L 1 , L 2 , ring A and ring B are the same as above;
  • the compound of formula (A) is a compound of formula (A2);
  • each of X 1 , Y, Z , X 2 , R 1 , R 2 , L 1 , L 2 , ring A, R 13 , and R 14 is as defined above; m0 is 1, 2, 3, 4, 5 or 6.
  • the compound of formula (A) is a compound of formula (Ia), a compound of formula (Ib), a compound of formula (Ic), a compound of formula (Id), a compound of formula (Ie), or a compound of formula (If);
  • X 1 , Y, Z, X 2 , R 1 , R 2 , L 1 , L 2 , ring A, and ring B are respectively defined as above.
  • the compound of formula (A) is a compound of formula (II-A);
  • R 1 , R 2 , L 1 , L 2 , ring A, ring B, and X 1 are each defined as above;
  • the compound of formula (A) is a compound of formula (II-B);
  • X 1 , R 1 , R 2 , L 1 , L 2 , Ring A, R 13 , R 14 are each as defined above; m0 is 1, 2, 3, 4, 5 or 6;
  • the compound of formula (A) is a compound of formula (A3);
  • X 1 , R 1 , R 2 , L 1 , L 2 , ring A, and ring B are each as defined above;
  • the compound of formula (A) is a compound of formula (A4)
  • X 1 , R 1 , R 2 , L 1 , L 2 , ring A, R 13 , and R 14 are each as defined above; m0 is 1, 2, 3, 4, 5 or 6.
  • the compound of formula (A) is a compound of formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe) or formula (IIf);
  • X 1 , R 1 , R 2 , L 1 , L 2 , ring A, and ring B are each as defined above.
  • the compound of formula (A) is a compound of formula (III-A);
  • L 1 , L 2 , Ring A, Ring B, and X 1 are the same as above;
  • the compound of formula (A) is a compound of formula (III-B);
  • X 1 , L 1 , L 2 , Ring A, R 13 , R 14 are as defined above; m0 is 1, 2, 3, 4, 5 or 6;
  • the compound of formula (A) is a compound of formula (A5);
  • the compound of formula (A) is a compound of formula (A6);
  • X 1 , L 1 , L 2 , ring A, R 13 , and R 14 are each as defined above; m0 is 1, 2, 3, 4, 5 or 6.
  • the compound of formula (A) is a compound of formula (III-1) or a compound of formula (III-2);
  • L 1 , L 2 , ring A, ring B, and X 1 are each as defined above.
  • the compound of formula (A) is a compound of formula (III-a), a compound of formula (III-b), a compound of formula (III-c) or a compound of formula (III-d);
  • L 1 , L 2 , ring A, ring B, and X 1 are each as defined above.
  • the compound of formula (A) is a compound of formula (IV-a), a compound of formula (IV-b), or a compound of formula (IV-c);
  • L 1 , L 2 , ring B, and X 1 are as defined above.
  • ring A is none; or ring A is selected from the group consisting of 3 to 6 membered carbocycle, 3 to 6 membered heterocycle, 5 to 6 membered heteroaryl, phenyl, said ring A is not Substituted or substituted by 1, 2 or 3 selected from OH, C 1-6 alkyl, halogen, and the remaining variables are as defined in the present invention.
  • ring A is none; or ring A is selected from the group consisting of cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, piperidine ring, piperazine ring, tetrahydropyrrole ring, pyrazole ring, imidazole ring ; Ring A is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from group S1, and the remaining variables are as defined in the present invention.
  • ring A is none; or ring A is selected from the group consisting of cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, piperidine ring, piperazine ring, tetrahydropyrrole ring, pyrazole ring, imidazole ring ; Ring A is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from S1 group; said group S group includes: hydroxyl, methyl, halogen, and the rest of the variables are as in the present invention defined.
  • Ring A is None; or Ring A is selected from the group consisting of:
  • Ring A is None; or Ring A is selected from the group consisting of:
  • ring B is selected from the group consisting of 3 to 6 membered carbocycles, 3 to 6 membered heterocycles, said ring B is unsubstituted or replaced by 1, 2 or 3 members selected from OH, C 1- 6 alkyl, halogen substitution, and other variables are as defined in the present invention.
  • Ring B is selected from the group consisting of cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, piperidine ring, piperazine ring, tetrahydropyrrole ring, pyrazole ring, imidazole ring; Ring B is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from group S1, and the remaining variables are as defined in the present invention.
  • Ring B is selected from the group consisting of: The remaining variables are as defined in the present invention
  • Ring B is selected from the group consisting of:
  • L 2 is -NR 11 -(CR 13 R 14 ) m1 -NR 12 -; R 11 , R 12 are independently hydrogen or methyl; each R 13 , R 14 are independently hydrogen, halogen or methyl; m1 is 1, 2, 3, 4, 5 or 6, and the remaining variables are as defined in the present invention.
  • L 2 is -O-(CR 13 R 14 ) m1 -NR 12 -;
  • R 12 is hydrogen or methyl;
  • each R 13 , R 14 is independently hydrogen, halogen or methyl;
  • m1 is 1, 2, 3, 4, 5 or 6, and the remaining variables are as defined in the present invention.
  • L 2 is -NR 11 -(CR 13 R 14 ) m1 -;
  • R 11 is hydrogen or methyl;
  • each R 13 , R 14 is independently hydrogen, halogen or methyl;
  • m1 is 1, 2, 3, 4, 5 or 6, and the remaining variables are as defined in the present invention.
  • L 2 is -(CR 13 R 14 ) m1 -NR 12 -;
  • R 12 is hydrogen or methyl;
  • each R 13 , R 14 is independently hydrogen, halogen or methyl;
  • m1 is 1, 2, 3, 4, 5 or 6, and the remaining variables are as defined in the present invention.
  • L 2 is -(CR 13 R 14 ) m1 -; each R 13 , R 14 is independently hydrogen, halogen or methyl; m1 is 1, 2, 3, 4, 5 or 6, and the rest Variables are as defined herein.
  • L 2 is -NR 11 -(CR 13 R 14 ) m5 -3 to 7-membered carbocycle-(CR 13 R 14 ) m6 -NR 12 -;
  • R 11 and R 12 are independently hydrogen or Methyl; each R 13 and R 14 are independently hydrogen, halogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4; said 3 to 7 members
  • the carbocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from group S1, the remaining variables are as defined in the present invention.
  • L 2 is -O-(CR 13 R 14 ) m5 -3 to 7 membered carbocycle -(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl;
  • each R 13 , R 14 are each independently hydrogen, halogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4;
  • the 3 to 7-membered carbocyclic ring is unsubstituted Or be substituted by 1, 2, 3, 4 or 5 groups selected from group S1, and the remaining variables are as defined in the present invention.
  • L 2 is -(CR 13 R 14 ) m5 -3 to 7 membered carbocycle -(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl; each of R 13 , R 14 are each independently hydrogen, halogen or methyl; m5 is 0, 1, 2, 3 or 4; m6 is 0, 1, 2, 3 or 4; the 3 to 7-membered carbocyclic ring is unsubstituted or replaced by 1, 2, 3, 4 or 5 groups selected from group S1 are substituted.
  • the 3- to 7-membered carbocycle is cyclobutyl, cyclopentyl, or cyclohexyl, with the remaining variables as defined herein.
  • L 2 is -NR 11 -(CR 13 R 14 ) m5 -3 to 7-membered heterocycle-(CR 13 R 14 ) m6 -NR 12 ;
  • R 11 and R 12 are independently hydrogen or methane each R 13 , R 14 are each independently hydrogen, halogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4; the 3 to 7-membered hetero
  • the ring is unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from group S1, and the remaining variables are as defined in the present invention.
  • L 2 is -O-(CR 13 R 14 ) m5 -3 to 7 membered heterocycle-(CR 13 R 14 ) m6 -NR 12 ;
  • R 12 is hydrogen or methyl;
  • each R 13 , R 14 are each independently hydrogen, halogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4;
  • the 3 to 7 membered heterocyclic ring is unsubstituted or Substituted by 1, 2, 3, 4 or 5 groups selected from group S1, and the remaining variables are as defined in the present invention.
  • L 2 is -(CR 13 R 14 ) m5 -3 to 7 membered heterocycle -(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl;
  • each R 13 , R 14 are each independently hydrogen, halogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4;
  • the 3 to 7-membered heterocyclic ring is unsubstituted or replaced by 1, 2, 3, 4 or 5 groups selected from group S1 are substituted, and the remaining variables are as defined in the present invention.
  • L 2 is -NR 11 -(CR 13 R 14 ) m5 -NR 10 -(CR 13 R 14 ) m6 -NR 12 -;
  • R 11 and R 12 are independently hydrogen or methyl; each R 13 and R 14 are each independently hydrogen, halogen or methyl;
  • R 10 is hydrogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and other variables as defined herein.
  • L 2 is -O-(CR 13 R 14 ) m5 -NR 10 -(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl; each R 13 , R 14 are each independently hydrogen, halogen or methyl;
  • R 10 is hydrogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and the remaining variables are as defined in the present invention.
  • L 2 is -(CR 13 R 14 ) m5 -NR 10 -(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl; each R 13 and R 14 are independently is hydrogen, halogen or methyl;
  • R 10 is hydrogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and the remaining variables are as defined in the present invention.
  • L 2 is -NR 11 -(CR 13 R 14 ) m5 -NR 10 C(O)-(CR 13 R 14 ) m6 -NR 12 -;
  • R 11 and R 12 are independently hydrogen or Methyl; each R 13 and R 14 are independently hydrogen, halogen or methyl;
  • R 10 is hydrogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4.
  • the remaining variables are as defined in the present invention.
  • L 2 is -O-(CR 13 R 14 ) m5 -NR 10 C(O)-(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl; each R 13 , R 14 are each independently hydrogen, halogen or methyl;
  • R 10 is hydrogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and the rest of the variables are as described herein invention defined.
  • L 2 is -(CR 13 R 14 ) m5 -NR 10 C(O)-(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl; each of R 13 , R 14 are each independently hydrogen, halogen or methyl;
  • R 10 is hydrogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and the rest of the variables are as described in the present invention definition.
  • L 2 is -NR 11 -(CR 13 R 14 ) m5 -C(O)NR 10 -(CR 13 R 14 ) m6 -NR 12 -;
  • R 11 and R 12 are independently hydrogen or Methyl; each R 13 and R 14 are independently hydrogen, halogen or methyl;
  • R 10 is hydrogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4.
  • the remaining variables are as defined in the present invention.
  • L 2 is -O-(CR 13 R 14 ) m5 -C(O)NR 10 -(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl; each R 13 , R 14 are each independently hydrogen, halogen or methyl;
  • R 10 is hydrogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and the rest of the variables are as described herein invention defined.
  • L 2 is -(CR 13 R 14 ) m5 -C(O)NR 10 -(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl; each of R 13 , R 14 are each independently hydrogen, halogen or methyl;
  • R 10 is hydrogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and the rest of the variables are as described in the present invention definition.
  • L 2 is -NR 11 -(CR 13 R 14 ) m5 -O-(CR 13 R 14 ) m6 -NR 12 -;
  • R 11 and R 12 are independently hydrogen or methyl; each R 13 and R 14 are each independently hydrogen, halogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and the remaining variables are as defined in the present invention.
  • L 2 is -O-(CR 13 R 14 ) m5 -O-(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl;
  • each R 13 and R 14 are independently m is hydrogen, halogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and other variables are as defined in the present invention.
  • L 2 is -(CR 13 R 14 ) m5 -O-(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl;
  • each R 13 , R 14 is independently hydrogen, halogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and other variables are as defined in the present invention.
  • L 2 is -NR 11 -(CR 13 R 14 ) m5 -OC(O)-(CR 13 R 14 ) m6 -NR 12 -;
  • R 11 and R 12 are independently hydrogen or methyl each R 13 ,
  • R 14 is independently hydrogen, halogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and other variables are as defined in the present invention.
  • L 2 is -O-(CR 13 R 14 ) m5 -OC(O)-(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl;
  • each R 13 , R 14 are each independently hydrogen, halogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and the remaining variables are as defined in the present invention.
  • L 2 is -(CR 13 R 14 ) m5 -OC(O)-(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl; each R 13 , R 14 are each independently hydrogen, halogen or methyl; m5 is 0, 1, 2, 3 or 4; m6 is 0, 1, 2, 3 or 4, and the remaining variables are as defined herein.
  • L 2 is -NR 11 -(CR 13 R 14 ) m5 -C(O)O-(CR 13 R 14 ) m6 -NR 12 -;
  • R 11 and R 12 are independently hydrogen or methane
  • Each R 13 and R 14 are independently hydrogen, halogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and the remaining variables are as defined in the present invention .
  • L 2 is -O-(CR 13 R 14 ) m5 -C(O)O-(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl;
  • each R 13 , R 14 are each independently hydrogen, halogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and other variables are as defined in the present invention.
  • L 2 is -(CR 13 R 14 ) m5 -C(O)O-(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl; each of R 13 , R 14 Each is independently hydrogen, halogen or methyl; m5 is 0, 1, 2, 3 or 4; m6 is 0, 1, 2, 3 or 4, and the remaining variables are as defined in the present invention.
  • L 2 is -NR 11 -(CR 13 R 14 ) m5 -CH ⁇ CH-(CR 13 R 14 ) m6 -NR 12 -;
  • R 11 and R 12 are independently hydrogen or methyl;
  • Each R 13 and R 14 is independently hydrogen, halogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and other variables are as defined in the present invention.
  • L 2 is -O-(CR 13 R 14 ) m5 -CH ⁇ CH-(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl; each of R 13 , R 14 Each is independently hydrogen, halogen or methyl; m5 is 0, 1, 2, 3 or 4; m6 is 0, 1, 2, 3 or 4, and the remaining variables are as defined in the present invention.
  • L 2 is -(CR 13 R 14 ) m5 -CH ⁇ CH-(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is hydrogen or methyl;
  • each R 13 and R 14 are independently m is hydrogen, halogen or methyl;
  • m5 is 0, 1, 2, 3 or 4;
  • m6 is 0, 1, 2, 3 or 4, and other variables are as defined in the present invention.
  • the groups of the S1 group include: oxo, hydroxy, cyano, halogen, methyl, ethyl, propyl, and other variables are as defined in the present invention.
  • the 3- to 7-membered carbocycle is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, with the remaining variables as defined herein.
  • the 3- to 7-membered heterocyclic ring is azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, or piperazinyl, and the remaining variables are as defined herein .
  • L is selected from one of the following groups:
  • L is selected from the group consisting of: The remaining variables are as defined herein.
  • L 1 is -N(CD 3 )-, -CH(CD 3 ), -N(CD 3 )-C(O)- or -C(O)-N(CD 3 ), and the rest Variables are as defined herein.
  • X 1 is N or C(R 4 ); wherein, R 4 is hydrogen, halogen, cyano, -S(O) 2 CH 3 or -P(O)(CH 3 ) 2 , and the rest Variables are as defined herein.
  • the compound of formula (A) is selected from one of the compounds in Table (I) below:
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect, its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • active substance of the present invention or “compound of the present invention” refers to the compound described in the first aspect, its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof.
  • the term "pharmaceutically acceptable carrier” refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention, which does not interfere with the biological activity of the active substance and has no toxic side effects on the host or the subject.
  • Carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity builders, skin penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine.
  • the pharmaceutical composition can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, cardiac Indoor, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir. Among them, oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the present invention may be prepared in any orally acceptable preparation form, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions. Carriers used for tablets generally include lactose and corn starch, and lubricating agents such as magnesium stearate may also be added.
  • Diluents used in capsule formulations generally include lactose and dried cornstarch.
  • Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may also be added to the above oral preparation forms.
  • the compound of the present invention When using locally, especially when treating the affected areas or organs that are easily accessible by local external application, such as eyes, skin or lower intestinal nerve diseases, the compound of the present invention can be made into different topical preparations according to different affected areas or organs
  • the compounds of the present invention may be formulated in the form of a micronized suspension or solution in the form of isotonic sterile saline at a certain pH with or without the addition of preservatives such as Benzyl alkoxide chloride.
  • the compounds may also be formulated in ointments such as petrolatum.
  • the compounds of the invention When applied topically to the skin, the compounds of the invention may be formulated in suitable ointments, lotions or creams wherein the active ingredients are suspended or dissolved in one or more carriers.
  • Carriers that can be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil Oil, sorbitan monostearate, Tween 60, cetyl esters wax, cetyl aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention can also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oily suspensions or sterile injectable solutions.
  • Vehicles and solvents that may be employed include water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils, such as mono- or diglycerides can also be employed as a solvent or suspending medium.
  • the present invention provides the use of the compound described in the first aspect, its stereoisomer, prodrug or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and/or preventing CDK7-related diseases.
  • the present invention provides the use of the compound described in the first aspect, its stereoisomer, prodrug or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and/or preventing cancer.
  • the present invention provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the first aspect, its stereoisomer, prodrug, or pharmaceutical acceptable salts above, or any combination of the above, or the step of administering the pharmaceutical composition described in the second aspect.
  • the present invention provides the use of the compound described in the first aspect, its stereoisomer, prodrug or pharmaceutically acceptable salt thereof in the preparation of a CDK7 inhibitor.
  • the CDK7-associated disease is a proliferative disease (eg, tumor or cancer), infectious disease, immune disease, autoimmune disease, and inflammatory disease.
  • the tumor or cancer includes solid tumors, hematological tumors.
  • the tumor or cancer includes melanoma, bone cancer (e.g., osteosarcoma, Ewing's sarcoma), breast cancer (e.g., hormone receptor positive (HR+) breast cancer (e.g., estrogen receptor positive (ER+) or progesterone receptor positive (PR+) breast cancer), hormone receptor negative breast cancer, triple negative breast cancer (TNBC; ER-/PR-/HER2-)), colorectal cancer, brain cancer, lung cancer (e.g.
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphoblastic Cell leukemia
  • T-ALL T-cell acute lymphoblastic leukemia
  • CML chronic myeloid leukemia
  • AML acute myelogenous leukemia
  • lymphoma multiple myeloma
  • glioblastoma Neuroblastoma.
  • the infectious disease includes AIDS, cholera, conjunctivitis, dengue fever, encephalitis, enterovirus infection (e.g., polio, non-poliomyelitis), E. coli infection, foot-and-mouth disease, hepatitis, zoster Herpes, flu, measles, etc.
  • enterovirus infection e.g., polio, non-poliomyelitis
  • E. coli infection e.g., foot-and-mouth disease
  • hepatitis hepatitis
  • zoster Herpes e.g., flu, measles, etc.
  • the immune and/or autoimmune diseases include asthma, diabetes, rheumatic diseases, AIDS, rejection of transplanted organs and tissues, rhinitis, chronic obstructive pulmonary disease, osteoporosis, ulcerative colitis , lupus erythematosus, allergies, rheumatoid arthritis, myasthenia gravis, Crohn's disease, psoriasis, etc.
  • the inflammatory disease is selected from inflammatory diseases of the central nervous system (CNS), inflammatory rheumatic diseases, inflammatory diseases of blood vessels, inflammatory diseases of the middle ear, inflammatory bowel diseases, cutaneous Inflammatory Diseases, Uveitis Inflammatory Diseases, and Inflammatory Diseases of the Throat.
  • CNS central nervous system
  • inflammatory rheumatic diseases inflammatory diseases of blood vessels
  • inflammatory diseases of the middle ear inflammatory diseases of the middle ear
  • inflammatory bowel diseases cutaneous Inflammatory Diseases
  • Uveitis Inflammatory Diseases Uveitis Inflammatory Diseases
  • Inflammatory Diseases of the Throat cutaneous Inflammatory Diseases of the Throat.
  • the term "subject” refers to an animal, especially a mammal, preferably a human.
  • the term "effective amount” or “therapeutically effective amount” refers to a non-toxic but sufficient amount of a drug or agent to achieve the desired effect.
  • the amount of a given drug depends on many factors, such as the specific dosing regimen, the type of disease or condition and its severity, the subject in need of treatment, or the uniqueness of the host (e.g. body weight), however, depending on the particular surrounding circumstances including, for example, the particular drug employed, the route of administration, the condition being treated, and the subject or host being treated, the dosage administered can be determined by those known in the art The method is routinely determined.
  • the administered dosage is typically in the range of 0.02-5000 mg/day, for example about 1-1500 mg/day.
  • the desired dose may conveniently be presented as one dose, or as divided doses administered simultaneously (or within a short period of time) or at appropriate intervals, for example as two, three, four or more divided doses per day.
  • the specific effective dose can be adjusted appropriately according to the condition of the patient and in combination with the doctor's diagnosis.
  • the term "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention that is pharmaceutically acceptable and that possesses the pharmacological activity of the parent compound.
  • Such salts include: acid addition salts formed with inorganic acids such as nitric acid, phosphoric acid, carbonic acid, etc.; said organic acids such as propionic acid, hexanoic acid, cypionic acid, Glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, etc.; or salts formed when the acidic protons present on the parent compound are replaced by metal ions, such as alkali metal ions or alkaline earth metal ions; or with organic bases Formed coordination compound, the organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert them to the compounds of the present invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.
  • stereoisomer includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers.
  • the compounds of the present invention may exist in the form of stereoisomers, and thus encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, tautomers, enantiomers, non- Enantiomers, atropisomers, etc., the compounds of the present invention can also be any combination or any mixture of the aforementioned stereoisomers, such as mesoforms, racemates, atropisomers It exists in the form of a mixture of equal amounts.
  • a single enantiomer, a single diastereoisomer or a mixture thereof, or a single atropisomer or a mixture thereof When the compounds described herein contain olefinic double bonds, unless otherwise specified, they include cis-isomers and trans-isomers, and any combination thereof.
  • Atropisomers of the present invention are stereoisomers based on axial or planar chirality resulting from restricted intramolecular rotation.
  • the compound of formula (A) has optical isomers derived from asymmetric carbon, axial asymmetry, etc., and if necessary, a single isomer can be resolved by methods known in the art, such as crystallization or chiral chromatography. .
  • hydrocarbyl refers to a straight or branched chain saturated aliphatic hydrocarbyl group.
  • C 1-6 hydrocarbon group refers to a straight or branched chain hydrocarbon group having 1 to 6 carbon atoms. Examples include C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and the like.
  • C 1-6 alkyl refers to a straight or branched chain alkyl having 1 to 6 carbon atoms. It is preferably C 1-4 alkyl, more preferably C 1-3 alkyl. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-Dimethylbutyl, 2-ethylbutyl, 2-
  • alkenyl refers to an alkyl group as defined above having one or more carbon-carbon double bonds at any position in the chain
  • C 2-6 alkenyl refers to an alkyl group having 2 to 6 carbons. Atoms and at least one (eg, 1 to 2) carbon-carbon double bond.
  • C 2-4 alkenyl ie, an alkenyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds
  • Specific examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, pentenyl, hexenyl, butadienyl, and the like.
  • alkynyl refers to an alkyl group as defined above having one or more carbon-carbon triple bonds at any position in the chain
  • C alkynyl refers to an alkyl group having 2 to 6 carbons. Atoms and at least one (eg, 1 to 2) carbon-carbon triple bond. More preferred is C 2-4 alkynyl (ie, an alkynyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds). Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo refers to fluoro, chloro, bromo or iodo.
  • halohydrocarbyl refers to a hydrocarbyl group in which one or more (eg, 1, 2, 3, 4 or 5) hydrogen atoms are replaced by halogen, wherein hydrocarbyl is as defined above.
  • haloC 1-6 alkyl refers to a haloalkyl group having 1 to 6 carbon atoms. It is preferably a halogenated C 1-4 alkyl group, more preferably a halogenated C 1-3 alkyl group.
  • Specific examples include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, Difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.
  • deuterated hydrocarbyl refers to a hydrocarbyl group in which one or more (eg, 1, 2, 3, 4 or 5) hydrogen atoms are replaced by deuterium atoms, wherein hydrocarbyl is as defined above.
  • deuterated C 1-6 alkyl refers to a deuterated alkyl group having 1 to 6 carbon atoms. It is preferably deuterated C 1-4 alkyl, more preferably deuterated C 1-3 alkyl. Specific examples include, but are not limited to, monodeuteromethyl, dideuuteromethyl, trideuteromethyl, and the like.
  • carbocyclyl and “carbocycle” are used interchangeably to refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group.
  • the term “3- to 14-membered carbocyclyl” or “C 3-14 carbocyclyl” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group having 3 to 14 carbon atoms. Examples include monocyclic carbocyclyl (such as 3 to 7 membered carbocyclyl or "C 3-7 carbocyclyl”) or polycyclic carbocyclyl (such as spiro carbocyclyl, fused carbocyclyl and bridged carbocyclyl, etc. ).
  • 3 to 7 membered carbocyclyl or " C3-7 carbocyclyl” can be used interchangeably, and both refer to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group having 3 to 7 ring carbon atoms. It is preferably a 3- to 6-membered monocyclic carbocyclyl, preferably a 4- to 6-membered monocyclic carbocyclyl, and more preferably a 3, 4, 5, or 6-membered monocyclic carbocyclyl.
  • monocyclic carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • spirocarbocyclyl and "spirocarbocyclyl ring” refer to a polycyclic cyclic hydrocarbon group formed by sharing one carbon atom (called a spiro atom) between two or more monocyclic rings. According to the number of spiro atoms shared between rings, spirocarbocyclyls are divided into single spirocarbocyclyls, double spirocarbocyclyls and polyspirocarbocyclyls.
  • 6- to 12-membered spirocarbocyclyl refers to a polycyclic cyclic hydrocarbon group having 6 to 12 ring carbon atoms, wherein the monocyclic ring sharing a spiro atom is a 3 to 7-membered monocyclic carbocyclic ring. It is preferably a 7- to 12-membered spirocarbocyclyl, more preferably a 7- to 12-membered monospirocarbocyclyl.
  • fused carbocyclyl and “fused carbocyclyl ring” refer to a polycyclic cyclic hydrocarbon group formed by two or more monocyclic rings sharing adjacent pairs of carbon atoms. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed carbocyclic groups.
  • the term “5 to 12 membered fused carbocyclyl” refers to a polycyclic cyclic hydrocarbon group having 5 to 12 ring carbon atoms, wherein the monocyclic rings sharing adjacent pairs of carbon atoms are 3 to 7 membered monocyclic carbocyclic rings. It is preferably a 7- to 12-membered condensed carbocyclic group.
  • fused carbocyclyls include, but are not limited to:
  • fused carbocyclic groups can be attached to the rest of the molecule through any ring atom.
  • bridged carbocyclyl and “bridged carbocyclyl ring” refer to a polycyclic cyclic hydrocarbon group formed by two or more monocyclic rings sharing two carbon atoms that are not directly connected. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged carbocyclic groups.
  • the term “5- to 12-membered bridged carbocyclyl” refers to a polycyclic cyclic hydrocarbon group having 5 to 12 ring carbon atoms, wherein any two rings share two carbon atoms that are not directly connected. It is preferably a 7- to 12-membered bridged carbocyclyl. Specific examples of bridged carbocyclyls include, but are not limited to:
  • bridging carbocyclyls can be attached to the rest of the molecule through any ring atom.
  • the carbocyclyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring where the ring bonded to the parent structure is a carbocyclyl ring, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • the above-mentioned various carbocyclic groups may be optionally substituted, and when substituted, the substituents are preferably one or more substituent groups described in the present application.
  • heterocyclyl and “heterocycle” are used interchangeably and refer to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic heterocyclyl, spiroheterocyclyl, fused Heterocyclyl and Bridged Heterocyclyl.
  • the ring carbon atoms of the heterocyclic group in the present invention may be optionally substituted by 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
  • the 3- to 14-membered heterocyclic groups in the present invention include monocyclic heterocyclic groups (such as 3- to 7-membered heterocyclic groups), spiro heterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups.
  • Preferred are 4 to 7 membered monocyclic heterocyclic groups having 4 to 7 ring atoms, of which 1 or 2 ring atoms are heteroatoms. More preferred are 5 or 6 membered monocyclic heterocyclyl groups having 5 or 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms.
  • the heteroatom when the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R being hydrogen or other substituents already defined herein).
  • the ring carbon atoms of the monocyclic heterocyclic group may be optionally substituted by 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
  • monocyclic heterocyclyl groups include, but are not limited to, aziridine, oxirane, azetidine, azetidin-2-one, oxazolidine, pyrrolidin-2-one, pyrrole Alkane-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidin-2-one, piperidine- 2,6-Diketone, Tetrahydro-2H-pyran-2-one, Imidazolidine, Tetrahydrofuran, Tetrahydrothiophene, Tetrahydropyrrole, 1,3-dioxolane-2-one, Oxazolidine-2 -ketone, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiomorpholin-3-one1, 1-dioxide, thi
  • the two ring atoms connected to the above-mentioned monocyclic heterocyclyl ring can optionally be combined with the monocyclic carbocyclyl ring, monocyclic heterocyclyl ring, monoaryl ring, 5 Or a carbocyclyl, heterocyclyl, aryl or heteroaryl such as a 6-membered monocyclic heteroaryl ring is fused to form a condensed polycyclic ring.
  • the 2 ring atoms attached to the monocyclic heterocyclic group forming a fused ring with other rings are preferably C-C.
  • the heteroatom is a nitrogen atom
  • the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R being hydrogen or other substituents already defined herein).
  • Each single ring can contain one or more double bonds, but no ring has a fully conjugated ⁇ -electron system.
  • spiroheterocyclyls are classified as single spiroheterocyclyls, double spiroheterocyclyls or polyspiroheterocyclyls.
  • the term "7 to 14 membered spiroheterocyclyl” refers to a spiroheterocyclyl having 7 to 14 ring atoms, of which 1 or 2 ring atoms are heteroatoms.
  • spiroheterocyclyls may be attached to the remainder of the molecule through any suitable ring atom.
  • the heteroatom is a nitrogen atom
  • the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R being hydrogen or other substituents already defined herein).
  • Each single ring can contain one or more double bonds, but no ring has a fully conjugated ⁇ -electron system.
  • Shared adjacent pairs of ring atoms may be CC or NC. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocyclic groups.
  • the term "5 to 14 membered fused heterocyclic group” refers to a condensed heterocyclic group having 5 to 14 ring atoms.
  • Preferred is a 6- to 10-membered condensed heterocyclic group having 6 to 10 ring atoms, of which 1 or 2 ring atoms are heteroatoms.
  • 8 to 10 membered fused heterocyclic groups having 8 to 10 ring atoms, of which 1 or 2 ring atoms are heteroatoms. Most preferred are 8-membered (5-membered monocyclic heterocyclyl ring fused to 5-membered monocyclic heterocyclyl ring), 9-membered (5-membered monocyclic heterocyclyl ring fused to 6-membered monocyclic heterocyclyl ring) Or a 10-membered (6-membered monocyclic heterocyclyl ring condensed with a 6-membered monocyclic heterocyclyl ring) bicyclic condensed heterocyclic group. Specific examples of fused heterocyclic groups include, but are not limited to:
  • fused heterocyclic groups may be attached to the remainder of the molecule through any suitable ring atom.
  • 5- to 14-membered bridged heterocyclic group refers to a saturated or partially unsaturated polycyclic heterocyclic group having 5 to 14 ring atoms, wherein any two rings share two ring atoms that are not directly connected, and each single Rings can contain one or more double bonds, but none have a fully conjugated ⁇ -electron system. It is preferably a 5- to 10-membered bridged heterocyclic group.
  • bridged heterocyclyl groups include, but are not limited to:
  • bridging heterocyclyl groups may be attached to the remainder of the molecule through any suitable ring atom.
  • the above-mentioned various heterocyclic groups may be optionally substituted, and when substituted, the substituents are preferably one or more substituent groups described in the present application.
  • aryl As used herein, the terms “aryl”, “aryl ring” and “aryl ring” are used interchangeably to refer to an all-carbon monocyclic ring, an all-carbon non-fused polycyclic ring (rings are covalently bonded, non-fused combined) or all-carbon fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) groups, at least one ring in the group is aromatic, that is, has a conjugated ⁇ -electron system.
  • C 5-12 aryl refers to an aryl group having 5 to 12 ring atoms, preferably a C 6-10 aryl group.
  • the C 5-12 aryl group in the present invention includes monocyclic aryl groups (such as phenyl), non-fused polycyclic aryl groups (such as biphenyl) and aromatic fused polycyclic groups.
  • the aromatic fused polycyclic ring can be a polycyclic ring formed by the fusion of a single aryl ring and one or more single aryl rings groups, non-limiting examples of which include naphthyl, anthracenyl, and the like.
  • the aromatic fused polycyclic ring can also be a single aryl ring (such as phenyl) fused with one or more non-aromatic rings A polycyclic group formed by synthesis, wherein the ring connected to the parent structure is an aromatic ring or a non-aromatic ring.
  • the non-aromatic ring includes but is not limited to 3 to 7 membered monocyclic heterocyclyl rings (preferably 5 or 6 membered monocyclic heterocyclyl rings, the ring carbon atoms of the monocyclic heterocyclyl rings can be replaced by 1 to 2 A oxo group is substituted to form a cyclic lactam or cyclic lactone structure), a 3 to 7-membered monocyclic carbocyclyl ring (preferably a 5 or 6-membered monocyclic carbocyclyl ring, the monocyclic carbocyclyl ring of which Ring carbon atoms can be substituted by 1 or 2 oxo groups to form a ring ketone structure).
  • the polycyclic group in which the above-mentioned single aryl ring is fused with one or more non-aromatic rings can be connected to other groups or parent structures through nitrogen atoms or carbon atoms, and the rings connected to the parent structure are single aryl rings or non-aromatic ring.
  • heteroaryl As used herein, the terms “heteroaryl”, “heteroaryl ring” and “heteroaryl ring” are used interchangeably to refer to a single or fused ring in which ring atoms are replaced by at least one heteroatom independently selected from nitrogen, oxygen or sulfur Polycyclic (i.e. sharing adjacent pairs of ring atoms which may be CC or NC) groups in which the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized.
  • the heteroaryl group has 6, 10 or 14 ⁇ -electrons shared, and at least one ring in the group is aromatic.
  • the heteroaryl group herein can be a monocyclic heteroaryl (eg 5 or 6 membered monocyclic heteroaryl), a fused bicyclic heteroaryl (eg 8 to 10 membered bicyclic heteroaryl) or a fused tricyclic heteroaryl .
  • monocyclic heteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, Azole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole , 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.
  • the fused bicyclic heteroaryl group can be a bicyclic group formed by the fusion of a monoaryl ring (such as phenyl) and a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring), or Can be a bicyclic group formed by the fusion of a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) and a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) .
  • any two ring atoms connected to each other on the above-mentioned monocyclic heteroaryl ring can be combined with the monocyclic carbocyclyl ring, monocyclic heterocyclyl ring, monoaryl ring, 5 Or a carbocyclyl, heterocyclyl, aryl or heteroaryl such as a 6-membered monocyclic heteroaryl ring is fused to form a condensed polycyclic ring.
  • Non-limiting examples of the 8- to 10-membered bicyclic heteroaryl include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]iso Thiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline , isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyridine A[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naph
  • the above-mentioned monocyclic heteroaryl group, or the bicyclic heteroaryl group formed by the fusion of the benzene ring and the monocyclic heteroaryl ring, or the bicyclic heteroaryl group formed by the fusion of the monocyclic heteroaryl ring and the monocyclic heteroaryl ring can be obtained by
  • the nitrogen or carbon atoms are linked to other groups or parent structures.
  • Specific examples of bicyclic heteroaryls include, but are not limited to: These groups may be attached to the remainder of the molecule through any suitable ring atom.
  • the ring attached to the parent structure can be a monocyclic heteroaryl ring or a benzene ring.
  • the fused bicyclic heteroaryl or fused tricyclic heteroaryl can be a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) with one or more A polycyclic group formed by the fusion of non-aromatic rings, in which the ring connected to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring.
  • the non-aromatic ring includes but is not limited to 3 to 6 membered monocyclic heterocyclyl rings (preferably 5 or 6 membered monocyclic heterocyclyl rings, the ring carbon atoms of the monocyclic heterocyclyl rings can be replaced by 1 to 2 A oxo group is substituted to form a cyclic lactam or cyclic lactone structure), a 3 to 6-membered monocyclic carbocyclyl ring (preferably a 5 or 6-membered monocyclic carbocyclyl ring, the monocyclic carbocyclyl ring of which Ring carbon atoms can be substituted by 1 or 2 oxo groups to form a ring ketone structure) and the like.
  • the polycyclic group formed by the fusion of the above-mentioned monocyclic heteroaryl ring and one or more non-aromatic rings can be connected to other groups or the parent structure through a nitrogen atom or a carbon atom, and the ring connected to the parent structure is a monocyclic heteroaryl base ring or non-aromatic ring.
  • the term "8- to 10-membered heteroarylheterocyclyl” or “8- to 10-membered heteroarylheterocyclyl ring” refers to a 5- or 6-membered monocyclic heteroaryl ring in combination with a 5- or 6-membered monocyclic heterocycle
  • An 8- to 10-membered fused bicyclic heteroaryl group formed by fused base rings that is, a fused 5- or 6-membered ring atom formed by two adjacent substituent groups on a 5- or 6-membered monocyclic heteroaryl group and the ring atoms connected to it
  • a membered monocyclic heterocyclyl ring, said 5 or 6 membered monocyclic heterocyclyl ring is as defined above.
  • the term "8 to 10 membered heteroarylcarbocyclyl” or “8 to 10 membered heteroarylcarbocyclyl ring” refers to a 5 or 6 membered monocyclic heteroaryl ring with a 5 or 6
  • Non-limiting examples of "8 to 10 membered heteroarylheterocyclyl” or “8 to 10 membered heteroarylcarbocyclyl” include: The aforementioned groups may be attached to the rest of the molecule through any suitable ring atom thereof.
  • the various heteroaryl groups mentioned above may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituent groups described in the present application.
  • hydroxyl refers to -OH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • benzyl refers to -CH2 -benzene.
  • alkylene means a divalent combination of an alkyl group.
  • C 0-6 alkylene means an alkylene group having 0 to 6 carbon atoms.
  • C 1 alkylene means an alkylene group having 1 carbon atom, eg -CH 2 -.
  • C2alkylene means an alkylene group having 2 carbon atoms, eg -CH2CH2- . and so on.
  • alkenylene means a divalent bond of alkenyl.
  • C 2-6 alkenylene means an alkenylene group having 2 to 6 carbon atoms.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are replaced.
  • Oxo substitution does not occur on aryl groups.
  • optionally substituted or “optionally substituted” means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically feasible basis.
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • the term “none” means that the two groups it is attached to are directly connected, such as When the ring A is nothing, L 1 and L 2 are directly connected, which is “L 1 -L 2 ".
  • this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring.
  • the carbon atom is attached to the group being substituted.
  • linking group listed does not indicate its linking direction
  • its linking direction is arbitrary, for example Among them, L is selected from -C(O)-NH-, at this time -C(O)-NH- can be connected to benzene ring and cyclopentane in the same direction as the reading order from left to right to form The benzene ring and cyclopentane can also be joined in the opposite direction to the left-to-right reading order to form
  • Combinations of the described linking groups, substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • the compound represented by formula (A) of the present invention can be prepared by using a synthetic method known in the art or by combining a method known in the art with the method described in the present invention. Solvents, temperatures and other reaction conditions given in the present invention are exemplary and can be varied according to methods well known in the art.
  • the example compounds described in the present invention can be synthesized according to the methods described in the examples using appropriate starting materials according to their specific structures, or can be synthesized using a method similar to that described in the examples.
  • the starting materials used to synthesize the compounds of the examples of the present invention can be prepared by known synthetic methods or similar methods described in literature or obtained from commercial sources.
  • the compound can be further resolved to obtain its stereoisomers by methods well known in the art, such as crystallization, chromatography, etc., if necessary, and the resolution conditions are easily obtained by those skilled in the art through routine means or limited experiments.
  • the compound of formula (A) of the present invention can be synthesized by the following method, wherein the solvent, temperature and other reaction conditions in each step can be the same or similar to those described in the following examples, or use known methods in the art reaction conditions.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art equivalent replacement.
  • Preferred embodiments include, but are not limited to, the examples of the present invention.
  • Step 1 Add [2-(2-hydroxyethoxy)ethyl]benzyl carbamate (5.0g, 20.92mmol) and dichloromethane (25mL) into a three-necked flask, stir and add triethylamine (6.34g, 62.76mmol) and 4-dimethylaminopyridine (510mg, 4.18mmol). The mixture was cooled to 0 °C and p-toluenesulfonyl chloride (3.97 g, 20.92 mmol) was added slowly. The reaction was stirred at room temperature for 2 hours, and the reaction of the raw materials was monitored by LC-MS to complete.
  • Step 2 2-(2-(((Benzyloxy)carbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (1000mg, 2.542mmol) and (S)-pyrrolidin-3-yl
  • potassium iodide 0.056mL, 0.508mmol
  • potassium carbonate 7.02mg, 5.083mmol
  • Step 3 Benzyl (S)-(2-(2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)ethoxy)ethyl)carbamate (730mg, 1.791 mmol) in dichloromethane (6.0 mL), was added trifluoroacetic acid (4.0 mL, 53.85 mmol). The reaction mixture was stirred at room temperature for 3 hours, and the reaction was complete. The reaction solution was concentrated and extracted by adding ethyl acetate (50mLX3) and saturated sodium bicarbonate (50mLX3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated.
  • Step 4 At room temperature, aluminum trichloride (12.9 g, 85.62 mmol). Raise the temperature to 90°C and react for 30 minutes. A solution of indole 6-methylcarboxylate (5.0 g, 28.54 mmol) in 1,2-dichloroethane (30.0 mL) was slowly added dropwise to the reaction solution. The reaction mixture was continued at 90°C for 18 hours. Cooled and poured into ice water (200 mL), and extracted with ethyl acetate (100 mL ⁇ 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated.
  • indole 6-methylcarboxylate 5.0 g, 28.54 mmol
  • 1,2-dichloroethane 30.0 mL
  • Step 5 Under nitrogen protection at room temperature, compound 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (450mg, 1.27mmol) and compound To a solution of benzyl (S)-(2-(2-(3-aminopyrrolidin-1-yl)ethoxy)ethyl)carbamate (583 mg, 1.9 mmol) in dioxane (6 mL) was added N , N-Diisopropylethylamine (1.56ml, 9.4mmol). The reaction mixture was warmed up to 120°C for 4 hours.
  • Step 6 At room temperature, the compound methyl (R)-3-(2-((1-(2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl)pyrrolidine-3 10% palladium on carbon ( 100mg, 0.945mmol). The reaction mixture was stirred for about 4 hours under hydrogen atmosphere.
  • Step 7 Under nitrogen protection at room temperature, the compound (R)-3-(2-((1-(2-(2-aminoethoxy)ethyl)pyrrolidin-3-yl)amino)-5-(tri)
  • methanol/water (10/5mL) methanol/water (10/5mL)
  • lithium hydroxide (197.3mg, 4.7mmol) was added. The reaction mixture was heated to 70°C for 3 hours. Cool and concentrate.
  • Step 8 Under the protection of nitrogen at room temperature, the N , N,N-Diisopropylethylamine (0.11ml, 0.66mmol) was added to a solution of N-dimethylformamide (15mL).
  • Compound (R)-3-(2-((1-(2-(2-aminoethoxy)ethyl)pyrrolidin-3-yl)amino)-5-(trifluoromethyl) was added under stirring the mixture
  • Step 1 Add di-tert-butyl dicarbonate (3.67 g, 16.856 mmol) to a solution of 4-amino-1-butanol (3.0 g, 33.7 mmol) in ethanol (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, the crude product was extracted with ethyl acetate (100 mL*3) and sodium bicarbonate (150 mL), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated.
  • the crude product was purified by silica gel column (ethyl acetate/petroleum ether: 0-100%) to obtain tert-butyl (4-hydroxybutyl)carbamate (5.8 g, 30.69 mmol, yield: 91%) as a colorless oily product.
  • Step 2 Under nitrogen protection, add oxalyl chloride (13ml, 23mmol, 2M dichloromethane) dropwise to the reaction solution of dimethyl sulfoxide (3.7ml) in dichloromethane (50ml) at -70°C, and continue Stir for 5 minutes. A solution of tert-butyl (4-hydroxybutyl)carbamate (4.1 g, 21.6 mmol) in dichloromethane (35.0 mL) was added dropwise at -70°C. The reaction mixture was gradually warmed to 0°C and stirred for 25 minutes. After the reaction was completed, it was poured into ice water, and extracted with ethyl acetate (50mLX3).
  • oxalyl chloride 13ml, 23mmol, 2M dichloromethane
  • Step 3 Under the protection of nitrogen at room temperature, compound 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (2.0g, 5.62mmol) and Add N,N-diisopropylethylamine ( 2.78ml, 16.78mmol). The reaction mixture was heated to 140°C for 0.5 hours. Cooled and poured into ice water, and extracted with ethyl acetate (50mLX3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step 4 Compound 3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidine-4- at room temperature
  • dichloromethane 10 mL
  • trifluoroacetic acid 1.0 mL, 13.56 mmol
  • the reaction solution was concentrated and extracted by adding ethyl acetate (50mL ⁇ 3) and saturated sodium bicarbonate (100mL).
  • Step 5 Compound methyl 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole at room temperature
  • -6-carboxylate 480 mg, 1.0 mmol
  • sodium cyanoborohydride 143.84 mg, 2.29 mmol
  • reaction solution was concentrated and extracted by adding ethyl acetate (50mL ⁇ 3) and saturated sodium bicarbonate (100mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step 6 Compound methyl 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclopentyl)amino)-5- at room temperature (Trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylate (356mg, 0.76mmol) in dichloromethane (5mL) solution, add trifluoroacetic acid (0.5mL, 6.75mmol) . The reaction mixture was stirred at room temperature for 1 hour, and the reaction was complete. The reaction solution was concentrated and extracted by adding ethyl acetate (50mL ⁇ 3) and saturated sodium bicarbonate (100mL).
  • Step 7 Under nitrogen protection at room temperature, the compound 3-(2-(((1S,3S)-3-((4-aminobutyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidine
  • methyl-4-yl)-1H-indole-6-carboxylate 384 mg, 0.78 mmol
  • lithium hydroxide 98.54 mg, 2.35 mmol
  • Step 8 Under the protection of nitrogen at room temperature, the N , N,N-Diisopropylethylamine (0.139ml, 0.84mmol) was added to the solution of N-dimethylformamide (5mL).
  • Step 1 Under nitrogen protection, add 3-N-tert-butoxycarbonyl-6-oxa-3-azabicyclo[3.1.0]hexane (5g, 26.99mmol) and cuprous bromide at -30°C (1) Allylmagnesium chloride (60.739mL, 121.48mmol, 2M/L) was slowly added dropwise in a tetrahydrofuran (150mL) solution of dimethyl sulfide complex (60.739mL, 121.48mmol), and the reaction solution was under nitrogen protection. The reaction was stirred at -10°C for 1 hour.
  • reaction solution was quenched with 10% aqueous ammonium chloride solution (100 mL) and ethyl acetate (100 mL), and then stirred at room temperature for 1 hr.
  • the reaction solution was extracted with ethyl acetate (50 mL ⁇ 3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness.
  • Step 2 Under the protection of nitrogen, add (3R,4S)-3-hydroxy-4-allylpyrrolidine-1-carboxylic acid tert-butyl ester (1.5g, 6.60mmol) to N,N-di Sodium hydride (0.32 g, 7.92 mmol, 60% purity) was added to the methylformamide (8 mL) solution, and the reaction solution was stirred and reacted at room temperature for 0.5 hours under the protection of nitrogen. Benzyl bromide (0.947 mL, 7.92 mmol) was added thereto, and the resulting reaction solution was stirred overnight at room temperature.
  • Step 3 To (3R,4S)-3-benzyloxy-4-allylpyrrolidine-1-carboxylic acid tert-butyl ester (800mg, 2.52mmol) and sodium periodate (1.62g, 7.56mmol) Potassium osmate (92.86 mg, 0.25 mmol) was added to a mixed solution of acetonitrile (15 mL) and water (6 mL), and the reaction solution was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL ⁇ 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness.
  • Step 4 Add (3R,4S)-3-benzyloxy-4-(2-acetaldehyde)pyrrolidine-1-carboxylic acid tert-butyl ester (480mg, 1.50mmol) and 3-(2-(( (1S,3S)-3-amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (630mg, 1.50mmol) , A small amount of acetic acid (0.086 mL, 1.50 mmol) was added to a solution of 2-dichloroethane (15 mL), and the reaction solution was stirred at room temperature for 0.5 hours.
  • Step five to 3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(benzyloxy)-1-(tert-butyloxycarbonyl)pyrrolyl- 3-yl)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (480mg, 0.66mmol) in tetrahydrofuran ( 2 mL) and methanol (2 mL) was added a solution of lithium hydroxide (139 mg, 3.32 mmol) in water (2 mL), and the reaction solution was stirred at room temperature overnight.
  • Step 6 3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(benzyloxy)-1-(tert-butyloxycarbonyl) )pyrrolyl-3-yl)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (390mg, 0.55mmol) A hydrochloric acid/dioxane (10 mL, 4N) solution was added, and the reaction solution was stirred at room temperature for 1 hour.
  • Step 7 To 3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(benzyloxy)pyrrolyl-3-yl)ethyl)amino) ring Pentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (320mg, 0.53mmol) in N,N-dimethylformamide (180mL) solution Pentafluorophenol (194mg, 1.05mmol) and N,N'-dicyclohexylcarbodiimide (217mg, 1.05mmol) were added sequentially, and the reaction solution was stirred overnight at room temperature.
  • Step 8 To (4 1 S,4 3 S,8 3 S,8 4 R)-8 4 -(benzyloxy)-2 5 -(trifluoromethyl)-1 1 H-3 at 0°C ,5-diaza-1(3,6)-indole-2(4,2)-pyrimidine-8(3,1)-pyrrolidine-4(1,3)-cyclopentanecyclononane- A solution of 9-ketone (30mg, 0.05mmol) in dichloromethane (2mL) was slowly added dropwise with a solution of boron trichloride (0.25mL, 1M), and the reaction solution was stirred at 0°C for 1.5 hours under nitrogen protection.
  • 9-ketone (30mg, 0.05mmol) in dichloromethane (2mL) was slowly added dropwise with a solution of boron trichloride (0.25mL, 1M), and the reaction solution was stirred at 0°C for 1.5 hours under nitrogen protection.
  • Step 1 Add N,N-diisopropylethylamine ( 2.61g, 20.0mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.10g, 5.0mmol), the reaction solution was stirred at 25°C for 14 hours. After the completion of the reaction detected by LCMS, the reaction solution was directly concentrated to obtain the crude product.
  • Step 5 To 1-(tert-butyl)6-methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole -1,6-Dicarboxylate (2.3g, 5.73mmol) in dioxane and aqueous solution (23mL) were added potassium carbonate (1.58g, 11.46mmol), palladium dichloride (0.28g, 0.38 mmol) and tert-butyl N-[(1S,3S)-3- ⁇ [4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino ⁇ cyclopentyl]carbamate (1.46g, 3.82 mmol), the reaction was stirred at 100°C for 3 hours.
  • Step 7 To 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxy Add sodium borohydride (0.39mL, 11.92mmol), tert-butyl 4-(2-oxoethyl)piperidine to a solution of methyl ester (1.00g, 2.38mmol) in 1,2-dichloroethane (10mL) -1-Carboxylate (0.54g, 2.38mmol), the reaction was stirred at room temperature overnight.
  • Step 8 To methyl 3-(2-(((1S,3S)-3-((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)amino)cyclopentyl) Amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylate (150 mg, 0.24 mmol) in THF/methanol/water (1:1:1) Lithium hydroxide (0.02 mL, 0.71 mmol) was added and the reaction was stirred at room temperature overnight. The pH of the reaction was adjusted to acidic with dilute hydrochloric acid.
  • Step 10 To 3-(2-((1S,3S)-3-((2-(piperidin-4-yl)ethyl)amino)cyclopentylamino)-5-(trifluoromethyl)pyrimidine -4-yl)-1H-indole-6-carboxylic acid (90mg, 0.17mmol) in N,N-dimethylformamide (5mL) solution was added 2-(7-azabenzotriazole )-N,N,N',N'-tetramethyluronium hexafluorophosphate (72mg, 0.19mmol) and N,N-diisopropylethylamine (88mg, 0.68mmol), the reaction solution was stirred at room temperature for 16 Hour.
  • Step 1 At room temperature, to 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(di Methylphosphoryl)-1H-indole-6-carboxylate (270mg, 0.55mmol) in N,N-dimethylformamide solution (5mL) was successively added tert-butyl (4-bromobutyl) Carbamate (138mg, 0.55mmol) and N,N-diisopropylethylamine (284mg, 2.20mmol), the reaction solution was stirred at 80°C for 16 hours under the protection of nitrogen.
  • reaction solution was added with 10% aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL ⁇ 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 2 To methyl 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclopentyl)amino)-5-(three Mixed solution of fluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (170mg, 0.26mmol) in tetrahydrofuran (2mL) and methanol (2mL) A solution of lithium hydroxide (66.0mg, 1.56mmol) in water (2mL) was added, and the reaction solution was stirred at 40°C overnight.
  • Step 3 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclopentyl)amino)-5- (Trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (160 mg, 0.25 mmol) in methanol (5 mL) was added hydrochloric acid/methanol ( 5mL, 4N) solution, the reaction solution was stirred and reacted at 25°C for 16 hours.
  • Step 4 To 3-(2-(((1S,3S)-3-((4-aminobutyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) 2-(7-aza Benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (91.2mg, 0.24mmol) and N,N-diisopropylethylamine (114mg, 0.88mmol), The reaction solution was stirred at 80°C for 16 hours.
  • Step 1 Add vinylmagnesium bromide in tetrahydrofuran (1M, 163mL, 163mmol) dropwise slowly to a solution of 2-bromo-3-nitrobenzoic acid (10.0g, 40.6mmol) in tetrahydrofuran (150mL) at -78°C ), after the dropwise addition, the reaction was continued to stir at -78°C for 3 hours under the protection of nitrogen, and then naturally rose to room temperature and stirred for 16 hours.
  • Step 2 Add iodomethane (6.66g, 46.9 mmol) and potassium carbonate (10.8g, 78.3mmol). The reaction solution was stirred at 25° C. for 16 hours under nitrogen protection. After the reaction was complete as detected by LCMS, the reaction solution was added with water (200 mL), and then extracted with ethyl acetate (200 mL ⁇ 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 3 At 25°C, add tris(dibenzylideneacetone)dipalladium (242mg, 0.393mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxa Anthracene (455mg, 0.787mmol) and 1,4-dioxane (20mL) solution was stirred for 30 minutes under nitrogen protection, and then 7-bromo-1H-indole-6-carboxylic acid methyl ester (2.0 g, 7.87mmol), potassium phosphate (1.67g, 7.87mmol) and dimethylphosphine oxide (0.61g, 7.87mmol). The reaction solution was stirred at 110°C for 14 hours.
  • Step 4 In a nitrogen atmosphere, in a dry 50mL three-necked flask, add aluminum trichloride (1.06g, 7.96mmol), and then add 7-(dimethylphosphoryl)-1H-indole-6- A solution of methyl carboxylate (1.00g, 3.98mmol) in 1.2-dichloroethane (10mL) was stirred at 80°C for 30 minutes, then 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.95 g, 4.38mmol) in 1.2-dichloroethane (1mL), the reaction solution was reacted at 80°C for 16 hours.
  • Step 5 In a 10mL microwave tube, sequentially add 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6- Methyl carboxylate (770mg, 1.78mmol), N-methylpyrrolidone (4mL), N,N-diisopropylethylamine (0.59mL, 3.57mmol) and tert-butyl ((1S,3S)-3- Aminocyclopentyl) carbamate (392mg, 1.96mmol), the reaction solution was stirred at 80°C to dissolve, and then microwaved at 130°C for 2 hours.
  • Step 6 At room temperature, methyl 3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidine- 4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (400 mg, 0.67 mmol) dissolved in hydrogen chloride/dioxane (5 mL, 4M) and methanol (2 mL) The mixed solution was reacted at 20°C for 16 hours.
  • Step 7 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl )-1H-indole-6-carboxylic acid methyl ester (500mg, 1.0mmol) was dissolved in N,N-dimethylformamide (3mL), tert-butyl (5-bromopentyl) carbamate ( 269 mg, 1.0 mmol) and N,N-diisopropylethylamine (0.67 mL, 4.0 mmol) were added sequentially and the reaction was stirred at 80°C for 16 hours.
  • Step 8 Methyl 3-(2-(((1S,3S)-3-((5-((tert-butoxycarbonyl)amino)pentyl)amino)cyclopentyl)amino)-5-(tri Fluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (360 mg, 0.53 mmol) dissolved in water (1 mL), methanol (1 mL) and THF (1 mL), then add lithium hydroxide monohydrate (111 mg, 2.65 mmol), and stir at 40°C for 16 hours.
  • Step 9 3-(2-(((1S,3S)-3-((5-((tert-butoxycarbonyl)amino)pentyl)amino)cyclopentyl)amino)-5-(trifluoromethyl Base) pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (320mg, 0.47mmol) was dissolved in hydrogen chloride/methanol (5mL, 4M), and the system was heated at 25°C Stir for 4 hours.
  • Step ten to 3-(2-(((1S,3S)-3-((5-aminopentyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) 2-(7-aza Benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (134mg, 0.35mmol) and N,N-diisopropylethylamine (0.23mL, 1.41mmol), The reaction solution was stirred at 60°C for 16 hours.
  • Step 1 At room temperature, to 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(di (2-(2-Bromoethoxy ) ethyl) tert-butyl carbamate (270mg, 1.00mmol) and N,N-diisopropylethylamine (0.67mL, 4.00mmol), the reaction solution was stirred at 70°C for 16 hours under nitrogen protection.
  • reaction solution was added with 10% aqueous ammonium chloride (100 mL), extracted with ethyl acetate (100 mL ⁇ 3), the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 2 To methyl 3-(2-(((1S,3S)-3-((2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)amino)cyclopentyl) Amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (350mg, 0.51mmol) in tetrahydrofuran (2mL) and A solution of lithium hydroxide (86.0 mg, 2.05 mmol) in water (2 mL) was added to a mixed solution of methanol (2 mL), and the reaction solution was stirred at 40° C. for 16 hours.
  • Step 3 3-(2-(((1S,3S)-3-((2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)amino) ring at 25°C Pentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (300mg, 0.45mmol) in methanol (5mL ) solution was added hydrochloric acid/methanol (5 mL, 4M) solution, and the reaction solution was stirred at 40° C. for 4 hours.
  • Step 4 To 3-(2-(((1S,3S)-3-((2-(2-aminoethoxy)ethyl)amino)cyclopentyl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (220mg, 0.39mmol) in N,N-dimethylformamide (8mL) solution was added successively 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (149mg, 0.39mmol) and N,N-diisopropylethylamine ( 182mg, 1.41mmol), the reaction solution was stirred at 60°C for 16 hours.
  • Step 1 In a 10mL microwave tube, sequentially add 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6- Methyl carboxylate (810mg, 1.88mmol), N-methylpyrrolidone (5mL), N,N-diisopropylethylamine (0.93mL, 5.63mmol) and tert-butyl ((1r,3r)-3- Aminocyclobutyl) carbamate (384mg, 2.06mmol), the reaction solution was stirred at 80°C to dissolve, and then microwaved at 130°C for 2 hours.
  • Step 2 At room temperature, methyl 3-(2-(((1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutyl)amino)-5-(trifluoromethyl)pyrimidine- 4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (500 mg, 0.86 mmol) dissolved in hydrogen chloride/dioxane (5 mL, 4M) and methanol (2 mL) The mixed solution was reacted at 25°C for 16 hours.
  • Step three 3-(2-(((1r,3r)-3-aminocyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethyl tert-Butyl (4-bromobutyl)amino Formate (157mg, 0.62mmol) and N,N-diisopropylethylamine (322mg, 2.49mmol), the reaction solution was stirred at 80°C for 16 hours under the protection of nitrogen.
  • reaction solution was added to saturated ammonium chloride solution (100 mL), and extracted with ethyl acetate (100 mL ⁇ 3), the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. .
  • Step 4 To methyl 3-(2-(((1r,3r)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclobutyl)amino)-5-(three Mixed solution of fluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (225 mg, 0.35 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) A solution of lithium hydroxide monohydrate (72.0 mg, 1.72 mmol) in water (2 mL) was added, and the reaction solution was stirred and reacted at 40° C. for 16 hours.
  • Step five to 3-(2-(((1r,3r)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclobutyl)amino)-5-(trifluoro
  • methanol methanol
  • hydrochloric acid/methanol 5mL, 4M
  • Step 6 To 3-(2-(((1r,3r)-3-((4-aminobutyl)amino)cyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) 2-(7-aza Benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (118mg, 0.31mmol) and N,N-diisopropylethylamine (200mg, 1.55mmol), the The reaction solution was stirred at 70°C for 16 hours.
  • Step 1 In a 10mL microwave tube, sequentially add 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6- Methyl carboxylate (450mg, 1.04mmol), N-methylpyrrolidone (5mL), N,N-diisopropylethylamine (0.52mL, 3.13mmol) and tert-butyl ((1S,3S)-3- Aminocyclohexyl) carbamate (235mg, 1.09mmol), the reaction solution was stirred at 80°C to dissolve, and then microwaved at 130°C for 2 hours.
  • Step 2 At room temperature, methyl 3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (470mg, 0.77mmol) was dissolved in a mixture of hydrogen chloride/dioxane (5mL, 4M) and methanol (2mL) solution, reacted at 25°C for 16 hours.
  • Step 3 3-(2-(((1S,3S)-3-aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl) -1H-indole-6-carboxylic acid methyl ester (310mg, 0.61mmol) was dissolved in N,N-dimethylformamide (3mL), tert-butyl (4-bromobutyl) carbamate (153mg , 0.61 mmol) and N,N-diisopropylethylamine (0.67 mL, 4.0 mmol) were added sequentially, and the reaction was stirred at 80°C for 16 hours.
  • Step 4 Methyl 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclohexyl)amino)-5-(trifluoro Methyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (200 mg, 0.29 mmol) was dissolved in water (1 mL), methanol (1 mL) and tetrahydrofuran ( 1 mL), then lithium hydroxide monohydrate (61.6 mg, 1.47 mmol) was added, and the reaction was stirred at 40°C for 16 hours.
  • Step five 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclohexyl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (180mg, 0.27mmol) was dissolved in hydrogen chloride/methanol (5mL, 4M), and the system was stirred at 15°C 4 hours.
  • Step 6 To 3-(2-(((1S,3S)-3-((4-aminobutyl)amino)cyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- Add 2-(7-azabenzene Triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (80.4mg, 0.21mmol) and N,N-diisopropylethylamine (0.14mL, 0.84mmol), The reaction solution was stirred at 60°C for 16 hours.
  • Step 1 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethyl 3-(tert-butoxycarbonylamino)propyl Bromine (144mg, 0.61mmol) and N,N-diisopropylethylamine (313mg, 2.42mmol), the reaction solution was stirred at 80°C for 16 hours under the protection of nitrogen.
  • reaction solution was added with 10% aqueous ammonium chloride (50 mL), extracted with ethyl acetate (50 mL ⁇ 3), the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 2 To 3-(2-(((1S,3S)-3-(3-(tert-butoxycarbonylaminopropyl)amino)cyclopentylamino)-5-(trifluoromethyl)pyrimidine-4 -yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid methyl ester (100 mg, 0.16 mmol) in tetrahydrofuran (1.5 mL) and methanol (1.5 mL) was added monohydrate Lithium hydroxide (33mg, 0.78mmol) in water (1.5mL) solution, the reaction solution was stirred and reacted at 40°C for 16 hours.
  • Step 3 3-(2-(((1S,3S)-3-((3-(tert-butoxycarbonyl)amino)propyl)amino)cyclopentyl)amino-5-(tri)
  • methanol 3mL
  • hydrochloric acid/methanol 6mL, 4N
  • Step 4 To 3-(2-(((1S,3S)-3-((3-aminopropyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) 2-(7-aza Benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (80mg, 0.21mmol) and N,N-diisopropylethylamine (300mg, 2.32mmol), the The reaction solution was stirred at 80°C for 16 hours.
  • Step 2 Add iodomethane (6.97g, 49.1 mmol) and potassium carbonate (11.3g, 81.9mmol). The reaction solution was stirred at 25° C. for 16 hours under nitrogen protection. After the completion of the reaction as detected by TLC, the reaction solution was added with water (200 mL), and then extracted with ethyl acetate (150 mL ⁇ 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 3 In a dry 50mL three-necked flask, add aluminum trichloride (1.27g, 9.54mmol), and add 7-chloro-1H-indole-6-carboxylic acid methyl ester (1.00g, 4.77mmol) under nitrogen protection 1.2-dichloroethane (10mL) solution, this system was stirred at 80°C for 30 minutes, then 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.09g, 5.01mmol) was added in 1.2-bis Chloroethane (1 mL) solution, and the reaction solution was reacted at 80° C. for 16 hours.
  • Step 4 In a 10mL microwave tube, add 7-chloro-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (420mg , 1.08mmol), N-methylpyrrolidone (2mL), N,N-diisopropylethylamine (0.53mL, 3.23mmol) and tert-butyl ((1S,3S)-3-aminocyclopentyl)amino Formic acid ester (237mg, 1.18mmol), the reaction solution was dissolved by stirring at 80°C, and then microwaved at 130°C for 2 hours.
  • Step 5 At room temperature, methyl 3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidine- 4-yl)-7-chloro-1H-indole-6-carboxylate (430mg, 0.72mmol) was dissolved in a mixed solution of hydrogen chloride/dioxane (4mL, 4M) and methanol (2mL), reacted at 15°C 16 hours.
  • Step 6 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-chloro-1H-indole -6-Carboxylic acid methyl ester (320mg, 0.71mmol) was dissolved in N,N-dimethylformamide (2mL), tert-butyl (4-bromobutyl) carbamate (178mg, 0.71mmol) and N,N-Diisopropylethylamine (0.58 mL, 3.53 mmol) was added sequentially and the reaction was stirred at 80°C for 16 hours.
  • Step 7 Methyl 3-(2-((1S,3S)-3-((4-((tert-butoxycarbonyl)amino)butyl)amino)cyclopentyl)amino)-5-(trifluoro Methyl)pyrimidin-4-yl)-7-chloro-1H-indole-6-carboxylate (230mg, 0.37mmol) was dissolved in a mixed system of water (1mL), methanol (1mL) and tetrahydrofuran (1mL) , then lithium hydroxide monohydrate (77.2mg, 1.84mmol) was added and the reaction was stirred at 40°C for 16 hours.
  • Step 8 3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonylamino)pentylamino)cyclopentyl)amino)-5-(trifluoromethyl) Pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (lithium salt, 340mg) was dissolved in hydrogen chloride/methanol (5mL, 4M), and the system was stirred at 25°C for 4 Hour.
  • Step 9 To 3-(2-(((1S,3S)-3-((4-aminobutyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) 2-(7-azabenzene Triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (108mg, 0.28mmol) and N,N-diisopropylethylamine (0.24mL, 1.42mmol), the The reaction solution was stirred at 60°C for 16 hours.
  • Step 1 3-(2-((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethyl Phosphoryl)-1H-indole-6-carboxylic acid methyl ester (750mg, 1.52mmol) in methanol solution (10mL) was successively added tert-butyl ((4-oxocyclohexyl)methyl)carbamate (414mg , 1.82mmol) and glacial acetic acid (0.1mL), the reaction solution was stirred and reacted at 25°C for 16 hours under the protection of nitrogen.
  • the obtained crude product was prepared and purified by reverse phase (chromatographic column: Ultimate XB-C18, 50*250mm, 10um (PARP-02); mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); flow rate: 70mL/min; column Temperature: 25°C) to obtain white solid methyl 3-(2-((1S,3S)-3-((tert-butoxycarbonyl)amino)methylcyclohexylamino)cyclopentylamino)-5-(trifluoro Methyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (P1: 340 mg, yield 32%).
  • Step 2 To methyl 3-(2-(((1S,3S)-3-((4-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)amino)cyclopentyl)amino)- 5-(Trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (P2: 340 mg, 0.48 mmol) in THF (3 mL) and methanol A solution of lithium hydroxide monohydrate (101 mg, 2.40 mmol) in water (3 mL) was added to the mixed solution of lithium hydroxide (3 mL), and the reaction solution was stirred and reacted at 40° C. overnight.
  • Step 3 3-(2-(((1S,3S)-3-((4-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)amino)cyclopentyl)amino at 25°C )-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (300mg, 0.43mmol) in methanol (3mL) was added Hydrochloric acid/dioxane (3 mL, 4N) solution, the reaction solution was stirred at 25°C for 16 hours.
  • Step 4 To 3-(2-(((1S,3S)-3-((4-(aminomethyl)cyclohexyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidine- 4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (30mg, 0.05mmol) in N,N-dimethylformamide (5mL) solution was added 2-( 7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19mg, 0.05mmol) and N,N-diisopropylethylamine (32mg, 0.25 mmol), the reaction solution was stirred at 70°C for 14 hours.
  • Step 1 Under nitrogen protection, add tert-butyl ((1S,3S)-3-hydroxycyclobutyl)(methyl)aminomethyl ester (200mg, 1.0mmol) in dichloromethane (4mL) at 25°C Dess-Martin reagent (843mg, 2.0mmol) was added, and the reaction solution was stirred and reacted at 25°C for 3 hours under the protection of nitrogen. After the reaction was complete as detected by LCMS, the reaction solution was extracted with water (10 mL) and ethyl acetate (20 mL ⁇ 3), and the combined organic layer was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated to dryness.
  • tert-butyl ((1S,3S)-3-hydroxycyclobutyl)(methyl)aminomethyl ester 200mg, 1.0mmol
  • Dess-Martin reagent 843mg, 2.0mmol
  • Step 2 Under nitrogen protection, 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-aminocyclopentyl] Amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (423mg, 0.85mmol) and ⁇ [(3-oxylidenecyclobutyl)methyl] Acetic acid (20 mg, 0.33 mmol) was added to a solution of 2-methylpropan-2-yl amino ⁇ methanoate (170 mg, 0.85 mmol) in methanol (3 mL), and the reaction was stirred at 25°C for 16 hours under nitrogen protection.
  • Step 3 Under nitrogen protection, at 25 ° C, to ⁇ [(3- ⁇ [(1S,3S)-3-[(4- ⁇ 7-[dimethyl(oxygenide)- ⁇ 5-methylphosphoryl]- 6-(methoxycarbonyl)-1H-indol-3-yl ⁇ -5-(trifluoromethyl)pyrimidin-2-yl)amino]cyclopentyl]amino ⁇ cyclobutyl)methyl]amino ⁇
  • lithium hydroxide monohydrate 117mg, 2.8mmol
  • Step 4 To 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3- ⁇ [3-(2,2-dimethyl -4-Oxylidene-5-aza-3-oxahex-6-yl)cyclobutyl]amino ⁇ cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)- To 1H-indole-6-carboxylic acid (300mg, 0.45mmol) in methanol (5mL) was added 4M methanolic hydrogen chloride solution (10mL), and the reaction solution was heated to 40°C under nitrogen protection and stirred for 2 hours.
  • Step five to 7-[dimethyl (oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3- ⁇ [3-(aminomethyl)cyclobutyl ]amino ⁇ cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (50mg, 0.089mmol) in N,N-dimethylformamide ( 5mL) solution was added 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (34mg, 0.089mmol) and N,N-di Isopropylethylamine (0.059mL, 0.35mmol), the reaction solution was stirred at 60°C for 2h.
  • Step 1 To a solution of ⁇ [(3S)-tetrahydro-1H-pyrrol-3-yl]amino ⁇ methanoic acid benzyl ester (225mg, 1.02mmol) in N,N-dimethylmethaneamide (6mL) successively [(5-Bromopentyl)amino]methanoate-2-methylpropan-2-yl ester (299mg, 1.12mmol) and N,N-diisopropylethylenediamine (528mg, 4.08mmol) were added, and the The reaction solution was stirred at 80° C. for 16 hours under a nitrogen atmosphere.
  • Step 2 To ⁇ [(3S)-1-(2,2-dimethyl-4-oxoylidene-5-aza-3-oxadec-10-yl)tetrahydro-1H-pyrrole-3 -Byl]amino ⁇ methanoic acid benzyl ester (500mg, 1.23mmol) in methanol (8mL) solution was added palladium carbon (50mg, 10% content, 60% water content), the reaction solution was stirred at 25°C under a hydrogen atmosphere for reaction 2 Hour. LCMS detected that the reaction was complete.
  • Step 3 To ( ⁇ 5-[(3S)-3-aminotetrahydro-1H-pyrrol-1-yl]pentyl ⁇ amino)methanoic acid-2-methylpropan-2-yl ester (334mg, 1.23mmol ) in N,N-dimethylmethaneamide (8mL) was sequentially added 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-7-[dimethyl(oxygenide) - ⁇ 5-methylphosphoryl]-1H-indole-6-carboxylic acid methyl ester (507mg, 1.23mmol) and N,N-diisopropylethylenediamine (477mg, 3.69mmol), the reaction solution was under nitrogen protection The temperature was raised to 80° C.
  • reaction solution was extracted with water (20 mL) and dichloromethane (30 mL ⁇ 5), and the combined organic layer was washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated to dryness.
  • Step 4 To 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(3S)-1-(2,2-dimethyl-4-oxygenidene -5-Aza-3-oxadec-10-yl)tetrahydro-1H-pyrrol-3-yl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole- Lithium hydroxide monohydrate (173 mg, 4.13 mmol) was added to a mixed solution of methyl 6-formate (550 mg, 0.83 mmol) in methanol (3 mL), water (3 mL), and tetrahydrofuran (3 mL), and the reaction solution was heated under nitrogen protection The reaction was stirred at 40°C for 2 hours.
  • Step 5 To 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(3S)-1-(2,2-dimethyl-4-oxygenidene -5-Aza-3-oxadec-10-yl)tetrahydro-1H-pyrrol-3-yl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole- 4M 1,4-dioxane hydrogen chloride solution (8 mL) was added to 6-formic acid (480 mg, 0.70 mmol), and the reaction solution was heated to 40° C. under nitrogen protection and stirred for 2 hours.
  • 6-formic acid 480 mg, 0.70 mmol
  • Step 6 To 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(3S)-1-(5-aminopentyl)tetrahydro-1H-pyrrole- 3-yl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (100 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) Add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (69mg, 0.18mmol) and N,N-diisopropyl Ethylamine (94mg, 0.12mmol), the reaction solution was stirred at 60°C for 16 hours.
  • Step 1 Add ⁇ [(3S)-hexahydropyridin-3-yl]amino ⁇ methanoic acid benzyl ester (242mg, 1.03mmol) to a solution of N,N-dimethylformamide (8mL) at 25°C [(5-Bromopentyl)amino]methanoate-2-methylpropan-2-yl ester (250mg, 0.939mmol), N,N-diisopropylethylamine (363mg, 2.82mmol) were added to the reaction The solution was stirred and reacted at 80° C. for 6 hours under the protection of nitrogen.
  • Step 2 Add ( ⁇ 5-[(3S)-3- ⁇ [(benzyloxy)carbonyl]amino ⁇ hexahydropyridin-1-yl]pentyl ⁇ amino)methanoic acid-2-methylpropan-2
  • the -yl ester 250 mg, 0.596 mmol
  • methanol 10 mL
  • palladium on carbon 100 mg, 10% content, 60% aqueous
  • Step 3 Add ( ⁇ 5-[(3S)-3-aminohexahydropyridin-1-yl]pentyl ⁇ amino)methanoic acid-2-methylpropan-2-yl ester (180mg, 0.63mmol ) in N,N-dimethylformamide (6mL) solution, add 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-7-[dimethyl(oxyethylene )- ⁇ 5 -methylphosphoryl]-1H-indole-6-carboxylic acid methyl ester (272mg, 0.63mmol), N,N-diisopropylethylamine (244mg, 1.89 mmol), the reaction solution was protected under nitrogen The reaction was stirred at 80°C for 16 hours.
  • Step 4 Adding 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(3S)-1-(2,2-dimethyl-4 -Oxylidene-5-aza-3-oxadec-10-yl)hexahydropyridin-3-yl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole
  • Lithium hydroxide hydrate (185mg, 4.41mmol) was added to methanol (4mL), water (4mL) and tetrahydrofuran (4mL) of methyl-6-carboxylate (300mg, 0.441mmol), and the reaction solution was heated under nitrogen protection at 40 The reaction was stirred at °C for 16 hours.
  • Step 5 Add 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(3S)-1-(2,2-dimethyl-4- Oxylidene-5-aza-3-oxadec-10-yl)hexahydropyridin-3-yl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-
  • dioxane hydrochloride 1.95 mL, 4 mol/L
  • Step six at room temperature to 7-[dimethyl (oxygenide)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(3S)-1-(5-aminopentyl)hexahydropyridine- 3-yl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (70mg, 0.12mmol) in N,N-dimethylformamide (5mL) Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (56.3mg, 0.14mmol), N,N-diisopropyl Ethylamine (77.4 mg, 0.6 mmol), and the reaction liquid was reacted at 65° C.
  • Step 1 7-[Dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-aminocyclopentyl]amino ⁇ -5-( Trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (300mg, 0.61mmol) was dissolved in N,N-dimethylformamide (3mL), [(4-bromobutyl Base)amino]methanoic acid-2-methylpropan-2-yl ester (153mg, 0.61mmol) and N,N-diisopropylethylamine (0.30mL, 1.83mmol) were added sequentially, and the reaction was stirred at 80°C for 16 Hour.
  • Step 2 Add 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-[(2,2-dimethyl-4 -Oxylidene-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6 - Methyl formate (150 mg, 0.225 mmol) was dissolved in methanol (3 mL), then paraformaldehyde (45.0 mg, 1.13 mmol), palladium on carbon (10 mg, 10% content, 60% water) and glacial acetic acid (0.1 mL) were added , and stirred the reaction at 70°C for 5 hours.
  • Step 4 Add 1,4-dioxane hydrochloride solution (5 mL, 4M) to the reaction solution in the previous step, and stir the system at 10° C. for 4 hours.
  • the solvent was directly spin-dried, and the obtained crude product was prepared by reverse phase (chromatographic column: Ultimate XB-C18, 50*250mm, 10um (PARP-02); mobile phase: acetonitrile-water (0.1% bicarbonate ammonium); flow rate: 70mL/min; column temperature: 25°C) to obtain white solid 7-[dimethyl(oxyethylene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S) -3-[(4-aminobutyl)(methyl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (20mg, Yield: 13%).
  • LCMS m/
  • Step 5 To 7-[dimethyl (oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-[(4-aminobutyl)(methyl )amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (20mg, 0.04mmol) in N,N-dimethylformamide ( 3mL) solution was added 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (14.8mg, 0.04mmol) and N,N- Diisopropylethylamine (0.03mL, 0.18mmol), the reaction solution was stirred at 60°C for 16 hours.
  • Step 1 In a 250mL three-necked flask, sequentially add N-[(benzyloxy)carbonyl]glycine (20g, 95.6mmol), tetrahydrofuran (130mL), magnesium chloride (4.55g, 47.8mmol), carbonyldiimidazole (15.5 g, 95.6mmol), [(3-methoxy-1,3-dioxylidene)oxy] potassium (12.2g, 71.7mmol), the reaction solution was replaced with nitrogen, refluxed at 70°C for 4 hours, TLC The detection response is complete.
  • Step 2 Dissolve benzyl [(1-methoxy-1,3-dioxylidenebut-4-yl)amino]methanoate (1.50g, 5.66mmol) in dichloromethane (30mL), and Add diethylaminosulfur trifluoride (1.00g, 6.22mmol) dropwise at 0°C, stir at 15°C for 16 hours, then add diethylaminosulfur trifluoride (1.00g, 6.22mmol) at 15°C, It was then stirred at 15°C for 4 hours.
  • Step 3 Dissolve benzyl (3,3-difluoro-1-methoxy-1-oxyylidenebut-4-yl)amino]methanoate (130mg, 0.45mmol) in tetrahydrofuran (3mL), and A solution of lithium aluminum hydride in tetrahydrofuran (1 mL, 1 M) was added dropwise at 0°C, and the reaction was stirred at 10°C for 2 hours.
  • Step 4 Dissolve [(2,2-difluoro-4-hydroxybutyl)amino]methanoic acid benzyl ester (120mg, 0.46mmol) in dichloromethane (1mL), then add pyridine (1mL) and p Methanesulfonyl chloride (265mg, 1.39mmol), the system was stirred at 10°C for 3 hours.
  • Step 5 In a 10mL single-necked bottle, 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-aminocyclopentyl ]Amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (173mg, 0.35mmol) was dissolved in N,N-dimethylformamide (3mL) , then added 4-methylbenzenesulfonic acid-6,6-difluoro-3-oxyylidene-1-phenyl-4-aza-2-oxahoct-8-yl ester (120mg, 0.29mmol) and N,N-Diisopropylethylamine (0.24 mL, 1.45 mmol).
  • Step 6 Add 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-[(6,6-difluoro-3- Oxylidene-1-phenyl-4-aza-2-oxahoct-8-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H- Methyl indole-6-carboxylate (90mg, 0.12mmol) was dissolved in a mixed system of water (1mL), methanol (1mL) and tetrahydrofuran (1mL), and then lithium hydroxide monohydrate (5.13mg, 0.12mmol) was added, The reaction was stirred at 40°C for 16 hours.
  • Step 7 In a 10mL single-necked bottle, add 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-[(6, 6-Difluoro-3-oxyylidene-1-phenyl-4-aza-2-oxahoct-8-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidine- 4-yl)-1H-indole-6-carboxylic acid (18 mg, 0.03 mmol) and trifluoroacetic acid (3 mL). Stir at 60°C for 1.5 hours.
  • Step 8 To 2,2-difluoro-4- ⁇ [(1S,3S)-3-[(4- ⁇ 5-[(Z)-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphonium Base] methylidene] -4-[(1Z)-ethylidene]-1H-pyrrol-3-yl ⁇ -5-(trifluoromethyl)pyrimidin-2-yl)amino]cyclopentyl]amino ⁇
  • 2-(7-azabenzotriazole)-N,N,N', N'-Tetramethyluronium hexafluorophosphate (9.95 mg, 0.03 mmol) and N,N-diisopropylethylamine (0.02 mL, 0.12 mmol).
  • Step 1 [(1-Hydroxybut-4-yl)(methyl)amino]methanoic acid-2-methylpropan-2-yl ester (400mg, 1.97mmol) in tetrahydrofuran (8mL) at 25°C Carbon tetrabromide (981 mg, 3.74 mmol) and triphenylphosphine (1.24 g, 3.74 mmol) were added to the solution. The reaction solution was stirred and reacted at 25° C. for 16 hours under the protection of nitrogen.
  • Step 2 Add [(1-bromobutyl-4-yl)(methyl)amino]methanoic acid-2-methylpropan-2-yl ester (240mg, 0.90mmol), 3-(2- ⁇ [(1S ,3S)-3-Aminocyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-7-[methyl(oxygenide)- ⁇ 5-methylphosphoryl]-1H-ind Indole-6-carboxylic acid methyl ester (447 mg, 0.90 mmol) was dissolved in acetonitrile (10 mL), and N,N-diisopropylethylamine (349 mg, 2.71 mmol) was added.
  • Step 3 To 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-[(2,2,5- Trimethyl-4-oxyethylene-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H - To a solution of methyl indole-6-carboxylate (220mg, 0.32mmol) in methanol (8mL) was added successively paraformaldehyde (145mg, 1.62mmol), acetic acid (244mg, 1.89mmol), palladium on carbon (20mg, 10% content , 60% water).
  • reaction was stirred at 80°C for 16 hours under hydrogen atmosphere. After the completion of the reaction detected by LCMS, an aqueous solution (50 mL) was added to the reaction solution, and extracted with dichloromethane (50 mL ⁇ 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness.
  • Step 4 To 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-(2,2,5-tri Methyl-4-oxyylidene-5,10-diaza-3-oxaundecane-10-yl)cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl) - To methyl 1H-indole-6-carboxylate (200 mg, 0.29 mmol) in methanol (3 mL), water (3 mL), tetrahydrofuran (3 mL) was added lithium hydroxide hydrate (121 mg, 2.88 mmol). The reaction was stirred at 40° C.
  • Step 5 To 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-(2,2,5-tri Methyl-4-oxyylidene-5,10-diaza-3-oxaundecane-10-yl)cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl) -
  • To 1H-indole-6-carboxylic acid (180 mg, 0.26 mmol) in dioxane (4 mL) was added dioxane hydrochloride (1.32 mL, 5.29 mmol, 4 mol/L). The reaction was stirred at 25° C. for 16 hours under the protection of nitrogen.
  • Step 6 To 7-[dimethyl (oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-(2,7-diazo N,N-dimethyl Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (55mg, 0.15mmol), N, N-Diisopropylethylamine (78 mg, 0.61 mmol). The reaction was carried out at 60° C. for 18 hours under nitrogen protection.
  • Step 1 Add 2-oxylidenetetrahydropyrrole-1-carboxylic acid-2-methylpropan-2-yl ester (2.00g, 10.8mmol) in tetrahydrofuran (30mL) at 0°C under nitrogen atmosphere Methylmagnesium bromide (15.1 mL, 15.1 mmol) was added dropwise. The reaction was stirred at 0 °C for 4 hours. After spotting the reaction to detect the completion of the reaction, water (30 mL) was added to quench the reaction, followed by extraction with ethyl acetate (100 mL ⁇ 3), the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness.
  • Step 2 Dissolve [(4-oxyethylenepentyl)amino]methanoic acid-2-methylpropan-2-yl ester (122mg, 0.61mmol) in tetrahydrofuran (5mL), then add isopropyl titanate ( 574mg, 2.0mmol), 7-[Dimethyl(oxysubunit)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-aminocyclopentyl]amino ⁇ -5- (Trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (250mg, 0.51mmol), the reaction was stirred at 70°C for 16 hours, cooled to room temperature, to which was added cyanoborohydrogenation Sodium (159mg, 2.53mmol), stirred at 25°C for 6 hours.
  • isopropyl titanate 574mg, 2.0mmol
  • Step 4 Add hydrogen chloride/1,4-dioxane solution (5 mL, 4M) to the reaction solution in Step 3, and stir the system at 40° C. for 4 hours.
  • the solvent was directly spin-dried to obtain the crude product, which was prepared by reverse phase (chromatographic column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% three Fluoroacetic acid), flow rate: 70mL/min, column temperature: 25°C) to obtain 7-[dimethyl(oxygenide)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3 -[(5-aminopent-2-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (150mg, yield 94 %), in the form of a white
  • Step 5 7-[Dimethyl(oxyethylene)- ⁇ 5-methylphosphonyl]-3-(2- ⁇ [(1S,3S)-3-[(5-aminopent-2-yl)amino] Cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (70 mg, 0.12 mmol) in N,N-dimethylformamide (3 mL) Add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (47mg, 0.12mmol) and N,N-diisopropyl Ethylamine (64mg, 0.50mmol), the reaction solution was stirred at 80°C for 18h.
  • Step 1 At 25°C, to 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-aminocyclopentyl]amino ⁇
  • [( 6-bromohexyl)amino]methanoic acid-2-methylpropan-2-yl ester (353 mg, 0.71 mmol)
  • N,N-diisopropylethylamine 460 mg, 3.57 mmol
  • Step 2 To 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-[(2,2-dimethyl Base-4-oxyethylene-5-aza-3-oxa-undecane-11-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H -To methyl indole-6-carboxylate (180 mg, 0.26 mmol) in methanol (3 mL), water (3 mL), tetrahydrofuran (3 mL) was added lithium hydroxide hydrate (109 mg, 2.59 mmol). The reaction was stirred at 40° C.
  • Step 3 To 7-[dimethyl(oxygenide)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-[(2,2-dimethyl Base-4-oxyethylene-5-aza-3-oxa-undecane-11-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H - To methanol (4 mL) of indole-6-carboxylic acid (160 mg, 0.24 mmol) was added methanolic hydrochloride (1.12 mL, 4 mol/L). The reaction solution was stirred and reacted at 40° C. for 16 hours under the protection of nitrogen.
  • Step 4 To 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-[(6-aminohexyl)amino) at room temperature ]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (70mg, 0.12mmol) in N,N-dimethylformamide (5mL) Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (55.2mg, 0.15mmol), N,N-diisopropyl Ethylamine (78 mg, 0.61 mmol).
  • Step 1 At room temperature, to (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-2 5 -(trifluoromethyl)-1 1 H-8-oxa-3 ,5,11-Triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecyclododecane-12-one 2,2, Paraformaldehyde (20 mg, 0.22 mmol) and isopropyl titanate (10.3 mg, 0.036 mmol) were successively added to a tetrahydrofuran solution (5 mL) of 2-trifluoroacetate (20 mg, 0.030 mmol). The reaction was stirred at 60° C. for 14 hours under the protection of nitrogen.
  • Step 1 Add [(6-bromohexyl)amino]methanoic acid-2-methylpropan-2-yl ester (300mg, 1.28mmol) to N,N-dimethylformamide (8mL) at 25°C Benzyl ⁇ [(3S)-hexahydropyridin-3-yl]amino ⁇ methanoate (395 mg, 1.41 mmol), N,N-diisopropylethylamine (662 mg, 5.12 mmol) were added to the solution. The reaction solution was stirred and reacted at 80° C. for 6 hours under the protection of nitrogen.
  • Step 2 Add ⁇ [(3S)-1-(2,2-dimethyl-4-oxyylidene-5-aza-3-oxaundecane-11-yl)hexahydropyridine-3- Benzyl]amino ⁇ methanoate (555 mg, 1.17 mmol) was dissolved in methanol (10 mL) and palladium on carbon (60 mg, 10% content, 60% aqueous) was added. The reaction solution was stirred and reacted at 25° C. for 3 hours under the protection of hydrogen.
  • Step 3 Add ⁇ 6-[(3S)-3-aminohexahydropyridin-1-yl]hexyl ⁇ amino (280mg, 0.94mmol) to a solution of N,N-dimethylformamide (8mL) at room temperature Add 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-7-[dimethyl(oxygenide)- ⁇ 5-methylphosphoryl]-1H-indole-6 in sequence -Methyl formate (404mg, 0.94mmol), N,N-diisopropylethylamine (483mg, 3.74mmol), the reaction solution was stirred and reacted at 80°C for 16 hours under the protection of nitrogen.
  • Step 4 To 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(3S)-1-(2,2-dimethyl-4 -Oxylidene-5-aza-3-oxaundecane-11-yl)hexahydropyridin-3-yl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H- Add lithium hydroxide hydrate (74mg, 1.75mmol) to methyl indole-6-carboxylate (243mg, 0.35mmol) in methanol (3mL), water (3mL) and tetrahydrofuran (3mL), and the reaction solution is under nitrogen protection The reaction was stirred at 40°C for 14 hours.
  • Step five to 7-[dimethyl (oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(3S)-1-(2,2-dimethyl-4 -Oxylidene-5-aza-3-oxaundecane-11-yl)hexahydropyridin-3-yl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-
  • methanol 4methanol
  • hydrogen chloride/methanol solution 6mL, 4mol/L
  • Step 6 To 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(3S)-1-(6-aminohexyl)hexahydropyridine- 3-yl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (100mg, 0.17mmol) in N,N-dimethylformamide (3mL) Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (65.4mg, 0.17mmol), N,N-diisopropyl Ethylamine (88.9 mg, 0.69 mmol), and the reaction liquid was reacted at 80° C.
  • Step 1 At 25°C, to ⁇ [2-(tetrahydro-1H-pyrrol-3-yl)ethyl]amino ⁇ methane acid-2-methylpropan-2-yl ester (200mg, 0.93mmol) N,N-Dimethylformamide (6mL) solution was added [(2-bromoethyl)amino]benzyl methane (241mg, 0.93mmol), N,N-diisopropylethylamine (602mg, 4.67 mmol). The reaction solution was stirred and reacted at 80° C. for 5 hours under the protection of nitrogen.
  • Step 2 To ( ⁇ 2-[1-(3-Oxylidene-1-phenyl-4-aza-2-oxahex-6-yl)tetrahydro-1H-pyrrole-3 -2-methylprop-2-yl-]ethyl ⁇ amino)methanoate (200 mg, 0.51 mmol) in methanol was added Pd/C (20 mg, 10% content, 60% aqueous). The reaction solution was stirred and reacted at 25° C. for 5 hours under the protection of hydrogen.
  • Step 3 To ( ⁇ 2-[1-(2-aminoethyl)tetrahydro-1H-pyrrol-3-yl]ethyl ⁇ amino)methanoic acid-2-methylpropan-2-yl at room temperature Ester (100mg, 0.39mmol) in N,N-dimethylformamide (6mL) was added 3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-7-[dimethyl (Oxylidene)- ⁇ 5-methylphosphonyl]-1H-indole-6-carboxylic acid methyl ester (168 mg, 0.39 mmol), N,N-diisopropylethylamine (150 mg, 1.17 mmol).
  • Step 4 To 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-[2-( ⁇ 2-[3-(2,2-dimethyl-4- Oxylidene-5-aza-3-oxahept-7-yl)tetrahydro-1H-pyrrol-1-yl]ethyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-4-yl] - To methyl 1H-indole-6-carboxylate (220 mg, 0.34 mmol) in methanol (3 mL), water (3 mL), tetrahydrofuran (3 mL) was added lithium hydroxide hydrate (141 mg, 3.37 mmol). The reaction was stirred at 40° C.
  • Step five at room temperature, to 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-[2-( ⁇ 2-[3-(2,2-dimethyl-4 -Oxylidene-5-aza-3-oxahept-7-yl)tetrahydro-1H-pyrrol-1-yl]ethyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-4-yl ]-1H-indole-6-carboxylic acid (200mg, 0.31mmol) in 1,4-dioxane (4mL) was added hydrochloride 1,4-dioxane (0.78mL, 3.13mmol, 4mol/L) .
  • Step 6 3-[2-( ⁇ 2-[3-(2-aminoethyl)tetrahydro-1H-pyrrol-1-yl]ethyl ⁇ amino)-5-(trifluoromethyl) at room temperature Base) pyrimidin-4-yl]-7-[dimethyl(oxyethylene)- ⁇ 5-methylphosphoryl]-1H-indole-6-carboxylic acid (70mg, 0.11mmol) N,N-dimethyl Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (51mg, 0.13mmol), N,N - Diisopropylethylamine (43 mg, 0.33 mmol).
  • Step 1 In a 50mL single-necked bottle, to (1-hydroxy-6-aza-3-oxahept-6-yl)methanoic acid-2-methylpropan-2-yl ester (300mg, 1.37mmol) Imidazole (140mg, 2.05mmol), triphenylphosphine (431mg, 1.64mmol) and iodine (521mg, 2.05mmol) were sequentially added to the dichloromethane (10mL) solution. Stir at 5°C for 2 hours under nitrogen protection.
  • Step 2 In a 50mL single-necked bottle, to (1-iodo-6-aza-3-oxahept-6-yl)methanoic acid-2-methylpropan-2-yl ester (350mg, 1.06mmol) Add 7-[dimethyl(oxygenide)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3- Aminocyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (553mg, 1.12mmol) and N,N-diisopropylethylamine (0.88 mL, 5.32 mmol).
  • Step 3 Add 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-[(2,2,5-trimethyl -4-Oxylidene-5-aza-3,8-dioxadec-10-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H - Methyl indole-6-carboxylate (610mg, 0.88mmol) was dissolved in a mixed system of water (3mL), methanol (3mL) and tetrahydrofuran (3mL).
  • Step 4 Add methanol solution of hydrochloric acid (5 mL, 4M) to the reaction solution in the previous step, and stir at 5° C. for 5 hours. After the LCMS detection is complete, the reaction solution is concentrated, and the crude product is prepared by reverse phase (chromatographic column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL/min, column temperature: 25°C) to obtain white solid 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-(6 -Aza-3-oxepept-1-ylamino)cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (260mg, 2 steps Yield 51%).
  • LCMS m/z (ES
  • Step 5 To 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-(6-aza-3-oxapeptyl -1-ylamino)cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (260mg, 0.45mmol) of N,N-dimethyl Add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (187mg, 0.49mmol) and N to the formamide (10mL) solution successively, N-Diisopropylethylamine (0.37 mL, 2.23 mmol).
  • Step 1 In a 10mL single-necked bottle, add (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-11-methyl-2 5 -(trifluoromethyl)-1 1 H- 8-oxa-3,5,11-triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecyclododecane-12 Paraformaldehyde (9.30 mg, 0.31 mmol) and tetraisopropyl titanate (35.2 mg, 0.12 mmol) were successively added to a solution of -ketone trifluoroacetate (35 mg, 0.06 mmol) in tetrahydrofuran (3 mL).
  • Step 1 At 25°C, to a solution of methyl 7-bromo-1H-indole-6-carboxylate (1.0g, 3.9mmol) in N,N dimethylformamide (10mL), add tetrakis(triphenyl Phosphine)palladium (0.45g, 0.39mmol) and zinc cyanide (0.46g, 3.9mmol). Blow nitrogen for one minute and put in microwave at 150°C for 1 hour.
  • Step 2 Add N-iodobutane to a solution of methyl 7-cyano-1H-indole-6-carboxylate (800mg, 4.0mmol) in N,N dimethylformamide (10mL) at 25°C Imide (1.35 g, 6.0 mmol). Nitrogen was replaced, stirred at 40°C for 3 hours, and the reaction was complete as detected by LCMS. Water (30 mL) was added to the reaction solution, extracted with ethyl acetate (40 mL ⁇ 2), the combined organic layers were washed with saturated brine (40 mL ⁇ 4), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 3 At 25°C, add 7-cyano-3-iodo-1H-indole-6-carboxylic acid methyl ester (740mg, 2.27mmol) and 4,4,5,5-tetramethyl-1,3, To a solution of 2-dioxaborolane (871mg, 6.81mmol) in tetrahydrofuran (15mL), tris(dibenzylideneacetone) dipalladium (312mg, 0.34mmol), 2-dicyclohexylphosphine- 2',4',6'-Triisopropylbiphenyl (108mg, 0.227mmol) and triethylamine (689mg, 6.81mmol).
  • Step 4 At 25°C, to 6-formyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-ind Indole-7-carbonitrile methane (600 mg, 1.84 mmol) and ⁇ [(1S,3S)-3- ⁇ [4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino ⁇ cyclopentyl] Amino ⁇ methanoic acid-2-methylpropan-2-yl ester (583mg, 1.53mmol) in tetrahydrofuran solution (10mL) was successively added chloro[(n-butylbis(1-adamantyl)phosphine)-2-( 2-Aminobiphenyl)] palladium (II) (102 mg, 0.153 mmol) and potassium phosphate (976 mg, 4.6 mmol) in water (2 mL).
  • Step 5 At 25°C, to 7-cyano-3-(2- ⁇ [(1S,3S)-3-( ⁇ [(2-methylpropan-2-yl)oxy]carbonyl ⁇ amino) ring Pentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (500mg, 0.92mmol) in dichloromethane (5mL) was added trifluoroacetic acid ( 2.5mL). The reaction was carried out at 20° C. for 3 hours, and the reaction was detected by LCMS to be complete.
  • Step 6 At room temperature, to 7-cyano-3-(2- ⁇ [(1S,3S)-3-aminocyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)- 1H-Indole-6-carboxylic acid methyl ester (100mg, 0.225mmol) in N,N-dimethylformamide solution (2mL), add [(4-bromobutyl)amino]methane acid-2-methane 2-ylpropan-2-yl ester (56mg, 0.225mmol) and N,N-diisopropylethylamine (116mg, 0.9mmol).
  • Step 7 To 7-cyano-3-(2- ⁇ [(1S,3S)-3-[(2,2-dimethyl-4-oxoylidene-5-aza-3-oxanonyl -9-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (70mg, 0.09mmol) in tetrahydrofuran (3mL) A solution of lithium hydroxide monohydrate (19.0 mg, 0.45 mmol) in water (3 mL) was added to the mixed solution of methanol (3 mL). The reaction was stirred at 40° C.
  • Step 8 To 7-cyano-3-(2- ⁇ [(1S,3S)-3-[(2,2-dimethyl-4-oxyylidene-5-aza-3-oxanonyl -9-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (20mg, 0.033mmol) in dichloromethane (0.9mL ) solution was added trifluoroacetic acid (0.1 mL). The reaction was stirred at 15°C for 45 minutes. After the reaction was detected by LCMS, N,N-diisopropylethylamine was added to the reaction solution to adjust the pH to 8.
  • Step 9 To 7-cyano-3-(2- ⁇ [(1S,3S)-3-[(4-aminobutyl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidine -4-yl)-1H-indole-6-carboxylic acid (12mg, 0.02mmol) in N,N-dimethylformamide (2mL) solution, add 2-(7-azabenzotriazole )-N,N,N',N'-tetramethyluronium hexafluorophosphate (15 mg, 0.04 mmol) and N,N-diisopropylethylamine (21 mg, 0.16 mmol).
  • Step 1 Add [(4-hydroxybutyl)(methyl)amino]methane acid to a solution of triphenylphosphine (129mg, 0.49mmol) in dichloromethane (3mL) successively under nitrogen atmosphere at 0°C- 2-Methylpropan-2-yl ester (100mg, 0.49mmol), elemental iodine (125mg, 0.49mmol), imidazole (50mg, 0.74mmol). After stirring at 0°C for 5 minutes and warming to room temperature, the reaction was stirred at room temperature for 4 hours.
  • triphenylphosphine 129mg, 0.49mmol
  • dichloromethane 3mL
  • elemental iodine 125mg, 0.49mmol
  • imidazole 50mg, 0.74mmol
  • Step 2 7-[Dimethyl(oxygenide)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-aminocyclopentyl]amino ⁇ -5-(three Fluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (27 mg, 0.054 mmol) was dissolved in N,N-dimethylformamide (2 mL). Add [(4-iodobutyl)(methyl)amino]methanoic acid-2-methylprop-2-yl ester (20mg, 0.065mmol), N,N-diisopropylethylamine (28mg, 0.218 mmol).
  • Step 3 Add 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-[(2,2,5-trimethyl- 4-Oxylidene-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-
  • Methyl 6-carboxylate 110mg, 0.162mmol
  • Lithium hydroxide (1 H2O, 34 mg, 0.808 mmol
  • Step 4 To 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-[(2,2,5-trimethyl- 4-Oxylidene-5-aza-3-oxanon-9-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole- Hydrogen chloride/methanol solution (5 mL, 4M) was added to 6-formic acid (110 mg, 0.164 mmol), and the system was stirred at 40°C for 4 hours.
  • Step five to 7-[dimethyl (oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3- ⁇ [4-(methylamino)butyl] Amino ⁇ cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (60mg, 0.106mmol) in N,N-dimethylformamide (5mL ) solution was added 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (40mg, 0.106mmol) and N,N-diiso Propylethylamine (68 mg, 0.530 mmol).
  • Step 1 To a solution of methyl 4-((benzyloxy)carbonyl)amino)-3-oxobutanoate (5.0 g, 18.9 mmol) in THF (100 mL) at 5° C. was added lithium aluminum hydride in THF solution (28.3 mL, 1 M, 28.3 mmol). The reaction solution was stirred and reacted at 5° C. for 2 hours under the protection of nitrogen.
  • Step 2 Add imidazole (0.68g, 10.04mmol) to a solution of benzyl (2,4-dihydroxybutyl) carbamate (1.2g, 5.02mmol) in dichloromethane (50mL) at 5°C , tert-butyldiphenylchlorosilane (1.38 g, 5.02 mmol). The reaction was stirred at 5° C. for 3 hours under the protection of nitrogen.
  • Step 3 Benzyl (4-((tert-butyldiphenylsilyl)oxy)-2-hydroxybutyl)carbamate (2.2g, 4.61mmol) was dissolved in dichloromethane (30mL), Diethylaminosulfur trifluoride (1.1 g, 6.92 mmol) was then added slowly at 0°C and the reaction was stirred at 5°C for 3 hours.
  • Step 4 Dissolve benzyl (4-((tert-butyldiphenylsilyl)oxy)-2-fluorobutyl)carbamate (700mg, 1.46mmol) in N,N-dimethylformaldehyde To the amide (5 mL), cesium fluoride (888 mg, 5.84 mmol) was added. The reaction was stirred at 5°C for 18 hours.
  • Step 5 Dissolve benzyl (2-fluoro-4-hydroxybutyl) carbamate (300mg, 1.24mmol) in dichloromethane (10mL) in a 50mL single-necked bottle, add imidazole (126mg, 1.86mmol) , triphenylphosphine (390mg, 1.50mmol) and elemental iodine (381mg, 1.50mmol). The reaction was stirred at 10°C for 1 hour.
  • Step 6 3-(2-((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl) -1H-indole-6-carboxylic acid methyl ester (220mg, 0.44mmol) was dissolved in N,N-dimethylformamide (5mL), and benzyl(2-fluoro-4-iodobutyl)aminomethyl ester (156mg, 0.44mmol) and N,N-diisopropylethylamine (286mg, 2.20mmol). Stir at 100°C for 18 hours.
  • Step 7 Methyl 3-(2-((1S,3S)-3-((benzyloxy)carbonyl)amino)-3-fluorobutylamino)cyclopentylamino)-5-(trifluoromethyl yl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylate (290mg, 0.40mmol) was dissolved in methanol (5mL), tetrahydrofuran (5mL) and water (5mL ) into the mixed system, lithium hydroxide monohydrate (84mg, 2.00mmol) was added. The reaction was stirred at 40°C for 18 hours.
  • Step 8 To 3-(2-((1S,3S)-3-((benzyloxy)carbonyl)amino)-3-fluorobutylamino)cyclopentylamino)-5-(trifluoromethyl) Add trifluoroacetic acid (5 mL) to a reaction flask of pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (300 mg, 0.43 mmol), and stir at 60° C. for 3 h.
  • Step 9 To 3-(2-((1S,3S)-3-((4-amino-3-fluorobutyl)amino)cyclopentyl)amino)-5-(trifluoromethyl) at room temperature )pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carboxylic acid (70mg, 0.12mmol) in N,N-dimethylformamide (5mL) was added successively 2 -(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (55mg, 0.15mmol), N,N-diisopropylethylamine (78mg ,0.61mmol).
  • Step 10 Reverse phase the crude product obtained in the previous step (chromatographic column: Ultimate XB-C18, 50*250mm, 10um (PARP-02), mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), flow rate: 70mL /min, column temperature: 25°C) to prepare and purify two isomeric compounds.
  • One of the isomeric compounds is arbitrarily designated as (4 1 S,4 3 S,8R)-1 7 -(dimethylphosphoryl)-8-fluoro-2 5 -(trifluoromethyl)-1 1 H- 3,5,10-Triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecycloundecane-11-one (4 1 S,4 3 S,8R)-1 7 -(dimethylphosphoryl)-8-fluoro-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indola-2( 4,2)-py rimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z68-1, 4 mg, yield 6%, trifluoroacetate salt), white solid.
  • Another isomeric compound is arbitrarily designated as (4 1 S,4 3 S,8S)-1 7 -(dimethylphosphoryl)-8-fluoro-2 5 -(trifluoromethyl)-1 1 H- 3,5,10-Triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecycloundecane-11-one (4 1 S,4 3 S,8S)-1 7 -(dimethylphosphoryl)-8-fluoro-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indola-2( 4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z68-2, 3 mg, yield 5%, trifluoroacetate salt).
  • Step 1 In a 250mL three-necked flask, add N-[(benzyloxy)carbonyl]-N-methylglycine (10.8g, 48.4mmol), tetrahydrofuran (100mL) and carbonyldiimidazole (7.8g, 48.4mmol) in sequence .
  • the reaction solution was replaced with nitrogen, stirred at 10°C for 12 hours, magnesium chloride (2.3g, 24.2mmol) and monomethyl malonate potassium salt (7.6g, 48.4mmol) were added, the temperature was raised to 60°C and stirred for 6 hours, TLC detected that the reaction was complete .
  • Step 2 Dissolve benzyl (3,5-dioxylidene-7-aza-2-oxahoct-7-yl)methanoate (5.8g, 20.8mmol) in dichloromethane (50mL), Diethylaminosulfur trifluoride (5.0 g, 31.2 mmol) was added dropwise at 0°C. Stir at 25°C for 16 hours.
  • Step 3 Dissolve benzyl (5,5-difluoro-3-oxylidene-7-aza-2-oxahoct-7-yl)methanoate (1.4g, 4.7mmol) in tetrahydrofuran (20mL ), added dropwise a tetrahydrofuran solution (4.7 mL, 1M) of lithium aluminum tetrahydrogen at 0°C, and stirred at 10°C for 2 hours.
  • Step 4 To a solution of benzyl [(2,2-difluoro-4-hydroxybutyl)(methyl)amino]methanoate (400mg, 1.46mmol) in pyridine (5mL), add p-methylsulfonyl chloride (558mg, 2.93mmol), stirred at 10°C for 3 hours.
  • Step 5 7-[Dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-aminocyclopentyl]amino ⁇ -5-( Trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (426mg, 0.86mmol) was dissolved in N,N-dimethylformamide (7mL), and 4-methylbenzene Sulfonic acid-6,6-difluoro-4-methyl-3-oxylidene-1-phenyl-4-aza-2-oxahoct-8-yl ester (350mg, 0.82mmol) and N, N-Diisopropylethylamine (0.68 mL, 4.09 mmol).
  • Step 6 Add 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-[(6,6-difluoro-4- Methyl-3-oxoylidene-1-phenyl-4-aza-2-oxa-oct-8-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidine-4- base)-1H-indole-6-carboxylic acid methyl ester (330mg, 0.46mmol) was dissolved in a mixed system of water (3mL), methanol (3mL) and tetrahydrofuran (3mL), and lithium hydroxide monohydrate (96.6mg, 2.30 mmol), stirred at 40°C for 16 hours.
  • Step 7 To 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-[(6,6-difluoro-4- Methyl-3-oxoylidene-1-phenyl-4-aza-2-oxa-oct-8-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidine-4- (1)-1H-indole-6-carboxylic acid (350mg, 0.48mmol) was added trifluoroacetic acid (5mL).
  • Step 8 To 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3- ⁇ [3,3-difluoro-4- N,N - Add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (149mg, 0.39mmol ) and N,N-diisopropylethylamine (0.30 mL, 1.78 mmol).
  • Step 1 In a 10mL single-necked bottle, add (4 1 S,4 3 S)-1 7 -(dimethylphosphoryl)-8,8-difluoro-10-methyl-2 5 -(trifluoro Methyl)-1 1 H-3,5,10-Triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecycloundec Paraformaldehyde (9 mg, 0.10 mmol) and tetraisopropyl titanate (28 mg, 0.10 mmol) were successively added to a solution of alkan-11-one (14 mg, 0.02 mmol, trifluoroacetate) in tetrahydrofuran (3 mL).
  • Step 1 Add L-proline (0.18g , 1.6mmol), ketone iodide (0.95g, 0.8mmol) and sodium methylsulfite (1.1g, 9.5mmol). The reaction was stirred at 90° C. for 16 hours under the protection of nitrogen. After LCMS detected that the reaction was complete, slowly add saturated ammonium chloride aqueous solution (30mL) to the reaction solution to quench, and extract with ethyl acetate (30mL ⁇ 3), the combined organic layer was washed 3 times with saturated brine, and anhydrous sodium sulfate Dry, filter and concentrate.
  • Step 2 Add N- Iodosuccinimide (1.5 g, 6.6 mmol). The reaction solution was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was complete as detected by LCMS, the reaction solution was added with water (30 mL), and then extracted with ethyl acetate (30 mL ⁇ 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration.
  • Step 3 At room temperature, add 3-iodo-7-(methylsulfonyl)-1H-indole-6-carboxylic acid methyl ester (1.8g, 4.7mmol), tris(dibenzylidene Dipalladium (0.44g, 0.47mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (0.45g, 0.94mmol), pinacol borane (0.91g, 7.1 mmol), triethylamine (1.4g, 14.1mmol) and tetrahydrofuran (15mL) solution. Stir at 90°C for 16 hours under nitrogen protection.
  • Step 4 At room temperature, sequentially add methyl 7-(methylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxy Boropentan-2-yl)-1H-indole-6-carboxylate (1.1g, 2.9mmol), chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2- Aminobiphenyl)] palladium (II) (0.19g, 0.29mmol), potassium phosphate (1.8g, 8.7mmol), tert-butyl ((1S,3S)-3-((4-chloro-5-(trifluoro A mixed solution of methyl)pyrimidin-2-yl)amino)cyclopentyl)carbamate (1.1 g, 2.9 mmol), tetrahydrofuran (25 mL) and water (5 mL).
  • Step 5 At room temperature, methyl 3-(2-((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl)-7-(methylsulfonyl)-1H-indole-6-carboxylate (570mg, 0.95mmol) was dissolved in a mixed solution of hydrogen chloride/ethyl acetate (5mL, 4M) and ethyl acetate (3mL) , reacted at 30°C for 16 hours.
  • a mixed solution of hydrogen chloride/ethyl acetate 5mL, 4M
  • ethyl acetate 3mL
  • Step 6 At room temperature, to 3-(2-((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylsulfonyl )-1H-indole-6-carboxylic acid methyl ester (300mg, 0.60mmol) in N,N-dimethylformamide (10mL) solution was added successively tert-butyl (2-(2-iodoethoxy) Ethyl)(methyl)carbamate (197mg, 0.60mmol) and N,N-diisopropylethylamine (310mg, 2.40mmol), stirred at 80°C for 16 hours.
  • Step 7 Methyl 3-(2-((1S,3S)-3-((2-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)ethyl)amino) ring Pentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylsulfonyl)-1H-indole-6-carboxylate (180mg, 0.26mmol) was dissolved in water ( 3 mL), methanol (3 mL) and tetrahydrofuran (3 mL), then added lithium hydroxide monohydrate (55 mg, 1.3 mmol), and stirred at 40°C for 16 hours.
  • Step 8 Add 3-(2-((1S,3S)-3-((2-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)ethyl)amino)cyclopentyl )amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylsulfonyl)-1H-indole-6-carboxylic acid (176mg, 0.26mmol) was dissolved in methanol (5mL) , then added hydrochloric acid/methanol (5 mL, 4M), and stirred at 40° C. for 16 hours.
  • Step 9 To 3-(2-((1S,3S)-3-((2-(methylamino)ethoxy)ethyl)amino)cyclopentylamino)-5-(trifluoromethyl)pyrimidine -4-yl)-7-(methylsulfonyl)-1H-indole-6-carboxylic acid (110mg, 0.16mmol, trifluoroacetate) in N,N-dimethylformamide (10mL) solution Add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (61mg, 0.16mmol) and N,N-diisopropyl ethyl Amine (83mg, 0.64mmol), stirred at 60°C for 16h.
  • Step 10 In a 10mL single-necked bottle, add (4 1 S,4 3 S)-11-methyl-1 7 -(methylsulfonyl)-2 5 -(trifluoromethyl)-1 1 H- 8-oxa-3,5,11-triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecyclododecane-12 Add paraformaldehyde (20mg, 0.221mmol) and tetraisopropyl titanate (63mg, 0.221mmol) successively to tetrahydrofuran (10mL) solution of -ketone (30mg, 0.044mmol, trifluoroacetate), and the reaction solution is Stir at 70°C for 14 hours, lower the reaction solution to 30°C, add sodium cyanoborohydride (41 mg, 0.660 mmol), and continue stirring at 30°C for 2 hours.
  • paraformaldehyde (20mg, 0.221mmol) and
  • Step 1 To a solution of N-[(benzyloxy)carbonyl]glycine (100.0 g, 478.49 mmol) in tetrahydrofuran (1000 mL) was added carbonyldiimidazole (85.3 g, 526.34 mmol) at 15°C. The reaction solution was stirred and reacted at 15° C. for 18 hours under the protection of nitrogen. Magnesium chloride (22.8 g, 239.25 mmol), monomethyl malonate potassium salt (82.2 g, 526.34 mmol) were then added to the reaction liquid. The reaction solution was stirred and reacted at 45° C. for 6 hours under the protection of nitrogen.
  • Step 2 Dissolve benzyl [(1-methoxy-1,3-dioxylidenebut-4-yl)amino]methanoate (85.3g, 321.89mmol) in tetrahydrofuran (900mL) at 15°C Lithium borohydride (14.0 g, 643.78 mmol) was added in portions to the solution. The reaction solution was stirred and reacted at 15° C. for 18 hours under the protection of nitrogen.
  • Step 3 At 15°C, add imidazole (22.2g, 326.37 mmol), and then slowly added tert-butyldiphenylchlorosilane (69.0 g, 251.05 mmol) dropwise. The reaction solution was stirred and reacted at 15° C. for 2 hours under the protection of nitrogen.
  • Step 4 Benzyl [(7-hydroxy-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silaoct-8-yl)amino]methanoate (88.0 g, 184.49mmol) was dissolved in dichloromethane (900mL), then diethylaminosulfur trifluoride (38.7g, 239.83mmol) was slowly added dropwise at room temperature. The reaction was stirred at 15°C for 2 hours.
  • Step five benzyl [(7-fluoro-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silaoct-8-yl)amino]methanoate (20.5 g, 42.80mmol) was dissolved in tetrahydrofuran (150mL), sodium hydrogen (5.1g, 60% content dispersed in mineral oil, 128.40mmol) was added in batches at room temperature, and then slowly added dropwise methyl iodide (12.2g, 85.60 mmol). The reaction was stirred at 15°C for 12 hours.
  • Step 6 Benzyl (7-fluoro-2,2-dimethyl-3,3-diphenyl-9-aza-4-oxa-3-siladec-9-yl)methanoate (10.0g, 20.24mmol) was dissolved in a solution of N,N-dimethylformamide (60mL), then cesium fluoride (15.4g, 101.20mmol) was added, and stirred at 50°C for 8 hours.
  • Step 7 Dissolve [(2-fluoro-4-hydroxybutyl)(methyl)amino]methanoic acid benzyl ester (4.4g, 17.25mmol) in a solution of dichloromethane (40mL) at room temperature , and then sequentially added imidazole (1.4g, 20.70mmol), triphenylphosphine (5.4g, 20.70mmol) and elemental iodine (5.3g, 20.70mmol). The reaction was stirred for an additional 2 hours at room temperature.
  • Step 8 In a 250mL single-necked bottle, add 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-aminocyclopentyl ]Amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid methyl ester (5.0g, 10.10mmol) was dissolved in N,N-dimethylformamide (70 mL ), then added benzyl [(2-fluoro-4-iodobutyl)(methyl)amino]methanoate (3.7g, 10.10mmol) and N,N-diisopropylethylamine (5.2g, 40.40 mmol), stirred at 100°C for 16 hours.
  • Step 9 Add 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-[(6-fluoro-4-methyl- 3-Oxylidene-1-phenyl-4-aza-2-oxa-oct-8-yl)amino]cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)- 1H-Indole-6-methyl carboxylate (7.0g, 9.56mmol) was dissolved in a mixed system of water (20mL), methanol (20mL) and tetrahydrofuran (20mL), and then lithium hydroxide monohydrate (1.6g, 38.24 mmol), the reaction was stirred at 40°C for 16 hours.
  • Step 11 To 7-[dimethyl(oxygenide)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3- ⁇ [3-fluoro-4-(methyl N,N- Add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.6g, 6.85mmol ) and N,N-diisopropylethylamine (3.6g, 27.4mmol), the reaction solution was stirred at 60°C for 16h.
  • One of the isomeric compounds is arbitrarily designated as (4 1 S,4 3 S,8R)-1 7 -(dimethylphosphoryl)-8-fluoro-10-methyl-2 5 -(trifluoromethyl) -1 1 H-3,5,10-Triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecycloundecane-11 -Keto(4 1 S,4 3 S,8R)-1 7 -(dimethylphosphoryl)-8-fluoro-10-methyl-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1( 3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z76, 0.7g, yield 18%, trifluoroacetic acid salt), off-white solid.
  • Another isomer compound is arbitrarily designated as (4 1 S,4 3 S,8S)-1 7 -(dimethylphosphoryl)-8-fluoro-10-methyl-2 5 -(trifluoromethyl)-1 1 H-3,5,10-tri Aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecycloundecane-11-one (4 1 S,4 3 S,8S )-1 7 -(dimethylphosphoryl)-8-fluoro-10-methyl-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indola-2(4,2 )-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one (Z77, 0.8g, yield 21%, trifluoroacetate salt), off-white solid.
  • Step 12 To (4 1 S,4 3 S,8R)-1 7 -(dimethylphosphoryl)-8-fluoro-10-methyl-2 5 -(trifluoromethyl)-1 1 H -3,5,10-Triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecycloundecane-11-one (Z76 , 220mg, 0.39mmol) in tetrahydrofuran (20mL) were successively added paraformaldehyde (176mg, 1.95mmol) and tetraisopropyl titanate (554mg, 1.95mmol), and the reaction solution was stirred at 70°C for 16h.
  • paraformaldehyde 176mg, 1.95mmol
  • tetraisopropyl titanate 554mg, 1.95mmol
  • Step 13 To (4 1 S,4 3 S,8S)-1 7 -(dimethylphosphoryl)-8-fluoro-10-methyl-2 5 -(trifluoromethyl)-1 1 H -3,5,10-Triaza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-cyclopentanecycloundecane-11-one (Z77 , 200mg, 0.35mmol) in tetrahydrofuran (20mL) were successively added paraformaldehyde (158mg, 1.75mmol) and tetraisopropyl titanate (497mg, 1.75mmol), and the reaction solution was stirred at 70°C for 16h.
  • paraformaldehyde 158mg, 1.75mmol
  • tetraisopropyl titanate 497mg, 1.75mmol
  • Step 1 To a solution of 7-bromo-1H-indole-6-carboxylate (5.0 g, 19.8 mmol) in N,N dimethylformamide (30 mL) at room temperature, add N-iodobutane Imide (6.7 g, 29.7 mmol). The reaction was stirred at 40°C for 2 hours under nitrogen protection. After the completion of the reaction as detected by LCMS, the reaction solution was added with saturated ammonium chloride solution (40 mL), and then extracted with ethyl acetate (40 mL ⁇ 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration.
  • Step 2 At room temperature, add 7-bromo-3-iodo-1H-indole-6-carboxylic acid methyl ester (6.5g, 17.2mmol), tris(dibenzylideneacetone) di Palladium (1.6g, 1.7mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (0.8g, 1.7mmol), pinacol borane (6.5g, 51.6mmol), tri Ethylamine (5.2 g, 51.6 mmol) and tetrahydrofuran (60 mL). Stir at 90°C for 15 hours under nitrogen protection.
  • Step 3 Add 7-bromo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1H-indole-6-carboxylic acid methyl ester (2.4g, 6.3mmol), bistriphenylphosphine palladium dichloride (0.44g, 0.63mmol), potassium carbonate (1.7g, 12.6mmol) , tert-butyl ((1S, 3S)-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)carbamate (2.4g, 6.3mmol) , a mixed solution of dioxane (30 mL) and water (6 mL).
  • Step 4 At room temperature, methyl 7-bromo-3-(2-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-5-(trifluoromethyl Base) pyrimidin-4-yl)-1H-indole-6-carboxylate (1.4g, 2.3mmol) was dissolved in a mixed solution of hydrogen chloride/ethyl acetate (15mL, 4M) and ethyl acetate (10mL), React at 40°C for 16 hours.
  • Step 5 At room temperature, methyl 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-bromo -1H-indole-6-carboxylate (500mg, 1.0mmol) in N,N-dimethylformamide (10mL) solution was added successively tert-butyl (4-iodobutyl) (methyl) aminomethyl Ester (344mg, 1.1mmol) and N,N-diisopropylethylamine (645mg, 5.0mmol), stirred at 70°C for 16 hours.
  • Step 6 Methyl 7-bromo-3-(2-(((1S,3S)-3-((4-(tert-butoxycarbonyl)(methyl)amino)butyl)amino)cyclopentyl) Amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylate (60mg, 0.09mmol) was dissolved in water (3mL), methanol (3mL) and tetrahydrofuran (3mL) Lithium hydroxide monohydrate (19mg, 0.45mmol) was added to the mixed system, and stirred at 40°C for 6 hours.
  • Step 7 7-bromo-3-(2-(((1S,3S)-3-((4-((tert-butoxycarbonyl)(methyl)amino)butyl)amino)cyclopentyl)amino )-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (60mg, 0.09mmol) was dissolved in methanol (5mL), then hydrochloric acid/methanol (5mL, 4M) was added , and stirred at 20°C for 16 hours.
  • Step 8 To 7-bromo-3-(2-(((1S,3S)-3-((4-(methylamino)butyl)amino)cyclopentyl)amino)-5-(trifluoromethyl 2-(7-azabenzo Triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19 mg, 0.05 mmol) and N,N-diisopropylethylamine (32 mg, 0.25 mmol). The reaction was stirred at 60°C for 18 hours.
  • Step 9 In a 50mL single-necked bottle, add (8S,11S)-20-bromo-17-methyl-3-(trifluoromethyl)-5,7,12,17,22,28-hexaaza Pentacyclic [17.4.3.1 2,6 .1 8,11 .0 21,24 ] twenty-eight-1(23),2(3),4,6(28),19(20),21(24) , 25-Heptaen-18-one (12mg, 0.022mmol, trifluoroacetate) in tetrahydrofuran (5mL) was added successively with paraformaldehyde (10mg, 0.11mmol) and tetraisopropyl titanate (31mg, 0.11 mmol), the reaction solution was stirred at 60°C for 14 hours, the reaction solution was lowered to 30°C, sodium cyanoborohydride (7 mg, 0.11 mmol) was added, and stirring was continued at 30°C for 4 hours.
  • paraformaldehyde 10
  • Step 10 At room temperature, sequentially add (8S,11S)-20-bromo-12,17-dimethyl-3-(trifluoromethyl)-5,7,12,17,22 into the microwave tube ,28-hexaazapentacyclo[17.4.3.1 2,6 .1 8,11 .0 21,24 ]28-1(23),2(3),4,6(28),19(20 ), 21(24), 25-heptaen-18-one (5mg, 0.009mmol), tetrakistriphenylphosphopalladium (2mg, 0.002mmol), zinc cyanide (3mg, 0.027mmol) and N,N-di Methylformamide (1 mL) solution. Microwave reaction at 150° C.
  • Embodiment 34 compound Z85, the synthesis of Z86
  • Step 1 At room temperature, add 4-methylbenzenesulfonic acid-7,7-difluoro-2,2,5-trimethyl-4-oxylidene-5-aza-3-oxanonyl-9 Add methylamine methanol solution (30% content, 20mL) and sodium iodide (60mg, 0.38mmol) to a methanol (10mL) solution of -yl ester (1.50g, 3.81mmol), and stir at 50°C for 14 hours. After LCMS detected that the reaction was complete, the reaction solution was concentrated to remove the solvent.
  • Step 2 Dissolve (4,4-difluoro-2,7-diazaoct-2-yl)methanoic acid-2-methylpropan-2-yl ester (1.10g, 3.49mmol) in tetrahydrofuran (10mL ), then added ethyl trifluoroacetate (2.48g, 17.4mmol) and triethylamine (1.5mL, 10.5mmol) successively, and stirred at 50°C for 14 hours. After the reaction was detected by LCMS, ethyl acetate ( 30ml) and water (20mL), the organic phase was separated and concentrated.
  • Step 3 Add (4,4,9,9,9-pentafluoro-7-methyl-8-oxyylidene-2,7-diazanon-2-yl)methanoic acid-2-methylpropane -2-yl ester (566mg, 1.63mmol) was dissolved in dichloromethane (5mL), then trifluoroacetic acid (1.0mL) was added to the reaction solution, and stirred at 25°C for 3 hours.
  • Step 4 Dissolve N-[3,3-difluoro-4-(methylamino)butyl]-2,2,2-trifluoro-N-methylacetamide (399mg, 1.61mmol) in methanol ( 5mL), then add ⁇ [(3S)-1-oxyethylenecyclopent-3-yl]amino ⁇ methanoic acid benzyl ester (562mg, 2.41mmol), 4A molecular sieves (100mg), glacial acetic acid (2 drops) After stirring at 25°C for 2 hours, sodium cyanoborohydride (303 mg, 4.82 mmol) was added to the reaction solution, and stirring was continued at 25°C for 14 hours.
  • Step 5 Add ⁇ [(3S)-1-(4,4,9,9,9-pentafluoro-7-methyl-8-oxyylidene-2,7-diazanon-2-yl) Cyclopent-3-yl]amino ⁇ methanoic acid benzyl ester (330mg, 2.21mmol) was dissolved in methanol (10mL), palladium carbon (30mg, 10% content, 55% water content), glacial acetic acid ( 30mg, 0.50mmol), replace the hydrogen, stir at 25°C for 2 hours, after TLC detects that the reaction is complete, filter and concentrate the organic phase to obtain the crude product as colorless oily N-(3,3-difluoro-4- ⁇ [(3S)- 3-Aminocyclopentyl](methyl)amino ⁇ butyl)-2,2,2-trifluoro-N-methylacetamide (310mg, yield 96%) can be directly used in the next reaction.
  • LCMS m/z (ESI
  • Step 6 Add N-(3,3-difluoro-4- ⁇ [(3S)-3-aminocyclopentyl](methyl)amino ⁇ butyl)-2,2,2-trifluoro-N- Methylacetamide (310mg, 0.94mmol) was dissolved in N,N-dimethylformamide (4ml), and 3-[2-chloro-5-(trifluoromethyl)pyrimidine-4- base]-7-[dimethyl(oxyethylene)- ⁇ 5 -methylphosphoryl]-1H-indole-6-carboxylic acid methyl ester (424mg, 0.98mmol), N,N-diisopropylethylamine (0.77mL, 4.68mmol), the reaction was stirred at 130°C for 5 hours under a nitrogen atmosphere, after the LCMS detected that the reaction was complete, water (10mL) was added to the reaction solution, then extracted with ethyl acetate (10mL ⁇ 2), and the combined organic layers , dried over anhydr
  • Step 7 Add 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-(4,4,9,9,9- Pentafluoro-7-methyl-8-oxyylidene-2,7-diazanon-2-yl)cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H -Methyl indole-6-carboxylate (125mg, 0.17mmol) was dissolved in a mixed solvent of water (1mL), methanol (3mL) and tetrahydrofuran (3mL), and lithium hydroxide (1 crystal water, 300mg, 7.09mmol ), stirred at 40°C for 14 hours.
  • Step 8 To 7-[dimethyl(oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S,3S)-3-(4,4-difluoro-2,7 N,N -N,N-Diisopropylethylamine (37.7mg, 0.29mmol) and 2-(7-azabenzotriazole)-N,N,N were added in turn to dimethylformamide (4mL) solution ', N'-Tetramethylurea hexafluorophosphate (74mg, 0.20mmol), stirred at 60°C for 14 hours.
  • dimethylformamide (4mL) solution ', N'-Tetramethylurea hexafluorophosphate 74mg, 0.20mmol
  • Embodiment 35 compound Z87, the synthesis of Z88
  • Step 2 Dissolve benzyl (4-fluoro-2,7-diazaoctyl-2-yl)carboxylate (1.50g, 5.59mmol) in dichloromethane (20mL), and then add 4-dimethylamino in sequence Pyridine (0.07g, 0.56mmol) and di-tert-butyl dicarbonate (1.46g, 6.71mmol) were stirred at 25°C for 14 hours. After the reaction was complete as detected by LCMS, the reaction solution was concentrated to remove the solvent.
  • Step 3 Benzyl (8-fluoro-2,2,5-trimethyl-4-oxyylidene-5,10-diaza-3-oxaundecane-10-yl)methanoate (1.20g, 3.26mmol) was dissolved in methanol (20mL), and palladium on carbon (120mg, 10% content, 55% water content) was added to the reaction solution.
  • Step 4 Dissolve (5-fluoro-2,7-diazaoct-2-yl)methanoic acid-2-methylpropan-2-yl ester (600mg, 2.56mmol) in methanol (15mL), and add ⁇ [(3S)-1-Oxylidenecyclopent-3-yl]amino ⁇ methanoic acid benzyl ester (597mg, 2.56mmol), glacial acetic acid (30mg, 0.50mmol), stirred at 25°C for 2 hours, and added to the reaction solution Sodium cyanoborohydride (483mg, 7.68mmol) was added, and stirring was continued at 25°C for 16 hours.
  • Step 5 Dissolve 3-aminocyclopent-1-ol hydrochloride (10.0g, 72.7mmol) in dichloromethane (100mL), add benzyloxycarbonyl succinimide (21.7g , 87.2mmol), triethylamine (14.7g, 145mmol). Under nitrogen atmosphere, stir at 25°C for 14 hours, LCMS detects that the reaction is complete, add water (100mL) to the reaction solution, extract with dichloromethane (200mL ⁇ 3), wash the combined organic layer with saturated brine, dry over anhydrous sodium sulfate, and filter concentrate.
  • Step 6 At -78°C, add dimethyl sulfoxide (1.69g, 21.7mmol) and oxalyl chloride (1.38g, 10.8mmol) to dichloromethane (20mL) successively, and stir the reaction solution at -78°C for 1h .
  • Benzyl [(3-hydroxycyclopentyl)amino]methanoate (1.7g, 7.23mmol) was added to the reaction solution, and the reaction solution was continued for 3h, and triethylamine (3.66g, 36.1mmol) was added to the reaction solution.
  • LCMS detected that the reaction was complete.
  • Step 7 Add ⁇ 7-[(3S)-3- ⁇ [(benzyloxy)carbonyl]amino ⁇ cyclopentyl]-5-fluoro-2,7-diazaoct-2-yl ⁇ methane -2-Methyl prop-2-yl ester (P1, 1.00g, 2.21mmol) was dissolved in methanol (20mL), palladium carbon (100mg, 10% content, 55% water content), glacial acetic acid ( 30.0mg, 0.50mmol), the reaction was stirred at 25°C for 14 hours under hydrogen atmosphere.
  • Step 8 Add ⁇ 7-[(3S)-3-aminocyclopentyl]-5-fluoro-2,7-diazaoct-2-yl ⁇ methanoic acid-2-methylpropan-2-yl ester (0.75g, 90% purity, 2.13mmol) was dissolved in N,N-dimethylformamide (10mL), and N,N-diisopropylethylamine (1.37g10.63mmol), 3 -[2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl]-7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-1H-indole-6-carboxylic acid methyl ester (1.01 g, 2.34 mmol).
  • Step 9 Add 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S)-3-(8-fluoro-2,2,5-trimethyl -4-Oxylidene-5,10-diaza-3-oxaundecane-10-yl)cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H -Methyl indole-6-carboxylate (1.01g, 1.42mmol) was dissolved in a mixed system of water (5mL), methanol (5mL) and tetrahydrofuran (5mL), then lithium hydroxide (1 crystal water, 0.30g , 7.09mmol), stirred at 40°C for 5 hours. After the completion of the reaction detected by LCMS, the reaction solution was directly used in the next reaction without any treatment.
  • LCMS: m/z (ESI): 699.4[M+H] + , t R 0.9
  • Step 10 Add hydrogen chloride/methanol solution (10 mL, 4M) to the reaction solution in step 7, and stir the system at 40° C. for 5 hours.
  • the solvent was directly spin-dried, and the obtained crude product was prepared by reverse-phase HPLC (chromatographic column: Ultimate XB-C18, 50*250mm, 10um (PARP-02); mobile phase: acetonitrile-water (0.1% bicarbonate ammonium); mobile phase: 70mL/min; column temperature: 25°C) to obtain 7-[dimethyl(oxygenide)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S)-3- (4-Fluoro-2,7-diazaoct-2-yl)cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (530mg , yield 62%) was white solid.
  • LCMS m/z (ESI)
  • Step 11 To 7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S)-3-(4-fluoro-2,7-diazapine -2-yl)cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (100mg, 0.17mmol) of N,N-dimethylformaldehyde Add N,N-diisopropylethylamine (108mg, 0.84mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (254mg, 0.67mmol), the reaction solution was stirred at 60°C for 14h.
  • (4 1 S)-1 7 - (dimethylphosphoryl)-7-fluoro-5,10-dimethyl-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina -4(1,3)-cyclopentanacycloundecaphan-11-one) (Z88, 8.24 mg; trifluoroacetate, yield 8.34%).
  • Embodiment 36 compound Z89, the synthesis of Z90
  • Step 1 Add ⁇ 7-[(3S)-3- ⁇ [(benzyloxy)carbonyl]amino ⁇ cyclopentyl]-5-fluoro-2,7-diazaoct-2-yl ⁇ methane -2-Methyl prop-2-yl ester (P2, 530mg, 1.17mmol) was dissolved in methanol (10mL), then palladium carbon (53mg, 10% content, 55% water content), glacial acetic acid ( 30mg, 0.50mmol). Under hydrogen atmosphere, stir at 25°C for 14 hours.
  • Step 2 ⁇ 7-[(3S)-3-aminocyclopentyl]-5-fluoro-2,7-diazaoct-2-yl ⁇ methanoic acid-2-methylpropan-2-yl ester (380mg, 90% purity, 1.08mmol) was dissolved in N,N-dimethylformamide (8mL), and N,N-diisopropylethylamine (696mg 5.39mmol), 3-[ 2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl]-7-[dimethyl(oxygenidene)- ⁇ 5-methylphosphonyl]-1H-indole-6-carboxylic acid methyl ester (465mg , 1.08mmol).
  • Step 3 7-[Dimethyl(oxygenide)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S)-3-(8-fluoro-2,2,5-trimethyl -4-Oxylidene-5,10-diaza-3-oxaundecane-10-yl)cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H -Methyl indole-6-carboxylate (330mg, 0.46mmol) was dissolved in a mixed system of water (3mL), methanol (3mL) and tetrahydrofuran (3mL), and lithium hydroxide (1 crystal water, 97mg, 2.32mmol ), and the reaction was stirred at 40°C for 5 hours. After the completion of the reaction detected by LCMS, the reaction solution was directly used in the next reaction without any treatment.
  • Step 4 Add hydrogen chloride/methanol solution (8 mL, 4M) to the reaction solution in Step 3, and stir the system at 40° C. for 5 hours.
  • the solvent was directly spin-dried, and the obtained crude product was prepared by reverse-phase HPLC (chromatographic column: Ultimate XB-C18, 50*250mm, 10um (PARP-02); mobile phase: acetonitrile-water (0.1% carbonic acid ammonium hydrogen); flow rate: 70mL/min; column temperature: 25°C) to obtain 7-[dimethyl(oxygenide)- ⁇ 5-methylphosphoryl]-3-(2- ⁇ [(1S)-3- (4-Fluoro-2,7-diazaoct-2-yl)cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (190mg , Yield 74%), white solid.
  • LCMS m/z (m/z)
  • Step five to 7-[dimethyl (oxygenidene)- ⁇ 5 -methylphosphoryl]-3-(2- ⁇ [(1S)-3-(4-fluoro-2,7-diazapine -2-yl)cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxylic acid (100mg, 0.17mmol) of N,N-dimethylformaldehyde Add N,N-diisopropylethylamine (172mg, 1.33mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (254mg, 0.67mmol), the reaction solution was stirred at 60°C for 14 hours.
  • (4 1 S)-1 7 - (dimethylphosphoryl)-7-fluoro-5,10-dimethyl-2 5 -(trifluoromethyl)-1 1 H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina -4(1,3)-cyclopentanacycloundecaphan-11-one) (Z90, 15.0 mg; yield 15.18%).
  • Step 1 In a 25mL microwave tube, add 6-chloro-1H-pyrrolo[2,3-b]pyridine (1.0g, 6.55mmol), N-methylpyrrolidone (15mL), zinc cyanide (0.77g , 6.55mmol), tetrakis(triphenylphosphine)palladium (0.76g, 0.66mmol) and zinc powder (0.21g, 3.28mmol), and microwaved at 150°C for 6 hours.
  • Step 2 Add N-iodosuccinyl to a solution of 1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (1.20g, 8.38mmol) in N,N dimethylformamide (25mL) Imine (2.26 g, 10.1 mmol). Stir at 45°C for 2 hours under nitrogen protection. After the reaction was complete as detected by LCMS, the reaction solution was added with water (50 mL), extracted with ethyl acetate (50 mL ⁇ 3), the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration.
  • Step 3 Add triethylamine (1.76g , 17.4mmol), 4-dimethylaminopyridine (0.17g, 1.39mmol) and di-tert-butyl dicarbonate (2.28g, 10.4mmol). Stir at room temperature for 14 hours. After the completion of the reaction was detected by LCMS, water (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (50 mL ⁇ 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration.
  • Step 4 Add 6-cyano-3-iodopyrrolo[2,3-b]pyridine-1-carboxylic acid-2-methylpropan-2-yl ester (1.90g, 5.15mmol ), tris(dibenzylideneacetone)dipalladium (470mg, 0.515mmol), tetrahydrofuran (20mL), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (242mg, 0.515 mmol), triethylamine (1.56 g, 15.4 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.98 g, 15.4 mmol).
  • Step five 6-cyano-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrrolo[2,3 -b]
  • pyridine-1-carboxylic acid-2-methylpropan-2-yl ester (1.30g, 3.52mmol) in tetrahydrofuran (13mL)
  • ⁇ [(1S,3S)-3- ⁇ [4-chloro -5-(trifluoromethyl)pyrimidin-2-yl]amino ⁇ cyclopentyl]amino ⁇ methanoic acid-2-methylpropan-2-yl ester (1.34g, 3.52mmol)
  • Step 6 To 6-cyano-3-(2- ⁇ [(1S,3S)-3-( ⁇ [(2-methylpropan-2-yl)oxy]carbonyl ⁇ amino)cyclopentyl at room temperature ]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)pyrrolo[2,3-b]pyridine-1-carboxylic acid-2-methylprop-2-yl ester (700mg, 1.20mmol) Trifluoroacetic acid (2 mL) was added to the dichloromethane (10 mL) solution, and the reaction solution was reacted at 25° C. for 2 hours.
  • Step 7 To 6-cyano-3-(2- ⁇ [(1S,3S)-3-aminocyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)pyrrolo [2,3-b]Pyridine-1-carboxylic acid-2-methylpropan-2-yl ester (300mg, 0.774mmol) in N-methylpyrrolidone (5mL) was added successively (1-iodo-6-nitro Hetero-3-oxahept-6-yl)-2-methylpropan-2-yl methane (255mg, 0.77mmol) and N,N-diisopropylethylamine (0.384mL, 2.32mmol), The reaction was stirred at 80°C for 16 hours.
  • Step 8 To (1- ⁇ [(1S,3S)-3- ⁇ [4-(6-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-( Trifluoromethyl)pyrimidin-2-yl]amino ⁇ cyclopentyl]amino ⁇ -6-aza-3-oxahept-6-yl)methanoic acid-2-methylpropan-2-yl ester (130mg , 0.221mmol) in methanol (5mL), add paraformaldehyde (100mg, 1.11mmol), acetic acid (0.1mL), 4A molecular sieves (130mg), and stir at 25°C for 2 hours under nitrogen protection.
  • Step 9 Adding ⁇ 8-[(1S,3S)-3- ⁇ [4-(6-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(tri Fluoromethyl)pyrimidin-2-yl]amino ⁇ cyclopentyl]-2,8-diaza-5-oxanon-2-yl ⁇ methanoic acid-2-methylpropan-2-yl ester (100mg ,0.167mmol) of acetic acid (4mL) was added concentrated hydrochloric acid (2mL), and the reaction solution was stirred at 120°C for 16 hours.
  • Step 10 To 3-(2- ⁇ [(1S,3S)-3-(2,8-diaza-5-oxanon-2-yl)cyclopentyl]amino ⁇ -5-(trifluoro Methyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (15mg, 0.029mmol) in N,N-dimethylformamide (3mL) solution, add in sequence N,N-Diisopropylethylamine (0.048mL, 0.29mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (54.7mg, 0.144mmol), the reaction solution was stirred at 60°C for 4h.
  • Step 1 At room temperature, 3-(2- ⁇ [(1S,3S)-3-aminocyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[ 2,3-b]pyridine-6-carbonitrile (220mg, 0.57mmol) in N-methylpyrrolidone (5mL), add [(4-iodobutyl)(methyl)amino]methane acid-2- Methylpropan-2-yl ester (178 mg, 0.57 mmol) and N,N-diisopropylethylamine (147 mg, 1.14 mmol).
  • Step 2 At room temperature, to [(4- ⁇ [(1S,3S)-3- ⁇ [4-(6-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-5 -(trifluoromethyl)pyrimidin-2-yl]amino ⁇ cyclopentyl]amino ⁇ butyl)(methyl)amino]methanoic acid-2-methylpropan-2-yl ester (120mg, 0.21mmol) To methanol (6 mL) solution, paraformaldehyde (94.0 mg, 1.05 mmol), acetic acid (30.0 mg), 4A molecular sieves (120 mg) were added, and the reaction was stirred at 25° C. for 2.0 hours under nitrogen protection.
  • Step 3 At room temperature, to ⁇ 7-[(1S,3S)-3- ⁇ [4-(6-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-5- (Trifluoromethyl)pyrimidin-2-yl]amino ⁇ cyclopentyl]-2,7-diazaoct-2-yl ⁇ methanoic acid-2-methylpropan-2-yl ester (110mg, 0.19mmol ) in acetic acid (4 mL) was added concentrated hydrochloric acid (2 mL), and stirred at 120°C for 14 hours.
  • Step 4 To 3-(2- ⁇ [(1S,3S)-3- ⁇ [4-(methylamino)butyl]amino ⁇ cyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidine- 4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (40.0mg, 0.08mmol) in N,N-dimethylformamide (5mL) solution, add N,N- Diisopropylethylamine (51.0mg, 0.40mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (36.0mg, 0.10 mmol), and the reaction solution was stirred at 60° C.
  • Step 1 At room temperature, to 6-cyano-3-(2- ⁇ [(1S,3S)-3-aminocyclopentyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)pyrrole And[2,3-b]pyridine-1-carboxylic acid-2-methylpropan-2-yl ester (2.0g, 5.16mmol) in N-methylpyrrolidone (20mL) solution, add 4-methylbenzene Sulfonic acid-7,7-difluoro-2,2,5-trimethyl-4-oxylidene-5-aza-3-oxanon-9-yl ester (2.44g, 6.20mmol), iodine Sodium chloride (0.15g, 1.03mmol) and N,N-diisopropylethylamine (2.56mL, 15.49mmol), the reaction was stirred at 80°C for 16 hours.
  • Step 2 At room temperature, to [(2,2-difluoro-4- ⁇ [(1S,3S)-3- ⁇ [4-(6-cyano-1H-pyrrolo[2,3-b]pyridine -3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino ⁇ cyclopentyl]amino ⁇ butyl)(methyl)amino]methanoate-2-methylpropan-2-yl ester (480mg, 0.789mmol) in methanol (5mL), add paraformaldehyde (118mg, 3.95mmol), acetic acid (0.1mL), 4A molecular sieves (480mg), and react under nitrogen protection at 25°C and stir for 2.0 hours.
  • paraformaldehyde 118mg, 3.95mmol
  • acetic acid 0.1mL
  • 4A molecular sieves 480mg
  • Step 3 At room temperature, to ⁇ 7-[(1S,3S)-3- ⁇ [4-(6-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-5- (Trifluoromethyl)pyrimidin-2-yl]amino ⁇ cyclopentyl]-4,4-difluoro-2,7-diazaoct-2-yl ⁇ methanoic acid-2-methylpropan-2- Concentrated hydrochloric acid (1 mL) was added to a solution of base ester (330 mg, 0.53 mmol) in acetic acid (2 mL), and the reaction solution was stirred at 120°C for 5 hours.
  • Step 4 To 3-(2- ⁇ [(1S,3S)-3-(5,5-difluoro-2,7-diazaoctyl-2-yl)cyclopentyl]amino ⁇ -5-( Trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (100mg, 0.19mmol) in N,N-dimethylformamide (2mL) solution, Add N,N-diisopropylethylamine (0.15mL, 0.92mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluoro Phosphate ester (280mg, 0.74mmol), the reaction solution was stirred at 60°C for 16 hours.
  • Test Example 1 In vitro inhibition experiment of CDK kinase activity
  • CDK2/Cyclin E1 was purchased from Byator; batch number: 20150228-BP469/477/691; CDK7/Cyclin H/MAT1 was purchased from Biotel; batch number: 20190326-BP487/492/479; CDK9/Cyclin T1 was purchased from Biotel Obtained; batch number: 20200727-BP488/792/691; CDK12/Cyclin K was purchased from Biotech; batch number: 20200526-BP1642/1648/691; MES was purchased from BioRoYee; batch number: 67GR9637; BSA was purchased from Aladdin ; Batch number: H1601024; ATP was purchased from VWR; Batch number: 97061-226; EDTA was purchased from Sinopharm Group; Batch number: 20200521;
  • This experiment is used to determine the inhibitory effect of compounds on the kinase activity of CDK2, CDK7, CDK9 and CDK12.
  • the kinase reaction carried out in the present invention is assayed in a 384-well plate, the final assay volume is 16 ⁇ l, and the reaction temperature is 27°C.
  • Kinase concentrations were determined by optimization experiments.
  • the specific experimental process is as follows:
  • Kinase solution (CDK2/Cyclin E1): Kinase was diluted in assay buffer (20 mM MES pH 6.75, 0.01% Tween 20, 0.05 mg/mL BSA, 2 mM MgCl 2 ) to obtain a corresponding 2.4 ⁇ concentration enzyme solution.
  • Kinase solution (CDK7/Cyclin H/MAT1): Kinase was diluted in assay buffer (20 mM MES pH 6.75, 0.01% Tween 20, 0.05 mg/mL BSA, 6 mM MgCl 2 ) to obtain a corresponding 2.4 ⁇ concentration enzyme solution.
  • Kinase solution (CDK9/Cyclin T1): Kinase was diluted in assay buffer (20 mM MES pH 6.75, 0.01% Tween 20, 0.05 mg/mL BSA, 10 mM MgCl 2 ) to obtain a corresponding 2.4 ⁇ concentration enzyme solution.
  • Kinase solution (CDK12/Cyclin K): Kinase was diluted in assay buffer (80 mM MES pH 6.5, 0.01% Tween 20, 0.05 mg/mL BSA, 10 mM MgCl 2 ) to obtain a corresponding 2.4 ⁇ concentration enzyme solution.
  • Compound solution configuration the compound was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10 mM. When used, the compound was diluted with DMSO to 10 concentration gradients from 25 nM to 500 ⁇ M, and diluted 8.3 times in ultrapure water to obtain Compound solution at 6X concentration.
  • DMSO dimethyl sulfoxide
  • Polypeptide substrate and ATP solution configuration The polypeptide substrate and ATP were diluted in the assay buffer to obtain a mixed solution of the polypeptide substrate and ATP at a concentration of 2.4 ⁇ .
  • ATP 100 ⁇ M
  • polypeptide substrate 5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK
  • CDK2/Cyclin E1 0.5 nM
  • ATP is 50 ⁇ M
  • polypeptide substrate (5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK) is 2 ⁇ M
  • CDK7/Cyclin H/MAT1 is 3 nM;
  • ATP 50 ⁇ M
  • peptide substrate FITC-Ahx-GSRTPMY-NH2
  • CDK9/Cyclin T1 8 nM
  • the CDK7 kinase activity inhibition of the compound of the present invention has reached the lower limit of the experiment, and the IC50 cannot accurately reflect the kinase activity inhibitory ability of the compound.
  • SPR surface plasmon resonance
  • CDK7/Cyclin H was purchased from Biotel; lot number: 20200309-BP487/492; MES buffer was purchased from BioRoYee; lot number: 67GR9637; CM5 sensor chip was purchased from Cytiva; lot number: 10305527; HEPES buffer was purchased from Cytiva; 32349.
  • CDK7/Cyclin H dimer at a concentration of 50 ⁇ g/mL was amino-coupled to the CM5 sensor chip at a flow rate of 5 ⁇ L/min.
  • the target protein is immobilized on the chip channel within 600 seconds, and generally reaches 7000-10000 response values.
  • Compounds were serially diluted 2-fold in 5 steps to a concentration range of 0.6-10 nM in 10 mM HEPES buffer pH 7.4 with 150 mM NaCl, 0.05% surfactant P20 and 2% DMSO. Each compound concentration cycle was run at 100 ⁇ L/min, 180 s contact time and 1800 s dissociation time.
  • K D (M) k off (s ⁇ 1 )/K on (M ⁇ 1 s ⁇ 1 ); wherein, K on (ka) is the association rate; K off (kd) is the dissociation rate; s ⁇ 1 ( per second) and M -1 s -1 (per mole per second) are the units of k off and k on .
  • Table 2 The results of some example compounds are shown in Table 2.
  • HCC70 was purchased from ATCC; Product No.: CRL-2315; RPMI1640 was purchased from Gibco; Product No.: 11875-093; Pancreatin (with EDTA) was purchased from Gibco; -Glo was purchased from Promega; article number: G7573; DMSO was purchased from VWR AMRESCO; article number: 0231-500ML; Staurosporine was purchased from Selleck; article number: S1421; ;Model: Envison.
  • HCC70 is human breast ductal carcinoma cell cultured in RPMI-1640 medium containing 10% FBS. The cells in the logarithmic growth phase were taken, digested with trypsin-EDTA, collected and counted, and seeded 2000 HCC70 cells/well in a 384-well cell plate, and cultured overnight in 5% CO 2 .
  • the cell group treated with DMSO was used as the experimental control (control), and the cell group treated with 5 ⁇ M Staurosporine was used as the blank control (blank).
  • control the experimental control
  • 5 ⁇ M Staurosporine was used as the blank control (blank).
  • the results show that the compound of the present invention has a strong inhibitory effect on the proliferation of HCC70 human breast ductal carcinoma cells.
  • the IC 50 of some compounds is lower than 1000nM or 500nM; even lower than 100nM or 50nM.
  • the results of some exemplary compounds are shown in Table 3 below.
  • OVCAR-3 was purchased from ATCC; Product No.: HTB-161; RPMI1640 was purchased from Gibco; Product No.: 11875-093; Pancreatin (with EDTA) was purchased from Gibco; ; CellTiter-Glo was purchased from Promega; Product No.: G7573; Bovine insulin was purchased from absin; Product No.: abs9169; DMSO was purchased from VWR AMRESCO; Model: NC-200; microplate reader purchased from PerkinElmer; model: Envison.
  • OVCAR-3 is a human ovarian adenocarcinoma cell cultured in RPMI-1640 medium containing 20% FBS and 0.01mg/mL Bovine insulin.
  • the cells in the logarithmic growth phase were taken, digested with trypsin-EDTA, collected and counted, and seeded 2000 OVCAR-3 cells/well in a 384-well cell plate, and cultured overnight in 5% CO 2 .
  • Use DMSO to prepare 1000X compound stock solution with 3.16 times gradient concentration, dilute 100 times to 10X compound stock solution with medium, add 10X compound stock solution to each cell culture well on the second day after cell seeding, and the final concentration is 1X with 0.1% DMSO.
  • the cell group treated with DMSO was used as the experimental control (control), and the cell group treated with 5 ⁇ M Staurosporine was used as the blank control (blank).
  • control the experimental control
  • 5 ⁇ M Staurosporine was used as the blank control (blank).
  • the IC 50 of some compounds is lower than 1000nM or 500nM; even lower than 100nM or 50nM.
  • the results of some exemplary compounds are shown in Table 4 below.
  • Test Example 5 In vivo pharmacokinetic experiment of the compound of the present invention
  • mice male Beagle dogs, 8-11kg, were purchased from Jiangsu Masi Biotechnology Co., Ltd. Three dogs were given intravenous injection of 0.2 mg/kg or 1.0 mg/kg of the compound to be tested (solvent: 2% DMSO+10% Kolliphor HS 15+88% (6.818% hydroxypropyl- ⁇ -cyclodextrin aqueous solution), 0.2mg/mL or 1.0mg/mL) and 3 dogs were given oral administration of 2mg/kg (solvent: 5% DMSO+95% (10% hydroxypropyl- ⁇ -cyclodextrin saline solution), 0.4mg/ mL).

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Abstract

一种嘧啶杂环化合物，其制法与医药上的用途。具体地，结构如式（A）所示的嘧啶杂环化合物或其药学上可接受的盐，各基团定义如说明书中所定义；包含所述化合物的药物组合物以及所述化合物在治疗细胞增殖性疾病（例如癌症）等中的用途。

Description

嘧啶杂环化合物，其制法与医药上的用途
本发明要求申请日为2021年12月22日的中国专利申请CN202111583828.0的优先权、申请日为2022年01月27日中国专利申请CN202210098381.6的优先权、申请日为2022年05月23日的中国专利申请CN202210562007.7的优先权、申请日为2022年12月07日的中国专利申请CN202211568373.X的优先权。本申请引用上述中国专利申请的部分或者全部。
技术领域
本发明属于医药领域，具体涉及嘧啶杂环化合物，其制法与医药上的用途。
背景技术
细胞周期蛋白依赖性激酶(CDK)/周期蛋白复合物被鉴定为RNA聚合酶II转录机制的保守组分。目前存在20种哺乳动物CDK。在哺乳动物CDK中，CDK7具有坚实的激酶活性，且仅有CDK7具有调控细胞周期进程和转录的双重功能。在胞质溶胶中，CDK7作为异源三聚体复合物存在并且被认为起着CDK1/2/4/6激活激酶(CAK)的作用，由此CDK7对CDK1/2/4/6中的保守残基的磷酸化是完全催化性CDK活性和细胞周期进程所必需的。在细胞核中，CDK7形成RNA聚合酶II转录因子复合物的激酶核心，并且负责磷酸化RNA聚合酶II的C-末端结构域(CTD)，这是基因转录起始的必要步骤。CDK7的两个功能(即CAK和CTD磷酸化)一起支持细胞增殖、细胞周期和转录的关键方面。
CDK7作为总体转录的调控因子，可作为治疗许多疾病和综合症的治疗性靶点。CDK7可在转录调控区中和多个转录因子、辅因子、染色质调控因子以及非编码RNA中的相互作用以调控转录。而这些转录因子、辅因子、染色质调控物或非编码RNA的突变可以导致癌症、自身免疫病、神经系统障碍、发育综合症、糖尿病、心血管疾病和肥胖症等疾病。其中一些转录因子可控制RNA聚合酶II介导的转录起始和延伸，并且当它们的表达或功能改变时，可以产生侵袭性肿瘤细胞(例如c-Myc引起的)或某些形式的自身免疫性(例如AIRE引起的)。因此，CDK7激酶可通过调控总体转录过程来促进与肿瘤相关的某些转录因子的异常表达，以及通过调控细胞周期关键激酶的磷酸化以促进肿瘤发展。更重要的是，与癌细胞中其他管家基因相比，CDK7更显著地调控致癌转录因子的表达。CDK7的抑制可以差异性影响某些癌基因和管家基因的转录，因此可以确保治疗窗口。通过调控CDK7介导的磷酸化修饰来进行转录调控和细胞周期调控，可用于治疗包括癌症在内的增殖异常疾病。作为转录的总体调控因子，CDK7也可作为治疗疾病如炎症、病毒复制例如HIV、EBV、癌症和心脏肥大的治疗靶点。
CDK家族成员激酶结构域的高度序列和结构相似性阻碍了CDK7选择性抑制剂的发现。因此，开发选择性CDK7抑制剂，对于临床应用有重要价值。
发明内容
本发明第一方面提供了式(A)所示的化合物或其药学上可接受的盐；
Figure PCTCN2022140669-appb-000001
其中，
Figure PCTCN2022140669-appb-000002
为
Figure PCTCN2022140669-appb-000003
环A为无；或环A选自下组：3至14元碳环、3至14元杂环、5至12元杂芳基、C 5-12芳基；环A为未取代的或被1、2、3、4或5个选自S1组的基团所取代；所述3至14元杂环具有1、2、3或4个独立地选自氮、氧和硫的杂原子；所述5至12元杂芳基具有1、2、3或4个独立地选自氮、氧和硫的杂原子；
L 3为无、C 1-6亚烷基、C 2-6亚烯基或环B(结构为
Figure PCTCN2022140669-appb-000004
)；其中，所述C 1-6亚烷基上的1、2、3、4或5个氢原子可以任选地各自独立地被R 13取代；所述C 2-6亚烯基上的1、2、3、4或5个氢原子可以任选地各自独立地被R 13取代；
环B选自下组：3至14元碳环、3至14元杂环、5至12元杂芳基、C 5-12芳基；环B为未取代的或被1、2、3、4或5个选自S1组的基团所取代；所述3至14元杂环具有1、2、3或4个独立地选自氮、氧和硫的杂原子；所述5至12元杂芳基具有1、2、3或4个独立地选自氮、氧和硫的杂原子；
L 1为无、C 1-6亚烷基、C 2-6亚烯基、-O-、-NR 10-、-C＝N-、C 5-12芳基、5至12元杂芳基、-C(O)-、-C(O)-NR 10-或-NR 10-C(O)-；其中，所述C 1-6亚烷基上的1、2、3、4或5个氢原子可以任选地各自独立地被R 13取代；所述C 2-6亚烯基上的1、2、3、4或5个氢原子可以任选地各自独立地被R 13取代；所述5至12元杂芳基具有1、2、3或4个独立地选自氮、氧和硫的杂原子；所述C 5-12芳基、5至12元杂芳基各自独立地为未取代的或被1、2、3、4或5个选自S1组的基团所取代；
L 2选自下组：
-(O) m2-(CR 13R 14) m1-(NR 12) m3-、
-(NR 11) m2-(CR 13R 14) m1-(NR 12) m3-、
-(O) m2-(CR 13R 14) m5-(3至7元碳环基) m4-(CR 13R 14) m6-(NR 12) m3-、
-(NR 11) m2-(CR 13R 14) m5-(3至7元碳环基) m4-(CR 13R 14) m6-(NR 12) m3-、
-(O) m2-(CR 13R 14) m5-(3至7元杂环基) m4-(CR 13R 14) m6-(NR 12) m3-、
-(NR 11) m2-(CR 13R 14) m5-(3至7元杂环基) m4-(CR 13R 14) m6-(NR 12) m3-、
-(O) m2-(CR 13R 14) m5-NR 10-(CR 13R 14) m6-(NR 12) m3-、
-(NR 11) m2-(CR 13R 14) m5-NR 10-(CR 13R 14) m6-(NR 12) m3-、
-(O) m2-(CR 13R 14) m5-NR 10C(O)-(CR 13R 14) m6-(NR 12) m3-、
-(NR 11) m2-(CR 13R 14) m5-NR 10C(O)-(CR 13R 14) m6-(NR 12) m3-、
-(O) m2-(CR 13R 14) m5-C(O)NR 10-(CR 13R 14) m6-(NR 12) m3-、
-(NR 11) m2-(CR 13R 14) m5-C(O)NR 10-(CR 13R 14) m6-(NR 12) m3-、
-(O) m2-(CR 13R 14) m5-O-(CR 13R 14) m6-(NR 12) m3-、
-(NR 11) m2-(CR 13R 14) m5-O-(CR 13R 14) m6-(NR 12) m3-、
-(O) m2-(CR 13R 14) m5-OC(O)-(CR 13R 14) m6-(NR 12) m3-、
-(NR 11) m2-(CR 13R 14) m5-OC(O)-(CR 13R 14) m6-(NR 12) m3-、
-(O) m2-(CR 13R 14) m5-C(O)O-(CR 13R 14) m6-(NR 12) m3-、
-(NR 11) m2-(CR 13R 14) m5-C(O)O-(CR 13R 14) m6-(NR 12) m3-、
-(O) m2-(CR 13R 14) m5-(CH＝CH) m7-(CR 13R 14) m6-(NR 12) m3-、
-(NR 11) m2-(CR 13R 14) m5-(CH＝CH) m7-(CR 13R 14) m6-(NR 12) m3-；
各个R 10各自独立地氢、C 1-6烷基、氘代C 1-6烷基、-3至7元碳环基、-C(O)-C 1-6烷基、-C(O)-C 1-4烷基-C 1-6烷氧基、-C(O)-3至7元碳环基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-NHC(O)-C 1-6烷基、-C 1-4烷基-NHC(O)-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-NHC(O)-3至7元碳环基或-C 1-4烷基-NRR’；
各个3至7元杂环基各自独立地具有1、2或3个独立地选自氮、氧和硫的杂原子；所述3至7元碳环各自独立地为未取代的或被1、2、3、4或5个选自S1组的基团所取代；
各个3至7元碳环基各自独立地为未取代的或被1、2、3、4或5个选自S1组的基团所取代；
各个R 11各自独立地为氢、C 1-6烷基或氘代C 1-6烷基；
各个R 12各自独立地为氢、C 1-6烷基或氘代C 1-6烷基；
各个R 13各自独立地为氢、氰基、羟基、卤素、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、-3至7元碳环基、-C 0-6亚烷基-NRR’、-C 1-6亚烷基-羟基或-C 0-6亚烷基-氰基；
各个R 14各自独立地为氢、氰基、羟基、卤素、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、-3至7元碳环基、-C 0-6亚烷基-NRR’、-C 1-6亚烷基-羟基或-C 0-6亚烷基-氰基；
各个m1各自独立地为1、2、3、4、5或6；
各个m2各自独立地为0或1；
各个m3各自独立地为0或1；
各个m4各自独立地为1或2；
各个m5各自独立地为0、1、2、3、4、5或6；
各个m6各自独立地为0、1、2、3、4、5或6；
各个m7各自独立地为1或2；
R 1为氢、卤素、氰基、C 1-6烷基或3至14元碳环基；所述C 1-6烷基、3至14元碳环基独立地为未取代的或被1、2、3、4或5个选自下组的基团所取代：氧代、羟基、卤素、C 1-6烷基、卤代C 1-6烷基；
R 2为氢、卤素、氰基、C 1-6烷基或3至14元碳环基；所述C 1-6烷基、3至14元碳环基独立地为未取代的或被1、2、3、4或5个选自下组的基团所取代：氧代、羟基、卤素、C 1-6烷基、卤代C 1-6烷基；
X 2为N或C(R 3)；
X 1为N或C(R 4)；
Y为N或C(R 4)；
Z为N或C(R 3)；
各个R 3独立地为氢、卤素、氰基、C 1-6烷基或卤代C 1-6烷基；
各个R 4独立地为氢、卤素、羟基、氰基、-C 2-4亚烯基-苯基、-C 2-4亚炔基-苯基、-S(O)-OH、-S(O) 2-OH、-S-(C 1-6烷基)、C 1-6烷基、-O-C 1-6烷基、-C 1-6亚烷基-O-C 1-6烷基、-O-C 1-6亚烷基-O-C 1-6烷基、-C 0-6亚烷基-NRR’、-C 0-6亚烷基-C(O)OH、-C 0-6亚烷基-C(O)-C 1-6烷基、-C 0-6亚烷基-C(O)-NRR’、-C 0-6亚烷基-NR-C(O)-C 1-6烷基、-C 0-6亚烷基-S(O) 2-C 1-6烷基、-C 0-6亚烷基-S(O) 2-NRR’、-C 0-6亚烷基-NR-S(O) 2-C 1-6烷基、-C 0-6亚烷基-NR-S(O) 2-NRR’、-C 0-6亚烷基-P(O)O-(C 1-6烷基) 2、-C 0-6亚烷基-P(O)-(C 1-6烷基)(O-C 1-6烷基)、-C 0-6亚烷基-P(O)-(C 1-6烷基) 2、-C 0-6亚烷基-3至14元碳环基、-C 0-6亚烷基-3至14元杂环基、-C 0-6亚烷基-5至12元杂芳基、-C 0-6亚烷基-C 5-12芳基、-C 0-6亚烷基-C(O)-3至14元杂环基、-C 0-6亚烷基-C(O)-5至12元杂芳基、-O-C 0-6亚烷基-O-C 1-6烷基、-O-C 0-6亚烷基-3至14元碳环基、-O-C 0-6亚烷基-3至14元杂环基、-O-C 0-6亚烷基-5至12元杂芳基、-O-C 0-6亚烷基-C 5-12芳基、-S(O)-C 1-6烷基；其中，所述C 1-6烷基、C 0-6亚烷基、C 2-4亚烯基、3至14元碳环基、3至14元杂环基、5至12元杂芳基、C 5-12芳基独立地为未取代的或被1、2、3、4或5个选自S1组的基团所取代；所述3至14元杂环具有1、2、3或4个独立地选自氮、氧和硫的杂原子；所述5至12元杂芳基具有1、2、3或4个独立地选自氮、氧和硫的杂原子；
所述S1组的基团包括：氧代、卤素、羟基、氰基、C 1-6烷基、-O-C 1-6烷基、-C 1-6亚烷基-O-C 1-6烷基、-O-C 1-6亚烷基-O-C 1-6烷基、-C 0-6亚烷基-NRR’、-C 0-6亚烷基-C(O)OH、-C 0-6亚烷基-C(O)-C 1-6烷基、-C 0-6亚烷基-C(O)-NRR’、-C 0-6亚烷基-NR-C(O)-C 1-6烷基、-C 0-6亚烷基-S(O) 2-C 1-6烷基、-C 0-6亚烷基-S(O) 2-NRR’、-C 0-6亚烷基-NR-S(O) 2-C 1-6烷基、-C 0-6亚烷基-NR-S(O) 2-NRR’、-C 0-6亚烷基-P(O)O-(C 1-6烷基) 2、-C 0-6亚烷基-P(O)-(C 1-6烷基)(O-C 1-6烷基)、-C 0-6亚烷基-P(O)-(C 1-6烷基) 2、-C 0-6亚烷基-3至14元碳环基、-C 0-6亚烷基-3至14元杂环基、-C 0-6亚烷基-5至12元杂芳基、-C 0-6亚烷基-C 5-12芳基、-C 0-6亚烷基-C(O)-3至14元杂环基、-C 0-6亚烷基-C(O)-5至12元杂芳基、-O-C 0-6亚烷基-O-C 1-6烷基、-O-C 0-6亚烷基-3至14元碳环基、-O-C 0-6亚烷基-3至14元杂环基、-O-C 0-6亚烷基-5至12元杂芳基、-O-C 0-6亚烷基-C 5-12芳基、-S(O)-C 1-6烷基；
R、R’各自独立地为氢、C 1-6烷基或氘代C 1-6烷基；或者R、R’任选与和它们相连的氮原子共同构成3至14元杂环基或5至12元杂芳基；其中，所述杂环基、杂芳基各自独立地除了已有的氮原子外还包含0、1或2个选自N、O、S的杂原子；
上述各基团中，所述C 0-6亚烷基上任意同一个碳原子上的2个氢原子还可以任选地同时被3至7元碳环或3至7元杂环螺环取代；
上述各基团中，所述C 1-6亚烷基上任意同一个碳原子上的2个氢原子还可以任选地同时被3至7元碳环或3至7元杂环螺环取代。
在一些实施方案中，R 1为氢、卤素、氰基、C 1-4烷基或3至7元碳环基；所述C 1-4烷基、3至7元碳环基独立地为未取代的或被1、2、3、4或5个选自下组的基团所取代：氧代、羟基、卤素、C 1-3烷基、卤代C 1-3烷基。
在一些实施方案中，R 1为氢、卤素、氰基、C 1-4烷基(例如甲基)、卤代C 1-4烷基(例如三氟甲基)、3至7元碳环基或卤代3至7元碳环基。
在一些实施方案中，R 2为氢、卤素、氰基、C 1-4烷基或3至7元碳环基；所述C 1-4烷基、3至7元碳环基独立地为未取代的或被1、2、3、4或5个选自下组的基团所取代：氧代、羟基、卤素、C 1-3烷基、卤代C 1-3烷基。
在一些实施方案中，R 2为氢、卤素、氰基、C 1-4烷基(例如甲基)、卤代C 1-4烷基(例如三氟甲基)、3至7元碳环基或卤代3至7元碳环基。
在一些实施方案中，X 1为N。
在一些实施方案中，X 1为C(R 4)；其中，R 4为氢、卤素、羟基、氰基、-C 2-4亚烯基-苯基、-C 2-4亚炔基-苯基、-S(O)-OH、-S(O) 2-OH、-S-(C 1-6烷基)或R 8；R 8为C 1-6烷基、-O-C 1-6烷基、-C 1-6亚烷基-O-C 1-6烷基、-O-C 1-6亚烷基-O-C 1-6烷基、-C 0-6亚烷基-NRR’、-C 0-6亚烷基-C(O)OH、-C 0-6亚烷基-C(O)-C 1-6烷基、-C 0-6亚烷基-C(O)-NRR’、-C 0-6亚烷基-NR-C(O)-C 1-6烷基、-C 0-6亚烷基-S(O) 2-C 1-6烷基、-C 0-6亚烷基-S(O) 2-NRR’、-C 0-6亚烷基-NR-S(O) 2-C 1-6烷基、-C 0-6亚烷基-NR-S(O) 2-NRR’、-C 0-6亚烷基-P(O)O-(C 1-6烷基) 2、-C 0-6亚烷基-P(O)-(C 1-6烷基)(O-C 1-6烷基)、-C 0-6亚烷基-P(O)-(C 1-6烷基) 2、-C 0-6亚烷基-3至14元碳环基、-C 0-6亚烷基-3至14元杂环基、-C 0-6亚烷基-5至12元杂芳基、-C 0-6亚烷基-C 5-12芳基、-C 0-6亚烷基-C(O)-3至14元杂环基、-C 0-6亚烷基-C(O)-5至12元杂芳基、-O-C 0-6亚烷基-O-C 1-6烷基、-O-C 0-6亚烷基-3至14元碳环基、-O-C 0-6亚烷基-3至14元杂环基、-O-C 0-6亚烷基-5至12元杂芳基、-O-C 0-6亚烷基-C 5-12芳基、-S(O)-C 1-6烷基；其中，所述C 1-6烷基、C 0-6亚烷基、C 2-4亚烯基、3至14元碳环基、3至14元杂环基、5至12元杂芳基、C 5-12芳基独立地为未取代的或被1、2、3、4或5个选自S1组的基团所取代；所述3至14元杂环具有1、2、3或4个独立地选自氮、氧和硫的杂原子；所述5至12元杂芳基具有1、2、3或4个独立地选自氮、氧和硫的杂原子；R、R’、S1组的基团定义同前。
在一些实施方案中，X 1为C(R 4)；其中，R 4为-C 0-6亚烷基-NRR’、-C 0-6亚烷基-C(O)OH、-C 0-6亚烷基-C(O)-C 1-6烷基、-C 0-6亚烷基-C(O)-NRR’、-C 0-6亚烷基-NR-C(O)-C 1-6烷基、-C 0-6亚烷基-S(O) 2-C 1-6烷基、-C 0-6亚烷基-S(O) 2-NRR’、-C 0-6亚烷基-NR-S(O) 2-C 1-6烷基、-C 0-6亚烷基-NR-S(O) 2-NRR’、-C 0-6亚烷基-P(O)O-(C 1-6烷基) 2、-C 0-6亚烷基-P(O)-(C 1-6烷基)(O-C 1-6烷基)或-C 0-6亚烷基-P(O)-(C 1-6烷基) 2；其中，所述C 1-6烷基、C 0-6亚烷基独立地为未取代的或被1、2、3、4或5个选自S1组的基团所取代；R、R’、S1组的基团定义同前。
在一些实施方案中，X 1为C(R 4)；其中，R 4为-C 0-6亚烷基-P(O)O-(C 1-6烷基) 2、-C 0-6亚烷基-P(O)-(C 1-6烷基)(O-C 1-6烷基)或-C 0-6亚烷基-P(O)-(C 1-6烷基) 2；其中，所述C 1-6烷基、C 0-6亚烷基独立地为未取代的或被1、2、3、4或5个选自S1组的基团所取代；S1组的基团定义同前。
在一些实施方案中，X 1为C(R 4)；其中，R 4为-P(O)O-(C 1-6烷基) 2、-P(O)-(C 1-6烷基)(O-C 1-6烷基)或-P(O)-(C 1-6烷基) 2；其中，所述C 1-6烷基独立地为未取代的或被1、2、3、4或5个选自S1组的基团所取代；S1组的基团定义同前。
在一些实施方案中，X 1为C(R 4)；其中，R 4为氢、卤素或氰基。
在一些实施方案中，X 1为C(R 4)；其中，R 4为-P(O)O-(CH 3) 2、-P(O)-(CH 3)(O-CH 3)或-P(O)-(CH 3) 2。
在一些实施方案中，X 2为C(R 3)；R 3为氢。
在一些实施方案中，Y为C(R 4)；R 4为氢。
在一些实施方案中，Z为C(R 3)；R 3为氢。
如本文提及的，C 0-6亚烷基上或C 0-6亚烷基上，同一个碳原子上的2个氢原子同时被3至7元碳环或3至7元杂环螺环取代，是指该碳原子上的2个氢原子被二价形式的取代基取代后，该二价形式的取代基与该碳原子共同形成3至7元碳环或3至7元杂环。例如，-CH 2-上碳原子上的2个氢原子被环丙基环螺环取代，是指-CH 2-上碳原子上的2个氢原子被二价形式的乙基(即亚乙基)取代后，该亚乙基与该碳原子共同形成环丙基。以此类推。
在一些实施方案中，
所述式(A)化合物为式(I-A)化合物；
Figure PCTCN2022140669-appb-000005
式中，X 1、Y、Z、X 2、R 1、R 2、L 1、L 2、环A、环B各自定义同前；
或
所述式(A)化合物为式(I-B)化合物；
Figure PCTCN2022140669-appb-000006
式中，X 1、Y、Z、X 2、R 1、R 2、L 1、L 2、环A、R 13、R 14各自定义同前；m0为1、2、3、4、5或6；
或
所述式(A)化合物为式(A1)化合物；
Figure PCTCN2022140669-appb-000007
式中，X 1、Y、Z、X 2、R 1、R 2、L 1、L 2、环A、环B各自定义同前；
或
所述式(A)化合物为式(A2)化合物；
Figure PCTCN2022140669-appb-000008
式中，X 1、Y、Z、X 2、R 1、R 2、L 1、L 2、环A、R 13、R 14各自定义同前；m0为1、2、3、4、5或6。
在一些实施方案中，所述式(A)化合物为式(Ia)化合物、式(Ib)化合物、式(Ic)化合物、式(Id)化合物、式(Ie)化合物或式(If)化合物；
Figure PCTCN2022140669-appb-000009
各式中，X 1、Y、Z、X 2、R 1、R 2、L 1、L 2、环A、环B各自定义同前。
在一些实施方案中，
所述式(A)化合物为式(II-A)化合物；
Figure PCTCN2022140669-appb-000010
式中，R 1、R 2、L 1、L 2、环A、环B、X 1各自定义同前；
或
所述式(A)化合物为式(II-B)化合物；
Figure PCTCN2022140669-appb-000011
式中，X 1、R 1、R 2、L 1、L 2、环A、R 13、R 14各自定义同前；m0为1、2、3、4、5或6；
或
所述式(A)化合物为式(A3)化合物；
Figure PCTCN2022140669-appb-000012
式中，X 1、R 1、R 2、L 1、L 2、环A、环B各自定义同前；
或
所述式(A)化合物为式(A4)化合物；
Figure PCTCN2022140669-appb-000013
式中，X 1、R 1、R 2、L 1、L 2、环A、R 13、R 14各自定义同前；m0为1、2、3、4、5或6。
在一些实施方案中，所述式(A)化合物为式(IIa)化合物、式(IIb)化合物、式(IIc)化合物、式(IId)化合物、式(IIe)化合物或式(IIf)化合物；
Figure PCTCN2022140669-appb-000014
各式中，X 1、R 1、R 2、L 1、L 2、环A、环B各自定义同前。
在一些实施方案中，
所述式(A)化合物为式(III-A)化合物；
Figure PCTCN2022140669-appb-000015
式中，L 1、L 2、环A、环B、X 1各自定义同前；
或
所述式(A)化合物为式(III-B)化合物；
Figure PCTCN2022140669-appb-000016
式中，X 1、L 1、L 2、环A、R 13、R 14各自定义同前；m0为1、2、3、4、5或6；
或
所述式(A)化合物为式(A5)化合物；
Figure PCTCN2022140669-appb-000017
式中，X 1、L 1、L 2、环A、环B各自定义同前；
或
所述式(A)化合物为式(A6)化合物；
Figure PCTCN2022140669-appb-000018
式中，X 1、L 1、L 2、环A、R 13、R 14各自定义同前；m0为1、2、3、4、5或6。
在一些实施方案中，所述式(A)化合物为式(III-1)化合物或式(III-2)化合物；
Figure PCTCN2022140669-appb-000019
各式中，L 1、L 2、环A、环B、X 1各自定义同前。
在一些实施方案中，所述式(A)化合物为式(III-a)化合物、式(III-b)化合物、式(III-c)化合物或式(III-d)化合物；
Figure PCTCN2022140669-appb-000020
各式中，L 1、L 2、环A、环B、X 1各自定义同前。
在一些实施方案中，所述式(A)化合物为式(IV-a)化合物、式(IV-b)化合物或式(IV-c)化合物；
Figure PCTCN2022140669-appb-000021
各式中，L 1、L 2、环B、X 1各自定义同前。
在一些实施方案中，环A为无；或环A选自下组：3至6元碳环、3至6元杂环、5至6元杂芳基、苯基，所述环A为未取代的或被1、2或3个选自OH、C 1-6烷基、卤素取代，其余变量如本发明所定义。
在一些实施方案中，环A为无；或环A选自下组：环丁环、环戊环、环己环、哌啶环、哌嗪环、四氢吡咯环、吡唑环、咪唑环；环A为未取代的或被1、2、3、4或5个选自S1组的基团所取代，其余变量如本发明所定义。
在一些实施方案中，环A为无；或环A选自下组：环丁环、环戊环、环己环、哌啶环、哌嗪环、四氢吡咯环、吡唑环、咪唑环；环A为未取代的或被1、2、3、4或5个选自S1组的基团所取代；所述S组的基团包括：羟基、甲基、卤素，其余变量如本发明所定义。
在一些实施方案中，环A为无；或环A选自下组：
Figure PCTCN2022140669-appb-000022
其余变量如本发明所定义。
在一些实施方案中，环A为无；或环A选自下组：
Figure PCTCN2022140669-appb-000023
在一些实施方案中，环B选自下组：3至6元碳环、3至6元杂环，所述环B为未取代的或被1、2或3个选自OH、C 1-6烷基、卤素取代，其余变量如本发明所定义。
在一些实施方案中，环B选自下组：环丁环、环戊环、环己环、哌啶环、哌嗪环、四氢吡咯环、吡唑环、咪唑环；环B为未取代的或被1、2、3、4或5个选自S1组的基团所取代，其余变量如本发明所定义。
在一些实施方案中，环B选自下组：
Figure PCTCN2022140669-appb-000024
其余变量如本发明所定义
在一些实施方案中，环B选自下组：
Figure PCTCN2022140669-appb-000025
在一些实施方案中，L 2为-NR 11-(CR 13R 14) m1-NR 12-；R 11、R 12独立地为氢或甲基；各个R 13、R 14独立地为氢、卤素或甲基；m1为1、2、3、4、5或6，其余变量如本发明所定义。
在一些实施方案中，L 2为-O-(CR 13R 14) m1-NR 12-；R 12为氢或甲基；各个R 13、R 14独立地为氢、卤素或甲基；m1为1、2、3、4、5或6，其余变量如本发明所定义。
在一些实施方案中，L 2为-NR 11-(CR 13R 14) m1-；R 11为氢或甲基；各个R 13、R 14独立地为氢、卤素或甲基；m1为1、2、3、4、5或6，其余变量如本发明所定义。
在一些实施方案中，L 2为-(CR 13R 14) m1-NR 12-；R 12为氢或甲基；各个R 13、R 14独立地为氢、卤素或甲基；m1为1、2、3、4、5或6，其余变量如本发明所定义。
在一些实施方案中，L 2为-(CR 13R 14) m1-；各个R 13、R 14独立地为氢、卤素或甲基；m1为1、2、3、4、5或6，其余变量如本发明所定义。
在一些实施方案中，L 2为-NR 11-(CR 13R 14) m5-3至7元碳环-(CR 13R 14) m6-NR 12-；R 11、R 12独立地为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4；所述3至7元碳环为未取代的或被1、2、3、4或5个选自S1组的基团所取代，其余变量如本发明所定义。
在一些实施方案中，L 2为-O-(CR 13R 14) m5-3至7元碳环-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4；所述3至7元碳环为未取代的或被1、2、3、4或5个选自S1组的基团所取代，其余变量如本发明所定义。
在一些实施方案中，L 2为-(CR 13R 14) m5-3至7元碳环-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4；所述3至7元碳环为未取代的或被1、2、3、4或5个选自S1组的基团所取代。在一些实施方案中，所述3至7元碳环为环丁基、环戊基或环己基，其余变量如本发明所定义。
在一些实施方案中，L 2为-NR 11-(CR 13R 14) m5-3至7元杂环-(CR 13R 14) m6-NR 12；R 11、R 12独立地为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4；所述3至7元杂环为未取代的或被1、2、3、4或5个选自S1组的基团所取代，其余变量如本发明所定义。
在一些实施方案中，L 2为-O-(CR 13R 14) m5-3至7元杂环-(CR 13R 14) m6-NR 12；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4；所述3至7 元杂环为未取代的或被1、2、3、4或5个选自S1组的基团所取代，其余变量如本发明所定义。
在一些实施方案中，L 2为-(CR 13R 14) m5-3至7元杂环-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4；所述3至7元杂环为未取代的或被1、2、3、4或5个选自S1组的基团所取代，其余变量如本发明所定义。
在一些实施方案中，L 2为-NR 11-(CR 13R 14) m5-NR 10-(CR 13R 14) m6-NR 12-；R 11、R 12独立地为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；R 10为氢或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-O-(CR 13R 14) m5-NR 10-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；R 10为氢或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-(CR 13R 14) m5-NR 10-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；R 10为氢或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-NR 11-(CR 13R 14) m5-NR 10C(O)-(CR 13R 14) m6-NR 12-；R 11、R 12独立地为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；R 10为氢或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-O-(CR 13R 14) m5-NR 10C(O)-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；R 10为氢或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-(CR 13R 14) m5-NR 10C(O)-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；R 10为氢或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-NR 11-(CR 13R 14) m5-C(O)NR 10-(CR 13R 14) m6-NR 12-；R 11、R 12独立地为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；R 10为氢或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-O-(CR 13R 14) m5-C(O)NR 10-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；R 10为氢或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-(CR 13R 14) m5-C(O)NR 10-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；R 10为氢或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-NR 11-(CR 13R 14) m5-O-(CR 13R 14) m6-NR 12-；R 11、R 12独立地为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-O-(CR 13R 14) m5-O-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-(CR 13R 14) m5-O-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-NR 11-(CR 13R 14) m5-OC(O)-(CR 13R 14) m6-NR 12-；R 11、R 12独立地为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-O-(CR 13R 14) m5-OC(O)-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-(CR 13R 14) m5-OC(O)-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-NR 11-(CR 13R 14) m5-C(O)O-(CR 13R 14) m6-NR 12-；R 11、R 12独立地为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-O-(CR 13R 14) m5-C(O)O-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-(CR 13R 14) m5-C(O)O-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-NR 11-(CR 13R 14) m5-CH＝CH-(CR 13R 14) m6-NR 12-；R 11、R 12独立地为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-O-(CR 13R 14) m5-CH＝CH-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，L 2为-(CR 13R 14) m5-CH＝CH-(CR 13R 14) m6-NR 12-；R 12为氢或甲基；各个R 13、R 14各自独立地为氢、卤素或甲基；m5为0、1、2、3或4；m6为0、1、2、3或4，其余变量如本发明所定义。
在一些实施方案中，所述S1组的基团包括：氧代、羟基、氰基、卤素、甲基、乙基、丙基，其余变量如本发明所定义。
在一些实施方案中，所述3至7元碳环为环丙基、环丁基、环戊基或环己基，其余变量如本发明所定义。
在一些实施方案中，所述3至7元杂环为氮杂环丁基、氧杂环丁基、四氢吡咯基、四氢呋喃基、哌啶基或哌嗪基，其余变量如本发明所定义。
在一些实施方案中，L 2选自下组之一：
Figure PCTCN2022140669-appb-000026
Figure PCTCN2022140669-appb-000027
Figure PCTCN2022140669-appb-000028
其余变量如本发明所定义。
在一些实施方案中，L 2选自下组：
Figure PCTCN2022140669-appb-000029
其余变量如本发明所定义。
在一些实施方案中，L 1为无、-O-、-N(CH 3)-、-CH＝CH-、-C＝N-、-CH 2-、-CH(CH 3)、-CH 2CH 2-、-CH(CH 3)CH 2-、-CH 2CH 2CH 2-、-CH 2CH 2CH(CH 3)-、-C(O)-、-NH-C(O)-、-N(CH 3)-C(O)-、-C(O)-N(CH 3)--C(O)-NH-CH 2-或-C(O)-NH-，其余变量如本发明所定义。
在一些实施方案中，L 1为-N(CD 3)-、-CH(CD 3)、-N(CD 3)-C(O)-或-C(O)-N(CD 3)，其余变量如本发明所定义。
在一些实施方案中，X 1为N或C(R 4)；其中，R 4为氢、卤素、氰基、-S(O) 2CH 3或-P(O)(CH 3) 2，其余变量如本发明所定义。
在一些实施方案中，式(A)化合物选自下表(I)中化合物之一：
表(I)
Figure PCTCN2022140669-appb-000030
Figure PCTCN2022140669-appb-000031
Figure PCTCN2022140669-appb-000032
Figure PCTCN2022140669-appb-000033
本发明第二方面提供了一种药物组合物，其包含第一方面所述的化合物、其立体异构体、前药或其药学上可接受的盐以及药学可接受的载体。
如本文所用，术语“本发明活性物质”或“本发明化合物”是指第一方面所述的化合物、其立体异构体、前药或其药学上可接受的盐。
如本文所用，术语“药学可接受的载体”是指能够递送有效量的本发明活性物质、不干扰活性物质的生物活性并且对宿主或者受试者无毒副作用的任何制剂或载体介质代表性的载体，包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。
所述药物组合物可以以下的任意方式施用：口服，喷雾吸入，直肠用药，鼻腔用药，颊部用药，局部用药，非肠道用药，如皮下，静脉，肌内，腹膜内，鞘内，心室内，胸骨内和颅内注射或输入，或借助一种外植储器用药。其中优选口服、腹膜内或静脉内给药方式。当口服用药时，本发明的化合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。当局部用药时，特别是治疗局部外敷容易达到的患面或器官，如眼睛、皮肤或下肠道神经性疾病时，可根据不同的患面或器官将本发明化合物制成不同的局部用药制剂形式，当眼部局部施用时，本发明的化合物可配制成一种微粉化悬浮液或溶液的制剂形式，所使用载体为等渗的一定pH的无菌盐水，其中可加入也可不加防腐剂如氯化苄基烷醇盐。对于眼用，也可将化合物制成膏剂形式如凡士林膏。当皮肤局部施用时，本发明的化合物可制成适当的软膏、洗剂或霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油，液体凡士林，白凡士林，丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油，脱水山梨糖醇单硬脂酸酯，吐温60，十 六烷酯蜡，十六碳烯芳醇，2-辛基十二烷醇，苄醇和水。本发明的化合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。此外灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
在另一个方面，本发明提供了第一方面所述的化合物、其立体异构体、前药或其药学上可接受的盐在制备治疗和/或预防CDK7相关疾病的药物中的用途。
在另一个方面，本发明提供了第一方面所述的化合物、其立体异构体、前药或其药学上可接受的盐在制备治疗和/或预防癌症的药物中的用途。
在另一个方面，本发明提供了一种治疗癌症的方法，其包括向有此需要的受试者施用治疗有效量的第一方面所述的化合物、其立体异构体、前药或其药学上可接受的盐，或上述的任意组合，或施用第二方面所述的药物组合物的步骤。
在另一个方面，本发明提供了第一方面所述的化合物、其立体异构体、前药或其药学上可接受的盐在制备CDK7抑制剂中的用途。
在一些实施方案中，所述CDK7相关疾病为增殖性疾病(例如肿瘤或癌症)、传染性疾病、免疫疾病、自身免疫疾病和炎性疾病。
在一些实施方案中，所述肿瘤或癌症包括实体瘤、血液瘤。在一些实施方案中，所述肿瘤或癌症包括黑色素瘤、骨癌(例如骨肉瘤、尤文氏肉瘤)、乳腺癌(例如激素受体阳性(HR+)乳腺癌(例如雌激素受体阳性(ER+)或孕酮受体阳性(PR+)乳腺癌)、激素受体阴性乳腺癌、三阴性乳腺癌(TNBC；ER-/PR-/HER2-))、结直肠癌、脑癌、肺癌(例如小细胞肺癌、非小细胞肺癌)、胰腺癌、卵巢癌、子宫内膜癌、宫颈癌、食道癌、胃癌、胆管癌、前列腺癌、肝癌、肾细胞癌、慢性淋巴细胞白血病(CLL)、急性成淋巴细胞白血病(ALL)、T-细胞急性成淋巴细胞白血病(T-ALL)、慢性髓细胞白血病(CML)、急性骨髓性白血病(AML)、淋巴瘤、多发性骨髓瘤、胶质母细胞瘤、神经母细胞瘤。
在一些实施方案中，所述传染性疾病包括AIDS、霍乱、结膜炎、登革热、脑炎、肠病毒感染(例如，脊髓灰质炎、非脊髓灰质炎)、大肠杆菌感染、口蹄疫、肝炎、带状疱疹、流感、麻疹等。
在一些实施方案中，所述免疫疾病和/或自身免疫疾病包括哮喘、糖尿病、风湿性疾病、AIDS、移植器官和组织的排斥、鼻炎、慢性阻塞性肺病、骨质疏松症、溃疡性结肠炎、红斑狼疮、过敏症、类风湿性关节炎、重症肌无力、克罗恩病、银屑病等。
在一些实施方案中，所述炎性疾病选自中枢神经系统(CNS)的炎性疾病、炎性风湿性疾病、血管的炎性疾病、中耳的炎性疾病、炎性肠病、皮肤的炎性疾病、葡萄膜炎炎性疾病和咽喉的炎性疾病。
如本文所用，术语“受试者”是指动物，特别是哺乳动物，优选人。
如本文所用，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。在本发明的实施方式中，在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)，但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
如本文所用，术语“药学上可接受的盐”是指在制药上可接受的并且具有母体化合物药理学活性的本发明化合物的盐。这类盐包括：与无机酸或与有机酸形成的酸加成的盐，所述的无机酸诸如硝酸， 磷酸，碳酸等；所述的有机酸诸如丙酸，己酸，环戊丙酸，乙醇酸，丙酮酸，葡糖酸，硬脂酸，粘康酸等；或在母体化合物上存在的酸性质子被金属离子，例如碱金属离子或碱土金属离子取代时形成的盐；或与有机碱形成的配位化合物，所述的有机碱诸如乙醇胺，二乙醇胺，三乙醇胺，N-甲基葡糖胺等。本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
如本文所用，术语“立体异构体”包括构象异构体和构型异构体，其中构型异构体主要包括顺反异构体和旋光异构体。本发明所述化合物可以以立体异构体的形式存在，并因此涵盖所有可能的立体异构体形式，包括但不限于顺反异构体、互变异构体、对映异构体、非对映异构体、阻转异构体等，本发明所述化合物也可以以前述的立体异构体的任何组合或任何混合物，例如内消旋体、外消旋体、阻转异构体的等量混合物等形式存在。例如单一对映异构体，单一非对映异构体或以上的混合物，或单一阻转异构体或其混合物。当本发明所述的化合物含有烯烃双键时，除非特别说明，否则其包括顺式异构体和反式异构体，以及其任何组合。本发明的阻转异构体为基于分子内旋转受限制而产生的轴向或平面手性的立体异构体。式(A)化合物具有源于不对称碳、轴向不对称等的光学异构体，必要时单一异构体可通过本领域已知的方法，例如结晶或手性色谱等方法进行拆分获得。
如本文所用，术语“烃基”指直链或支链饱和脂肪族烃基基团。术语“C 1-6烃基”指具有1至6个碳原子的直链或支链烃基。例如包括C 1-6烷基、C 2-6烯基、C 2-6炔基等。
如本文所用，术语“C 1-6烷基”指具有1至6个碳原子的直链或支链烷基。优选是C 1-4烷基，更优选是C 1-3烷基。具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基，及其各种支链异构体等。
如本文所用，术语“烯基”指在链的任何位点上具有一个或多个碳-碳双键的如上定义的烷基，术语“C 2-6烯基”指具有2至6个碳原子和至少一个(例如1至2个)碳-碳双键的烯基。优选为C 2-4烯基(即具有2至4个碳原子和1至2个碳-碳双键的烯基)。具体实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基、戊烯基、己烯基、丁间二烯基等。
如本文所用，术语“炔基”指在链的任何位点上具有一个或多个碳-碳三键的如上定义的烷基，术语“C 2-6炔基”指具有2至6个碳原子和至少一个(例如1至2个)碳-碳三键的炔基。更优选为C 2-4炔基(即具有2至4个碳原子和1至2个碳-碳三键的炔基)。具体实例包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。
如本文所用，术语“卤素”指氟、氯、溴或碘。
如本文所用，术语“卤代”指氟代、氯代、溴代或碘代。
如本文所用，术语“卤代烃基”指一个或多个(如1、2、3、4或5个)氢原子被卤素取代的烃基，其中烃基的定义如上所述。术语“卤代C 1-6烷基”指具有1至6个碳原子的卤代烷基。优选为卤代C 1-4烷基，更优选为卤代C 1-3烷基。具体实例包括但不限于一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2- 二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基等。
如本文所用，术语“氘代烃基”指一个或多个(如1、2、3、4或5个)氢原子被氘原子取代的烃基，其中烃基的定义如上所述。术语“氘代C 1-6烷基”指具有1至6个碳原子的氘代烷基。优选为氘代C 1-4烷基，更优选为氘代C 1-3烷基。具体实例包括但不限于一氘代甲基、二氘代甲基、三氘代甲基等。
如本文所用，术语“碳环基”和“碳环”可互换使用，指饱和或部分不饱和的单环或多环的环状烃基。术语“3至14元碳环基”或“C 3-14碳环基”指具有3至14个碳原子的饱和或部分不饱和单环或多环的环状烃基。例如包括单环碳环基(例如3至7元碳环基或“C 3-7碳环基”)或多环碳环基(例如螺碳环基、稠碳环基和桥碳环基等)。
术语“3至7元碳环基”或“C 3-7碳环基”可以互换使用，均指具有3至7个环碳原子的饱和或部分不饱和的单环环状烃基。优选3至6元单环碳环基，优选4至6元单环碳环基，更优选为3、4、5、6单环碳环基。单环碳环基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基等。
术语“螺碳环基”和“螺碳环基环”指两个或两个以上的单环之间共用一个碳原子(称螺原子)形成的多环环状烃基。根据环与环之间共用螺原子的数目将螺碳环基分为单螺碳环基、双螺碳环基和多螺碳环基。术语“6至12元螺碳环基”指具有6至12个环碳原子的多环环状烃基，其中共用螺原子的单环为3至7元单环碳环。优选为7至12元螺碳环基，更优选为7至12元单螺碳环基。更优选为7元(4元单环碳环基环/4元单环碳环基环)、8元(4元单环碳环基环/5元单环碳环基环)、9元(4元单环碳环基环/6元单环碳环基环，5元单环碳环基环/5元单环碳环基环)、10元(5元单环碳环基环/6元单环碳环基环)或11元(6元单环碳环基环/6元单环碳环基环)单螺碳环基。螺碳环基的具体实例包括但不限于：
Figure PCTCN2022140669-appb-000034
这些螺碳环基可通过任意一个环原子与分子其余部分连接。
术语“稠碳环基”和“稠碳环基环”指两个或两个以上的单环通过共享毗邻的一对碳原子形成的多环环状烃基。根据形成环的数目可以分为双环、三环、四环或多环稠碳环基。术语“5至12元稠碳环基”指具有5至12个环碳原子的多环环状烃基，其中共享毗邻碳原子对的单环为3至7元单环碳环。优选为7至12元稠碳环基。更优选为7至10元双稠碳环基。最优选为8元(5元单环碳环基环与5元单环碳环基环稠合)、9元(5元单环碳环基环与6元单环碳环基环稠合)或10元(6元单环碳环基环与6元单环碳环基环稠合)双稠碳环基。稠碳环基的具体实例包括但不限于：
Figure PCTCN2022140669-appb-000035
这些稠碳环基可通过任意一个环原子与分子其余部分连接。
术语“桥碳环基”和“桥碳环基环”指两个或两个以上的单环之间通过共用两个不直接连接的碳原子形成的多环环状烃基。根据形成环的数目可以分为双环、三环、四环或多环桥碳环基。术语“5至12元桥碳环基”指具有5至12个环碳原子的多环环状烃基，其中任意两个环共用两个不直接连接的碳原子。优选为7至12元桥碳环基。桥碳环基的具体实例包括但不限于：
Figure PCTCN2022140669-appb-000036
这些桥碳环基可通过任意一个环原子与分子其余部分连接。
所述碳环基环可以稠合于芳基、杂芳基或杂环基环上，其中与母体结构连接在一起的环为碳环基环，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。在本发明中，上述各类碳环基可以是任选取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。
如本文所用，术语“杂环基”和“杂环”可互换使用，指饱和或部分不饱和单环或多环的环状烃基，例如包括单环杂环基、螺杂环基、稠杂环基和桥杂环基。本发明中所述杂环基的环碳原子可任选地被1、2或3个氧代基取代形成环酮、环内酯或环内酰胺结构。术语“3至14元杂环基”指具有3至14个环原子的饱和或部分不饱和单环或多环的环状烃基，其中一个或多个(优选为1、2、3或4个)环原子为选自氮、氧或S(＝O) m’(其中m’是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。其中当环原子为氮原子时，其可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。本发明所述的3至14元杂环基包括单环杂环基(例如3至7元杂环基)、螺杂环基、稠杂环基和桥杂环基。
术语“3至7元杂环基”和“3至7元杂环基环”指具有3至7个环原子，其中1、2或3个环原子为选自氮、氧或S(＝O) m’(其中m’是整数0至2)的杂原子的饱和或部分不饱和单环环状烃基。优选为具有4至7个环原子，其中1或2个环原子为杂原子的4至7元单环杂环基。更优选为具有5或6个环原子，其中1或2个环原子为杂原子的5或6元单环杂环基。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。当杂原子为硫原子时，硫原子可以为任选地被氧化(即S(＝O) m’，m’是整数0至2)。所述单环杂环基的环碳原子可任选地被1、2或3个氧代基取代形成环酮、环内酯或环内酰胺结构。单环的杂环基的具体实例包括但不限于氮丙环、环氧乙烷、氮杂环丁烷、氮杂环丁烷-2-酮、噁唑烷、吡咯烷-2-酮、吡咯烷-2,5-二酮、1,3-二氧戊环、二氢呋喃-2(3H)-酮、二氢呋喃-2,5-二酮、哌啶-2-酮、哌啶-2,6-二酮、四氢-2H-吡喃-2-酮、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、1,3-二氧戊环-2-酮、噁唑烷-2-酮、咪唑烷-2-酮、哌啶、哌嗪、哌嗪-2-酮、吗啉、吗啉-3-酮、吗啉-2-酮、硫代吗啉-3-酮1,1-二氧化物、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶、1,3-噁嗪烷、六氢嘧啶、1,4-二噁烷、四氢嘧啶-2(1H)-酮、1,4-二噁烷-2-酮、5,6-二氢-2H-吡喃-2-酮、5,6-二氢嘧啶-4(3H)-酮、3,4-二氢吡啶-2(1H)-酮、5,6-二氢吡啶-2(1H)-酮、5,6-二氢嘧啶-4(1H)-酮、嘧啶-4(3H)-酮、嘧啶-4(1H)-酮、4,5-二氢-1H-咪唑、2,3-二氢-1H-咪唑、2,3-二氢噁唑、1,3-二氧杂环戊烯、2,3-二氢噻吩、2,5-二氢噻吩、3,4-二氢-2H-1,4-噁嗪、3,4-二氢-2H-1,4-噻嗪1,1-二氧化物、1,2,3,4-四氢吡嗪、1,3-二氢-2H-吡咯-2-酮、1,5-二氢-2H-吡咯-2-酮、1H-吡咯-2,5-二酮、呋喃-2(3H)-酮、呋喃-2(5H)-酮、1,3-二氧杂环戊烯-2-酮、噁唑-2(3H)-酮、1,3-二氢-2H-咪唑-2-酮、呋喃-2,5-二酮、3,6-二氢吡啶-2(1H)-酮、吡啶-2,6-(1H，3H)-二酮、5,6-二氢-2H-吡喃-2-酮、3,6-二氢-2H-吡喃-2-酮、3,4-二氢-2H-1,3-噁嗪、3,6-二氢-2H-1,3-噁嗪、1,2,3,4-四氢嘧啶等。
上述单环杂环基环上相连的2个环原子，包括C-C、N-C均可任选地与本发明所定义的单环碳环基环、单环杂环基环、单芳基环、5或6元单环杂芳基环等碳环基、杂环基、芳基或杂芳基稠合形成稠合多环。与其他环形成稠合环的单环杂环基上相连的2个环原子优选地为C-C。
术语“螺杂环基”和“螺杂环基环”指两个或两个以上的饱和或部分不饱和单环之间共用一个碳原子(称螺原子)形成的多环杂环基，其中一个或多个(如1、2或3个)环原子为选自氮、氧或S(＝O) m’(其中m’是整数0至2)的杂原子，其余环原子为碳。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。每个单环中可以含有一个或多个双键，但没 有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基。术语“7至14元螺杂环基”指具有7至14个环原子的螺杂环基，其中1或2个环原子为杂原子。优选为7元(4元单环杂环基环/4元单环杂环基环或4元单环杂环基环/4元单环碳环基或4元单环碳环基环/4元单环杂环基环)、8元(4元单环杂环基环/5元单环杂环基环)、9元(4元单环杂环基环/6元单环杂环基环，5元单环杂环基环/5元单环杂环基环)、10元(5元单环杂环基环/6元单环杂环基环)或11元(6元单环杂环基环/6元单环杂环基环)单螺杂环基。螺杂环基的具体实例包括但不限于：
Figure PCTCN2022140669-appb-000037
这些螺杂环基可通过任意一个合适的环原子与分子其余部分连接。
术语“稠杂环基”和“稠杂环基环”指两个或两个以上的饱和或部分不饱和单环通过共享毗邻的一对环原子形成的多环杂环基，其中一个或多个(如1、2或3个)环原子为选自氮、氧或S(＝O) m’(其中m’是整数0至2)的杂原子，其余环原子为碳。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。每个单环中可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。共享的毗邻环原子对可以是C-C或N-C。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基。术语“5至14元稠杂环基”指具有5至14个环原子的稠杂环基。优选为具有6至10个环原子，其中1或2个环原子为杂原子的6至10元稠杂环基。更优选为具有8至10个环原子，其中1或2个环原子为杂原子的8至10元稠杂环基。最优选为8元(5元单环杂环基环与5元单环杂环基环稠合)、9元(5元单环杂环基环与6元单环杂环基环稠合)或10元(6元单环杂环基环与6元单环杂环基环稠合)双环稠杂环基。稠杂环基的具体实例包括但不限于：
Figure PCTCN2022140669-appb-000038
这些稠杂环基可通过任意一个合适的环原子与分子其余部分连接。
术语“桥杂环基”和“桥杂环基环”指两个或两个以上的饱和或部分不饱和单环通过共用两个不直接连接的环原子形成的多环杂环基，其中一个或多个(如1、2或3个)环原子为选自氮、氧或S(＝O) m’(其中m’是整数0至2)的杂原子，其余环原子为碳。根据形成环的数目可以分为双环、三环、四环或多环桥碳环基。术语“5至14元桥杂环基”指具有5至14个环原子的饱和或部分不饱和多环杂环基团，其中任意两个环共用两个不直接连接的环原子，每个单环中可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为5至10元桥杂环基。桥杂环基的具体实例包括但不限于：
Figure PCTCN2022140669-appb-000039
Figure PCTCN2022140669-appb-000040
这些桥杂环基可通过任意一个合适的环原子与分子其余部分连接。
在本发明中，上述各类杂环基可以是任选取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。
如本文所用，术语“芳基”，“芳基环”和“芳环”可互换使用，指全碳单环、全碳非稠合多环(环与环通过共价键连接，非稠合)或全碳稠合多环(也就是共享毗邻碳原子对的环)基团，基团中至少一个环为芳香性的，即具有共轭的π电子体系。术语“C 5-12芳基”是指具有5至12个环原子的芳基，优选为C 6-10芳基。本发明中C 5-12芳基包括单环芳基(例如苯基)、非稠合多环芳基(例如联苯基)和芳香稠合多环。
在一些实施方案中，当C 5-12芳基为芳香稠合多环时，所述的芳香稠合多环可以为单芳基环与一个或多个单芳基环稠合形成的多环基团，其非限制性实例包括萘基，蒽基等。
在一些实施方案中，当C 5-12芳基为芳香稠合多环时，所述的芳香稠合多环也可以为单芳基环(如苯基)与一个或多个非芳香环稠合形成的多环基团，其中与母体结构连接的环为芳香环或非芳香环。所述非芳香环包括但不限于3至7元单环杂环基环(优选为5或6元单环杂环基环，所述单环杂环基环的环碳原子可被1至2个氧代基取代，形成环内酰胺或环内酯结构)，3至7元单环碳环基环(优选为5或6元单环碳环基环，所述单环碳环基环的环碳原子可被1或2个氧代基取代，形成环酮结构)。上述单芳基环与一个或多个非芳香环稠合的多环基团可通过氮原子或碳原子与其他基团或母体结构连接，与母体结构连接的环为单芳基环或非芳香环。
如本文所用，术语“杂芳基”，“杂芳基环”和“杂芳环”可互换使用，指环原子被至少一个独立选自氮、氧或硫的杂原子取代的单环或稠合多环(即共享毗邻环原子对，共享的毗邻环原子对可以是C-C或N-C)基团，其中氮和硫原子可任选地被氧化，氮原子可任选地被季铵化。所述杂芳基具有共享的6、10或14个π电子，基团中至少一个环是芳族的。术语“5至12元杂芳基”指具有5至12个环原子，其中1、2、3或4个环原子为选自氮、氧或S(＝O) m’(其中m’是整数0至2)的杂原子的杂芳基。优选为具有5至10个环原子，其中1、2、3或4个环原子为杂原子的5至10元杂芳基。本文的杂芳基可以为单环杂芳基(例如5或6元单环杂芳基)、稠合双环杂芳基(例如8至10元双环杂芳基)或稠合三环杂芳基。
如本文所用，术语“5或6元单环杂芳基”或“5或6元杂芳基”指具有5或6个环原子，其中1、2或3个环原子为选自氮、氧或S(＝O) m’(其中m’是整数0至2)的杂原子的单环杂芳基。单环杂芳基的具体实例包括但不限于噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪等。
如本文所用，术语“8至10元双环杂芳基”指具有8至10个环原子，其中1、2、3、4或5个环原子为选自氮、氧或S(＝O) m’(其中m’是整数0至2)的杂原子的稠合双环杂芳基。所述稠合双环杂芳基既可以是单芳基环(如苯基)与单环杂芳基环(优选为5或6元单环杂芳基环)稠合形成的双环基团，也可以是单环杂芳基环(优选为5或6元单环杂芳基环)与单环杂芳基环(优选为5或6元单环杂芳基环)稠合形成的双环基团。
上述单环杂芳基环上任意相连的2个环原子，包括C-C、N-C、N-N均可与本发明所定义的单环碳环基环、单环杂环基环、单芳基环、5或6元单环杂芳基环等碳环基、杂环基、芳基或杂芳基稠合形成稠合多环。所述8至10元双环杂芳基的非限制性实例包括：苯并[d]异噁唑、1H-吲哚、异吲哚、1H-苯并[d]咪唑、苯并[d]异噻唑、1H-苯并[d][1,2,3]三唑、苯并[d]噁唑、苯并[d]噻唑、吲唑、苯并呋喃、苯并[b]噻吩、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并 [3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶、吡唑并[1,5-a]嘧啶、咪唑并[1,2-b]哒嗪等。
上述单环杂芳基，或苯环与单环杂芳基环稠合形成的双环杂芳基，或单环杂芳基环与单环杂芳基环稠合形成的双环杂芳基可通过氮原子或碳原子与其他基团或母体结构连接。双环杂芳基具体实例包括但不限于：
Figure PCTCN2022140669-appb-000041
Figure PCTCN2022140669-appb-000042
Figure PCTCN2022140669-appb-000043
这些基团可通过任意一个合适的环原子与分子其余部分连接。与母体结构连接的环可以为单环杂芳基环或苯环。
在一些实施方案中，所述的稠合双环杂芳基或稠合三环杂芳基可以是单环杂芳基环(优选为5或6元单环杂芳基环)与一个或多个非芳香环稠合形成的多环基团，其中与母体结构连接的环为单环杂芳基环或非芳香环。所述非芳香环包括但不限于3至6元单环杂环基环(优选为5或6元单环杂环基环，所述单环杂环基环的环碳原子可被1至2个氧代基取代，形成环内酰胺或环内酯结构)，3至6元单环碳环基环(优选为5或6元单环碳环基环，所述单环碳环基环的环碳原子可被1或2个氧代基取代，形成环酮结构)等。上述单环杂芳基环与一个或多个非芳香环稠合形成的多环基团可通过氮原子或碳原子与其他基团或母体结构连接，与母体结构连接的环为单环杂芳基环或非芳香环。例如，术语“8至10元杂芳基杂环基”或“8至10元杂芳基杂环基环”指5或6元单环杂芳基环与一个5或6元单环杂环基环稠合形成的8至10元稠合双环杂芳基，即由5或6元单环杂芳基上相邻两个取代基团与其所连接的环原子形成一个稠合的5或6元单环杂环基环，所述5或6元单环杂环基环如上文中所定义。又例如，如本文所用，术语“8至10元杂芳基碳环基”或“8至10元杂芳基碳环基环”指5或6元单环杂芳基环与一个5或6元单环碳环基环稠合形成的8至10元稠合双环杂芳基，即由5或6元单环杂芳基上相邻两个取代基团与其所连接的环原子形成一个稠合的5或6元单环碳环基环，所述5或6元单环碳环基环如上文中所定义。“8至10元杂芳基杂环基”或“8至10元杂芳基碳环基”非限制性实例包括：
Figure PCTCN2022140669-appb-000044
Figure PCTCN2022140669-appb-000045
上述基团可以通过其任意合适的环原子与分子其他部分连接。
在本发明中，上述各类杂芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。
如本文所用，术语“羟基”指-OH。
如本文所用，术语“氨基”指-NH 2。
如本文所用，术语“氰基”指-CN。
如本文所用，术语“硝基”指-NO 2。
如本文所用，术语“苄基”指-CH 2-苯。
如本文所用，术语“氧代基”指＝O。
如本文所用，术语“亚烷基”表示烷基的二价结合形式。例如，“C 0-6亚烷基”表示具有0至6个碳原子的亚烷基。例如，“C 1亚烷基”表示具有1个碳原子的亚烷基，例如-CH 2-。例如，“C 2亚烷基”表示具有2个碳原子的亚烷基，例如-CH 2CH 2-。以此类推。
如本文所用，术语“亚烯基”表示烯基的二价结合形式。例如，“C 2-6亚烯基”表示具有2至6个碳原子的亚烯基。例如，“C 2亚烯基”表示具有2个碳原子的亚烯基，例如-CH＝CH-。以此类推。
如本文所用，术语“取代”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代基(即＝O)时，意味着两个氢原子被取代。氧代基取代不会发生在芳香基上。术语“任选取代”或“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
如本文所用，术语“无”表示其连接的两个基团直接相连，比如
Figure PCTCN2022140669-appb-000046
当环A为无时，L 1和L 2直接相连，为“L 1-L 2”。
当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如
Figure PCTCN2022140669-appb-000047
中，L选自-C(O)-NH-，此时-C(O)-NH-既可以按与从左往右的读取顺序相同的方向连接苯环和环戊烷构成
Figure PCTCN2022140669-appb-000048
也可以按照与从左往右的读取顺序相反的方向连接苯环和环戊烷构成
Figure PCTCN2022140669-appb-000049
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
本发明式(A)所示的化合物可使用本领域已知的合成方法或使用本领域已知的方法与本发明记载的方法组合制备得到。本发明给出的溶剂、温度和其它反应条件均为示例性的，可根据本领域熟知的方法而变化。本发明所记载的实施例化合物可根据其具体结构，使用适当的起始原料按照实施例中记载的方法合成，也可以使用与实施例中记载的类似方法合成得到。用于合成本发明实施例化合物的起始原料可通过已知合成方法或文献记载的类似方法制备得到或从商业来源获得。化合物可根据需要， 进一步通过本领域熟知的方法，例如结晶、色谱法等拆分得到其立体异构体，其拆分条件是本领域技术人员通过常规手段或有限试验而容易获得的。作为进一步说明，本发明式(A)化合物可利用以下的方法合成，其中每个步骤中的溶剂、温度及其它反应条件可与下述实施例中记载的相同或类似，或使用本领域已知的反应条件。
具体实施方式
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式。优选的实施方式包括但不限于本发明的实施例。
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1化合物Z1的合成
Figure PCTCN2022140669-appb-000050
步骤一：三口烧瓶中加入[2-(2-羟基乙氧基)乙基]氨基甲酸苄酯(5.0g,20.92mmol)和二氯甲烷(25mL)，搅拌并加入三乙胺(6.34g,62.76mmol)和4-二甲氨基吡啶(510mg,4.18mmol)。混合物降温至0℃并缓慢加入对甲苯磺酰氯(3.97g,20.92mmol)。室温搅拌反应2小时，LC-MS监测原料反应完全。将混合物倒入饱和的碳酸氢钠(100mL)并用二氯甲烷萃取(50mLX3)，合并有机相，无水硫酸钠干燥并浓缩。粗品用硅胶柱纯化(乙酸乙酯/石油醚：20％～50％)得油状产品2-(2-(((苄氧基)羰基)氨基)乙氧基)乙基4-甲基苯磺酸酯(3.84g,收率:46.7％)。 1H NMR(400MHz,CDCl 3)δ7.79(d,J＝8.4Hz,2H),7.42–7.28(m,7H),5.10(s,3H),4.35–4.07(m,2H),3.68–3.58(m,2H),3.47(t,J＝5.0Hz,2H),3.32(dd,J＝10.4,5.2Hz,2H),2.41(s,3H).
步骤二：2-(2-(((苄氧基)羰基)氨基)乙氧基)乙基4-甲基苯磺酸酯(1000mg,2.542mmol)和(S)-吡咯烷-3-基氨基甲酸叔丁酯(394mg,2.12mmol)的N,N-二甲基甲酰胺(15.0mL)溶液中于室温下加入碘化钾(0.056mL,0.508mmol)和碳酸钾(702.54mg,5.083mmol)固体。反应混合物搅拌下于70℃反应16 小时。反应完毕倒入冰水(100mL)中，并用乙酸乙酯萃取数次(50mLX3)。合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩。粗品用硅胶柱层析纯化(乙酸乙酯/石油醚：10％～100％)得黄色油状产品(S)-(2-(2-(3-((叔丁氧基羰基)氨基)吡咯烷-1-基)乙氧基)乙基)氨基甲酸苄酯(630mg,1.314mmol,收率:51.70％)。LCMS m/z(ESI):[M+H] +＝408.2。
步骤三：室温下(S)-(2-(2-(3-((叔丁氧基羰基)氨基)吡咯烷-1-基)乙氧基)乙基)氨基甲酸苄酯(730mg,1.791mmol)的二氯甲烷(6.0mL)溶液中，加入三氟乙酸(4.0mL,53.85mmol)。反应混合物室温下搅拌3小时，反应完全。反应液浓缩并加入乙酸乙酯(50mLX3)和饱和碳酸氢钠(50mLX3)萃取。合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩。粗品用硅胶柱层析纯化(甲醇/二氯甲烷：0～10％)得黄色油状产品化合物(S)-(2-(2-(3-氨基吡咯烷-1-基)乙氧基)乙基)氨基甲酸苄酯(520mg,1.66mmol,收率:92.55％)。LCMS m/z(ESI):[M+H] +＝308.2。
步骤四：室温下，2,4二氯-5-(三氟甲基)嘧啶(7.44g,34.29mmol)的1,2-二氯乙烷(30.0mL)溶液中加入三氯化铝(12.9g,85.62mmol)。升温到90℃反应30分钟。6-甲酸甲酯吲哚(5.0g,28.54mmol)的1,2-二氯乙烷(30.0mL)溶液缓慢滴加到反应液中。反应混合物继续于90℃反应18小时。冷却并倒入冰水(200mL)中，并用乙酸乙酯(100mLX3)萃取。合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩。粗品用硅胶柱层析纯化(甲醇/二氯甲烷：0～10％)得黄色固体3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸甲酯(2.5g,6.26mmol,收率:21.92％)。 1H NMR(400MHz,DMSO-d 6)δ12.50(s,1H),9.08(d,J＝3.4Hz,1H),8.39(d,J＝8.4Hz,1H),8.28(d,J＝2.6Hz,1H),8.20(t,J＝6.4Hz,1H),7.89–7.77(m,1H),3.89(s,3H).
步骤五：室温氮气保护下，化合物3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸甲酯(450mg,1.27mmol)和化合物(S)-(2-(2-(3-氨基吡咯烷-1-基)乙氧基)乙基)氨基甲酸苄酯(583mg,1.9mmol)的二氧六环(6mL)溶液中加入N,N-二异丙基乙胺(1.56ml,9.4mmol)。反应混合物升温到120℃反应4小时。冷却并倒入冰水(50mL)中，并用乙酸乙酯萃取(50mL*3)。合并有机相，饱和食盐水洗(100mL)，无水硫酸钠干燥，浓缩。粗品用硅胶柱纯化(甲醇/二氯甲烷：0～10％)得黄色油状产品甲基(R)-3-(2-((1-(2-(2-(((苄氧基)羰基)氨基)乙氧基)乙基)吡咯烷-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸酯(286mg,0.32mmol,收率:25.25％)。LCMS m/z(ESI):[M+H] +＝627.3。
步骤六：室温下，化合物甲基(R)-3-(2-((1-(2-(2-(((苄氧基)羰基)氨基)乙氧基)乙基)吡咯烷-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸酯(660mg,1.05mmol)的甲醇(50mL)溶液中加入10％钯碳(100mg,0.945mmol)。反应混合物在氢气气氛中搅拌反应4小时左右。过滤并浓缩，粗品用硅胶柱纯化(甲醇/二氯甲烷：0～20％)得灰黑色油状产品(R)-3-(2-((1-(2-(2-氨基乙氧基)乙基)吡咯烷-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸甲酯(460mg,0.65mmol,收率:62.08％)。LCMS m/z(ESI):[M+H] +＝493.0。
步骤七：室温氮气保护下，化合物(R)-3-(2-((1-(2-(2-氨基乙氧基)乙基)吡咯烷-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸甲酯(386mg,0.76mmol)的甲醇/水(10/5mL)溶液中加入氢氧化锂(197.3mg,4.7mmol)。反应混合物升温到70℃反应3小时。冷却并浓缩。粗品反相柱纯化(乙腈/水：0～70％)得白色固体产品(R)-3-(2-((1-(2-(2-氨基乙氧基)乙基)吡咯烷-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸(106mg,0.19mmol,收率:24.03％)。LCMS m/z(ESI):[M+H] +＝479.2。
步骤八：室温氮气保护下，N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(126mg,0.33mmol)的N,N-二甲基甲酰胺(15mL)溶液中加入N,N-二异丙基乙胺(0.11ml,0.66mmol)。混合物搅拌下加入化合物(R)-3-(2-((1-(2-(2-氨基乙氧基)乙基)吡咯烷-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚 -6-羧酸(106mg,0.22mmol)的N,N-二甲基甲酰胺(1ml)溶液。反应物室温下反应30分钟。倒入冰水(50mL)中，并用乙酸乙酯(50mLX3)萃取。合并有机相，饱和食盐水洗干燥，浓缩。粗品制备纯化(色谱柱:Waters Xbridge C18 10um OBD 19*250mm；流动相:水/乙腈(0.1％碳酸氢铵)；流速:20mL/min；检测波长:254nm/214nm；柱温:室温)得产品(4 3S)-2 5-(三氟甲基)-1 1H-7-氧杂-3,10-二氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(3,1)-吡咯烷环十一烷-11-酮((4 3S)-2 5-(trifluoromethyl)-1 1H-7-oxa-3,10-diaza-1(3,6)-indola-2(4,2)-pyrimidina-4(3,1)-pyrrolidinacycloundecaphan-11-one)(Z1,2.3mg,收率:2.25％)。LCMS m/z(ESI):[M+H] +＝461.2。 1H NMR(400MHz,DMSO-d 6)δ11.91(s,1H),8.58(s,1H),8.22(d,J＝8.6Hz,1H),8.06(s,1H),7.87(s,1H),7.61(s,2H),7.39(s,1H),4.08(s,1H),3.57(s,3H),3.25(s,3H),3.08(s,2H),2.71(d,J＝82.0Hz,3H),2.00(d,J＝90.2Hz,3H). 19F NMR(400MHz,DMSO)δ-56.63。
实施例2化合物Z2的合成
Figure PCTCN2022140669-appb-000051
步骤一：室温下，4-氨基-1-丁醇(3.0g,33.7mmol)的乙醇(30mL)溶液中加入二碳酸二叔丁酯(3.67g,16.856mmol)。反应混合物室温搅拌反应4小时。反应液浓缩，粗品用乙酸乙酯(100mL*3)和碳酸氢钠(150mL)萃取，合并有机相，无水硫酸钠干燥并浓缩。粗品用硅胶柱纯化(乙酸乙酯/石油醚：0～100％)得无色油状产品(4-羟基丁基)氨基甲酸叔丁酯(5.8g,30.69mmol,收率:91％)。
步骤二：氮气保护下，于-70℃的二甲基亚砜(3.7ml)的二氯甲烷(50ml)的反应溶液中滴加草酰氯(13ml,23mmol,2M二氯甲烷)，滴完继续搅拌5分钟。在-70℃下滴加(4-羟基丁基)氨基甲酸叔丁酯(4.1g,21.6mmol)的二氯甲烷(35.0mL)溶液。反应混合物逐渐升温到0℃并搅拌25分钟。反应完毕倒入冰水中，并用乙酸乙酯(50mLX3)萃取。合并有机相，饱和食盐水洗(150mL)，无水硫酸钠干燥，浓缩。粗品硅胶柱纯化(乙酸乙酯/石油醚：0～50％)得黄色油状产品(4-氧代丁基)氨基甲酸叔丁酯(4.0g,24.59mmol,收率:84.55％)。
步骤三：室温氮气保护下，化合物3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸甲酯(2.0g,5.62mmol)和化合物((1S,3S)-3-氨基环戊基)氨基甲酸叔丁酯(1.02g,5.06mmol)的N-甲基吡咯烷酮(30mL)溶液中加入N,N-二异丙基乙胺(2.78ml,16.78mmol)。反应混合物升温到140℃反应0.5小时。冷却并倒入冰水中，并用乙酸乙酯萃取(50mLX3)。合并有机相，饱和食盐水洗(150mL)，无水硫酸钠干燥，浓缩。粗品用硅胶柱纯化(甲醇/二氯甲烷：0～10％)得到灰色固体3-(2-(((1S,3S)-3-((叔丁氧基羰基)氨基) 环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸甲酯(2.0g,3.84mmol,收率:68.47％)。LCMS m/z(ESI):[M+H] +＝519.2。 1H NMR(400MHz,DMSO-d 6)δ12.11(s,1H),8.64–8.51(m,1H),8.48–8.31(m,1H),8.15(d,J＝5.8Hz,1H),8.01(d,J＝21.1Hz,2H),7.88–7.69(m,1H),7.06–6.83(m,1H),4.44(s,1H),4.07–3.81(m,4H),2.16–1.77(m,4H),1.51(d,J＝33.4Hz,2H),1.41–1.34(m,9H).
步骤四：室温下化合物3-(2-(((1S,3S)-3-((叔丁氧基羰基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸甲酯(520mg,1.0mmol)的二氯甲烷(10mL)溶液中，加入三氟乙酸(1.0mL,13.56mmol)。反应混合物室温下搅拌1小时，反应完全。反应液浓缩并加入乙酸乙酯(50mLX3)和饱和碳酸氢钠(100mL)萃取。合并有机相，饱和食盐水(100mL)洗，无水硫酸钠干燥，浓缩得到黄色油状粗品甲基3-(2-(((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸酯(520mg,1.66mmol,收率:92.55％)，不经纯化直接用于下一步反应。LCMS m/z(ESI):[M+H] +＝419.1。
步骤五：室温下化合物甲基3-(2-(((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸酯(480mg,1.0mmol)的四氢呋喃(5mL)溶液中，加入化合物(4-氧代丁基)氨基甲酸叔丁酯(192.86mg,1.03mmol)。混合物室温下搅拌30分钟后加入氰基硼氢化钠(143.84mg,2.29mmol)。反应混合物室温下搅拌2小时，反应完全。反应液浓缩并加入乙酸乙酯(50mLX 3)和饱和碳酸氢钠(100mL)萃取。合并有机相，饱和食盐水(100mL)洗，无水硫酸钠干燥，浓缩。粗品用柱层析纯化(甲醇/二氯甲烷：0～10％)后得到黄色固体化合物甲基3-(2-(((1S,3S)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸酯(356mg,0.6mmol,收率:52.66％)。LCMS m/z(ESI):[M+H] +＝590.2。
步骤六：室温下化合物甲基3-(2-(((1S,3S)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸酯(356mg,0.76mmol)的二氯甲烷(5mL)溶液中，加入三氟乙酸(0.5mL,6.75mmol)。反应混合物室温下搅拌1小时，反应完全。反应液浓缩并加入乙酸乙酯(50mLX3)和饱和碳酸氢钠(100mL)萃取。合并有机相，饱和食盐水(100mL)洗，无水硫酸钠干燥，浓缩得到黄色油状粗品化合物3-(2-(((1S,3S)-3-((4-氨基丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸甲酯(387mg,0.47mmol,78.54％)，不经纯化直接用于下一步反应。LCMS m/z(ESI):[M+H] +＝490.2。
步骤七：室温氮气保护下，化合物3-(2-(((1S,3S)-3-((4-氨基丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸甲酯(384mg,0.78mmol)的四氢呋喃/水(10/5mL)溶液中加入氢氧化锂(98.54mg,2.35mmol)。反应混合物搅拌反应0.5小时。冷却并浓缩。粗品用反相柱纯化(乙腈/水：0～70％)得白色固体产品3-(2-(((1S,3S)-3-((4-氨基丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸(208mg,0.44mmol,收率:55.76％)。LCMS m/z(ESI):[M+H] +＝476.2。
步骤八：室温氮气保护下，N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(239mg,0.63mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入N,N-二异丙基乙胺(0.139ml,0.84mmol)。混合物搅拌下加入化合物3-(2-(((1S,3S)-3-((4-氨基丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸(106mg,0.22mmol)的N,N-二甲基甲酰胺(5ml)溶液。反应物室温下反应30分钟。倒入冰水(50mL)中，并用乙酸乙酯(50mL*3)萃取。合并有机相，饱和食盐水(100mL)洗，无水硫酸钠干燥，浓缩。粗品制备纯化(色谱柱:Waters Xbridge C18 10um OBD 19*250mm；流动相:水/乙腈(0.1％碳酸氢铵)；流速:20mL/min；检测波长:254nm/214nm；柱温:25℃)得产品(4 1S,4 3S)-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮((4 1S,4 3S)-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one)(Z2,1.02mg,收率：0.35％)。LCMS m/z(ESI):[M+H] +＝458.2。 1H NMR(400MHz,CD 3OD)δ8.39(s,1H),7.79(s,1H),7.47(s,1H),7.34–7.24(m,1H),7.23–7.07(m,1H),2.95(s,2H),2.27(d,J＝23.4Hz,2H),2.08(d,J＝8.5Hz, 2H),1.41(m,4H),1.19(m,6H)。 19F NMR(377MHz,CD 3OD)δ-59.28(s).
实施例3化合物Z3的合成
Figure PCTCN2022140669-appb-000052
步骤一：氮气保护下，于-30℃向3-N-叔丁氧羰基-6-氧杂-3-氮杂二环[3.1.0]己烷(5g,26.99mmol)和溴化亚铜(I)二甲硫醚络合物(60.739mL,121.48mmol)的四氢呋喃(150mL)溶液中缓慢滴加烯丙基氯化镁(60.739mL,121.48mmol,2M/L),该反应液在氮气保护下于-10℃搅拌反应1小时。反应液用10％氯化铵水溶液(100mL)和乙酸乙酯(100mL)淬灭，然后于室温下搅拌1小时。反应液用乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩至干。得到的粗品经硅胶柱(石油醚/乙酸乙酯＝10/1～55/45)层析纯化得到黄色油状物(3R,4S)-3-羟基-4-烯丙基吡咯烷-1-羧酸叔丁基酯(1.55g,收率:25.26％)。LCMS m/z(ESI):[M+H-56] +＝172。
步骤二：氮气保护下，于0℃向(3R,4S)-3-羟基-4-烯丙基吡咯烷-1-羧酸叔丁基酯(1.5g,6.60mmol)的N,N-二甲基甲酰胺(8mL)溶液中加入氢化钠(0.32g,7.92mmol，60％纯度)，该反应液在氮气保护下于室温搅拌反应0.5小时。溴化苄(0.947mL,7.92mmol)加入其中，得到的反应液于室温下搅拌过夜。将反应液倒入水(50mL)中，用乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩至干燥。得到的粗品经硅胶柱(石油醚/乙酸乙酯＝10/1～9/1)层析纯化得到黄色油状物(3R,4S)-3-苄氧基-4-烯丙基吡咯烷-1-羧酸叔丁基酯(0.9g,收率:42.96％)。LCMS m/z(ESI):[M+H-56] +＝262,[M+H-100] +＝218。 1H NMR(400MHz,CDCl 3)δ7.38–7.25(m,5H),5.82–5.66(m,1H),5.11–4.97(m,2H),4.60–4.44(m,2H),3.83–3.72(m,1H),3.64–3.49(m,2H),3.42–3.32(m,1H),3.20–3.03(m,1H),2.37–2.25(m,1H),2.24–2.14(m,1H),2.09–1.93(m,1H),1.45(s,9H).
步骤三：向(3R,4S)-3-苄氧基-4-烯丙基吡咯烷-1-羧酸叔丁基酯(800mg,2.52mmol)和高碘酸钠(1.62g,7.56mmol)的乙腈(15mL)和水(6mL)的混合溶液中加入锇酸钾(92.86mg,0.25mmol)，该反应液室温搅拌反应2小时。向反应液中加水(10mL)并用乙酸乙酯(10mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩至干燥。得到的粗品经硅胶柱(石油醚/乙酸乙酯＝10/1～55/45)层析纯化得到黄色油状物(3R,4S)-3-苄氧基-4-(2-乙醛基)吡咯烷-1-羧酸叔丁基酯(500mg，收率:62.11％).LCMS:MS m/z(ESI):[M+H-56] +＝264,[M+H-100] +＝220。
步骤四：向(3R,4S)-3-苄氧基-4-(2-乙醛基)吡咯烷-1-羧酸叔丁基酯(480mg,1.50mmol)和3-(2-(((1S,3S)-3-氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(630mg,1.50mmol)的1,2-二氯乙烷(15mL)溶液中加入少量的醋酸(0.086mL,1.50mmol)，该反应液室温搅拌反应0.5小时。醋酸硼氢化 钠(951mg,4.51mmol)加入其中，得到的反应液于室温下搅拌过夜。向反应液中加水(20mL)中，并用乙酸乙酯(10mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩至干。得到的粗品经硅胶柱(二氯甲烷/甲醇＝100/1～95/5)层析纯化得到黄色油状物3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(苄氧基)-1-(叔丁氧羰基)吡咯基-3-基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(460mg,收率:42.37％).LCMS:MS m/z(ESI):[M+H] +＝723。
步骤五：向3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(苄氧基)-1-(叔丁基氧羰基)吡咯基-3-基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(480mg,0.66mmol)的四氢呋喃(2mL)和甲醇(2mL)的混合溶液中加入氢氧化锂(139mg,3.32mmol)的水(2mL)溶液，该反应液室温搅拌反应过夜。反应液用0.5M的盐酸水溶液酸化至pH＝3-4，并用乙酸乙酯(5mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩至干。得到的粗品经硅胶柱(二氯甲烷/甲醇＝100/1～85/15)层析纯化得到黄色油状物3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(苄氧基)-1-(叔丁氧羰基)吡咯基-3-基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(460mg,收率:98.2％)。LCMS:MS m/z(ESI):[M+H] +＝709。
步骤六：在0℃下向3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(苄氧基)-1-(叔丁基氧羰基)吡咯基-3-基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(390mg,0.55mmol)中加入盐酸/二氧六环(10mL,4N)溶液，该反应液室温搅拌反应1小时。反应液浓缩至干燥，得到黄色固体3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(苄氧基)吡咯基-3-基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(320mg,收率:95.55％)。LCMS:MS m/z(ESI):[M+H] +＝609。
步骤七：向3-(2-(((1S,3S)-3-((2-((3S,4R)-4-(苄氧基)吡咯基-3-基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(320mg,0.53mmol)的N,N-二甲基甲酰胺(180mL)溶液中依次加入五氟苯酚(194mg,1.05mmol)和N,N'-二环己基碳二亚胺(217mg,1.05mmol)，该反应液室温搅拌反应过夜。反应液浓缩至干，得到的粗品经硅胶柱(二氯甲烷/甲醇＝100/1～90/10)层析纯化得到棕色固体(4 1S,4 3S,8 3S,8 4R)-8 4-(苄氧基)-2 5-(三氟甲基)-1 1H-3,5-二氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-8(3,1)-吡咯烷-4(1,3)-环戊烷环壬烷-9-酮(100mg,收率:32.26％)。LCMS:MS m/z(ESI):[M+H] +＝591。
步骤八：在0℃下向(4 1S,4 3S,8 3S,8 4R)-8 4-(苄氧基)-2 5-(三氟甲基)-1 1H-3,5-二氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-8(3,1)-吡咯烷-4(1,3)-环戊烷环壬烷-9-酮(30mg,0.05mmol)的二氯甲烷(2mL)溶液中缓慢滴加三氯化硼(0.25mL,1M)溶液，该反应液在氮气保护下于0℃搅拌反应1.5小时。反应液用甲醇(0.1mL)淬灭，并且浓缩至干燥，得到的粗品经制备HPLC(色谱柱:Xbridge Prep C18 10um OBO TM 19*250nm；流动相:乙腈/水(0.05％氨水)；流速:20ml/min)纯化得到(4 1S,4 3S,8 3S,8 4R)-8 4-(羟基)-2 5-(三氟甲基)-1 1H-3,5-二氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-8(3,1)-吡咯烷-4(1,3)-环戊烷环壬烷-9-酮((4 1S,4 3S,8 3S,8 4R)-8 4-hydroxy-2 5-(trifluoromethyl)-1 1H-3,5-diaza-1(3,6)-indola-2(4,2)-pyrimidina-8(3,1)-pyrrolidina-4(1,3)-cyclopentanacyclononaphan-9-one)(Z3,2.6mg,收率:8.0％)。LCMS:MS m/z(ESI):[M+H] +＝501。 1H NMR(400MHz,CD 3OD)δ8.79–8.19(m,2H),7.86(d,J＝76.7Hz,1H),7.51–7.45(m,1H),7.25–7.15(m,1H),4.64–4.48(m,1H),4.29–4.18(m,1H),4.15–3.87(m,2H),3.58–3.37(m,1H),3.26–3.18(m,1H),2.86–2.67(m,1H),2.59–2.47(m,1H),2.29–2.19(m,2H),2.13–1.96(m,2H),1.88–1.74(m,1H),1.70–1.58(m,2H),1.56–1.44(m,1H),1.36–1.09(m,2H)。
实施例4化合物Z4的合成
Figure PCTCN2022140669-appb-000053
步骤一：向叔丁基((1S,3S)-3-氨基环戊基)氨基甲酸酯(1g,5.0mmol)的四氢呋喃(25mL)溶液中加入N,N-二异丙基乙胺(2.61g,20.0mmol)和2,4-二氯-5-(三氟甲基)嘧啶(1.10g,5.0mmol)，该反应液在25℃搅拌反应14小时。LCMS检测反应完全后，将反应液直接浓缩得到粗品。粗品经硅胶柱(石油醚/乙酸乙酯＝30/1～15/1)层析纯化得到N-[(1S,3S)-3-{[4-氯-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]氨基甲酸叔丁酯(0.76g,收率:40％)。LCMS:MS m/z(ESI):[M+H] +＝381.2,t R＝1.56min。
步骤二：1H-吲哚-6-羧酸甲酯(3.00g,17.12mmol)在N,N-二甲基甲酰胺(30mL)中的溶液，0℃时，加入1-碘-吡咯烷-2,5-二酮(4.62g,20.55mmol)。将反应在室温下搅拌3小时。TLC(石油醚:乙酸乙酯＝1:1)显示反应完成。用乙酸乙酯(200mL×3)和水(60ml)萃取。然后加入饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩。硅胶柱层析纯化(石油醚/乙酸乙酯＝1:1)得到化合物3-碘-1H-吲哚-6-羧酸甲酯(3.5g,收率:67.89％)。
步骤三：向3-碘-1H-吲哚-6-羧酸甲酯(3.50g,11.62mmol)的二氯甲烷(35mL)溶液中加入三乙胺(3.23mL,23.25mmol)、4-二甲氨基吡啶(0.36g,2.91mmol)，0℃时，加入二碳酸二叔丁酯(2.99mL,13.95mmol)。将反应在室温下搅拌18小时。TLC(石油醚:乙酸乙酯＝5:1)显示反应完成。反应液用二氯甲烷(200mL×3)和水(60ml)萃取，加入饱和氯化钠溶液洗涤，加入无水硫酸钠干燥，过滤，浓缩。硅胶柱层析纯化(石油醚/乙酸乙酯＝3:1)得到化合物1-(叔丁基)6-甲基3-碘-1H-吲哚-1,6-二甲酸酯(3.8g,收率:81.48％)。
步骤四：向1-(叔丁基)6-甲基3-碘-1H-吲哚-1,6-二甲酸酯(3.60g,8.97mmol)在二氧六环(36mL)中 的溶液中加入醋酸钾(1.76g,17.95mmol)、二氯化钯(0.66g,0.91mmol)和4,4,5,5-四甲基-1,3,2-二氧硼烷(1.95mL,13.46mmol)，在70℃下搅拌3小时。TLC(石油醚:乙酸乙酯＝5:1)显示反应完成。收集混合物，真空浓缩。粗品用硅胶柱层析纯化(石油醚/乙酸乙酯＝20:1)得到化合物1-(叔丁基)6-甲基3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-吲哚-1,6-二甲酸酯(2.5g,产率:69.43％)。
步骤五：向1-(叔丁基)6-甲基3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-吲哚-1,6-二甲酸酯(2.3g,5.73mmol)在二氧六环和水溶液(23mL)中的溶液中加入碳酸钾(1.58g,11.46mmol)、二氯化钯(0.28g,0.38mmol)和N-[(1S,3S)-3-{[4-氯-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]氨基甲酸叔丁酯(1.46g,3.82mmol)，反应100℃下搅拌3小时。TLC(石油醚:乙酸乙酯＝3:1)显示反应完成。收集混合物，真空浓缩。粗品用硅胶柱层析纯化(石油醚/乙酸乙酯洗脱＝3:1)得到化合物1-(叔丁基)6-甲基3-(2-(((1S,3S)-3-((叔丁氧羰基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-1,6-二甲酸酯(2.2g,收率:90％)。
步骤六：向含有1-(叔丁基)6-甲基3-(2-(((1S,3S)-3-((叔丁氧羰基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-1,6-二甲酸酯(2.20g,3.55mmol)的烧瓶中加入二氧六环(15mL,3.55mmol)，然后加入氯化氢(15mL,3.55mmol)。混合物在25℃下搅拌2小时。TLC(二氯甲烷:甲醇＝10:1)显示反应完成。浓缩，将所得固体用甲基叔丁基醚溶解，过滤，得淡黄色固体化合物3-(2-(((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸甲酯(2.6g,粗品,盐酸盐)。ES-API:[M+H] +＝419.2。 1H NMR(400MHz,DMSO-d 6)δ12.17(s,1H),8.60(d,J＝15.4Hz,1H),8.38(d,J＝30.4Hz,1H),8.05(s,2H),7.78(d,J＝24.6Hz,1H),4.53(d,J＝6.1Hz,1H),3.88(s,3H),3.56(s,2H),2.16(s,2H),2.00(d,J＝9.2Hz,3H),1.63(s,2H),1.23(s,2H).
步骤七：向3-(2-(((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸甲酯(1.00g,2.38mmol)的1,2-二氯乙烷(10mL)溶液中加入硼氢化钠(0.39mL,11.92mmol)、叔丁基4-(2-氧乙基)哌啶-1-羧酸酯(0.54g,2.38mmol)，将反应在室温下搅拌过夜。反应液用二氯甲烷(60mL×3)和碳酸氢钠饱和溶液萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩。粗品用薄层层析纯化(二氯甲烷:甲醇＝30:1)得到甲基3-(2-(((1S,3S)-3-((2-(1-(叔丁氧羰基)哌啶-4-基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸酯(300mg,收率:19.46％)。ES-API:[M+H] +＝630.31。
步骤八：向甲基3-(2-(((1S,3S)-3-((2-(1-(叔丁氧羰基)哌啶-4-基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸酯(150mg,0.24mmol)在四氢呋喃/甲醇/水(1:1:1)中的溶液中加入氢氧化锂(0.02mL,0.71mmol)，将反应在室温下搅拌过夜。用稀盐酸将反应物的pH值调至酸性。反应用乙酸乙酯(6mL×3)和水(2ml)稀释，然后加入饱和氯化钠溶液进行分离。收集有机层，无水硫酸钠干燥，浓缩得到化合物3-(2-(((1S,3S)-3-((2-(1-(叔丁氧基羰基)哌啶-4-基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸(150mg，收率:98.79％)。 1H NMR(400MHz,DMSO-d 6)δ12.26(d,J＝14.1Hz,1H),9.16(s,3H),8.85(s,1H),8.58(s,1H),8.32(s,1H),8.16–7.98(m,3H),7.76(d,J＝17.5Hz,1H),4.52(s,1H),3.21(d,J＝12.1Hz,4H),2.84(d,J＝29.6Hz,5H),2.19(d,J＝6.3Hz,3H),1.78(s,3H),1.60(s,4H),1.28(d,J＝40.2Hz,9H).
步骤九：向含有3-(2-(((1S,3S)-3-((2-(1-(叔丁氧基羰基)哌啶-4-基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸(330mg,0.52mmol)的烧瓶中加入二氧六环(3mL,0.52mmol)，然后加入氯化氢(3mL)。混合物在25℃下搅拌2小时。TLC(二氯甲烷:甲醇＝7:1)显示反应完成。真空浓缩有机层。将所得固体用甲基叔丁基醚溶解，过滤，得淡黄色固体化合物3-(2-(((1S,3S)-3-((2-(哌啶-4-基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸(350mg,收率:126.00％)。ES-API: [M+H] +＝517.4。 1H NMR(400MHz,DMSO-d 6)δ12.54(s,1H),9.39(d,J＝41.9Hz,3H),9.13(s,1H),8.59(d,J＝12.7Hz,1H),8.37(dd,J＝40.4,8.0Hz,1H),8.07(d,J＝60.1Hz,3H),7.76(dd,J＝33.4,8.0Hz,1H),4.51(s,1H),3.18(d,J＝11.9Hz,3H),2.91–2.71(m,4H),2.20(dd,J＝13.6,6.8Hz,3H),1.79(d,J＝8.9Hz,3H),1.66(d,J＝19.7Hz,4H),1.37(d,J＝9.5Hz,2H).
步骤十：向3-(2-((1S,3S)-3-((2-(哌啶-4-基)乙基)氨基)环戊基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸(90mg,0.17mmol)的N,N-二甲基甲酰胺(5mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(72mg,0.19mmol)和N,N-二异丙基乙胺(88mg,0.68mmol)，该反应液室温搅拌16小时。LCMS检测反应完全后，反应液浓缩至干，得到的粗品经反相制备(色谱柱:Ultimate XBC18,50*250mm,10um(PARP-06)；流速:70mL/min；流动相:乙腈-水(0.1％三氟醋酸)；柱温:25℃)得到(4 1S,4 3S)-2 5-(三氟甲基)-1 1H-3,5-二氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-8(4,1)-哌啶-4(1,3)-环戊烷环壬烷-9-酮((4 1S,4 3S)-2 5-(trifluoromethyl)-1 1H-3,5-diaza-1(3,6)-indola-2(4,2)-pyrimidina-8(4,1)-piperidina-4(1,3)-cyclopentanacyclononaphan-9-one)(Z4)的三氟乙酸盐(1.7mg,收率:1.3％)。LCMS:MS m/z(ESI):[M+H] +＝499.2,t R＝1.22min。 1H NMR(400MHz,CD 3OD):δ8.64(d,J＝8.0Hz,1H),8.56(s,1H),8.12(s,1H),7.52(s,1H),7.39(d,J＝8.0Hz,1H),4.53–4.50(m,1H),4.48–4.37(m,1H),3.72(s,1H),3.26–3.19(m,1H),3.09–2.97(m,1H),2.80–2.55(m,3H),2.42–2,40(m,2H),2.11–1.97(m,2H),1.92–1.60(m,8H),1.36–1.29(m,1H).
实施例5化合物Z5的合成
Figure PCTCN2022140669-appb-000054
步骤一：在室温下，向3-(2-(((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(270mg,0.55mmol)的N,N-二甲基甲酰胺溶液(5mL)中依次加入叔丁基(4-溴丁基)氨基甲酸酯(138mg,0.55mmol)和N,N-二异丙基乙胺(284mg,2.20mmol)，反应液在氮气保护下于80℃搅拌反应16小时。LCMS检测反应完全后，反应液加入10％氯化铵水溶液(100mL)并用乙酸乙酯(100mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。得到的粗品经硅胶柱(石油醚/乙酸乙酯＝2/1～1/1)层析纯化得到白色固体甲基3-(2-(((1S,3S)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(170mg,收率:46％)。LCMS:MS m/z(ESI):[M+H] +＝667.3,t R＝1.28min.
步骤二：向甲基3-(2-(((1S,3S)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(170mg,0.26mmol)的四氢呋喃(2mL)和甲醇(2mL)的混合溶液中加入氢氧化锂(66.0mg,1.56mmol)的水(2mL)溶液，该反应液在40℃搅拌反应过夜。 LCMS检测反应完全后，反应液用1.0M的盐酸水溶液酸化至pH＝3-4，用二氯甲烷(10mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到白色固体3-(2-(((1S,3S)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(160mg,收率:94％)，不经纯化直接用于下一步反应。LCMS:MS m/z(ESI):[M+H] +＝653.2,t R＝1.12min.
步骤三：在25℃下向3-(2-(((1S,3S)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(160mg,0.25mmol)的甲醇(5mL)溶液中加入盐酸/甲醇(5mL,4N)溶液，该反应液在25℃搅拌反应16小时。LCMS检测反应完全后，反应液浓缩得到白色固体3-(2-(((1S,3S)-3-((4-氨基丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(120mg,收率:87％)。LCMS:MS m/z(ESI):553.2[M+H] +,t R＝1.00min.
步骤四：向3-(2-(((1S,3S)-3-((4-氨基丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(120mg,0.22mmol)的N,N-二甲基甲酰胺(5mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(91.2mg,0.24mmol)和N,N-二异丙基乙胺(114mg,0.88mmol)，该反应液在80℃搅拌16小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱:Ultimate XBC18,50*250mm,10um(PARP-06)；流动相:乙腈-水(0.1％三氟醋酸)；流速:70mL/min；柱温:25℃)得到(4 1S,4 3S)-1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮((4 1S,4 3S)-1 7-(dimethylphosphoryl)-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one)(Z5)的三氟乙酸盐(17.2mg,收率:17％)。LCMS:MS m/z(ESI):[M+H] +＝535.2,t R＝1.55min. 1H NMR(400MHz,DMSO-d 6):δ12.00(s,1H),8.61(s,1H),8.53–8.31(m,3H),8.18(d,J＝4.0Hz,1H),8.13–8.05(m,1H),8.00(s,1H),7.29-7.26(m,1H),4.34–4.20(m,1H),2.85–2.75(m,1H),2.73–2.57(m,4H),2.20-2.12(m,2H),1.95–1.85(m,6H),1.81–1.52(m,6H),1.50–1.40(m,1H).
实施例6化合物Z6的合成
Figure PCTCN2022140669-appb-000055
步骤一：在-78℃下向2-溴-3-硝基苯甲酸(10.0g,40.6mmol)的四氢呋喃(150mL)溶液中缓慢滴加乙烯基溴化镁的四氢呋喃溶液(1M,163mL,163mmol)，滴加完再在氮气保护下于-78℃继续搅拌反应3小时，然后自然升至室温搅拌16小时。LCMS检测反应完全后，向反应液中缓慢加入饱和氯化铵水溶液(300mL)淬灭，并用1M的盐酸调节pH 4-5，然后用二氯甲烷(300mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。得到的粗品经硅胶柱(二氯甲烷/甲醇＝30/1)层析纯化得到黄色固体7-溴-1H-吲哚-6-羧酸(9.4g,收率:96.5％)。LCMS:m/z(ESI):239.8[M+H] +,t R＝1.21min.
步骤二：在25℃下向7-溴-1H-吲哚-6-羧酸(9.40g,39.2mmol)的N,N二甲基甲酰胺(80mL)溶液中加入碘甲烷(6.66g,46.9mmol)和碳酸钾(10.8g,78.3mmol)。该反应液在氮气保护下在25℃搅拌16小时。LCMS检测反应完全后，反应液加水(200mL)，然后用乙酸乙酯(200mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。得到的粗品经硅胶柱(石油醚/乙酸乙酯＝10/1)层析纯化得到黄色固体7-溴-1H-吲哚-6-羧酸甲酯(3.90g,收率:37％)。LCMS:m/z(ESI):254.0[M+H] +,t R＝1.46min. 1H NMR(400MHz,DMSO-d 6):δ11.63(s,1H),7.62(dd,J＝13.6,5.6Hz,2H),7.51(d,J＝8.0Hz,1H),6.66(d,J＝3.2Hz,1H),3.87(s,3H).
步骤三：在25℃下，向闷罐中依次加入三(二亚苄基丙酮)二钯(242mg,0.393mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(455mg,0.787mmol)和1,4-二氧六环(20mL)溶液，在氮气保护下搅拌30分钟，然后再依次加入7-溴-1H-吲哚-6-羧酸甲酯(2.0g,7.87mmol)、磷酸钾(1.67g,7.87mmol)和二甲基氧化膦(0.61g,7.87mmol)。该反应液在110℃搅拌14小时。LCMS检测反应完全后，反应液直接浓缩得到，得到的粗品经硅胶柱(石油醚/乙酸乙酯＝1/1～纯乙酸乙酯)层析纯化得到黄色固体7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(1.00g,收率:51％)。LCMS:m/z(ESI):[M+H] +＝252.0,t R＝1.30 min。 1H NMR(400MHz,DMSO-d 6):δ12.12(s,1H),7.86(d,J＝8.4Hz,1H),7.69(dd,J＝8.4,3.6Hz,1H),7.65(t,J＝2.8Hz,1H),6.59(s,1H),3.88(s,3H),1.95(s,3H),1.92(s,3H).
步骤四：在氮气气氛中，在干燥的50mL三口瓶中，加入三氯化铝(1.06g,7.96mmol)，然后用注射器加入7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(1.00g,3.98mmol)的1.2-二氯乙烷(10mL)溶液，在80℃搅拌30分钟，然后加入2,4-二氯-5-(三氟甲基)嘧啶(0.95g,4.38mmol)的1.2-二氯乙烷(1mL)溶液，该反应液在80℃下反应16小时。LCMS检测反应完全后，反应液加水(20mL)，然后用乙酸乙酯(20mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到的粗品经柱层析(石油醚/乙酸乙酯＝3/5)纯化得到白色固体3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(800mg,收率:47％)。LCMS:m/z(ESI):[M+H] +＝432.0,t R＝1.58min。 1H NMR(400MHz,CDCl 3):δ13.15(s,1H),8.83(s,1H),8.77(dd,J＝8.8,1.6Hz,1H),8.20(d,J＝2.0Hz,1H),8.07(dd,J＝8.8,4.0Hz,1H),3.96(s,3H),2.10(d,J＝14.4Hz,6H).
步骤五：在10mL微波管中，依次加入3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(770mg,1.78mmol)，N-甲基吡咯烷酮(4mL)、N,N-二异丙基乙胺(0.59mL,3.57mmol)和叔丁基((1S,3S)-3-氨基环戊基)氨基甲酸酯(392mg,1.96mmol)，该反应液80℃搅拌溶清，然后130℃微波反应2小时。LCMS检测反应完全后，反应液加水(20mL)，然后用乙酸乙酯(20mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到的粗品经柱层析(石油醚/乙酸乙酯＝1:1)纯化得到类白色固体甲基3-(2-(((1S,3S)-3-((叔丁氧羰基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(500mg,收率:58％)。LCMS:m/z(ESI):[M+H] +＝595.8,t R＝1.58min。 1H NMR(400MHz,DMSO-d 6):δ12.67(s,1H),8.59(s,2H),8.16(s,1H),8.01–7.68(m,2H),6.78(s,1H),4.46(dd,J＝13.8,6.8Hz,1H),3.94(s,3H),2.23–2.10(m,2H),2.00(d,J＝14.2Hz,6H),1.96–1.87(m,3H),1.66–1.47(m,2H),1.40(s,9H).
步骤六：室温下，将甲基3-(2-(((1S,3S)-3-((叔丁氧羰基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(400mg,0.67mmol)溶于氯化氢/二氧六环(5mL,4M)和甲醇(2mL)的混合溶液，20℃反应16小时。LCMS检测反应完全后，反应液加入饱和碳酸氢钠溶液(40mL)，然后用二氯甲烷(20mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到的粗品经柱层析(二氯甲烷/甲醇＝30:1)纯化得到白色固体3-(2-(((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(160mg,收率:48％)。LCMS:m/z(ESI):496.2[M+H] +,t R＝1.40min。
步骤七：将3-(2-(((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(500mg,1.0mmol)溶于N,N-二甲基甲酰胺(3mL)中，叔丁基(5-溴戊基)氨基甲酸酯(269mg,1.0mmol)和N,N-二异丙基乙胺(0.67mL,4.0mmol)依次加入，反应在80℃搅拌16小时。LCMS检测反应完全后，旋干，柱层析(二氯甲烷/甲醇＝100/7)纯化得到类白色固体甲基3-(2-(((1S,3S)-3-((5-((叔丁氧羰基)氨基)戊基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(420mg,收率:61％)。LCMS:m/z(ESI):[M+H] +＝681.2,t R＝1.54min。
步骤八：将甲基3-(2-(((1S,3S)-3-((5-((叔丁氧羰基)氨基)戊基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(360mg,0.53mmol)溶于水(1mL)、甲醇(1mL)和四氢呋喃(1mL)的混合体系中，然后加入一水合氢氧化锂(111mg,2.65mmol)，40℃搅拌16小时。LCMS检测反应完全后，加入水(20mL)，用盐酸(1M)调至pH＝4-5，用二氯甲烷(20mL×9)萃取，合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品3-(2-(((1S,3S)-3-((5-((叔丁氧羰基) 氨基)戊基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(320mg,收率:91％)呈白色固体，不经纯化直接用于下一步反应。LCMS:m/z(ESI):[M+H] +＝667.2,t R＝1.50min。
步骤九：将3-(2-(((1S,3S)-3-((5-((叔丁氧羰基)氨基)戊基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(320mg,0.47mmol)溶于氯化氢/甲醇(5mL,4M)中，体系在25℃搅拌4小时。LCMS检测反应完全后，溶剂旋干得到白色固体3-(2-(((1S,3S)-3-((5-氨基戊基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(260mg,收率:98％)，不经纯化直接用于下一步反应。LCMS:m/z(ESI):[M+H] +＝567.3,t R＝0.92min。
步骤十：向3-(2-(((1S，3S)-3-((5-氨基戊基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(200mg,0.35mmol)的N,N-二甲基甲酰胺(20mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(134mg,0.35mmol)和N,N-二异丙基乙胺(0.23mL,1.41mmol)，该反应液在60℃搅拌16小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱:Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相:乙腈-水(0.1％三氟醋酸)；流速:70mL/min；柱温:25℃)得到(4 1S,4 3S)-1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-3,5,11-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十二烷-12-酮((4 1S,4 3S)-1 7-(dimethylphosphoryl)-2 5-(trifluoromethyl)-1 1H-3,5,11-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclododecaphan-12-one)(Z6)的三氟乙酸盐(34.3mg,收率:15％)。LCMS:m/z(ESI):[M+H] +＝549.2,t R＝0.70min。 1H NMR(400MHz,DMSO-d 6):δ11.84–11.94(m,1H),8.70–8.30(m,3H),8.30–8.07(m,3H),7.87–8.10(m,1H),7.62–7.22(m,1H),4.39–4.18(m,1H),3.50–3.05(m,1H),3.01–2.80(m,3H),2.70–2.52(m,1H),2.45–2.33(s,1H),2.22–2.01(m,2H),2.00–1.37(m,15H).
实施例7化合物Z7的合成
Figure PCTCN2022140669-appb-000056
步骤一：在室温下，向3-(2-(((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(500mg,1.00mmol)的N,N-二甲基甲酰胺溶液(5mL)中依次加入(2-(2-溴乙氧基)乙基)氨基甲酸叔丁酯(270mg,1.00mmol)和N,N-二异丙基乙胺(0.67mL,4.00mmol)，该反应液在氮气保护下于70℃搅拌反应16小时。LCMS检测反应完全后，反应液加入10％氯化铵水溶液(100mL)，用乙酸乙酯(100mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。得到的粗品经硅胶柱(二氯甲烷/甲醇＝50/1～10/1)层析纯化得到黄色固体甲基3-(2-(((1S,3S)-3-((2-(2-((叔丁氧羰基)氨基)乙氧基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(170mg,收率:46％)。LCMS:MS m/z(ESI):[M+H] +＝683.4,t R ＝1.18min。
步骤二：向甲基3-(2-(((1S,3S)-3-((2-(2-((叔丁氧羰基)氨基)乙氧基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(350mg,0.51mmol)的四氢呋喃(2mL)和甲醇(2mL)的混合溶液中加入氢氧化锂(86.0mg,2.05mmol)的水(2mL)溶液，该反应液在40℃搅拌下反应16小时。LCMS检测反应完全后，反应液用1.0M的盐酸水溶液酸化至pH＝3-4，用二氯甲烷/甲醇(10:1,60mL×6)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到黄色固体3-(2-(((1S,3S)-3-((2-(2-((叔丁氧基羰基)氨基)乙氧基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(314mg，收率:92％)。粗产品无需纯化直接用于下一步反应。LCMS:MS m/z(ESI):[M+H] +＝669.2,t R＝1.10min。
步骤三：在25℃下向3-(2-(((1S,3S)-3-((2-(2-((叔丁氧基羰基)氨基)乙氧基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(300mg,0.45mmol)的甲醇(5mL)溶液中加入盐酸/甲醇(5mL,4M)溶液，该反应液在40℃下搅拌4小时。LCMS检测反应完全后，反应液直接浓缩得到黄色固体3-(2-(((1S,3S)-3-((2-(2-氨基乙氧基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(244mg,收率:96％)。粗品无需纯化直接用于下一步反应。LCMS:MS m/z(ESI):[M+H] +＝569.2,t R＝0.95min。
步骤四：向3-(2-(((1S,3S)-3-((2-(2-氨基乙氧基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(220mg,0.39mmol)的N,N-二甲基甲酰胺(8mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(149mg,0.39mmol)和N,N-二异丙基乙胺(182mg,1.41mmol)，该反应液在60℃搅拌16小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；色谱条件：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)得到(4 1S,4 3S)-1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-8-氧杂-3,5,11-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十二烷-12-酮((4 1S,4 3S)-1 7-(dimethylphosphoryl)-2 5-(trifluoromethyl)-1 1H-8-oxa-3,5,11-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclododecaphan-12-one)(Z7)的三氟乙酸盐(33.5mg,收率:16％)。LCMS:MS m/z(ESI):[M+H] +＝551.2,t R＝0.69min。 1H NMR(400MHz,DMSO-d 6):δ12.06–12.05(m,1H),8.69(d,J＝8.0Hz,2H),8.64–8.48(m,2H),8.13(d,J＝4.4Hz,1H),8.07(d,J＝2.4Hz,1H),7.86–7.75(m,1H),7.42(dd,J＝8.0,3.2Hz,1H),4.32–4.18(m,1H),3.82–3.72(m,5H),3.46(t,J＝7.2Hz,1H),3.31–3.17(m,2H),3.16–3.08(m,1H),2.72(dd,J＝14.4,7.2Hz,1H),2.30–2.20(m,1H),2.19–2.11(m,1H),2.02–1.86(m,6H),1.82–1.62(m,3H).
实施例8化合物Z8的合成
Figure PCTCN2022140669-appb-000057
步骤一：在10mL微波管中，依次加入3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(810mg,1.88mmol)、N-甲基吡咯烷酮(5mL)、N,N-二异丙基乙胺(0.93mL,5.63mmol)和叔丁基((1r,3r)-3-氨基环丁基)氨基甲酸酯(384mg,2.06mmol)，反应液80℃搅拌溶清，然后在130℃微波反应2小时。LCMS检测反应完全后，反应液加水(20mL)，然后用乙酸乙酯(20mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到的粗品经柱层析(石油醚/乙酸乙酯＝1/1)纯化得到类白色固体甲基3-(2-(((1r,3r)-3-((叔丁氧羰基)氨基)环丁基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(970mg,收率:89％)。LCMS:MS m/z(ESI):[M+H] +＝582.2,t R＝1.89min。
步骤二：室温下，将甲基3-(2-(((1r,3r)-3-((叔丁氧羰基)氨基)环丁基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(500mg,0.86mmol)溶于氯化氢/二氧六环(5mL,4M)和甲醇(2mL)的混合溶液，25℃反应16小时。LCMS检测反应完全后，反应液加入饱和碳酸氢钠溶液(40mL)，然后用乙酸乙酯(30mL×10)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到的粗品经硅胶柱(二氯甲烷/甲醇＝10/1)层析纯化得到白色固体3-(2-(((1r,3r)-3-氨基环丁基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(220mg,收率:53％)。LCMS:MS m/z(ESI):[M+H] +＝482.2,t R＝1.35min。
步骤三：在室温下向3-(2-(((1r,3r)-3-氨基环丁基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(300mg,0.62mmol)的N,N-二甲基甲酰胺溶液(5mL)中依次加入叔丁基(4-溴丁基)氨基甲酸酯(157mg,0.62mmol)和N,N-二异丙基乙胺(322mg,2.49mmol)，该反应液在氮气保护下于80℃搅拌反应16小时。LCMS检测反应完全后，反应液加入饱和氯化铵溶液(100mL)，并用乙酸乙酯(100mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩至干。得到的粗品经硅胶柱(二氯甲烷/甲醇＝50/1到10/1)层析纯化得到黄色固体物甲基3-(2-(((1r,3r)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环丁基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(225mg,收率:55％)。LCMS:MS m/z(ESI):[M+H] +＝653.3,t R＝1.19min。
步骤四：向甲基3-(2-(((1r,3r)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环丁基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(225mg,0.35mmol)的四氢呋喃(2mL)和甲醇(2mL)的混合溶液中加入一水合氢氧化锂(72.0mg,1.72mmol)的水(2mL)溶液，该反应液在40℃搅拌反 应16小时。LCMS检测反应完全后，反应液用1.0M的盐酸水溶液酸化至pH＝3-4，并用二氯甲烷/甲醇(10:1,60mL×6)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到黄色固体3-(2-(((1r,3r)-3-((4-((叔丁氧基羰基)氨基)丁基)氨基)环丁基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(300mg,收率95％)。粗产品无需纯化直接用于下一步反应。LCMS:MS m/z(ESI):[M+H] +＝639.2,t R＝1.40min。
步骤五：向3-(2-(((1r,3r)-3-((4-((叔丁氧基羰基)氨基)丁基)氨基)环丁基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(300mg,0.33mmol)的甲醇(5mL)溶液中加入盐酸/甲醇(5mL,4M)溶液，该反应液在40℃搅拌反应16小时。LCMS检测反应完全后，反应液浓缩至干得到黄色固体3-(2-(((1r,3r)-3-((4-氨基丁基)氨基)环丁基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(270mg,收率:94％)。粗品无需纯化直接用于下一步反应。LCMS:MS m/z(ESI):[M+H] +＝639.2,t R＝1.31min。
步骤六：向3-(2-(((1r,3r)-3-((4-氨基丁基)氨基)环丁基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(270mg,0.31mmol)的N,N-二甲基甲酰胺(5mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(118mg,0.31mmol)和N,N-二异丙基乙胺(200mg,1.55mmol)，该反应液在70℃搅拌16小时。LCMS检测反应完全后，反应液浓缩至干燥，得到的粗品经反相制备(70mL/min,25℃,Ultimate XB-C18,50*250mm,10um(PARP-02),乙腈-水(0.1％三氟醋酸))得到(4 1r,4 3r)-1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环丁烷环十一烷-11-酮((4 1r,4 3r)-1 7-(dimethylphosphoryl)-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclobutanacycloundecaphan-11-one)(Z8)的三氟乙酸盐(3.9mg,收率:2.4％)。LCMS:MS m/z(ESI):[M+H] +＝551.3,t R＝1.05min。 1H NMR(400MHz,DMSO-d 6):δ11.94(s,1H),8.79(d,J＝8.0Hz,1H),8.56(s,1H),8.29(d,J＝4.4Hz,1H),8.07–7.92(m,2H),7.42–7.32(m,1H),4.82–4.68(m,1H),4.05(s,1H),2.86–2.78(m,2H),2.36–2.28(m,2H),2.26–2.18(m,2H),2.08–1.94(m,3H),1.91(s,3H),1.87(s,3H),1.76–1.68(m,2H),1.56–1.48(m,2H).
实施例9化合物Z9的合成
Figure PCTCN2022140669-appb-000058
步骤一：在10mL微波管中，依次加入3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(450mg,1.04mmol)，N-甲基吡咯烷酮(5mL)、N,N-二异丙基乙胺(0.52mL,3.13mmol)和叔丁基((1S,3S)-3-氨基环己基)氨基甲酸酯(235mg,1.09mmol)，该反应液80℃搅拌溶清，然后在130℃微波反应2小时。LCMS检测反应完全后，反应液加水(20mL)，然后用乙酸乙酯(20mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到的粗品经柱层析(石油醚/乙酸乙酯＝1/1)纯化得到类白色固体甲基3-(2-(((1S,3S)-3-((叔丁氧羰基)氨基)环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(470mg,收率:74％)。LCMS:m/z(ESI):[M+H] +＝610.2,t R＝1.98min。
步骤二：室温下，将甲基3-(2-(((1S,3S)-3-((叔丁氧羰基)氨基)环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(470mg,0.77mmol)溶于氯化氢/二氧六环(5mL,4M)和甲醇(2mL)的混合溶液，25℃反应16小时。LCMS检测反应完全后，反应液加入饱和碳酸氢钠溶液(40mL)，然后用乙酸乙酯(30mL×10)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到的粗品经硅胶柱(二氯甲烷/甲醇＝10/1)层析纯化得到白色固体3-(2-(((1S,3S)-3-氨基环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(310mg,收率:79％)。LCMS:m/z(ESI):[M+H] +＝510.5,t R＝1.42min。
步骤三：将3-(2-(((1S,3S)-3-氨基环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(310mg,0.61mmol)溶于N,N-二甲基甲酰胺(3mL)中，叔丁基(4-溴丁基)氨基甲酸酯(153mg,0.61mmol)和N,N-二异丙基乙胺(0.67mL,4.0mmol)依次加入，反应在80℃搅拌16小时。LCMS检测反应完全后，旋干，柱层析(二氯甲烷/甲醇＝100/7)纯化得到类黄色固体甲基3-(2-(((1S,3S)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(200mg,收率:48％)。LCMS:m/z(ESI):[M+H] +＝681.2,t R＝1.60min。
步骤四：将甲基3-(2-(((1S,3S)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(200mg,0.29mmol)溶于水(1mL)、甲醇(1mL)和四氢 呋喃(1mL)的混合体系中，然后加入一水合氢氧化锂(61.6mg,1.47mmol)，反应在40℃搅拌16小时。LCMS检测反应完全后，旋干溶剂得到粗品3-(2-(((1S,3S)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(180mg,收率:92％)，呈黄色固体，不经纯化直接用于下一步反应。LCMS:m/z(ESI):[M+H] +＝667.2,t R＝1.43min。
步骤五：将3-(2-(((1S,3S)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(180mg,0.27mmol)溶于氯化氢/甲醇(5mL,4M)中，体系在15℃搅拌4小时。LCMS检测反应完全后，直接将溶剂旋干得到黄色固体3-(2-(((1S,3S)-3-((4-氨基丁基)氨基)环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(120mg,收率:78％)，不经纯化直接用于下一步反应。LCMS:m/z(ESI):[M+H] +＝567.2,t R＝1.43min。
步骤六：向3-(2-(((1S，3S)-3-((4-氨基丁基)氨基)环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(120mg,0.21mmol)的N,N-二甲基甲酰胺(10mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(80.4mg,0.21mmol)和N,N-二异丙基乙胺(0.14mL,0.84mmol)，该反应液在60℃搅拌16小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate SFC18,50*250mm,10um(PARP-02)；流动相:乙腈-水(0.1％三氟醋酸)；流速:70mL/min；柱温:25℃)得到(4 1S,4 3S)-1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环己烷环十一烷-11-酮((4 1S,4 3S)-1 7-1 7-(dimethylphosphoryl)-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclohexanacycloundecaphan-11-one)(Z9)的三氟乙酸盐(8.2mg,收率:5.8％)。LCMS:m/z(ESI):[M+H] +＝549.2,t R＝0.72min。 1H NMR(400MHz,DMSO-d 6):δ11.87(d,1H),8.62(s,1H),8.27–8.09(m,2H),7.97(m,2H),7.88–7.76(m,2H),7.29(m,1H),4.05(m,1H),2.83(m,3H),2.71–2.58(m,2H),2.36(m,1H),1.88(m,8H),1.58(m,9H).
实施例10化合物Z10的合成
Figure PCTCN2022140669-appb-000059
步骤一：在室温下向3-(2-(((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(300mg,0.61mmol)的N,N-二甲基甲酰胺溶液(3mL)中依次加入3-(叔丁氧羰基氨基)丙基溴(144mg,0.61mmol)和N,N-二异丙基乙胺(313mg,2.42mmol)，该反应液在氮气保护下于80℃搅拌反应16小时。LCMS检测反应完全后，反应液加入10％氯化铵水溶液(50mL)，用乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。得到的粗品经硅胶柱(二氯甲烷/甲醇＝40/1～15/1)层析纯化得到黄色固体3-(2-(((1S,3S)-3-(3-(叔丁氧羰基氨基丙基)氨基)环戊基氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(100mg,收率:25％)。LCMS:MS m/z(ESI):[M+H] +＝653.6,t R＝1.53min.
步骤二：向3-(2-(((1S,3S)-3-(3-(叔丁氧羰基氨基丙基)氨基)环戊基氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(100mg,0.16mmol)的四氢呋喃(1.5mL)和甲醇(1.5mL)的混合溶液中加入一水合氢氧化锂(33mg,0.78mmol)的水(1.5mL)溶液，该反应液在40℃搅拌反应16小时。LCMS检测反应完全后，反应液用1.0M的盐酸水溶液酸化至pH＝3-4，并用二氯甲烷(10mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到白色固体3-(2-(((1S,3S)-3-((3-(叔丁氧羰基)氨基)丙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(90mg,收率92％)，不经纯化直接用下一步反应。LCMS:MS m/z(ESI):[M+H] +＝639.2,t R＝1.10min。
步骤三：在25℃下向3-(2-(((1S,3S)-3-((3-(叔丁氧羰基)氨基)丙基)氨基)环戊基)氨基-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(90mg,0.14mmol)的甲醇(3mL)溶液中加入盐酸/甲醇(6mL,4N)溶液，该反应液在40℃搅拌反应2小时。LCMS检测反应完全后，反应液浓缩得到白色固体3-(2-(((1S,3S)-3-((3-氨丙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(70mg,收率:93％)。LCMS:MS m/z(ESI):[M+H] +＝539.6,t R＝1.33min。
步骤四：向3-(2-(((1S,3S)-3-((3-氨丙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(65mg,0.12mmol)的N,N-二甲基甲酰胺(8mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(80mg,0.21mmol)和N,N-二异丙基乙胺(300mg,2.32mmol)，该反应液在80℃搅拌16小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XBC18,50*250mm,10um(PARP-06)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；室温：25℃)纯化得到(4 1S,4 3S)-1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-3,5,9-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环癸烷-10-酮((4 1S,4 3S)-1 7-(dimethylphosphoryl)-2 5-(trifluoromethyl)-1 1H-3,5,9-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclodecaphan-10-one)(Z10)的三氟乙酸盐(1.6mg,收率:3％)。LCMS:MS m/z(ESI):[M+H] +＝521.2,t R＝1.26min。
实施例11化合物Z11的合成
Figure PCTCN2022140669-appb-000060
步骤一：在-78℃下，向2-氯-3-硝基苯甲酸(10.0g,49.6mmol)的四氢呋喃(120mL)溶液中缓慢滴加乙烯基溴化镁的四氢呋喃溶液(198mL,198mmol,1M)，滴加完再在氮气保护下于-78℃继续搅拌反应3小时。LCMS检测反应完全后，向反应液中缓慢加入饱和氯化铵水溶液(300mL)淬灭，并用1M的盐酸调节pH至4-5，然后用二氯甲烷(300mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品棕黄色固体7-氯-1H-吲哚-6-羧酸(8.03g,收率:83％)，不经纯化直接用于下一步反应。LCMS:m/z(ESI):[M+H] +＝196.0,t R＝1.53min。
步骤二：在25℃下向7-氯-1H-吲哚-6-羧酸(8.00g,40.9mmol)的N,N二甲基甲酰胺(85mL)溶液中加入碘甲烷(6.97g,49.1mmol)和碳酸钾(11.3g,81.9mmol)。该反应液在氮气保护下在25℃搅拌16小时。TLC检测反应完全后，反应液加水(200mL)，然后用乙酸乙酯(150mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。得到的粗品经硅胶柱(石油醚/乙酸乙酯＝10/1)层析纯化得到黄色固体7-氯-1H-吲哚-6-羧酸甲酯(5.8g,收率:67％)。LCMS:m/z(ESI):[M+H] +＝210.1,t R＝1.45min。 1H NMR(400MHz,CDCl 3):δ8.67(s,1H),7.72(d,J＝8.4Hz,1H),7.55(d,J＝8.4Hz,1H),7.40(m,1H),6.62(dd,J＝3.2,2.0Hz,1H),3.95(s,3H).
步骤三：在干燥50mL三口瓶中，加入三氯化铝(1.27g,9.54mmol)，在氮气保护下加入7-氯-1H-吲哚-6-羧酸甲酯(1.00g,4.77mmol)的1.2-二氯乙烷(10mL)溶液，此体系在80℃搅拌30分钟，然后加入2,4-二氯-5-(三氟甲基)嘧啶(1.09g,5.01mmol)的1.2-二氯乙烷(1mL)溶液，该反应液在80℃下反应16小时。TLC检测反应完全后，反应液加水(30mL)，然后用乙酸乙酯(30mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到的粗品经柱层析(石油醚/乙酸乙酯＝3/5)纯化得到白色固体7-氯-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸甲酯(0.38g, 收率:20％)。LCMS:m/z(ESI):[M+H] +＝392.0,t R＝1.70min。 1H NMR(400MHz,DMSO-d 6):δ12.86(s,1H),9.10(s,1H),8.25(d,J＝8.4Hz,1H),8.08(d,J＝2.4Hz,1H),7.73(d,J＝8.4Hz,1H),3.91(s,3H).
步骤四：在10mL微波管中，依次加入7-氯-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸甲酯(420mg,1.08mmol)，N-甲基吡咯烷酮(2mL)、N,N-二异丙基乙胺(0.53mL,3.23mmol)和叔丁基((1S,3S)-3-氨基环戊基)氨基甲酸酯(237mg,1.18mmol)，该反应液80℃搅拌溶清，然后在130℃微波反应2小时。LCMS检测反应完全后，反应液加水(20mL)，然后用乙酸乙酯(20mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到的粗品经柱层析(石油醚/乙酸乙酯＝1/1)纯化得到类白色固体甲基3-(2-(((1S,3S)-3-((叔丁氧羰基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-氯-1H-吲哚-6-羧酸酯(430mg,收率:72％)。LCMS:m/z(ESI):[M+H] +＝554.0,t R＝2.05min。
步骤五：室温下，将甲基3-(2-(((1S,3S)-3-((叔丁氧羰基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-氯-1H-吲哚-6-羧酸酯(430mg,0.72mmol)溶于氯化氢/二氧六环(4mL,4M)和甲醇(2mL)的混合溶液，15℃反应16小时。LCMS检测反应完全后，反应液加入饱和碳酸氢钠溶液(40mL)，然后用二氯甲烷(20mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到的粗品经柱层析(二氯甲烷/甲醇＝30:1)纯化得到白色固体3-(2-(((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-氯-1H-吲哚-6-羧酸甲酯(320mg,收率:89％)。LCMS:m/z(ESI):[M+H] +＝454.0,t R＝1.38min。
步骤六：将3-(2-(((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-氯-1H-吲哚-6-羧酸甲酯(320mg,0.71mmol)溶于N,N-二甲基甲酰胺(2mL)中，叔丁基(4-溴丁基)氨基甲酸酯(178mg,0.71mmol)和N,N-二异丙基乙胺(0.58mL,3.53mmol)依次加入，反应在80℃搅拌16小时。LCMS检测反应完全后，旋干，柱层析(二氯甲烷/甲醇＝100/7)纯化得到黄色固体甲基3-(2-(((1S,3S)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-氯-1H-吲哚-6-羧酸酯(230mg,收率:52％)。LCMS:m/z(ESI):[M+H] +＝625.4,t R＝1.07min。
步骤七：将甲基3-(2-((1S,3S)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-氯-1H-吲哚-6-羧酸酯(230mg,0.37mmol)溶于水(1mL)、甲醇(1mL)和四氢呋喃(1mL)的混合体系中，然后加入一水合氢氧化锂(77.2mg,1.84mmol)，反应在40℃搅拌16小时。LCMS检测反应完全后，旋干溶剂得到粗品3-(2-(((1S,3S)-3-((4-((叔丁氧羰基)氨基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-氯-1H-吲哚-6-羧酸(锂盐,340mg,收率:91％)呈黄色固体，不经纯化直接用于下一步反应。LCMS:m/z(ESI):[M+H] +＝611.4,t R＝0.98min。
步骤八：将3-(2-(((1S,3S)-3-((4-((叔丁氧羰基氨基)戊基氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(锂盐,340mg)溶于氯化氢/甲醇(5mL,4M)中，体系在25℃搅拌4小时。LCMS检测反应完全后，旋干溶剂得到棕色固体3-(2-(((1S,3S)-3-((4-氨基丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-氯-1H-吲哚-6-羧酸(含氯化锂,300mg,收率:88％)，不经纯化直接用于下一步反应。LCMS:m/z(ESI):[M+H] +＝511.2,t R＝0.61min。
步骤九：向3-(2-(((1S,3S)-3-((4-氨基丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-氯-1H-吲哚-6-羧酸(含氯化锂,290mg,0.28mmol)的N,N-二甲基甲酰胺(10mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(108mg,0.28mmol)和N,N-二异丙基乙胺(0.24mL,1.42mmol)，该反应液在60℃搅拌16小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备纯化(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)得到(4 1S,4 3S)-1 7-氯-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)- 嘧啶-4(1,3)-环戊基环十一烷-11-酮((4 1S,4 3S)-1 7-chloro-25-(trifluoromethyl)-11H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one)(Z11)的三氟乙酸盐(30.8mg,收率:22％)。LCMS:m/z(ESI):[M+H] +＝493.2,t R＝1.27min。 1H NMR(400MHz,DMSO-d 6):δ12.33(s,1H),8.64(s,1H),8.43(s,1H),8.34–8.04(m,3H),7.99(s,1H),7.78(s,1H),7.26(d,J＝8.4Hz,1H),3.60(s,2H),2.88(s,1H),2.55(s,1H),2.47–2.38(m,1H),2.30–1.95(m,3H),1.83–1.41(m,6H),1.30–1.25(m,2H).
实施例12化合物Z12的合成
Figure PCTCN2022140669-appb-000061
步骤一：在室温下向3-(2-((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(750mg,1.52mmol)的甲醇溶液(10mL)中依次加入叔丁基((4-氧环己基)甲基)氨基甲酸酯(414mg,1.82mmol)和冰醋酸(0.1mL)，该反应液在氮气保护下于25℃搅拌反应16小时。然后加入氰基硼氢化钠(287mg,4.56mmol)，该反应液在25℃搅拌反应2小时。LCMS检测反应完全后，向反应液加入饱和氯化铵溶液(20mL)，用乙酸乙酯(30mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩至干。得到的粗品经反相制备纯化得到(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)得到白色固体甲基3-(2-((1S,3S)-3-((叔丁氧羰基)氨基)甲基环己基氨基)环戊基氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸盐(P1:340mg,收率32％)。LCMS:MS m/z(ESI):707.4[M+H] +,t R＝7.43min。甲基3-(2-((1S,3S)-3-((叔丁氧羰基)氨基)甲基环己基氨基)环戊基氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸盐(P2:340mg,收率:32％)。LCMS:MS m/z(ESI):707.4[M+H] +,t R＝7.53min。
步骤二：向甲基3-(2-(((1S,3S)-3-((4-(((叔丁氧羰基)氨基)甲基)环己基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸盐(P2:340mg,0.48mmol)的四氢呋喃(3mL)和甲醇(3mL)的混合溶液中加入氢氧化锂一水合物(101mg,2.40mmol)的水(3mL)溶液，该反应液在40℃搅拌反应过夜。LCMS检测反应完全后，反应液用1.0M的盐酸水溶液酸化至pH＝3-4，并用二氯甲烷(10mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩白色固体3-(2-(((1S,3S)-3-((4-(((叔丁氧羰基)氨基)甲基)环己基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(300mg,收率:90％)，粗品不经纯化直接用于下一步反应。LCMS:MS m/z (ESI):[M+H] +＝692.6,t R＝1.14min。
步骤三：在25℃下向3-(2-(((1S,3S)-3-((4-(((叔丁氧羰基)氨基)甲基)环己基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(300mg,0.43mmol)的甲醇(3mL)溶液中加入盐酸/二氧六环(3mL,4N)溶液，该反应液在25℃搅拌反应16小时。LCMS检测反应完全后，反应液浓缩，经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)得到白色固体3-(2-(((1S,3S)-3-((4-(氨甲基)环己基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(140mg,收率:55％)。LCMS:MS m/z(ESI):[M+H] +＝592.8,t R＝0.94min。
步骤四：向3-(2-(((1S,3S)-3-((4-(氨甲基)环己基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(30mg,0.05mmol)的N,N-二甲基甲酰胺(5mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(19mg,0.05mmol)和N,N-二异丙基乙胺(32mg,0.25mmol)，该反应液在70℃搅拌14小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XBC18,50*250mm,10um(PARP-06)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)得到(4 1S,4 3S)-1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-3,5,8-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-6(1,4)-环己基-4(1,3)-环戊烷环壬烷-9-酮((4 1S,4 3S)-1 7-(dimethylphosphoryl)-2 5-(trifluoromethyl)-1 1H-3,5,8-triaza-1(3,6)-indola-2(4,2)-pyrimidina-6(1,4)-cyclohexana-4(1,3)-cyclopentanacyclononaphan-9-one)(Z12)的三氟乙酸盐(2.0mg,收率:9％)。LCMS:MS m/z(ESI):[M+H] +＝575.3,t R＝1.55min。 1H NMR(400MHz,CD 3OD):δ11.44(s,1H),8.63(s,1H),7.94(d,J＝6.8Hz,1H),7.80(s,1H),7.21(dd,J＝8.0,3.2Hz,1H),3.94–3.68(m,2H),3.17–2.94(m,3H),2.68-2.63(m,1H),2.48-2.41(m,1H),2.28(d,J＝12.8Hz,1H),2.16-2.11(m,1H),2.02-1.97(m,8H),1.94-1.85(m,1H),1.78–1.53(m,6H),1.37-1.29(m,1H),1.00-0.85(m,1H).
实施例13化合物Z13的合成
Figure PCTCN2022140669-appb-000062
步骤一：氮气保护下，于25℃向叔丁基((1S,3S)-3-羟基环丁基)(甲基)氨基甲酯(200mg,1.0mmol)的二氯甲烷(4mL)溶液中加入戴斯-马丁试剂(843mg,2.0mmol)，该反应液在氮气保护下25℃搅拌反应3小时。LCMS检测反应完全后，反应液用水(10mL)和乙酸乙酯(20mL×3)萃取，合并的有机层用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤浓缩至干。得到的粗品经硅胶柱(石油醚/乙酸乙酯＝10/1～5/1)层析纯化得到白色固体物{[(3-氧亚基环丁基)甲基]氨基}甲烷酸-2-甲基丙-2-基酯(170mg,收率:86％)。LCMS:m/z(ESI):[M+H-56] +＝144.2,t R＝1.58min。
步骤二：氮气保护下，于25℃向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(423mg,0.85mmol)和{[(3-氧亚基环丁基)甲基]氨基}甲烷酸-2-甲基丙-2-基酯(170mg,0.85mmol)的甲醇(3mL)溶液中加入醋酸(20mg,0.33mmol)，氮气保护下25℃搅拌反应16小时。再向反应液中加入氰基硼氢化钠(268mg,4.26mmol)，该反应在氮气保护下25℃继续反应6小时。LCMS检测反应完毕。反应液用水(10mL)和乙酸乙酯(30mL×3)萃取，合并的有机层用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤浓缩至干。得到的粗品经硅胶柱(二氯甲烷/甲醇＝60/1～30/1)层析纯化得到白色固体{[(3-{[(1S,3S)-3-[(4-{7-[二甲基(氧亚基)-λ5-甲磷基]-6-(甲氧基羰基)-1H-吲哚-3-基}-5-(三氟甲基)嘧啶-2-基)氨基]环戊基]氨基}环丁基)甲基]氨基}甲烷酸-2-甲基丙-2-基酯(380mg,收率:67％)。LCMS:m/z(ESI):[M+H] +＝679.4,t R＝1.19min。
步骤三：氮气保护下，于25℃向{[(3-{[(1S,3S)-3-[(4-{7-[二甲基(氧亚基)-λ5-甲磷基]-6-(甲氧基羰基)-1H-吲哚-3-基}-5-(三氟甲基)嘧啶-2-基)氨基]环戊基]氨基}环丁基)甲基]氨基}甲烷酸-2-甲基丙-2-基酯的甲醇(4mL)、四氢呋喃(4mL)、水(4mL)混合溶液中加入一水合氢氧化锂(117mg,2.8mmol)，该反应液在氮气保护下升温至40℃搅拌反应16小时，LCMS检测反应完毕。向反应液中缓慢加入2M的盐酸溶液调节pH至4-5，并用乙酸乙酯(50mL×5)萃取，合并的有机层用饱和食盐水(10mL) 洗涤，无水硫酸钠干燥，过滤浓缩至干得到的粗品无色油状物7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-{[3-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂己-6-基)环丁基]氨基}环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(400mg,纯度:70％,收率:75％)，不经纯化直接用于下一步反应。LCMS:m/z(ESI):[M+H] +＝664.6,t R＝1.11min。
步骤四：向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-{[3-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂己-6-基)环丁基]氨基}环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(300mg,0.45mmol)的甲醇(5mL)溶液中加入4M的甲醇氯化氢溶液(10mL)，该反应液在氮气保护下升温至40℃搅拌反应2小时。LCMS检测反应完全后，向反应液中缓慢加入饱和的碳酸氢钠溶液(30mL)中，并用乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩至干。得到的粗品经制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)纯化得到白色固体7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-{[3-(氨基甲基)环丁基]氨基}环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(185mg,收率:73％)。LCMS:MS m/z(ESI):[M+H] +＝565.2,t R＝1.25min。
步骤五：向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-{[3-(氨基甲基)环丁基]氨基}环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(50mg,0.089mmol)的N,N-二甲基甲酰胺(5mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(34mg,0.089mmol)和N,N-二异丙基乙胺(0.059mL,0.35mmol)，该反应液在60℃搅拌2h。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)纯化得到(4 1S,4 3S)-1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-3,5,8-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷-6(1,3)-环丁烷环壬烷-9-酮((4 1S,4 3S)-1 7-(dimethylphosphoryl)-2 5-(trifluoromethyl)-1 1H-3,5,8-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentana-6(1,3)-cyclobutanacyclononaphan-9-one)(Z13)的三氟乙酸盐(2.43mg,收率:5％)。LCMS:MS m/z(ESI):[M+H] +＝547.3,t R＝0.83min。 1H NMR(400MHz,CD 3OD):δ8.61(s,1H),8.00–7.90(m,1H),7.77(s,1H),7.16(dd,J＝8.0,2.8Hz,1H),4.00–3.90(m,1H),3.70–3.65(m,1H),3.61–3.52(m,1H),3.25–3.15(m,1H),2.90–2.80(m,1H),2.65–2.56(m,2H),2.40–2.30(m,3H),2.15–2.05(m,1H),1.99(s,3H),1.96(s,3H),1.84–1.75(m,1H),1.73–1.61(m,2H),1.56–1.40(m,2H).
实施例14化合物Z14的合成
Figure PCTCN2022140669-appb-000063
步骤一：向{[(3S)-四氢-1H-吡咯-3-基]氨基}甲烷酸苄基酯(225mg,1.02mmol)的N,N-二甲基甲烷酰胺(6mL)溶液中依次加入[(5-溴戊基)氨基]甲烷酸-2-甲基丙-2-基酯(299mg,1.12mmol)和N,N-二异丙基乙二胺(528mg,4.08mmol)，该反应液在80℃氮气氛围下搅拌16小时。LCMS检测反应完全后，反应液用水(15mL)和乙酸乙酯(25mL×3)萃取，合并的有机层用饱和食盐水(15mL×2)洗涤，无水硫酸钠干燥，过滤浓缩至干。得到的粗品经硅胶柱(二氯甲烷/甲醇＝30/1～10/1)层析纯化得到黄色固体物{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂癸-10-基)四氢-1H-吡咯-3-基]氨基}甲烷酸苄基酯(373mg,收率:90％)。LCMS:m/z(ESI):[M+H] +＝406.2,t R＝0.80min。
步骤二：向{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂癸-10-基)四氢-1H-吡咯-3-基]氨基}甲烷酸苄基酯(500mg,1.23mmol)的甲醇(8mL)溶液中加入钯碳(50mg,10％含量,60％含水)，反应液在25℃，氢气氛围下搅拌反应2小时。LCMS检测反应完毕。反应液过滤，旋干得到粗品({5-[(3S)-3-氨基四氢-1H-吡咯-1-基]戊基}氨基)甲烷酸-2-甲基丙-2-基酯(370mg,纯度约85％,收率:94％)，粗品无需进行纯化直接用于下一步反应。LCMS:m/z(ESI):[M+H] +＝272.2,t R＝0.46min。
步骤三：向({5-[(3S)-3-氨基四氢-1H-吡咯-1-基]戊基}氨基)甲烷酸-2-甲基丙-2-基酯(334mg,1.23mmol)的N,N-二甲基甲烷酰胺(8mL)中依次加入3-[2-氯-5-(三氟甲基)嘧啶-4-基]-7-[二甲基(氧亚基)-λ5-甲磷基]-1H-吲哚-6-甲酸甲酯(507mg,1.23mmol)和N,N-二异丙基乙二胺(477mg,3.69mmol)，该反应液在氮气保护下升温至80℃搅拌反应16小时，LCMS检测反应完毕。反应液用水(20mL)和二氯甲烷(30mL×5)萃取，合并的有机层用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤浓缩至干。得到的粗品经硅胶柱(二氯甲烷/甲醇＝30/1～10/1)层析纯化得到黄色固体物7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂癸-10-基)四氢-1H-吡咯-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(550mg,收率:67％)。LCMS:m/z(ESI):[M+H] +＝667.4,t R＝0.92min。
步骤四：向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂癸-10-基)四氢-1H-吡咯-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(550mg,0.83mmol)的甲醇(3mL)、水(3mL)、四氢呋喃(3mL)混合溶液中加入一水合氢氧化锂(173mg,4.13mmol)，该反应液在氮气保护下升温至40℃搅拌反应2小时。LCMS检测反应完全后，减压浓缩除去溶剂得到的粗产品黄色固体7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂癸-10-基)四氢-1H-吡咯-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(480mg，纯度约85％,收率:95％)。LCMS:MS m/z(ESI):[M+H] +＝653.2,t R＝0.83min。
步骤五：向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂癸-10-基)四氢-1H-吡咯-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(480mg,0.70mmol)中加入4M的1,4-二氧六环氯化氢溶液(8mL)，该反应液在氮气保护下升温至40℃搅拌反应2小时。LCMS检测反应完全后，向反应液中缓慢加入饱和的碳酸氢钠溶液(30mL)中，并用乙酸乙酯(40mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩至干。得到的粗品经反向制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)纯化得到黄色固体7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(5-氨基戊基)四氢-1H-吡咯-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(300mg,收率:77％)。LCMS:MS m/z(ESI):553.2[M+H] +,t R＝0.61min。
步骤六：向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(5-氨基戊基)四氢-1H-吡咯-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(100mg,0.18mmol)的N,N-二甲基甲酰胺(5mL)溶液 中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(69mg,0.18mmol)和N,N-二异丙基乙胺(94mg,0.12mmol)，该反应液在60℃搅拌16小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)纯化得到(4 3S)-1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-3,10-二氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(3,1)-吡咯烷环十一烷-11-酮((4 3S)-1 7-(dimethylphosphoryl)-2 5-(trifluoromethyl)-1 1H-3,10-diaza-1(3,6)-indola-2(4,2)-pyrimidina-4(3,1)-pyrrolidinacycloundecaphan-11-one)(Z14)的三氟乙酸盐(13.8mg,收率:14％)。LCMS:MS m/z(ESI):[M+H] +＝535.2,t R＝0.63min。 1H NMR(400MHz,CD 3OD):δ8.63(s,1H),8.43(s,1H),7.97(s,1H),7.32(dd,J＝8.0,3.6Hz,1H),4.50–4.37(m,1H),3.97–3.85(m,1H),3.63–3.50(m,1H),3.26–3.20(m,1H),3.17–3.08(m,2H),3.02–2.84(m,2H),2.59–2.46(m,1H),2.23–2.12(m,1H),2.01(d,J＝3.6Hz,3H),1.98(d,J＝3.6Hz,3H),1.82–1.65(m,2H),1.52–1.37(m,4H).
实施例15化合物Z15的合成
Figure PCTCN2022140669-appb-000064
步骤一：在25℃下，向{[(3S)-六氢吡啶-3-基]氨基}甲烷酸苄基酯(242mg,1.03mmol)的N,N-二甲基甲酰胺(8mL)溶液中加入[(5-溴戊基)氨基]甲烷酸-2-甲基丙-2-基酯(250mg,0.939mmol)，N,N-二异丙基乙胺(363mg,2.82mmol)该反应液在氮气保护下于80℃搅拌反应6小时。LCMS检测反应完全后，反应液加水(50mL)，然后用乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经柱层析(石油醚/乙酸乙酯＝10/1～3/1)纯化得到无色油状物({5-[(3S)-3-{[(苄基氧基)羰基]氨基}六氢吡啶-1-基]戊基}氨基)甲烷酸-2-甲基丙-2-基酯(280mg,收率:64％)。LCMS:m/z(ESI):[M+H] +＝420.4,t R＝0.80min。
步骤二：将({5-[(3S)-3-{[(苄基氧基)羰基]氨基}六氢吡啶-1-基]戊基}氨基)甲烷酸-2-甲基丙-2-基酯(250mg,0.596mmol)溶于甲醇(10mL)溶液中加入钯碳(100mg,10％含量,60％含水)。该反应液在氢气保护下于25℃搅拌反应3小时。LCMS检测反应完全后，反应液过滤浓缩得到的无色油状物({5-[(3S)-3-氨基六氢吡啶-1-基]戊基}氨基)甲烷酸-2-甲基丙-2-基酯(180mg,粗品)。LCMS:m/z(ESI):[M+H] +＝286.0,t R＝0.80min。
步骤三：在室温下向({5-[(3S)-3-氨基六氢吡啶-1-基]戊基}氨基)甲烷酸-2-甲基丙-2-基酯(180mg,0.63mmol)的N,N-二甲基甲酰胺(6mL)溶液中依次加入3-[2-氯-5-(三氟甲基)嘧啶-4-基]-7-[二甲基(氧亚基)-λ 5-甲磷基]-1H-吲哚-6-甲酸甲酯(272mg,0.63mmol)、N,N-二异丙基乙胺(244mg,1.89 mmol)，该反应液在氮气保护下于80℃搅拌反应16小时。LCMS检测反应完全后，向反应液加入水溶液(50mL)，并用二氯甲烷(50mL×3)萃取，合并的有机层用无水硫酸钠干燥，过滤浓缩至干。得到的粗品经硅胶柱(二氯甲烷/甲醇＝50/1～10/1)层析纯化得到无色油状物7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂癸-10-基)六氢吡啶-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(300mg,收率:70％)。LCMS:MS m/z(ESI):[M+H] +＝681.1,t R＝1.11min。
步骤四：在室温下向7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂癸-10-基)六氢吡啶-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(300mg,0.441mmol)的甲醇(4mL)、水(4mL)、四氢呋喃(4mL)中加入氢氧化锂水合物(185mg,4.41mmol)，该反应液在氮气保护下于40℃搅拌反应16小时。LCMS检测反应完全后，浓缩至干得到白色固体物7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂癸-10-基)六氢吡啶-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(260mg,粗品)。LCMS:MS m/z(ESI):[M+H] +＝667.2,t R＝0.79min。
步骤五：在室温下向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂癸-10-基)六氢吡啶-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(260mg,0.390mmol)的二氧六环(4mL)中加入盐酸二氧六环(1.95mL,4mol/L)。该反应液在氮气保护下于40℃搅拌反应3小时。LCMS检测反应完全后，浓缩除去盐酸，得到的粗品粗品经反相制备纯化(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)得到白色固体物7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(5-氨基戊基)六氢吡啶-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(200mg,收率:95％)。LCMS:MS m/z(ESI):567.2[M+H] +,t R＝0.82min。
步骤六：在室温下向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(5-氨基戊基)六氢吡啶-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(70mg,0.12mmol)的N,N-二甲基甲酰胺(5mL)中依次加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(56.3mg,0.14mmol)、N,N-二异丙基乙胺(77.4mg,0.6mmol)，该反应液氮气保护于65℃反应3小时。LCMS检测反应完全后，浓缩得到的粗品经反相(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(10mmol NH 4HCO 3)；流速:70mL/min；柱温：25℃)纯化得到(4 3S)-1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-3,10-二氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(3,1)-哌啶环十一烷-11-酮((4 3S)-1 7-(dimethylphosphoryl)-2 5-(trifluoromethyl)-1 1H-3,10-diaza-1(3,6)-indola-2(4,2)-pyrimidina-4(3,1)-piperidinacycloundecaphan-11-one)(Z15)(1.2mg,收率:1.9％)。LCMS:MS m/z(ESI):549.3[M+H] +,t R＝0.81min。 1H NMR(400MHz,DMSO-d 6):δ8.61(s,1H),7.91(d,J＝8.0Hz,1H),7.79(s,1H),7.22-7.19(m,1H),2.96-2.78(m,4H),2.46–2.40(m,2H),2.08-2.03(m,1H),1.96(d,J＝14.4Hz,3H),1.83(d,J＝13.6Hz,3H),1.71(s,1H),1.73–1.56(m,5H),1.38–1.14(m,6H).
实施例16化合物Z16的合成
Figure PCTCN2022140669-appb-000065
步骤一：将7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(300mg,0.61mmol)溶于N,N-二甲基甲酰胺(3mL)中，[(4-溴丁基)氨基]甲烷酸-2-甲基丙-2-基酯(153mg,0.61mmol)和N,N-二异丙基乙胺(0.30mL,1.83mmol)依次加入，在80℃搅拌反应16小时。LCMS检测反应完全后，直接加入适量硅胶，旋干拌样，经柱层析(二氯甲烷/甲醇＝100/7)纯化得到类白色固体7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂壬-9-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(200mg,收率:50％)。LCMS:m/z(ESI):[M+H] +＝667.2,t R＝0.91min。
步骤二：将7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂壬-9-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(150mg,0.225mmol)溶于甲醇(3mL)，然后加入多聚甲醛(45.0mg,1.13mmol)、钯炭(10mg,10％含量,60％水)和冰醋酸(0.1mL)，在70℃搅拌反应5小时。LCMS检测反应完全后，滤掉钯炭，滤液直接加入硅胶拌样，经柱层析(二氯甲烷/甲醇＝100/7)纯化得到白色固体7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-(2,2-二甲基-4-氧亚基-5,10-二氮杂-3-氧杂十一烷-10-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(130mg,收率:85％)。LCMS:m/z(ESI):[M+H] +＝681.2,t R＝0.93min。
步骤三：将7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-(2,2-二甲基-4-氧亚基-5,10-二氮杂-3-氧杂十一烷-10-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(130mg,0.191mmol)溶于水(1mL)、甲醇(1mL)和四氢呋喃(1mL)的混合体系中，然后加入一水合氢氧化锂(40.1mg,0.955mmol)，在40℃搅拌反应16小时。LCMS检测反应完全后，此反应液不经任何处理，直接应用于下一步反应。LCMS:m/z(ESI):667.4[M+H] +＝667.4,t R＝0.76min。
步骤四：向上一步的反应液中加入盐酸1,4-二氧六环溶液(5mL,4M)，体系在10℃搅拌4小时。LCMS检测反应完全后，直接将溶剂旋干，得到的粗品经反相制备(色谱柱:Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％碳酸氢铵)；流速：70mL/min；柱温：25℃)得到白色固体7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(4-氨基丁基)(甲基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(20mg,收率:13％)。LCMS:m/z(ESI):[M+H] +＝567.2,t R＝0.59min。
步骤五：向7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(4-氨基丁基)(甲基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(20mg,0.04mmol)的N,N-二甲基甲酰胺(3mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(14.8mg,0.04mmol)和N,N-二异丙基乙胺(0.03mL,0.18mmol)，该反应液在60℃搅拌16小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)得到(4 1S,4 3S)-1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮((4 1S,4 3S)-1 7-(dimethylphosphoryl)-5-methyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one)(Z16)的三氟乙酸盐(5.88mg,收率:30％)。LCMS:m/z(ESI):[M+H] +＝549.2,t R＝0.67min。 1H NMR(400MHz,CD 3OD):δ8.57(s,1H),8.53(d,J＝7.6Hz,1H),7.99(s,1H),7.31(dd,J＝8.4,3.2Hz,1H),4.25-4.31(m,1H),3.91-4.04(m,1H),3.24–3.11(m,1H),2.86-2.91(m,2H),2.78(s,1H),2.72(s,2H),2.52-2.57(m,1H),2.38–2.22(m,2H),2.14–1.70(m,12H),1.57-1.66(m,1H),1.29-1.37(m,1H).
实施例17化合物Z19的合成
Figure PCTCN2022140669-appb-000066
步骤一：在一个250mL三口瓶中，依次加入N-[(苄基氧基)羰基]甘氨酸(20g,95.6mmol)、四氢呋喃(130mL)、氯化镁(4.55g,47.8mmol)、羰基二咪唑(15.5g,95.6mmol)、[(3-甲氧基-1,3-二氧亚基丙基)氧基]钾(12.2g,71.7mmol)，反应液用氮气置换，70℃回流4小时，TLC检测反应完全。反应液浓缩，加水(100mL)稀释，再用乙酸乙酯(50mL×3)萃取，加入无水硫酸钠干燥，浓缩得到粗品，经硅胶柱层析(二氯甲烷/甲醇＝10/3)纯化得到[(1-甲氧基-1,3-二氧亚基丁-4-基)氨基]甲烷酸苄基酯(3.7g,收率15％)，呈类白色固体。 1H NMR(400MHz,CD 3OD):δ7.42-7.26(m,5H),5.12(s,2H),4.21(d,J＝5.2Hz,2H),3.74(s,3H),3.50(s,2H).
步骤二：将[(1-甲氧基-1,3-二氧亚基丁-4-基)氨基]甲烷酸苄基酯(1.50g,5.66mmol)溶于二氯甲烷(30mL)，然后于0℃滴加二乙胺基三氟化硫(1.00g,6.22mmol)，在15℃搅拌16小时，然后于15℃补加二乙胺基三氟化硫(1.00g,6.22mmol)，然后在15℃搅拌4小时。LCMS检测反应完全后，加水(20mL)淬灭反应，再用乙酸乙酯(20mL×3)萃取，加入无水硫酸钠干燥，浓缩的粗品经反相 制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)，流速：70mL/min,柱温：25℃)得到黄色油状(3,3-二氟-1-甲氧基-1-氧亚基丁-4-基)氨基]甲烷酸苄基酯(0.15g,收率9％)。LCMS:m/z(ESI):[M+H] +＝288.0,t R＝0.97min.
步骤三：将(3,3-二氟-1-甲氧基-1-氧亚基丁-4-基)氨基]甲烷酸苄基酯(130mg,0.45mmol)溶于四氢呋喃(3mL)，然后于0℃滴加四氢铝锂的四氢呋喃溶液(1mL,1M)，反应在10℃搅拌2小时。LCMS检测反应完全后，加水(20mL)淬灭反应，再用乙酸乙酯(20mL×3)萃取，加入无水硫酸钠干燥，浓缩得到粗品黄色油状物[(2,2-二氟-4-羟基丁基)氨基]甲烷酸苄基酯(100mg,收率85％)，不经纯化直接用于下一步。LCMS:m/z(ESI):[M+H] +＝260.0,t R＝0.88min.
步骤四：将[(2,2-二氟-4-羟基丁基)氨基]甲烷酸苄基酯(120mg,0.46mmol)溶于二氯甲烷(1mL)中，再加入吡啶(1mL)和对甲基磺酰氯(265mg,1.39mmol)，体系在10℃搅拌3小时。LCMS检测反应完全后，直接加入硅胶，油泵旋干拌样，经硅胶柱层析(二氯甲烷100％)纯化得到黄色油状物4-甲基苯磺酸-6,6-二氟-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基酯(130mg,收率68％)。LCMS:m/z(ESI):[M+H] +＝414.0,t R＝1.20min.
步骤五：在一个10mL单口瓶中，将7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(173mg,0.35mmol)溶于N,N-二甲基甲酰胺(3mL)中，然后加入4-甲基苯磺酸-6,6-二氟-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基酯(120mg,0.29mmol)和N,N-二异丙基乙胺(0.24mL,1.45mmol)。体系在100℃搅拌20小时。LCMS检测反应完全后，加硅胶油泵旋干拌样，经硅胶柱层析(二氯甲烷:甲醇＝10:1)纯化得到黄色油状物7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(6,6-二氟-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(81mg,收率38％)。LCMS:m/z(ESI):[M+H] +＝737.2,t R＝0.96min.
步骤六：将7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(6,6-二氟-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(90mg,0.12mmol)溶于水(1mL)、甲醇(1mL)和四氢呋喃(1mL)的混合体系中，然后加入一水合氢氧化锂(5.13mg,0.12mmol)，反应在40℃搅拌16小时。LCMS检测反应完全后，过滤，滤液反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％碳酸氢铵)，流速：70mL/min,柱温：25℃)得到白色固体7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(6,6-二氟-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(30mg,收率34％)。LCMS:m/z(ESI):[M+H] +＝723.2,t R＝0.87min.
步骤七：在一个10mL单口瓶中，加入7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(6,6-二氟-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(18mg,0.03mmol)和三氟乙酸(3mL)。60℃搅拌1.5小时，LCMS检测反应完全后，反应液旋干得粗品2,2-二氟-4-{[(1S,3S)-3-[(4-{5-[(Z)-[二甲基(氧亚基)-λ 5-甲磷基]甲亚基]-4-[(1Z)-乙亚基]-1H-吡咯-3-基}-5-(三氟甲基)嘧啶-2-基)氨基]环戊基]氨基}丁-1-胺甲酸(14mg,96％)，灰色固体，无需纯化直接用于下一步。LCMS:m/z(ESI):[M+H] +＝589.2,t R＝0.62min.
步骤八：向2,2-二氟-4-{[(1S,3S)-3-[(4-{5-[(Z)-[二甲基(氧亚基)-λ 5-甲磷基]甲亚基]-4-[(1Z)-乙亚基]-1H-吡咯-3-基}-5-(三氟甲基)嘧啶-2-基)氨基]环戊基]氨基}丁-1-胺甲酸(14mg,0.02mmol)的N,N-二甲基甲酰胺(2mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(9.95mg,0.03mmol)和N,N-二异丙基乙胺(0.02mL,0.12mmol)。60℃搅拌16小时，LCMS检测反应完 全，反应液浓缩，粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)，流速：70mL/min,柱温：25℃)得(4 1S,4 3S)-1 7-(二甲基磷酰基)-8,8-二氟-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(4 1S,4 3S)-1 7-(dimethylphosphoryl)-8,8-difluoro-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z19)(1.22mg,收率9％,三氟乙酸盐)。LCMS:m/z(ESI):[M+H] +＝571.2,t R＝0.67min. 1H NMR(400MHz,CD 3OD):δ8.57-8.58(m,2H),8.01(s,1H),7.32(d,J＝5.6Hz,1H),4.16-4.18(m,1H),3.86-3.87(m,1H),3.47-3.49(m,1H),2.89-2.93(m,2H),2.70-2.73(m,1H),2.48-2.27(m,4H),1.98-2.02(m,6H),1.81-1.86(m,2H),1.28-1.29(m,2H).
实施例18化合物Z27的合成
Figure PCTCN2022140669-appb-000067
步骤一：在25℃下，向[(1-羟基丁-4-基)(甲基)氨基]甲烷酸-2-甲基丙-2-基酯(400mg,1.97mmol)的四氢呋喃(8mL)溶液中加入四溴化碳(981mg,3.74mmol)、三苯基膦(1.24g,3.74mmol)。该反应液在氮气保护下于25℃搅拌反应16小时。LCMS检测反应完全后，反应液加水(50mL)，然后用乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经硅胶柱层析(石油醚/乙酸乙酯＝10/1到3/1)纯化得到无色油状物[(1-溴丁-4-基)(甲基)氨基]甲烷酸-2-甲基丙-2-基酯(400mg,收率46％)。LCMS:m/z(ESI):[M+H-56] +＝210.0,t R＝2.03min.
步骤二：将[(1-溴丁-4-基)(甲基)氨基]甲烷酸-2-甲基丙-2-基酯(240mg,0.90mmol)、3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-7-[甲基(氧亚基)-λ5-甲磷基]-1H-吲哚-6-甲酸甲酯(447mg,0.90mmol)溶于乙腈(10mL)，加入N,N-二异丙基乙胺(349mg,2.71mmol)。氮气保护下于80℃搅拌反应16小时。LCMS检测反应完全后，反应液浓缩，得到的无色油状物7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2,5-三甲基-4-氧亚基-5-氮杂-3-氧杂壬-9-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(220mg,收率36％)。LCMS:m/z(ESI):[M+H] +＝681.4,t R＝0.96min.
步骤三：在室温条件下向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2,5-三甲基-4-氧亚基-5-氮杂-3-氧杂壬-9-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(220mg，0.32mmol)的甲醇(8mL)溶液中依次加入多聚甲醛(145mg,1.62mmol)、醋酸(244mg,1.89mmol)、钯碳(20mg,10％含量,60％含水)。氢气下80℃搅拌反应16小时。LCMS检测反应完全后，向反应液加入水溶液(50mL)，并用二氯甲烷(50mL×3)萃取。合并的有机层用无水硫酸钠干燥，过滤浓缩 至干燥。得到的粗品经硅胶柱层析(二氯甲烷/甲醇＝50/1到10/1)纯化得到无色油状物7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-(2,2,5-三甲基-4-氧亚基-5,10-二氮杂-3-氧杂十一烷-10-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(200mg,收率71％)。LCMS:MS m/z(ESI):[M+H] +＝695.7,t R＝1.19min.
步骤四：在室温条件下向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-(2,2,5-三甲基-4-氧亚基-5,10-二氮杂-3-氧杂十一烷-10-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(200mg,0.29mmol)的甲醇(3mL)、水(3mL)、四氢呋喃(3mL)中加入氢氧化锂水合物(121mg,2.88mmol)。氮气保护下于40℃搅拌反应16小时。LCMS检测反应完全后，浓缩至干燥得到粗品白色固体物7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-(2,2,5-三甲基-4-氧亚基-5,10-二氮杂-3-氧杂十一烷-10-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(180mg,收率83％)。LCMS:MS m/z(ESI):[M+H] +＝681.4,t R＝0.93min.
步骤五：在室温条件下向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-(2,2,5-三甲基-4-氧亚基-5,10-二氮杂-3-氧杂十一烷-10-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(180mg,0.26mmol)的二氧六环(4mL)中加入盐酸二氧六环(1.32mL,5.29mmol,4mol/L)。氮气保护下25℃搅拌反应16小时。LCMS检测反应完全后，浓缩，粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)，流速：70mL/min,柱温：25℃)纯化得到白色固体物7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-(2,7-二氮杂辛-2-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(80mg,收率50％)。LCMS:MS m/z(ESI):[M+H] +＝581.2,t R＝1.00min.
步骤六：在室温条件下向7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-(2,7-二氮杂辛-2-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(70mg,0.12mmol)的N,N-二甲基甲酰胺(5mL)中依次加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(55mg,0.15mmol)、N,N-二异丙基乙胺(78mg,0.61mmol)。氮气保护于60℃反应18小时。LCMS检测反应完全后，浓缩，粗品经反相(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)，流速：70mL/min,柱温：25℃)制备纯化得到(4 1S,4 3S)-1 7-(二甲基磷酰基)-5,10-二甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮2,2,2-三氟乙酸(4 1S,4 3S)-1 7-(dimethylphosphoryl)-5,10-dimethyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z27)(26mg,收率36％)。LCMS:MS m/z(ESI):[M+H] +＝563.2,t R＝1.30min. 1H NMR(400MHz,DMSO-d 6):δ11.98(s,1H),9.50–9.00(m,1H),8.62(s,1H),8.25(d,J＝5.2Hz,1H),7.97(s,1H),7.23(dd,J＝11.2,1.2Hz,1H),4.22–3.84(m,2H),3.53(s,3H),3.22–3.05(m,2H),3.00(s,3H),2.92–2.84(m,1H),2.68-2.66(m,1H),2.59(d,J＝4.0Hz,2H),2.45-2.37(m,1H),2.17–2.08(m,2H),1.91–1.49(m,11H).
实施例19化合物Z58的合成
Figure PCTCN2022140669-appb-000068
步骤一：在0℃，氮气氛围下，向2-氧亚基四氢吡咯-1-甲酸-2-甲基丙-2-基酯(2.00g,10.8mmol)的四氢呋喃(30mL)溶液中缓慢滴加甲基溴化镁(15.1mL,15.1mmol)。反应在0℃下搅拌4小时。点板检测反应完全后，加水(30mL)淬灭反应，随后用乙酸乙酯(100mL×3)进行萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩至干燥。得到的粗品经硅胶柱层析(石油醚/乙酸乙酯＝10/1到3/1)纯化得到无色油状物[(4-氧亚基戊基)氨基]甲烷酸-2-甲基丙-2-基酯(1.20g,收率56％)。 1H NMR(400MHz,CD 3OD):δ3.02(t,J＝7.2Hz,2H),2.50(t,J＝7.2Hz,2H),2.13(s,3H),1.69(p,J＝7.2Hz,1H),1.43(s,9H).
步骤二：将[(4-氧亚基戊基)氨基]甲烷酸-2-甲基丙-2-基酯(122mg,0.61mmol)溶于四氢呋喃(5mL)，然后加入钛酸异丙酯(574mg,2.0mmol)、7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(250mg,0.51mmol)，反应在70℃搅拌16小时后，冷却至室温，向其中加入氰基硼氢化钠(159mg,2.53mmol)，在25℃下搅拌6小时。LCMS检测反应完全后，反应液过滤除去固体杂质，有机相浓缩得到粗产品，随后粗产品经制备薄层层析(二氯甲烷/甲醇＝10/1)纯化得到7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂癸-9-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(270mg,收率79％)，为黄色油状物。LCMS:m/z(ESI):[M+H] +＝681.4,t R＝0.99min.
步骤三：将7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂癸-9-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(220mg,0.32mmol)溶于水(2mL)、甲醇(2mL)和四氢呋喃(2mL)的混合体系中，加入氢氧化锂(1个结晶水,68mg,1.62mmol)，反应在40℃搅拌14小时。LCMS检测反应完全后，此反应液不经任何处理，直接应用于下一步反应。LCMS:m/z(ESI):[M+H] +＝667.4,t R＝0.91min.
步骤四：向步骤三的反应液中加入氯化氢/1,4-二氧六环溶液(5mL,4M)，体系在40℃搅拌4小时。LCMS检测反应完全后，直接将溶剂旋干，得到粗品，粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)，流速：70mL/min,柱温：25℃)得到7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(5-氨基戊-2-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(150mg,收率94％)，呈白色固体。LCMS:m/z(ESI):[M+H] +＝567.2,t R＝0.87min.
步骤五：7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(5-氨基戊-2-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(70mg,0.12mmol)的N,N-二甲基甲酰胺(3mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(47mg,0.12mmol)和N,N-二异丙基乙胺(64mg,0.50mmol)，该反应液在80℃搅拌18h。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)，流速：70mL/min,柱温：25℃)得到(4 1S,4 3S)-1 7-(二甲基磷酰基)-6-甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(4 1S,4 3S)-1 7-(dimethylphosphoryl)-6-methyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z58)(10.50mg,收率15％,三氟乙酸盐)。LCMS:m/z(ESI):[M+H] +＝549.2,t R＝0.69min. 1H NMR(400MHz,CD 3OD):δ8.58(s,1H),8.51–8.36(m,1H),7.97(s,1H),7.45–7.29(m,1H),4.42–4.11(m,1H),3.95–3.74(m,1H),3.30–3.17(m,1H),3.13–2.99(m,1H),2.98–2.74(m,2H),2.66–2.50(m,1H),2.36–2.27(m,1H),2.27–2.19(m,1H),2.15–2.05(m,1H),2.03–1.96(m,6H),1.95–1.85(m,1H),1.80–1.66(m,2H),1.56–1.50(m,1H),1.47–1.34(m,1H),1.26(t,J＝6.0Hz,3H).
实施例20化合物Z59的合成
Figure PCTCN2022140669-appb-000069
步骤一：在25℃下，向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(200mg,0.71mmol)的N,N-二甲基甲酰胺(6mL)溶液中加入[(6-溴己基)氨基]甲烷酸-2-甲基丙-2-基酯(353mg,0.71mmol)、N,N-二异丙基乙胺(460mg,3.57mmol)。氮气保护下于80℃搅拌反应16小时。LCMS检测反应完全后，反应液加水(50mL)，乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经硅胶柱层析(石油醚/乙酸乙酯＝10/1到3/1)纯化得到无色油状物7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂十一烷-11-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(180mg,收率33％)。LCMS:m/z(ESI):[M+H] +＝694.7,t R＝1.33min.
步骤二：在室温条件下向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂十一烷-11-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(180mg,0.26mmol)的甲醇(3mL)、水(3mL)、四氢呋喃(3mL)中加入氢氧化锂水合物(109mg,2.59mmol)。氮气保护下于40℃搅拌反应16小时。LCMS检测反应完全后，浓缩至干燥得到粗品白色固体物7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂十一烷-11-基)氨基] 环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(180mg,粗品)。LCMS:MS m/z(ESI):[M+H] +＝681.3,t R＝0.87min.
步骤三：在室温条件下向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂十一烷-11-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(160mg,0.24mmol)的甲醇(4mL)中加入盐酸甲醇(1.12mL,4mol/L)。该反应液在氮气保护下于40℃搅拌反应16小时。LCMS检测反应完全后，浓缩除去盐酸，得到的粗品经反相(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)，流速：70mL/min,柱温：25℃)制备纯化得到白色固体物7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(6-氨基己基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(80mg,收率56％)。LCMS:MS m/z(ESI):[M+H] +＝581.4,t R＝0.68min.
步骤四：在室温条件下向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(6-氨基己基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(70mg,0.12mmol)的N,N-二甲基甲酰胺(5mL)中依次加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(55.2mg,0.15mmol)、N,N-二异丙基乙胺(78mg,0.61mmol)。氮气保护于60℃反应16小时。LCMS检测反应完全后，浓缩得到的粗品经反相(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)，流速：70mL/min,柱温：25℃)纯化得到(4 1S,4 3S)-1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-3,5,12-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十三烷-13-酮2,2,2-三氟乙酸(4 1S,4 3S)-1 7-(dimethylphosphoryl)-2 5-(trifluoromethyl)-1 1H-3,5,12-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclotridecaphan-13-one(Z59)(14mg,收率18％)。LCMS:MS m/z(ESI):[M+H] +＝563.0,t R＝0.68min. 1H NMR(400MHz,DMSO-d 6):δ11.99(s,1H),8.62(s,1H),8.60-8.57(m,1H),8.51(d,J＝8.4Hz,1H),8.04(s,1H),7.46(dd,J＝8.4,3.2Hz,1H),4.27-4.20(m,1H),3.73-3.71(m,1H),3.63-3.55(m,2H),3.19-3.14(m,1H),2.95-2.92(m,2H),2.18-2.05(m,2H),2.01-1.89(m,7H),1.82-1.74(m,1H),1.69-1.48(m,9H).
实施例21化合物Z60的合成
Figure PCTCN2022140669-appb-000070
步骤一：在室温条件下，向(4 1S,4 3S)-1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-8-氧杂-3,5,11-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十二烷-12-酮2,2,2-三氟乙酸盐(20mg,0.030mmol)的四氢呋喃溶液(5mL)中依次加入多聚甲醛(20mg,0.22mmol)和钛酸异丙酯(10.3mg,0.036mmol)。氮气保护下于60℃搅拌反应14小时。将反应液降温至30℃后，加入氰基硼氢化钠(20mg,0.318mmol)，保温反应4小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)，流速：70mL/min,柱温：25℃)得到(4 1S,4 3S)-1 7-(二甲基磷酰基)-5-甲基-2 5-(三氟甲基)-1 1H-8-氧杂-3,5,11-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十二烷-12-酮-2,2,2-三氟乙酸盐(4 1S,4 3S)-1 7-(dimethylphosphoryl)-5-methyl-2 5-(trifluoromethyl)-1 1H-8-oxa-3,5,11-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanac yclododecaphan-12-one(Z60)(7.8mg,收率38％)。LCMS:MS m/z(ESI):[M+H] +＝565.2,t R＝0.73min. 1H NMR(400MHz,CD 3OD):δ8.58(s,1H),8.50–8.28(m,1H),7.94–7.89(m,1H),7.69–7.50(m,1H),4.28–4.15(m,1H),3.99–3.68(m,6H),3.52–3.42(m,1H),3.24–3.14(m,1H),2.97–2.85(m,3H),2.78–2.59(m,1H),2.37–2.15(m,3H),2.14–1.92(m,7H),1.87–1.70(m,2H).
实施例22化合物Z61的合成
Figure PCTCN2022140669-appb-000071
步骤一：在25℃下，向[(6-溴己基)氨基]甲烷酸-2-甲基丙-2-基酯(300mg,1.28mmol)的N,N-二甲基甲酰胺(8mL)溶液中加入{[(3S)-六氢吡啶-3-基]氨基}甲烷酸苄基酯(395mg,1.41mmol)、N,N-二异丙基乙胺(662mg,5.12mmol)。该反应液在氮气保护下于80℃搅拌反应6小时。LCMS检测反应完全后，反应液加水(30mL)，然后用乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经硅胶柱层析(二氯甲烷/甲醇＝30/1到10/1)纯化得到无色油状物{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂十一烷-11-基)六氢吡啶-3-基]氨基}甲烷酸苄基酯(555mg,收率92％)。LCMS:m/z(ESI):[M+H] +＝434.2,t R＝1.57min.
步骤二：将{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂十一烷-11-基)六氢吡啶-3-基]氨基}甲烷酸苄基酯(555mg,1.17mmol)溶于甲醇(10mL)溶液中加入钯碳(60mg,10％含量,60％含水)。该反应液在氢气保护下于25℃搅拌反应3小时。LCMS检测反应完全后，反应液过滤浓缩，得到的无色油状物({6-[(3S)-3-氨基六氢吡啶-1-基]己基}氨基)甲烷酸-2-甲基丙-2-基酯(350mg,粗品)。LCMS:m/z(ESI):[M+H] +＝300.0,t R＝0.98min.
步骤三：在室温条件下向{6-[(3S)-3-氨基六氢吡啶-1-基]己基}氨基(280mg,0.94mmol)的N,N-二甲基甲酰胺(8mL)溶液中依次加入3-[2-氯-5-(三氟甲基)嘧啶-4-基]-7-[二甲基(氧亚基)-λ5-甲磷基]-1H-吲哚-6-甲酸甲酯(404mg,0.94mmol)、N,N-二异丙基乙胺(483mg,3.74mmol)，该反应液在氮气保护下于80℃搅拌反应16小时。LCMS检测反应完全后，向反应液加入水溶液(40mL)，并用二氯甲烷(50mL×3)萃取，合并的有机层用无水硫酸钠干燥，过滤浓缩至干燥。得到的粗品经硅胶柱层析(二氯甲烷/甲醇＝30/1到10/1)纯化得到黄色油状物7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂十一烷-11-基)六氢吡啶-3-基]氨基}-5-(三氟甲基) 嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(473mg，收率72％)。LCMS:MS m/z(ESI):[M+H] +＝695.4,t R＝1.15min.
步骤四：在室温条件下向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂十一烷-11-基)六氢吡啶-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(243mg,0.35mmol)的甲醇(3mL)、水(3mL)、四氢呋喃(3mL)中加入氢氧化锂水合物(74mg,1.75mmol)，该反应液在氮气保护下于40℃搅拌反应14小时。LCMS检测反应完全后，浓缩至干燥得到粗品黄色固体7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂十一烷-11-基)六氢吡啶-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(320mg,粗品,90％纯度)。LCMS:MS m/z(ESI):[M+H] +＝680.8,t R＝1.21min.
步骤五：在室温条件下向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂十一烷-11-基)六氢吡啶-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(420mg,粗品,90％纯度)的甲醇(4mL)溶液中加入氯化氢/甲醇溶液(6mL,4mol/L)。该反应液在氮气保护下于40℃搅拌反应4小时。LCMS检测反应完全后，浓缩除去盐酸，得到的粗品粗品经反相(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)，流速：70mL/min,柱温：25℃)制备纯化得到白色固体物7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(6-氨基己基)六氢吡啶-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(275mg,收率85％)。LCMS:MS m/z(ESI):[M+H] +＝581.4,t R＝0.64min.
步骤六：在室温条件下向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(3S)-1-(6-氨基己基)六氢吡啶-3-基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(100mg,0.17mmol)的N,N-二甲基甲酰胺(3mL)中依次加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(65.4mg,0.17mmol)、N,N-二异丙基乙胺(88.9mg,0.69mmol)，该反应液氮气保护于80℃反应16小时。LCMS检测反应完全后，浓缩得到的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)纯化得到(4 3S)-1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-3,11-二氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-哌啶环十二烷-12-酮(4 3S)-1 7-(dimethylphosphoryl)-2 5-(trifluoromethyl)-1 1H-3,11-diaza-1(3,6)-indola-2(4,2)-pyrimidina-4(3,1)-piperidinacyclododecaphan-12-one(Z61)(18.90mg,收率19％,三氟乙酸盐)。LCMS:MS m/z(ESI):[M+H] +＝563.2,t R＝0.67min. 1H NMR(400MHz,CD 3OD):δ8.64(s,1H),8.22(dd,J＝8.4,1.2Hz,1H),7.91(s,1H),7.65(dd,J＝8.4,3.6Hz,1H),4.22–4.02(m,1H),4.01–3.49(m,3H),3.29–3.21(m,1H),3.19–3.09(m,2H),2.95–2.87(m,1H),2.87–2.69(m,1H),2.16–1.89(m,9H),1.80–1.27(m,9H).
实施例23化合物Z56的合成
Figure PCTCN2022140669-appb-000072
步骤一：在25℃下，向{[2-(四氢-1H-吡咯-3-基)乙基]氨基}甲烷酸-2-甲基丙-2-基酯(200mg,0.93mmol)的N,N-二甲基甲酰胺(6mL)溶液中加入[(2-溴乙基)氨基]甲烷酸苄基酯(241mg,0.93mmol)、N,N-二异丙基乙胺(602mg,4.67mmol)。该反应液在氮气保护下于80℃搅拌反应5小时。LCMS检测反应完全后，反应液加水(20mL)，然后用乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经硅胶柱层析(石油醚/乙酸乙酯＝10/1到3/1)纯化得到无色油状物({2-[1-(3-氧亚基-1-苯基-4-氮杂-2-氧杂己-6-基)四氢-1H-吡咯-3-基]乙基}氨基)甲烷酸-2-甲基丙-2-基酯(218mg,收率54％)。LCMS:m/z(ESI):[M+H] +＝392.4,t R＝1.40min.
步骤二：在室温条件下向({2-[1-(3-氧亚基-1-苯基-4-氮杂-2-氧杂己-6-基)四氢-1H-吡咯-3-基]乙基}氨基)甲烷酸-2-甲基丙-2-基酯(200mg,0.51mmol)的甲醇中加入Pd/C(20mg,10％含量,60％含水)。该反应液在氢气保护下于25℃搅拌反应5小时。LCMS检测反应完全后，浓缩至干燥得到粗品白色固体物({2-[1-(2-氨基乙基)四氢-1H-吡咯-3-基]乙基}氨基)甲烷酸-2-甲基丙-2-基酯(100mg,收率53％)。LCMS:MS m/z(ESI):[M+H] +＝258.2,t R＝0.47min.
步骤三：在室温条件下向({2-[1-(2-氨基乙基)四氢-1H-吡咯-3-基]乙基}氨基)甲烷酸-2-甲基丙-2-基酯(100mg,0.39mmol)的N,N-二甲基甲酰胺(6mL)中加入3-[2-氯-5-(三氟甲基)嘧啶-4-基]-7-[二甲基(氧亚基)-λ5-甲磷基]-1H-吲哚-6-甲酸甲酯(168mg,0.39mmol)、N,N-二异丙基乙胺(150mg,1.17mmol)。该反应液在氮气保护下于80℃搅拌反应16小时。LCMS检测反应完全后，反应液加水(20mL)，然后用乙酸乙酯(30mL×3)萃取，合并的有机层用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经硅胶柱层析(石油醚/乙酸乙酯＝10/1到3/1)纯化得到无色油状物7-[二甲基(氧亚基)-λ5-甲磷基]-3-[2-({2-[3-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂庚-7-基)四氢-1H-吡咯-1-基]乙基}氨基)-5-(三氟甲基)嘧啶-4-基]-1H-吲哚-6-甲酸甲酯(220mg,收率78％)。LCMS:MS m/z(ESI):[M+H] +＝653.2,t R＝1.41min.
步骤四：在室温条件下向7-[二甲基(氧亚基)-λ5-甲磷基]-3-[2-({2-[3-(2,2-二甲基-4-氧亚基-5-氮杂 -3-氧杂庚-7-基)四氢-1H-吡咯-1-基]乙基}氨基)-5-(三氟甲基)嘧啶-4-基]-1H-吲哚-6-甲酸甲酯(220mg,0.34mmol)的甲醇(3mL)、水(3mL)、四氢呋喃(3mL)中加入氢氧化锂水合物(141mg,3.37mmol)。氮气保护下于40℃搅拌反应16小时。LCMS检测反应完全后，浓缩至干燥得到粗品白色固体物7-[二甲基(氧亚基)-λ5-甲磷基]-3-[2-({2-[3-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂庚-7-基)四氢-1H-吡咯-1-基]乙基}氨基)-5-(三氟甲基)嘧啶-4-基]-1H-吲哚-6-甲酸(200mg)。LCMS:MS m/z(ESI):[M+H] +＝638.7,t R＝1.11min.
步骤五：在室温条件下，向7-[二甲基(氧亚基)-λ5-甲磷基]-3-[2-({2-[3-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂庚-7-基)四氢-1H-吡咯-1-基]乙基}氨基)-5-(三氟甲基)嘧啶-4-基]-1H-吲哚-6-甲酸(200mg,0.31mmol)的1,4-二氧六环(4mL)中加入盐酸1,4-二氧六环(0.78mL,3.13mmol,4mol/L)。氮气保护下，40℃搅拌3小时。LCMS检测反应完全后，浓缩，粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)，流速：70mL/min,柱温：25℃)纯化得到白色固体物3-[2-({2-[3-(2-氨基乙基)四氢-1H-吡咯-1-基]乙基}氨基)-5-(三氟甲基)嘧啶-4-基]-7-[二甲基(氧亚基)-λ5-甲磷基]-1H-吲哚-6-甲酸(70mg,收率37％)。LCMS:MS m/z(ESI):[M+H] +＝538.8,t R＝0.98min.
步骤六：在室温条件下向3-[2-({2-[3-(2-氨基乙基)四氢-1H-吡咯-1-基]乙基}氨基)-5-(三氟甲基)嘧啶-4-基]-7-[二甲基(氧亚基)-λ5-甲磷基]-1H-吲哚-6-甲酸(70mg,0.11mmol)的N,N-二甲基甲酰胺(5mL)中依次加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(51mg,0.13mmol)、N,N-二异丙基乙胺(43mg,0.33mmol)。氮气氛围下于65℃反应3小时。LCMS检测反应完全后，浓缩，粗品经反相(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)，流速：70mL/min,柱温：25℃)制备纯化得到1 7-(二甲基磷酰基)-2 5-(三氟甲基)-1 1H-3,9-二氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-6(1,3)-吡咯烷环十烷-10-酮1 7-(dimethylphosphoryl)-2 5-(trifluoromethyl)-1 1H-3,9-diaza-1(3,6)-indola-2(4,2)-pyrimidina-6(1,3)-pyrrolidinacyclodecaphan-10-one(Z56)(6.0mg,收率10％,三氟乙酸盐)。LCMS:MS m/z(ESI):[M+H] +＝521.3,t R＝0.71min. 1H NMR(400MHz,CD 3OD):δ8.65(s,1H),8.58–8.43(m,1H),8.03(s,1H),7.57(s,1H),4.09-3.82(m,3H),3.63–3.36(m,4H),3.18–2.98(m,2H),2.78-2.57(m,1H),2.49-2.35(m,1H),2.23–1.99(m,7H),1.70-1.14(m,3H).
实施例24化合物Z64的合成
Figure PCTCN2022140669-appb-000073
步骤一：在50mL单口瓶中，向(1-羟基-6-氮杂-3-氧杂庚-6-基)甲烷酸-2-甲基丙-2-基酯(300mg,1.37mmol)的二氯甲烷(10mL)溶液中依次加入咪唑(140mg,2.05mmol)、三苯基膦(431mg,1.64mmol)和碘单质(521mg,2.05mmol)。氮气保护下5℃搅拌2小时。LCMS检测反应完全，反应液加水(20mL)稀释，然后用二氯甲烷(10mL×3)萃取，无水硫酸钠干燥，浓缩得到粗品，经硅胶柱层析(石油醚:乙酸乙酯＝5:1)纯化得淡黄色油状物(1-碘-6-氮杂-3-氧杂庚-6-基)甲烷酸-2-甲基丙-2-基酯(314mg,收率70％)。LCMS:m/z(ESI):[M-100+H] +＝230.0,t R＝1.20min.
步骤二：在50mL单口瓶中，向(1-碘-6-氮杂-3-氧杂庚-6-基)甲烷酸-2-甲基丙-2-基酯(350mg,1.06mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(553mg,1.12mmol)和N,N-二异丙基乙胺(0.88mL,5.32mmol)。氮气保护下100℃搅拌16小时。LCMS检测反应完全后，反应液加水(30mL)稀释，乙酸乙酯(15mL×3)萃取，无水硫酸钠干燥，浓缩得到粗品，经硅胶柱层析(二氯甲烷:甲醇＝100:6)纯化得到淡黄色固体7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2,5-三甲基-4-氧亚基-5-氮杂-3,8-二氧杂癸-10-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(610mg,收率82％)。LCMS:m/z(ESI):[M+H] +＝697.4,t R＝0.97min.
步骤三：将7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2,5-三甲基-4-氧亚基-5-氮杂-3,8-二氧杂癸-10-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(610mg,0.88mmol)溶于水(3mL)、甲醇(3mL)和四氢呋喃(3mL)的混合体系中。加入一水合氢氧化锂(184mg,4.38mmol)，40℃搅拌16小时。LCMS检测反应完全后，得到含7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2,5-三甲基-4-氧亚基-5-氮杂-3,8-二氧杂癸-10-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸的反应液，此反应液不经处理直接用于下一步。LCMS:m/z(ESI):[M+H] +＝683.3,t R＝0.86min.
步骤四：在上步反应液中，加入盐酸的甲醇溶液(5mL,4M)，5℃搅拌5小时。LCMS检测完全后，反应液浓缩，粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)得到白色固体7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-(6-氮杂-3-氧杂庚-1-基氨基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(260mg,2步收率51％)。LCMS:m/z(ESI):[M+H] +＝582.6,t R＝0.92min.
步骤五：向7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-(6-氮杂-3-氧杂庚-1-基氨基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(260mg,0.45mmol)的N,N-二甲基甲酰胺(10mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(187mg,0.49mmol)和N,N-二异丙基乙胺(0.37mL,2.23mmol)。60℃搅拌反应16小时。LCMS检测反应完全后，反应液浓缩，粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)得到淡黄色固体(4 1S,4 3S)-1 7-(二甲基磷酰基)-11-甲基-2 5-(三氟甲基)-1 1H-8-氧杂-3,5,11-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十二烷-12-酮((4 1S,4 3S)-1 7-(dimethylphosphoryl)-11-methyl-2 5-(trifluoromethyl)-1 1H-8-oxa-3,5,11-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclododecaphan-12-one)(Z64)(120mg,收率48％,三氟乙酸盐)。LCMS:m/z(ESI):[M+H] +＝564.8,t R＝0.97min. 1H NMR(400MHz,CD 3OD):δ8.57(s,1H),8.43(br,1H),7.96(s,1H),7.44(dd,J＝8.4,3.2Hz,1H),4.36-4.39(m,1H),3.88-3.91(m,1H),3.78-3.83(m,2H),3.53-3.72(m,3H),3.67-3.42(m,1H),3.23-3.61(m,1H),3.13(s,3H),2.65-2.71(m,1H),2.32-2.39(m,1H),2.21-2.23(m,1H),2.14–1.62(m,10H).
实施例25化合物Z63的合成
Figure PCTCN2022140669-appb-000074
步骤一：在10mL单口瓶中，向(4 1S,4 3S)-1 7-(二甲基磷酰基)-11-甲基-2 5-(三氟甲基)-1 1H-8-氧杂-3,5,11-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十二烷-12-酮三氟乙酸盐(35mg,0.06mmol)的四氢呋喃(3mL)溶液中依次加入多聚甲醛(9.30mg,0.31mmol)和钛酸四异丙酯(35.2mg,0.12mmol)。该反应液在70℃搅拌16小时，将反应液降至35℃，再加入氰基硼氢化钠(7.79mg,0.12mmol)，继续35℃搅拌3小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)，流速：70mL/min,柱温：25℃)得到(4 1S,4 3S)-1 7-(二甲基磷酰基))-5,11-二甲基-2 5-(三氟甲基)-1 1H-8-氧杂-3,5,11-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十二烷-12-酮((4 1S,4 3S)-1 7-(dimethylphosphoryl)-5,11-dimethyl-2 5-(trifluoromethyl)-1 1H-8-oxa-3,5,11-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclododecaphan-12-one)(Z63)(2mg,收率6％,三氟乙酸盐)。LCMS:m/z(ESI):[M+H] +＝579.2,t R＝0.77min. 1H NMR(400MHz,CD 3OD):δ8.24-8.58(m,2H),7.88-8.01(m,1H),7.41-7.43(m,1H),4.11-4.18(m,1H),3.94-3.97(m,1H),3.79-3.85(m,3H),3.66-3.70(m,2H),3.36-3.41(m,1H),3.13-3.18(m,4H),2.86(s,2H),2.55-2.73(m,2H),2.25-2.32(m,3H),1.82-1.97(m,9H).
实施例26化合物Z23的合成
Figure PCTCN2022140669-appb-000075
步骤一：25℃下，向7-溴-1H-吲哚-6-甲酸甲酯(1.0g,3.9mmol)的N,N二甲基甲酰胺(10mL)溶液中，加入四(三苯基膦)钯(0.45g,0.39mmol)和氰化锌(0.46g,3.9mmol)。氮气吹一分钟放入微波150℃反应1小时。LCMS检测反应完全后，向反应液中缓慢加入水(20mL)，乙酸乙酯(30mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，粗品经过柱机(石油醚/乙酸乙酯＝5/1)层析纯化得7-氰基-1H-吲哚-6-甲酸甲酯(黄色固体,800mg,收率81％)。LCMS:m/z(ESI):201.2[M+H] +,t R＝1.22min.
步骤二：25℃下，向7-氰基-1H-吲哚-6-甲酸甲酯(800mg,4.0mmol)的N,N二甲基甲酰胺(10mL)溶液中加入N-碘代丁二酰亚胺(1.35g,6.0mmol)。置换氮气，40℃搅拌3小时，LCMS检测反应完全。向反应液加入水(30mL)，乙酸乙酯(40mL×2)萃取，合并的有机层用饱和食盐水(40mL×4)洗涤，无水硫酸钠干燥，过滤浓缩。粗品经硅胶柱(石油醚/乙酸乙酯＝1/1)层析纯化得7-氰基-3-碘-1H-吲哚-6-甲酸甲酯(灰白色固体,740mg,收率51％)。LCMS:m/z(ESI):327.0[M+H] +,t R＝1.95min.
步骤三：25℃下，向7-氰基-3-碘-1H-吲哚-6-甲酸甲酯(740mg,2.27mmol)和4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(871mg,6.81mmol)的四氢呋喃(15mL)溶液中，依次加入三(二亚苄基丙酮)二钯(312mg,0.34mmol)、2-二环己基膦-2',4',6'-三异丙基联苯(108mg,0.227mmol)和三乙胺(689mg,6.81mmol)。置换氮气，90℃条件下反应14小时，LCMS检测反应完全。向反应液中加入水(20mL)，乙酸乙酯(30mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，粗品经硅胶柱(石油醚/乙酸乙酯＝5/1至1/1)层析纯化，得到6-甲酰基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吲哚-7-甲腈甲烷(黄色固体,600mg,收率81％)LCMS:m/z(ESI):327.2[M+H] +,t R＝1.26min.
步骤四：25℃下，向6-甲酰基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吲哚-7-甲腈甲烷(600mg,1.84mmol)和{[(1S,3S)-3-{[4-氯-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]氨基}甲烷酸-2-甲基丙-2-基酯(583mg,1.53mmol)的四氢呋喃溶液(10mL)中依次加入氯[(正丁基二(1-金刚烷基)膦)-2-(2-氨基联苯)]钯(II)(102mg,0.153mmol)和磷酸钾(976mg,4.6mmol)的水(2mL)溶液。置换氮气，60℃反应14小时，LCMS检测反应完全。向反应液中加入水(20mL)，乙酸乙酯(20mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，粗品经过柱机(石油醚/乙酸乙酯＝5/1)层析纯化，得7-氰基-3-(2-{[(1S,3S)-3-({[(2-甲基丙-2-基)氧基]羰基}氨基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(黄色油状,580mg,收率69％)。LCMS:m/z(ESI):544.8[M+H] +,t R＝1.66min.
步骤五：25℃下，向7-氰基-3-(2-{[(1S,3S)-3-({[(2-甲基丙-2-基)氧基]羰基}氨基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(500mg,0.92mmol)的二氯甲烷(5mL)溶液加入三氟醋酸(2.5mL)。20℃反应3小时，LCMS检测反应完全。反应液加入饱和碳酸氢钠溶液(30mL)，二氯甲烷和甲醇(5:1)的混合溶液(50mL×6)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩得粗品7-氰基-3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(黄色油状,500mg,纯度75％,收率92％)。LCMS:MS m/z(ESI):445.2[M+H] +,t R＝0.79min.
步骤六：室温下，向7-氰基-3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(100mg,0.225mmol)的N,N-二甲基甲酰胺溶液(2mL)中，依次加入[(4-溴丁基)氨基]甲烷酸-2-甲基丙-2-基酯(56mg,0.225mmol)和N,N-二异丙基乙胺(116mg,0.9mmol)。置换氮气，80℃搅拌反应16小时，LCMS检测反应完全。反应液加入饱和氯化铵溶液(10mL)，并用乙酸乙酯(20mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。得到的粗品经硅胶柱(二氯甲烷/甲醇＝20/1到10/1)层析纯化，得7-氰基-3-(2-{[(1S,3S)-3-[(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂壬-9-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(黄色油状,70mg,收率40％)。LCMS:MS m/z(ESI):615.8[M+H] +,t R＝1.28min.
步骤七：向7-氰基-3-(2-{[(1S,3S)-3-[(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂壬-9-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(70mg,0.09mmol)的四氢呋喃(3mL)和甲醇(3mL)的混合溶液中加入一水合氢氧化锂(19.0mg,0.45mmol)的水(3mL)溶液。40℃搅拌反应12h，LCMS检测反应完全。反应液直接浓缩，粗品经反相制备(色谱柱：Ultimate XB-C18-08,50*250mm,10um(PARP-02),流动相:乙腈-水(0.1％碳酸氢铵),流速:70mL/min,柱温:25℃)得7-氰基-3-(2-{[(1S,3S)-3-[(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂壬-9-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(白色固体,30mg,收率55％)。LCMS:MS m/z(ESI):602.2[M+H] +,t R＝0.86min.
步骤八：向7-氰基-3-(2-{[(1S,3S)-3-[(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂壬-9-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(20mg,0.033mmol)的二氯甲烷(0.9mL)溶液中加入三氟醋酸(0.1mL)。15℃搅拌反应45分钟。LCMS检测反应完全后，向反应液中加入N,N-二异丙基乙胺调节pH＝8。浓缩得7-氰基-3-(2-{[(1S,3S)-3-[(4-氨基丁基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(黄色油状物,12mg,收率72％)。粗产品直接用于下一步反应。LCMS:MS m/z(ESI):502.0[M+H] +,t R＝1.20min.
步骤九：向7-氰基-3-(2-{[(1S,3S)-3-[(4-氨基丁基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(12mg,0.02mmol)的N,N-二甲基甲酰胺(2mL)溶液中，依次加入2-(7-氮杂苯并三氮 唑)-N,N,N',N'-四甲基脲六氟磷酸酯(15mg,0.04mmol)和N,N-二异丙基乙胺(21mg,0.16mmol)。80℃搅拌14h，LCMS检测反应完全。浓缩，粗品经反相制备(色谱柱:Ultimate XB-C18-08,50*250mm,10um(PARP-02),流动相:乙腈-水(0.1％碳酸氢铵),流速:70mL/min,柱温:25℃)得(4 1S,4 3S)-11-氧杂-2 5-(三氟甲基)-1 1H-3,5,11-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-1 7-甲腈(4 1S,4 3S)-11-oxo-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphane-1 7-carbonitrile(Z23,0.8mg,收率7％)。LCMS:MS m/z(ESI):484.2[M+H] +,t R＝0.84min. 1H NMR(400MHz,CD 3OD):δ8.73(d,J＝8.4Hz,1H),8.53(s,1H),7.96(s,1H),7.46(d,J＝8.4Hz,1H),4.18-4.13(m,1H),3.28-3.23(m,1H),3.11-3.00(m,1H),2.91-2.80(m,1H),2.52-2.48(m,1H),2.34-2.08(m,4H),1.84-1.73(m,1H),1.72-1.61(m,1H),1.56-1.39(m,5H).
实施例27化合物Z62的合成
Figure PCTCN2022140669-appb-000076
步骤一：在0℃，氮气氛围下，向三苯基膦(129mg,0.49mmol)的二氯甲烷(3mL)溶液中依次加入[(4-羟基丁基)(甲基)氨基]甲烷酸-2-甲基丙-2-基酯(100mg,0.49mmol)、碘单质(125mg,0.49mmol)、咪唑(50mg,0.74mmol)。0℃下搅拌5分钟后升温到室温，反应在室温下搅拌4小时。LCMS反应完全后，加水(10mL)稀释，二氯甲烷(20mL×3)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥有机相，过滤浓缩。得到的粗品经硅胶柱(石油醚/乙酸乙酯＝10/1到3/1)层析纯化，得到无色油状物[(4-碘丁基)(甲基)氨基]甲烷酸-2-甲基丙-2-基酯(120mg,收率78％)。LCMS:m/z(ESI):258.0[M+H-56] +,t R＝1.63min.
步骤二：将7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(27mg,0.054mmol)溶于N,N-二甲基甲酰胺(2mL)。依次加入[(4-碘丁 基)(甲基)氨基]甲烷酸-2-甲基丙-2-基酯(20mg,0.065mmol)、N,N-二异丙基乙胺(28mg,0.218mmol)。80℃搅拌16小时，LCMS检测反应完全。反应液过滤除去固体杂质，有机相浓缩得粗产品，经制备TLC(二氯甲烷/甲醇＝10/1)纯化得7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2,5-三甲基-4-氧亚基-5-氮杂-3-氧杂壬-9-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(黄色固体,28mg,收率75％)。LCMS:m/z(ESI):681.3[M+H] +,t R＝1.17min.
步骤三：将7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2,5-三甲基-4-氧亚基-5-氮杂-3-氧杂壬-9-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(110mg,0.162mmol)溶于水(2mL)、甲醇(2mL)和四氢呋喃(2mL)的混合体系中。加入氢氧化锂(1个结晶水,34mg,0.808mmol)。40℃搅拌6小时。LCMS检测反应完全后，旋干除去溶剂得粗产品7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2,5-三甲基-4-氧亚基-5-氮杂-3-氧杂壬-9-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(黄色固体,110mg,收率94％)，直接用于下一步反应。LCMS:m/z(ESI):667.4[M+H] +,t R＝1.04min.
步骤四：向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-[(2,2,5-三甲基-4-氧亚基-5-氮杂-3-氧杂壬-9-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(110mg,0.164mmol)中加入氯化氢/甲醇溶液(5mL,4M)，体系在40℃搅拌4小时。LCMS检测反应完全后，旋干，粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)得7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-{[4-(甲基氨基)丁基]氨基}环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(白色固体,80mg,收率94％)。LCMS:m/z(ESI):567.3[M+H] +,t R＝0.83min.
步骤五：向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S,3S)-3-{[4-(甲基氨基)丁基]氨基}环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(60mg,0.106mmol)的N,N-二甲基甲酰胺(5mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(40mg,0.106mmol)和N,N-二异丙基乙胺(68mg,0.530mmol)。80℃搅拌4h，LCMS检测反应完全后。浓缩，粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)得(4 1S,4 3S)-1 7-(二甲基磷酰基)-10-甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(4 1S,4 3S)-1 7-(dimethylphosphoryl)-10-methyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z62,16mg,收率28％,三氟乙酸盐)。LCMS:m/z(ESI):549.2[M+H] +,t R＝0.84min. 1H NMR(400MHz,CD 3OD):δ8.72-8.36(m,2H),8.05-7.89(m,1H),7.36-7.19(m,1H),3.86-3.73(m,1H),3.23-3.13(m,1H),3.11(s,3H),3.08-2.98(m,1H),2.83-2.63(m,3H),2.41-2.06(m,4H),2.00-1.55(m,12H).
实施例28化合物Z68-1和Z68-2的合成
Figure PCTCN2022140669-appb-000077
步骤一：在5℃下，向4-((苄氧基)羰基)氨基)-3-氧代丁酸甲酯(5.0g,18.9mmol)的四氢呋喃(100mL)溶液中加入氢化铝锂的四氢呋喃溶液(28.3mL,1M,28.3mmol)。该反应液在氮气保护下于5℃搅拌反应2小时。LCMS检测反应完全后，反应液加饱和氯化铵水溶液(100mL)，乙酸乙酯(100mL×3)萃取，合并的有机层用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤浓缩，粗品经过柱机(石油醚/乙酸乙酯＝10/1到0/1)层析纯化，得到无色油状物苄基(2,4-二羟基丁基)氨基甲酸酯(1.2g,收率27％)。LCMS:m/z(ESI):239.8[M+H] +,t R＝0.99min.
步骤二：在5℃下，向苄基(2,4-二羟基丁基)氨基甲酸酯(1.2g,5.02mmol)的二氯甲烷(50mL)溶液中加入咪唑(0.68g,10.04mmol)、叔丁基二苯基氯硅烷(1.38g,5.02mmol)。氮气保护下于5℃搅拌反应3小时。LCMS检测反应完全后，反应液加水(50mL)，乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤浓缩，粗品经过柱机(石油醚/乙酸乙酯＝10/1到1/1)层析纯化，得到无色油状物苄基(4-((叔丁基二苯基硅基)氧基)-2-羟基丁基)氨基甲酸酯(2.2g,收率92％)。LCMS:m/z(ESI):400.2[M+H] +,t R＝1.69min.
步骤三：将苄基(4-((叔丁基二苯基硅基)氧基)-2-羟基丁基)氨基甲酸酯(2.2g,4.61mmol)溶于二氯甲烷(30mL)，然后于0℃缓慢加入二乙氨基三氟化硫(1.1g,6.92mmol)，该反应在5℃搅拌3小时。TLC检测反应完全后，加水(20mL)淬灭，乙酸乙酯(30mL×3)萃取，合并的有机层用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤浓缩，粗品经过柱机(石油醚/乙酸乙酯＝15/1到1/1)层析纯化，得到无色油状物苄基(4-((叔丁基二苯基硅基)氧基)-2-氟丁基)氨基甲酸酯(0.7g,收率29％)。 1H NMR(400MHz,DMSO-d 6):δ7.80–7.18(m,16H),5.04(s,2H),4.77(d,J＝50.4Hz,1H),3.74(d,J＝5.6H,2H),3.32–3.22(m,2H),1.85–1.70(m,2H),0.99(s,9H).
步骤四：将苄基(4-((叔丁基二苯基硅基)氧基)-2-氟丁基)氨基甲酸酯(700mg,1.46mmol)溶于N,N- 二甲基甲酰胺(5mL)中，再加入氟化铯(888mg,5.84mmol)。该反应在5℃搅拌18小时。LCMS检测反应完全后，加水(20mL)，乙酸乙酯(30mL×3)萃取，合并的有机层用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤浓缩，粗品经过柱机(石油醚/乙酸乙酯＝15/1到0/1)层析纯化，得到无色油状物苄基(2-氟-4-羟基丁基)氨基甲酸酯(300mg,收率85％)。LCMS:m/z(ESI):242.0[M+H] +,t R＝1.13min.
步骤五：50mL单口瓶中，将苄基(2-氟-4-羟基丁基)氨基甲酸酯(300mg,1.24mmol)溶于二氯甲烷(10mL)中，加入咪唑(126mg,1.86mmol)、三苯基膦(390mg,1.50mmol)和单质碘(381mg,1.50mmol)。该反应在10℃搅拌1小时。TLC点板检测反应完全后，直接加入硅胶，油泵旋干拌样，经过柱机(石油醚/乙酸乙酯＝20/1到3/1)层析纯化，得到无色油状物苄基(2-氟-4-碘丁基)氨基甲酸酯(330mg,收率76％)。
步骤六：将3-(2-((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸甲酯(220mg,0.44mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入苄基(2-氟-4-碘丁基)氨基甲酸酯(156mg,0.44mmol)和N,N-二异丙基乙胺(286mg,2.20mmol)。100℃搅拌18小时。LCMS检测反应完全后，直接加入硅胶，油泵旋干拌样，经过柱机(二氯甲烷/甲醇＝40/1到5/1)层析纯化，得到白色固体甲基3-(2-((1S,3S)-3-((苄氧基)羰基)氨基)-3-氟丁基氨基)环戊基氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(290mg,收率92％)。LCMS:m/z(ESI):719.2[M+H] +,t R＝1.12min.
步骤七：将甲基3-(2-((1S,3S)-3-((苄氧基)羰基)氨基)-3-氟丁基氨基)环戊基氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸酯(290mg,0.40mmol)溶于甲醇(5mL)、四氢呋喃(5mL)和水(5mL)的混合体系中，加入一水合氢氧化锂(84mg,2.00mmol)。该反应于40℃搅拌18小时，LCMS检测反应完全后，反应液浓缩，得到粗品白色固体3-(2-((1S,3S)-3-((苄氧基)羰基)氨基)-3-氟丁基氨基)环戊基氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(300mg)。LCMS:m/z(ESI):705.2[M+H] +,t R＝0.94min.
步骤八：向3-(2-((1S,3S)-3-((苄氧基)羰基)氨基)-3-氟丁基氨基)环戊基氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(300mg,0.43mmol)的反应瓶中加入三氟乙酸(5mL)，60℃搅拌3h。LCMS检测反应完全后，反应液浓缩，粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)，得到白色固体3-(2-((1S,3S)-3-((4-氨基-3-氟丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(140mg,收率57％,三氟乙酸盐)。LCMS:m/z(ESI):571.2[M+H] +,t R＝0.97min.
步骤九：在室温条件下向3-(2-((1S,3S)-3-((4-氨基-3-氟丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-羧酸(70mg,0.12mmol)的N,N-二甲基甲酰胺(5mL)中依次加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(55mg,0.15mmol)、N,N-二异丙基乙胺(78mg,0.61mmol)。氮气保护于60℃反应18小时。LCMS检测反应完全后，浓缩得到粗品(4 1S,4 3S)-1 7-(二甲基磷酰基)-8-氟-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮。
步骤十：将上一步反应得到的粗品经反相(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)制备纯化得到两个异构体化合物。其中一个异构体化合物任意指定为(4 1S,4 3S,8R)-1 7-(二甲基磷酰基)-8-氟-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮 (4 1S,4 3S,8R)-1 7-(dimethylphosphoryl)-8-fluoro-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-py rimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z68-1,4mg,收率6％,三氟乙酸盐)，白色固体物。LCMS:MS m/z(ESI):553.2[M+H] +,t R＝1.07min. 1H NMR(400MHz,CD 3OD):δ8.57(s,1H),8.45–8.42(m,1H),7.96(s,1H),7.32(dd,J＝8.0,3.2Hz,1H),4.80-4.61(m,1H),4.22-4.08(m,1H),3.88-3.78(m,1H),3.28-3.17(m,2H),2.96-2.86(m,1H),2.85–2.64(m,2H),2.40-2.26(m,2H),2.11–1.94(m,8H),1.92–1.69(m,3H)。另一个异构体化合物任意指定为(4 1S,4 3S,8S)-1 7-(二甲基磷酰基)-8-氟-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(4 1S,4 3S,8S)-1 7-(dimethylphosphoryl)-8-fluoro-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z68-2,3mg,收率5％,三氟乙酸盐)。LCMS:MS m/z(ESI):553.3[M+H] +,t R＝1.08min. 1H NMR(400MHz,CD 3OD):δ8.57(s,1H),8.50(d,J＝8.0Hz,1H),7.99(s,1H),7.28(dd,J＝8.0,3.2Hz,1H),4.83-4.73(m,1H),4.27–4.09(m,1H),3.88-3.78(m,1H),3.27–3.08(m,2H),2.92-2.72(m,2H),2.67–2.51(m,1H),2.40–2.17(m,2H),2.08–1.71(m,11H).
实施例29化合物Z66的合成
Figure PCTCN2022140669-appb-000078
步骤一：250mL三口瓶中，依次加入N-[(苄基氧基)羰基]-N-甲基甘氨酸(10.8g,48.4mmol)、四氢呋喃(100mL)和羰基二咪唑(7.8g,48.4mmol)。反应液用氮气置换，10℃搅拌12小时，加入氯化镁(2.3g,24.2mmol)和丙二酸单甲酯钾盐(7.6g,48.4mmol)，升温至60℃搅拌6小时，TLC检测反应完全。反应液浓缩，加水(100mL)稀释，乙酸乙酯(50mL×3)萃取，无水硫酸钠干燥，浓缩得到粗品，经过柱机(乙酸乙酯/石油醚＝50/50)层析纯化得(3,5-二氧亚基-7-氮杂-2-氧杂辛-7-基)甲 烷酸苄基酯(5.8g,收率43％)，呈淡黄色油状液体。 1H NMR(400MHz,CD 3OD):δ7.47–7.21(m,5H),5.13–5.06(m,2H),4.29–4.25(m,2H),3.70–3.64(m,3H),2.94–2.91(m,3H).
步骤二：将(3,5-二氧亚基-7-氮杂-2-氧杂辛-7-基)甲烷酸苄基酯(5.8g,20.8mmol)溶于二氯甲烷(50mL)，0℃滴加二乙胺基三氟化硫(5.0g,31.2mmol)。25℃搅拌16小时。LCMS检测反应完全后，加水(40mL)淬灭，二氯甲烷(50mL×3)萃取，无水硫酸钠干燥，浓缩的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流速:乙腈-水(0.1％三氟醋酸),流速:70mL/min,柱温:25℃)，得到类白色固体(5,5-二氟-3-氧亚基-7-氮杂-2-氧杂辛-7-基)甲烷酸苄基酯(1.4g,收率22％)。LCMS:m/z(ESI):301.8[M+H] +,t R＝1.48min.
步骤三：将(5,5-二氟-3-氧亚基-7-氮杂-2-氧杂辛-7-基)甲烷酸苄基酯(1.4g,4.7mmol)溶于四氢呋喃(20mL)，0℃滴加四氢铝锂的四氢呋喃溶液(4.7mL,1M)，10℃搅拌2小时。LCMS检测反应完全后，加水(20mL)淬灭，乙酸乙酯(20mL×3)萃取，无水硫酸钠干燥，浓缩得到粗品，经过柱机(乙酸乙酯/石油醚＝80/20)层析纯化，得[(2,2-二氟-4-羟基丁基)(甲基)氨基]甲烷酸苄基酯(1.0g,收率80％)，呈无色油状液体。LCMS:m/z(ESI):274.2[M+H] +,t R＝1.14min.
步骤四：向[(2,2-二氟-4-羟基丁基)(甲基)氨基]甲烷酸苄基酯(400mg,1.46mmol)的吡啶(5mL)溶液中，加入对甲基磺酰氯(558mg,2.93mmol)，10℃搅拌3小时。LCMS检测反应完全后，直接加入硅胶，油泵旋干拌样，经过柱机(二氯甲烷100％)层析纯化得到黄色油状物4-甲基苯磺酸-6,6-二氟-4-甲基-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基酯(370mg,收率59％)。LCMS:m/z(ESI):428.2[M+H] +,t R＝1.44min.
步骤五：将7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(426mg,0.86mmol)溶于N,N-二甲基甲酰胺(7mL)中，加入4-甲基苯磺酸-6,6-二氟-4-甲基-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基酯(350mg,0.82mmol)和N,N-二异丙基乙胺(0.68mL,4.09mmol)。100℃搅拌16小时。LCMS检测反应完全后，加硅胶油泵旋干拌样，经过柱机(二氯甲烷:甲醇＝100:6)层析纯化得到黄色固体7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(6,6-二氟-4-甲基-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(350mg,收率57％)。LCMS:m/z(ESI):751.3[M+H] +,t R＝1.15min.
步骤六：将7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(6,6-二氟-4-甲基-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(330mg,0.46mmol)溶于水(3mL)、甲醇(3mL)和四氢呋喃(3mL)的混合体系中，加入一水合氢氧化锂(96.6mg,2.30mmol)，40℃搅拌16小时。LCMS检测反应完全后，直接浓缩，得7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(6,6-二氟-4-甲基-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸，无需任何处理直接用于下一步反应。LCMS:m/z(ESI):737.4[M+H] +,t R＝1.43min.
步骤七：向7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(6,6-二氟-4-甲基-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(350mg,0.48mmol)中加入三氟乙酸(5mL)。60℃搅拌1.5小时，LCMS检测完全后，浓缩，粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)得白色固体7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-{[3,3-二氟-4-(甲基氨基)丁基]氨基}环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(215mg,两步收率81％)。LCMS:m/z (ESI):603.2[M+H] +,t R＝0.78min.
步骤八：向7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-{[3,3-二氟-4-(甲基氨基)丁基]氨基}环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(215mg,0.36mmol)的N,N-二甲基甲酰胺(10mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(149mg,0.39mmol)和N,N-二异丙基乙胺(0.30mL,1.78mmol)。60℃搅拌16h，LCMS检测反应完全，浓缩，粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)得(4 1S,4 3S)-1 7-(二甲基磷酰基)-8,8-二氟-10-甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(4 1S,4 3S)-1 7-(dimethylphosphoryl)-8,8-difluoro-10-methyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z66,22mg,收率11％,三氟乙酸盐)。LCMS:m/z(ESI):585.2[M+H] +,t R＝0.87min. 1H NMR(400MHz,CD 3OD):δ8.45-8.65(m,2H),7.93(s,1H),7.26(s,1H),4.00-4.38(m,1H),3.96-3.47(m,3H),3.25(s,3H),3.01-2.52(m,3H),2.52-2.09(m,4H),2.08-1.51(m,9H).
实施例30化合物Z65的合成
Figure PCTCN2022140669-appb-000079
步骤一：在一个10mL单口瓶中，向(4 1S,4 3S)-1 7-(二甲基磷酰基)-8,8-二氟-10-甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(14mg,0.02mmol,三氟乙酸盐)的四氢呋喃(3mL)溶液中依次加入多聚甲醛(9mg,0.10mmol)和钛酸四异丙酯(28mg,0.10mmol)。70℃搅拌14小时，将反应液降至25℃，加入氰基硼氢化钠(4mg,0.06mmol)，25℃搅拌2小时。LCMS检测反应完全后，反应液浓缩，粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)得(4 1S,4 3S)-1 7-(二甲基磷酰基)-8,8-二氟-5,10-二甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(4 1S,4 3S)-1 7-(dimethylphosphoryl)-8,8-difluoro-5,10-dimethyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z65,2mg,收率14％,三氟乙酸盐)。LCMS:m/z(ESI):599.2[M+H] +,t R＝1.31min. 1H NMR(400MHz,CD 3OD):δ8.86–8.41(m,2H),8.00(s,1H),7.23(dd,J＝8.0,3.2Hz,1H),4.28–4.06(m,1H),3.92-3.76(m,1H),3.68-3.47(m,2H),3.25(s,3H),2.90-2.77(m,1H),2.46-2.38(m,1H),2.33-2.16(m,5H),2.13–1.94(m,6H),1.90–1.86(m,3H),1.78–1.55(m,3H).
实施例31化合物Z72和Z75的合成
Figure PCTCN2022140669-appb-000080
步骤一：在室温条件下向7-溴-1H-吲哚-6-羧酸甲酯(2.0g,7.9mmol)的二甲基亚砜(15mL)溶液中加入L-脯氨酸(0.18g,1.6mmol)、碘化亚酮(0.95g,0.8mmol)和甲基亚硫酸钠(1.1g,9.5mmol)。氮气保护下于90℃搅拌反应16小时。LCMS检测反应完全后，向反应液中缓慢加入饱和氯化铵水溶液(30mL)淬灭，并用乙酸乙酯(30mL×3)萃取，合并的有机层用饱和食盐水洗涤3次，无水硫酸钠干燥，过滤浓缩。得到的粗品经硅胶柱(石油醚/乙酸乙酯＝30/1～2/1)层析纯化，得到白色固体7-(甲磺酰基)-1H-吲哚-6-羧酸甲酯(1.4g,收率70％)。LCMS:m/z(ESI):254.0[M+H] +,t R＝1.10min.
步骤二：在室温下向7-(甲磺酰基)-1H-吲哚-6-羧酸甲酯(1.4g,5.5mmol)的N,N二甲基甲酰胺(15mL)溶液中加入N-碘代丁二酰亚胺(1.5g,6.6mmol)。该反应液在氮气保护下在室温搅拌16小时。LCMS检测反应完全后，反应液加水(30mL)，然后用乙酸乙酯(30mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。得到的粗品经硅胶柱(石油醚/乙酸乙酯＝20/1～1:1)层析纯化，得到3-碘-7-(甲磺酰基)-1H-吲哚-6-羧酸甲酯(1.8g,收率86％)。LCMS:m/z(ESI):380.0[M+H] +,t R＝1.25min.
步骤三：在室温条件下，向封管中依次加入3-碘-7-(甲磺酰基)-1H-吲哚-6-羧酸甲酯(1.8g,4.7mmol)、三(二亚苄基丙酮)二钯(0.44g,0.47mmol)、2-二环己基膦-2,4,6-三异丙基联苯(0.45g,0.94mmol)、频哪醇硼烷(0.91g,7.1mmol)、三乙胺(1.4g,14.1mmol)和四氢呋喃(15mL)溶液。氮气保护下于90℃搅拌16小时。LCMS检测反应完全后，反应液直接旋蒸浓缩得到粗品，粗品经硅胶柱(石油醚/乙酸乙酯＝10/1～2/1)层析纯化，得到白色固体甲基7-(甲磺酰基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊烷-2-基)-1H-吲哚-6-羧酸酯(1.1g,收率61％).LCMS:m/z(ESI):380.2[M+H] +,t R＝1.35min.
步骤四：在室温条件下，向干燥的50mL单口瓶中依次加入甲基7-(甲磺酰基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊烷-2-基)-1H-吲哚-6-羧酸酯(1.1g,2.9mmol)、氯[(正丁基二(1-金刚烷基)膦)-2-(2-氨基联苯)]钯(II)(0.19g,0.29mmol)、磷酸钾(1.8g,8.7mmol)、叔丁基((1S,3S)-3-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)环戊基)氨基甲酸酯(1.1g,2.9mmol)、四氢呋喃(25mL)和水(5mL)的混合溶液。该反应在氮气保护下于60℃搅拌16小时。LCMS检测反应完全后，反应液直接旋蒸浓缩得到粗品，粗品经硅胶柱(石油醚/乙酸乙酯＝10/1～0/1)层析纯化，得到白色固体甲基3-(2-((1S,3S)-3-((叔丁氧羰基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(甲磺酰基)-1H-吲哚-6-羧酸酯(0.57g,收率33％).LCMS:m/z(ESI):598.2[M+H] +,t R＝1.38min.
步骤五：室温下，将甲基3-(2-((1S,3S)-3-((叔丁氧羰基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(甲磺酰基)-1H-吲哚-6-羧酸酯(570mg,0.95mmol)溶于氯化氢/乙酸乙酯(5mL,4M)和乙酸乙酯(3mL)的混合溶液中，30℃下反应16小时。LCMS检测反应完全后，反应液加入饱和碳酸氢钠溶液(30mL)，然后用二氯甲烷(20mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经过柱机(二氯甲烷/甲醇＝20:1)层析纯化，得到白色固体3-(2-((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(甲磺酰基)-1H-吲哚-6-羧酸甲酯(300mg,收率64％)。LCMS:m/z(ESI):498.3[M+H] +,t R＝1.12min.
步骤六：室温下，向3-(2-((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(甲磺酰基)-1H-吲哚-6-羧酸甲酯(300mg,0.60mmol)的N,N-二甲基甲酰胺(10mL)溶液中依次加入叔丁基(2-(2-碘乙氧基)乙基)(甲基)氨基甲酸酯(197mg,0.60mmol)和N,N-二异丙基乙胺(310mg,2.40mmol)，80℃搅拌16小时。LCMS检测反应完全后，反应液加入饱和碳酸氢钠溶液(30mL)，然后用乙酸乙酯(20mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经过柱机(二氯甲烷/甲醇＝30:1)层析纯化，得到白色固体甲基3-(2-((1S,3S)-3-((2-(2-((叔丁氧羰基)(甲基)氨基)乙氧基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(甲基磺酰基)-1H-吲哚-6-羧酸酯(180mg,收率43％)。LCMS:m/z(ESI):699.4[M+H] +,t R＝1.29min.
步骤七：将甲基3-(2-((1S,3S)-3-((2-(2-((叔丁氧羰基)(甲基)氨基)乙氧基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(甲基磺酰基)-1H-吲哚-6-羧酸酯(180mg,0.26mmol)溶于水(3mL)、甲醇(3mL)和四氢呋喃(3mL)的混合体系中，然后加入一水合氢氧化锂(55mg,1.3mmol)，40℃搅拌16小时。LCMS检测反应完全后，将反应液用旋蒸直接旋干，得到粗产品3-(2-((1S,3S)-3-((2-(2-((叔丁氧羰基)(甲基)氨基)乙氧基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(甲基磺酰基)-1H-吲哚-6-羧酸(176mg,收率100％)，无需任何纯化直接用于下一步。LCMS:m/z(ESI):685.3[M+H] +,t R＝1.21min.
步骤八：将3-(2-((1S,3S)-3-((2-(2-((叔丁氧羰基)(甲基)氨基)乙氧基)乙基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(甲基磺酰基)-1H-吲哚-6-羧酸(176mg,0.26mmol)溶于甲醇(5mL)中，然后加入盐酸/甲醇(5mL,4M)，40℃搅拌16小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经 反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)，得到白色固体3-(2-((1S,3S)-3-((2-(甲氨基)乙氧基)乙基)氨基)环戊基氨基)-5-(三氟甲基)嘧啶-4-基)-7-(甲磺酰基)-1H-吲哚-6-羧酸(110mg,收率72％,三氟乙酸盐)。LCMS:m/z(ESI):585.2[M+H] +,t R＝0.78min.
步骤九：向3-(2-((1S,3S)-3-((2-(甲氨基)乙氧基)乙基)氨基)环戊基氨基)-5-(三氟甲基)嘧啶-4-基)-7-(甲磺酰基)-1H-吲哚-6-羧酸(110mg,0.16mmol,三氟乙酸盐)的N,N-二甲基甲酰胺(10mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(61mg,0.16mmol)和N,N-二异丙基乙胺(83mg,0.64mmol)，60℃搅拌16h。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)，得到白色固体(4 1S,4 3S)-11-甲基-1 7-(甲基磺酰基)-2 5-(三氟甲基)-1 1H-8-氧杂-3,5,11-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十二烷-12-酮(4 1S,4 3S)-11-methyl-1 7-(methylsulfonyl)-2 5-(trifluoromethyl)-1 1H-8-oxa-3,5,11-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclododecaphan-12-one(Z72,55mg,收率51％,三氟乙酸盐)。LCMS:m/z(ESI):567.2[M+H] +,t R＝1.12min. 1H NMR(400MHz,CD 3OD):δ8.59(s,1H),8.34(d,J＝8.0Hz,1H),7.86(s,1H),7.39(d,J＝8.0,1H),4.48–4.10(m,1H),4.05–3.89(m,1H),3.86-3.70(m,2H),3.68-3.60(m,1H),3.57–3.39(m,3H),3.33(s,3H),3.25-3.16(m,2H),3.16–3.09(m,3H),2.80–2.52(m,1H),2.44–2.25(m,1H),2.24–1.90(m,2H),1.86–1.53(m,2H).
步骤十：在一个10mL单口瓶中，向(4 1S,4 3S)-11-甲基-1 7-(甲基磺酰基)-2 5-(三氟甲基)-1 1H-8-氧杂-3,5,11-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十二烷-12-酮(30mg,0.044mmol,三氟乙酸盐)的四氢呋喃(10mL)溶液中依次加入多聚甲醛(20mg,0.221mmol)和钛酸四异丙酯(63mg,0.221mmol)，该反应液在70℃搅拌14小时，将反应液降至30℃，加入氰基硼氢化钠(41mg,0.660mmol)，继续在30℃下搅拌2小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)，得到(4 1S,4 3S)-5,11-二甲基-1 7-(甲基磺酰基)-2 5-(三氟甲基)-1 1H-8-氧杂-3,5,11-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十二烷-12-酮(4 1S,4 3S)-5,11-dimethyl-1 7-(methylsulfonyl)-2 5-(trifluoromethyl)-1 1H-8-oxa-3,5,11-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclododecaphan-12-one(Z75,8mg,收率26％,三氟乙酸盐)。LCMS:m/z(ESI):581.2[M+H] +,t R＝1.12min. 1H NMR(400MHz,CD 3OD):δ8.60(s,1H),8.25(d,J＝8.0Hz,1H),7.82(s,1H),7.36(d,J＝8.0Hz,1H),4.19–4.03(m,1H),3.98-3.89(m,1H),3.88–3.72(m,3H),3.70-3.52(m,2H),3.49-3.37(m,1H),3.32(s,3H),3.19-3.11(m,5H),2.87–2.82(m,3H),2.61–2.43(m,1H),2.31–2.21(m,3H),1.86-1.73(m,2H).
实施例32化合物Z76、Z77、Z78、Z79的合成
Figure PCTCN2022140669-appb-000081
步骤一：在15℃下，向N-[(苄基氧基)羰基]甘氨酸(100.0g,478.49mmol)的四氢呋喃(1000mL)溶液中加入羰基二咪唑(85.3g,526.34mmol)。该反应液在氮气保护下于15℃搅拌反应18小时。然后向反应液中加入氯化镁(22.8g,239.25mmol)、丙二酸单甲酯钾盐(82.2g,526.34mmol)。该反应液在氮气保护下于45℃继续搅拌反应6小时。LCMS检测反应完全后，反应液加水(600mL)，然后用乙酸乙酯(500mL×3)萃取，合并的有机层用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经过柱机(石油醚/乙酸乙酯＝15/1到3/1)层析纯化，得到无色油状物[(1-甲氧基-1,3-二氧亚基丁-4-基)氨基]甲烷酸苄基酯(85.3g,收率67％)。LCMS:m/z(ESI):220.0[M-44+H] +,t R＝1.58min.
步骤二：在15℃下，向[(1-甲氧基-1,3-二氧亚基丁-4-基)氨基]甲烷酸苄基酯(85.3g,321.89mmol)的四氢呋喃(900mL)溶液中分批加入硼氢化锂(14.0g,643.78mmol)。该反应液在氮气保护下于15℃搅拌反应18小时。TLC检测反应完全后，反应液加入饱和氯化铵溶液(400mL)，然后用乙酸 乙酯(600mL×3)萃取，合并的有机层用饱和食盐水(600mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经过柱机(石油醚/乙酸乙酯＝5/1到1/2)层析纯化，得到无色油状物[(2,4-二羟基丁基)氨基]甲烷酸苄基酯(60.0g,收率78％)。
步骤三：在15℃下，向[(2,4-二羟基丁基)氨基]甲烷酸苄基酯(60.0g,251.05mmol)的二氯甲烷(600mL)溶液中加入咪唑(22.2g,326.37mmol)，然后慢慢滴加叔丁基二苯基氯硅烷(69.0g,251.05mmol)。该反应液在氮气保护下于15℃搅拌反应2小时。LCMS检测反应完全后，反应液加入饱和氯化铵溶液(400mL)，然后用乙酸乙酯(600mL×3)萃取，合并的有机层用饱和食盐水(600mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经过柱机(石油醚/乙酸乙酯＝10/1到2/1)层析纯化，得到无色油状物[(7-羟基-2,2-二甲基-3,3-二苯基-4-氧杂-3-硅杂辛-8-基)氨基]甲烷酸苄基酯(88.0g,收率74％)。LCMS:m/z(ESI):402.2[M-77+H] +,t R＝1.74min.
步骤四：将[(7-羟基-2,2-二甲基-3,3-二苯基-4-氧杂-3-硅杂辛-8-基)氨基]甲烷酸苄基酯(88.0g,184.49mmol)溶于二氯甲烷(900mL)中，然后室温下缓慢滴加二乙胺基三氟化硫(38.7g,239.83mmol)。该反应在15℃搅拌2小时。TLC检测反应完全后，反应液加入饱和氯化铵溶液(400mL)，然后用乙酸乙酯(600mL×3)萃取，合并的有机层用饱和食盐水(600mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经过柱机(石油醚/乙酸乙酯＝30/1到5/1)层析纯化，得到无色油状物[(7-氟-2,2-二甲基-3,3-二苯基-4-氧杂-3-硅杂辛-8-基)氨基]甲烷酸苄基酯(20.5g,收率23％)。LCMS:m/z(ESI):502.2[M+Na] +,t R＝1.74min.
步骤五：将[(7-氟-2,2-二甲基-3,3-二苯基-4-氧杂-3-硅杂辛-8-基)氨基]甲烷酸苄基酯(20.5g,42.80mmol)溶于四氢呋喃(150mL)中，于室温下分批加入钠氢(5.1g,60％含量分散在矿物油中,128.40mmol)，然后再缓慢滴加碘甲烷(12.2g,85.60mmol)。该反应在15℃搅拌12小时。LCMS检测反应完全后，反应液加入饱和氯化铵溶液(200mL)，然后用乙酸乙酯(200mL×3)萃取，合并的有机层用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经过柱机(石油醚/乙酸乙酯＝30/1到5/1)层析纯化，得到无色油状物(7-氟-2,2-二甲基-3,3-二苯基-9-氮杂-4-氧杂-3-硅杂癸-9-基)甲烷酸苄基酯(16.5g,收率78％)。LCMS:m/z(ESI):516.2[M+Na] +,t R＝1.85min.
步骤六：将(7-氟-2,2-二甲基-3,3-二苯基-9-氮杂-4-氧杂-3-硅杂癸-9-基)甲烷酸苄基酯(10.0g,20.24mmol)溶于N,N-二甲基甲酰胺(60mL)的溶液中，然后加入氟化铯(15.4g,101.20mmol)，50℃搅拌8小时。LCMS检测反应完全后，反应液加入饱和氯化铵溶液(100mL)，然后用乙酸乙酯(100mL×3)萃取，合并的有机层用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经过柱机(石油醚/乙酸乙酯＝10/1到2/1)层析纯化，得到无色油状物[(2-氟-4-羟基丁基)(甲基)氨基]甲烷酸苄基酯(4.4g,收率85％)。LCMS:m/z(ESI):256.2[M+H] +,t R＝1.08min.
步骤七：在室温条件下，将[(2-氟-4-羟基丁基)(甲基)氨基]甲烷酸苄基酯(4.4g,17.25mmol)溶于二氯甲烷(40mL)的溶液中，然后依次加入咪唑(1.4g,20.70mmol)、三苯基膦(5.4g,20.70mmol)和单质碘(5.3g,20.70mmol)。该反应在室温下继续搅拌2小时。LCMS检测反应完全后，反应液加入饱和氯化铵溶液(50mL)，然后用二氯甲烷(50mL×3)萃取，合并的有机层用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经过柱机(石油醚/乙酸乙酯＝30/1到10/1)层析纯化，得到无色油状物[(2-氟-4-碘丁基)(甲基)氨基]甲烷酸苄基酯(5.0g,收率79％)。LCMS:m/z(ESI):366.0[M+H] +,t R＝1.44min.
步骤八：在一个250mL单口瓶中，将7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(5.0g,10.10mmol)溶于N,N-二甲基甲酰胺(70 mL)中，然后加入[(2-氟-4-碘丁基)(甲基)氨基]甲烷酸苄基酯(3.7g,10.10mmol)和N,N-二异丙基乙胺(5.2g,40.40mmol)，100℃搅拌16小时。LCMS检测反应完全后，直接加入硅胶，油泵旋干拌样，经过柱机(二氯甲烷:甲醇＝100:8)层析纯化得到黄色固体7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(6-氟-4-甲基-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(7.0g,收率95％)。LCMS:m/z(ESI):733.2[M+H] +,t R＝1.14min.
步骤九：将7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(6-氟-4-甲基-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(7.0g,9.56mmol)溶于水(20mL)、甲醇(20mL)和四氢呋喃(20mL)的混合体系中，然后加入一水合氢氧化锂(1.6g,38.24mmol)，反应在40℃搅拌16小时。LCMS检测反应完全后，油泵旋掉其中的溶剂，得到7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-[(6-氟-4-甲基-3-氧亚基-1-苯基-4-氮杂-2-氧杂辛-8-基)氨基]环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(粗品含盐)，不经纯化直接用于下一步反应。LCMS:m/z(ESI):719.2[M+H] +,t R＝1.09min.
步骤十：将上步粗品，加入三氟乙酸(30mL)，60℃搅拌3小时，LCMS检测完全后，反应液浓缩，得到的粗品经反相制备(70mL/min,25℃,Ultimate XB-C18,50*250mm,10um(PARP-02),乙腈-水(0.1％三氟醋酸))得7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-{[3-氟-4-(甲基氨基)丁基]氨基}环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(4.0g,两步收率72％,白色固体)。LCMS:m/z(ESI):585.2[M+H] +,t R＝1.13min.
步骤十一：向7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-{[3-氟-4-(甲基氨基)丁基]氨基}环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(4.0g,6.85mmol)的N,N-二甲基甲酰胺(60mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2.6g,6.85mmol)和N,N-二异丙基乙胺(3.6g,27.4mmol)，该反应液在60℃搅拌16h。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)得到两个异构体化合物。其中一个异构体化合物任意指定为(4 1S,4 3S,8R)-1 7-(二甲基磷酰基)-8-氟-10-甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(4 1S,4 3S,8R)-1 7-(dimethylphosphoryl)-8-fluoro-10-methyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z76,0.7g,收率18％,三氟乙酸盐)，类白色固体。LCMS:m/z(ESI):567.2[M+H] +,t R＝0.86min. 1H NMR(400MHz,CD 3OD):δ8.55(s,1H),8.30-7.70(m,2H),7.30(m,1H),5.69-4.98(m,1H),4.28-3.95(m,1H),3.87-3.76(m,1H),3.69-3.37(m,2H),3.21(s,3H),2.89-2.78(m,1H),2.74-2.64(m,1H),2.48-2.14(m,3H),2.12-1.54(m,11H).另一个异构体化合物任意指定为(4 1S,4 3S,8S)-1 7-(二甲基磷酰基)-8-氟-10-甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(4 1S,4 3S,8S)-1 7-(dimethylphosphoryl)-8-fluoro-10-methyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z77,0.8g,收率21％,三氟乙酸盐)，类白色固体。LCMS:m/z(ESI):567.2[M+H] +,t R＝0.87min. 1H NMR(400MHz,CD 3OD):δ8.58(s,1H),8.40(s,1H),7.93(s,1H),7.21(dd,J＝8.0,3.2Hz,1H),5.26-4.96(m,1H),4.32-3.97(m,1H),3.86-3.72(m,1H),3.54-3.31(m,2H),3.22(s,3H),2.91-2.79(m,1H),2.73-2.37(m,2H),2.36-2.16(m,2H),2.12-1.65(m,11H).
步骤十二：向(4 1S,4 3S,8R)-1 7-(二甲基磷酰基)-8-氟-10-甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(Z76,220mg,0.39mmol)的四氢呋喃(20mL) 溶液中依次加入多聚甲醛(176mg,1.95mmol)和钛酸四异丙酯(554mg,1.95mmol)，该反应液在70℃搅拌16h。然后将反应冷却至10℃，向反应液中加入氰基硼氢化钠(74mg,1.17mmol)并继续搅拌2小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)，得到(4 1S,4 3S,8R)-1 7-(二甲基磷酰基)-8-氟-5,10-二甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(4 1S,4 3S,8R)-1 7-(dimethylphosphoryl)-8-fluoro-5,10-dimethyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z78,45mg,收率20％,三氟乙酸盐)，类白色固体。LCMS:m/z(ESI):581.2[M+H] +,t R＝0.92min. 1H NMR(400MHz,CD 3OD):δ8.57(s,1H),8.24-7.73(m,2H),7.27(s,1H),5.46-4.85(m,1H),4.49-3.80(m,2H),3.80-3.46(m,1H),3.27-3.09(m,4H),2.83-2.66(m,4H),2.58-2.47(m,1H),2.45-2.21(m,3H),2.13-1.65(m,11H).
步骤十三：向(4 1S,4 3S,8S)-1 7-(二甲基磷酰基)-8-氟-10-甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(Z77,200mg,0.35mmol)的四氢呋喃(20mL)溶液中依次加入多聚甲醛(158mg,1.75mmol)和钛酸四异丙酯(497mg,1.75mmol)，该反应液在70℃搅拌16h。然后将反应冷却至10℃,向反应液中加入氰基硼氢化钠(66mg,1.05mmol)并继续搅拌2小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸),流速：70mL/min,柱温：25℃)，得到(4 1S,4 3S,8S)-1 7-(二甲基磷酰基)-8-氟-5,10-二甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(4 1S,4 3S,8S)-1 7-(dimethylphosphoryl)-8-fluoro-5,10-dimethyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z79,30mg,收率15％,三氟乙酸盐)。LCMS:m/z(ESI):581.2[M+H] +,t R＝0.92min. 1H NMR(400MHz,CD 3OD):δ8.57(s,2H),8.22-7.91(m,1H),7.56-7.05(m,1H),5.27-4.99(m,1H),4.37-4.19(m,1H),4.07-3.82(m,1H),3.74-3.44(m,1H),3.41-3.35(m,1H),3.24(s,3H),2.88-2.64(m,3H),2.57-2.44(m,1H),2.40-2.23(m,3H),2.16-1.64(m,12H).
实施例33化合物Z84的合成
Figure PCTCN2022140669-appb-000082
步骤一：在室温下向7-溴-1H-吲哚-6-羧酸甲酯(5.0g,19.8mmol)的N,N二甲基甲酰胺(30mL)溶液中加入N-碘代丁二酰亚胺(6.7g,29.7mmol)。该反应在氮气保护下于40℃下搅拌2小时。LCMS检测反应完全后，反应液加入饱和氯化铵溶液(40mL)，然后用乙酸乙酯(40mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。得到的粗品经硅胶柱(石油醚/乙酸乙酯＝20/1～1:1)层析纯化，得到类白色固体7-溴-3-碘-1H-吲哚-6-羧酸甲酯(6.5g,收率87％)。LCMS:m/z(ESI):379.8[M+H] +,t R＝1.32min.
步骤二：在室温条件下，向封管中依次加入7-溴-3-碘-1H-吲哚-6-羧酸甲酯(6.5g,17.2mmol)、三(二亚苄基丙酮)二钯(1.6g,1.7mmol)、2-二环己基膦-2,4,6-三异丙基联苯(0.8g,1.7mmol)、频哪醇硼烷(6.5g,51.6mmol)、三乙胺(5.2g,51.6mmol)和四氢呋喃(60mL)。氮气保护下于90℃搅拌15小时。LCMS检测反应完全后，反应液直接旋蒸浓缩得到粗品，粗品经硅胶柱(石油醚/乙酸乙酯＝10/1～2/1)层析纯化，得到类白色固体7-溴-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吲哚-6-羧酸甲酯(2.4g,收率37％)。LCMS:m/z(ESI):380.0[M+H] +,t R＝1.48min.
步骤三：在室温条件下，向干燥的100mL单口瓶中依次加入7-溴-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吲哚-6-羧酸甲酯(2.4g,6.3mmol)、双三苯基磷二氯化钯(0.44g,0.63mmol)、碳酸钾(1.7g,12.6mmol)、叔丁基((1S，3S)-3-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)环戊基)氨基甲酸酯(2.4g,6.3mmol)、二氧六环(30mL)和水(6mL)的混合溶液。该反应在氮气保护下于90℃搅拌16小时。LCMS检测反应完全后，反应液直接旋蒸浓缩得到粗品，粗品经硅胶柱(石油醚/乙酸乙酯＝10/1～0/1) 层析纯化，得到白色固体甲基7-溴-3-(2-(((1S,3S)-3-((叔丁氧羰基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸盐(1.4g,收率37％)。LCMS:m/z(ESI):598.2[M+H] +,t R＝1.46min.
步骤四：室温下，将甲基7-溴-3-(2-(((1S,3S)-3-((叔丁氧羰基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸盐(1.4g,2.3mmol)溶于氯化氢/乙酸乙酯(15mL,4M)和乙酸乙酯(10mL)的混合溶液中，40℃下反应16小时。LCMS检测反应完全后，反应液加入饱和碳酸氢钠溶液(50mL)，然后用二氯甲烷(40mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经过柱机(二氯甲烷/甲醇＝20:1)层析纯化，得到白色固体甲基3-(2-(((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-溴-1H-吲哚-6-羧酸酯(0.8g,收率69％)。LCMS:m/z(ESI):498.0[M+H] +,t R＝1.08min.
步骤五：室温下，向甲基3-(2-(((1S,3S)-3-氨基环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-溴-1H-吲哚-6-羧酸酯(500mg,1.0mmol)的N,N-二甲基甲酰胺(10mL)溶液中依次加入叔丁基(4-碘丁基)(甲基)氨基甲酸酯(344mg,1.1mmol)和N,N-二异丙基乙胺(645mg,5.0mmol)，70℃搅拌16小时。LCMS检测反应完全后，反应液加入饱和碳酸氢钠溶液(30mL)，然后用乙酸乙酯(20mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经过柱机(二氯甲烷/甲醇＝30:1)层析纯化，得到白色固体甲基7-溴-3-(2-(((1S，3S)-3-((4-((叔丁氧羰基)(甲基)氨基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸盐(60mg,收率9％)。LCMS:m/z(ESI):683.2[M+H] +,t R＝1.32min.
步骤六：将甲基7-溴-3-(2-(((1S,3S)-3-((4-(叔丁氧羰基)(甲基)氨基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸盐(60mg,0.09mmol)溶于水(3mL)、甲醇(3mL)和四氢呋喃(3mL)的混合体系中，然后加入一水合氢氧化锂(19mg,0.45mmol)，40℃搅拌6小时。LCMS检测反应完全后，将反应液用旋蒸直接旋干，得到粗产品7-溴-3-(2-(((1S,3S)-3-((4-((叔丁氧羰基)(甲基)氨基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸(60mg,收率大于100％)，粗品无需任何纯化直接用于下一步反应。LCMS:m/z(ESI):669.2[M+H] +,t R＝1.34min.
步骤七：将7-溴-3-(2-(((1S,3S)-3-((4-((叔丁氧羰基)(甲基)氨基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸(60mg,0.09mmol)溶于甲醇(5mL)中，然后加入盐酸/甲醇(5mL,4M)，20℃搅拌16小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备HPLC(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流速:70mL/min；柱温：25℃)纯化得到白色固体7-溴-3-(2-(((1S，3S)-3-((4-(甲胺基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸(30mg,收率59％,三氟乙酸盐)。LCMS:m/z(ESI):569.3[M+H] +,t R＝8.51min.
步骤八：向7-溴-3-(2-(((1S,3S)-3-((4-(甲胺基)丁基)氨基)环戊基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-羧酸(30mg,0.053mmol)的N,N-二甲基甲酰胺(5mL)溶液中依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(19mg,0.05mmol)和N,N-二异丙基乙胺(32mg,0.25mmol)。该反应于60℃搅拌18小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备HPLC(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)纯化得到白色固体(8S,11S)-20-溴-17-甲基-3-(三氟甲基)-5,7,12,17,22,28-六氮杂五环[17.4.3.1 2,6.1 8,11.0 21,24]二十八-1(23),2(3),4,6(28),19(20),21(24),25-七烯-18-酮(12mg,收率41％,三氟乙酸盐)。LCMS:m/z(ESI):551.2[M+H] +,t R＝0.87min.
步骤九：在一个50mL单口瓶中，向(8S,11S)-20-溴-17-甲基-3-(三氟甲基)-5,7,12,17,22,28-六氮杂 五环[17.4.3.1 2,6.1 8,11.0 21,24]二十八-1(23),2(3),4,6(28),19(20),21(24),25-七烯-18-酮(12mg,0.022mmol,三氟乙酸盐)的四氢呋喃(5mL)溶液中依次加入多聚甲醛(10mg,0.11mmol)和钛酸四异丙酯(31mg,0.11mmol)，该反应液在60℃搅拌14小时，将反应液降至30℃，加入氰基硼氢化钠(7mg,0.11mmol)，继续在30℃下搅拌4小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备HPLC(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)纯化得到白色固体(8S,11S)-20-溴-12,17-二甲基-3-(三氟甲基)-5,7,12,17,22,28-六氮杂五环[17.4.3.1 2,6.1 8,11.0 21,24]二十八-1(23),2(3),4,6(28),19(20),21(24),25-七烯-18-酮(5mg,收率40％,三氟乙酸盐)。LCMS:m/z(ESI):567.2[M+H] +,t R＝0.86min.
步骤十：在室温条件下，向微波管中依次加入(8S,11S)-20-溴-12,17-二甲基-3-(三氟甲基)-5,7,12,17,22,28-六氮杂五环[17.4.3.1 2,6.1 8,11.0 21,24]二十八-1(23),2(3),4,6(28),19(20),21(24),25-七烯-18-酮(5mg,0.009mmol)、四三苯基磷钯(2mg,0.002mmol)、氰化锌(3mg,0.027mmol)和N,N-二甲基甲酰胺(1mL)溶液。氮气保护下于150℃微波反应1小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备HPLC(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水；流速：70mL/min；柱温：25℃)纯化得到(4 1S,4 3S)-5,10-二甲基-11-氧杂-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-1 7-甲腈((4 1S,4 3S)-5,10-dimethyl-11-oxo-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphane-1 7-carbonitrile)(Z84,1.6mg,收率35％)。LCMS:m/z(ESI):512.2[M+H] +,t R＝0.85min. 1H NMR(400MHz,CD 3OD):δ8.59(d,J＝8.4Hz,1H),8.54(s,1H),7.94(s,1H),7.37(d,J＝8.4Hz,1H),4.15-4.06(m,1H),3.19-3.04(m,5H),2.57-2.45(m,1H),2.41-2.32(m,1H),2.23-2.11(m,4H),2.05-1.90(m,3H),1.76-1.61(m,3H),1.47-1.36(m,3H),1.35-1.29(m,1H).
实施例34化合物Z85，Z86的合成
Figure PCTCN2022140669-appb-000083
步骤一：室温下，向4-甲基苯磺酸-7,7-二氟-2,2,5-三甲基-4-氧亚基-5-氮杂-3-氧杂壬-9-基酯(1.50g,3.81mmol)的甲醇(10mL)溶液中加入甲胺甲醇溶液(30％含量,20mL)和碘化钠(60mg,0.38mmol)，50℃下搅拌14小时。LCMS检测反应完全后，反应液浓缩除去溶剂。得到的粗品经硅胶柱(二氯甲烷/甲醇＝100/1到10/1)层析纯化，得到无色油状物(4,4-二氟-2,7-二氮杂辛-2-基)甲烷酸-2-甲基丙-2-基酯(1.0g,收率83％)。LCMS:m/z(ESI):253.2[M+H] +,t R＝1.09min.
步骤二：将(4,4-二氟-2,7-二氮杂辛-2-基)甲烷酸-2-甲基丙-2-基酯(1.10g,3.49mmol)溶于四氢呋喃(10mL)，然后依次加入三氟乙酸乙酯(2.48g,17.4mmol)和三乙胺(1.5mL,10.5mmol)，50℃搅拌14小时，LCMS检测反应完全后，向反应液中加入乙酸乙酯(30ml)和水(20mL)，将有机相分离，浓缩。得到的粗品经硅胶柱(石油醚/乙酸乙酯＝100/1到5/1)层析纯化，得到无色油状物(4,4,9,9,9-五氟-7-甲基-8-氧亚基-2,7-二氮杂壬-2-基)甲烷酸-2-甲基丙-2-基酯(660mg,收率54％)。LCMS:m/z(ESI):249.1[M+H-99] +,t R＝1.35min.
步骤三：将(4,4,9,9,9-五氟-7-甲基-8-氧亚基-2,7-二氮杂壬-2-基)甲烷酸-2-甲基丙-2-基酯(566mg,1.63mmol)溶于二氯甲烷(5mL)中，然后向反应液中加入三氟乙酸(1.0mL)，25℃搅拌3小时，LCMS检测反应完全后，向反应液中加入乙酸乙酯(10mL)和饱和的碳酸氢钠溶液(5mL)，浓缩有机相得到粗品为无色油状物N-[3,3-二氟-4-(甲基氨基)丁基]-2,2,2-三氟-N-甲基乙酰胺(400mg,收率99％)，可直接用于下一步反应。LCMS:m/z(ESI):249.2[M+H] +,t R＝0.89min.
步骤四：将N-[3,3-二氟-4-(甲基氨基)丁基]-2,2,2-三氟-N-甲基乙酰胺(399mg,1.61mmol)溶于甲醇(5mL)，然后依次加入{[(3S)-1-氧亚基环戊-3-基]氨基}甲烷酸苄基酯(562mg,2.41mmol)、4A分子筛(100mg)、冰醋酸(2滴)，25℃搅拌2小时后，再向反应液中加入氰基硼氢化钠(303mg,4.82mmol)，继续在25℃下搅拌14小时。LCMS检测反应完全后，过滤除去固体杂质，得到的粗品经反相制备HPLC(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)纯化得到无色油状物{[(3S)-1-(4,4,9,9,9-五氟-7-甲基-8-氧亚基-2,7-二氮杂壬-2-基)环戊-3-基]氨基}甲烷酸苄基酯(380mg,收率50％)。LCMS:m/z(ESI):466.4[M+H] +,t R＝1.33min.
步骤五：将{[(3S)-1-(4,4,9,9,9-五氟-7-甲基-8-氧亚基-2,7-二氮杂壬-2-基)环戊-3-基]氨基}甲烷酸苄基酯(330mg,2.21mmol)溶于甲醇(10mL)中，向反应液中加入钯碳(30mg,10％含量,55％含水)、冰醋酸(30mg,0.50mmol)，置换氢气，25℃搅拌2小时，TLC检测反应完全后，过滤，浓缩有机相得到粗品为无色油状N-(3,3-二氟-4-{[(3S)-3-氨基环戊基](甲基)氨基}丁基)-2,2,2-三氟-N-甲基乙酰胺(310mg,收率96％)，可直接用于下一步反应。LCMS:m/z(ESI):332.2[M+H] +,t R＝0.99min.
步骤六：将N-(3,3-二氟-4-{[(3S)-3-氨基环戊基](甲基)氨基}丁基)-2,2,2-三氟-N-甲基乙酰胺(310mg,0.94mmol)溶于N,N-二甲基甲酰胺(4ml)，向反应液中依次加入3-[2-氯-5-(三氟甲基)嘧啶-4-基]-7-[二甲基(氧亚基)-λ 5-甲磷基]-1H-吲哚-6-甲酸甲酯(424mg,0.98mmol)、N,N-二异丙基乙胺(0.77mL,4.68mmol)，反应在氮气氛围下，130℃搅拌5小时，LCMS检测反应完全后，向反应液加水(10mL)，然后用乙酸乙酯(10mL×2)萃取，合并的有机层，无水硫酸钠干燥，过滤浓缩。得到的粗品反相制备HPLC(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02),流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)纯化得到白色固体7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-(4,4,9,9,9-五氟-7-甲基-8-氧亚基-2,7-二氮杂壬-2-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(125mg,收率18％)。LCMS:m/z(ESI):727.4[M+H] +,t R＝1.38min.
步骤七：将7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-(4,4,9,9,9-五氟-7-甲基-8-氧亚基-2,7-二 氮杂壬-2-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(125mg,0.17mmol)溶于水(1mL)、甲醇(3mL)和四氢呋喃(3mL)的混合溶剂中，加入氢氧化锂(1个结晶水,300mg,7.09mmol)，40℃搅拌14小时。LCMS检测反应完全后，将反应液浓缩，得到的粗品反相制备HPLC(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％碳酸氢铵)；流速：70mL/min；柱温：25℃)纯化得到白色固体7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-(4,4-二氟-2,7-二氮杂辛-2-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(60mg,收率57％)。LCMS:m/z(ESI):617.4[M+H] +,t R＝1.13min.
步骤八：向7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S,3S)-3-(4,4-二氟-2,7-二氮杂辛-2-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(30mg,0.05mmol)的N,N-二甲基甲酰胺(4mL)溶液中依次加入N,N-二异丙基乙胺(37.7mg,0.29mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(74mg,0.20mmol)，60℃搅拌14小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备HPLC(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％碳酸氢铵)；流速：70mL/min；柱温：25℃)纯化得到(4 1S,4 3S)-1 7-(二甲基磷酰基)-7,7-二氟-5,10-二甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(4 1S,4 3S)-1 7-(dimethylphosphoryl)-7,7-difluoro-5,10-dimethyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z85,1.51mg,收率5.2％)，白色固体。LCMS:m/z(ESI):599.2[M+H] +,t R＝0.91min. 1H NMR(400MHz,CD 3OD):δ8.65(d,J＝7.6Hz,1H),8.51(s,1H),8.02(d,J＝5.6Hz,1H),7.32(dd,J＝8.0,3.6Hz,1H),4.31–4.16(m,1H),3.29–3.18(m,3H),3.13(s,3H),2.88–2.77(m,1H),2.70–2.53(m,1H),2.47–2.08(m,8H),2.05–1.93(m,4H),1.91–1.81(m,3H),1.65–1.52(m,2H).
(4 1S,4 3S)-1 7-(二甲基磷酰基)-7,7-二氟-5,10-二甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(4 1S,4 3S)-1 7-(dimethylphosphoryl)-7,7-difluoro-5,10-dimethyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z86,1.27mg,收率4.4％)。LCMS:m/z(ESI):599.3[M+H] +,t R＝0.93min. 1H NMR(400MHz,CD 3OD):δ8.53(s,1H),8.16–8.12(m,1H),7.83(s,1H),7.24(dd,J＝8.0,3.2Hz,1H),3.74–3.68(m,1H),3.12(s,3H),2.96–2.77(m,2H),2.68–2.41(m,4H),2.32(s,3H),2.06–1.84(m,9H),1.76–1.58(m,4H).
实施例35化合物Z87,Z88的合成
Figure PCTCN2022140669-appb-000084
步骤一：室温下，向(2-氟-4-碘丁基)(甲基)氨基甲酸苄酯(2.07g,5.67mmol)的甲醇(20mL)溶液中加入甲胺甲醇溶液(30％含量,5.87g,56.7mmol)，50℃下搅拌16小时。LCMS检测反应完全后，反应液浓缩除去溶剂。得到的粗品经硅胶柱(二氯甲烷/甲醇＝100/1到20/1)层析纯化，得到无色油状物(4-氟-2,7-二氮杂辛基-2-基)甲酸苄酯(1.50g,收率98％)。LCMS:m/z(ESI):269.2[M+H] +,t R＝1.17min.
步骤二：将(4-氟-2,7-二氮杂辛基-2-基)甲酸苄酯(1.50g,5.59mmol)溶于二氯甲烷(20mL)，然后依次加入4-二甲氨基吡啶(0.07g,0.56mmol)、二碳酸二叔丁酯(1.46g,6.71mmol)，25℃搅拌14小时，LCMS检测反应完全后，反应液浓缩除去溶剂。得到的粗品经硅胶柱(二氯甲烷/甲醇＝100/1到20/1)层析纯化，得到无色油状物(8-氟-2,2,5-三甲基-4-氧亚基-5,10-二氮杂-3-氧杂十一烷-10-基)甲烷酸苄基酯(1.20g,收率58％)。LCMS:m/z(ESI):269.2[M+H-99] +,t R＝1.71min.
步骤三：将(8-氟-2,2,5-三甲基-4-氧亚基-5,10-二氮杂-3-氧杂十一烷-10-基)甲烷酸苄基酯(1.20g,3.26mmol)溶于甲醇(20mL)中，向反应液中加入钯碳(120mg,10％含量,55％含水)。置换氢气，25℃搅拌14小时，LCMS检测反应完全后，过滤，浓缩有机相得到粗品为无色油状物(5-氟-2,7-二氮杂辛-2-基)甲烷酸-2-甲基丙-2-基酯(0.70g,收率92％)，可直接用于下一步反应。LCMS:m/z(ESI): 235.2[M+H] +,t R＝1.08min.
步骤四：将(5-氟-2,7-二氮杂辛-2-基)甲烷酸-2-甲基丙-2-基酯(600mg,2.56mmol)溶于甲醇(15mL)，依次加入{[(3S)-1-氧亚基环戊-3-基]氨基}甲烷酸苄基酯(597mg,2.56mmol)、冰醋酸(30mg,0.50mmol)，25℃搅拌2小时，向反应液中加入氰基硼氢化钠(483mg,7.68mmol)，继续在25℃下搅拌16小时。LCMS检测反应完全后，过滤，旋干，得到的粗品经反相制备HPLC(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)纯化得到白色固体{7-[(3S)-3-{[(苄基氧基)羰基]氨基}环戊基]-5-氟-2,7-二氮杂辛-2-基}甲烷酸-2-甲基丙-2-基酯(P1,240mg,收率20.7％)。LCMS:m/z(ESI):452.3[M+H] +,t R＝3.21min.{7-[(3S)-3-{[(苄基氧基)羰基]氨基}环戊基]-5-氟-2,7-二氮杂辛-2-基}甲烷酸-2-甲基丙-2-基酯(P2,360mg,收率31.1％)。LCMS:m/z(ESI):452.3[M+H] +,t R＝3.22min.
步骤五：将3-氨基环戊-1-醇盐酸盐(10.0g,72.7mmol)溶于二氯甲烷(100mL)中，向反应液中加入苯甲氧羰酰琥珀酰亚胺(21.7g,87.2mmol)、三乙胺(14.7g,145mmol)。氮气氛围下，25℃搅拌14小时，LCMS检测反应完全，向反应液加水(100mL)，二氯甲烷(200mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。得到的粗品经硅胶柱(二氯甲烷/甲醇＝100/1到20/1)层析纯化浓缩有机相得到无色油状物[(3-羟基环戊基)氨基]甲烷酸苄基酯(9.0g,收率53％)。LCMS:m/z(ESI):236.2[M+H] +,t R＝1.26min.
步骤六：-78℃下，向二氯甲烷(20mL)中依次加入二甲基亚砜(1.69g,21.7mmol)和草酰氯(1.38g,10.8mmol)，该反应液在-78℃搅拌1h。反应液中加入[(3-羟基环戊基)氨基]甲烷酸苄基酯(1.7g,7.23mmol)，反应液继续反应3h，反应液中加入三乙胺(3.66g,36.1mmol)。LCMS检测反应完全，向反应液加水(30mL)，二氯甲烷(50mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。得到的粗品经硅胶柱(二氯甲烷/甲醇＝100/1到30/1)层析纯化浓缩有机相得到无色油状物[(3-氧亚基环戊基)氨基]甲烷酸苄基酯(1.0g,收率59％)。LCMS:m/z(ESI):256.1[M+Na] +,t R＝1.00min.
步骤七：将{7-[(3S)-3-{[(苄基氧基)羰基]氨基}环戊基]-5-氟-2,7-二氮杂辛-2-基}甲烷酸-2-甲基丙-2-基酯(P1,1.00g,2.21mmol)溶于甲醇(20mL)中，向反应液中加入钯碳(100mg,10％含量,55％含水)、冰醋酸(30.0mg,0.50mmol)，反应在氢气氛围下，25℃搅拌14小时。LCMS检测反应完全后，过滤除去固体杂质，浓缩有机相得到粗品为无色油状物{7-[(3S)-3-氨基环戊基]-5-氟-2,7-二氮杂辛-2-基}甲烷酸-2-甲基丙-2-基酯(0.75g,90％纯度,收率96％)，可直接用于下一步反应。LCMS:m/z(ESI):318.4[M+H] +,t R＝0.99min.
步骤八：将{7-[(3S)-3-氨基环戊基]-5-氟-2,7-二氮杂辛-2-基}甲烷酸-2-甲基丙-2-基酯(0.75g,90％纯度,2.13mmol)溶于N,N-二甲基甲酰胺(10mL)中，向反应液中加入N,N-二异丙基乙胺(1.37g10.63mmol)、3-[2-氯-5-(三氟甲基)嘧啶-4-基]-7-[二甲基(氧亚基)-λ5-甲磷基]-1H-吲哚-6-甲酸甲酯(1.01g,2.34mmol)。氮气氛围下，130℃搅拌5小时，TLC检测反应完全后，向反应液加水(20mL)，乙酸乙酯(30mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。得到的粗品经硅胶柱(二氯甲烷/甲醇＝100/1到20/1)层析纯化浓缩有机相得到白色固体7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S)-3-(8-氟-2,2,5-三甲基-4-氧亚基-5,10-二氮杂-3-氧杂十一烷-10-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(1.01g,收率67％)。
步骤九：将7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S)-3-(8-氟-2,2,5-三甲基-4-氧亚基-5,10-二氮杂-3-氧杂十一烷-10-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(1.01g,1.42mmol) 溶于水(5mL)、甲醇(5mL)和四氢呋喃(5mL)的混合体系中，然后加入氢氧化锂(1个结晶水,0.30g,7.09mmol)，40℃搅拌5小时。LCMS检测反应完全后，此反应液不经任何处理，直接应用于下一步反应。LCMS:m/z(ESI):699.4[M+H] +,t R＝0.93min.
步骤十：向步骤七的反应液中加入氯化氢/甲醇溶液(10mL,4M)，体系在40℃搅拌5小时。LCMS检测反应完全后，直接将溶剂旋干，所得粗品经反相制备HPLC(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％碳酸氢铵)；流动相：70mL/min；柱温：25℃)纯化得到7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S)-3-(4-氟-2,7-二氮杂辛-2-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(530mg,收率62％)呈白色固体。LCMS:m/z(ESI):599.2[M+H] +,t R＝0.73min.
步骤十一：向7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S)-3-(4-氟-2,7-二氮杂辛-2-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(100mg,0.17mmol)的N,N-二甲基甲酰胺(8mL)溶液中依次加入N,N-二异丙基乙胺(108mg,0.84mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(254mg,0.67mmol)，该反应液在60℃搅拌14h。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流动相：70mL/min；柱温：25℃)，得到(4 1S)-1 7-(二甲基磷酰基)-7-氟-5,10-二甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮((4 1S)-1 7-(dimethylphosphoryl)-7-fluoro-5,10-dimethyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one)(Z87,12.22mg；收率12.4％,三氟乙酸盐)。LCMS:m/z(ESI):581.3[M+H] +,t R＝0.85min. 1H NMR(400MHz,CD 3OD):δ8.70–8.16(m,2H),7.88(s,1H),7.18(dd,J＝7.6,2.4Hz,1H),4.34–4.08(m,1H),3.96–3.80(m,1H),3.35–3.25(m,1H),3.14–3.05(m,2H),3.04(s,3H),2.96–2.81(m,1H),2.71(s,3H),2.48–2.36(m,1H),2.30–2.12(m,3H),2.06–1.46(m,11H).
(4 1S)-1 7-(二甲基磷酰基)-7-氟-5,10-二甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮((4 1S)-1 7-(dimethylphosphoryl)-7-fluoro-5,10-dimethyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one)(Z88,8.24mg；三氟乙酸盐,收率8.34％)。LCMS:m/z(ESI):581.2[M+H] +,t R＝0.88min. 1H NMR(400MHz,CD 3OD):δ8.63–8.39(m,2H),7.92(s,1H),7.21(dd,J＝8.0,3.2Hz,1H),4.36–4.20(m,1H),3.98–3.86(m,1H),3.55–3.43(m,1H),3.13–3.00(m,5H),2.72–2.55(m,4H),2.49–2.40(m,1H),2.28–1.69(m,13H),1.63–1.44(m,1H).
实施例36化合物Z89,Z90的合成
Figure PCTCN2022140669-appb-000085
步骤一：将{7-[(3S)-3-{[(苄基氧基)羰基]氨基}环戊基]-5-氟-2,7-二氮杂辛-2-基}甲烷酸-2-甲基丙-2-基酯(P2,530mg,1.17mmol)溶于甲醇(10mL)中，然后向反应液中加入钯碳(53mg,10％含量,55％含水)、冰醋酸(30mg,0.50mmol)。氢气氛围下，25℃搅拌14小时，LCMS检测反应完全后，过滤除去固体杂质，浓缩有机相得到粗品为无色油状物{7-[(3S)-3-氨基环戊基]-5-氟-2,7-二氮杂辛-2-基}甲烷酸-2-甲基丙-2-基酯(380mg,90％纯度,收率92％)，可直接用于下一步反应。LCMS:m/z(ESI):318.3[M+H] +,t R＝1.01min.
步骤二：将{7-[(3S)-3-氨基环戊基]-5-氟-2,7-二氮杂辛-2-基}甲烷酸-2-甲基丙-2-基酯(380mg,90％纯度,1.08mmol)溶于N,N-二甲基甲酰胺(8mL)中，向反应液中加入N,N-二异丙基乙胺(696mg 5.39mmol)、3-[2-氯-5-(三氟甲基)嘧啶-4-基]-7-[二甲基(氧亚基)-λ5-甲磷基]-1H-吲哚-6-甲酸甲酯(465mg,1.08mmol)。氮气氛围下，130℃搅拌5小时，LCMS检测反应完全后，向反应液加水(20mL)，乙酸乙酯(30mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。得到的粗品经硅胶柱(二氯甲烷/甲醇＝100/1到20/1)层析纯化得到白色固体7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S)-3-(8-氟-2,2,5-三甲基-4-氧亚基-5,10-二氮杂-3-氧杂十一烷-10-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(440mg,收率57％)。LCMS:m/z(ESI):713.3[M+H] +,t R＝1.34min.
步骤三：将7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S)-3-(8-氟-2,2,5-三甲基-4-氧亚基-5,10-二氮杂-3-氧杂十一烷-10-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸甲酯(330mg,0.46mmol)溶于水(3mL)、甲醇(3mL)和四氢呋喃(3mL)的混合体系中，加入氢氧化锂(1个结晶水,97mg,2.32mmol)，反应在40℃搅拌5小时。LCMS检测反应完全后，此反应液不经任何处理，直接应用于下一步反应。LCMS:m/z(ESI):699.3[M+H] +,t R＝1.22min.
步骤四：向步骤三的反应液中加入氯化氢/甲醇溶液(8mL,4M)，体系在40℃搅拌5小时。LCMS检测反应完全后，直接将溶剂旋干，得到的粗品经反相制备HPLC(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％碳酸氢铵)；流速：70mL/min；柱温：25℃)纯化得到7-[二甲基(氧亚基)-λ5-甲磷基]-3-(2-{[(1S)-3-(4-氟-2,7-二氮杂辛-2-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(190mg,收率74％)，呈白色固体。LCMS:m/z(ESI):599.4[M+H] +,t R＝ 0.72min.
步骤五：向7-[二甲基(氧亚基)-λ 5-甲磷基]-3-(2-{[(1S)-3-(4-氟-2,7-二氮杂辛-2-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲酸(100mg,0.17mmol)的N,N-二甲基甲酰胺(8mL)溶液中依次加入N,N-二异丙基乙胺(172mg,1.33mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(254mg,0.67mmol)，该反应液在60℃搅拌14小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备HPLC(色谱柱：Ultimate XB-C18,50*250mm,10um(PARP-02)；流动相：乙腈-水(0.1％三氟醋酸)；流速：70mL/min；柱温：25℃)纯化得到产物(P1与P2,三氟乙酸盐)，分别将得到的产物用乙酸乙酯溶解，依次用饱和的碳酸氢钠溶液和饱和的食盐水洗涤，将有机相浓缩，冻干得到(4 1S)-1 7-(二甲基磷酰基)-7-氟-5,10-二甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(4 1S)-1 7-(dimethylphosphoryl)-7-fluoro-5,10-dimethyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z89,17.0mg；收率17.21％)。LCMS:m/z(ESI):581.1[M+H] +,t R＝0.73min. 1H NMR(400MHz,CD 3OD):δ8.55(s,1H),8.10–7.90(m,1H),7.80(s,1H),7.31–7.20(m,1H),4.73–4.47(m,1H),3.92–3.59(m,1H),3.29–2.98(m,5H),2.84(m,2H),2.58–2.46(m,1H),2.38–2.17(m,4H),2.16–1.95(m,5H),1.92–1.72(m,6H),1.67–1.54(m,2H).
(4 1S)-1 7-(二甲基磷酰基)-7-氟-5,10-二甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吲哚-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮((4 1S)-1 7-(dimethylphosphoryl)-7-fluoro-5,10-dimethyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one)(Z90,15.0mg；收率15.18％)。LCMS:m/z(ESI):581.3[M+H] +,t R＝0.76min. 1H NMR(400MHz,CDCl 3):δ11.76(s,1H),8.60–8.45(m,2H),8.00–7.90(m,1H),7.13(s,1H),6.00–5.50(br,1H),4.55–4.45(s,1H),3.15–3.10(m,2H),2.99–2.90(m,3H),2.60–2.20(m,6H),2.13–1.82(m,15H).
实施例37化合物Z91的合成
Figure PCTCN2022140669-appb-000086
步骤一：在25mL微波管中，依次加入6-氯-1H-吡咯并[2,3-b]吡啶(1.0g,6.55mmol)、N-甲基吡咯烷酮(15mL)、氰化锌(0.77g,6.55mmol)、四(三苯基膦)钯(0.76g,0.66mmol)和锌粉(0.21g,3.28mmol)，微波150℃反应6小时。LCMS检测反应完全后，反应液加水(20mL)，乙酸乙酯(30mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经硅胶柱(石油醚/乙酸乙酯＝1.5/1)层析纯化，得到类白色固体1H-吡咯并[2,3-b]吡啶-6-甲腈(250mg,收率26％)。LCMS:m/z(ESI):144.2[M+H] +,t R＝1.20min.
步骤二：向1H-吡咯并[2,3-b]吡啶-6-甲腈(1.20g,8.38mmol)的N,N二甲基甲酰胺(25mL)溶液中加入N-碘代丁二酰亚胺(2.26g,10.1mmol)。氮气保护下在45℃搅拌2小时。LCMS检测反应完全后，反应液加水(50mL)，乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。得到的粗品经硅胶柱(石油醚/乙酸乙酯＝4/1)层析纯化，得到褐色固体3-碘-1H-吡咯并[2,3-b]吡啶-6-甲腈(1.87g,收率83％)。LCMS:m/z(ESI):270.0[M+H] +,t R＝1.49min.
步骤三：室温下向3-碘-1H-吡咯并[2,3-b]吡啶-6-甲腈(1.87g,6.95mmol)的二氯甲烷(25mL)溶液中加入三乙胺(1.76g,17.4mmol)、4-二甲氨基吡啶(0.17g,1.39mmol)和二碳酸二叔丁酯(2.28g,10.4mmol)。室温搅拌14小时。LCMS检测反应完全后，反应液加水(50mL)，然后用乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。粗品经硅胶柱(石油醚/乙酸乙酯＝10/1)层析纯化，得到黄色固体6-氰基-3-碘吡咯并[2,3-b]吡啶-1-甲酸-2-甲基丙-2-基酯(1.90g,收率74％)。LCMS:m/z(ESI):314.0[M+H-56] +,t R＝1.77min.
步骤四：室温下向封管中依次加入6-氰基-3-碘吡咯并[2,3-b]吡啶-1-甲酸-2-甲基丙-2-基酯(1.90g,5.15mmol)、三(二亚苄基丙酮)二钯(470mg,0.515mmol)、四氢呋喃(20mL)、2-二环己基磷-2′,4′,6′- 三异丙基联苯(242mg,0.515mmol)、三乙胺(1.56g,15.4mmol)和4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(1.98g,15.4mmol)。氮气保护下90℃搅拌14小时。LCMS检测反应完全后，反应液加水(20mL)，乙酸乙酯(20mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，粗品经硅胶柱(石油醚/乙酸乙酯＝5/1)层析纯化，得到白色固体6-氰基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡咯并[2,3-b]吡啶-1-甲酸-2-甲基丙-2-基酯(1.30g,收率68％)。LCMS:m/z(ESI):314.4[M+H-56] +,t R＝1.61min.
步骤五：室温下向6-氰基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡咯并[2,3-b]吡啶-1-甲酸-2-甲基丙-2-基酯(1.30g,3.52mmol)的四氢呋喃(13mL)溶液中，加入{[(1S,3S)-3-{[4-氯-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]氨基}甲烷酸-2-甲基丙-2-基酯(1.34g,3.52mmol)、氯[(正丁基二(1-金刚烷基)膦)-2-(2-氨基联苯)]钯(II)(0.24g,0.352mmol)和磷酸钾(2.24g,10.6mmol)的水溶液(3mL)。该反应液在氮气保护下60℃搅拌16小时。LCMS检测反应完全后，反应液加水(20mL)，然后用乙酸乙酯(20mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经硅胶柱(石油醚/乙酸乙酯＝2:1)层析纯化，得到类白色固体6-氰基-3-(2-{[(1S,3S)-3-({[(2-甲基丙-2-基)氧基]羰基}氨基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)吡咯并[2,3-b]吡啶-1-甲酸-2-甲基丙-2-基酯(1.20g,收率58％)。LCMS:m/z(ESI):588.2[M+H] +,t R＝1.88min.
步骤六：室温下向6-氰基-3-(2-{[(1S,3S)-3-({[(2-甲基丙-2-基)氧基]羰基}氨基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)吡咯并[2,3-b]吡啶-1-甲酸-2-甲基丙-2-基酯(700mg,1.20mmol)的二氯甲烷(10mL)溶液中加入三氟乙酸(2mL)，反应液在25℃反应2小时。LCMS检测反应完全后，用饱和碳酸氢钠溶液(10mL)调节pH至8左右，乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经硅胶柱层析(水/甲醇＝5:1)纯化，得到黄色固体6-氰基-3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)吡咯并[2,3-b]吡啶-1-甲酸-2-甲基丙-2-基酯(450mg,收率98％)。LCMS:m/z(ESI):388.2[M+H] +,t R＝1.18min.
步骤七：室温下向6-氰基-3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)吡咯并[2,3-b]吡啶-1-甲酸-2-甲基丙-2-基酯(300mg,0.774mmol)的N-甲基吡咯烷酮(5mL)中，依次加入(1-碘-6-氮杂-3-氧杂庚-6-基)甲烷酸-2-甲基丙-2-基酯(255mg,0.77mmol)和N,N-二异丙基乙胺(0.384mL,2.32mmol)，反应在80℃搅拌16小时。LCMS检测反应完全后，反应液加水(30mL)，乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经硅胶柱(二氯甲烷/甲醇＝10:1)层析纯化，得到黄色油状物(1-{[(1S,3S)-3-{[4-(6-氰基-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]氨基}-6-氮杂-3-氧杂庚-6-基)甲烷酸-2-甲基丙-2-基酯(75mg,收率17％)。LCMS:m/z(ESI):589.4[M+H] +,t R＝1.45min.
步骤八：室温下向(1-{[(1S,3S)-3-{[4-(6-氰基-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]氨基}-6-氮杂-3-氧杂庚-6-基)甲烷酸-2-甲基丙-2-基酯(130mg,0.221mmol)的甲醇(5mL)溶液中，加入多聚甲醛(100mg,1.11mmol)、醋酸(0.1mL)、4A分子筛(130mg)，氮气保护下25℃搅拌2小时。再向反应液中加入氰基硼氢化钠(41.7mg,0.663mmol)继续反应14小时。LCMS检测反应完全后，直接过滤浓缩。得到的粗品经硅胶柱(二氯甲烷/甲醇＝10:1)层析纯化，得到黄色油状物{8-[(1S,3S)-3-{[4-(6-氰基-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]-2,8-二氮杂-5-氧杂壬-2-基}甲烷酸-2-甲基丙-2-基酯(100mg,收率75％)。LCMS:m/z(ESI):603.4[M+H] +,t R＝1.10min.
步骤九：室温下向{8-[(1S,3S)-3-{[4-(6-氰基-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基] 氨基}环戊基]-2,8-二氮杂-5-氧杂壬-2-基}甲烷酸-2-甲基丙-2-基酯(100mg,0.167mmol)的醋酸(4mL)溶液中加入浓盐酸(2mL)，反应液在120℃下搅拌16小时。LCMS检测反应完全后，直接将溶剂旋干，得到粗品经反相制备HPLC(色谱柱：Ultimate XB-C18-08,25*150mm,10um(PARP-02)；流动相：乙腈-水(0.1％NH 4HCO 3)；流速：25mL/min；柱温：25℃)纯化得到3-(2-{[(1S,3S)-3-(2,8-二氮杂-5-氧杂壬-2-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-甲酸(30mg,收率35％)。LCMS:m/z(ESI):522.2[M+H] +,t R＝1.06min.
步骤十：向3-(2-{[(1S,3S)-3-(2,8-二氮杂-5-氧杂壬-2-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-甲酸(15mg,0.029mmol)的N,N-二甲基甲酰胺(3mL)溶液中，依次加入N,N-二异丙基乙胺(0.048mL,0.29mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(54.7mg,0.144mmol)，该反应液在60℃搅拌4h。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备HPLC(色谱柱：Ultimate XB-C18-08,25*150mm,10um(PARP-02)；流动相：乙腈-水(0.1％NH 4HCO 3)；流速：25mL/min；柱温：25℃)纯化得到(4 1S,4 3S)-5,11-二甲基-2 5-(三氟甲基)-1 1H-8-氧杂-3,5,11-三氮杂-1(3,6)-吡咯并[2,3-b]吡啶-2(4,2)-嘧啶-4(1,3)-环戊烷环十二烷-12-酮(4 1S,4 3S)-5,11-dimethyl-2 5-(trifluoromethyl)-1 1H-8-oxa-3,5,11-triaza-1(3,6)-pyrrolo[2,3-b]pyridina-2(4,2)-pyrimidina-4(1,3)-cyclopentanacyclododecaphan-12-one(Z91,2.5mg,收率17％)。LCMS:m/z(ESI):504.2[M+H] +,t R＝0.77min. 1H NMR(400MHz,CD 3OD):δ8.66(d,J＝8.0Hz,1H),8.50(s,1H),7.92(s,1H),7.41(d,J＝8.0Hz,1H),4.31–4.13(m,1H),3.71–3.36(m,5H),3.22(m,2H),3.15(s,3H),2.72–2.56(m,1H),2.46–2.26(m,2H),2.16(s,3H),2.14–2.08(m,1H),2.00(m,1H),1.70–1.53(m,3H).
实施例38化合物Z92的合成
Figure PCTCN2022140669-appb-000087
步骤一：室温下，向3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-甲腈(220mg,0.57mmol)的N-甲基吡咯烷酮(5mL)中，依次加入[(4-碘丁基)(甲基)氨基]甲烷酸-2-甲基丙-2-基酯(178mg,0.57mmol)和N,N-二异丙基乙胺(147mg,1.14mmol)。130℃搅拌16小时，LCMS检测反应完全后，反应液加水(30mL)，乙酸乙酯(50mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经硅胶柱(二氯甲烷/甲醇＝10:1)层析纯化，得到黄色油状物[(4-{[(1S,3S)-3-{[4-(6-氰基-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]氨基}丁基)(甲基)氨基]甲烷酸-2-甲基丙-2-基酯(70.0mg,收率22％)。LCMS:m/z(ESI): 573.4[M+H] +,t R＝1.45min.
步骤二：室温下，向[(4-{[(1S,3S)-3-{[4-(6-氰基-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]氨基}丁基)(甲基)氨基]甲烷酸-2-甲基丙-2-基酯(120mg,0.21mmol)的甲醇(6mL)溶液中，加入多聚甲醛(94.0mg,1.05mmol)、醋酸(30.0mg)、4A分子筛(120mg)，反应在氮气保护下25℃搅拌2.0小时。再向反应液中加入氰基硼氢化钠(40.0mg,0.63mmol)继续反应14小时。LCMS检测反应完全后，直接过滤浓缩。得到的粗品经硅胶柱(二氯甲烷/甲醇＝10:1)层析纯化，得到黄色油状物{7-[(1S,3S)-3-{[4-(6-氰基-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]-2,7-二氮杂辛-2-基}甲烷酸-2-甲基丙-2-基酯(120mg,收率98％)。LCMS:m/z(ESI):587.0[M+H] +,t R＝1.13min.
步骤三：在室温下，向{7-[(1S,3S)-3-{[4-(6-氰基-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]-2,7-二氮杂辛-2-基}甲烷酸-2-甲基丙-2-基酯(110mg,0.19mmol)的醋酸(4mL)溶液中加入浓盐酸(2mL)，120℃搅拌14小时。LCMS检测反应完全后，直接将溶剂旋干，得到粗品经反相制备HPLC(色谱柱：Ultimate XB-C18-08,25*150mm,10um(PARP-02)；流动相乙腈-水(0.1％NH 4HCO 3)；流速：25mL/min；柱温：25℃)纯化得到白色固体3-(2-{[(1S,3S)-3-{[4-(甲基氨基)丁基]氨基}环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-甲酸(54mg,收率57％)。LCMS:m/z(ESI):506.2[M+H] +,t R＝0.96min.
步骤四：向3-(2-{[(1S,3S)-3-{[4-(甲基氨基)丁基]氨基}环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-甲酸(40.0mg,0.08mmol)的N,N-二甲基甲酰胺(5mL)溶液中，依次加入N,N-二异丙基乙胺(51.0mg,0.40mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(36.0mg,0.10mmol)，该反应液在60℃搅拌16小时。LCMS检测反应完全后，反应液浓缩，得到的粗品经反相制备HPLC(色谱柱：Ultimate XB-C18-08,25*150mm,10um(PARP-02)；流动相乙腈-水(0.1％NH 4HCO 3)；流速：25mL/min；柱温：25℃)纯化得到(4 1S,4 3S)-5,10-二甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吡咯并[2,3-b]吡啶-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮(4 1S,4 3S)-5,10-dimethyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-pyrrolo[2,3-b]pyridina-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one(Z92,4.70mg,收率12％)。LCMS:m/z(ESI):488.2[M+H] +,t R＝0.77min. 1H NMR(400MHz,CD 3OD):δ8.77(d,J＝8.0Hz,1H),8.56(s,1H),8.01(s,1H),7.44(d,J＝8.0Hz,1H),4.26–4.07(m,1H),3.33–3.27(m,1H),3.17(s,3H),3.14–2.98(m,2H),2.55–2.27(m,2H),2.25–2.10(m,4H),2.09–1.84(m,3H),1.80–1.63(m,3H),1.54–1.43(m,1H),1.42–1.27(m,2H).
实施例39化合物Z93的合成
Figure PCTCN2022140669-appb-000088
步骤一：室温下，向6-氰基-3-(2-{[(1S,3S)-3-氨基环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)吡咯并[2,3-b]吡啶-1-甲酸-2-甲基丙-2-基酯(2.0g,5.16mmol)的N-甲基吡咯烷酮(20mL)溶液中，依次加入4-甲基苯磺酸-7,7-二氟-2,2,5-三甲基-4-氧亚基-5-氮杂-3-氧杂壬-9-基酯(2.44g,6.20mmol)、碘化钠(0.15g,1.03mmol)和N,N-二异丙基乙胺(2.56mL,15.49mmol)，反应在80℃搅拌16小时。LCMS检测反应完全后，反应液加水(50mL)，乙酸乙酯(100mL×3)萃取，合并的有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗品经硅胶柱(二氯甲烷/甲醇＝10:1)层析纯化，得到黄色油状物[(2,2-二氟-4-{[(1S,3S)-3-{[4-(6-氰基-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]氨基}丁基)(甲基)氨基]甲烷酸-2-甲基丙-2-基酯(480mg,收率15％)。LCMS:m/z(ESI):609.5[M+H] +,t R＝1.33min.
步骤二：室温下，向[(2,2-二氟-4-{[(1S,3S)-3-{[4-(6-氰基-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]氨基}丁基)(甲基)氨基]甲烷酸-2-甲基丙-2-基酯(480mg,0.789mmol)的甲醇(5mL)溶液中，加入多聚甲醛(118mg,3.95mmol)、醋酸(0.1mL)、4A分子筛(480mg)，反应在氮气保护下25℃搅拌2.0小时。再向反应液中加入氰基硼氢化钠(149mg,2.37mmol)继续反应14小时。LCMS检测反应完全后，直接过滤浓缩。得到的粗品经硅胶柱(二氯甲烷/甲醇＝10:1)层析纯化，得到黄色油状物{7-[(1S,3S)-3-{[4-(6-氰基-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]-4,4-二氟-2,7-二氮杂辛-2-基}甲烷酸-2-甲基丙-2-基酯(330mg,收率67％)。LCMS:m/z(ESI):623.3[M+H] +,t R＝1.12min.
步骤三：在室温下，向{7-[(1S,3S)-3-{[4-(6-氰基-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基]氨基}环戊基]-4,4-二氟-2,7-二氮杂辛-2-基}甲烷酸-2-甲基丙-2-基酯(330mg,0.53mmol)的醋酸(2mL)溶液中加入浓盐酸(1mL)，反应液在120℃下搅拌5小时。LCMS检测反应完全后，直接将 溶剂旋干，得到粗品经反相制备HPLC(色谱柱：Ultimate XB-C18-08,25*150mm,10um(PARP-02)；流动相：乙腈-水(0.1％NH 4HCO 3)；流速：25mL/min；柱温：25℃)纯化得到白色固体3-(2-{[(1S,3S)-3-(5,5-二氟-2,7-二氮杂辛-2-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-甲酸(220mg,收率76％)。LCMS:m/z(ESI):542.2[M+H] +,t R＝1.05min.
步骤四：向3-(2-{[(1S,3S)-3-(5,5-二氟-2,7-二氮杂辛-2-基)环戊基]氨基}-5-(三氟甲基)嘧啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-甲酸(100mg,0.19mmol)的N,N-二甲基甲酰胺(2mL)溶液中，依次加入N,N-二异丙基乙胺(0.15mL,0.92mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(280mg,0.74mmol)，该反应液在60℃搅拌16小时。将反应液浓缩，得到的粗品经反相制备HPLC(色谱柱：Ultimate XB-C18-08,25*150mm,10um(PARP-02)；流动相：乙腈-水(0.1％NH 3·H 2O)；流速：25mL/min；柱温：25℃)纯化得到(4 1S,4 3S)-8,8-二氟-5,10-二甲基-2 5-(三氟甲基)-1 1H-3,5,10-三氮杂-1(3,6)-吡咯并[2,3-b]吡啶-2(4,2)-嘧啶-4(1,3)-环戊烷环十一烷-11-酮((4 1S,4 3S)-8,8-difluoro-5,10-dimethyl-2 5-(trifluoromethyl)-1 1H-3,5,10-triaza-1(3,6)-pyrrolo[2,3-b]pyridine-2(4,2)-pyrimidina-4(1,3)-cyclopentanacycloundecaphan-11-one)(Z93,2.50mg,收率2.6％)。LCMS:m/z(ESI):524.4[M+H] +,t R＝1.10min. 1H NMR(400MHz,CD 3OD):δ9.06–8.61(m,1H),8.56–8.23(m,1H),8.20–7.91(m,1H),7.71–7.32(m,1H),4.77–4.18(m,2H),4.13–3.38(m,2H),3.29–3.17(m,3H),3.15–2.38(m,3H),2.34–2.15(m,3H),2.13–1.82(m,5H),1.79–1.48(m,2H).
下表所示化合物可根据上述实施例的合成方法制备或根据已有文献的方法进行合成得到。
表A
Figure PCTCN2022140669-appb-000089
Figure PCTCN2022140669-appb-000090
Figure PCTCN2022140669-appb-000091
Figure PCTCN2022140669-appb-000092
测试例1：CDK激酶活性的体外抑制实验
CDK2/Cyclin E1购自佰翱得；批号：20150228-BP469/477/691；CDK7/Cyclin H/MAT1购自佰翺得； 批号：20190326-BP487/492/479；CDK9/Cyclin T1购自佰翺得；批号：20200727-BP488/792/691；CDK12/Cyclin K购自佰翺得；批号:20200526-BP1642/1648/691；MES购自BioRoYee(宝如亿)；批号：67GR9637；BSA购自Aladdin；批号：H1601024；ATP购自VWR；批号：97061-226；EDTA购自国药集团；批号：20200521；星胞菌素购自Selleckchem；批号：S1421。
本实验用于测定化合物对CDK2、CDK7、CDK9和CDK12激酶活性的抑制作用。本发明所进行的激酶反应在384孔板中进行测定，最终测定体积是16μl，反应温度为27℃。激酶的浓度由优化实验决定。具体实验过程如下：
1)激酶溶液配置：
激酶溶液(CDK2/Cyclin E1):激酶稀释于测定缓冲液(20mM MES pH 6.75，0.01％Tween 20，0.05mg/mL BSA，2mM MgCl 2)中得到相应2.4×浓度的酶溶液。
激酶溶液(CDK7/Cyclin H/MAT1):激酶稀释于测定缓冲液(20mM MES pH 6.75，0.01％Tween 20，0.05mg/mL BSA，6mM MgCl 2)中得到相应2.4×浓度的酶溶液。
激酶溶液(CDK9/Cyclin T1):激酶稀释于测定缓冲液(20mM MES pH 6.75，0.01％Tween 20，0.05mg/mL BSA，10mM MgCl 2)中得到相应2.4×浓度的酶溶液。
激酶溶液(CDK12/Cyclin K):激酶稀释于测定缓冲液(80mM MES pH 6.5，0.01％Tween 20，0.05mg/mL BSA，10mM MgCl 2)中得到相应2.4×浓度的酶溶液。
2)化合物溶液配置：化合物以10mM的浓度溶于二甲基亚砜(DMSO)中，使用时化合物用DMSO稀释至25nM到500μM的10个浓度梯度，分别8.3倍稀释于超纯水中，得到6X浓度的化合物溶液。
3)多肽底物及ATP溶液配置：多肽底物及ATP稀释于测定缓冲液中，得到2.4×浓度的多肽底物及ATP混合溶液。
4)激酶反应过程：
将2ul测试化合物溶液，5ul多肽底物及ATP混合溶液与5ul酶溶液混合27℃孵育(CDK2为60分钟，CDK7为70分钟，CDK9为70分钟，CDK12为280分钟)，然后通过向每种样品中加入4ul浓度为150mM的EDTA来终止反应。以含有20μM星胞菌素的测定缓冲液代替化合物溶液作为100％抑制，以DMSO代替化合物溶液作为0％抑制。每个试验至少2个平行对照。
CDK2测定中试剂的最终浓度：ATP为100μM；多肽底物(5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK)为2μM；CDK2/Cyclin E1为0.5nM；
CDK7测定中试剂的最终浓度：ATP为50μM；多肽底物(5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK)为2μM；CDK7/Cyclin H/MAT1为3nM；
CDK9测定中试剂的最终浓度：ATP为50μM；多肽底物(FITC-Ahx-GSRTPMY-NH2)为2μM；CDK9/Cyclin T1为8nM；
CDK12测定中试剂的最终浓度：ATP为30μM；多肽底物(FITC-Ahx-GSRTPMY-NH2)为2μM；CDK12/Cyclin K为50nM。
5)数据计算和分析：在Caliper EZ Reader II上通过荧光底物和磷酸化产物进行电泳分离来对反应混合物进行分析。数据使用GraphPad Prism version 9.0进行计算，IC 50值通过使用剂量反应曲线的非线性回归模型调整得到。计算公式：Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。其中，X为剂量或浓度的log值(log of dose or concentration)；Y为随着X的增加而增加的抑制率(％inhibition,increasing as x increases)；Top为最大响应；Bottom基线响应；HillSlope为曲线斜率。由于CDK7/Cyclin H/MAT1激酶活性实验的检测下限限制，本发明化合物对的CDK7激酶活性抑制已达实验检测下限， IC 50不能准确反映化合物的激酶活性抑制能力，我们采用表面等离子体共振(SPR)方法来检测化合物的结合亲和力K D。化合物对CDK2,CDK9,CDK12激酶活性的抑制作用，以Km ATP条件下检测拟合得到的IC 50用于计算K i(Cheng and Prusoff,Biochem.Pharmacol.,22(23)3099-3108,1973)，换算公式如下:IC 50＝K i(1+[底物/K m])+[酶/2]。本发明示例化合物的结果如表1所示。
表1
编号 CDK7/CyclinH/MAT1 IC 50assay(nM) CDK2 Ki CDK9 Ki CDK12 Ki
Z1 11.0 153.7 52.25 62.65
Z2 4.58 9.8 10.6 22.74
Z5 - 25.65 95.55 26.06
Z7 - 33.4 216.8 61.35
Z65 - 30.33 257.7 61.6
Z79 - 23.29 134.25 92.8
测试例2：CDK7/Cyclin H表面等离子体共振(SPR)测定方法
CDK7/Cyclin H购自佰翱得；批号：20200309-BP487/492；MES缓冲液购自BioRoYee；批号：67GR9637；CM5传感芯片购自Cytiva；批号：10305527；HEPES缓冲液购自Cytiva；批号：32349。
本实验采用Biacore S200表面等离子共振设备(GE Healthcare)测试了CDK7/Cyclin H二聚体和化合物的动力学和亲和力参数。
在pH 6.5的10mM MES缓冲液条件下，浓度为50μg/mL的CDK7/Cyclin H二聚体在5μL/min流速下被氨基偶联至CM5传感芯片。在600秒内目的蛋白被固定到芯片通道上，一般情况下达到7000-10000响应值。在具有150mM NaCl、0.05％表面活性剂P20和2％DMSO的pH7.4的10mM HEPES缓冲液中把化合物2倍梯度稀释5步达到0.6-10nM浓度范围。每个化合物浓度循环都以100μL/min，180秒接触时间和1800秒解离时间被运行。对于每个化合物，0nM化合物对照和参比通道的结合都被扣减来移除背景信号和归一化数据。使用Biacore S200评价软件和动力学模型对化合物滴定整体拟合。最优化拟合数据，测定CDK7/Cyclin H结合速率和解离速率参数，用以下的等式来计算化合物亲和力参数K D。K D(M)＝k off(s -1)/K on(M -1s -1)；其中，K on(ka)是结合速率；K off(kd)是解离速率；s -1(每秒)和M -1s -1(每摩尔每秒)是k off和k on的单位。基于脱靶CDK的K i值相对于CDK7的直接化合物结合K D(通过SPR测量)的比率，根据以下等式确定CDK7相对于CDK2、CDK9或CDK12的化合物选择性。选择性＝K i,脱靶/K D,CDK7。结果显示：相对于CDK2/CDK9/CDK12，本发明化合物对CDK7具有优异的选择性，本发明化合物对CDK7的特异性为对其它CDK的至少100倍或300倍；甚至可以是500倍以上。部分示例化合物结果如表2所示。
表2
Figure PCTCN2022140669-appb-000093
Figure PCTCN2022140669-appb-000094
测试例3：HCC70肿瘤细胞增殖抑制活性实验
HCC70购自ATCC；货号：CRL-2315；RPMI1640购自Gibco；货号：11875-093；胰酶(含EDTA)购自Gibco；货号：25200-072；FBS购自Gibco；货号：10099-141C；CellTiter-Glo购自Promega；货号：G7573；DMSO购自VWR AMRESCO；货号：0231-500ML；Staurosporine购自Selleck；货号：S1421；细胞计数仪购自CHEMOMETEC；型号：NC-200；酶标仪购自PerkinElmer；型号：Envison。
HCC70为人乳腺导管癌细胞，培养于含10％FBS的RPMI-1640培养基中。取对数生长期的细胞，用胰酶-EDTA消化、收集和计数细胞，并接种2000个HCC70细胞/孔于384孔细胞板中，置于5％CO 2培养过夜。使用DMSO配制1000X的化合物3.16倍梯度浓度储液，使用培养基稀释100倍至10X化合物储液，于细胞接种后的第二天，向每个细胞培养孔中加入10X化合物储液，终浓度为1X，DMSO含量为0.1％。使用DMSO处理细胞组作为实验对照(control)，5μM Staurosporine处理细胞组为空白对照(blank)。加入化合物后继续培养细胞3天后，向每孔加入25μl CellTiter-Glo工作液，混匀，室温孵育5分钟，读取luminescence化学发光值，计算细胞增殖抑制率IR(％)＝(RLU 对照-RLU 化合物)/(RLU 对 照-RLU 空白)×100％，使用XLFit四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率，计算出IC 50值。结果显示，本发明化合物对HCC70人乳腺导管癌细胞增殖具有很强的抑制作用。部分化合物IC 50低于1000nM或500nM；甚至低于100nM或50nM。部分示例性化合物的结果如下表3所示。
表3
编号 HCC70 IC 50(nM) 编号 HCC70 IC 50(nM)
Z2 207.0 Z16 23.0
Z5 42.7 Z19 15.4
Z6 222.4 Z27 9.7
Z7 41.1 Z59 422
Z9 99.77 Z60 89
Z10 161.53 Z58 233
Z11 186 Z61 389.7
Z23 66.60 Z63 134.23
Z64 42.78 Z62 24.64
Z68-1 10.35 Z68-2 3.18
Z66 10.51 Z65 46.93
Z72 869.32 Z73 233.42
Z74 1250 Z78 43.97
Z79 66.5 Z76 21.91
Z77 9.87 Z84 263.1
Z85 517.14 Z86 >10000
Z89 >10000 Z90 >10000
Z87 242.9 Z88 241.1
Z91 438.5 Z92 106.76
Z93 5211.0    
测试例4：OVCAR-3肿瘤细胞增殖抑制活性实验
OVCAR-3购自ATCC；货号：HTB-161；RPMI1640购自Gibco；货号：11875-093；胰酶(含EDTA)购自Gibco；货号：25200-072；FBS购自Gibco；货号：10091-148；CellTiter-Glo购自Promega；货号：G7573；Bovine insulin购自absin；货号：abs9169；DMSO购自VWR AMRESCO；货号：0231-500ML；Staurosporine购自Selleck；货号：S1421；细胞计数仪购自CHEMOMETEC；型号：NC-200；酶标仪购自PerkinElmer；型号：Envison。
OVCAR-3为人卵巢腺癌细胞，培养于含20％FBS和0.01mg/mL Bovine insulin的RPMI-1640培养基中。取对数生长期的细胞，用胰酶-EDTA消化、收集和计数细胞，并接种2000个OVCAR-3细胞/孔于384孔细胞板中，置于5％CO 2培养过夜。使用DMSO配制1000X的化合物3.16倍梯度浓度储液，使用培养基稀释100倍至10X化合物储液，于细胞接种后的第二天，向每个细胞培养孔中加入10X化合物储液，终浓度为1X，DMSO含量为0.1％。使用DMSO处理细胞组作为实验对照(control)，5μM Staurosporine处理细胞组为空白对照(blank)。加入化合物后继续培养细胞3天后，向每孔加入25μl CellTiter-Glo工作液，混匀，室温孵育5分钟，读取luminescence化学发光值，计算细胞增殖抑制率IR(％)＝(RLU 对照-RLU 化合物)/(RLU 对照-RLU 空白)×100％，使用XLFit四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率，计算出IC 50值。结果显示，本发明化合物对OVCAR-3为人卵巢腺癌细胞增殖具有很强的抑制作用。部分化合物IC 50低于1000nM或500nM；甚至低于100nM或50nM。部分示例性化合物的结果如下表4所示。
表4
编号 OVCAR-3 IC 50(nM) 编号 OVCAR-3 IC 50(nM)
Z23 134.85 Z63 195.06
Z64 98.6 Z62 15.91
Z68-1 35.8 Z68-2 8.84
Z66 21.24 Z65 253.96
Z73 1054 Z74 3457
Z78 62.6 Z79 84.05
Z76 31.5 Z77 11.8
Z84 198.2 Z85 1802.3
Z86 >10000 Z89 >10000
Z90 >10000 Z91 810.54
Z92 342.9 Z93 >10000
测试例5：本发明化合物的体内药代动力学实验
实验方法和条件：雄性比格犬，8～11kg，采购于江苏玛斯生物技术有限公司。分别给予3只犬静脉注射给予待测化合物0.2mg/kg或1.0mg/kg(溶剂：2％DMSO+10％Kolliphor HS 15+88％(6.818％羟丙基-β-环糊精水溶液)，0.2mg/mL或1.0mg/mL)和3只犬口服灌胃给药2mg/kg(溶剂：5％DMSO+95％(10％羟丙基-β-环糊精食盐水溶液)，0.4mg/mL)。给药后，5min，15min，30min，1h，2h，4h， 8h，24h经头静脉采血，每个样品采集约500μL。采集后置于冰上，并于15分钟内离心分离血浆待测。血浆中药物浓度的检测采用液相串联质谱法(LC/MS/MS)，测得浓度运用Phoenix WinNonlin软件计算药代动力学参数。实验结果如下表5和表6所示。
表5本发明化合物口服给药(2mg/kg)的体内药代动力学
编号 T 1/2(h) C max(ng/mL) AUC 0～inf(ng*h/mL) F(％)
Z65 4.44 6623 45620 147
化合物101 6.61 123 1591 65.8
表6本发明化合物静脉注射给药的体内药代动力学
编号 Dose(mg/kg) T 1/2(h) AUC 0～inf(ng*h/mL) V ss(L/kg) CL(mL/min/kg)
Z65 0.2 3.42 3097 0.24 1.23
化合物101 1.0 6.88 1228 7.57 14.5
可见，根据本发明化合物相对于现有技术(化合物101,WO2020093006，
Figure PCTCN2022140669-appb-000095
)其药代动力学具有显著更低的代谢清除率(CL)和更高的血浆暴露量(AUC 0～inf)。
尽管本发明的具体实施方式已经得到详细的描述，根据已经公开的所有教导，本领域技术人员可以对本发明技术方案的细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (12)

  1. 式(A)所示的化合物或其药学上可接受的盐；
    Figure PCTCN2022140669-appb-100001
    其中，
    Figure PCTCN2022140669-appb-100002
    为
    Figure PCTCN2022140669-appb-100003
    环A为无；或环A选自下组：3至14元碳环、3至14元杂环、5至12元杂芳基、C 5-12芳基；环A为未取代的或被1、2、3、4或5个选自S1组的基团所取代；所述3至14元杂环具有1、2、3或4个独立地选自氮、氧和硫的杂原子；所述5至12元杂芳基具有1、2、3或4个独立地选自氮、氧和硫的杂原子；
    L 3为无、C 1-6亚烷基、C 2-6亚烯基或环B；其中，所述C 1-6亚烷基上的1、2、3、4或5个氢原子可以任选地各自独立地被R 13取代；所述C 2-6亚烯基上的1、2、3、4或5个氢原子可以任选地各自独立地被R 13取代；
    环B选自下组：3至14元碳环、3至14元杂环、5至12元杂芳基、C 5-12芳基；环B为未取代的或被1、2、3、4或5个选自S1组的基团所取代；所述3至14元杂环具有1、2、3或4个独立地选自氮、氧和硫的杂原子；所述5至12元杂芳基具有1、2、3或4个独立地选自氮、氧和硫的杂原子；
    L 1为无、C 1-6亚烷基、C 2-6亚烯基、-O-、-NR 10-、-C＝N-、C 5-12芳基、5至12元杂芳基、-C(O)-、-C(O)-NR 10-或-NR 10-C(O)-；其中，所述C 1-6亚烷基上的1、2、3、4或5个氢原子可以任选地各自独立地被R 13取代；所述C 2-6亚烯基上的1、2、3、4或5个氢原子可以任选地各自独立地被R 13取代；所述5至12元杂芳基具有1、2、3或4个独立地选自氮、氧和硫的杂原子；所述C 5-12芳基、5至12元杂芳基各自独立地为未取代的或被1、2、3、4或5个选自S1组的基团所取代；
    L 2选自下组：
    -(O) m2-(CR 13R 14) m1-(NR 12) m3-、
    -(NR 11) m2-(CR 13R 14) m1-(NR 12) m3-、
    -(O) m2-(CR 13R 14) m5-(3至7元碳环基) m4-(CR 13R 14) m6-(NR 12) m3-、
    -(NR 11) m2-(CR 13R 14) m5-(3至7元碳环基) m4-(CR 13R 14) m6-(NR 12) m3-、
    -(O) m2-(CR 13R 14) m5-(3至7元杂环基) m4-(CR 13R 14) m6-(NR 12) m3-、
    -(NR 11) m2-(CR 13R 14) m5-(3至7元杂环基) m4-(CR 13R 14) m6-(NR 12) m3-、
    -(O) m2-(CR 13R 14) m5-NR 10-(CR 13R 14) m6-(NR 12) m3-、
    -(NR 11) m2-(CR 13R 14) m5-NR 10-(CR 13R 14) m6-(NR 12) m3-、
    -(O) m2-(CR 13R 14) m5-NR 10C(O)-(CR 13R 14) m6-(NR 12) m3-、
    -(NR 11) m2-(CR 13R 14) m5-NR 10C(O)-(CR 13R 14) m6-(NR 12) m3-、
    -(O) m2-(CR 13R 14) m5-C(O)NR 10-(CR 13R 14) m6-(NR 12) m3-、
    -(NR 11) m2-(CR 13R 14) m5-C(O)NR 10-(CR 13R 14) m6-(NR 12) m3-、
    -(O) m2-(CR 13R 14) m5-O-(CR 13R 14) m6-(NR 12) m3-、
    -(NR 11) m2-(CR 13R 14) m5-O-(CR 13R 14) m6-(NR 12) m3-、
    -(O) m2-(CR 13R 14) m5-OC(O)-(CR 13R 14) m6-(NR 12) m3-、
    -(NR 11) m2-(CR 13R 14) m5-OC(O)-(CR 13R 14) m6-(NR 12) m3-、
    -(O) m2-(CR 13R 14) m5-C(O)O-(CR 13R 14) m6-(NR 12) m3-、
    -(NR 11) m2-(CR 13R 14) m5-C(O)O-(CR 13R 14) m6-(NR 12) m3-、
    -(O) m2-(CR 13R 14) m5-(CH＝CH) m7-(CR 13R 14) m6-(NR 12) m3-、
    -(NR 11) m2-(CR 13R 14) m5-(CH＝CH) m7-(CR 13R 14) m6-(NR 12) m3-；
    各个R 10各自独立地氢、C 1-6烷基、氘代C 1-6烷基、-3至7元碳环基、-C(O)-C 1-6烷基、-C(O)-C 1-4烷基-C 1-6烷氧基、-C(O)-3至7元碳环基、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-NHC(O)-C 1-6烷基、-C 1-4烷基-NHC(O)-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-NHC(O)-3至7元碳环基或-C 1-4烷基-NRR’；
    各个3至7元杂环基各自独立地具有1、2或3个独立地选自氮、氧和硫的杂原子；所述3至7元碳环各自独立地为未取代的或被1、2、3、4或5个选自S1组的基团所取代；
    各个3至7元碳环基各自独立地为未取代的或被1、2、3、4或5个选自S1组的基团所取代；
    各个R 11各自独立地为氢、C 1-6烷基或氘代C 1-6烷基；
    各个R 12各自独立地为氢、C 1-6烷基或氘代C 1-6烷基；
    各个R 13各自独立地为氢、氰基、羟基、卤素、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、-3至7元碳环基、-C 0-6亚烷基-NRR’、-C 1-6亚烷基-羟基或-C 0-6亚烷基-氰基；
    各个R 14各自独立地为氢、氰基、羟基、卤素、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、-3至7元碳环基、-C 0-6亚烷基-NRR’、-C 1-6亚烷基-羟基或-C 0-6亚烷基-氰基；
    各个m1各自独立地为1、2、3、4、5或6；
    各个m2各自独立地为0或1；
    各个m3各自独立地为0或1；
    各个m4各自独立地为1或2；
    各个m5各自独立地为0、1、2、3、4、5或6；
    各个m6各自独立地为0、1、2、3、4、5或6；
    各个m7各自独立地为1或2；
    R 1为氢、卤素、氰基、C 1-6烷基或3至14元碳环基；所述C 1-6烷基、3至14元碳环基独立地为未取代的或被1、2、3、4或5个选自下组的基团所取代：氧代、羟基、卤素、C 1-6烷基、卤代C 1-6烷基；
    R 2为氢、卤素、氰基、C 1-6烷基或3至14元碳环基；所述C 1-6烷基、3至14元碳环基独立地为未取代的或被1、2、3、4或5个选自下组的基团所取代：氧代、羟基、卤素、C 1-6烷基、卤代C 1-6烷基；
    X 2为N或C(R 3)；
    X 1为N或C(R 4)；
    Y为N或C(R 4)；
    Z为N或C(R 3)；
    各个R 3独立地为氢、卤素、氰基、C 1-6烷基或卤代C 1-6烷基；
    各个R 4独立地为氢、卤素、羟基、氰基、-C 2-4亚烯基-苯基、-C 2-4亚炔基-苯基、-S(O)-OH、-S(O) 2-OH、-S-(C 1-6烷基)、C 1-6烷基、-O-C 1-6烷基、-C 1-6亚烷基-O-C 1-6烷基、-O-C 1-6亚烷基-O-C 1-6烷基、-C 0-6亚烷基-NRR’、-C 0-6亚烷基-C(O)OH、-C 0-6亚烷基-C(O)-C 1-6烷基、-C 0-6亚烷基-C(O)-NRR’、-C 0-6亚烷基-NR-C(O)-C 1-6烷基、-C 0-6亚烷基-S(O) 2-C 1-6烷基、-C 0-6亚烷基-S(O) 2-NRR’、-C 0-6亚烷基-NR-S(O) 2-C 1-6烷基、-C 0-6亚烷基-NR-S(O) 2-NRR’、-C 0-6亚烷基-P(O)O-(C 1-6烷基) 2、-C 0-6亚烷基-P(O)-(C 1-6烷基)(O-C 1-6烷基)、-C 0-6亚烷基-P(O)-(C 1-6烷基) 2、-C 0-6亚烷基-3至14元碳环基、-C 0-6亚烷基-3至14元杂环基、-C 0-6亚烷基-5至12元杂芳基、-C 0-6亚烷基-C 5-12芳基、-C 0-6亚烷基-C(O)-3至14元杂环基、-C 0-6亚烷基-C(O)-5至12元杂芳基、-O-C 0-6亚烷基-O-C 1-6烷基、-O-C 0-6亚烷基-3至14元碳环基、-O-C 0-6亚烷基-3至14元杂环基、-O-C 0-6亚烷基-5至12元杂芳基、-O-C 0-6亚烷基-C 5-12芳基、-S(O)-C 1-6烷基；其中，所述C 1-6烷基、C 0-6亚烷基、C 2-4亚烯基、3至14元碳环基、3至14元杂环基、5至12元杂芳基、C 5-12芳基独立地为未取代的或被1、2、3、4或5个选自S1组的基团所取代；所述3至14元杂环具有1、2、3或4个独立地选自氮、氧和硫的杂原子；所述5至12元杂芳基具有1、2、3或4个独立地选自氮、氧和硫的杂原子；
    所述S1组的基团包括：氧代(＝O)、卤素、羟基、氰基、C 1-6烷基、-O-C 1-6烷基、-C 1-6亚烷基-O-C 1-6烷基、-O-C 1-6亚烷基-O-C 1-6烷基、-C 0-6亚烷基-NRR’、-C 0-6亚烷基-C(O)OH、-C 0-6亚烷基-C(O)-C 1-6烷基、-C 0-6亚烷基-C(O)-NRR’、-C 0-6亚烷基-NR-C(O)-C 1-6烷基、-C 0-6亚烷基-S(O) 2-C 1-6烷基、-C 0-6亚烷基-S(O) 2-NRR’、-C 0-6亚烷基-NR-S(O) 2-C 1-6烷基、-C 0-6亚烷基-NR-S(O) 2-NRR’、-C 0-6亚烷基-P(O)O-(C 1-6烷基) 2、-C 0-6亚烷基-P(O)-(C 1-6烷基)(O-C 1-6烷基)、-C 0-6亚烷基-P(O)-(C 1-6烷基) 2、-C 0-6亚烷基-3至14元碳环基、-C 0-6亚烷基-3至14元杂环基、-C 0-6亚烷基-5至12元杂芳基、-C 0-6亚烷基-C 5-12芳基、-C 0-6亚烷基-C(O)-3至14元杂环基、-C 0-6亚烷基-C(O)-5至12元杂芳基、-O-C 0-6亚烷基-O-C 1-6烷基、-O-C 0-6亚烷基-3至14元碳环基、-O-C 0-6亚烷基-3至14元杂环基、-O-C 0-6亚烷基-5至12元杂芳基、-O-C 0-6亚烷基-C 5-12芳基、-S(O)-C 1-6烷基；
    R、R’各自独立地为氢、C 1-6烷基或氘代C 1-6烷基；或者R、R’任选与和它们相连的氮原子共同构成3至14元杂环基或5至12元杂芳基；其中，所述杂环基、杂芳基各自独立地除了已有的氮原子外还包含0、1或2个选自N、O、S的杂原子；
    上述各基团中，所述C 0-6亚烷基上任意同一个碳原子上的2个氢原子还可以任选地同时被3至7元碳环或3至7元杂环螺环取代；
    上述各基团中，所述C 1-6亚烷基上任意同一个碳原子上的2个氢原子还可以任选地同时被3至7元碳环或3至7元杂环螺环取代。
  2. 如权利要求1所述的化合物或其药学上可接受的盐；其特征在于，
    所述式(A)化合物为式(I-A)化合物；
    Figure PCTCN2022140669-appb-100004
    式中，X 1、Y、Z、X 2、R 1、R 2、L 1、L 2、环A、环B各自如权利要求1所定义；
    或
    所述式(A)化合物为式(I-B)化合物；
    Figure PCTCN2022140669-appb-100005
    式中，X 1、Y、Z、X 2、R 1、R 2、L 1、L 2、环A、R 13、R 14各自如权利要求1所定义；m0为1、2、3、4、5或6；
    或
    所述式(A)化合物为式(A1)化合物；
    Figure PCTCN2022140669-appb-100006
    式中，X 1、Y、Z、X 2、R 1、R 2、L 1、L 2、环A、环B各自如权利要求1所定义；
    或
    所述式(A)化合物为式(A2)化合物；
    Figure PCTCN2022140669-appb-100007
    式中，X 1、Y、Z、X 2、R 1、R 2、L 1、L 2、环A、R 13、R 14各自如权利要求1所定义；m0为1、2、3、4、5或6。
  3. 如权利要求1所述的化合物或其药学上可接受的盐；其特征在于，
    所述式(A)化合物为式(II-A)化合物；
    Figure PCTCN2022140669-appb-100008
    式中，R 1、R 2、L 1、L 2、环A、环B、X 1各自如权利要求1所定义；
    或
    所述式(A)化合物为式(II-B)化合物；
    Figure PCTCN2022140669-appb-100009
    式中，X 1、R 1、R 2、L 1、L 2、环A、R 13、R 14各自如权利要求1所定义；m0为1、2、3、4、5或6；
    或
    所述式(A)化合物为式(A3)化合物；
    Figure PCTCN2022140669-appb-100010
    式中，X 1、R 1、R 2、L 1、L 2、环A、环B各自如权利要求1所定义；
    或
    所述式(A)化合物为式(A4)化合物；
    Figure PCTCN2022140669-appb-100011
    式中，X 1、R 1、R 2、L 1、L 2、环A、R 13、R 14各自如权利要求1所定义；m0为1、2、3、4、5或6。
  4. 如权利要求1所述的化合物或其药学上可接受的盐；其特征在于，
    所述式(A)化合物为式(III-A)化合物；
    Figure PCTCN2022140669-appb-100012
    式中，L 1、L 2、环A、环B、X 1各自如权利要求1所定义；
    或
    所述式(A)化合物为式(III-B)化合物；
    Figure PCTCN2022140669-appb-100013
    式中，X 1、L 1、L 2、环A、R 13、R 14各自如权利要求1所定义；m0为1、2、3、4、5或6；
    或
    所述式(A)化合物为式(A5)化合物；
    Figure PCTCN2022140669-appb-100014
    式中，X 1、L 1、L 2、环A、环B各自如权利要求1所定义；
    或
    所述式(A)化合物为式(A6)化合物；
    Figure PCTCN2022140669-appb-100015
    式中，X 1、L 1、L 2、环A、R 13、R 14各自如权利要求1所定义；m0为1、2、3、4、5或6；
    或，所述式(A)化合物为式(IV-a)化合物，
    Figure PCTCN2022140669-appb-100016
    式中，X 1、L 1、L 2、环B各自如权利要求1所定义；
    或，所述式(A)化合物为式(IV-b)化合物，
    Figure PCTCN2022140669-appb-100017
    式中，X 1、L 1、L 2、环B各自如权利要求1所定义；
    Figure PCTCN2022140669-appb-100018
    式中，X 1、L 1、L 2、环B各自如权利要求1所定义。
  5. 如权利要求1-4所述的化合物或其药学上可接受的盐；其特征在于，环A为无；或环A选自下组：环丁环、环戊环、环己环、哌啶环、哌嗪环、四氢吡咯环、吡唑环、咪唑环、吡啶环；环A为未取代的或被1、2、3、4或5个选自S1组的基团所取代。
  6. 如权利要求1-4所述的化合物或其药学上可接受的盐；其特征在于，环B选自下组：环丁环、环戊环、环己环、哌啶环、哌嗪环、四氢吡咯环、吡唑环、咪唑环；环B为未取代的或被1、2、3、4或5个选自S1组的基团所取代。
  7. 如权利要求1-4所述的化合物或其药学上可接受的盐；其特征在于，X 1为N或C(R 4)；其中，R 4为氢、卤素、氰基、-S(O) 2CH 3或-P(O)(CH 3) 2。
  8. 如权利要求1-4所述的化合物或其药学上可接受的盐；其特征在于，所述化合物选自表(I)。
  9. 一种药物组合物，所述药物组合物包含权利要求1-8任一项所述的化合物或其药学上可接受的盐；以及药学可接受的载体。
  10. 如权利要求1-8任一项所述的化合物或其药学上可接受的盐或如权利要求9所述的药物组合物在制备预防和/或治疗CDK7相关疾病的药物中的用途。
  11. 如权利要求1-8任一项所述的化合物或其药学上可接受的盐或如权利要求9所述的药物组合物在制备CDK7抑制剂中的用途。
  12. 如权利要求11所述的用途，其特征在于，所述CDK7相关疾病为增殖性疾病(例如肿瘤或癌症)、传染性疾病、免疫疾病、自身免疫疾病和炎性疾病。
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