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WO2024260325A1 - 大环类化合物的合成及其在医药上的用途 - Google Patents

大环类化合物的合成及其在医药上的用途 Download PDF

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Publication number
WO2024260325A1
WO2024260325A1 PCT/CN2024/099735 CN2024099735W WO2024260325A1 WO 2024260325 A1 WO2024260325 A1 WO 2024260325A1 CN 2024099735 W CN2024099735 W CN 2024099735W WO 2024260325 A1 WO2024260325 A1 WO 2024260325A1
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Prior art keywords
alkyl
cycloalkyl
alkylene
membered
optionally substituted
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PCT/CN2024/099735
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English (en)
French (fr)
Inventor
陆洪福
丁晓
任峰
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英矽智能科技知识产权有限公司
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Publication of WO2024260325A1 publication Critical patent/WO2024260325A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the invention belongs to the field of medicine, and specifically relates to the synthesis of macrocyclic compounds and their use in medicine.
  • CDK7 Cyclin-dependent kinase/cyclin complexes have been identified as conserved components of the RNA polymerase II transcription machinery.
  • CDK7 has a solid kinase activity, and only CDK7 has the dual function of regulating cell cycle progression and transcription.
  • CDK7 exists as a heterotrimeric complex and is thought to play the role of CDK1/2/4/6 activating kinase (CAK), whereby phosphorylation of conserved residues in CDK1/2/4/6 by CDK7 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, which is an essential step for the initiation of gene transcription.
  • CTD C-terminal domain
  • CDK7 can be used as a therapeutic target for the treatment of many diseases and syndromes.
  • CDK7 can regulate transcription by interacting with multiple transcription factors, cofactors, chromatin regulators, and non-coding RNAs in transcriptional regulatory regions. Mutations in these transcription factors, cofactors, chromatin regulators, or non-coding RNAs can lead to diseases such as cancer, autoimmune diseases, nervous system disorders, developmental syndromes, diabetes, cardiovascular diseases, and obesity.
  • Some of these transcription factors control RNA polymerase II-mediated transcription initiation and elongation, and when their expression or function changes, invasive tumor cells (such as those caused by c-Myc) or certain forms of autoimmunity (such as those caused by AIRE) can be produced.
  • CDK7 kinase can promote the abnormal expression of certain 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, compared with other housekeeping genes in cancer cells, CDK7 more significantly regulates the expression of oncogenic transcription factors. The inhibition of CDK7 can differentially affect the transcription of certain oncogenes and housekeeping genes, thus ensuring a therapeutic window.
  • CDK7-mediated phosphorylation modification to perform transcriptional regulation and cell cycle regulation, it can be used to treat abnormal proliferation diseases including cancer.
  • CDK7 can also be used as a therapeutic target for treating diseases such as inflammation, viral replication such as HIV, EBV, cancer and cardiac hypertrophy.
  • the WO2018013867A1 patent application discloses a CDK7 inhibitor. Studies have shown that the compound disclosed in the patent application has poor permeability and efflux rate in the human Caco-2 monolayer permeation experimental model.
  • One object of the present invention is to provide a class of CDK7 inhibitors with novel structures.
  • the compounds of the present invention also have at least one of the following technical effects: 1. Good biological activity, 2. Good membrane permeability, 3. Low efflux ratio.
  • Oral administration of drugs needs to be absorbed into the blood circulation system through the gastrointestinal tract and distributed to the corresponding tissues to exert pharmacological effects in the body. Therefore, membrane permeability reflects the absorption and transport capacity of the compound in the body, which is crucial for oral absorption of drugs.
  • the low efflux ratio of oral drugs is more conducive to the absorption of drugs in the gastrointestinal tract.
  • the present invention provides a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
  • V is selected from a single bond or -O-;
  • X1 is selected from N or C( Rx1 );
  • X2 is selected from N or C( Rx2 );
  • X3 is selected from N or C( Rx3 );
  • Y is selected from N or C( RY );
  • Z is selected from N or C (R Z );
  • L is selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 2-8 alkenyl or C 2-8 alkynyl, wherein the C 1-8 alkyl, C 1-8 heteroalkyl, C 2-8 alkenyl or C 2-8 alkynyl is optionally substituted with one or more RL ;
  • RLs are on the same or different atoms and are linked together to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more RLs ;
  • R La are each independently selected from halogen, cyano, -NO 2 , hydroxyl, -OR a , -NR c R d , -C( ⁇ O)R a , -C( ⁇ O)OR b , -C( ⁇ O)NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl or C 1-6 heteroalkyl;
  • Ra , Rb , Rc and Rd are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-6 alkyl (cycloalkyl), C1-6 alkyl (heterocyclyl), C1-6 alkyl (aryl) or C1-6 alkyl (heteroaryl), the C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl , heteroaryl, C1-6 alkyl (cycloalkyl), C1-6 alkyl (heterocyclyl), C1-6 alkyl (aryl) or C1-6 alky
  • R c and R d are linked together to form a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more R;
  • R x3 are each independently selected from H, halogen, cyano, C 1-12 alkyl or C 1-12 haloalkyl;
  • R 1 is selected from H, halogen, cyano, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 hydroxyalkyl, C 1-12 heteroalkyl, cycloalkyl or heterocycloalkyl, wherein the C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 hydroxyalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R 111 ;
  • R 2 is selected from H, halogen, cyano, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 hydroxyalkyl, C 1-12 heteroalkyl, cycloalkyl or heterocycloalkyl, wherein the C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 hydroxyalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R 222 ;
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more R aa ;
  • R aa is each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1-6 alkyl (cycloalkyl), C 1-6 alkyl (heterocyclyl), C 1-6 alkyl (aryl) or C 1-6 alkyl (heteroaryl), wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1-6 alkyl (cycloalkyl), C 1-6 alkyl (heterocyclyl) , C
  • the heteroalkyl, heteroaryl or heterocyclyl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C( ⁇ O), C( ⁇ O)O, S( ⁇ O), S( ⁇ O) 2 and N.
  • the present invention also provides a compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
  • X1 is selected from N or C( Rx1 );
  • X2 is selected from N or C( Rx2 );
  • X3 is selected from N or C( Rx3 );
  • Y is selected from N or C( RY );
  • Z is selected from N or C (R Z );
  • L is selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 2-8 alkenyl or C 2-8 alkynyl, wherein the C 1-8 alkyl, C 1-8 heteroalkyl, C 2-8 alkenyl or C 2-8 alkynyl is substituted with one or more optional RL ;
  • RLs are on the same or different atoms and are linked together to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more RLs ;
  • R La are each independently selected from halogen, cyano, -NO 2 , hydroxyl, -OR a , -NR c R d , -C( ⁇ O)R a , -C( ⁇ O)OR b , -C( ⁇ O)NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl or C 1-6 heteroalkyl;
  • Ra , Rb , Rc and Rd are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-6 alkyl (cycloalkyl), C1-6 alkyl (heterocyclyl), C1-6 alkyl (aryl) or C1-6 alkyl (heteroaryl), the C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl , heteroaryl, C1-6 alkyl (cycloalkyl), C1-6 alkyl (heterocyclyl), C1-6 alkyl (aryl) or C1-6 alky
  • R c and R d are linked together to form a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more R;
  • R x3 are each independently selected from H, halogen, cyano, C 1-12 alkyl or C 1-12 haloalkyl;
  • R 1 is selected from H, halogen, cyano, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 hydroxyalkyl, C 1-12 heteroalkyl, cycloalkyl or heterocycloalkyl, wherein the C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 hydroxyalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R 111 ;
  • R 2 is selected from H, halogen, cyano, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 hydroxyalkyl, C 1-12 heteroalkyl, cycloalkyl or heterocycloalkyl, wherein the C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 hydroxyalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R 222 ;
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more R aa ;
  • R aa is each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1-6 alkyl (cycloalkyl), C 1-6 alkyl (heterocyclyl), C 1-6 alkyl (aryl) or C 1-6 alkyl (heteroaryl), wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1-6 alkyl (cycloalkyl), C 1-6 alkyl (heterocyclyl) , C
  • the heteroalkyl, heteroaryl or heterocyclyl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C( ⁇ O), C( ⁇ O)O, S( ⁇ O), S( ⁇ O) 2 and N.
  • the compound represented by formula (I) has the structure represented by formula (Ia);
  • the compound represented by formula (Ia) has the structure represented by formula (Iaa);
  • the compound represented by formula (Iaa) has the structure represented by formula (Iaaa);
  • R Z1 and R Z2 are independently selected from C 1-6 alkyl groups, and L, R 1 and R 2 are as defined in the present invention.
  • the compound represented by formula (Iaaa) has a structure represented by formula (Iaaa-1) or formula (Iaaa-2);
  • R Z1 and R Z2 are independently selected from C 1-6 alkyl groups, and Y, L, R 1 and R 2 are as defined in the present invention.
  • the compound represented by formula (Iaaa) has the structure represented by formula (Iaaaa);
  • R Z1 and R Z2 are independently selected from C 1-6 alkyl
  • Lx is selected from L2A - L3A - L4A or L;
  • RL4 is selected from H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl;
  • R L5 is selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl;
  • the compound represented by formula (Iaaa) has a structure represented by formula (Iaaaa-1) or formula (Iaaaa-2);
  • R Z1 , R Z2 , R Z3 , L X , R 1 and R 2 are as defined in the present invention.
  • the compound represented by formula (Ia) has the structure represented by formula (Iab);
  • Y, L, R 1 , R 2 , R 3 and Ring A are as defined in the present invention.
  • the compound represented by formula (Iab) has the structure represented by formula (Iabb);
  • L, R 1 and R 2 are as defined in the present invention.
  • the compound represented by formula (Iabb) has a structure represented by formula (Iabb-1) or formula (Iabb-2);
  • L, R 1 and R 2 are as defined in the present invention.
  • the compound represented by formula (Iabb) has the structure represented by formula (Iabbb);
  • R Z3 are independently selected from H, C 1-6 alkyl or C 3-12 cycloalkyl, wherein the C 1-6 alkyl or C 3-12 cycloalkyl is optionally substituted by 1, 2 or 3 halogens or OH,
  • Lx is selected from L2A - L3A - L4A or L;
  • RL4 is selected from H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl;
  • R L5 is selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl;
  • Y, R 1 and R 2 are as defined in the present invention.
  • the compound represented by formula (Iabbb) has a structure represented by formula (Iabbb-1) or formula (Iabbb-2);
  • R Z3 , L X , R 1 , and R 2 are as defined in the present invention.
  • R c is independently selected from H, C 1-3 alkyl or C 3-6 cycloalkyl, wherein the C 1-3 alkyl or C 3-6 cycloalkyl is optionally substituted with 1, 2 or 3 halogens or OH, and the remaining variables are as defined in the present invention.
  • R Z3 are independently selected from H, methyl, ethyl, cyclopropyl, CH 2 CF 3 or CH 2 CHF 2 , and the remaining variables are as defined in the present invention.
  • R Z1 and R Z2 are independently selected from methyl or ethyl, and the remaining variables are as defined in the present invention.
  • -L- is selected from -L 1A -L 2A -L 3A -L 4A -L 5A -, wherein L 1A , L 2A , L 3A , L 4A or L 5A are independently selected from a single bond, -O-, -C( ⁇ O)-, -S-, -S( ⁇ O)-, -S( ⁇ O) 2 -, optionally substituted C 1-3 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, -NR L4 -, RL4 is selected from H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl; RL5 is selected from H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C1-6 haloal
  • the remaining variables are as defined in the present invention.
  • the 3-6- membered cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with 1, 2, 3 or 4 halogens, OH, CN, NH 2 or C 1-6 alkyl, and the remaining variables are as defined herein.
  • RL4 is selected from H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl or optionally substituted cycloalkyl, and the remaining variables are as defined herein.
  • RL4 is selected from H, optionally substituted C1-6 alkyl, and the remaining variables are as defined herein.
  • RL4 is selected from H, optionally substituted C1-3 alkyl, and the remaining variables are as defined herein.
  • -L- is selected from the following groups:
  • R and R' are each independently hydrogen or C 1-6 alkyl; or R and R' optionally form a 3- to 14-membered heterocyclic group or a 5- to 12-membered heteroaryl group together with the nitrogen atom to which they are attached; wherein the heterocyclic group and the heteroaryl group each independently contain 0, 1 or 2 heteroatoms selected from N, O and S in addition to the existing nitrogen atom;
  • the 3- to 7-membered heterocyclic groups each independently have 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; the C 3-7 cycloalkyl groups each independently are unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from Group S1;
  • C 3-7 cycloalkyl is independently selected from unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from Group S1;
  • R 11 is independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7 membered heterocyclyl is optionally substituted with 1, 2, or 3 halogens, CN, OH or C 1-6 alkyl;
  • R 12 is independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7 membered heterocyclyl is optionally substituted with 1, 2, or 3 halogens, CN, OH or C 1-6 alkyl;
  • R 13 is independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -C 3-7 cycloalkyl, -C 0-6 alkylene-NRR', -C 1-6 alkylene-hydroxyl or -C 0-6 alkylene-cyano;
  • R 14 is independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -C 3-7 cycloalkyl, -C 0-6 alkylene-NRR', -C 1-6 alkylene-hydroxyl or -C 0-6 alkylene-cyano;
  • R 13 and R 14 are linked together, and the same carbon atom or different carbon atoms to which they are linked together form a 3-6 membered heterocyclic group or a C 3-6 cycloalkyl group, and the 3-6 membered heterocyclic group or the C 3-6 cycloalkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups selected from Group S1;
  • n1 is independently 1, 2, 3, 4, 5 or 6;
  • n2 are independently 0 or 1;
  • n3 is independently 0 or 1;
  • n4 are each independently 1 or 2;
  • n5 is independently 0, 1, 2, 3, 4, 5 or 6;
  • n6 is independently 0, 1, 2, 3, 4, 5 or 6;
  • n 1 or 2
  • n 1 or 2
  • R 13 is independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, -C 3-7 cycloalkyl, -C 0-6 alkylene-NRR', -C 1-6 alkylene-hydroxyl or -C 0-6 alkylene-cyano, and the remaining variables are as defined in the present invention.
  • R 13 is independently selected from H, cyano, hydroxyl, halogen, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -5 to 6 membered cycloalkyl, -C 0-3 alkylene-NRR', -C 1-3 alkylene-hydroxyl or -C 0-3 alkylene-cyano, and the remaining variables are as defined in the present invention.
  • R 13 is independently selected from H, F, Cl, Br, I, methyl or ethyl, and the remaining variables are as defined in the present invention.
  • R 14 is independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, -C 3-7 cycloalkyl, -C 0-6 alkylene-NRR', -C 1-6 alkylene-hydroxyl or -C 0-6 alkylene-cyano, and the remaining variables are as defined in the present invention.
  • R 14 is independently selected from H, cyano, hydroxyl, halogen, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, -5 to 6 membered cycloalkyl, -C 0-3 alkylene-NRR', -C 1-3 alkylene-hydroxyl or -C 0-3 alkylene-cyano, and the remaining variables are as defined in the present invention.
  • R 14 is independently selected from H, F, Cl, Br, I, methyl or ethyl, and the remaining variables are as defined in the present invention.
  • R 11 is independently selected from H, C 1-3 alkyl, C 3-6 cycloalkyl or 3 to 6 membered heterocyclyl.
  • C 1-3 alkyl, C 3-6 cycloalkyl or 3 to 6 membered heterocyclyl is optionally substituted with 1, 2, or 3 halogens, CN, OH or C 1-6 alkyl, and the remaining variables are as defined in the present invention.
  • R 12 is independently selected from H, C 1-3 alkyl, C 3-6 cycloalkyl or 3 to 6 membered heterocyclyl.
  • C 1-3 alkyl, C 3-6 cycloalkyl or 3 to 6 membered heterocyclyl is optionally substituted with 1, 2, or 3 halogens, CN, OH or C 1-6 alkyl, and the remaining variables are as defined in the present invention.
  • R 11 is independently selected from H, methyl, ethyl, cyclopropyl, CH 2 CF 3 or CH 2 CHF 2 , and the remaining variables are as defined in the present invention.
  • R 12 is independently selected from H, methyl, ethyl, cyclopropyl, CH 2 CF 3 or CH 2 CHF 2 , and the remaining variables are as defined in the present invention.
  • R 13 is independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, -C 3-7 cycloalkyl, -C 0-6 alkylene-NRR', -C 1-6 alkylene-hydroxyl or -C 0-6 alkylene-cyano, and the remaining variables are as defined in the present invention.
  • R 13 is independently selected from H, cyano, hydroxyl, halogen or C 1-6 alkyl, and the remaining variables are as defined in the present invention.
  • R 14 is independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, -C 3-7 cycloalkyl, -C 0-6 alkylene-NRR', -C 1-6 alkylene-hydroxyl or -C 0-6 alkylene-cyano, and the remaining variables are as defined in the present invention.
  • R 14 is independently selected from H, cyano, hydroxyl, halogen or C 1-6 alkyl, and the remaining variables are as defined in the present invention.
  • R 13 and R 14 are connected together and the same carbon atom or different carbon atoms to which they are connected together form a 3-6 membered heterocyclic group or a C 3-6 cycloalkyl group, wherein the 3-6 membered heterocyclic group or the C 3-6 cycloalkyl group is optionally substituted with 1 or 2 3 halogens or OH, and the remaining variables are as defined in the present invention.
  • R 13 and R 14 are connected together and the same carbon atom to which they are connected together forms a C 3-6 cycloalkyl group, wherein the C 3-6 cycloalkyl group is optionally substituted with 1 or 2 3 halogens or OH, and the remaining variables are as defined in the present invention.
  • R 13 and R 14 are linked together and the same carbon atom to which they are linked together forms a C 3-6 cycloalkyl group, and the remaining variables are as defined in the present invention.
  • -L- is selected from the following groups:
  • -L- is selected from the following groups:
  • L is -NR 11 -(CR 13 R 14 ) m1 -NR 12 -;
  • R 11 and R 12 are independently hydrogen or methyl;
  • each R 13 and 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 is -O-(CR 13 R 14 ) m1 -NR 12 -;
  • R 12 is hydrogen or methyl;
  • each R 13 and 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 is -NR 11 -(CR 13 R 14 ) m1 -;
  • R 11 is hydrogen or methyl;
  • each R 13 and 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 is -(CR 13 R 14 ) m1 -NR 12 -;
  • R 12 is hydrogen or methyl;
  • each R 13 and 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 is -(CR 13 R 14 ) m1 -; each R 13 and 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 is -NR 11 -(CR 13 R 14 ) m5 -C 3-7 cycloalkyl-(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;
  • the C 3-7 cycloalkyl 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 is -O-(CR 13 R 14 ) m5 -C 3-7 cycloalkyl-(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is 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;
  • the C 3-7 cycloalkyl 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 is -(CR 13 R 14 ) m5 -C 3-7 cycloalkyl-(CR 13 R 14 ) m6 -NR 12 -;
  • R 12 is 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;
  • the C 3-7 cycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from Group S1.
  • the C 3-7 cycloalkyl is cyclobutyl, cyclopentyl or cyclohexyl, and the remaining variables are as defined in the present invention.
  • L 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 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;
  • the 3 to 7 membered heterocycle 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 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 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;
  • the 3 to 7 membered heterocycle 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 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 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;
  • the 3 to 7 membered heterocycle 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 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 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 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 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, and the remaining are The amount is as defined in the present invention.
  • L 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 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.
  • 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, and the remaining variables are as defined in the present invention.
  • R 12 is 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, and the remaining variables are as defined in the present invention.
  • R 12 is 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, and the remaining variables are as defined in the present invention.
  • 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, and the remaining variables are as defined in the present invention.
  • R 12 is 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, and the remaining variables are as defined in the present invention.
  • R 12 is 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, and the remaining variables are as defined in the present invention.
  • L 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 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 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 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 is -(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 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.
  • 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 the remaining variables are as defined in the present invention.
  • R 12 is 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 the remaining variables are as defined in the present invention.
  • R 12 is 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 the remaining variables are as defined in the present invention.
  • 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 the remaining variables are as defined in the present invention.
  • R 12 is 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 the remaining variables are as defined in the present invention.
  • R 12 is 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 the remaining variables are as defined in the present invention.
  • 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 the remaining variables are as defined in the present invention.
  • R 12 is 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 the remaining variables are as defined in the present invention.
  • R 12 is 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 the remaining variables are as defined in the present invention.
  • the groups of group S1 include: oxo, hydroxyl, cyano, halogen, methyl, ethyl, propyl, etc.
  • the remaining variables are as defined in the present invention.
  • the C 3-7 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the remaining variables are as defined in the present invention.
  • the 3- to 7-membered heterocyclyl is azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl or piperazinyl, and the remaining variables are as defined in the present invention.
  • L is selected from one of the following structures:
  • L is selected from The upper end is connected to ring B, the lower end is connected to V, and the remaining variables are as defined in the present invention.
  • L is selected from The remaining variables are as defined in the present invention.
  • R x1 is selected from H, F, Cl, Br, I, -P(O)-(CH 3 ) 2 or -S(O) 2 -CH 3 , and the remaining variables are as defined in the present invention.
  • R 1 is selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3 to 6 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3 to 6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R 111 , and the remaining variables are as defined herein.
  • R 1 is selected from H, halogen, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 5-6 cycloalkyl or 5 to 6 membered heterocycloalkyl, wherein the C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 5-6 cycloalkyl or 5 to 6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R 111 , and the remaining variables are as defined herein.
  • R 1 is selected from H, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl or C 1-6 haloalkyl is optionally substituted with 1, 2 or 3 R 111 , and the remaining variables are as defined in the present invention.
  • R 1 is selected from H, halogen, cyano, C 1-3 alkyl or C 1-3 haloalkyl, wherein the C 1-3 alkyl or C 1-3 haloalkyl is optionally substituted with 1, 2 or 3 R 111 , and the remaining variables are as defined in the present invention.
  • R 1 is selected from H or C 1-3 haloalkyl, and the remaining variables are as defined herein.
  • R 1 is selected from H or CF 3 , and the remaining variables are as defined in the present invention.
  • R 1 is selected from CF 3 , and the remaining variables are as defined in the present invention.
  • R 2 is selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3 to 6 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3 to 6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R 222 , and the remaining variables are as defined herein.
  • R 2 is selected from H, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl or C 1-6 haloalkyl is optionally substituted with 1, 2 or 3 R 222 , and the remaining variables are as defined in the present invention.
  • R 2 is selected from H, halogen, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 5-6 cycloalkyl or 5 to 6 membered heterocycloalkyl, wherein the C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 heteroalkyl, C 5-6 cycloalkyl or 5 to 6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R 222 , and the remaining variables are as defined herein.
  • R2 is selected from H, halogen, cyano, C1-3 alkyl or C1-3 haloalkyl, wherein the C1-3 alkyl or C1-3 haloalkyl
  • the alkyl group is optionally substituted with 1, 2 or 3 R 222 , and the remaining variables are as defined herein.
  • R 2 is selected from H or C 1-3 haloalkyl, and the remaining variables are as defined herein.
  • R 2 is selected from H or CF 3 , and the remaining variables are as defined herein.
  • R 2 is selected from H, and the remaining variables are as defined in the present invention.
  • Ring A is selected from C 3-12 cycloalkyl, 3 to 12 membered heterocyclyl, C 6-12 aryl or 5 to 12 membered heteroaryl, wherein the C 3-12 cycloalkyl, 3 to 12 membered heterocyclyl, C 6-12 aryl or 5 to 12 membered heteroaryl is optionally substituted with one or more R aa , and the remaining variables are as defined herein.
  • Ring A is selected from C 3-12 cycloalkyl or 3-12 membered heterocyclyl, wherein the C 3-12 cycloalkyl or 3 to 12 membered heterocyclyl is optionally substituted with one or more R aa , and the remaining variables are as defined herein.
  • Ring A is selected from C 3-9 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5 to 6 membered heteroaryl, wherein the C 3-9 cycloalkyl, 5 to 6 membered heterocyclyl, phenyl or 5 to 6 membered heteroaryl is optionally substituted with 1, 2 or 3 R aa , and the remaining variables are as defined herein.
  • Ring A is selected from C 3-6 cycloalkyl or 5- to 6-membered heterocyclyl, wherein the C 3-6 cycloalkyl or 5- to 6-membered heterocyclyl is optionally substituted with 1, 2 or 3 R aa , and the remaining variables are as defined herein.
  • Ring A is selected from cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolyl or imidazolyl, wherein the cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolyl or imidazolyl is optionally substituted with 1, 2 or 3 R aa , and the remaining variables are as defined herein.
  • Ring A is selected from C 3-6 cycloalkyl or 5- to 6-membered heterocyclyl, and the remaining variables are as defined herein.
  • Ring A is selected from C 3-6 cycloalkyl, and the remaining variables are as defined herein.
  • Ring A is selected from C 5-6 cycloalkyl, and the remaining variables are as defined herein.
  • Ring A is selected from cyclobutyl, cyclopentyl or cyclohexyl, wherein the cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with 1, 2 or 3 R aa , and the remaining variables are as defined herein.
  • Ring A is selected from cyclobutyl, cyclopentyl or cyclohexyl, and the remaining variables are as defined herein.
  • Ring A is selected from The remaining variables are as defined in the present invention.
  • Ring A is selected from The remaining variables are as defined in the present invention.
  • Ring A is selected from The remaining variables are as defined in the present invention.
  • Ring A is selected from The remaining variables are as defined in the present invention.
  • the present invention also proposes the following compound, its stereoisomer or its pharmaceutically acceptable salt, which is selected from
  • the present invention also provides a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which has one of the structures in Table 1 or Table 2.
  • the present invention also provides a pharmaceutical composition.
  • the pharmaceutical composition comprises the aforementioned compound, its stereoisomer or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • the present invention also proposes the use of the compound of formula (II), its stereoisomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of drugs for preventing and/or treating CDK7-related diseases.
  • the CDK7-related disease is a proliferative disease (eg, tumor or cancer), an infectious disease, an immune disease, an autoimmune disease or an inflammatory disease.
  • the present invention also proposes the use of the compound of formula (II), its stereoisomer or pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of CDK7 inhibitors.
  • the present invention also proposes the use of the compound of formula (II), its stereoisomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preventing and/or treating CDK7-related diseases.
  • the present invention also provides a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for preventing and/or treating CDK7-related diseases.
  • the CDK7-related disease is a proliferative disease (eg, tumor or cancer), an infectious disease, an immune disease, an autoimmune disease or an inflammatory disease.
  • the compound of the present invention has a novel structure
  • the compounds of the present invention have good CDK7 inhibitory activity
  • the compounds of the present invention have high membrane permeability, which helps to solve the problem of low oral absorption permeability of the prior art compounds;
  • the compounds of the present invention have a lower efflux rate (Efflux Ratio), which helps to solve the problem of high efflux in the prior art compounds.
  • “Plurality” means two, three, four or more.
  • the numerical ranges recorded in this specification and claims are equivalent to recording at least each specific integer value therein.
  • the numerical range “1-12” is equivalent to recording each integer value in the numerical range "1-12", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups connected to it are directly connected. For example, when L is selected from a single bond, ring B and O are directly connected.
  • linking direction is arbitrary, for example
  • the connecting group M is selected from hour, You can connect cyclohexyl and phenyl groups in the same direction as reading from left to right to form It is also possible to connect cyclohexyl and phenyl groups in the opposite direction of the reading order from left to right. Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.
  • Halogen or "halo" means fluorine, chlorine, bromine, or iodine.
  • alkyl means a straight or branched saturated hydrocarbon containing 1 to 12 carbon atoms.
  • C 1-6 alkyl means a straight and branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,
  • hydroxyalkyl refers to an alkyl group substituted by one or more -OH groups.
  • the alkyl group mentioned herein has the same definition as the above alkyl group.
  • Examples of hydroxyalkyl groups include HO—CH 2 —, HO—CH 2 CH 2 —, and CH 2 —CH(OH)—.
  • haloalkyl means an alkyl group substituted by one or more halogens.
  • the alkyl mentioned therein has the same definition as the above-mentioned alkyl.
  • Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.
  • alkenyl means a straight or branched unsaturated hydrocarbon containing 2-12 carbon atoms.
  • An "alkenyl” group contains at least one double bond in the chain. The double bond of the alkenyl group can be unconjugated or conjugated with another unsaturated group.
  • C2-6 alkenyl means a straight or branched unsaturated hydrocarbon with 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include vinyl, propenyl, n-butenyl, isobutylene, pentenyl or hexenyl. Alkenyl groups can be unsubstituted or substituted and can be straight or branched.
  • alkynyl means a straight or branched unsaturated hydrocarbon containing 2-12 carbon atoms.
  • C2-6 alkynyl means a straight or branched unsaturated hydrocarbon having 2, 3, 4, 5 or 6 carbon atoms.
  • An "alkynyl” group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propargyl, n-butynyl, isobutynyl, pentynyl or hexynyl. Alkynyl groups can be unsubstituted or substituted.
  • heteroalkyl by itself or in combination with another term refers to a stable straight or branched alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group.
  • the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized.
  • the heteroalkyl is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl is C 1-3 heteroalkyl.
  • heteroatom or heteroatom group may be placed at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the terms "alkoxy,”"alkylamino,” and “alkylthio” (or thioalkoxy) are conventional expressions and refer to those alkyl groups attached to the remainder of the molecule through an oxygen, amino or sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive,
  • cycloalkyl means a monocyclic or polycyclic saturated or partially unsaturated non-aromatic carbocyclic ring containing 3-18 carbon atoms. In some embodiments, the cycloalkyl is a saturated non-aromatic carbocyclic ring.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norboranyl, norborenyl, bicyclo [2.2.2] octyl, or bicyclo [2.2.2] octenyl and derivatives thereof.
  • (C 3 -C 8 ) cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms.
  • the cycloalkyl group can be fused (e.g., decalin) or bridged (e.g., norbornane).
  • the term "C 3-12 cycloalkyl” is understood to mean a saturated monovalent monocyclic, bicyclic (such as fused, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 12 carbon atoms, "C 3-10 cycloalkyl", more preferably "C 3-8 cycloalkyl".
  • C 3-12 cycloalkyl is understood to mean a saturated monovalent monocyclic, bicyclic (such as bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.
  • the C 3-12 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group, such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonanyl, 2,6-diaza
  • heterocyclyl or “heterocycloalkyl” means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen or sulfur (O, N or S), and wherein there is no shared non-localized n electrons (aromaticity) between the ring carbons or heteroatoms.
  • the heterocycloalkyl ring structure can be substituted by one or more substituents. These substituents themselves can be optionally substituted.
  • heterocycloalkyl rings include, but are not limited to, oxetane, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxolinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, aza Oxalic acid Base, diazepine
  • the heterocyclic group may refer to a saturated or unsaturated non-aromatic ring or ring system having 3 to 14 members, for example, a 3-, 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-,
  • the sulfur atom of the ring may be optionally oxidized to an S-oxide.
  • the nitrogen atom of the ring may be optionally oxidized to an N-oxide.
  • the heterocyclyl group is a heterocyclyl group consisting of 5-12 atoms; in other embodiments, the heterocyclyl group is a heterocyclyl group consisting of 5-8 atoms; in yet other embodiments, the heterocyclyl group is a heterocyclyl group consisting of 5-7 atoms; in still other embodiments, the heterocyclyl group is a heterocyclyl group consisting of 5-6 atoms.
  • the heterocyclyl group may also be a bicyclic heterocyclyl group; in some embodiments, the heterocyclyl group is a bicyclic heterocyclyl group consisting of 7-12 atoms; in other embodiments, the heterocyclyl group is a bicyclic heterocyclyl group consisting of 7-10 atoms; in yet other embodiments, the heterocyclyl group is a bicyclic heterocyclyl group consisting of 8-10 atoms.
  • aryl means a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings (including monocyclic or bicyclic groups), such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group are optionally connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group is optionally substituted with one or more substituents at any point of attachment, such as 1 to 5 substituents.
  • C 6-14 aryl should be understood to mean a monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic hydrocarbon ring with 6 to 14 carbon atoms, which may be a single aromatic ring or multiple aromatic rings fused together, such as “C 6-10 aryl”.
  • C 6-14 aryl should be understood to mean a cyclic aromatic or partially aromatic hydrocarbon ring with 6 to 14 carbon atoms.
  • a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring of 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (“C 6-14 aryl”), in particular a ring of 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or a ring of 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or a ring of 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring of 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring of 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6-20 aryl When the C 6-20 aryl is substituted, it may be monosubstituted or polysubstituted.
  • heteroaryl means a monovalent monocyclic aromatic group or polycyclic aromatic group of 5 to 24 ring atoms, which contains one or more ring heteroatoms selected from N, O, or S, and the remaining ring atoms are C.
  • Heteroaryl as defined herein also means a bicyclic heteroaromatic group, wherein the heteroatoms are selected from N, O, or S.
  • Aromatic groups are optionally substituted independently with one or more substituents described herein.
  • heteroaryl should be understood to include such monovalent monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic aromatic ring systems: for example, it has 5-14 ring atoms and contains 1-5 heteroatoms independently selected from N, O and S, such as "5-10 membered heteroaryl".
  • the term "5-14 membered heteroaryl” is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which contain 1 to 5, or 1 to 3 heteroatoms each independently selected from N, O and S and which, in each case, may additionally be benzo-fused.
  • Heteroaryl also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring.
  • Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3- , 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnoliny
  • Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl.
  • the 5-14 membered heteroaryl group When the 5-14 membered heteroaryl group is connected to other groups to form the compound of the present invention, it can be a carbon atom on the 5-14 membered heteroaryl ring connected to other groups, or it can be a heteroatom on the 5-14 membered heteroaryl ring connected to other groups.
  • the 5-14 membered heteroaryl group When the 5-14 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted.
  • substitution site for example, a hydrogen atom connected to a carbon atom on a heteroaryl ring may be substituted, or a hydrogen atom connected to a heteroatom on a heteroaryl ring may be substituted.
  • spirocyclic refers to a ring system in which two rings share one ring-forming atom.
  • fused ring refers to a ring system in which two rings share two ring atoms.
  • bridged ring refers to a ring system in which two rings share three or more ring atoms.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • Halo means substituted with one or more halogens.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • radioactive isotope labeled compounds may be used, such as deuterium ( 2H ), tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ). All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • H is deuterium or tritium.
  • Salt means the product of the reaction between the ionic form of the parent compound or the parent compound and a suitable acid or base to prepare an acid salt or basic salt of the parent compound.
  • Salts of the compounds of the present disclosure can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Typically, salts are prepared by reacting the free basic or acidic parent compound with a stoichiometric amount or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or a combination of different solvents.
  • “Pharmaceutically acceptable salt” means a salt of a compound of the present disclosure which, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit/risk ratio, is generally water-soluble or oil-soluble or dispersible, and is effective for its intended purpose.
  • the term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Since the compounds of the present disclosure are useful in both free base form and salt form, in practice the use of the salt form is equivalent to the use of the base form. Lists of suitable salts are found, for example, in SM Birge et al., J. Pharm. Sci. [Journal of Pharmaceutical Sciences], 1977, 66, pp. 1-19, which is incorporated by reference. The entire text of which is hereby incorporated herein.
  • “Pharmaceutically acceptable acid addition salts” means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable and are prepared by addition of an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, nitric acid, phosphoric acid, etc.) and an organic acid (e.g., acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid,
  • the present invention can be used to prepare the present invention comprises amino acid, glycolic acid, glycerophosphoric acid,
  • “Pharmaceutically acceptable base addition salts” refers to those salts that retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable and are formed with inorganic bases such as ammonia or hydroxides, carbonates, or bicarbonates, or metal cations such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, quaternary ammonium compounds, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine , caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium
  • “Isomers” means compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ with respect to the arrangement or configuration of the atoms in space.
  • the term includes stereoisomers and geometric isomers.
  • Stepoisomer or “optical isomer” means a stable isomer having at least one chiral atom or restricted rotation resulting in a vertical asymmetric plane (e.g., some biphenyls, propadiene and spiro compounds) and can rotate plane polarized light. Because asymmetric centers and other chemical structures are present in the compounds of the present disclosure that can cause stereoisomerism, the present disclosure contemplates stereoisomers and mixtures thereof.
  • the compounds of the present disclosure and their salts include asymmetric carbon atoms and can therefore exist as a single stereoisomer, a racemate, and a mixture of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture.
  • stereoisomers i.e., as individual enantiomers or diastereomers, or as a mixture enriched in stereoisomers.
  • individual stereoisomers of a compound are prepared by synthesis from optically active starting materials containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution (e.g., conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of a chiral resolving agent, or direct separation of enantiomers on a chiral chromatographic column).
  • Starting compounds of specific stereochemistry are either commercially available or prepared by the methods described below and resolved by techniques well known in the art.
  • Enantiomers means a pair of stereoisomers that are non-superimposable mirror images of one another.
  • Diastereomers or “diastereomers” means optical isomers that are not mirror images of one another.
  • Racemic mixture or “racemate” means a mixture containing equal parts of individual enantiomers.
  • Non-racemic mixture means a mixture containing unequal parts of individual enantiomers.
  • Some compounds of the present disclosure can exist in more than one tautomeric form. As mentioned above, the compounds of the present disclosure include all such tautomers.
  • composition refers to a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof in a form suitable for oral or parenteral administration, and at least one pharmaceutically acceptable carrier.
  • Carrier encompasses carriers, excipients, and diluents, and means a material, composition, or vehicle involved in carrying or transporting a pharmaceutical agent from one organ or part of a subject's body to another, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.
  • terapéuticaally effective amount refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition.
  • Preventing disease e.g., preventing a disease,
  • HATU stands for 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • Triphenylphosphine (95.1 g, 362 mmol) and p-nitrobenzoic acid (60.6 g, 362 mmol) were added to a solution of compound 1-7 (51.0 g, 181 mmol) in THF (500 mL).
  • the reaction solution was cooled to 0°C under nitrogen protection and diethyl azodicarboxylate (63.1 g, 362 mmol) was added. Stir at 25°C for 3 hours.
  • the reaction solution was poured into ice water (1 L) and extracted with ethyl acetate (500 mL ⁇ 2, and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • lithium hydroxide monohydrate (27.8 g, 622 mmol) was added to a mixed solution of water (50 mL), methanol (150 mL) and tetrahydrofuran (150 mL) of compound 1-8 (57.0 g, 132 mmol).
  • the reaction solution was stirred at 50°C for 3 hours.
  • the reaction solution was diluted with water (200 mL), extracted with ethyl acetate (50 mL ⁇ 3), and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • the crude product was purified by silica gel column chromatography to obtain compound 1-9 (30.0 g, yield 81%).
  • reaction solution was added to a saturated aqueous ammonium chloride solution (500 mL ⁇ 3) for quenching, extracted with ethyl acetate (300 mL ⁇ 3), and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • the crude product was purified by silica gel column chromatography to obtain compound 1-10 (1.90 g, yield 23%).
  • N,N-diisopropylethylamine (4.00 mL, 24.2 mmol) to a solution of 1-5 (2.10 g, 4.83 mmol) and 1-12 (1.80 g, 4.83 mmol) in NMP (20 mL). After stirring at 130 ° C for 4 hours, cool to room temperature, add water (10 mL) to dilute the reaction solution, and then extract with ethyl acetate (5 mL ⁇ 3). The combined organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to obtain compound 1-13 (2.20 g, yield 47%).
  • HATU (289 mg, 0.80 mmol) and N,N-diisopropylethylamine (0.52 mL, 3.16 mmol) were added to a DMSO (20 mL) solution of compound 1-15 (350 mg, 0.63 mmol). The reaction solution was stirred at 60 ° C for 18 hours. After the reaction was completed, water (1 mL) was added, and the reaction solution was purified by reverse phase preparation (Xtimate C18, 80*250mm, 10um, 0.1% TFA) to obtain compound 1 (79.5 mg, yield 24%).
  • Triphenylphosphine (64.5 g, 246 mmol) and imidazole (17 g, 246 mmol) were added to a solution of compound 2-2 (21.0 g, 92.9 mmol) in dichloromethane (300 mL) at 25 °C.
  • the reaction solution was cooled to 0 °C under nitrogen protection, and iodine (62.0 g, 246 mmol) was added and then heated to 25 °C and stirred for 2 hours.
  • the reaction solution was quenched with saturated sodium thiosulfate and then extracted with dichloromethane (500 mL ⁇ 2).
  • the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • the crude product was purified by silica gel column chromatography to obtain compound 2-3 (30.0 g, yield 78%).
  • HATU (321 mg, 0.84 mmol) and N,N-diisopropylethylamine (0.35 mL, 2.11 mmol) were added to a DMF (10 mL) solution of compound 2-8 (400 mg, 0.700 mmol) in sequence, and the reaction solution was stirred at 60°C for 2 h. After the reaction was completed, the reaction solution was concentrated to obtain a crude product which was purified by reverse phase preparation (Xtimate C18, 21.2*250 mm, 5 um, 0.1% TFA) to obtain compound 2 (123 mg, yield 31%).
  • LCMS m/z (ESI): 550.0 [M+H] + .
  • N-iodosuccinimide (157 mg, 0.699 mmol) was added to a DMF (1 mL) solution of compound 3-3 (100 mg, 0.699 mmol). The reaction solution was stirred for 18 hours under nitrogen protection. The reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (10 mL ⁇ 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 3-4 (140 mg, 74%). LCMS: m/z (ESI): 270.0 [M+1] + .
  • compound 4-2 (10.0g, 28.1mmol), NMP (300mL), N,N-diisopropylethylamine (13.9mL, 84.3mmol) and ((1S, 3S)-3-aminocyclopentyl)carbamic acid tert-butyl ester (6.20g, 30.9mmol) were added in sequence.
  • the reaction was carried out at 130°C for 4 hours, and the reaction solution was diluted with water (100mL) and extracted with ethyl acetate (200mL ⁇ 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • the crude product was purified by silica gel column chromatography to obtain compound 4-3 (8.00g, 54%).
  • HATU (279 mg, 0.73 mmol) and N,N-diisopropylethylamine (0.30 mL, 1.83 mmol) were added to a DMF (5 mL) solution of compound 4-8 (300 mg, 0.61 mmol) in sequence.
  • the reaction solution was stirred at 60 ° C for 16 h. After the reaction was completed, the reaction solution was concentrated by rotary evaporation.
  • the crude product was purified by reverse phase preparation (Xtimate C18, 50*250 mm, 10 um, 0.1% TFA) to obtain compound 4 (19.2 mg).
  • the synthesis of compound 5 refers to the synthetic route of compound 4, and the raw material (4-iodobutyl)(methyl)carbamic acid tert-butyl ester used as the synthetic raw material of intermediate 5-1 replaces the raw material (4-bromobutyl)carbamic acid tert-butyl ester used as the synthetic raw material of intermediate 4-5.
  • diethylaminosulfur trifluoride (20.9 g, 130 mmol) was added to a DCM (200 mL) solution of compound 6-2 (15.0 g, 64.9 mmol). The reaction solution was stirred under this condition for 18 hours. After the reaction was completed, the reaction solution was diluted with water (200 mL), extracted with ethyl acetate (200 mL ⁇ 3), and the combined organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was obtained by reverse phase preparation to obtain compound 6-3 (2.3 g, yield 14%).
  • the synthesis of compound 6 refers to the synthetic route of compound 4, and the raw material 6-5 of the synthetic intermediate 6-6 replaces the raw material (4-bromobutyl)carbamic acid tert-butyl ester of the synthetic intermediate 4-5.
  • the synthesis of compound 7 refers to the synthetic route of compound 6, and the synthetic intermediate 7-1 replaces the raw material 6-1 for synthesizing compound 6.
  • compound 8-4 (420mg, 1.08mmol), NMP (2mL), N,N-diisopropylethylamine (0.53mL, 3.23mmol) and ((1S, 3S)-3-aminocyclopentyl)carbamic acid tert-butyl ester (237mg, 1.18mmol) were added in sequence.
  • the reaction solution was heated to 80°C and stirred until it became clear, and then reacted in a microwave at 130°C for 2 hours. After the reaction was completed, the reaction solution was diluted with water (20mL) and extracted with ethyl acetate (20mL ⁇ 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 8-6 (430mg, yield 72%).
  • compound 8-6 (430 mg, 0.72 mmol) was dissolved in a mixed solution of hydrogen chloride/dioxane (4 mL, 4 M) and MeOH (2 mL). The mixture was reacted at 15 ° C for 16 hours. After the reaction was completed, a saturated sodium bicarbonate solution (40 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL ⁇ 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 8-7 (320 mg, yield 89%).
  • Test Example 1 CDK7/Cyclin H Surface Plasmon Resonance (SPR) Assay Method
  • CDK7/Cyclin H was purchased from Bio-Tech; batch number: 20200309-BP487/492; MES buffer was purchased from BioRoYee; batch number: 67GR9637; CM5 sensor chip was purchased from Cytiva; batch number: 10305527; HEPES buffer was purchased from Cytiva; batch number: 32349.
  • CDK7/Cyclin H dimer was amino coupled to a CM5 sensor chip at a concentration of 50 ⁇ g/mL in 10 mM MES buffer at pH 6.5 at a flow rate of 5 ⁇ L/min.
  • the target protein was immobilized on the chip channel within 600 seconds, typically reaching 7000-10000 responses.
  • Compounds were diluted 2-fold in 5 steps to a concentration range of 0.6-10 nM in 10 mM HEPES buffer at pH 7.4 with 150 mM NaCl, 0.05% surfactant P20 and 2% DMSO. Each compound concentration cycle was run at 100 ⁇ L/min with a contact time of 180 seconds and a dissociation time of 1800 seconds.
  • KD (M) koff (s -1 )/ Kon (M -1s - 1 ); wherein Kon (ka) is the association rate; Koff (kd) is the dissociation rate; s -1 (per second) and M - 1s -1 (per mole per second) are the units of koff and kon .
  • the compound selectivity of CDK7 relative to CDK2, CDK9 or CDK12 was determined according to the following equation.
  • Selectivity K i, off-target / KD, CDK7 .
  • the results show that the compounds of the present invention have excellent selectivity for CDK7 relative to CDK2/CDK9/CDK12, and the specificity of the compounds of the present invention for CDK7 is at least 100 times or 300 times that for other CDKs; it can even be more than 500 times.
  • the results of some exemplary compounds are shown in Table 3.
  • OVCAR-3 was purchased from ATCC; Catalog No.: HTB-161; RPMI1640 was purchased from Gibco; Catalog No.: 22400-089; Trypsin (containing EDTA) was purchased from Gibco; Catalog No.: 25200-072; FBS was purchased from Excell; Catalog No.: FND500; CellTiter-Glo was purchased from Promega; Catalog No.: G7573; Bovine insulin was purchased from Yeasen; Catalog No.: 40107ES25; DMSO was purchased from SIGMA; Catalog No.: D2650-1000ML; Phosphate buffered saline (DPBS) was purchased from Corning; Catalog No.: 21-031-CVR; Cell counter was purchased from Beckman; Model: Vi-CELLXR Cell Viability Analyzer; Microplate reader was purchased from PerkinElmer; Model: 2105
  • OVCAR-3 is a human ovarian adenocarcinoma cell line, and is cultured in an incubator at 37°C and 5% CO2 using RPMI-1640 medium containing 20% FBS and 0.01 mg/mL Bovine insulin. Cells in the logarithmic growth phase were taken for plating, digested, collected and counted with 0.25% trypsin-EDTA, and 8000 OVCAR-3 cells/well were inoculated in a 96-well cell plate and cultured overnight in 5% CO2 . 1000X compound 3-fold gradient concentration stock solution was prepared using DMSO, and the compound stock solution was diluted 100 times to 10X using culture medium.
  • the inhibition rate of the compound at different concentrations was calculated in Excel, and then the inhibition curve was plotted and related parameters were calculated using GraphPad Prism software, including Relative IC 50 , Bottom (%), Top (%); Absolute IC 50 and Max (%).
  • the results showed that the compounds of the present invention had a strong inhibitory effect on the proliferation of OVCAR-3 human ovarian adenocarcinoma cells.
  • the results of the exemplary compounds are shown in Table 4 below, where "A” represents IC 50 less than 500 nM; "B” represents ⁇ IC 50 of 500 nM to less than 2000 nM; "C” represents ⁇ IC 50 equal to or greater than 2000 nM.
  • Table 4 OVCAR-3 tumor cell proliferation inhibitory activity of the compounds of the present invention
  • the compounds of the present invention have excellent OVCAR3 cell inhibitory activity.
  • Preheat Preheat Hanks' Balanced Salt Buffer (HBSS) in a 37°C water bath.
  • HBSS Hanks' Balanced Salt Buffer
  • Blank solution on the dosing side 1) Blank solution on the dosing side (A-B direction): Transport buffer (pH 7.4) containing 0.3% DMSO and 5 ⁇ M Lucifer Yellow (LY): add 150 ⁇ L DMSO and 50 ⁇ L of 5mM LY stock solution into 50mL HBSS; Transport buffer (pH 7.4) containing 0.2% DMSO and 5 ⁇ M LY: add 100 ⁇ L DMSO and 50 ⁇ L of 5mM LY stock solution into 50mL HBSS; Transport buffer (pH 7.4) containing 0.1% DMSO and 5 ⁇ M LY: add 50 ⁇ L DMSO and 50 ⁇ L of 5mM LY stock solution into 50mL HBSS.
  • Transport buffer (pH 7.4) containing 0.1% DMSO and 5 ⁇ M LY add 50 ⁇ L DMSO and 50 ⁇ L of 5mM LY stock solution into 50mL HBSS.
  • Receiving side blank solution 1) Receiving side blank solution (A-B direction): transport buffer containing 0.4% DMSO (pH 7.4): add 200 ⁇ L DMSO into 50 mL HBSS; 2) Receiving side blank solution (B-A direction): transport buffer containing 0.4% DMSO and 5 ⁇ M fluorescent yellow LY (pH 7.4): add 200 ⁇ L DMSO and 50 ⁇ L 5 mM LY stock solution into 50 mL HBSS; transport buffer containing 0.3% DMSO and 5 ⁇ M fluorescent yellow LY (pH 7.4): add 150 ⁇ L DMSO and 50 ⁇ L 5 mM LY stock solution into 50 mL HBSS.
  • Top side LYT0 sample Take out 100 ⁇ L of sample from each well of the top side plate and put it into the black fluorescence measurement plate for preparing LY T0 sample.
  • Preheating Place the top side plate and the basal side plate in a 37°C incubator for preheating for 5 minutes, and then combine the top side plate and the basal side plate to start the transport experiment.
  • Cell culture Place the cell plate in an incubator at 37°C for 90 minutes.
  • Termination of transport After 90 minutes of incubation, separate the apical plate from the basal plate to terminate the transport experiment.
  • LY measurement 100 ⁇ L of sample was taken from each well of the basolateral plate and placed in a black fluorescence measurement plate to prepare LY T90 sample. The response values of LY T0 and LY T90 samples were measured using an ELISA reader (excitation wavelength 485 nm, emission wavelength 535 nm).
  • the permeability (Papp, unit 10 -6 , cm/s) and efflux rate (ER) of the compound in Caco-2 cells were calculated based on the specific concentrations at the receiving and administering ends.

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Abstract

本发明提供了一种大环类化合物的合成及其在医药上的用途，具体地，本发明提供了式(II)所示化合物、其立体异构体或其药学上可接受的盐，其可作为CDK7抑制剂。

Description

大环类化合物的合成及其在医药上的用途
本申请要求享有于2023年06月19日向中国国家知识产权局提交的，专利申请号为202310728137.8，名称为“大环类化合物的合成及其在医药上的用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本发明中。
技术领域
本发明属于医药领域，具体涉及大环类化合物的合成及其在医药上的用途。
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
WO2018013867A1专利申请中公开了一种CDK7抑制剂，研究表明，该专利申请中公开的化合物具有人Caco-2单细胞层渗透实验模型中的透膜性和外排率欠佳的问题。
本发明的一个目的是提供一类结构新颖的CDK7抑制剂。此外，本发明的化合物还至少具有如下技术效果之一：1、较好的生物学活性，2、较好的透膜性，3、较低的外排率(Efflux Ratio)。药物口服给药需要通过胃肠道吸收进入血液循环系统，并分布到达相应的组织从而在体内发挥药理作用。因此，透膜性反映了化合物在体内的吸收转运能力，对药物口服吸收至关重要。同时，口服药物的外排率低，更有助于药物在胃肠道内的吸收。
在本发明的一方面，本发明提出了一种式(II)所示化合物、其立体异构体或其药学上可接受的盐；
其中，V选自单键或-O-；
结构单元选自
X1选自N或C(Rx1)；
X2选自N或C(Rx2)；
X3选自N或C(Rx3)；
Y选自N或C(RY)；
Z选自N或C(RZ)；
L选自C1-8烷基、C1-8杂烷基、C2-8烯基或C2-8炔基，所述C1-8烷基、C1-8杂烷基、C2-8烯基或C2-8炔基任选被1个或多个RL取代；
RL分别独立地选自卤素、氰基、-NO2、羟基、-ORa、-NRcRd、-C(＝O)Ra、-C(＝O)ORb、-C(＝O)NRcRd、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基或杂环基；
或两个RL在同一个原子上，且连接在一起，形成＝O；
或两个RL在相邻的两个原子上，且连接在一起，形成一个单键；
或两个RL在同一个或不同原子上，且连接在一起形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基或杂芳基任选被1个或多个RLa取代；
RLa分别独立地选自卤素、氰基、-NO2，羟基、-ORa、-NRcRd、-C(＝O)Ra、-C(＝O)ORb、-C(＝O)NRcRd、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基或C1-6杂烷基；
Ra、Rb、Rc和Rd分别独立地选自H、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基、杂环基、芳基、杂芳基、C1-6烷基(环烷基)、C1-6烷基(杂环基)、C1-6烷基(芳基)或C1-6烷基(杂芳基)，所述C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基，杂环基、芳基、杂芳基、C1-6烷基(环烷基)、C1-6烷基(杂环基)、C1-6烷基(芳基)或C1-6烷基(杂芳基)任选被1个或多个R取代；
或Rc和Rd连接在一起形成杂环基，所述杂环基任选被1个或多个R取代；
Rx1、Rx2、RY、RZ、R3分别独立地选自H、卤素、羟基、氰基、-C2-4亚烯基-苯基、-C2-4亚炔基-苯基、-S(＝O)-OH、-S(＝O)2-OH、-S-(C1-6烷基)、C1-6烷基、-O-C1-6烷基、-C1-6亚烷基-O-C1-6烷基、-O-C1-6亚烷基-O-C1-6烷基、-C0-6亚烷基-NRR’、-C0-6亚烷基-C(＝O)OH、-C0-6亚烷基-C(＝O)-C1-6烷基、-C0-6亚烷基-C(＝O)-NRR’、-C0-6亚烷基-NR-C(＝O)-C1-6烷基、-C0-6亚烷基-S(＝O)2-C1-6烷基、-C0-6亚烷基-S(＝O)(＝NH)-C1-6烷基、-C0-6亚烷基-S(＝O)2-NRR’、-C0-6亚烷基-NR-S(＝O)2-C1-6烷基、-C0-6亚烷基-NR-S(＝O)2-NRR’、-C0-6亚烷基-P(＝O)O-(C1-6烷基)2、-C0-6亚烷基-P(＝O)-(C1-6烷基)(O-C1-6烷基)、-C0-6亚烷基-P(＝O)-(C1-6烷基)2、-C0-6亚烷基-3至14元环烷基、-C0-6亚烷基-3至14元杂环基、-C0-6亚烷基-5至12元杂芳基、-C0-6亚烷基-C6-12芳基、-C0-6亚烷基-C(＝O)-3至14元杂环基、-C0-6亚烷基-C(＝O)-5至12元杂芳基、-O-C0-6亚烷基-O-C1-6烷基、-O-C0-6亚烷基-3至14元环烷基、-O-C0-6亚烷基-3至14元杂环基、-O-C0-6亚烷基-5至12元杂芳基、-O-C0-6亚烷基-C6-12芳基、-S(＝O)-C1-6烷基；其中，所述C1-6烷基、C0-6亚烷基、C2-4亚烯基、3至14元环烷基、3至14元杂环基、5至12元杂芳基、C6-12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、C1-6烷基、-O-C1-6烷基、-C1-6亚烷基-O-C1-6烷基、-O-C1-6亚烷基-O-C1-6烷基、-C0-6亚烷基-NRR’、-C0-6亚烷基-C(＝O)OH、-C0-6亚烷基-C(＝O)-C1-6烷基、-C0-6亚烷基-C(＝O)-NRR’、-C0-6亚烷基-NR-C(＝O)-C1-6烷基、-C0-6亚烷基-S(＝O)2-C1-6烷基、-C0-6亚烷基-S(＝O)2-NRR’、-C0-6亚烷基-NR-S(＝O)2-C1-6烷基、-C0-6亚烷基-NR-S(＝O)2-NRR’、-C0-6亚烷基-P(＝O)O-(C1-6烷基)2、-C0-6亚烷基-P(＝O)-(C1-6烷基)(O-C1-6烷基)、-C0-6亚烷基-P(＝O)-(C1-6烷基)2、-C0-6亚烷基-3至14元环烷基、-C0-6亚烷基-3至14元杂环基、-C0-6亚烷基-5至12元杂芳基、-C0-6亚烷基-C6-12芳基、-C0-6亚烷基-C(＝O)-3至14元杂环基、-C0-6亚烷基-C(＝O)-5至12元杂芳基、-O-C0-6亚烷基-O-C1-6烷基、-O-C0-6亚烷基-3至14元环烷基、-O-C0-6亚烷基-3至14元杂环基、-O-C0-6亚烷基-5至12元杂芳基、-O-C0-6亚烷基-C6-12芳基、-S(＝O)-C1-6烷基；
Rx3分别独立地选自H、卤素、氰基、C1-12烷基或C1-12卤代烷基；
R1选自H、卤素、氰基、C1-12烷基、C1-12卤代烷基、C1-12羟基烷基、C1-12杂烷基、环烷基或杂环烷基，所述C1-12烷基、C1-12卤代烷基、C1-12羟基烷基、环烷基或杂环烷基任选被1个或多个R111取代；
R2选自H、卤素、氰基、C1-12烷基、C1-12卤代烷基、C1-12羟基烷基、C1-12杂烷基、环烷基或杂环烷基，所述C1-12烷基、C1-12卤代烷基、C1-12羟基烷基、环烷基或杂环烷基任选被1个或多个R222取代；
环A选自环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基或杂芳基任选被1个或多个Raa取代；
Raa分别独立地选自H、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基、杂环基、芳基、杂芳基、C1-6烷基(环烷基)、C1-6烷基(杂环基)、C1-6烷基(芳基)或C1-6烷基(杂芳基)，所述C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基，杂环基、芳基、杂芳基、C1-6烷基(环烷基)、C1-6烷基(杂环基)、C1-6烷基(芳基)或C1-6烷基(杂芳基)任选被1个或多个R取代；
R、R’、R111、R222分别独立地选自卤素、氰基、羟基、-OCH3、-S(＝O)CH3、-S(＝O)2CH3、-S(＝O)2NH2、-S(＝O)2NHCH3、-S(＝O)2N(CH3)2、-NH2、-NHCH3、-N(CH3)2、-C(＝O)CH3、-C(＝O)OH、-C(＝O)OCH3、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基或C1-6杂烷基；
所述杂烷基、杂芳基或杂环基包含1、2或3个独立选自O、NH、S、C(＝O)、C(＝O)O、S(＝O)、S(＝O)2和N的杂原子或杂原子团。
在本发明的另一方面，本发明还提出了式(I)所示化合物、其立体异构体或其药学上可接受的盐；
其中，结构单元选自
X1选自N或C(Rx1)；
X2选自N或C(Rx2)；
X3选自N或C(Rx3)；
Y选自N或C(RY)；
Z选自N或C(RZ)；
L选自C1-8烷基、C1-8杂烷基、C2-8烯基或C2-8炔基，所述C1-8烷基、C1-8杂烷基、C2-8烯基或C2-8炔基被1个或多个任选RL取代；
RL分别独立地选自卤素、氰基、-NO2、羟基、-ORa、-NRcRd、-C(＝O)Ra、-C(＝O)ORb、-C(＝O)NRcRd、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基或杂环基；
或两个RL同一个原子上，且连接在一起，形成＝O；
或两个RL在相邻的两个原子上，且连接在一起，形成一个单键；
或两个RL在同一个或不同原子上，且连接在一起形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基或杂芳基任选被1个或多个RLa取代；
RLa分别独立地选自卤素、氰基、-NO2，羟基、-ORa、-NRcRd、-C(＝O)Ra、-C(＝O)ORb、-C(＝O)NRcRd、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基或C1-6杂烷基；
Ra、Rb、Rc和Rd分别独立地选自H、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基、杂环基、芳基、杂芳基、C1-6烷基(环烷基)、C1-6烷基(杂环基)、C1-6烷基(芳基)或C1-6烷基(杂芳基)，所述C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基，杂环基、芳基、杂芳基、C1-6烷基(环烷基)、C1-6烷基(杂环基)、C1-6烷基(芳基)或C1-6烷基(杂芳基)任选被1个或多个R取代；
或Rc和Rd连接在一起形成杂环基，所述杂环基任选被1个或多个R取代；
Rx1、Rx2、RY、RZ、R3分别独立地选自H、卤素、羟基、氰基、-C2-4亚烯基-苯基、-C2-4亚炔基-苯基、-S(＝O)-OH、-S(O)2-OH、-S-(C1-6烷基)、C1-6烷基、-O-C1-6烷基、-C1-6亚烷基-O-C1-6烷基、-O-C1-6亚烷基-O-C1-6烷基、-C0-6亚烷基-NRR’、-C0-6亚烷基-C(＝O)OH、-C0-6亚烷基-C(＝O)-C1-6烷基、-C0-6亚烷基-C(＝O)-NRR’、-C0-6亚烷基-NR-C(＝O)-C1-6烷基、-C0-6亚烷基-S(＝O)2-C1-6烷基、-C0-6亚烷基-S(＝O)(＝NH)-C1-6烷基、-C0-6亚烷基 -S(＝O)2-NRR’、-C0-6亚烷基-NR-S(＝O)2-C1-6烷基、-C0-6亚烷基-NR-S(＝O)2-NRR’、-C0-6亚烷基-P(＝O)O-(C1-6烷基)2、-C0-6亚烷基-P(＝O)-(C1-6烷基)(O-C1-6烷基)、-C0-6亚烷基-P(＝O)-(C1-6烷基)2、-C0-6亚烷基-3至14元环烷基、-C0-6亚烷基-3至14元杂环基、-C0-6亚烷基-5至12元杂芳基、-C0-6亚烷基-C6-12芳基、-C0-6亚烷基-C(＝O)-3至14元杂环基、-C0-6亚烷基-C(＝O)-5至12元杂芳基、-O-C0-6亚烷基-O-C1-6烷基、-O-C0-6亚烷基-3至14元环烷基、-O-C0-6亚烷基-3至14元杂环基、-O-C0-6亚烷基-5至12元杂芳基、-O-C0-6亚烷基-C6-12芳基、-S(＝O)-C1-6烷基；其中，所述C1-6烷基、C0-6亚烷基、C2-4亚烯基、3至14元环烷基、3至14元杂环基、5至12元杂芳基、C6-12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、C1-6烷基、-O-C1-6烷基、-C1-6亚烷基-O-C1-6烷基、-O-C1-6亚烷基-O-C1-6烷基、-C0-6亚烷基-NRR’、-C0-6亚烷基-C(＝O)OH、-C0-6亚烷基-C(＝O)-C1-6烷基、-C0-6亚烷基-C(＝O)-NRR’、-C0-6亚烷基-NR-C(＝O)-C1-6烷基、-C0-6亚烷基-S(＝O)2-C1-6烷基、-C0-6亚烷基-S(＝O)2-NRR’、-C0-6亚烷基-NR-S(＝O)2-C1-6烷基、-C0-6亚烷基-NR-S(＝O)2-NRR’、-C0-6亚烷基-P(＝O)O-(C1-6烷基)2、-C0-6亚烷基-P(＝O)-(C1-6烷基)(O-C1-6烷基)、-C0-6亚烷基-P(＝O)-(C1-6烷基)2、-C0-6亚烷基-3至14元环烷基、-C0-6亚烷基-3至14元杂环基、-C0-6亚烷基-5至12元杂芳基、-C0-6亚烷基-C6-12芳基、-C0-6亚烷基-C(＝O)-3至14元杂环基、-C0-6亚烷基-C(＝O)-5至12元杂芳基、-O-C0-6亚烷基-O-C1-6烷基、-O-C0-6亚烷基-3至14元环烷基、-O-C0-6亚烷基-3至14元杂环基、-O-C0-6亚烷基-5至12元杂芳基、-O-C0-6亚烷基-C6-12芳基、-S(＝O)-C1-6烷基；
Rx3分别独立地选自H、卤素、氰基、C1-12烷基或C1-12卤代烷基；
R1选自H、卤素、氰基、C1-12烷基、C1-12卤代烷基、C1-12羟基烷基、C1-12杂烷基、环烷基或杂环烷基，所述C1-12烷基、C1-12卤代烷基、C1-12羟基烷基、环烷基或杂环烷基任选被1个或多个R111取代；
R2选自H、卤素、氰基、C1-12烷基、C1-12卤代烷基、C1-12羟基烷基、C1-12杂烷基、环烷基或杂环烷基，所述C1-12烷基、C1-12卤代烷基、C1-12羟基烷基、环烷基或杂环烷基任选被1个或多个R222取代；
环A选自环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基或杂芳基任选被1个或多个Raa取代；
Raa分别独立地选自H、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基、杂环基、芳基、杂芳基、C1-6烷基(环烷基)、C1-6烷基(杂环基)、C1-6烷基(芳基)或C1-6烷基(杂芳基)，所述C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基，杂环基、芳基、杂芳基、C1-6烷基(环烷基)、C1-6烷基(杂环基)、C1-6烷基(芳基)或C1-6烷基(杂芳基)任选被1个或多个R取代；
R、R’、R111、R222分别独立地选自卤素、氰基、羟基、-OCH3、-S(＝O)CH3、-S(＝O)2CH3、-S(＝O)2NH2、-S(＝O)2NHCH3、-S(＝O)2N(CH3)2、-NH2、-NHCH3、-N(CH3)2、-C(＝O)CH3、-C(＝O)OH、-C(＝O)OCH3、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基或C1-6杂烷基；
所述杂烷基、杂芳基或杂环基包含1、2或3个独立选自O、NH、S、C(＝O)、C(＝O)O、S(＝O)、S(＝O)2和N的杂原子或杂原子团。
在本发明的一些实施例中，式(I)所示化合物具有式(Ia)所示的结构；
其中，X1、X2、X3、Y、L、R1、R2、R3、环A如本发明所定义。
在本发明的一些实施例中，式(Ia)所示化合物具有式(Iaa)所示的结构；
其中，RZ1、RZ2分别独立地选自C1-6烷基，L、R1、R2、R3、环A如本发明所定义。
在本发明的一些实施例中，式(Iaa)所示化合物具有式(Iaaa)所示的结构；
其中，RZ1、RZ2分别独立地选自C1-6烷基，L、R1、R2如本发明所定义。
在本发明的一些实施例中，式(Iaaa)所示化合物具有式(Iaaa-1)或式(Iaaa-2)所示的结构；
其中，RZ1、RZ2分别独立地选自C1-6烷基，Y、L、R1、R2如本发明所定义。
在本发明的一些实施例中，式(Iaaa)所示化合物具有式(Iaaaa)所示的结构；
其中，RZ1、RZ2分别独立地选自C1-6烷基；
RZ3分别独立地选自H、C1-6烷基或C3-12环烷基，所述C1-6烷基或C3-12环烷基任选被1、2或3个卤素或OH取代；
Lx选自L2A-L3A-L4A或L；
所述L2A、L3A或L4A分别独立地选自单键、-O-、-C(＝O)-、-S-、-S(＝O)-、-S(＝O)2-、任选取代的C1-3烷基、任选取代的环烷基、任选取代的杂环基、任选取代的杂芳基、任选取代的芳基、-NRL4-、
RL4选自H、任选取代的C1-6烷基、任选取代的C1-6卤代烷基、任选取代的环烷基或任选取代的杂环基；
RL5选自H、任选取代的C1-6烷基、任选取代的C1-6卤代烷基、任选取代的环烷基或任选取代的杂环基；
L、Y、R1、R2如本发明所定义。
在本发明的一些实施例中，式(Iaaaa)所示化合物具有式(Iaaaa-1)或式(Iaaaa-2)所示的结构；
其中，RZ1、RZ2、RZ3、LX、R1、R2如本发明所定义。
在本发明的一些实施例中，式(Ia)所示化合物具有式(Iab)所示的结构；
其中，Y、L、R1、R2、R3、环A如本发明所定义。
在本发明的一些实施例中，式(Iab)所示化合物具有式(Iabb)所示的结构；
其中，L、R1、R2如本发明所定义。
在本发明的一些实施例中，式(Iabb)所示化合物具有式(Iabb-1)或式(Iabb-2)所示的结构；
其中，L、R1、R2如本发明所定义。
在本发明的一些实施例中，式(Iabb)所示化合物具有式(Iabbb)所示的结构；
其中，RZ3分别独立地选自H、C1-6烷基或C3-12环烷基，所述C1-6烷基或C3-12环烷基任选被1、2或3个卤素或OH取代，
Lx选自L2A-L3A-L4A或L；
所述L2A、L3A或L4A分别独立地选自单键、-O-、-C(＝O)-、-S-、-S(＝O)-、-S(＝O)2-、任选取代的C1-3烷基、任选取代的环烷基、任选取代的杂环基、任选取代的杂芳基、任选取代的芳基、-NRL4-、
RL4选自H、任选取代的C1-6烷基、任选取代的C1-6卤代烷基、任选取代的环烷基或任选取代的杂环基；
RL5选自H、任选取代的C1-6烷基、任选取代的C1-6卤代烷基、任选取代的环烷基或任选取代的杂环基；
Y、R1、R2如本发明所定义。
在本发明的一些实施例中，式(Iabbb)所示化合物具有式(Iabbb-1)或式(Iabbb-2)所示的结构；
其中，RZ3、LX、R1、R2如本发明所定义。在本发明的一些实施例中，Rc分别独立地选自H、C1-3烷基或C3-6环烷基，所述C1-3烷基或C3-6环烷基任选被1、2或3个卤素或OH取代，其余变量如本发明所定义。
在本发明的一些实施例中，RZ3分别独立地选自H、甲基、乙基、环丙基、CH2CF3或CH2CHF2其余变量如本发明所定义。
在本发明的一些实施例中，RZ1、RZ2分别独立地选自C1-3烷基，其余变量如本发明所定义。
在本发明的一些实施例中，RZ1、RZ2分别独立地选自甲基或乙基，其余变量如本发明所定义。
在本发明的一些实施例中，-L-选自-L1A-L2A-L3A-L4A-L5A-，所述L1A、L2A、L3A、L4A或L5A分别独立地选自单键、-O-、-C(＝O)-、-S-、-S(＝O)-、-S(＝O)2-、任选取代的C1-3烷基、任选取代的环烷基、任选取代的杂环基、任选取代的杂芳基、任选取代的芳基、-NRL4-、RL4选自H、任选取代的C1-6烷基、任选取代的C1-6卤代烷基、任选取代的环烷基或任选取代的杂环基；RL5选自H、任选取代的C1-6烷基、任选取代的C1-6卤代烷基、任选取代的环烷基或任选取代的杂环基，其余变量如本发明所定义。
在本发明的一些实施例中，所述L1A、L2A、L3A、L4A或L5A分别独立地选自单键、-O-、-C(＝O)-、-S-、-S(＝O)-、-S(＝O)2-、任选取代的C1-3烷基、任选取代的C3-6环烷基、任选取代的3至6元杂环基、任选取代的5至12元杂芳基、任选取代的C6-12芳基、-NRL4-、其余变量如本发明所定义。
在本发明的一些实施例中，所述L1A、L2A、L3A、L4A或L5A分别独立地选自单键、-O-、-C(＝O)-、-S-、 -S(＝O)-、-S(＝O)2-、C1-3烷基、C3-6环烷基、3至6元杂环基、5至6元杂芳基、苯基、-NRL4-、所述C1-3烷基、C3-6环烷基、3至6元杂环基、5至6元杂芳基、苯基、-NRL4-、任选被1、2、3或4个RL6取代，RL4选自H、C1-6烷基、C1-6卤代烷基、C3-6环烷基或3至6元杂环基；RL5选自H、C1-6烷基、C1-6卤代烷基、C3-6环烷基或3至6元杂环基；RL6分别独立地选自C1-6烷基、C3-6环烷基、3至6元杂环基、5至6元杂芳基或苯基，所述C1-6烷基、C3-6环烷基、3至6元杂环基、5至6元杂芳基或苯基任选被1、2、3或4个卤素、0H、CN、NH2或C1-6烷基取代，或两个RL6在同一个碳原子上，且连在一起，形成C3-6环烷基或3至6元杂环基，所述C3-6环烷基或3至6元杂环基任选被1、2、3或4个卤素、0H、CN、NH2或C1-6烷基取代，其余变量如本发明所定义。
在本发明的一些实施例中，所述L1A、L2A、L3A、L4A或L5A分别独立地选自单键、-O-、-C(＝O)-、任选取代的C1-3烷基、任选取代的C3-6环烷基、任选取代的5至6元杂芳基、任选取代的苯基或-NRL4-，其余变量如本发明所定义。
在本发明的一些实施例中，所述L1A、L2A、L3A、L4A或L5A分别独立地选自单键、-O-、-C(＝O)-、任选被卤素取代的C1-3烷基、任选取代的C3-6环烷基、任选取代的5至6元杂芳基或-NRL4-，其余变量如本发明所定义。
在本发明的一些实施例中，所述L1A、L2A、L3A、L4A或L5A分别独立地选自单键、-O-、-C(＝O)-、C1-3烷基、C1-3卤代烷基、环丙基、环丁基、环戊基、环烷基、咪唑基或-NRL4-，其余变量如本发明所定义。
在本发明的一些实施例中，RL4选自H、任选取代的C1-6烷基、任选取代的C1-6卤代烷基或任选取代的环烷基，其余变量如本发明所定义。
在本发明的一些实施例中，RL4选自H、任选取代的C1-6烷基，其余变量如本发明所定义。
在本发明的一些实施例中，RL4选自H、任选取代的C1-3烷基，其余变量如本发明所定义。
在本发明的一些实施例中，-L-选自如下基团：
-(O)m2-(CR13R14)m1-(NR12)m3-、
-(NR11)m2-(CR13R14)m1-(NR12)m3-、
-(O)m2-(CR13R14)m5-(C3-7环烷基)m4-(CR13R14)m6-(NR12)m3-、
-(NR11)m2-(CR13R14)m5-(C3-7环烷基)m4-(CR13R14)m6-(NR12)m3-、
-(O)m2-(CR13R14)m5-(3至7元杂环基)m4-(CR13R14)m6-(NR12)m3-、
-(O)m2-(CR13R14)m5-(3至7元杂环基)m4-(CR13R14)m6-NR10C(＝O)-(CR13R14)m6-(NR12)m3-、
-(NR11)m2-(CR13R14)m5-(3至7元杂环基)m4-(CR13R14)m6-(NR12)m3-、
-(O)m2-(CR13R14)m5-(3至6元杂芳基)m4-(CR13R14)m6-(NR12)m3-、
-(NR11)m2-(CR13R14)m5-(3至6元杂芳基)m4-(CR13R14)m6-(NR12)m3-、
-(O)m2-(CR13R14)m5-NR10-(CR13R14)m6-(NR12)m3-、
-(NR11)m2-(CR13R14)m5-NR10-(CR13R14)m6-(NR12)m3-、
-(O)m2-(CR13R14)m5-NR10C(＝O)-(CR13R14)m6-(NR12)m3-、
-(NR11)m2-(CR13R14)m5-NR10C(＝O)-(CR13R14)m6-(NR12)m3-、
-(O)m2-(CR13R14)m5-C(＝O)NR10-(CR13R14)m6-(NR12)m3-、
-(O)m2-(CR13R14)m5-C(＝O)NR10-(CR13R14)m6-(O)m2-(CR13R14)m5、
-(NR11)m2-(CR13R14)m5-C(＝O)NR10-(CR13R14)m6-(NR12)m3-、
-(O)m2-(CR13R14)m5-O-(CR13R14)m6-(NR12)m3-、
-(NR11)m2-(CR13R14)m5-O-(CR13R14)m6-(NR12)m3-、
-(O)m2-(CR13R14)m5-OC(＝O)-(CR13R14)m6-(NR12)m3-、
-(NR11)m2-(CR13R14)m5-OC(＝O)-(CR13R14)m6-(NR12)m3-、
-(O)m2-(CR13R14)m5-C(＝O)O-(CR13R14)m6-(NR12)m3-、
-(NR11)m2-(CR13R14)m5-C(＝O)O-(CR13R14)m6-(NR12)m3-、
-(O)m2-(CR13R14)m5-(CH＝CH)m7-(CR13R14)m6-(NR12)m3-、
-(NR11)m2-(CR13R14)m5-(CH＝CH)m7-(CR13R14)m6-(NR12)m3-；
R10分别独立地选自H、C1-6烷基、-C3-7环烷基、-C(＝O)-C1-6烷基、-C(＝O)-C1-4烷基-C1-6烷氧基、-C(＝O)-C3-7环烷基、-C1-4烷基-羟基、-C1-4烷基-氰基、-C1-4烷基-C1-6烷氧基、-C1-4烷基-NHC(＝O)-C1-6烷基、-C1-4烷基-NHC(＝O)-C1-4烷基-C1-6烷氧基、-C1-4烷基-NHC(＝O)-C3-7环烷基或-C1-4烷基-NRR’；
R、R’各自独立地为氢、C1-6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；
3至7元杂环基分别独立地具有1、2或3个独立地选自氮、氧和硫的杂原子；所述C3-7环烷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；
C3-7环烷基分别独立地选自未取代的或被1、2、3、4或5个选自S1组的基团所取代；
R11分别独立地选自H、C1-6烷基、C3-7环烷基或3至7元杂环基，所述C1-6烷基、C3-7环烷基或3至7元杂环基任选被1、2、或3个卤素、CN、OH或C1-6烷基取代；
R12分别独立地选自H、C1-6烷基、C3-7环烷基或3至7元杂环基，所述C1-6烷基、C3-7环烷基或3至7元杂环基任选被1、2、或3个卤素、CN、OH或C1-6烷基取代；
R13分别独立地选自H、氰基、羟基、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-C3-7环烷基、-C0-6亚烷基-NRR’、-C1-6亚烷基-羟基或-C0-6亚烷基-氰基；
R14分别独立地选自H、氰基、羟基、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-C3-7环烷基、-C0-6亚烷基-NRR’、-C1-6亚烷基-羟基或-C0-6亚烷基-氰基；
或R13、R14连接在一起，并与其相连的同一个碳原子或者不同的碳原子共同形成3-6元杂环基或C3-6环烷基，所述3-6元杂环基或C3-6环烷基任选被1、2、3、4或5个选自S1组的基团所取代；
m1分别独立地为1、2、3、4、5或6；
m2分别独立地为0或1；
m3分别独立地为0或1；
m4分别独立地为1或2；
m5分别独立地为0、1、2、3、4、5或6；
m6分别独立地为0、1、2、3、4、5或6；
m7分别独立地为1或2，其余变量如本发明所定义。
在本发明的一些实施例中，R13分别独立地选自H、氰基、羟基、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-C3-7环烷基、-C0-6亚烷基-NRR’、-C1-6亚烷基-羟基或-C0-6亚烷基-氰基，其余变量如本发明所定义。
在本发明的一些实施例中，R13分别独立地选自H、氰基、羟基、卤素、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、卤代C1-3烷氧基、-5至6元环烷基、-C0-3亚烷基-NRR’、-C1-3亚烷基-羟基或-C0-3亚烷基-氰基，其余变量如本发明所定义。
在本发明的一些实施例中，R13分别独立地选自H、F、Cl、Br、I、甲基或乙基，其余变量如本发明所定义。
在本发明的一些实施例中，R14分别独立地选自H、氰基、羟基、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-C3-7环烷基、-C0-6亚烷基-NRR’、-C1-6亚烷基-羟基或-C0-6亚烷基-氰基，其余变量如本发明所定义。
在本发明的一些实施例中，R14分别独立地选自H、氰基、羟基、卤素、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、卤代C1-3烷氧基、-5至6元环烷基、-C0-3亚烷基-NRR’、-C1-3亚烷基-羟基或-C0-3亚烷基-氰基，其余变量如本发明所定义。
在本发明的一些实施例中，R14分别独立地选自H、F、Cl、Br、I、甲基或乙基，其余变量如本发明所定义。
在本发明的一些实施例中，R11分别独立地选自H、C1-3烷基、C3-6环烷基或3至6元杂环基C1-3烷基、C3-6环烷基或3至6元杂环基任选被1、2、或3个卤素、CN、OH或C1-6烷基取代，其余变量如本发明所定义。
在本发明的一些实施例中，R12分别独立地选自H、C1-3烷基、C3-6环烷基或3至6元杂环基C1-3烷基、C3-6环烷基或3至6元杂环基任选被1、2、或3个卤素、CN、OH或C1-6烷基取代，其余变量如本发明所定义。
在本发明的一些实施例中，R11分别独立地选自H、甲基、乙基、环丙基、CH2CF3或CH2CHF2，其余变量如本发明所定义。
在本发明的一些实施例中，R12分别独立地选自H、甲基、乙基、环丙基、CH2CF3或CH2CHF2，其余变量如本发明所定义。
在本发明的一些实施例中，R13分别独立地选自H、氰基、羟基、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-C3-7环烷基、-C0-6亚烷基-NRR’、-C1-6亚烷基-羟基或-C0-6亚烷基-氰基，其余变量如本发明所定义。
在本发明的一些实施例中，R13分别独立地选自H、氰基、羟基、卤素或C1-6烷基，其余变量如本发明所定义。
在本发明的一些实施例中，R14分别独立地选自H、氰基、羟基、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-C3-7环烷基、-C0-6亚烷基-NRR’、-C1-6亚烷基-羟基或-C0-6亚烷基-氰基，其余变量如本发明所定义。
在本发明的一些实施例中，R14分别独立地选自H、氰基、羟基、卤素或C1-6烷基，其余变量如本发明所定义。
在本发明的一些实施例中，R13、R14连接在一起，并与其相连的同一个碳原子或者不同的碳原子共同形成3-6元杂环基或C3-6环烷基，所述3-6元杂环基或C3-6环烷基任选被1、2个3卤素或OH取代，其余变量如本发明所定义。
在本发明的一些实施例中，R13、R14连接在一起，并与其相连的同一个碳原子共同形成C3-6环烷基，所述C3-6环烷基任选被1、2个3卤素或OH取代，其余变量如本发明所定义。
在本发明的一些实施例中，R13、R14连接在一起，并与其相连的同一个碳原子共同形成C3-6环烷基，其余变量如本发明所定义。
在本发明的一些实施例中，-L-选自如下基团：
-(O)m2-(CR13R14)m5-(3至7元杂环基)m4-(CR13R14)m6-NR10C(＝O)-(CR13R14)m6-(NR12)m3-、
-(O)m2-(CR13R14)m5-C(＝O)NR10-(CR13R14)m6-(NR12)m3-、
-(O)m2-(CR13R14)m5-C(＝O)NR10-(CR13R14)m6-(O)m2-(CR13R14)m5，其余变量如本发明所定义。
在本发明的一些实施例中，-L-选自如下基团：
-(3至7元杂环基)m4-(CR13R14)m6-NR10C(＝O)-、
-C(＝O)NR10-(CR13R14)m6-、
-C(＝O)NR10-(CR13R14)m6-(O)m2-(CR13R14)m5，其余变量如本发明所定义。
在本发明的一些实施例中，L为-NR11-(CR13R14)m1-NR12-；R11、R12独立地为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-O-(CR13R14)m1-NR12-；R12为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-NR11-(CR13R14)m1-；R11为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-(CR13R14)m1-NR12-；R12为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-(CR13R14)m1-；各个R13、R14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。
在本发明的一些实施例中，L为-NR11-(CR13R14)m5-C3-7环烷基-(CR13R14)m6-NR12-；R11、R12独立地为氢或甲基；各个R13、R14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C3-7环烷基为未取代的或被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。
在本发明的一些实施例中，L为-O-(CR13R14)m5-C3-7环烷基-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14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C3-7环烷基为未取代的或被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。
在本发明的一些实施例中，L为-(CR13R14)m5-C3-7环烷基-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14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C3-7环烷基为未取代的或被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C3-7环烷基为环丁基、环戊基或环己基，其余变量如本发明所定义。
在本发明的一些实施例中，L为-NR11-(CR13R14)m5-3至7元杂环-(CR13R14)m6-NR12；R11、R12独立地为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-O-(CR13R14)m5-3至7元杂环-(CR13R14)m6-NR12；R12为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-(CR13R14)m5-3至7元杂环-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-NR11-(CR13R14)m5-NR10-(CR13R14)m6-NR12-；R11、R12独立地为氢或甲基；各个R13、R14各自独立地为氢、卤素或甲基；R10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。
在本发明的一些实施例中，L为-O-(CR13R14)m5-NR10-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14各自独立地为氢、卤素或甲基；R10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。
在本发明的一些实施例中，L为-(CR13R14)m5-NR10-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14各自独立地为氢、卤素或甲基；R10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。
在本发明的一些实施例中，L为-NR11-(CR13R14)m5-NR10C(＝O)-(CR13R14)m6-NR12-；R11、R12独立地为氢或甲基；各个R13、R14各自独立地为氢、卤素或甲基；R10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。
在本发明的一些实施例中，L为-O-(CR13R14)m5-NR10C(＝O)-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14各自独立地为氢、卤素或甲基；R10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。
在本发明的一些实施例中，L为-(CR13R14)m5-NR10C(＝O)-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14各自独立地为氢、卤素或甲基；R10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。
在本发明的一些实施例中，L为-NR11-(CR13R14)m5-C(＝O)NR10-(CR13R14)m6-NR12-；R11、R12独立地为氢或甲基；各个R13、R14各自独立地为氢、卤素或甲基；R10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。
在本发明的一些实施例中，L为-O-(CR13R14)m5-C(＝O)NR10-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14各自独立地为氢、卤素或甲基；R10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。
在本发明的一些实施例中，L为-(CR13R14)m5-C(＝O)NR10-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14各自独立地为氢、卤素或甲基；R10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。
在本发明的一些实施例中，L为-NR11-(CR13R14)m5-O-(CR13R14)m6-NR12-；R11、R12独立地为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-O-(CR13R14)m5-O-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-(CR13R14)m5-O-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-NR11-(CR13R14)m5-OC(＝O)-(CR13R14)m6-NR12-；R11、R12独立地为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-O-(CR13R14)m5-OC(＝O)-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-(CR13R14)m5-OC(＝O)-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-NR11-(CR13R14)m5-C(＝O)O-(CR13R14)m6-NR12-；R11、R12独立地为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-O-(CR13R14)m5-C(＝O)O-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-(CR13R14)m5-C(＝O)O-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-NR11-(CR13R14)m5-CH＝CH-(CR13R14)m6-NR12-；R11、R12独立地为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-O-(CR13R14)m5-CH＝CH-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，L为-(CR13R14)m5-CH＝CH-(CR13R14)m6-NR12-；R12为氢或甲基；各个R13、R14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。
在本发明的一些实施例中，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。
在本发明的一些实施例中，所述C3-7环烷基为环丙基、环丁基、环戊基或环己基，其余变量如本发明所定义。
在本发明的一些实施例中，所述3至7元杂环基为氮杂环丁基、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。
在本发明的一些实施例中，L选自如下结构之一：
其余变量如本发明所定义。
在本发明的一些实施例中，L选自 上端与环B连接，下端与V连接，其余变量如本发明所定义。
在本发明的一些实施例中，L选自其余变量如本发明所定义。
在本发明的一些实施例中，Rx1选自H、卤素、羟基、氰基、-C0-3亚烷基-P(O)-(C1-3烷基)2、-C0-3亚烷基-S(O)(＝NH)-C1-3烷基或-C0-3亚烷基-S(O)2-C1-3烷基，其余变量如本发明所定义。
在本发明的一些实施例中，Rx1选自H、F、Cl、Br、I、羟基、氰基、-P(O)-(CH3)2、-P(O)-(CH2CH3)2、-S(O)2-CH3、-S(O)(＝NH)-CH3或-S(O)2-CH2CH3，其余变量如本发明所定义。
在本发明的一些实施例中，Rx1选自H、F、Cl、Br、I、-P(O)-(CH3)2或-S(O)2-CH3，其余变量如本发明所定义。
在本发明的一些实施例中，R1选自H、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6杂烷基、C3-6环烷基或3至6元杂环烷基，所述C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6杂烷基、C3-6环烷基或3至6元杂环烷基任选被1个、2个或3个R111取代，其余变量如本发明所定义。
在本发明的一些实施例中，R1选自H、卤素、氰基、C1-3烷基、C1-3卤代烷基、C1-3羟基烷基、C1-3杂烷基、C5-6环烷基或5至6元杂环烷基，所述C1-3烷基、C1-3卤代烷基、C1-3羟基烷基、C1-3杂烷基、C5-6环烷基或5至6元杂环烷基任选被1个、2个或3个R111取代，其余变量如本发明所定义。
在本发明的一些实施例中，R1选自H、卤素、氰基、C1-6烷基或C1-6卤代烷基，所述C1-6烷基或C1-6卤代烷基任选被1个、2个或3个R111取代，其余变量如本发明所定义。
在本发明的一些实施例中，R1选自H、卤素、氰基、C1-3烷基或C1-3卤代烷基，所述C1-3烷基、C1-3卤代烷基任选被1个、2个或3个R111取代，其余变量如本发明所定义。
在本发明的一些实施例中，R1选自H或C1-3卤代烷基，其余变量如本发明所定义。
本发明的一些实施例中，R1选自H或CF3，其余变量如本发明所定义。
本发明的一些实施例中，R1选自CF3，其余变量如本发明所定义。
在本发明的一些实施例中，R2选自H、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6杂烷基、C3-6环烷基或3至6元杂环烷基，所述C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6杂烷基、C3-6环烷基或3至6元杂环烷基任选被1个、2个或3个R222取代，其余变量如本发明所定义。
在本发明的一些实施例中，R2选自H、卤素、氰基、C1-6烷基或C1-6卤代烷基，所述C1-6烷基或C1-6卤代烷基任选被1个、2个或3个R222取代，其余变量如本发明所定义。
在本发明的一些实施例中，R2选自H、卤素、氰基、C1-3烷基、C1-3卤代烷基、C1-3羟基烷基、C1-3杂烷基、C5-6环烷基或5至6元杂环烷基，所述C1-3烷基、C1-3卤代烷基、C1-3羟基烷基、C1-3杂烷基、C5-6环烷基或5至6元杂环烷基任选被1个、2个或3个R222取代，其余变量如本发明所定义。
在本发明的一些实施例中，R2选自H、卤素、氰基、C1-3烷基或C1-3卤代烷基，所述C1-3烷基或C1-3卤代 烷基任选被1个、2个或3个R222取代，其余变量如本发明所定义。
在本发明的一些实施例中，R2选自H或C1-3卤代烷基，其余变量如本发明所定义。
在本发明的一些实施例中，R2选自H或CF3，其余变量如本发明所定义。
本发明的一些实施例中，R2选自H，其余变量如本发明所定义。
在本发明的一些实施例中，环A选自C3-12环烷基、3至12元杂环基、C6-12芳基或5至12元杂芳基，所述C3-12环烷基、3至12元杂环基、C6-12芳基或5至12元杂芳基任选被1个或多个Raa取代，其余变量如本发明所定义。
在本发明的一些实施例中，环A选自C3-12环烷基或3-12元杂环基，所述C3-12环烷基或3至12元杂环基任选被1个或多个Raa取代，其余变量如本发明所定义。
在本发明的一些实施例中，环A选自C3-9环烷基、5-6元杂环基、苯基或5至6元杂芳基，所述C3-9环烷基、5至6元杂环基、苯基或5至6元杂芳基任选被1个、2个或3个Raa取代，其余变量如本发明所定义。
在本发明的一些实施例中，环A选自C3-6环烷基或5至6元杂环基，所述C3-6环烷基或5至6元杂环基任选被1个、2个或3个Raa取代，其余变量如本发明所定义。
在本发明的一些实施例中，环A选自环丁基、环戊基、环己基、哌啶基、哌嗪基、四氢吡咯基、吡唑基或咪唑基，所述环丁基、环戊基、环己基、哌啶基、哌嗪基、四氢吡咯基、吡唑基或咪唑基任选被1个、2个或3个Raa取代，其余变量如本发明所定义。
在本发明的一些实施例中，环A选自C3-6环烷基或5至6元杂环基，其余变量如本发明所定义。
在本发明的一些实施例中，环A选自C3-6环烷基，其余变量如本发明所定义。
在本发明的一些实施例中，环A选自C5-6环烷基，其余变量如本发明所定义。
在本发明的一些实施例中，环A选自环丁基、环戊基或环己基，所述环丁基、环戊基或环己基任选被1个、2个或3个Raa取代，其余变量如本发明所定义。
在本发明的一些实施例中，环A选自环丁基、环戊基或环己基，其余变量如本发明所定义。
在本发明的一些实施例中，环A选自其余变量如本发明所定义。
在本发明的一些实施例中，环A选自其余变量如本发明所定义。
在本发明的一些实施例中，环A选自 其余变量如本发明所定义。
在本发明的一些实施例中，环A选自其余变量如本发明所定义。
在本发明的另一方面，本发明还提出了下式化合物、其立体异构体或其药学上可接受的盐，其选自


在本发明的另一方面，本发明还提出了一种化合物、其立体异构体或其药学上可接受的盐，其具有表1或表2中的结构之一。
表1
表2

在本发明的另一方面，本发明还提出了一种药物组合物。在本发明的一些实施例中，所述药物组合物包含前面所述化合物、其立体异构体或其药学上可接受的盐；以及，药学可接受的载体。
在本发明的另一方面，本发明还提出了式(II)所述化合物、其立体异构体或其药学上可接受的盐或所述的药物组合物制备预防和/或治疗CDK7相关疾病的药物中的用途。
在本发明的一些实施例中，所述CDK7相关疾病为治增殖性疾病(例如肿瘤或癌症)、传染性疾病、免疫疾病、自身免疫疾病或炎性疾病。
在本发明的另一方面，本发明还提出了式(II)所述化合物、其立体异构体或其药学上可接受的盐或前面所述的药物组合物制备CDK7抑制剂中的用途。
在本发明的另一方面，本发明还提出了式(II)所述化合物、其立体异构体或其药学上可接受的盐或所述的药物组合物在预防和/或治疗CDK7相关疾病中的用途。
在本发明的另一方面，本发明还提出了用于预防和/或治疗CDK7相关疾病的式(II)所述化合物、其立体异构体或其药学上可接受的盐或所述的药物组合物。
在本发明的一些实施例中，所述CDK7相关疾病为治增殖性疾病(例如肿瘤或癌症)、传染性疾病、免疫疾病、自身免疫疾病或炎性疾病。
有益效果
本发明具有如下优势至少之一：
1、本发明的化合物结构新颖；
2、本发明的化合物具有较好的CDK7抑制活性；
3、本发明的化合物具有较高的透膜性，有助于解决现有技术化合物存在的口服吸收低渗透性问题；
4、本发明的化合物具有较低的外排率(Efflux Ratio)，有助于解决现有技术化合物存在的高外排性的问题。
术语定义与说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当被理解为本申请说明书和/或权利要求书记载的范围内。
本申请通式定义中的术语“任选的”(或“任选地”、“任选”)意味着被零个、一个或多个取代基所取代的情形，例如“任选被一个或多个R取代”意味着可以不被R取代(无取代)或可以选择被一个、两个、三个或者更多个R取代。
“多个”表示二个、三个、四个或者更多个。
除非另有说明，本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如，数值范围“1-12”相当于记载了数值范围“1-12”中的每一个整数数值，即1、2、3、4、5、6、7、8、9、10、11、12。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如当L选自单键时，环B和O直接相连。
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，例如中连接基团M选自时，既可以按与从左往右的读取顺序相同的方向连接环己烷基和苯基构成也可以按照与从左往右的读取顺序相反的方向连接环己烷基和苯基构成所述连接基团、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。
卤素或“卤代”意指氟、氯、溴、或碘。
术语“烷基”意指含有1-12个碳原子的直链或支链饱和烃。术语“C1-6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。其可以是一价(如CH3)、二价(-CH2-)或者多价(如次)。
术语“羟基烷基”意指被一个或多个-OH基团取代的烷基基团。其中提到的烷基具有上述烷基相同定义。 羟基烷基基团的实例包括HO-CH2-、HO-CH2CH2-和CH2-CH(OH)-。
术语“卤代烷基”意指被一个或多个卤素取代的烷基基团。其中提到的烷基具有上述烷基相同定义。卤代烷基基团的实例包括但不限于三氟甲基、二氟甲基、五氟乙基、三氯甲基等。
术语“烯基”意指含有2-12个碳原子的直链或支链不饱和烃。“烯基”基团在链中含有至少一个双键。烯基基团的双键可以是未缀合的或与另一个不饱和基团缀合的。术语“C2-6烯基”表示具有2、3、4、5或6个碳原子的直链或支链不饱和烃。烯基基团的实例包括乙烯基、丙烯基、正丁烯基、异丁烯、戊烯基、或己烯基。烯基基团可以是未取代的或取代的，并且可以是直链或支链的。
术语“炔基”意指含有2-12个碳原子的直链或支链不饱和烃。术语“C2-6炔基”表示具有2、3、4、5或6个碳原子的直链或支链不饱和烃。“炔基”基团在链中含有至少一个三键。炔基基团的实例包括乙炔基、炔丙基、正丁炔基、异丁炔基、戊炔基、或己炔基。炔基基团可以是未取代的或取代的。
术语“杂烷基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烷基原子团或其组合物。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂烷基为C1-6杂烷基；在另一些实施方案中，所述杂烷基为C1-3杂烷基。杂原子或杂原子团可以位于杂烷基的任何内部位置，包括该烷基与分子其余部分的连接位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。杂烷基的实例包括但不限于-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH2(CH3)2、-CH2-CH2-O-CH3、-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)(CH2CH3)、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH2(CH3)2、-CH2-SCH2-CH3、-CH2-CH2、-S(＝O)-CH3、-CH2-CH2-S(＝O)2-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。
术语“环烷基”意指含有3-18个碳原子的单环或多环饱和或部分不饱和非芳香族碳环。在一些实施例中，环烷基是饱和的非芳香族碳环。环烷基基团的实例包括而不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、降冰片烷基(norboranyl)、降冰片烯基(norborenyl)、双环[2.2.2]辛基、或双环[2.2.2]辛烯基及其衍生物。(C3-C8)环烷基是含有3个与8个之间的碳原子的环烷基基团。环烷基基团可以稠合(例如，十氢化萘)或桥接(例如，降冰片烷(norbornane))。术语“C3-12环烷基”应理解为表示饱和的一价单环、二环(如稠环、桥环、螺环)烃环或三环烷烃，其具有3～12个碳原子，“C3-10环烷基”，更优选“C3-8环烷基”。术语“C3-12环烷基”应理解为表示饱和的一价单环、双环(如桥环、螺环)烃环或三环烷烃，其具有3、4、5、6、7、8、9、10、11或12个碳原子。所述C3-12环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如龙脑基、吲哚基、六氢吲哚基、四氢萘基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6,6-二甲基二环[3.1.1]庚基、2,6,6-三甲基二环[3.1.1]庚基、二环[2.2.2]辛基、2,7-二氮杂螺[3,5]壬烷基、2,6-二氮杂螺[3,4]辛烷基，或者是三环烃基如金刚烷基。
术语“杂环基”或“杂环烷基”意指含有碳和至少一个选自氧、氮或硫(O、N或S)的杂原子的饱和的或部分饱和的单环或多环的环，并且其中在环碳或杂原子之间没有共用的非定域的n电子(芳香性)。杂环烷基环结构可以被一个或多个取代基取代。这些取代基本身可以是任选地取代的。杂环烷基环的实例包括但不限于氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、吡咯烷基、噁唑啉基、噁唑烷基、噻唑啉基、噻唑烷基、吡喃基、噻喃基、四氢吡喃基、二噁啉基、哌啶基、吗啉基、硫代吗啉基、硫代吗啉基S-氧化物、硫代吗啉基S-二氧化物、哌嗪基、氮杂基、氧杂基、二氮杂基、托烷基、噁唑烷酮基、1,4-二噁烷基、二氢呋喃基、1,3-二氧戊环基、咪唑烷基、咪唑啉基、二硫戊环基、和同托烷基(homotropanyl)。杂环基可以是指饱和的或不饱和的具有3至14元的非芳族的环或环系，例如，其是3-、4-、5-、6-或7-元的单环、7-、8-、9-、10-、11-或12-元的二环(如稠环、桥环、螺环)或者10-、11-、12-、13-或14-元的三环环系，并且含有至少一个，例如1、2、3、4、5个或更多个选自O、S和N的杂原子，其中N和S还可以任选被氧化成各种氧化状态，以形成氮氧化物、-S(O)-或-S(O)2-的状态。除非另外说明，杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。在一些实施方案中，杂环基为5-12个原子组成的杂环基；在另一些实施方案中，杂环基为5-8个原子组成的杂环基；在又一些实施方案中，杂环基为5-7个原子组成的杂环基；还在一些实施方案中，杂环基为5-6个原子组成的杂环基。杂环基还可以是双环杂环基；在一些实施方案中，杂环基是7-12个原子组成的双环杂环基；在另一些实施方案中，杂环基是7-10个原子组成的双环杂环基；在又一些实施方案中，杂环基是8-10个原子组成的双环杂环基。
术语“芳基”意指具有1个至3个芳香族环(包括单环或双环基团)的环芳香族烃基团，例如苯基、联苯基、或萘基。当含有两个芳香族环(双环等)时，芳基基团的芳香族环任选地在单个点处连接(例如，联苯基)或稠合(例如，萘基)。芳基基团在任何附接点处任选地被一个或多个取代基取代，例如1个至5个取代基。术语“C6-14芳基”应理解为表示具有6～14个碳原子的一价芳香性或部分芳香性的单环、二环(如稠环、桥环、螺环)或三环烃环，其可以是单芳族环或稠合在一起的多芳族环，如“C6-10芳基”。术语“C6-14芳基”应理解为表示具有6、 7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-14芳基”)，特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者是具有13个碳原子的环(“C13芳基”)，例如芴基，或者是具有14个碳原子的环(“C14芳基”)，例如蒽基。当所述C6-20芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。
术语“杂芳基”意指5个至24个环原子的单价单环芳香族基团或多环芳香族基团，其含有选自N、O、或S的一个或多个环杂原子，剩余的环原子是C。如本文所定义的杂芳基还意指双环杂芳香族基团，其中杂原子选自N、O、或S。芳香族基团任选地独立地被本文描述的一个或多个取代基取代。术语“杂芳基”应理解为包括这样的一价单环、二环(如稠环、桥环、螺环)或三环芳族环系：例如其具有5-14个环原子且包含1-5个独立选自N、O和S的杂原子，例如“5-10元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9、10、11、12、13或14个环原子，特别是5或6或9或10个碳原子，且其包含1-5个，或1-3各独立选自N、O和S的杂原子并且，另外在每一种情况下可为苯并稠合的。“杂芳基”还指其中杂芳族环与一个或多个芳基、脂环族或杂环基环稠合的基团，其中所述连接的根基或点在杂芳族环上。非限制性实例包括1-、2-、3-、5-、6-、7-或8-吲嗪基、1-、3-、4-、5-、6-或7-异吲哚基、2-、3-、4-、5-、6-或7-吲哚基、2-、3-、4-、5-、6-或7-吲唑基、2-、4-、5-、6-、7-或8-嘌呤基、1-、2-、3-、4-、6-、7-、8-或9-喹嗪基、2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-异喹啉基、1-、4-、5-、6-、7-或8-酞嗪基(phthalazinyl)、2-、3-、4-、5-或6-萘啶基、2-、3-、5-、6-、7-或8-喹唑啉基、3-、4-、5-、6-、7-或8-噌啉基、2-、4-、6-或7-蝶啶基、1-、2-、3-、4-、5-、6-、7-或8-4aH咔唑基、1-、2-、3-、4-、5-、6-、7-或8-咔唑基咔唑基、1-、3-、4-、5-、6-、7-、8-或9-咔啉基、1-、2-、3-、4-、6-、7-、8-、9-或10-菲啶基、1-、2-、3-、4-、5-、6-、7-、8-或9-吖啶基、1-、2-、4-、5-、6-、7-、8-或9-啶基、2-、3-、4-、5-、6-、8-、9-或10-菲咯啉基、1-、2-、3-、4-、6-、7-、8-或9-吩嗪基、1-、2-、3-、4-、6-、7-、8-、9-或10-吩噻嗪基、1-、2-、3-、4-、6-、7-、8-、9-或10-吩嗪基、2-、3-、4-、5-、6-或1-、3-、4-、5-、6-、7-、8-、9-或10-苯并异喹啉基、2-、3-、4-或噻吩并[2,3-b]呋喃基、2-、3-、5-、6-、7-、8-、9-、10-或11-7H-吡嗪并[2,3-c]咔唑基、2-、3-、5-、6-或7-2H-呋喃并[3,2-b]-吡喃基、2-、3-、4-、5-、7-或8-5H-吡啶并[2,3-d]-邻-嗪基、1-、3-或5-1H-吡唑并[4,3-d]-唑基、2-、4-或54H-咪唑并[4,5-d]噻唑基、3-、5-或8-吡嗪并[2,3-d]哒嗪基、2-、3-、5-或6-咪唑并[2,1-b]噻唑基、1-、3-、6-、7-、8-或9-呋喃并[3,4-c]噌啉基、1-、2-、3-、4-、5-、6-、8-、9-、10或11-4H-吡啶并[2,3-c]咔唑基、2-、3-、6-或7-咪唑并[1,2-b][1,2,4]三嗪基、7-苯并[b]噻吩基、2-、4-、5-、6-或7-苯并唑基、2-、4-、5-、6-或7-苯并咪唑基、2-、4-、4-、5-、6-或7-苯并噻唑基、1-、2-、4-、5-、6-、7-、8-或9-苯并氧杂基(benzoxapinyl)、2-、4-、5-、6-、7-或8-苯并嗪基、1-、2-、3-、5-、6-、7-、8-、9-、10-或11-4H-吡咯并[1,2-b][2]苯并氮杂基(benzazapinyl)。典型的稠合杂芳基包括但不限于2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-异喹啉基、2-、3-、4-、5-、6-或7-吲哚基、2-、3-、4-、5-、6-或7-苯并[b]噻吩基、2-、4-、5-、6-或7-苯并唑基、2-、4-、5-、6-或7-苯并咪唑基和2-、4-、5-、6-或7-苯并噻唑基。当所述5-14元杂芳基与其它基团相连构成本发明的化合物时，可以为5-14元杂芳基环上的碳原子与其它基团相连，也可以为5-14元杂芳基环上的杂原子与其它基团相连。当所述5-14元杂芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为杂芳基环上与碳原子相连的氢被取代，或者杂芳基环上与杂原子相连的氢被取代。
术语“螺环”是指两个环共用1个成环原子的环系。
术语“稠环”是指两个环共用2个成环原子的环系。
术语“桥环”是指两个环共用3个以上成环原子的环系。
术语“卤素”表示氟、氯、溴和碘。
“卤代”指被一个或多个卤素取代。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘(2H)，氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。在本发明的一些方案中，H为氘或氚。
“盐”意指母体化合物的离子形式或母体化合物与合适的酸或碱之间的反应以制备母体化合物的酸式盐或碱式盐的产物。本披露的化合物的盐可以通过传统化学方法从含有碱性或酸性部分的母体化合物合成。通常，通过使游离碱性或酸性母体化合物与化学计量的量或与过量的所需成盐无机或有机酸或碱在合适的溶剂或不同的溶剂组合中反应来制备盐。
“药学上可接受的盐”意指本披露的化合物的盐，其在合理的医学判断范围内，适合用于与人和低等动物的组织接触，而没有过度的毒性、刺激、过敏反应等，与合理的利益/风险比相称，通常为水溶性或油溶性或可分散的，并且使其预期用途有效。该术语包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。由于本披露的化合物在游离碱形式和盐形式两者中是有用的，实际上使用盐形式相当于使用碱形式。合适的盐的列表发现于例如，S.M.Birge等人，J.Pharm.Sci.[药物科学杂志]，1977，66，第1-19页，将其通过引用 以其全文特此并入。
“药学上可接受的酸加成盐”意指那些保留游离碱的生物学有效性和特性且并非是生物学或在其他方面不希望的盐，这些盐是与无机酸(例如盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、硝酸、磷酸等)和有机酸(例如乙酸、三氯乙酸、三氟乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、2-乙酰氧基苯甲酸、丁酸、樟脑酸、樟脑磺酸、肉桂酸、柠檬酸、二葡萄糖酸、乙磺酸、谷氨酸、乙醇酸、甘油磷酸、半硫酸、庚酸、己酸、甲酸、富马酸、2-羟基乙磺酸(羟乙基磺酸)、乳酸、马来酸、羟基马来酸、苹果酸、丙二酸、扁桃酸、均三甲苯磺酸、甲磺酸、萘磺酸、烟酸、2-萘磺酸、草酸、双羟萘酸、果胶酸、苯基乙酸、3-苯基丙酸、苦味酸、新戊酸、丙酸、丙酮酸、丙酮酸、水杨酸、硬脂酸、琥珀酸、对氨基苯磺酸、酒石酸、对甲苯磺酸、十一烷酸等)形成的。
“药学上可接受的碱加成盐”意指那些保留游离酸的生物学有效性和特性且并非是生物学或在其他方面不希望的盐，这些盐是与无机碱(例如氨或氢氧化物、碳酸盐、或碳酸氢铵)或金属阳离子(如钠、钾、锂、钙、镁、铁、锌、铜、锰、铝等)形成的。衍生自药学上可接受的有机无毒碱的盐包括以下物质的盐：伯胺、仲胺和叔胺、季胺化合物，取代的胺(包括天然存在的取代的胺)，环胺和碱性离子交换树脂，如甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、异丙胺、三丙胺、三丁胺、乙醇胺、二乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、海巴明(hydrabamine)、胆碱、甜菜碱、乙二胺、葡糖胺、甲葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、四甲基铵化合物、四乙基铵化合物、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二环己胺、二苄胺、N,N-二苄基苯乙胺、1-二苯羟甲胺、N,N'-二苄基乙烯二胺、多胺树脂等。
如下所讨论的本披露的化合物包括其游离碱或酸或其盐，特别是其药学上可接受的形式。此类形式(特别是药学上可接受的形式)旨在包括在所附权利要求中。
“异构体”意指具有相同数量和种类原子、并因此具有相同的分子量，但在空间中原子的排列或构型方面不同的化合物。该术语包括立体异构体和几何异构体。
“立体异构体”或“光学异构体”意指具有至少一个手性原子或受限旋转导致具有垂直的不对称平面(例如，某些联苯基、丙二烯和螺环化合物)并且可以使平面偏振光旋转的稳定异构体。因为不对称中心和其他化学结构存在于可以导致立体异构现象的本披露的化合物中，本披露考虑了立体异构体及其混合物。本披露的化合物及其盐包括不对称碳原子，因此可以作为单个立体异构体、外消旋体、以及对映异构体和非对映异构体的混合物存在。典型地，此类化合物将以外消旋混合物进行制备。然而，如果需要，此类化合物可以制备或分离成立体异构体，即作为单独的对映异构体或非对映异构体，或作为富集立体异构体的混合物。如下文更详细讨论的，化合物的单独的立体异构体通过从含有所需手性中心的光学活性起始材料合成来制备，或通过制备对映异构体产物的混合物随后分离或拆分(如转化成非对映异构体的混合物随后分离或重结晶、色谱技术，使用手性拆分剂、或在手性色谱柱上直接分离对映异构体)来制备。特定立体化学的起始化合物是可商购的或通过下文描述的方法制备并通过本领域熟知的技术拆分的。
“对映异构体”意指彼此为不能重叠镜像的一对立体异构体。
“非对映异构体”或“非对映体”意指彼此之间不构成镜像的光学异构体。
“外消旋混合物”或“外消旋体”意指含有等份的单个对映异构体的混合物。
“非外消旋混合物”意指含有不等份的单个对映异构体的混合物。
“几何异构体”意指由双键(例如，顺式-2-丁烯和反式-2-丁烯)或环结构(例如，顺式-1,3-二氯环丁烷和反式-1,3-二氯环丁烷)中的旋转自由度限制产生的稳定异构体。因为碳-碳双(烯属)键、C＝N双键、环结构等可以存在于本披露的化合物中，本披露考虑了由这些双键周围和这些环结构中的取代基排列产生的不同的稳定的几何异构体及其混合物中的每一种。使用顺式/反式惯例或使用E或Z系统表示取代基和异构体，其中术语“E”意指更高次序的取代基在双键的相对侧，术语“Z”意指更高次序的取代基在双键的同一侧。有关E和Z异构现象的详尽讨论提供于：J.March,Advanced Organic Chemistry:Reactions,Mechanisms,and Structure[高等有机化学：反应、机制和结构],第4版,John Wiley&Sons[约翰威立父子出版公司]，1992，将其通过引用以其全文特此并入。以下几个实例代表单个E异构体、单个Z异构体和E/Z异构体的混合物。E和Z异构体的确定可以通过分析方法进行，例如X射线晶体学、1H NMR、和13C NMR。
本披露的一些化合物能以多于一种的互变异构形式存在。如上所提及的，本披露的化合物包括所有此类互变异构体。
如本文所使用的，术语“药物组合物”是指呈适于口服施用或肠胃外施用的形式的本披露的化合物或其药学上可接受的盐或立体异构体，以及至少一种药学上可接受的载体。
“载体”涵盖载体、赋形剂、和稀释剂，并且意指涉及从一个器官或受试者的身体部分向另一个器官或受试者的身体部分携带或运输药物药剂的材料、组合物或媒介物，例如液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。
术语“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。
术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。
具体实施方式
下文将结合具体实施例对本公开的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本公开，而不应被解释为对本公开保护范围的限制。凡基于本公开上述内容所实现的技术均涵盖在本公开旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
本发明所采用的缩写贯穿本发明。
HATU代表2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
实施例1
在-78℃条件下向化合物1-1(50.0g,203mmol)的THF(300mL)溶液中缓慢滴加乙烯基溴化镁的THF溶液(1M,812mL,812mmol)，滴加完毕后，在氮气保护下自然升至室温并搅拌16小时。反应液用1M盐酸调节pH至4～5，乙酸乙酯(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、过滤浓缩得粗产品化合物1-2(50.0g)，未经纯化直接用于下一步反应。
在25℃下向化合物1-2(50.0g，209mmol)的DMF(250mL)溶液中加入碘甲烷(32.5g,229mmol)和碳酸钾(57.5g,417mmol)。反应液在25℃、氮气保护下搅拌16小时。反应液加水(500mL)，用乙酸乙酯(500mL×3)萃取，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产品经硅胶柱层析纯化，得化合物1-3(27.5g，收率53％)。
LCMS:m/z(ESI):253.7[M+H]+。
在25℃下向化合物1-3(20.0g,78.7mmol)的二甲基亚砜(250mL)的溶液依次加入醋酸钯(2.65g,11.8mmol)、1,4-双(二苯基膦)丁烷(5.04g,11.8mmol)、磷酸钾(157g,33.4mmol)。在氮气保护下搅拌5分钟，加入二甲基氧化膦(12.3g,157mmol)，升温至60℃搅拌0.5小时，继续加热至135℃搅拌2小时。 反应液加水(200mL)稀释后，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、粗产品经硅胶柱层析纯化，得化合物1-4(9.0g，收率45％)。LCMS:m/z(ESI):252.0[M+H]+。
在一50mL三口瓶中加入三氯化铝(5.57g,41.8mmol)，置换氮气，加入化合物1-4(5.00g，19.9mmol)的1,2-二氯乙烷(50mL)溶液，在85℃下搅拌30分钟，加入2,4-二氯-5-(三氟甲基)嘧啶(4.75g,21.9mmol)的1,2-二氯乙烷(5mL)溶液，在85℃下继续反应16小时。反应液加水(100mL)稀释后用乙酸乙酯(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。得粗产品经柱层析纯化，得化合物1-5(4.2g，收率49％)。LCMS:m/z(ESI):431.7[M+H]+。
向化合物1-6(500mg，3.63mmol)的DMF(10mL)溶液中加入溴化苄(1.86g,10.9mmol)和碳酸钾(2.05g,14.8mol)。该反应液在氮气保护下在25℃搅拌16小时。反应液加水(30mL)稀释，用乙酸乙酯(15mL×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。得到的粗产品经硅胶柱层析纯化，得到化合物1-7(800mg，收率58％)。
LCMS:m/z(ESI):282.0[M+H]+.1H NMR(400MHz,DMSO-d6):δ7.36–7.27(m,8H),7.24–7.16(m,2H),4.50(d,J＝3.6Hz,1H),4.32–3.90(m,1H),3.62–3.49(m,4H),3.15–3.03(m,1H),1.97–1.88(m,1H),1.78–1.56(m,2H),1.54–1.36(m,3H)。
向化合物1-7(51.0g，181mmol)的THF(500mL)溶液中加入三苯基膦(95.1g,362mmol)和对硝基苯甲酸(60.6g,362mmol)。该反应液在氮气保护下冷却至0℃加入偶氮二甲酸二乙酯(63.1g,362mmol)。在25℃下搅拌3小时。反应液倒入冰水(1L)中，用乙酸乙酯(500mL×2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。所得粗产品经硅胶柱层析纯化，得到化合物1-8(57.0g，收率73％)。LCMS:m/z(ESI):431.2[M+H]+.1H NMR(400MHz,DMSO-d6):δ8.31(d,J＝8.8Hz,2H),8.08(d,J＝8.8Hz,2H),7.39–7.27(m,8H),7.26–7.15(m,2H),5.41–5.31(m,1H),3.65–3.55(m,4H),3.51–3.39(m,1H),2.21–2.10(m,1H),2.01–1.93(m,2H),1.93–1.83(m,1H),1.76–1.56(m,2H)。
在25℃条件下，向化合物1-8(57.0g，132mmol)的水(50mL)、甲醇(150mL)和四氢呋喃(150mL)的混合溶液加入一水合氢氧化锂(27.8g,622mmol)。该反应液在50℃搅拌3个小时。反应液加水(200mL)稀释，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。得到粗产品经硅胶柱层析纯化，得到化合物1-9(30.0g，收率81％)。LCMS:m/z(ESI):282.0[M+H]+.1H NMR(400MHz,DMSO-d6):δ7.38–7.25(m,8H),7.24–7.16(m,2H),4.37(d,J＝3.2Hz,1H),4.17–4.03(m,1H),3.52(s,4H),3.43–3.35(m,1H),1.86–1.72(m,2H),1.70–1.55(m,2H),1.55–1.44(m,1H),1.44–1.31(m,1H).
在0℃、氮气保护下，向化合物1-9(5.00g，17.8mmol)的DMF(200mL)溶液中缓慢加入氢化钠(7.11g,178mmol,60％wt.)。该温度下搅拌0.5小时后加入1,4-二碘代丁烷(55.0g,178mmol)，然后升温至50℃搅拌3小时。将反应液加入到饱和氯化铵水溶液(500mL×3)淬灭，乙酸乙酯(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。粗品经硅胶柱层析纯化得到化合物1-10(1.90g,收率23％)。LCMS:m/z(ESI):464.0[M+H]+。1H NMR(400MHz,DMSO-d6):δ7.41–7.25(m,8H),7.25–7.14(m,2H),3.90–3.76(m,1H),3.57–3.50(m,4H),3.33–3.22(m,5H),2.08–1.61(m,6H),1.61–1.17(m,4H)。
向化合物1-10(1.90g，4.10mmol)的DMF(50mL)溶液中加入双(叔丁氧羰基)胺(1.80g,8.20mmol)和碳酸铯(4.00g,12.3mmol)。该反应液在25℃下搅拌16小时。向反应液加水(300mL)淬灭，然后用乙酸乙酯(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。得到的粗产品经硅胶柱层析纯化，得到化合物1-11(2.20g，收率97％)。
LCMS:m/z(ESI):553.6[M+H]+。1H NMR(400MHz,DMSO-d6):δ7.37–7.25(m,8H),7.23–7.16(m,2H),3.87–3.78(m,1H),3.53(s,4H),3.43(t,J＝7.2Hz,2H),3.27–3.18(m,3H),1.98–1.41(m,28H)。
向化合物1-11(3.00g，5.4mmol)的异丙醇(30mL)溶液中加入Pd/C(300mg,10％wt.,55％水)。该反应液在氢气条件下80℃搅拌18小时。反应液过滤浓缩得到化合物1-12(1.82g，收率90％)。该粗产品未经纯化直接用于下一步反应。LCMS:m/z(ESI):373.2[M+H]+。
向1-5(2.10g，4.83mmol)和1-12(1.80g，4.83mmol)的NMP(20mL)溶液中加入N,N-二异丙基乙胺(4.00mL,24.2mmol)。在130℃下搅拌4小时后，降至室温，向反应液中加水(10mL)稀释，然后用乙酸乙酯(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。得到的粗产品经硅胶柱层析纯化，得到化合物1-13(2.20g，收率47％)。
LCMS:m/z(ESI):768.2[M+H]+。
将化合物1-13(2.20g，2.87mmol)溶于THF(30mL)、甲醇(30mL)和水(10mL)的混合溶剂中，加入一水合氢氧化锂(0.60g,14.3mmol)。该反应液在50℃下搅拌18小时。反应完成后将反应液旋蒸浓缩得到化合物1-14(2.90g)。该粗产品未经纯化直接用于下一步反应。
LCMS:m/z(ESI):654.2[M+H]+。
向化合物1-14(2.90g)的乙腈(30mL)溶液中加入盐酸(30mL,4M二氧六环溶液)。该反应液在45℃下搅拌1小时。反应完成后将反应液浓缩旋干，得到残余物经反相制备(Xtimate C18,50*250mm,10um,10mM NH4HCO3)纯化得到化合物1-15(0.35g)。LCMS:m/z(ESI):554.2[M+H]+。
向化合物1-15(350mg，0.63mmol)的DMSO(20mL)溶液中加入HATU(289mg,0.80mmol)和N,N-二异丙基乙胺(0.52mL,3.16mmol)。该反应液在60℃搅拌18小时。反应完成后加入水(1mL)，反应液经反相制备(Xtimate C18,80*250mm,10um,0.1％ TFA)纯化得到化合物1(79.5mg,收率24％)。
LCMS:m/z(ESI):536.2[M+H]+。1H NMR(400MHz,CD3OD):δ8.81(d,J＝8.4Hz,1H),8.50(s,1H),8.11(s,1H),7.31(dd,J＝8.4,3.2Hz,1H),4.59–4.42(m,1H),4.05–3.91(m,1H),3.22–3.08(m,2H),2.92–2.78(m,2H),2.63–2.48(m,1H),2.26–2.13(m,2H),2.05–1.94(m,6H),1.89–1.70(m,2H),1.68–1.55(m,3H),1.48–1.38(m,1H),1.36–1.28(m,1H)。
实施例2
在25℃下将化合物2-1(35g，228mmol)加入到33％的甲胺乙醇溶液(400mL)中。该反应液在氮气保护下室温搅拌12小时。将反应液旋蒸浓缩干后加入二氯甲烷(500mL)、二碳酸二叔丁酯(102mL,446mmol)和三乙胺(93mL,669mmol)，并在室温下继续搅拌16小时。反应完毕后，反应液加水(300mL)稀释，然后用二氯甲烷(500mL×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。得到的粗产品经硅胶柱层析纯化，得到化合物2-2(21.0g,收率45％)。LCMS:m/z(ESI):226.0[M+Na]+。
在25℃下向化合物2-2(21.0g,92.9mmol)的二氯甲烷(300mL)溶液中加入三苯基膦(64.5g,246mmol)和咪唑(17g,246mmol)。该反应液在氮气保护下冷却至0℃，加入碘单质(62.0g,246mmol)后升温至25℃搅拌2小时。反应液加饱和硫代硫酸钠淬灭，然后用二氯甲烷(500mL×2)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。得到的粗产品经硅胶柱层析纯化，得到化合物2-3(30.0g，收率78％)。LCMS:m/z(ESI):258.2[M-56]+。
在冰水浴温度下，向化合物1-9(5.00g，17.7mmol)的DMF(100mL)溶液中加入氢化钠(3.60g,88.8mmol,60％wt)。该反应液在氮气保护下搅拌1小时。加入化合物2-3(6.70g，21.3mmol)后升温至25℃搅拌18小时。反应液加饱和氯化铵水溶液(50mL)淬灭，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。得到的粗产品经硅胶柱层析纯化，得到化合物2-4(2.75g，收率33％)。LCMS:m/z(ESI):467.2[M+1]+.1H NMR(400MHz,DMSO-d6):δ7.33–7.18(m,10H),3.84–3.82(m,1H),3.55–3.50(m,4H),3.30–3.24(m,3H),3.11–3.08(m,2H),2.71(s,3H),1.86–1.60(m,4H),1.51–1.37(m,15H)。
在25℃下向化合物2-4(2.75g，5.89mmol)的异丙醇(30mL)溶液中加入钯碳(600mg,5.89mmol，10％wt.,50％水)。加热到80℃在氢气体系下搅拌16小时。然后过滤浓缩得到的粗产品化合物2-5(1.60g，收率95％)，不经纯化直接用于下一步反应。LCMS:m/z(ESI):287.4[M+H]+。
在一个100mL单口瓶中，依次加入化合物2-5(1.60g，5.57mmol)、N-甲基吡咯烷酮(20mL)、N,N-二异丙基乙胺(0.580mL,3.49mmol)和化合物1-5(1.50g，3.49mmol)。在130℃下反应2小时后反应液加水(15mL)稀释，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，得到的粗产品经硅胶柱层析纯化，得到化合物2-6(2.00g，收率84％)。LCMS:m/z(ESI):682.2[M+H]+。
将化合物2-6(2.00g，2.93mmol)溶于水(15mL)、甲醇(3mL)和四氢呋喃(15mL)的混合体系中，然后加入一水合氢氧化锂(100mg,2.93mmol)，在50℃下搅拌6小时，反应完成后，直接将溶剂旋干，得 到粗产品化合物2-7(2.00g，收率91％)，未经纯化直接用于下一步反应。LCMS:m/z(ESI):668.3[M+H]+。
将化合物2-7(2.00g,2.99mmol)溶于氯化氢/二氧六环(20mL,4M)中，在60℃下搅拌1小时，反应完毕后直接将溶剂旋干，得到粗产物经反相制备(Xtimate C18,50*250mm,5um,10mM NH4HCO3)纯化得到化合物2-8(850mg，收率50％)。LCMS:m/z(ESI):568.2[M+H]+。
向化合物2-8(400mg，0.700mmol)的DMF(10mL)溶液中依次加入HATU(321mg,0.84mmol)和N,N-二异丙基乙胺(0.35mL,2.11mmol)，该反应液在60℃下搅拌2h。反应完毕后，反应液浓缩得到的粗产品经反相制备(Xtimate C18,21.2*250mm,5um,0.1％ TFA)纯化得到化合物2(123mg,收率31％)。LCMS:m/z(ESI):550.0[M+H]+。1H NMR(400MHz,CD3OD):δ8.71(d,J＝7.6Hz,1H),8.51(s,1H),8.10(s,1H),7.27(dd,J＝8.4,3.2Hz,1H),4.59–4.50(m,1H),4.01–3.94(m,1H),3.20–3.03(m,6H),2.93–2.85(m,1H),2.54–2.50(m,1H),2.24–2.11(m,2H),1.98–1.84(m,7H),1.80–1.31(m,6H)。
实施例3
向化合物2-5(2.23g，7.79mmol)的THF(40mL)溶液中，加入2,4-二氯-5-(三氟甲基)嘧啶(1.69g,7.79mmol)和N,N-二异丙基乙胺(3.02g,23.4mmol)。反应液在20℃下搅拌18个小时。反应液加水(50mL)稀释，用乙酸乙酯(100mL×2)萃取。合并的有机层用饱和食盐水(50mL)洗涤、无水硫酸钠干燥、过滤浓缩至干燥。得到的粗产品经硅胶柱层析纯化，得到化合物3-1(1.2g)。LCMS:m/z(ESI):467.4[M+H]+.1H NMR(400MHz,CDCl3):δ8.53–8.30(m,1H),5.74–5.48(m,1H),4.53–4.41(m,1H),4.01–3.95(m,1H),3.38(t,J＝6.0Hz,2H),3.26–3.18(m,2H),2.83(s,1H),2.32–2.16(m,2H),2.03–1.94(m,1H),1.83–1.70(m,2H),1.67–1.60(m,1H),1.59–1.50(m,4H),1.45(s,9H)。
向100mL单口瓶中依次加入化合物3-2(300mg，1.96mmol)、DMF(5mL)、氰化锌(253mg,2.16mmol)和四三苯基膦钯(227mg,0.197mmol)。在120℃下反应18小时。反应完毕后，反应液加水(20mL)稀释，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，得到的粗产品经硅胶柱层析纯化，得到化合物3-3(100mg,35％)。
LCMS:m/z(ESI):144.0[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.25(s,1H),8.18(d,J＝8.0Hz,1H),7.84(d,J＝3.2Hz,1H),7.62(d,J＝8.0Hz,1H),6.64(d,J＝3.2Hz,1H)。
在25℃下，向化合物3-3(100mg，0.699mmol)的DMF(1mL)溶液中加入N-碘代丁二酰亚胺(157mg，0.699mmol)。该反应液在氮气保护下搅拌18个小时。反应液加水(15mL)稀释，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，得到的粗产品经硅胶柱层析纯化，得到化合物3-4(140mg，74％)。LCMS:m/z(ESI):270.0[M+1]+。1H NMR(400MHz,DMSO-d6):δ12.70(s,1H),8.10(d,J＝2.4Hz,1H),7.91(d,J＝8.0Hz,1H),7.71(d,J＝8.0Hz,1H)。
在氮气保护下，向化合物3-4(10.5g，39.0mmol)的二氯甲烷(120mL)溶液中，加入4-二甲氨基吡啶(500mg,3.90mmol)、三乙胺(11.9g,117mmol)和二碳酸二叔丁酯(10.2g,46.8mmol)。反应液在20℃下搅拌7个小时。反应完成后，反应液加水(100mL)稀释，乙酸乙酯(200mL×2)萃取，合并的有机层用饱和食盐水(100mL)洗涤、无水硫酸钠干燥、过滤浓缩至干燥。得到的粗产品经硅胶柱层析纯化，得到化合 物3-5(12.0g，83％)。LCMS:m/z(ESI):313.8[M+H-56]+.1H NMR(400MHz,DMSO-d6):δ8.30(s,1H),8.00(d,J＝8.0Hz,1H),7.94(d,J＝8.0Hz,1H),1.62(s,9H)。
在氮气保护下，向耐压管中依次加入化合物3-5(2.00g，5.42mmol)的THF(20mL)溶液中加入Pd2(dba)3(248mg,0.271mmol)、XPhos(129mg,0.271mmol)、三乙胺(2.74g,27.1mmol)和频那醇硼烷(3.47g,27.1mmol)。该反应液在90℃搅拌10个小时。反应完毕后，反应液加水(50mL)稀释，然后用乙酸乙酯(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。得到的粗产品经硅胶柱层析纯化，得到化合物3-6(1.10g，55％)。
LCMS:m/z(ESI):314.4[M+H-56]+。1H NMR(400MHz,CDCl3):δ8.35(d,J＝8.0Hz,1H),8.26(s,1H),7.61(d,J＝8.0Hz,1H),1.69(S,9H),1.37(s,12H)。
向化合物3-6(1.00g，2.71mmol)的四氢呋喃(10mL)和水(2mL)的混合溶剂中，加入化合物3-1(1.26g,2.71mmol)、氯[(正丁基二(1-金刚烷基)膦)-2-(2-氨基联苯)]钯(II)(181mg,0.27mmol)和磷酸三钾(1.73g,8.13mmol)。该反应液在60℃搅拌16个小时。反应完毕后，反应液加水(30mL)稀释，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。得到的粗产品经硅胶柱层析纯化，得到化合物3-7(1.50g，82％)。
LCMS:m/z(ESI):696.4[M+Na]+。
化合物3-7(1.50g,2.23mmol)的乙酸(10mL)和浓盐酸(5mL)混合溶液在120℃下搅拌16个小时。反应完全后，将反应液直接旋干。得到的粗产品经反相制备(Xtimate C18,80*250mm,10um,0.05％NH3.H2O)得到化合物3-8(800mg,73％)。LCMS:m/z(ESI):493.2[M+H]+.1H NMR(400MHz,DMSO-d6):δ8.89–8.69(m,1H),8.63–8.51(m,1H),8.19(s,1H),8.06–7.83(m,2H),7.30–7.09(m,2H),4.64–4.41(m,1H),4.04–3.90(m,1H),2.96–2.83(m,2H),2.56(s,3H),2.35–2.19(m,3H),2.15–1.90(m,2H),1.79–1.39(m,8H)。
向化合物3-8(500mg,1.02mmol)的DMF(30mL)溶液中加入N,N-二异丙基乙胺(393mg,3.05mmol)和HATU(463mg,1.22mmol)。该反应液在60℃搅拌24个小时。反应完全后，将反应液过滤浓缩。所得粗产品经反相(Xtimate C18,21.2*250mm,5um,0.1％ TFA)制备得到化合物3(56mg,11％)。LCMS:m/z(ESI):475.0[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.39(d,J＝2.4Hz,1H),8.67(d,J＝8.0Hz,1H),8.58(s,1H),8.07(d,J＝5.6Hz,1H),7.91(d,J＝2.0Hz,1H),7.19(d,J＝8.0Hz,1H),4.23–4.12(m,1H),3.93–3.80(m,1H),2.97(s,3H),2.92–2.74(m,4H),2.44–2.35(m,1H),2.13–1.94(m,2H),1.83–1.69(m,1H),1.64–1.47(m,2H),1.45–1.35(m,1H),1.34–1.24(m,2H),1.19–1.06(m,1H)。
实施例4
在氮气保护下，向干燥的500mL三口瓶中加入三氯化铝(38.0g,285mmol)，化合物4-1(25.0g，143mmol)的1,2-二氯乙烷(300mL)溶液。在80℃下搅拌30分钟后，加入2,4-二氯-5-(三氟甲基)嘧啶(31.0g,143mmol)的1,2-二氯乙烷溶液(50mL)。在80℃条件下继续反应16小时。反应完全后，反应液加水(100mL)淬灭，用乙酸乙酯(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 的粗产品经反向制备纯化得化合物4-2(20.0g，39％)。LCMS:m/z(ESI):356.2[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.51(s,1H),9.07(s,1H),8.39(d,J＝8.4Hz,1H),8.28(d,J＝2.4Hz,1H),8.21(d,J＝1.6Hz,1H),7.84(dd,J＝8.4,1.6HZ,1H),3.89(s,3H)。
在一个250mL单口瓶中，依次加入化合物4-2(10.0g,28.1mmol)、NMP(300mL)、N,N-二异丙基乙胺(13.9mL,84.3mmol)和((1S，3S)-3-氨基环戊基)氨基甲酸叔丁酯(6.20g,30.9mmol)。在130℃反应4小时，反应液加水(100mL)稀释，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。得到的粗产品经硅胶柱层析纯化，得到化合物4-3(8.00g,54％)。LCMS:m/z(ESI):520.2[M+H]+。
室温下，向化合物4-3(8.10g,15.5mmol)的甲醇(40mL)溶液中加入氯化氢/乙酸乙酯溶液(40mL,4M)。在40℃下反应2小时后，反应液加入饱和碳酸氢钠溶液(100mL)淬灭，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。得到的粗产品经硅胶柱层析纯化得到化合物4-4(4.00g,61％)。LCMS:m/z(ESI):420.2[M+H]+。
在化合物4-4(2.00g,4.76mmol)的DMF溶液(30mL)中，依次加入(4-溴丁基)氨基甲酸叔丁酯(1.80g,7.15mmol)、N,N-二异丙基乙胺(4.74mL,28.6mmol)和碘化钠(71.4mg,0.47mmol)。在80℃下搅拌12小时后冷却至室温，向反应液加水(100mL)稀释，然后用乙酸乙酯(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。得到的粗产品经硅胶柱层析纯化，得到化合物4-5(1.30g,46％)。LCMS:m/z(ESI):591.2[M+H]+。
在化合物4-5(1.30g,2.20mmol)的甲醇溶液(20mL)中，依次加入多聚甲醛(660mg,22.0mmol)、醋酸(0.01mL)、钯碳(400mg，10％wt.,55％水)。反应在氢气氛围、70℃下搅拌2小时。反应完全后，过滤掉钯碳，将滤液中溶剂旋干，加水(20mL)稀释，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。得到的粗产品经柱层析纯化得到化合物4-6(1.20g,90％)。LCMS:m/z(ESI):605.2[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.27–12.02(m,1H),8.68–8.53(m,1H),8.49–8.28(m,2H),8.21–7.97(m,2H),7.84–7.73(m,1H),6.89–6.75(m,1H),4.46–4.34(m,1H),3.94–3.87(m,3H),3.19(s,3H),3.15–3.03(m,1H),2.96–2.87(m,2H),2.48–2.40(m,2H),2.28–2.17(m,3H),2.16–2.05(m,1H),2.00–1.89(m,4H),1.88–1.78(m,1H),1.68–1.56(m,1H),1.38–1.34(m,9H)。
将化合物4-6(1.20g,1.98mmol)溶于水-甲醇-四氢呋喃(21mL,1:3:3)的混合溶剂中，然后加入一水合氢氧化锂(416mg,9.92mmol)。反应液在50℃下搅拌3个小时，反应完全后直接将溶剂旋干。得到粗产品化合物4-7(1.20g,82％)不经纯化直接用于下一步反应。
LCMS:m/z(ESI):591.2[M+H]+。
将化合物4-7(1.20g,2.03mmol)溶于盐酸二氧六环溶液(15mL,4M)中。在50℃下搅拌1个小时，反应完毕后，直接将溶剂旋干。得到的粗产品经反相制备(Xtimate C18,50*250mm,10um,10mM NH4HCO3)纯化得到化合物4-8(500mg,50％)。LCMS:m/z(ESI):491.2[M+H]+。
向化合物4-8(300mg,0.61mmol)的DMF(5mL)溶液中依次加入HATU(279mg,0.73mmol)和N,N-二异丙基乙胺(0.30mL,1.83mmol)。该反应液在60℃下搅拌16h，反应完毕后，将反应液旋蒸浓缩。得到的粗产品经反相制备(Xtimate C18,50*250mm,10um,0.1％ TFA)纯化得到化合物4(19.2mg)。
LCMS:m/z(ESI):473.0[M+H]+。1H NMR(400MHz,CD3OD):δ8.55(s,1H),8.31(d,J＝8.4Hz,1H),7.89(s,1H),7.64(s,1H),7.34(d,J＝8.4Hz,1H),4.37–4.23(m,1H),4.06–3.84(m,1H),3.20–2.96(m,3H),2.82–2.74(m,1H),2.73(s,3H),2.63–2.53(m,1H),2.32–2.19(m,2H),1.98–1.70(m,6H),1.63–1.53(m,1H)。
实施例5
化合物5的合成参考化合物4的合成路线，中间体5-1的合成原料(4-碘丁基)(甲基)氨基甲酸叔丁酯替代合成中间体4-5的原料(4-溴丁基)氨基甲酸叔丁酯。
得到化合物5(16.2mg)。LCMS:m/z(ESI):487.2[M+H]+。1H NMR(400MHz,CD3OD):δ8.48(s,1H),8.38(d,J＝8.4Hz,1H),7.89(s,1H),7.57(d,J＝0.8Hz,1H),7.26(dd,J＝8.4,1.6Hz,1H),4.25–4.09(m,1H),3.29–3.25(m,2H),3.10(s,3H),3.08–2.98(m,1H),2.69–2.56(m,1H),2.53–2.40(m,1H),2.21–2.10(m,4H),2.08–1.95(m,3H),1.88–1.57(m,3H),1.54–1.31(m,3H)。
实施例6
在5℃、氮气保护下，向化合物6-1(20.0g,114mmol)的四氢呋喃(200mL)溶液中加入羰基二咪唑(20.4g,126mmol)。反应液在该条件下搅拌反应14小时。向反应液中加入氯化镁(12.0g,126mmol)、丙二酸单甲酯钾盐(17.8g,114mmol)。升温至45℃继续搅拌反应4小时。反应完毕后，反应液加水(200mL)稀释，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。粗产品经柱层析纯化得到化合物6-2(25.3g,收率96％)。1H NMR(400MHz,DMSO-d6):δ7.12(t,J＝5.6Hz,1H),3.85(d,J＝6.0Hz,2H),3.63(s,3H),3.59(s,2H),1.38(s,9H)。
在5℃、在氮气保护下，向化合物6-2(15.0g,64.9mmol)的DCM(200mL)溶液中加入二乙胺基三氟化硫(20.9g,130mmol)。该反应液于该条件下搅拌反应18小时。反应完毕后，反应液加水(200mL)稀释，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。得到粗产品经反相制备得化合物6-3(2.3g,收率14％)。1H NMR(400MHz,CDCl3):δ4.89(s,1H),3.75(s,3H),3.69(dt,J＝13.6,6.8Hz,2H),2.97(t,J＝15.2Hz,2H),1.45(s,9H)。
在-50℃下，向化合物6-3(1g,3.95mmol)的THF(10mL)溶液中，滴加四氢铝锂的THF溶液(1.9mL,4.74mmol,2.5M)。滴加完毕后，反应液在5℃下搅拌2小时。反应完毕后，加水(50mL)淬灭，用乙酸乙酯(30mL×3)萃取。合并有机相用无水硫酸钠干燥、过滤浓缩。得粗产品6-4(725mg,收率82％)。LCMS:m/z(ESI):170.0[M-56+H]+。
向化合物6-4(725mg,3.22mmol)的吡啶(10mL)溶液中，加入对甲基磺酰氯(1.23g,6.44mmol)。在10℃下搅拌2小时。反应完毕后，浓缩蒸干。粗产品经硅胶柱层析纯化得到化合物6-5(650mg,收率53％)。LCMS:m/z(ESI):280.0[M-100+H]+。
化合物6的合成参考化合物4的合成路线，合成中间体6-6的中间体原料6-5替代合成中间体4-5的原料(4-溴丁基)氨基甲酸叔丁酯。
得到化合物6(9.3mg)。LCMS:m/z(ESI):509.0[M+H]+.1H NMR(400MHz,CD3OD):δ8.55(s,1H),8.26(d,J＝9.2Hz,1H),7.87(s,1H),7.66(s,1H),7.33(d,J＝8.0Hz,1H),4.35–4.19(m,1H),3.99–3.90(m,1H),3.63–3.58(m,2H),3.11–3.05(m,1H),3.00–2.90(m,1H),2.81(s,3H),2.60–2.41(m,2H),2.33–2.18(m,3H),2.02–1.81(m,3H)。
实施例7
化合物7的合成参考化合物6的合成路线，合成中间体7-1替代合成化合物6的原料6-1。
得到化合物7(23.7mg)。LCMS:m/z(ESI):523.0[M+H]+。1H NMR(400MHz,DMSO-d6):δ8.55(s,1H),8.33(d,J＝8.4Hz,1H),8.03(d,J＝5.6Hz,1H),7.91(d,J＝2.0Hz,1H),7.55(s,1H),7.18–7.10(m,1H),4.16–4.02(m,1H),3.85–3.51(m,4H),3.11(s,3H),2.66–2.56(m,1H),2.25–2.16(m,1H),2.03(s,3H),1.99–1.93(m,1H),1.90–1.80(m,2H),1.79–1.69(m,1H),1.60–1.41(m,2H),1.28–1.19(m,1H),1.16–1.06(m,1H)。
实施例8
在-78℃、氮气保护下，向化合物8-1(10.0g,49.6mmol)的THF(120mL)溶液中缓慢滴加乙烯基溴化镁的THF溶液(198mL,198mmol,1M)。滴加完毕后，反应液在该条件下搅拌3小时。反应完毕后，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。得到粗产品8-2(8.03g,收率83％)，未经纯化直接用于下一步反应。
LCMS:m/z(ESI):196.0[M+H]+。
在25℃、氮气保护下，向化合物8-2的(8.00g,40.9mmol)的DMF(85mL)溶液中加入碘甲烷(6.97g,49.1mmol)和碳酸钾(11.3g,81.9mmol)。该反应液在该条件下搅拌16小时。反应完毕后，反应液加水(200mL) 稀释，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。得到的粗产品经硅胶柱层析纯化，得到化合物8-3(5.8g,收率67％)。
LCMS:m/z(ESI):210.0[M+H]+。1H NMR(400MHz,CDCl3):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)。
在一个干燥的50mL三口瓶中，加入三氯化铝(1.27g,9.54mmol)，在氮气体系下加入化合物8-3(1.00g,4.77mmol)的1.2-二氯乙烷(10mL)溶液。反应液在80℃下搅拌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℃条件下反应16小时。反应完毕后，反应液加水(30mL)稀释，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，得到的粗产品经硅胶柱层析纯化，得到化合物8-4(0.38g,收率20％)。
LCMS:m/z(ESI):390.0。1H NMR(400MHz,DMSO-d6):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)。
在一个10mL微波管中，依次加入化合物8-4(420mg,1.08mmol)，NMP(2mL)、N,N-二异丙基乙胺(0.53mL,3.23mmol)和((1S，3S)-3-氨基环戊基)氨基甲酸叔丁酯(237mg,1.18mmol)。该反应液加热到80℃搅拌变溶清，然后在微波130℃反应2小时。反应完毕后，反应液加水(20mL)稀释，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层析纯化，得到化合物8-6(430mg,收率72％)。
LCMS:m/z(ESI):554.0[M+H]+。
室温下，将化合物8-6(430mg,0.72mmol)溶于氯化氢/二氧六环(4mL,4M)和MeOH(2mL)的混合溶液。在15℃反应16小时。反应完毕后，反应液加入饱和碳酸氢钠溶液(40mL)，并用二氯甲烷(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、过滤浓缩得到的粗产品经过硅胶柱层析纯化，得到化合物8-7(320mg,收率89％)。
LCMS:m/z(ESI):454.0[M+H]+。
化合物8的合成参考化合物7的合成路线，合成中间体8-7替代合成化合物7的中间体4-4。
得到化合物8(10.9mg)。LCMS:m/z(ESI):543.2[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.63–11.85(m,1H),8.58(s,1H),8.46–8.18(m,1H),8.08(s,1H),7.89–7.62(m,1H),7.33–6.79(m,1H),4.21–3.72(m,1H),3.61–3.47(m,2H),3.12(s,3H),2.27–2.17(m,1H),2.14–1.85(m,5H),1.81–1.72(m,1H),1.68–1.43(m,2H),1.31–1.08(m,3H)。
测试例1：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KD。KD(M)＝koff(s-1)/Kon(M-1s-1)；其中，Kon(ka)是结合速率；Koff(kd)是解离速率；s-1(每秒)和M-1s-1(每摩尔每秒)是koff和kon的单位。基于于CDK7的直接化合物结合KD(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＝Ki,脱靶/KD,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3所示。
表3本发明化合物的CDK7/Cyclin H SPR KD
测试例2：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：22400-089；胰酶(含EDTA)购自Gibco；货号：25200-072；FBS购自Excell；货号：FND500；CellTiter-Glo购自Promega；货号：G7573；Bovine insulin购自Yeasen；货号：40107ES25；DMSO购自SIGMA；货号：D2650-1000ML；磷酸盐缓冲液(DPBS)购自Corning；货号：21-031-CVR；细胞计数仪购自Beckman；型号：Vi-CELLXR Cell Viability Analyzer；酶标仪购自PerkinElmer；型号：2105
OVCAR-3为人卵巢腺癌细胞，使用含20％ FBS和0.01mg/mL Bovine insulin的RPMI-1640培养基在37℃，5％ CO2的培养箱中进行培养中。铺板时取对数生长期的细胞，用0.25％胰酶-EDTA消化、收集和计数细胞，并接种8000个OVCAR-3细胞/孔于96孔细胞板中，置于5％ CO2培养过夜。使用DMSO配制1000X的化合物3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处理细胞组作为溶媒对照(control)，不含细胞的培养基组为空白对照(blank)。加入化合物后继续培养细胞3天后，向每孔加入75μL CellTiter-Glo工作液，混匀，室温孵育20分钟，读取luminescence化学发光值，计算检测化合物的抑制率(Inhibition rate，IR)：IR(％)＝(1–(RLU化合物–RLU blank)/(RLU溶媒对照–RLU blank)*100％。在Excel中计算不同浓度化合物的抑制率，然后用GraphPad Prism软件作抑制曲线图和计算相关参数，包括Relative IC50,Bottom(％),Top(％)；Absolute IC50和Max(％)。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。示例性化合物的结果如下表4所示，其中“A”代表IC50为小于500nM；“B”代表<IC50为500nM至小于2000nM；“C”代表<IC50为等于或大于2000nM。
表4：本发明化合物的OVCAR-3肿瘤细胞增殖抑制活性
由表4可以看出，本发明化合物具有优异的OVCAR3细胞抑制活性。
测试例3：Caco-2透膜性和外排率的测定
1.预热：将汉克斯平衡盐缓冲液(HBSS)在37℃水浴中预热。
2.超声：将化合物从-20℃中取出，超声几分钟(不少于1分钟)。
3.空白溶液的配制
a).给药侧空白溶液：1)给药侧空白溶液(A-B方向)：含0.3％ DMSO与5μM荧光黄(LY)的转运缓冲液(pH7.4)：将150μL DMSO及50μL的5mM LY储备液加入50mL的HBSS；含0.2％ DMSO与5μM LY的转运缓冲液(pH7.4)：将100μL DMSO及50μL的5mM LY储备液加入50mL的HBSS；含0.1％ DMSO与5μM LY的转运缓冲液(pH7.4)：将50μL DMSO及50μL的5mM LY储备液加入50mL的HBSS。2)给药侧空白溶液(B-A方向)：含0.3％ DMSO的转运缓冲液(pH7.4)：将150μL DMSO加入50mL的HBSS；含0.1％ DMSO的转运缓冲液(pH7.4)：将50μL DMSO加入50mL的HBSS。
接收侧空白溶液：1)接收侧空白溶液(A-B方向)：含0.4％ DMSO的转运缓冲液(pH7.4)：将200μL DMSO加入50mL的HBSS；2)接收侧空白溶液(B-A方向)：含0.4％ DMSO与5μM荧光黄LY的转运缓冲液(pH7.4)：将200μL DMSO及50μL的5mM LY储备液加入50mL的HBSS；含0.3％ DMSO与5μM荧光黄LY的转运缓冲液(pH7.4)：将150μL DMSO及50μL的5mM LY储备液加入50mL的HBSS。
b).受试化合物和参照化合物工作液的配制
表5
4.离心：给药前将受试化合物和参照化合物工作液(步骤3)4000转/分钟离心5分钟。
5.给药：根据下表中列出的体积添加溶液(确保有额外的100μL给药溶液作为受试化合物和参照化合物的T0样品)。
表6

6.顶侧LYT0样品：从顶侧板每孔取出100μL样品放入黑色荧光测量板中用于制备LYT0样品。
7.预热：上述顶侧板和基底侧板分别放入37℃培养箱预热5分钟，然后把顶侧板和基底侧板组合启动转运实验。
8.细胞培养：将细胞板置于培养箱中37℃培养90分钟。
9.标曲溶液的配制
配制20×终浓度溶液
配制300μM工作储备液溶液：将6μL 10mM受试化合物溶液加入到194μL MeOH(MeOH/H2O＝v/v:1/1)中。
表7
配制1×终浓度溶液
3μL(20×)+57μL的HBSS(0.4％ DMSO)+60μL加内标的ACN(丙咪嗪)。
10.转运终止：90分钟培养结束后，将顶侧板与基底侧板分开终止转运实验。
11.LY的测量：从基底侧板每孔取出100μL样品放入黑色荧光测量板中用于制备LYT90样品。用酶标仪(激发波长485nm，发射波长535nm)测定LYT0和LYT90样品的响应值。
12.制备样品用于LC-MS/MS分析：1)给药侧样品用HBSS(0.4％ DMSO)稀释；2)60μL稀释的给药侧样品或未稀释的接收侧样品+60μL加内标的ACN(丙咪嗪)+50μL水。
通过接收端和给药端的具体浓度计算化合物在Caco-2细胞中的渗透率(Papp，单位10-6,cm/s)以及外排率(ER)。
表8：本发明化合物的Caco-2透膜性和外排率
由表8可以看出根据本发明化合物具有较高的Caco-2透膜性(Papp(A-B))以及较低的外排率(ER)。
以上对本公开技术方案的实施方式进行了示例性的说明。应当理解，本公开的保护范围不拘囿于上述实施方式。凡在本公开的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。

Claims (14)

  1. 式(I)所示化合物、其立体异构体或其药学上可接受的盐；
    其中，结构单元选自
    X1选自N或C(Rx1)；
    X2选自N或C(Rx2)；
    X3选自N或C(Rx3)；
    Y选自N或C(RY)；
    Z选自N或C(RZ)；
    L选自C1-8烷基、C1-8杂烷基、C2-8烯基或C2-8炔基，所述C1-8烷基、C1-8杂烷基、C2-8烯基或C2-8炔基任选被1个或多个RL取代；
    RL分别独立地选自卤素、氰基、-NO2、羟基、-ORa、-NRcRd、-C(＝O)Ra、-C(＝O)ORb、-C(＝O)NRcRd、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基或杂环基；
    或两个RL在同一个原子上，且连接在一起，形成＝O；
    或两个RL在相邻的两个原子上，且连接在一起，形成一个单键；
    或两个RL在同一个或不同原子上，且连接在一起形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基或杂芳基任选被1个或多个RLa取代；
    RLa分别独立地选自卤素、氰基、-NO2，羟基、-ORa、-NRcRd、-C(＝O)Ra、-C(＝O)ORb、-C(＝O)NRcRd、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基或C1-6杂烷基；
    Ra、Rb、Rc和Rd分别独立地选自H、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基、杂环基、芳基、杂芳基、C1-6烷基(环烷基)、C1-6烷基(杂环基)、C1-6烷基(芳基)或C1-6烷基(杂芳基)，所述C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基，杂环基、芳基、杂芳基、C1-6烷基(环烷基)、C1-6烷基(杂环基)、C1-6烷基(芳基)或C1-6烷基(杂芳基)任选被1个或多个R取代；
    或Rc和Rd连接在一起形成杂环基，所述杂环基任选被1个或多个R取代；
    Rx1、Rx2、RY、RZ、R3分别独立地选自H、卤素、羟基、氰基、-C2-4亚烯基-苯基、-C2-4亚炔基-苯基、-S(＝O)-OH、-S(＝O)2-OH、-S-(C1-6烷基)、C1-6烷基、-O-C1-6烷基、-C1-6亚烷基-O-C1-6烷基、-O-C1-6亚烷基-O-C1-6烷基、-C0-6亚烷基-NRR’、-C0-6亚烷基-C(＝O)OH、-C0-6亚烷基-C(＝O)-C1-6烷基、-C0-6亚烷基-C(＝O)-NRR’、-C0-6亚烷基-NR-C(＝O)-C1-6烷基、-C0-6亚烷基-S(＝O)2-C1-6烷基、-C0-6亚烷基-S(＝O)(＝NH)-C1-6烷基、-C0-6亚烷基-S(＝O)2-NRR’、-C0-6亚烷基-NR-S(＝O)2-C1-6烷基、-C0-6亚烷基-NR-S(＝O)2-NRR’、-C0-6亚烷基-P(＝O)O-(C1-6烷基)2、-C0-6亚烷基-P(＝O)-(C1-6烷基)(O-C1-6烷基)、-C0-6亚烷基-P(＝O)-(C1-6烷基)2、-C0-6亚烷基-3至14元环烷基、-C0-6亚烷基-3至14元杂环基、-C0-6亚烷基-5至12元杂芳基、-C0-6亚烷基-C6-12芳基、-C0-6亚烷基-C(＝O)-3至14元杂环基、-C0-6亚烷基-C(＝O)-5至12元杂芳基、-O-C0-6亚烷基-O-C1-6烷基、-O-C0-6亚烷基-3至14元环烷基、-O-C0-6亚烷基-3至14元杂环基、-O-C0-6亚烷基-5至12元杂芳基、-O-C0-6亚烷基-C6-12芳基、-S(＝O)-C1-6烷基；其中，所述C1-6烷基、C0-6亚烷基、C2-4亚烯基、3至14元环烷基、3至14元杂环基、5至12元杂芳基、C6-12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元杂环基具有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、C1-6烷基、-O-C1-6烷基、-C1-6亚烷基-O-C1-6烷基、-O-C1-6亚烷基-O-C1-6烷基、-C0-6亚烷基-NRR’、-C0-6亚烷基-C(O)OH、-C0-6亚烷基-C(＝O)-C1-6烷基、-C0-6亚烷 基-C(＝O)-NRR’、-C0-6亚烷基-NR-C(＝O)-C1-6烷基、-C0-6亚烷基-S(＝O)2-C1-6烷基、-C0-6亚烷基-S(＝O)2-NRR’、-C0-6亚烷基-NR-S(＝O)2-C1-6烷基、-C0-6亚烷基-NR-S(＝O)2-NRR’、-C0-6亚烷基-P(＝O)O-(C1-6烷基)2、-C0-6亚烷基-P(＝O)-(C1-6烷基)(O-C1-6烷基)、-C0-6亚烷基-P(＝O)-(C1-6烷基)2、-C0-6亚烷基-3至14元环烷基、-C0-6亚烷基-3至14元杂环基、-C0-6亚烷基-5至12元杂芳基、-C0-6亚烷基-C6-12芳基、-C0-6亚烷基-C(＝O)-3至14元杂环基、-C0-6亚烷基-C(＝O)-5至12元杂芳基、-O-C0-6亚烷基-O-C1-6烷基、-O-C0-6亚烷基-3至14元环烷基、-O-C0-6亚烷基-3至14元杂环基、-O-C0-6亚烷基-5至12元杂芳基、-O-C0-6亚烷基-C6-12芳基、-S(＝O)-C1-6烷基；
    Rx3分别独立地选自H、卤素、氰基、C1-12烷基或C1-12卤代烷基；
    R1选自H、卤素、氰基、C1-12烷基、C1-12卤代烷基、C1-12羟基烷基、C1-12杂烷基、环烷基或杂环烷基，所述C1-12烷基、C1-12卤代烷基、C1-12羟基烷基、环烷基或杂环烷基任选被1个或多个R111取代；
    R2选自H、卤素、氰基、C1-12烷基、C1-12卤代烷基、C1-12羟基烷基、C1-12杂烷基、环烷基或杂环烷基，所述C1-12烷基、C1-12卤代烷基、C1-12羟基烷基、环烷基或杂环烷基任选被1个或多个R222取代；
    环A选自环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基或杂芳基任选被1个或多个Raa取代；
    Raa分别独立地选自H、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基、杂环基、芳基、杂芳基、C1-6烷基(环烷基)、C1-6烷基(杂环基)、C1-6烷基(芳基)或C1-6烷基(杂芳基)，所述C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、环烷基，杂环基、芳基、杂芳基、C1-6烷基(环烷基)、C1-6烷基(杂环基)、C1-6烷基(芳基)或C1-6烷基(杂芳基)任选被1个或多个R取代；
    R、R’、R111、R222分别独立地选自卤素、氰基、羟基、-OCH3、-S(＝O)CH3、-S(＝O)2CH3、-S(＝O)2NH2、-S(＝O)2NHCH3、-S(＝O)2N(CH3)2、-NH2、-NHCH3、-N(CH3)2、-C(＝O)CH3、-C(＝O)OH、-C(＝O)OCH3、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基或C1-6杂烷基；
    所述杂烷基、杂芳基或杂环基包含1、2或3个独立选自O、NH、S、C(＝O)、C(＝O)O、S(＝O)、S(＝O)2和N的杂原子或杂原子团。
  2. 根据权利要求1所述的式(I)所示化合物、其立体异构体或其药学上可接受的盐，其具有式(Ia)所示的结构；
  3. 根据权利要求1或2所述的化合物、其立体异构体或其药学上可接受的盐，其中，
    -L-选自-L1A-L2A-L3A-L4A-L5A-，所述L1A、L2A、L3A、L4A或L5A分别独立地选自单键、-O-、-C(＝O)-、-S-、-S(＝O)-、-S(＝O)2-、任选取代的C1-3烷基、任选取代的环烷基、任选取代的杂环基、任选取代的杂芳基、任选取代的芳基、-NRL4-、
    RL4选自H、任选取代的C1-6烷基、任选取代的C1-6卤代烷基、任选取代的环烷基或任选取代的杂环基；
    RL5选自H、任选取代的C1-6烷基、任选取代的C1-6卤代烷基、任选取代的环烷基或任选取代的杂环基；
    任选地，所述L1A、L2A、L3A、L4A或L5A分别独立地选自单键、-O-、-C(＝O)-、-S-、-S(＝O)-、-S(＝O)2-、C1-3烷基、C3-6环烷基、3至6元杂环基、5至6元杂芳基、苯基、-NRL4-、所述C1-3烷基、C3-6环烷基、3至6元杂环基、5至6元杂芳基、苯基、-NRL4-、任选被1、2、3或4个RL6取代，
    RL4选自H、C1-6烷基、C1-6卤代烷基、C3-6环烷基或3至6元杂环基；
    RL5选自H、C1-6烷基、C1-6卤代烷基、C3-6环烷基或3至6元杂环基；
    RL6分别独立地选自C1-6烷基、C3-6环烷基、3至6元杂环基、5至6元杂芳基或苯基，所述C1-6烷基、C3-6环烷基、3至6元杂环基、5至6元杂芳基或苯基任选被1、2、3或4个卤素、0H、CN、NH2或C1-6烷基取代，
    或两个RL6在同一个碳原子上，且连在一起，形成C3-6环烷基或3至6元杂环基，所述C3-6环烷基或3至6元杂环基任选被1、2、3或4个卤素、0H、CN、NH2或C1-6烷基取代。
  4. 根据权利要求1或2所述的化合物、其立体异构体或其药学上可接受的盐，其中，
    -L-选自如下基团。
    -(O)m2-(CR13R14)m1-(NR12)m3-、
    -(NR11)m2-(CR13R14)m1-(NR12)m3-、
    -(O)m2-(CR13R14)m5-(C3-7环烷基)m4-(CR13R14)m6-(NR12)m3-、
    -(NR11)m2-(CR13R14)m5-(C3-7环烷基)m4-(CR13R14)m6-(NR12)m3-、
    -(O)m2-(CR13R14)m5-(3至7元杂环基)m4-(CR13R14)m6-(NR12)m3-、
    -(O)m2-(CR13R14)m5-(3至7元杂环基)m4-(CR13R14)m6-NR10C(O)-(CR13R14)m6-(NR12)m3-、
    -(NR11)m2-(CR13R14)m5-(3至7元杂环基)m4-(CR13R14)m6-(NR12)m3-、
    -(O)m2-(CR13R14)m5-(3至6元杂芳基)m4-(CR13R14)m6-(NR12)m3-、
    -(NR11)m2-(CR13R14)m5-(3至6元杂芳基)m4-(CR13R14)m6-(NR12)m3-、
    -(O)m2-(CR13R14)m5-NR10-(CR13R14)m6-(NR12)m3-、
    -(NR11)m2-(CR13R14)m5-NR10-(CR13R14)m6-(NR12)m3-、
    -(O)m2-(CR13R14)m5-NR10C(O)-(CR13R14)m6-(NR12)m3-、
    -(NR11)m2-(CR13R14)m5-NR10C(O)-(CR13R14)m6-(NR12)m3-、
    -(O)m2-(CR13R14)m5-C(O)NR10-(CR13R14)m6-(NR12)m3-、
    -(O)m2-(CR13R14)m5-C(O)NR10-(CR13R14)m6-(O)m2-(CR13R14)m5、
    -(NR11)m2-(CR13R14)m5-C(O)NR10-(CR13R14)m6-(NR12)m3-、
    -(O)m2-(CR13R14)m5-O-(CR13R14)m6-(NR12)m3-、
    -(NR11)m2-(CR13R14)m5-O-(CR13R14)m6-(NR12)m3-、
    -(O)m2-(CR13R14)m5-OC(O)-(CR13R14)m6-(NR12)m3-、
    -(NR11)m2-(CR13R14)m5-OC(O)-(CR13R14)m6-(NR12)m3-、
    -(O)m2-(CR13R14)m5-C(O)O-(CR13R14)m6-(NR12)m3-、
    -(NR11)m2-(CR13R14)m5-C(O)O-(CR13R14)m6-(NR12)m3-、
    -(O)m2-(CR13R14)m5-(CH＝CH)m7-(CR13R14)m6-(NR12)m3-、
    -(NR11)m2-(CR13R14)m5-(CH＝CH)m7-(CR13R14)m6-(NR12)m3-；
    R10分别独立地选自H、C1-6烷基、-C3-7环烷基、-C(O)-C1-6烷基、-C(O)-C1-4烷基-C1-6烷氧基、-C(O)-C3-7环烷基、-C1-4烷基-羟基、-C1-4烷基-氰基、-C1-4烷基-C1-6烷氧基、-C1-4烷基-NHC(O)-C1-6烷基、-C1-4烷基-NHC(O)-C1-4烷基-C1-6烷氧基、-C1-4烷基-NHC(O)-C3-7环烷基或-C1-4烷基-NRR’；
    R、R’各自独立地为氢、C1-6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；
    3至7元杂环基分别独立地具有1、2或3个独立地选自氮、氧和硫的杂原子；所述C3-7环烷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；
    C3-7环烷基分别独立地选自未取代的或被1、2、3、4或5个选自S1组的基团所取代；
    R11分别独立地选自H、C1-6烷基、C3-7环烷基或3至7元杂环基，所述C1-6烷基、C3-7环烷基或3至7元杂环基任选被1、2、或3个卤素、CN、OH或C1-6烷基取代；
    R12分别独立地选自H、C1-6烷基、C3-7环烷基或3至7元杂环基，所述C1-6烷基、C3-7环烷基或3至7元杂环基任选被1、2、或3个卤素、CN、OH或C1-6烷基取代；
    R13分别独立地选自H、氰基、羟基、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-C3-7环烷基、-C0-6亚烷基-NRR’、-C1-6亚烷基-羟基或-C0-6亚烷基-氰基；
    R14分别独立地选自H、氰基、羟基、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-C3-7环烷基、-C0-6亚烷基-NRR’、-C1-6亚烷基-羟基或-C0-6亚烷基-氰基；
    或R13、R14连接在一起，并与其相连的同一个碳原子或者不同的碳原子共同形成3-6元杂环基或C3-6环烷基，所述3-6元杂环基或C3-6环烷基任选被1、2、3、4或5个选自S1组的基团所取代；
    m1分别独立地为1、2、3、4、5或6；
    m2分别独立地为0或1；
    m3分别独立地为0或1；
    m4分别独立地为1或2；
    m5分别独立地为0、1、2、3、4、5或6；
    m6分别独立地为0、1、2、3、4、5或6；
    m7分别独立地为1或2。
  5. 根据权利要求1-4任一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，
    L选自 上端与环B连接，下端与V连接，。
  6. 根据权利要求1-5任一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，
    Rx1选自H、卤素、羟基、氰基、-C0-3亚烷基-P(＝O)-(C1-3烷基)2、-C0-3亚烷基-S(＝O)2-C1-3烷基、-C0-3亚烷基-S(O)(＝NH)-C1-3烷基或-C0-3亚烷基-S(＝O)(＝NH)-C1-3烷基；
    任选地，Rx1选自H、F、Cl、Br、I、羟基、氰基、-P(＝O)-(CH3)2、-P(＝O)-(CH2CH3)2、-S(＝O)2-CH3、-S(＝O)2-CH2CH3、-S(O)(＝NH)-CH3或-S(＝O)(＝NH)CH3。
  7. 根据权利要求1-6任一项所述的化合物、其立体异构体及其药学上可接受的盐，其中，
    R1选自H、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6杂烷基、C3-6环烷基或3-6元杂环烷基，所述C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6杂烷基、C3-6环烷基或3-6元杂环烷基任选被1个、2个或3个R111取代；
    任选地，R1选自H、卤素、氰基、C1-6烷基或C1-6卤代烷基，所述C1-6烷基或C1-6卤代烷基任选被1个、2个或3个R111取代；
    任选地，R2选自H、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6杂烷基、C3-6环烷基或3-6元杂环烷基，所述C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6杂烷基、C3-6环烷基或3-6元杂环烷基任选被1个、2个或3个R222取代；
    任选地，R2选自H、卤素、氰基、C1-6烷基或C1-6卤代烷基，所述C1-6烷基或C1-6卤代烷基任选被1个、2个或3个R222取代；
    任选地，R1选自H或CF3；
    任选地，R2选自H或CF3。
  8. 根据权利要求1-7任一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，
    环A选自C3-12环烷基或3-12元杂环基，所述C3-12环烷基或3-12元杂环基任选被1个或多个Raa取代；
    任选地，环A选自C3-6环烷基或3-6元杂环基，所述C3-6环烷基或3-6元杂环基任选被1个、2个或3个Raa取代；
    任选地，环A选自C5-6环烷基或5-6元杂环基，所述C5-6环烷基或5-6元杂环基任选被1个、2个或3个Raa取代；
    任选地，环A选自C5-6环烷基或5-6元杂环基；
    任选地，环A选自
  9. 下式化合物、其立体异构体或其药学上可接受的盐，其选自

  10. 一种化合物、其立体异构体或其药学上可接受的盐，其具有表1或表2中的结构之一。
  11. 一种药物组合物，其特征在于，包含权利要求1-10任一项所述化合物、其立体异构体或其药学上可接受的盐；
    以及，药学可接受的载体。
  12. 权利要求1-10任一项化合物、其立体异构体或其药学上可接受的盐或权利要求11所述的药物组合物制备预防和/或治疗CDK7相关疾病的药物中的用途。
  13. 根据权利要求12所述的用途，其特征在于，所述CDK7相关疾病为治增殖性疾病、传染性疾病、免疫疾病、自身免疫疾病或炎性疾病。
  14. 权利要求1-10任一项化合物、其立体异构体或其药学上可接受的盐或权利要求11所述的药物组合物制备CDK7抑制剂中的用途。
PCT/CN2024/099735 2023-06-19 2024-06-18 大环类化合物的合成及其在医药上的用途 WO2024260325A1 (zh)

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