WO2021139817A1 - 作为激酶抑制剂的多环化合物 - Google Patents

作为激酶抑制剂的多环化合物 Download PDF

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WO2021139817A1
WO2021139817A1 PCT/CN2021/071144 CN2021071144W WO2021139817A1 WO 2021139817 A1 WO2021139817 A1 WO 2021139817A1 CN 2021071144 W CN2021071144 W CN 2021071144W WO 2021139817 A1 WO2021139817 A1 WO 2021139817A1
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compound
alkyl
cancer
hydrogen
formula
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PCT/CN2021/071144
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English (en)
French (fr)
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张汉承
程鑫
贾薇
蔡聪聪
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杭州英创医药科技有限公司
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Priority to US17/757,944 priority Critical patent/US20230095043A1/en
Priority to AU2021206100A priority patent/AU2021206100A1/en
Priority to JP2022542781A priority patent/JP2023509994A/ja
Priority to EP21738700.0A priority patent/EP4089092A4/en
Priority to KR1020227027456A priority patent/KR20220140731A/ko
Priority to CN202180004135.3A priority patent/CN114174296B/zh
Priority to CA3164345A priority patent/CA3164345A1/en
Publication of WO2021139817A1 publication Critical patent/WO2021139817A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a new type of derivatives containing tricyclic heteroaryl groups, its synthesis method and its use as a variety of kinase inhibitors including CDK and/or TRK.
  • the preparation of the medicine is used in the treatment of tumors and other related diseases.
  • Cancer also known as malignant tumor, is one of the diseases with the highest morbidity and mortality in the world. It is characterized by abnormal cell proliferation and metastasis, which spreads and metastasizes in a short or relatively short time after the onset of disease.
  • Traditional treatment options include surgical treatment (if the conditions for resection are met), radiotherapy, and chemotherapy.
  • the targeted therapy developed in recent years has the advantages of reducing toxicity and negative effects, and improving survival rate. However, after using targeted drugs for a period of time, drug resistance will develop, and then the growth and spread of cancer cells will be extremely rapid.
  • Common cancers are: blood cancer, lung cancer, breast cancer, liver cancer, bladder cancer, rectal cancer, stomach cancer, etc.
  • the regulation of the cell cycle is mainly affected by a series of serine/threonine kinases.
  • This type of serine/threonine kinase is also called Cyclin-dependent kinase (CDK).
  • CDK Cyclin-dependent kinase
  • the human CDK family has more than 20 subtypes, which are divided into two major categories according to different functions: one type of CDK regulates the cell cycle, such as CDK2/4/6, etc.; the other type of CDK participates in transcription regulation/RNA processing, such as CDK7/ 9 and so on.
  • CDK kinase binds to the cyclin protein to form a specific complex, which is then activated.
  • CDK is overactive or CDK-inhibiting proteins do not work, leading to abnormal proliferation and division of cancer cells. Therefore, CDK has become an important target of anti-tumor drugs.
  • CDK2 and CDK4/6 are key regulators of the cell cycle.
  • G0 phase the transcriptional activity of the transcription factor E2F is inhibited by retinoblastoma protein (Rb).
  • Rb retinoblastoma protein
  • Cyclin D Cyclin D
  • CDK4/6 phosphorylates Rb, leading to the activation of E2F.
  • E2F remains bound to the Rb protein, but can transcribe proteins such as CCNE1, CCNA2, CCNB1, and CDK2.
  • CyclinE binds to and activates CDK2, and CDK2 further phosphorylates Rb, leading to the complete release of Rb and activation of E2F.
  • E2F then induces the transcription of S-phase proteins such as CyclinA and CyclinE.
  • CDK2/CyclinA and CDK1 maintain the phosphorylation of Rb protein to ensure the process of cell division.
  • CDK2/CyclinA assists the conversion process of S/G2 phase. Therefore, inhibiting the kinase activity of CDK2 and CDK4/6 can block the progress of the cell cycle and achieve the purpose of inhibiting tumor proliferation.
  • CDK4/6 inhibitors Palbociclib, Ribociclib, and Abemaciclib have been approved for marketing, and there is currently no effective CDK2 inhibitor.
  • CDK9 mainly regulates the RNA transcription process. CDK9 and the corresponding Cyclin form a forward transcription elongation factor complex-b (P-TEFb). Most of CDK9 binds CyclinT1, only a small amount of CDK9 binds CyclinT2a, CyclinT2b and CyclinK.
  • CDK9 is the catalytic subunit in the P-TEF complex, which can phosphorylate the C-terminal domain of RNA polymerase II and promote the RNA transcription elongation process of many oncogenes, such as MYC and MCL-1.
  • CDK9/CyclinK complex also plays an important role in maintaining genome stability.
  • the overexpression of CDK9 is closely related to a variety of hematoma, lung cancer, liver cancer, breast cancer, colon cancer, bladder cancer and brain tumors.
  • CDK9 also plays an important role in the replication of human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • CDK9/CyclinT1 phosphorylates RNA polymerase II, promotes the interaction of polymerase and HIV key protein Tat activation domain, and stimulates the transcription process of HIV-1. Therefore, inhibiting the catalytic activity of CDK9 can inhibit the transcription of oncogenes such as MYC, control the growth and survival of cancer cells, and control the replication of HIV virus.
  • CDK16 is expressed in a variety of human cells and tissue types. The tissues with the highest expression are the brain and testis. The activation of CDK16 depends on CyclinY. Knockout of CDK16 will not affect the normal growth of mice, but will cause infertility in male mice, indicating that CDK16 plays an important role in sperm production. Overexpression of CDK16 can promote the growth and invasion of a variety of cancer cells, such as lung cancer and liver cancer. This effect may be related to the down-regulation of tumor suppressor p27 by CDK16.
  • CDK5 is a special protein in the CDK family. Although the protein sequence has many similarities with other CDK members, the main function of CDK5 depends on non-Cyclin proteins, such as p35 and p39. CDK5 is expressed in many human tissues, but most of its activating factors p35 and p39 are expressed in neurons, so its function is mainly concentrated in the nervous system. By phosphorylating a variety of neuronal proteins, such as Tau, Axin, CRMP2 and Neurofilament, CDK5 can regulate the physiological functions of a variety of neurons, such as neuronal migration, axon growth, synapse formation, memory formation, and pain perception, etc. .
  • neuronal proteins such as Tau, Axin, CRMP2 and Neurofilament
  • CDK5 In the neurons of neurodegenerative patients, CDK5 more stably binds to the splice body p25 of p35, and abnormal activation occurs, leading to the degeneration and death of nerve cells. In addition, CDK5 also plays a role in immune response, angiogenesis, cell cycle regulation, DNA damage response, cell senescence and apoptosis. Therefore, CDK5 has gradually become an important target against neurodegenerative diseases and cancer.
  • the Neurotrophin Receptor Kinase (NTRK) family includes TRKA, TRKB, and TRKC, which are encoded by NTRK1, NTRK2, and NTRK3 genes, respectively, and are usually expressed in nerve tissues.
  • TRK receptors can be activated by a variety of neurotrophic factors. Among them, NGF mainly activates TRKA, BDNF and NT-4/5 mainly activate TRKB, and BT-3 mainly activates TRKC. After TRK binds to the corresponding ligand, dimerization and phosphorylation will occur, which in turn activates downstream signaling pathways such as PI3K/AKT, RAS/RAF/MEK and PLC-gamma to promote cell proliferation and survival.
  • NTRK gene fusion mutations have been proved to be related to a variety of cancers. Gene fusion allows NTRK genes (mainly NTRK1 and NTRK3) to be fused with other genes, and then transcribed and translated into continuously activated TRK protein, driving tumors with TRK fusion mutations Cell growth and proliferation. The probability of NTRK fusion mutation accounts for about 0.31% of the total number of adult cancers and 0.34% of the total number of juvenile cancers. NTRK3 fusion mutations are more common in some rare tumors, such as secretory breast cancer, fibrosarcoma, and salivary gland cancer. NTRK1 mutations mainly exist in the lungs. In common cancer types such as adenocarcinoma and colon cancer, the incidence of mutations is relatively low. In addition, the excessive activation of the NGF-TRKA signaling pathway also plays an important role in the pathogenesis of inflammatory pain and cancer pain.
  • NTRK genes mainly NTRK1 and NTRK3
  • the present invention provides a new type of kinase inhibitor, which can be used to inhibit various kinases such as CDK and TRK.
  • X is hydrogen, deuterium, halogen, C 1-4 alkyl, OR 1 , NR 1 R 2 , or NR 1 C(O)R 3 ;
  • G is NR f , O, S, S(O), S(O) 2 or CR g R g ;
  • p 0, 1, 2, or 3;
  • n and n are independently 0, 1, 2, or 3; the prerequisite is that m and n cannot be 0 at the same time;
  • R 1 and R 2 are each independently hydrogen or C 1-4 alkyl
  • R 3 is C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl;
  • R f is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, cyano substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl , 4- to 8-membered heterocyclic group, aryl, heteroaryl, C(O)R 4 , C(O)OR 1 , C(O)NR 1 R 2 , S(O) 2 R 4 , or S(O) 2 NR 1 R 2 ;
  • R 4 is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl;
  • each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups is optionally and each independently by 1 to 3 substituents each independently selected from the following group Substitution: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, Aryl, heteroaryl, CN, NO 2 , OR 1 , SR 1 , NR 1 R 2 , C(O)R 4 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C( O) R 4 , or S(O) 2 R 4 , provided that the chemical structure formed is stable and meaningful; wherein the definitions of R 1 , R 2 , and R 4 are as described above;
  • aryl groups are aromatic groups containing 6-12 carbon atoms; heteroaryl groups are 5- to 15-membered heteroaromatic groups; cyclic structures are saturated or unsaturated, containing heteroatoms Or cyclic groups without heteroatoms.
  • X is hydrogen, deuterium, halogen, C 1-4 alkyl, OR 1 , NR 1 R 2 , or NR 1 C(O)R 3 ;
  • G is NR f , O, S, S(O), S(O) 2 or CR g R g ;
  • p 0, 1, 2, or 3;
  • n are each independently 1, 2, or 3;
  • R 1 and R 2 are each independently hydrogen or C 1-4 alkyl
  • R 3 is C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl;
  • R f is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclic group , Aryl, heteroaryl, C(O)R 4 , C(O)OR 1 , C(O)NR 1 R 2 , or S(O) 2 R 4 ;
  • R 4 is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl;
  • each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups is optionally and each independently by 1 to 3 substituents each independently selected from the following group Substitution: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, Aryl, heteroaryl, CN, NO 2 , OR 1 , SR 1 , NR 1 R 2 , C(O)R 4 , C(O)OR 1 , C(O)NR 1 R 2 , NR 1 C( O) R 4 , or S(O) 2 R 4 , provided that the chemical structure formed is stable and meaningful; wherein the definitions of R 1 , R 2 , and R 4 are as described above;
  • aryl groups are aromatic groups containing 6-12 carbon atoms; heteroaryl groups are 5- to 15-membered heteroaromatic groups; cyclic structures are saturated or unsaturated, containing heteroatoms Or cyclic groups without heteroatoms.
  • the 4- to 8-membered heterocyclic group is a 4- to 6-membered heterocyclic group.
  • formula (I) is:
  • G is NR f , O, or CR g R g ; m and n are each independently 1 or 2; wherein R f is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclic group, aryl, heteroaryl, C(O)R 4 , or S(O) 2 R 4 ; wherein R 4 is C 1-4 alkane Group, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclic group.
  • the It is a 4- or 6-membered ring.
  • formula (I) is:
  • X is hydrogen, halogen, C 1-4 alkyl
  • G is NR f , O, or CR g R g ; m and n are each independently 1 or 2; wherein R f is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl , 4- to 8-membered heterocyclic group, aryl, heteroaryl, C(O)R 4 , or S(O) 2 R 4 ; wherein R 4 is C 1-4 alkyl, C 2-4 alkene Group, C 2-4 alkynyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclic group.
  • formula (I) is:
  • X is hydrogen, halogen, C 1-4 alkyl
  • G is NR f , O, or CR g R g ; m and n are each independently 1 or 2; wherein R f is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl , 4- to 8-membered heterocyclic group, aryl, heteroaryl, C(O)R 4 , or S(O) 2 R 4 ; wherein R 4 is C 1-4 alkyl, C 2-4 alkene Group, C 2-4 alkynyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclic group.
  • R f is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, cyano substituted C 1-4 alkyl, C 3-8 cycloalkyl, C(O)R 4 , Or S(O) 2 R 4 ; wherein R 4 is a C 1-4 alkyl group.
  • each R g is independently hydrogen or halogen.
  • X is hydrogen, fluorine, or methyl
  • G is NR f , O, or CR g R g ; m and n are each independently 1 or 2; wherein R f is hydrogen, methyl, ethyl, CH 2 CF 3 , CH 2 CN, cyclopropyl, C( O) CH 3 , or S(O) 2 CH 3 ; each R g is independently hydrogen or fluorine.
  • the compound of formula (I) is a compound selected from the following group, or a mixture with its corresponding enantiomer:
  • the salt is hydrochloride.
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of the compound of formula I according to the first aspect of the present invention, or an optical isomer thereof, which is pharmaceutically acceptable Salts, prodrugs, deuterated forms, hydrates, solvates.
  • the pharmaceutical composition includes: (i) an effective amount of the compound of formula I according to the first aspect of the present invention, or an optical isomer thereof, a pharmaceutically acceptable salt, or a prodrug , Deuterated forms, hydrates, solvates; and (ii) pharmaceutically acceptable carriers.
  • the third aspect of the present invention provides a compound as described in the first aspect of the present invention, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated form, hydrate, solvate thereof, Or the use of the pharmaceutical composition according to the second aspect of the present invention for:
  • the kinase is selected from the following group: CDK and/or TRK.
  • the fourth aspect of the present invention provides a compound as described in the first aspect of the present invention, or its optical isomers, pharmaceutically acceptable salts and prodrugs, deuterated forms, hydrates, and solvates, Or the use of the pharmaceutical composition according to the second aspect of the present invention as a kinase inhibitor, or for the treatment of diseases related to high kinase expression; wherein the kinase is selected from the group consisting of CDK and/or TRK.
  • the fifth aspect of the present invention provides a method for inhibiting kinase activity, the method comprising the step of: administering an inhibitory effective amount of the compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof, to a subject to be inhibited , Pharmaceutically acceptable salts, prodrugs, deuterated forms, hydrates, solvates, or administering an inhibitory effective amount of the pharmaceutical composition according to the second aspect of the present invention to a subject to be inhibited; wherein the kinase Selected from the group: CDK and/or TRK.
  • the disease is selected from the group consisting of DNA and RNA virus infection, B-cell lymphoma, monocytic leukemia, splenomegaly, eosinophilia syndrome, and primary thrombocytopenia Disease, systemic giant cell disease, hematoma, solid tumor, neurodegenerative disease.
  • the disease is selected from the following group: allergic asthma, myelofibrosis, rheumatoid arthritis, inflammatory pain, cancer pain, AIDS, sporangial virus and influenza virus, secretory breast cancer , Fibrosarcoma, salivary gland cancer, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glioma, ovarian cancer, Head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, stomach cancer, multiple bone marrow cancer, brain tumor, lung cancer, Alzheimer's disease, Parkinson's disease.
  • the sixth aspect of the present invention provides a method for preparing the compound according to the first aspect of the present invention, the method comprising the steps:
  • the compound of formula Ia is reacted with the compound of formula Ib to obtain the compound of formula I.
  • the method further includes the steps:
  • the inventors unexpectedly discovered a class of polycyclic compounds with novel structures as kinase inhibitors, as well as their preparation methods and applications.
  • the compounds of the present invention can be applied to the treatment of various diseases related to the activity of various kinases including CDK, TRK, etc. Based on the above findings, the inventor completed the present invention.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • alkyl refers to a linear (ie, unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of linear and branched groups .
  • the number of carbon atoms in front of the alkyl group is limited (such as C 1-10 ), it means that the alkyl group contains 1-10 carbon atoms.
  • C 1-8 alkyl refers to an alkyl group containing 1-8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or Similar groups.
  • alkenyl refers to a straight or branched chain carbon chain group with at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When the alkenyl group has a limited number of carbon atoms (such as C 2-8 ), it means that the alkenyl group contains 2-8 carbon atoms.
  • C 2-8 alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or the like group.
  • alkynyl refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
  • the alkynyl group can be linear or branched, or a combination thereof.
  • the alkynyl group has a limited number of carbon atoms (such as C 2-8 alkynyl), it means that the alkynyl group contains 2-8 carbon atoms.
  • C 2-8 alkynyl refers to a straight-chain or branched alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, S-butynyl, tert-butynyl, or similar groups.
  • cycloalkyl refers to a saturated or partially saturated unitary ring, bicyclic or polycyclic (fused, bridged, or spiro) ring system group .
  • a certain cycloalkyl group has a limit on the number of carbon atoms (such as C 3-10 ), it means that the cycloalkyl group contains 3-10 carbon atoms.
  • C 3-8 cycloalkyl refers to a saturated or partially saturated monocyclic or bicyclic alkyl group with 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl Group, cycloheptyl group, or similar group.
  • Spirocycloalkyl refers to a bicyclic or polycyclic group that shares one carbon atom (called a spiro atom) between single rings. These can contain one or more double bonds, but none of the rings have fully conjugated ⁇ electrons. system.
  • “Fused cycloalkyl” refers to a full carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double Bond, but none of the rings have a fully conjugated ⁇ -electron system.
  • “Bridged cycloalkyl” refers to all-carbon polycyclic groups in which any two rings share two carbon atoms that are not directly connected. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system .
  • the atoms contained in the cycloalkyl group are all carbon atoms.
  • the following are some examples of cycloalkyl groups, and the present invention is not limited to the following cycloalkyl groups.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) groups with a conjugated ⁇ -electron system, such as phenyl and naphthyl.
  • the aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen or sulfur, and the point of connection to the parent must be in a conjugated ⁇ -electron system.
  • Aryl groups can be substituted or unsubstituted. The following are some examples of aryl groups, and the present invention is not limited to the following aryl groups.
  • Heteroaryl refers to an aromatic monocyclic or polycyclic group containing one to more heteroatoms (optionally from nitrogen, oxygen, and sulfur), or a heterocyclic group (containing one to more heteroatoms).
  • Heteroaryl groups can be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups. The present invention is not limited to the following heteroaryl groups.
  • Heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl.
  • the polycyclic heterocyclic group refers to a heterocyclic group including a spiro ring, a condensed ring, and a bridged ring.
  • “Spirocyclic heterocyclyl” refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between each ring in the system and other rings in the system, wherein one or more ring atoms are selected from nitrogen and oxygen. Or sulfur, and the remaining ring atoms are carbon.
  • “Fused ring heterocyclic group” refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but no A ring has a fully conjugated ⁇ -electron system, and one or more of the ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon.
  • “Bridged heterocyclic group” refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system , And one or more of the ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If there are both saturated and aromatic rings in the heterocyclic group (for example, the saturated ring and the aromatic ring are fused together), the point of connection to the parent must be on the saturated ring. Note: When the point of attachment to the parent is on the aromatic ring, it is called a heteroaryl group, not a heterocyclic group. The following are some examples of heterocyclic groups, and the present invention is not limited to the following heterocyclic groups.
  • halogen refers to F, Cl, Br, and I when alone or as part of other substituents.
  • substituted refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent.
  • the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
  • an arbitrarily substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
  • a cyclic substituent, such as a heterocyclic group can be connected to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, that is, two rings have a common carbon atom.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are for example (but not limited to): C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic group , Aryl, heteroaryl, halogen, hydroxyl, carboxy (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino.
  • the term "pharmaceutically acceptable salt” refers to a salt suitable for contact with the tissue of a subject (e.g., a human) without causing unpleasant side effects.
  • the pharmaceutically acceptable salt of a certain compound of the present invention includes a salt of the compound of the present invention having an acidic group (e.g., potassium salt, sodium salt, magnesium salt, calcium salt) or a salt with basic The group is a salt of the compound of the present invention (for example: sulfate, hydrochloride, phosphate, nitrate, carbonate).
  • the present invention provides a class of compounds of formula (I), or their deuterated forms, their pharmaceutically acceptable salts, optical isomers (enantiomers or diastereomers, if any Case), hydrates, solvates, or pharmaceutical combinations comprising compounds represented by formula (I), optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated forms, hydrates, and solvates
  • kinase activity wherein the kinase includes but not limited to CDK and/or TRK.
  • the compound of the present invention can be used as a kinase inhibitor.
  • the kinase is CDK and/or TRK.
  • the expression or activity of the various protein kinases mentioned above are significantly increased. These overexpression and/or abnormal protein kinase activity levels are directly related to the occurrence and development of tumors.
  • the compounds of the invention are single and/or dual inhibitors of these protein kinases. By regulating the activity of these protein kinases, diseases can be prevented, alleviated or cured.
  • the diseases referred to include allergic asthma, myelofibrosis, rheumatoid arthritis, inflammatory pain, cancer pain, AIDS, spore virus and influenza virus and other DNA and RNA virus infections, B cell lymphoma, monocytic leukemia, Splenomegaly, eosinophilia syndrome, primary thrombocytopenia, systemic giant cell disease, secretory breast cancer, fibrosarcoma, salivary gland cancer, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small Cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer , Skin cancer, lymphoma, gastric cancer, brain tumor, lung cancer, multiple bone marrow cancer and other blood tumors and solid tumors, as well as neurodegenerative diseases such as
  • multi-target kinase inhibitors interfere with several different kinases at the same time, and the anti-tumor effects produced are often additive, so they have the potential to treat various cancers more effectively.
  • the compounds of the present invention can be combined with other small molecule drugs or biological agents such as PD-1 inhibitors (such as with ) As a combination medicine to treat various cancers and related diseases.
  • compositions can be administered to humans or animals for the treatment of disorders, symptoms and diseases.
  • the composition can be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injections, sterile powders and the like.
  • the pharmaceutical composition is a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders.
  • the amount of the compound or the pharmaceutical composition administered to the patient is not fixed, and is usually administered in a pharmaceutically effective amount.
  • the amount of the compound actually administered can be determined by the physician according to the actual situation, including the disease to be treated, the route of administration selected, the actual compound administered, the individual condition of the patient, and so on.
  • the dosage of the compound of the present invention depends on the specific use of the treatment, the mode of administration, the state of the patient and the judgment of the physician.
  • the ratio or concentration of the compound of the present invention in the pharmaceutical composition depends on a variety of factors, including dosage, physical and chemical properties, route of administration and the like.
  • the compound of formula I of the present invention can be prepared by the following method:
  • each group is as described above.
  • the reagents and conditions of each step can be selected from the conventional reagents or conditions of this type of preparation method in the art. After the structure of the compound of the present invention is disclosed, the above selection can be carried out by those skilled in the art according to the knowledge in the field.
  • the compound represented by the general formula I of the present invention can be prepared by the following method, but the conditions of the method, such as reactants, solvent, base, amount of compound used, reaction temperature, reaction time required, etc. are not limited to the following explanation of.
  • the compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • each reaction is usually carried out in an inert solvent, and the reaction temperature is usually -20 to 150°C (preferably 0 to 120°C).
  • the reaction time of each step is usually 0.5 ⁇ 48h, preferably 2 ⁇ 12h.
  • the compound of the present invention has excellent inhibitory activity against a series of protein kinases
  • the compound of the present invention and its various crystal forms, optical isomers, pharmaceutically acceptable inorganic or organic salts, prodrugs, deuterated forms, hydrated Compounds or solvates, and pharmaceutical compositions containing the compound of the present invention as the main active ingredients can be used to treat, prevent and alleviate diseases related to the activity or expression of kinases such as CDK and TRK.
  • the pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 5-200 mg of the compound of the present invention/agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include, but are not limited to, fillers (or diluents), disintegrants, lubricants, binders, bases, emulsifiers, wetting agents, coloring agents, flavoring agents, stabilizers, Antioxidants, preservatives, pyrogen-free water, etc.
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier).
  • the dosage form may also contain buffering agents.
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, propellant and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the dosage when administered is the effective dosage considered pharmaceutically, for a person with a body weight of 60 kg, the daily dosage is It is usually 1 to 2000 mg, preferably 5 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
  • CDK CDK2, CDK4, CDK5, CDK6, CDK9, CDK16 and TRKA, TRKB, TRKC, etc.
  • TRK including CDK2, CDK4, CDK5, CDK6, CDK9, CDK16 and TRKA, TRKB, TRKC, etc.
  • the activity of the above-mentioned protein kinase can be inhibited at the same concentration.
  • a class of pharmaceutical compositions for treating diseases related to kinase activity such as CDK and TRK is provided.
  • kinase inhibitor such as CDK and TRK with good oral absorption.
  • the Caliper mobility shift assay was used to determine the CDK2/CycA2, CDK4/CycD3 and CDK6/cycD3 protein kinase activities.
  • the compound was dissolved in DMSO and diluted with kinase buffer (CDK2/CycA2and CDK6/cycD3 with 50mM HEPES (pH 7.5), 10mM MgCl2, 0.0015% Brij-35, and 2mM dithiothreitol; CDK4/CycD3 with 20mM HEPES (pH 7.5), 10mM MgCl2, 0.01% Triton X-100, and 2mM dithiothreitol), add 5 ⁇ l of compound (10% DMSO) at 5 times the final concentration of the reaction in a 384-well plate.
  • Caliper mobility shift assay was used to measure TRKA protein kinase activity.
  • the compound was dissolved in DMSO to prepare a 10 mM stock solution.
  • the test compound was transferred to the target plate 3573 using a dispenser Echo 550 at a final concentration of 250 nl100x.
  • the ADP-Glo Kinase Assay was used to determine the activity of CDK5/p35NCK, CDK9/CycT1 and CDK16/CycY protein kinases. Dilute the positive drug and test compound (10mM stock solution) 25 times with 100% DMSO, and dilute 4 times in a 96-well dilution plate. Take 1 ⁇ L of the compound and add 49 ⁇ L of kinase reaction buffer (1mM Tris, 20mM MgCl). 2 , 0.10% BSA, and 0.5mM DTT), shake on a microplate shaker for 20 minutes.
  • Transfer 2 ⁇ L of 2x kinase to the 384 reaction plate add 1 ⁇ L of the test compound to the 384 reaction plate, centrifuge at 1000 rpm/min, centrifuge for 1 min, and incubate at 25° C. for 10 min.
  • the compound of the present invention has comparable CDK4 and CDK6 inhibitory activity to the CDK4/6 selective inhibitor Palbociclib (Ref-A) in the prior art, and also has stronger CDK2, CDK5, CDK9, CDK16 and TRKA kinases. Its inhibitory activity is a multi-target kinase inhibitor.
  • Animals 3 male SD rats with a weight range of 200-220g. After purchase, they will be kept in the laboratory of the Experimental Animal Center for 2 days and then used. They will be fasted for 12 hours before and 4 hours after the drug. Free water during the test period. After the rats were gavage, blood samples were taken according to the established time point.
  • Solvent 0.5% Methycellulose (aqueous solution containing 0.4% Tween 80 and 1% ethanol). Preparation of the solution for intragastric administration: accurately weigh the compound, add it to the solvent, and ultrasonically at room temperature for 5 minutes to completely dissolve the drug to prepare a 0.3 mg/ml solution.
  • compositions representative compounds of the structure shown in formula (I) of the patent of the present invention.
  • multiple samples with similar structures are taken, accurately weighed, and administered together (cassette PK).
  • cassette PK administered together
  • a single administration was also used to study the pharmacokinetics of the drug sample in rats.
  • Ref-A and Ref-B are shown in the following formula:
  • the compound of the present invention also has good inhibitory activity against other CDK subtypes (including CDK2, CDK5, CDK9, and CDK16). Therefore, it is a pan-CDK inhibitor, and is also a pan-CDK inhibitor.
  • Kinase also has good inhibitory activity. However, there is no record in the prior art that such compounds have inhibitory activity against the above-mentioned CDK subtypes and TRK kinase.
  • the compound of the present invention also has significantly improved pharmacokinetic properties compared with such compounds as CDK inhibitors currently in the art. After administration, the peak plasma concentration and exposure of the compound of the present invention in rats increased significantly, suggesting that the compound of the present invention can be administered at a lower dose.

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Abstract

本发明提供了一类作为激酶抑制剂的多环化合物。具体地，本发明提供了如下式(I)所示结构的化合物（各基团定义如说明书中所述）、含有式(I)化合物的药物组合物及所述化合物，以及这些化合物的其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物等等。其能够有效抑制包括CDK和/或TRK在内的多种激酶，从而起到治疗各种肿瘤等相关多种疾病的作用。

Description

作为激酶抑制剂的多环化合物 技术领域
本发明涉及药物化学领域；具体地说，本发明涉及一类新型含有三环杂芳基的衍生物，其合成方法及其作为一种包括CDK和/或TRK在内的多种激酶抑制剂在制备药物用于治疗肿瘤等相关多种疾病中的应用。
背景技术
癌症亦称恶性肿瘤，是世界上发病率和死亡率最高的疾病之一，其特点是细胞异常增殖及转移，在发病后短时间内或相对短时间内扩散，转移。传统的治疗方案包括手术治疗(如果符合切除条件)、放疗、化疗。近年来发展起来的靶向治疗法，有降低毒性和负作用，及提高生存率等优点。但在使用靶向药物一段时间后又会产生抗药性，之后癌细胞的生长扩散就会异常迅猛。常见的癌症有：血癌、肺癌、乳腺癌、肝癌、膀胱癌、直肠癌、胃癌等。
细胞周期的调控主要受一系列丝氨酸/苏氨酸激酶的影响，这类丝氨酸/苏氨酸激酶又被称作细胞周期蛋白依赖性激酶(Cyclin-dependent kinase,CDK)，它们通过与其相对应的调节亚基周期素(cyclins)相结合，推动细胞周期的进行、遗传信息的转录和细胞的正常分裂增殖。人的CDK家族有20多种亚型，根据不同的功能主要分为两大类：一类CDK调控细胞周期，如CDK2/4/6等；一类CDK参与转录调控/RNA加工，如CDK7/9等。CDK激酶结合到细胞周期素蛋白上，形成特定的复合体，从而被激活。在许多人类癌症中，CDK过度活跃或抑制CDK的蛋白质不起作用，导致癌细胞的异常增殖分裂。因此，CDK成为抗肿瘤药物的重要靶标。
CDK2和CDK4/6是细胞周期的关键调节因子。在细胞静息状态(G0期)下，转录因子E2F的转录活性被视网膜母细胞瘤蛋白(Rb)抑制。当细胞接受分裂信号刺激时，细胞进入G1期。在G1期，细胞周期素D(CyclinD)结合并激活CDK4/6，激活的CDK4/6磷酸化Rb，导致E2F的激活。此时E2F保持和Rb蛋白的结合，但是可以转录CCNE1、CCNA2、CCNB1和CDK2等蛋白。在G1期后期(限制点之后)，CyclinE结合并激活CDK2，CDK2进一步磷酸化Rb，导致Rb彻底释放和激活E2F，E2F接下来诱导CyclinA和CyclinE等S期蛋白的转录。CDK2/CyclinA和CDK1等维持Rb蛋白的磷酸化，确保细胞分裂的进程。CDK2/CyclinA辅助S/G2期的转换过程。因此，抑制CDK2和CDK4/6的激酶活性，可以阻滞细胞周期的进程，达到抑制肿瘤增殖的目的。CDK4/6抑制剂Palbociclib、Ribociclib、Abemaciclib已获批上市，目前尚无有效的CDK2抑制剂。CDK9主要调控RNA转录过程，CDK9和相对应的Cyclin形成正向转录延长因子复合体-b(P-TEFb)。大部分的CDK9结合CyclinT1，只有少量CDK9结合CyclinT2a、CyclinT2b和CyclinK。CDK9是P-TEF复合体中的催化亚基，可以磷酸化RNA聚合酶II的C末端结构域，促进多种癌基因的RNA转录延长过程，如MYC和MCL-1等。MYC和MCL-1在多种癌症种类中都有明显的异常过表达，但是目前尚没有有效的靶向抑制剂。另外，在细胞复制压力下，CDK9/CyclinK复合体对维持基因组稳定性也起着重要的作用。CDK9的过表达和多种血液瘤、肺癌，肝 癌、乳腺癌、结肠癌、膀胱癌和脑瘤等密切相关。在人免疫缺陷型病毒(HIV)的复制中，CDK9也起着重要的作用。CDK9/CyclinT1磷酸化RNA聚合酶II，促进聚合酶和HIV关键蛋白Tat激活结构域的相互作用，刺激HIV-1的转录过程。因此，抑制CDK9的催化活性可以抑制MYC等癌基因的转录，控制癌细胞的生长和存活，以及控制HIV病毒的复制等。
CDK16在人的多种细胞和组织类型中都有表达，表达最高的组织是脑部和睾丸。CDK16的激活依赖CyclinY。敲除CDK16不会影响小鼠的正常生长，但是会导致雄性小鼠不育，说明CDK16对精子生成起着很重要的作用。CDK16的过表达可以促进多种癌细胞，如肺癌和肝癌等的生长和侵袭，这种作用可能和CDK16下调肿瘤抑制因子p27有关。
CDK5是CDK家族中一个比较特殊的蛋白，尽管蛋白序列和其他CDK成员有很多相似性，但是CDK5的主要功能依赖于非Cyclin蛋白，如p35和p39等。CDK5在人的很多组织中都有表达，但它的激活因子p35和p39等大部分表达在神经元中，所以它的功能主要集中在神经系统中。通过磷酸化多种神经元蛋白，如Tau、Axin、CRMP2和Neurofilament等，CDK5可以调控多种神经元的生理功能，如神经元迁移、轴突生长、神经突触形成、记忆形成和疼痛感知等。在神经退行性患者的神经元中，CDK5更稳定地结合p35的剪切体p25，发生异常激活，导致神经细胞的退化和死亡。此外，CDK5在免疫响应、血管生成、细胞周期调控、DNA损伤应答、细胞衰老和凋亡等方面也发挥着一定的作用。因此，CDK5逐渐成为抗神经退行性疾病和癌症等的重要靶标。
神经营养因子受体激酶(NeuroTrophin Receptor Kinase，NTRK)家族包含TRKA、TRKB和TRKC，它们分别由NTRK1、NTRK2和NTRK3基因编码，通常在神经组织中表达。TRK受体可以被多种神经营养因子激活，其中NGF主要激活TRKA，BDNF和NT-4/5主要激活TRKB，BT-3因子主要激活TRKC。TRK结合相应的配体后，会发生二聚化、磷酸化，进而激活下游的PI3K/AKT、RAS/RAF/MEK和PLC-gamma等信号通路，促进细胞增殖和存活。
NTRK基因融合突变被证明与多种癌症相关，基因融合使得NTRK基因(主要是NTRK1和NTRK3)与其他的基因融合在一起，继而转录，翻译为持续性激活的TRK蛋白，驱动TRK融合突变的肿瘤细胞的生长和增殖。NTRK融合突变概率约占成人癌症总数的0.31％和青少年癌症总数的0.34％，NTRK3的融合突变在一些罕见肿瘤，如分泌性乳腺癌、纤维肉瘤、唾液腺癌等比较常见，NTRK1突变主要存在于肺腺癌，结肠癌等常见的癌症种类中，突变发生率比较低。另外，NGF-TRKA信号通路的过度激活在炎症性疼痛和癌痛的发病机制中也起着重要的作用。
综上所述，开发新型、针对不同亚型的CDK、TRK等激酶抑制剂具有重要的意义。
发明内容
本发明提供一类新型的激酶抑制剂，所述的抑制剂可以用于CDK、TRK等多种激酶的抑制。
本发明的第一方面，提供了一种如下式(I)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物：
Figure PCTCN2021071144-appb-000001
“*”表示手性中心；
X为氢、氘、卤素、C 1-4烷基、OR 1、NR 1R 2、或NR 1C(O)R 3；
各个R各自独立为氢或C 1-4烷基；或当两个R同时连接到同一个碳原子上时，这两个R与其相连的碳原子可以任选共同形成羰基(C＝O)；
G为NR f、O、S、S(O)、S(O) 2或CR gR g；
p为0、1、2、或3；
m和n各自独立为0、1、2、或3；前提条件是m和n不能同时为0；
R 1和R 2各自独立为氢或C 1-4烷基；
R 3为C 1-4烷基、C 2-4烯基、或C 2-4炔基；
R f为氢、C 1-4烷基、C 1-4卤代烷基、氰基取代C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基、芳基、杂芳基、C(O)R 4、C(O)OR 1、C(O)NR 1R 2、S(O) 2R 4、或S(O) 2NR 1R 2；
各个R g各自独立地选自下组：氢、卤素、或C 1-4烷基；或两个R g与其相连的碳原子共同形成羰基(C＝O)；或两个R g与其连接的碳原子一起形成3-至8-元环状结构，此环状结构任选地含有0、1或2个选自N、O、S的杂原子；
R 4为C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基、芳基、或杂芳基；
其中，各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR 1、SR 1、NR 1R 2、C(O)R 4、C(O)OR 1、C(O)NR 1R 2、NR 1C(O)R 4、或S(O) 2R 4，前提条件是所形成的化学结构是稳定的和有意义的；其中，R 1、R 2、R 4的定义如上所述；
除非特别说明，上述的芳基为含有6-12个碳原子的芳香基团；杂芳基为5-至15-元杂芳香基团；环状结构为饱和的或不饱和的、含杂原子或不含杂原子的环状基团。
在另一优选例中，“*”表示手性中心；
X为氢、氘、卤素、C 1-4烷基、OR 1、NR 1R 2、或NR 1C(O)R 3；
各个R各自独立为氢或C 1-4烷基；或当两个R同时连接到同一个碳原子上时，这两个R与其相连的碳原子可以任选共同形成羰基(C＝O)；
G为NR f、O、S、S(O)、S(O) 2或CR gR g；
p为0、1、2、或3；
m和n各自独立为1、2、或3；
R 1和R 2各自独立为氢或C 1-4烷基；
R 3为C 1-4烷基、C 2-4烯基、或C 2-4炔基；
R f为氢、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基、芳基、杂芳基、C(O)R 4、C(O)OR 1、C(O)NR 1R 2，或S(O) 2R 4；
各个R g各自独立地选自下组：氢、卤素、或C 1-4烷基；或两个R g与其相连的碳原子共同形成羰基(C＝O)；或两个R g与其连接的碳原子一起形成3-至8-元环状结构，此环状结构任选地含有0、1或2个选自N、O、S的杂原子；
R 4为C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基、芳基、或杂芳基；
其中，各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR 1、SR 1、NR 1R 2、C(O)R 4、C(O)OR 1、C(O)NR 1R 2、NR 1C(O)R 4、或S(O) 2R 4，前提条件是所形成的化学结构是稳定的和有意义的；其中，R 1、R 2、R 4的定义如上所述；
除非特别说明，上述的芳基为含有6-12个碳原子的芳香基团；杂芳基为5-至15-元杂芳香基团；环状结构为饱和的或不饱和的、含杂原子或不含杂原子的环状基团。
在另一优选例中，所述的4-至8-元杂环基为4-至6-元杂环基。
在另一优选例中，式(I)为：
Figure PCTCN2021071144-appb-000002
“*”表示手性中心；
X、R、G、p、m、和n的定义如本发明第一方面中所述。
在另一优选例中，X为氢、卤素、C 1‐4烷基；R为氢，或两个R与其相连的碳原子共同形成羰基(C＝O)。
在另一优选例中，G为NR f、O、或CR gR g；m和n各自独立为1或2；其中R f为氢、C 1-4烷基、C 1-4卤代烷基、C 3-8环烷基、4-至8-元杂环基、芳基、杂芳基、C(O)R 4、或S(O) 2R 4；其中R 4为C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基。
在另一优选例中，所述的
Figure PCTCN2021071144-appb-000003
为4或6元环。
在另一优选例中，式(I)为：
Figure PCTCN2021071144-appb-000004
“*”表示手性中心；
X为氢、卤素、C 1-4烷基；
G为NR f、O、或CR gR g；m和n各自独立为1或2；其中R f为氢、C 1-4烷基、C 1-4卤代烷基、C 3-8环烷基、4-至8-元杂环基、芳基、杂芳基、C(O)R 4、或S(O) 2R 4；其中R 4为C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基。
在另一优选例中，式(I)为：
Figure PCTCN2021071144-appb-000005
“*”表示手性中心；
X为氢、卤素、C 1-4烷基；
G为NR f、O、或CR gR g；m和n各自独立为1或2；其中R f为氢、C 1-4烷基、C 1-4卤代烷基、C 3-8环烷基、4-至8-元杂环基、芳基、杂芳基、C(O)R 4、或S(O) 2R 4；其中R 4为C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基。
在另一优选例中，R f为氢、C 1-4烷基、C 1-4卤代烷基、氰基取代C 1-4烷基、C 3-8环烷基、C(O)R 4、或S(O) 2R 4；其中R 4为C 1-4烷基。
在另一优选例中，各个R g各自独立为氢或卤素。
在另一优选例中，式(IV)或式(V)中：
“*”表示手性中心；
X为氢、氟、或甲基；
G为NR f、O、或CR gR g；m和n各自独立为1或2；其中R f为氢、甲基、乙基、CH 2CF 3、CH 2CN、环丙烷基、C(O)CH 3、或S(O) 2CH 3；各个R g各自独立为氢或氟。
在另一优选例中，所述的式(I)化合物为选自下组的化合物，或与与其对应的对映异构体的混合物：
Figure PCTCN2021071144-appb-000006
Figure PCTCN2021071144-appb-000007
Figure PCTCN2021071144-appb-000008
Figure PCTCN2021071144-appb-000009
在另一优选例中，所述的盐为盐酸盐。
本发明的第二方面，提供了一种药物组合物，所述的药物组合物包括有效量的如本发明第一方面所述的式I化合物、或其光学异构体，药学上可接受的盐、前药、氘代形式、水合物、溶剂合物。
在另一优选例中，所述的药物组合物包括：(i)有效量的如本发明第一方面所述的式I化合物、或其光学异构体，药学上可接受的盐、前药、氘代形式、水合物、溶剂合物；和(ii)药学上可接受的载体。
本发明的第三方面，提供了一种如本发明第一方面所述的化合物、或其光学异构体、药学上可接受的盐、前药、氘代形式、水合物、溶剂合物，或如本发明第二方面所述的药物组合物的用途，用于：
(a)制备治疗与激酶活性或表达量相关的疾病的药物；
(b)制备激酶靶向抑制剂；和/或
(c)体外非治疗性地抑制激酶的活性；
其中，所述的激酶选自下组：CDK和/或TRK。
本发明的第四方面，提供了一种如本发明第一方面所述的化合物、或其光学异构体、药学上可接受的盐及前药、氘代形式、水合物、溶剂合物，或如本发明第二方面所述的药物组合物的用途，作为激酶抑制剂，或用于治疗与激酶高表达相关的疾病；其中，所述的激酶选自下组：CDK和/或TRK。
本发明的第五方面，提供了一种抑制激酶活性的方法，所述方法包括步骤：对抑制对象施用抑制有效量的如本发明第一方面所述的式I化合物、或其光学异构体、药学上可接受的盐、前药、氘代形式、水合物、溶剂合物、或对抑制对象施用抑制有效量的如本发明第二方面所述的药物组合物；其中，所述的激酶选自下组：CDK和/或TRK。
在另一优选例中，所述的疾病选自下组：DNA和RNA病毒感染、B细胞淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征、原发性血小板减少症、系统性巨细胞疾病、血液瘤、实体瘤、神经退行性疾病。
在另一优选例中，所述的疾病选自下组：过敏性哮喘、骨髓纤维化、类风湿性关节炎、炎症性疼痛、癌痛、艾滋病、孢疹病毒和流感病毒、分泌性乳腺癌、纤维肉瘤、唾液腺癌、肝癌、直肠癌、膀胱癌、咽喉癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、淋巴瘤、胃癌、多发性骨髓癌、脑瘤、肺癌、阿兹海默症、帕金森。
本发明的第六方面，提供了一种如本发明第一方面所述化合物的制备方法，该方法包括步骤：
Figure PCTCN2021071144-appb-000010
在惰性溶剂中，用式Ia化合物与式Ib化合物反应，得到式I化合物。
在另一优选例中，所述的方法还包括步骤：
Figure PCTCN2021071144-appb-000011
(1)在惰性溶剂中，用式1-A3化合物进行脱保护，得到式1-A3-a化合物；
(2)在惰性溶剂中，用式1-A3-a化合物与式1-A3-b化合物进行还原胺化反应，得到式1-A4化合物；
(3)在惰性溶剂中，用式1-A4化合物进行还原反应，得到式Ia化合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地发现了一类结构新颖的作为激酶抑制剂的多环化合物，以及它们的制备方法和应用。本发明化合物可以应用于与包括CDK、TRK等在内的多种激酶活性相关的各种疾病的治疗。基于上述发现，发明人完成了本发明。
术语
除特别说明之处，本文中提到的“或”具有与“和/或”相同的意义(指“或”以及“和”)。
除特别说明之处，本发明的所有化合物之中，各手性碳原子(手性中心)可以任选地为R构型或S构型，或R构型和S构型的混合物。
如本文所用，在单独或作为其他取代基一部分时，术语“烷基”指只含碳原子的直链(即，无支链)或支链饱和烃基，或直链和支链组合的基团。当烷基前具有碳原子数限定(如C 1-10)时，指所述的烷基含有1-10个碳原子。例如，C 1-8烷基指含有1-8个碳原子的烷基，包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“烯基”是指直链或支链，具有至 少一个碳-碳双键的碳链基团。烯基可以是取代的或未取代的。当烯基前具有碳原子数限定(如C 2-8)时，指所述的烯基含有2-8个碳原子。例如，C 2-8烯基指含有2-8个碳原子烯基，包括乙烯基、丙烯基、1,2-丁烯基、2,3-丁烯基、丁二烯基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“炔基”是指具有至少一个碳-碳三键的脂肪族碳氢基团。所述的炔基可以是直链或支链的，或其组合。当炔基前具有碳原子数限定(如C 2-8炔基)时，指所述的炔基含有2-8个碳原子。例如，术语“C 2-8炔基”指具有2-8个碳原子的直链或支链炔基，包括乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、仲丁炔基、叔丁炔基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“环烷基”指具有饱和的或部分饱和的单元环，二环或多环(稠环、桥环或螺环)环系基团。当某个环烷基前具有碳原子数限定(如C 3-10)时，指所述的环烷基含有3-10个碳原子。在一些优选实施例中，术语“C 3-8环烷基”指具有3-8个碳原子的饱和或部分饱和的单环或二环烷基，包括环丙基、环丁基、环戊基、环庚基、或类似基团。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的二环或多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳二环或多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。所述环烷基所含原子全部为碳原子。如下是环烷基的一些例子，本发明并不仅局限下述的环烷基。
Figure PCTCN2021071144-appb-000012
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环)，但不能含有杂原子如氮、氧或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。如下是芳基的一些例子，本发明并不仅局限下述的芳基。
Figure PCTCN2021071144-appb-000013
“杂芳基”指包含一个到多个杂原子(任选自氮、氧和硫)的具有芳香性的单环或多环基团，或者包含杂环基(含一个到多个杂原子任选自氮、氧和硫)与芳基稠合形成的多环基团，且连接位点位于芳基上。杂芳基可以是任选取代的或未取代的。如下是 杂芳基的一些例子，本发明并不仅局限下述的杂芳基。
Figure PCTCN2021071144-appb-000014
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基。多环杂环基指包括螺环、稠环和桥环的杂环基。“螺环杂环基”指系统中的每个环与体系中的其他环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。“稠环杂环基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，而且其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。“桥环杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，而且其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。如果杂环基里同时有饱和环和芳环存在(比如说饱和环和芳环稠合在一起)，连接到母体的点一定是在饱和的环上。注：当连接到母体的点在芳环上时，称为杂芳基，不称为杂环基。如下是杂环基的一些例子，本发明并不仅局限下述的杂环基。
Figure PCTCN2021071144-appb-000015
如本文所用，在单独或作为其他取代基一部分时，术语“卤素”指F、Cl、Br和I。
如本文所用，术语“取代”(在有或无“任意地”修饰时)指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现 的取代基。除非特别说明，某个任意取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环基，可以与另一个环相连，例如环烷基，从而形成螺二环系，即两个环具有一个共用碳原子。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C 1-8醛基、C 2-10酰基、C 2-10酯基、氨基。
为了方便以及符合常规理解，术语“任意取代”或“任选取代”只适用于能够被取代基所取代的位点，而不包括那些化学上不能实现的取代。
如本文所用，除非特别说明，术语“药学上可接受的盐”指适合与对象(例如，人)的组织接触，而不会产生不适度的副作用的盐。在一些实施例中，本发明的某一化合物的药学上可接受的盐包括具有酸性基团的本发明的化合物的盐(例如：钾盐、钠盐、镁盐、钙盐)或具有碱性基团的本发明的化合物的盐(例如：硫酸盐、盐酸盐、磷酸盐、硝酸盐、碳酸盐)。
用途：
本发明提供了一类式(I)的化合物，或它们的氘代形式、它们的药学上可接受的盐、光学异构体(对映异构体或非对映异构体，如果存在的情况下)、水合物、溶剂合物、或包含式(I)所示化合物、其光学异构体、药学上可接受的盐、前药、氘代形式、水合物、溶剂合物的药物组合物用于抑制激酶活性的用途，其中，所述的激酶包括但并不限于CDK和/或TRK。
本发明化合物可用作激酶抑制剂，优选地，所述的激酶为CDK和/或TRK。
在癌症病人体内，上述所提到的各种蛋白激酶的表达或活性都明显增高。这些过度表达和/或异常的蛋白激酶活性水平与肿瘤的发生发展直接关联。本发明化合物是这些蛋白激酶的单一和/或双重抑制剂。通过调节这些蛋白激酶活性得到预防、缓解或治愈疾病。所指疾病包括过敏性哮喘、骨髓纤维化、类风湿性关节炎、炎症性疼痛、癌痛、艾滋病、孢疹病毒和流感病毒等DNA和RNA病毒感染、B细胞淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征、原发性血小板减少症、系统性巨细胞疾病、分泌性乳腺癌、纤维肉瘤、唾液腺癌、肝癌、直肠癌、膀胱癌、咽喉癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、淋巴瘤、胃癌、脑瘤、肺癌、多发性骨髓癌等各种血液瘤和实体瘤，以及阿兹海默症和帕金森等神经退行性疾病。
从某种角度上说，多靶点激酶抑制剂同时干扰几种不同的激酶，所产生的抗肿瘤效果往往具有叠加性，因此具有更有效治疗各种癌症的潜力。
本发明化合物可与其它小分子药物或生物制剂如PD-1抑制剂(如
Figure PCTCN2021071144-appb-000016
和
Figure PCTCN2021071144-appb-000017
)作为组合药物治疗各种癌症及相关疾病。
可将本发明化合物及其氘代形式，以及药学上可接受的盐或其异构体(如果存在的情况下)或其水合物和/或组合物与药学上可接受的赋形剂或载体配制在一起，得到的组合物可在给予人或动物，用于治疗病症、症状和疾病。组合物可以是：片剂、丸剂、 混悬剂、溶液剂、乳剂、胶囊、气雾剂、无菌注射液，无菌粉末等。在优选的实施方式中，所述药物组合物是适于口服的剂型，包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。向患者施用本发明化合物或药物组合物的量不固定，通常按药用有效量给药。同时，实际给予的化合物的量可由医师根据实际情况决定，包括治疗的病症、选择的给药途径、给予的实际化合物、患者的个体情况等。本发明化合物的剂量取决于治疗的具体用途、给药方式、患者状态、医师判断。本发明化合物在药物组合物中的比例或浓度取决于多种因素，包括剂量、理化性质、给药途径等。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。
化合物的通用合成方法
本发明的式I化合物可以通过以下方法制备得到：
反应式1:
Figure PCTCN2021071144-appb-000018
在惰性溶剂中，用(Ia)化合物与(Ib)反应，得到(I)化合物；
上述各式中，各基团的定义如上文中所述。各步骤的试剂和条件可以选用本领域进行该类制备方法常规的试剂或条件，在本发明的化合物结构公开后，上述选择可以由本领域技术人员根据本领域知识进行。
更具体地，本发明通式I所示化合物可通过如下的方法制得，然而该方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易地进行。
在本发明的制备方法中，各反应通常在惰性溶剂中，反应温度通常为-20～150℃(优选0～120℃)下进行。各步反应时间通常为0.5～48h，较佳地为2～12h。
化合物IIa和IIIa是化合物I的一部分。反应式2描述了化合物IIa和IIIa的通用合成方法：
反应式2:
Figure PCTCN2021071144-appb-000019
上述反应式1-2中X、R、G、m、n、p的定义与本发明第一方面中表述相同。
中间体Ib是根据Journal of Medicinal Chemistry,2005,2371-2387及里面所引用的文献来制备的。
药物组合物和施用方法
由于本发明化合物具有优异的对一系列蛋白激酶的抑制活性，因此本发明化合物及其各种晶型、光学异构体、药学上可接受的无机或有机盐、前药、氘代形式、水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与CDK、TRK等激酶活性或表达量相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药 理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子包括但不限于填充剂(或称稀释剂)、崩解剂、润滑剂、粘合剂、基质、乳化剂、润湿剂、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的人或动物，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的CDK、TRK(包括CDK2、CDK4、CDK5、CDK6、CDK9、CDK16和TRKA、TRKB、TRKC等)等激酶抑制剂及其制备和应用，所述的抑制剂在低浓度下即可抑制上述蛋白激酶的活性。
3.提供了一类治疗与CDK、TRK等激酶活性相关疾病的药物组合物。
4.提供了一种口服吸收良好的的CDK、TRK等激酶抑制剂。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1:化合物1S的制备
Figure PCTCN2021071144-appb-000020
将化合物1S-a(600mg，2.21mmol)溶于甲醇(20mL)中，再加入四氢吡喃酮(1S-b，265mg，2.65mmol)和三乙胺(224mg，2.21mmol)。该反应混合物在50℃下搅拌2小时。随后在室温下加入氰基硼氢化钠(208mg,3.31mmol)并搅拌3小时。TLC监测反应完毕。反应混合物减压除去甲醇，然后加水(10mL)，再用二氯甲烷萃取(3×20mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后滤液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:乙酸乙酯＝1:1)得黄色固体化合物1S-c(580mg,收率82％)。MS m/z 320.4[M+H] +。
室温下向化合物1S-c(580mg,1.82mmol)的甲醇(15mL)溶液中加入钯碳催化剂(10％,70mg)。该反应混合物在室温和1大气压的氢气氛围下搅拌3小时。TLC监测反应完毕。反应混合物经过硅藻土过滤，滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝50:1)得到棕色固体化合物1S-d(460mg,收率88％)。MS m/z 290.4[M+H] +。
将化合物1S-d(200mg,0.69mmol)和Ib(230mg,0.69mmol)溶于甲苯(6mL)中。该反应混合物在90℃下搅拌3小时。TLC监测反应完毕。待反应液冷却至室温后，减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝80:1)得到黄色固体化合物1S(290mg,收率75％)。MS m/z 559.8[M+H] +。
将化合物1S(290mg,0.52mmol)溶于二氯甲烷(10mL)中，冰浴下加入盐酸甲醇溶液(4.0M,0.13mL,0.52mmol)。该反应混合物在室温下搅拌1小时后减压浓缩除去溶 剂。所得粗品加水(5mL)后再冻干得到黄色固体化合物1S盐酸盐(290mg)。 1H NMR(500MHz,CD 3OD)δ8.77(s,1H),7.16(s,1H),6.99(s,2H),5.90-5.75(m,1H),4.37(dd,J＝10.9,2.4Hz,1H),4.17(d,J＝13.2Hz,1H),4.11-4.04(m,3H),3.82-3.70(m,2H),3.63-3.49(m,2H),3.45(t,J＝11.5Hz,2H),3.29-3.22(m,1H),3.20-3.06(m,1H),2.96(t,J＝11.8Hz,1H),2.47(s,3H),2.33(s,3H),2.30-2.19(m,2H),2.18-2.10(m,2H),2.01-1.76(m,6H),1.67-1.53(m,2H)ppm。MS m/z 559.8[M+H] +。
实施例2:化合物2S的制备
Figure PCTCN2021071144-appb-000021
将化合物1S-a(500mg,1.84mmol)、N-甲基哌啶酮(2S-a,416mg,3.68mmol)和2滴醋酸加入甲醇(15mL)中并在室温下搅拌1小时。随后加入氰基硼氢化钠(231mg,3.68mmol)，反应混合物在室温下搅拌过夜。TLC监测反应完毕。反应混合物减压除去甲醇，然后加水(10mL)，再用二氯甲烷萃取(3×20mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后滤液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝30:1)得到黄色固体化合物2S-b(500mg)直接用于下一步反应。
室温下向甲醇(15mL)中加入化合物2S-b(500mg,1.50mmol)和钯碳催化剂(10％,70mg)。该反应混合物在室温和1大气压的氢气氛围下搅拌3小时。TLC监测反应完毕。反应混合物经过硅藻土过滤，滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1)得到棕色固体化合物2S-c(280mg,收率62％)。
将化合物2S-c(280mg,0.93mmol)和Ib(310mg,0.93mmol)溶于甲苯(8mL)中。该反应混合物在90℃下搅拌3小时。TLC监测反应完毕。待反应液冷却至室温后，减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1)得到黄色固体化合物2S(180mg,收率34％)。 1H NMR(500MHz,DMSO-d 6)δ9.86(bs,1H),8.90(s,1H),7.16(d,J＝2.1Hz,1H),7.06(d,J＝8.9Hz,1H),6.81(d,J＝8.9Hz,1H),5.91-5.70(m,1H),4.23 (dd,J＝10.5,2.4Hz,1H),3.89(dd,J＝10.5,9.0Hz,1H),3.69(d,J＝11.3Hz,1H),3.00–2.88(m,3H),2.79(d,J＝11.2Hz,2H),2.59–2.53(m,1H),2.41(s,3H),2.34–2.16(m,7H),2.14(s,3H),1.94–1.73(m,9H),1.62-1.51(m,2H),1.48–1.36(m,2H)ppm。MS m/z 572.8[M+H] +。
将化合物2S(180mg,0.31mmol)溶于二氯甲烷(10mL)中，冰浴下加入盐酸甲醇溶液(4.0M,0.08mL,0.32mmol)。该反应混合物在室温下搅拌1小时后减压浓缩除去溶剂。所得粗品加水(5mL)后再冻干得到黄色固体化合物2S盐酸盐(185mg)。 1H NMR(500MHz,CD 3OD)δ8.79(s,1H),7.21(s,1H),7.05-6.97(m,2H),5.92-5.80(m,1H),4.42-4.35(m,1H),4.19(d,J＝13.0Hz,1H),4.11-4.07(m,1H),3.81-3.71(m,4H),3.68-3.54(m,2H),3.21-3.11(m,4H),3.06-3.00(m,1H),2.92(s,3H),2.58-2.50(m,2H),2.47(s,3H),2.34(s,3H),2.32-2.23(m,2H),2.22-2.11(m,2H),1.98-1.77(m,4H),1.67-1.56(m,2H)ppm。MS m/z 572.8[M+H] +。
实施例3:化合物2R的制备
Figure PCTCN2021071144-appb-000022
将化合物2R-a(100mg,0.43mmol)，N-甲基-4-哌啶酮(2S-a,144mg,1.28mmol)和2滴醋酸的甲醇(6mL)混合液在室温下搅拌1小时。随后加入氰基硼氢化钠(80mg,1.28mmol)，反应混合物在室温下搅拌过夜。TLC监测反应完毕。反应混合物减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝20:1,2％氨水)得到黄色固体化合物2R-b(200mg)直接用于下一步反应。MS m/z 333.5[M+H] +。
室温下向甲醇(6mL)中加入化合物2R-b(200mg,0.60mmol)和钯碳催化剂(10％,80mg)，该反应混合物在室温和1大气压的氢气氛围下搅拌1小时。TLC监测反应完毕。反应混合物经过硅藻土过滤，滤液经减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝20:1,2％氨水)得到黄色油状化合物2R-c(93mg,两步收率72％)。MS m/z 303.5[M+H] +。
将化合物2R-c(50mg,0.17mmol)和化合物Ib(55mg,0.17mmol)的甲苯(1mL)混合液置于封管中，加热至100℃搅拌过夜。TLC监测反应完毕。反应混合物冷却至室温后减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1)得到黄色固体化合物2R(43mg,收率45％)。 1H NMR(500MHz,DMSO-d 6)δ9.87(bs,1H),8.90(s,1H), 7.16(d,J＝2.0Hz,1H),7.06(d,J＝8.0Hz,1H),6.81(d,J＝8.9Hz,1H),5.91-5.70(m,1H),4.23(dd,J＝10.5,2.4Hz,1H),3.89(dd,J＝10.4,9.1Hz,1H),3.69(d,J＝11.3Hz,1H),3.02-2.89(m,3H),2.80(d,J＝11.0Hz,2H),2.58-2.51(m,1H),2.41(s,3H),2.34-2.15(m,7H),2.14(s,3H),1.95-1.68(m,9H),1.63-1.52(m,2H),1.48-1.36(m,2H)ppm。MS m/z572.8[M+H] +。
实施例4:化合物3S的制备
Figure PCTCN2021071144-appb-000023
将化合物1S-a(1g,4.25mmol)溶于甲醇(20mL)中，再加入N-叔丁氧羰基-4-哌啶酮(3S-a,2.54g,12.75mmol)和4滴醋酸。该反应混合物在室温下搅拌1小时。随后加入氰基硼氢化钠(801mg,12.75mmol)反应混合物在室温下搅拌过夜。TLC监测反应完毕。反应混合物减压除去甲醇，然后加入水(10mL)，再用二氯甲烷萃取(3×20mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后滤液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1)得黄色固体化合物3S-b(1.39g,收率78％)。MS m/z 419.5[M+H] +。
室温下向甲醇(5mL)中加入化合物3S-b(190mg,0.45mmol)和钯碳催化剂(10％,60mg)。该反应混合物在室温和1大气压的氢气氛围下搅拌3小时。TLC监测反应完毕。反应混合物经过硅藻土过滤，滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝40:1)得到黄色固体化合物3S-c(80mg,收率45％)。MS m/z 389.5[M+H] +。
将化合物3S-c(80mg,0.21mmol)和Ib(69mg,0.21mmol)溶于甲苯(1mL)中。该反应混合物在90℃下搅拌过夜。TLC监测反应完毕。待反应液冷却至室温后，减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝30:1)得到黄色固体化合物3S-d(30mg,收率22％)。MS m/z 658.8[M+H] +。
将化合物3S-d(30mg,0.45mmol)溶于甲醇(2mL)中，冰浴下加入盐酸二氧六环溶液(4.0M,1.1mL,4.4mmol)。该反应混合物在室温下搅拌1小时后减压浓缩除去溶剂。向所得浓缩液中加入饱和碳酸氢钠溶液调节pH至7～8，再用二氯甲烷萃取(3×10mL)。 合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后滤液减压浓缩。所得粗品经制备型薄板层析分离纯化(二氯甲烷:甲醇＝20:1)得黄色固体3S(13mg,收率51％)。 1H NMR(500MHz,CDCl 3)δ8.70(s,1H),7.11(bs,1H),7.11(d,J＝2.5Hz,1H),6.97(dd,J＝9.0,2.5Hz,1H),6.76(d,J＝9.0Hz,1H),5.88-5.80(m,1H),4.20(dd,J＝10.0,2.0Hz,1H),4.03(t,J＝10.0Hz,1H),3.67(d,J＝12.0Hz,1H),3.22-3.10(m,3H),3.03(d,J＝11.0Hz,1H),2.89(d,J＝10.5Hz,1H),2.82-2.75(m,1H),2.61(t,J＝11.5Hz,2H),2.54(s,3H),2.54-2.47(m,1H),2.44-2.39(m,1H),2.34(s,3H),2.34-2.25(m,2H),2.07(t,J＝10.8Hz,1H),1.99-1.89(m,2H),1.86-1.79(m,4H),1.67-1.56(m,2H),1.49-1.38(m,2H)ppm。MS m/z 558.8[M+H] +。
实施例5:化合物4S的制备
Figure PCTCN2021071144-appb-000024
将化合物3S-b(500mg,1.19mmol)溶于甲醇(10mL)中，冰浴下加入盐酸二氧六环溶液(4.0M,3mL,12mmol)。该反应混合物在室温下搅拌1小时后减压浓缩除去溶剂得到黄色粗品化合物4S-a(500mg)。该粗品化合物直接用于下一步反应。MS m/z 319.5[M+H] +。
将化合物4S-a(140mg,0.36mmol)溶于甲醇(5mL)中，再缓慢滴加DIPEA(0.2mL,1.32mmol)和碘乙烷(137mg,0.88mmol)。该反应混合液在50℃条件下反应过夜。TLC监测反应完毕。反应混合物减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1)得到黄色油状化合物4S-b(56mg,收率45％)。MS m/z 347.5[M+H] +。
室温下向甲醇(3mL)中加入化合物4S-b(56mg,0.16mmol)和钯碳催化剂(10％,30mg)。该反应混合物在室温和1大气压的氢气氛围下搅拌3小时。TLC监测反应完毕。反应混合物经过硅藻土过滤，滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝20:1)得到黄色固体化合物4S-c(36mg,收率70％)。MS m/z 317.5[M+H] +。
将化合物4S-c(36mg,0.11mmol)和Ib(45mg,0.14mmol)溶于甲苯(1mL)中。该 反应混合物在90℃下搅拌过夜。TLC监测反应完毕。待反应液冷却至室温后，减压浓缩。所得粗品经制备型薄板层析分离纯化(二氯甲烷:甲醇＝30:1)得到黄色固体化合物4S(25mg,收率38％)。 1H NMR(500MHz,CDCl 3)δ8.70(s,1H),7.23(bs,1H),7.11(d,J＝2.5Hz,1H),6.95(dd,J＝9.0,2.5Hz,1H),6.76(d,J＝9.0Hz,1H),5.88-5.80(m,1H),4.19(dd,J＝10.5,2.5Hz,1H),4.02(dd,J＝10.5,9.5Hz,1H),3.66(d,J＝11.5Hz,1H),3.17-3.10(m,1H),3.07(d,J＝10.5Hz,2H),3.01(d,J＝9.5Hz,1H),2.86(d,J＝10.0Hz,1H),2.81-2.75(m,1H),2.54(s,3H),2.54-2.42(m,3H),2.39-2.27(m,3H),2.34(s,3H),2.08(t,J＝10.8Hz,1H),2.05-1.75(m,8H),1.70-1.56(m,4H),1.13(t,J＝7.0Hz,3H)ppm。MS m/z586.8[M+H] +。
实施例6:化合物5S的制备
Figure PCTCN2021071144-appb-000025
在0℃下向化合物4S-a(200mg,0.63mmol)的二氯甲烷(5mL)溶液中加入DIPEA(0.3mL,1.88mmol)，接着缓慢滴加乙酰氯(98mg，1.26mmol)的二氯甲烷(1.0mL)稀释液。滴加完毕后，将反应液在室温下搅拌1小时。TLC监测反应完毕。反应液中加入水(10mL)，再用二氯甲烷(3 x 10mL)萃取。合并的有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝30:1)得到黄色色固体化合物5S-a(170mg,收率92％)。MS m/z 361.5[M+H] +。
室温下向甲醇(3mL)中加入化合物5S-a(170mg,0.47mmol)和钯碳催化剂(10％,60mg)。该反应混合物在室温和1大气压的氢气氛围下搅拌3小时。TLC监测反应完毕。反应混合物经过硅藻土过滤，滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝20:1)得到黄色固体化合物5S-b(130mg,收率83％)。MS m/z 331.5[M+H] +。
将化合物5S-b(65mg,0.20mmol)和Ib(79mg,0.24mmol)溶于甲苯(1mL)中。该反应混合物在90℃下搅拌过夜。TLC监测反应完毕。待反应液冷却至室温后，减压浓缩。 所得粗品经制备型薄板层析分离纯化(二氯甲烷:甲醇＝20:1)得到黄色固体化合物5S(15mg,收率13％)。 1H NMR(500MHz,CD 3OD)δ8.81(s,1H),7.18(d,J＝2.0Hz,1H),6.97(d,J＝8.5Hz,1H),6.83(d,J＝8.5Hz,1H),6.02-5.83(m,1H),4.57(d,J＝12.5Hz,1H),4.25(d,J＝10.0Hz,1H),4.04-3.92(m,2H),3.78(d,J＝11.0Hz,1H),3.19-2.99(m,4H),2.78-2.59(m,3H),2.58-2.50(m,1H),2.47(s,3H),2.38-2.25(m,2H),2.35(s,3H),2.17-2.08(m,1H),2.11(s,3H),2.05-1.89(m,4H),1.87-1.78(m,2H),1.68-1.59(m,2H),1.56-1.49(m,1H),1.45-1.37(m,1H)ppm。MS m/z 600.8[M+H] +。
实施例7:化合物6S的制备
Figure PCTCN2021071144-appb-000026
将化合物6S-a(250mg,1.06mmol)，1-环丙基-4-哌啶酮(6S-b,444mg,3.19mmol)和2滴醋酸的甲醇(15mL)混合液在室温下搅拌1小时。随后加入氰基硼氢化钠(200mg,3.19mmol)，反应混合物在室温下搅拌过夜。TLC监测反应完毕。反应混合物减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物6S-c(200mg,收率53％)。MS m/z 359.4[M+H] +。
室温下向甲醇(8mL)中加入化合物6S-c(200mg,0.56mmol)和钯碳催化剂(10％,80mg)，该反应混合物在室温和1大气压的氢气氛围下搅拌1小时。TLC监测反应完毕。反应混合物经过硅藻土过滤，滤液经减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝20:1,2％氨水)得到黄色油状化合物6S-d(128mg,收率70％)。MS m/z 329.5[M+H] +。
将化合物6S-d(88mg,0.27mmol)和化合物Ib(89mg,0.27mmol)的甲苯(1.5mL)混合液置于封管中，加热至100℃搅拌过夜。TLC监测反应完毕。反应混合物冷却至室温后减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1)得到黄色固体化合物6S(96mg,收率60％)。 1H NMR(500MHz,DMSO-d 6)δ9.87(bs,1H),8.90(s,1H),7.16(d,J＝1.9Hz,1H),7.06(d,J＝8.3Hz,1H),6.81(d,J＝8.9Hz,1H),5.91-5.76(m,1H),4.22(dd,J＝10.5,2.2Hz,1H),3.93-3.84(m,1H),3.69(d,J＝11.0Hz,1H),3.04-2.78(m,5H),2.58-2.51(m,1H),2.41(s,3H),2.37-2.06(m,6H),2.29(s,3H), 1.95-1.83(m,3H),1.81-1.68(m,4H),1.61-1.52(m,3H),1.41-1.27(m,2H),0.43-0.34(m,2H),0.32-0.21(m,2H)ppm。MS m/z 598.8[M+H] +。
实施例8:化合物7S的制备
Figure PCTCN2021071144-appb-000027
将化合物6S-a(500mg,2.13mmol)，1-Boc-3-氮杂环丁酮(7S-a,1.09g,6.38mmol)和4滴醋酸的甲醇(10mL)混合液在室温下搅拌1小时。随后加入氰基硼氢化钠(400mg,6.38mmol)，反应混合物在室温下搅拌过夜。TLC监测反应完毕。反应混合物减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物7S-b(1.24g)直接用于下一步反应。MS m/z 391.4[M+H] +。
室温下将化合物7S-b(1.24g,3.18mmol)溶于甲醇(15mL)中，再滴加HCl甲醇溶液(4.0M,4mL)。该混合液在60℃下搅拌1小时。TLC监测反应完毕。反应混合液减压浓缩除去大部分甲醇，再加入饱和碳酸氢钠溶液调节pH到7～8，再减压浓缩除去水。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝10:1,2％氨水)得到黄色固体化合物7S-c(410mg,两步收率66％)。MS m/z 291.3[M+H] +。
将化合物7S-c(410mg,1.41mmol)，多聚甲醛(127mg,4.24mmol)和3滴醋酸的甲醇(8mL)混合液在室温下搅拌1小时。随后加入氰基硼氢化钠(266mg,4.24mmol)，反应混合物在室温下搅拌2小时。TLC监测反应还有部分原料剩余，停止反应。将反应混合液过滤，滤液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝20:1,2％氨水)得到粗品黄色固体化合物7S-d(254mg,纯度80％,收率47％)直接用于下一步反应。MS m/z 305.3[M+H] +。
室温下向甲醇(3mL)中加入化合物7S-d(100mg,0.28mmol)和钯碳催化剂(10％,80mg)，该反应混合物在室温和1大气压的氢气氛围下搅拌1小时。TLC监测反应完毕。反应混合物经过硅藻土过滤，滤液经减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝20:1,2％氨水)得到黄色固体化合物7S-e(47mg,收率51％)。MS m/z 275.4[M+H] +。
将化合物7S-e(47mg,0.17mmol)和化合物Ib(57mg,0.17mmol)的甲苯(1.5mL)混合液置于封管中，加热至100℃搅拌过夜。TLC监测反应完毕。反应混合液冷却至室温后减压浓缩。所得粗品经制备型薄板层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物7S(5mg,收率5％)。MS m/z 544.7[M+H] +。
实施例9:化合物8S的制备
Figure PCTCN2021071144-appb-000028
化合物8S-a(100mg,0.42mmol)、8S-b(91mg,0.42mmol)和氢氧化钾(71mg,1.26mmol)溶于二甲亚砜(5mL)中，室温下搅拌3小时，再在60℃下搅拌3小时。反应完毕后，待反应混合物冷却后将其倒入冰水中，室温下搅拌1小时。混合物再用二氯甲烷萃取(3 x 25mL)。合并的有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤后滤液减压浓缩。所得粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯＝10:1)得到黄色固体化合物8S-c(64mg,收率37％)和黄色固体化合物8S-d(64mg,收率37％)。8S-c: 1H NMR(500MHz,CDCl 3)δ8.03(d,J＝2.5Hz,1H),7.71(d,J＝2.6Hz,1H),4.26-4.15(m,2H),3.86-3.78(m,2H),3.60(dd,J＝13.8,4.1Hz,1H),3.52-3.36(m,2H),3.29-3.15(m,2H),1.48(s,9H)；8S-d: 1H NMR(500MHz,CDCl 3)δ7.94(d,J＝2.5Hz,1H),7.63(d,J＝2.5Hz,1H),4.49-4.44(m,1H),4.28-4.04(m,3H),3.71(d,J＝11.3Hz,1H),3.22-3.15(m,1H),3.10-3.01(m,1H),2.88-2.79(m,1H),2.66-2.57(m,1H),1.49(s,9H)ppm。
将化合物8S-c(64mg,0.16mmol)、四甲基锡(56mg,0.31mmol)、四三苯基膦钯(9mg,0.01mmol)和氯化锂(13mg,0.31mmol)的N,N-二甲基甲酰胺(2mL)混合液加热至90℃，搅拌过夜。反应完毕后，将反应混合物过滤，滤液减压浓缩。所得粗品经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝10:1)得到黄色固体化合物8S-e(33mg,收率60％)。 1H NMR(500MHz,CDCl 3)δ7.65(d,J＝2.5Hz,1H),7.59(d,J＝2.6Hz,1H),4.24-4.14(m,2H),3.89-3.78(m,2H),3.60-3.49(m,1H),3.39-3.30(m,1H),3.28-3.18(m,1H),3.10-2.98(m,2H),2.37(s,3H),1.48(s,9H)。
将化合物8S-e(200mg,0.57mmol)溶于甲醇(2mL)中，冰浴下滴加盐酸甲醇溶 液(1mL,4M)。滴加完毕后，室温搅拌1小时。TLC检测反应完全。反应混合物减压浓缩，再加入饱和碳酸氢钠水溶液(10mL)，用乙酸乙酯(3 x 10mL)萃取。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩得到黄色固体化合物8S-f(100mg,收率70％)。MS m/z 250.3[M+H] +。
将化合物8S-f(100mg,0.40mmol)、N-甲基哌啶酮(2S-a,227mg,2.00mmol)和2滴醋酸的甲醇(5mL)混合液在室温下搅拌1小时。随后加入氰基硼氢化钠(75mg,1.21mmol)，反应混合物在室温下搅拌过夜。反应完毕后，反应混合物减压浓缩，再经二氯甲烷萃取(3×15mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝30:1)得到黄色固体化合物8S-g(140mg)直接用于下一步反应。MS m/z 347.4[M+H] +。
室温下向甲醇(5mL)中加入化合物8S-g(101mg,0.29mmol)和钯碳催化剂(10％,20mg)。该反应混合物在室温氢气氛围下搅拌3小时。TLC监测反应完毕。反应混合物经过硅藻土过滤，滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝50:1)得到棕色固体化合物8S-h(63mg,收率68％)。MS m/z 317.4[M+H] +。
将化合物8S-h(53mg,0.17mmol)和Ib(56mg,0.17mmol)溶于甲苯(1mL)中。该反应混合物在100℃下搅拌过夜。TLC监测反应完毕。待反应液冷却至室温后，减压浓缩。所得粗品经制备型薄板层析分离纯化(二氯甲烷:甲醇＝20:1)得到黄色固体化合物8S(12mg,收率12％)。 1H NMR(500MHz,CDCl 3)δ8.72(s,1H),7.15(bs,1H),7.03(s,1H),6.96(s,1H),5.93-5.84(m,1H),4.60(t,J＝10.7Hz,1H),4.00(dd,J＝10.6,2.8Hz,1H),3.19(d,J＝10.5Hz,1H),3.13-3.01(m,3H),2.92-2.85(m,2H),2.82(d,J＝11.5Hz,2H),2.62-2.55(m,1H),2.54(s,3H),2.46-2.39(m,3H),2.35(s,3H),2.34-2.30(m,3H),2.29(s,3H),2.04-1.73(m,9H),1.69-1.55(m,3H)ppm。MS m/z 586.8[M+H] +。
实施例10:化合物9S的制备
Figure PCTCN2021071144-appb-000029
将化合物9S-a(1.0g,5.65mmol)、8S-b(1.22g,5.65mmol)和氢氧化钾(950mg,16.94mmol)溶于二甲亚砜(15mL)中，先室温下搅拌3小时，再在60℃下搅拌3小时。TLC监测反应完毕。待反应混合物冷却后将其倒入冰水中，室温下搅拌1小时。所得混 合物再用二氯甲烷萃取(3×30mL)。合并的有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯:二氯甲烷＝5:1:1)得到黄色固体化合物9S-b(1.45g,收率73％)。MS m/z 354.4[M+H] +。
室温下将化合物9S-b(1.45g,4.10mmol)溶于甲醇(15mL)中，再滴加HCl甲醇溶液(4.0M,4mL)。所得混合液在60℃下搅拌1小时。TLC监测反应完毕。反应混合物减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝10:1,2％氨水)得到黄色固体化合物9S-c(1.25g,收率100％)。MS m/z 254.3[M+H] +。
将化合物9S-c(500mg,1.73mmol)、N-甲基-4-哌啶酮(2S-a,587mg,5.18mmol)和4滴醋酸的甲醇(8mL)混合液在室温下搅拌1小时。随后加入氰基硼氢化钠(326mg,5.18mmol)，反应混合物在室温下搅拌过夜。反应完毕后，反应混合物减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝20:1,2％氨水)得到黄色固体化合物9S-d(704mg)直接用于下一步反应。MS m/z 351.4[M+H] +。
室温下向甲醇(3mL)中加入化合物9S-d(80mg,0.23mmol)和钯碳催化剂(10％,80mg)，该反应混合物在室温和1大气压的氢气氛围下搅拌1小时。TLC监测反应完成。反应混合物经过硅藻土过滤，滤液经减压浓缩得到粗品。随后该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色油状化合物9S-e(50mg,收率68％)。MS m/z 321.5[M+H] +。
将化合物9S-e(50mg,0.16mmol)和化合物Ib(52mg,0.16mmol)的甲苯(1.5mL)混合液置于封管中，加热至100℃搅拌过夜。TLC监测反应完毕。反应混合物冷却至室温后减压浓缩。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物9S(13mg,收率14％)。 1H NMR(500MHz,CDCl 3)δ8.72(s,1H),7.13(s,1H),7.07(dd,J＝14.6,2.5Hz,1H),6.83(s,1H),5.91-5.79(m,1H),4.17-4.08(m,2H),3.79-3.68(m,1H),3.27-3.19(m,1H),3.13-3.03(m,3H),2.89-2.77(m,2H),2.66-2.58(m,1H),2.54(s,3H),2.49-2.27(m,7H),2.36(s,3H),2.04-1.93(m,3H),1.92-1.80(m,6H),1.73-1.59(m,3H)ppm。MS m/z 590.8[M+H] +。
实施例11:化合物10S的制备
Figure PCTCN2021071144-appb-000030
将化合物10S-a(2.95g，13.6mmol)和化合物10S-b(2.17g，13.6mmol)溶于DMSO(30mL)中，再加入KOH(2.30g，40.9mmol)。室温搅拌至化合物10S-a原料点消失。加热至60℃搅拌过夜，TLC监测反应完毕。加水终止反应，将混合物用乙酸乙酯萃取。合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤和减压浓缩得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯＝1:1)分离纯化得化合物10S-c(2.30g，50％)。MS m/z 336.4[M+H] +，280.4[M-55] +。 1H NMR(500MHz,CDCl 3)δ7.83-7.75(m,1H),7.65(d,J＝2.6Hz,1H),6.75(d,J＝9.1Hz,1H),4.29(dd,J＝11.0,3.0Hz,1H),4.27-4.01(m,2H),3.98(dd,J＝11.0,8.0Hz,1H),3.78(d,J＝11.4Hz,1H),3.36-3.27(m,1H),3.12-2.99(m,1H),2.98-2.89(m,1H),2.76-2.53(m,1H),1.48(s,9H)ppm。
将化合物10S-c(6.10g，18.19mmol)溶于甲醇(100mL)中，再加入7％钯碳(500mg)，氢气氛围下室温搅拌1小时。TLC监测反应完毕，将反应液经硅藻土过滤，滤液减压浓缩得粗品，粗品经硅胶柱层析(二氯甲烷:甲醇:氨水＝30:1:0.3)纯化得化合物10S-d 4.70g，85％)。MS m/z 306.4[M+H] +。 1H NMR(500MHz,CDCl 3)δ6.64(d,J＝8.5Hz,1H),6.32(dd,J＝8.5,2.6Hz,1H),6.29(d,J＝2.5Hz,1H),4.23-4.01(m,3H),3.96(dd,J＝10.6,9.0Hz,1H),3.56(d,J＝11.3Hz,1H),3.15-2.90(m,2H),2.71-2.49(m,2H),1.48(s,9H)ppm。
将化合物10S-d(4.7g，15.39mmol)和化合物Ib(5.64g，16.93mmol)溶于甲苯(30mL)中，90～100℃加热搅拌过夜。TLC监测反应完毕。将反应液冷却至室温并过滤。滤饼以乙酸乙酯洗涤，得黄色固体粗品。粗品经硅胶柱层析(二氯甲烷:甲醇:氨水＝50:1:0.5)纯化得化合物10S-e黄色固体(5.30g，60％)。MS m/z 575.7[M+H] +。
将化合物10S-e(5.30g，9.22mmol)溶于甲醇(60mL)中，再加入盐酸甲醇溶液(4M，10mL)，40℃加热搅拌3小时。TLC监测反应完毕。将反应液减压浓缩，再加入饱和碳酸氢钠溶液调节pH至碱性，以二氯甲烷萃取，有机层合并后以饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得化合物10S-f(4.30g，98％)。MS m/z 475.6[M+H] +。
将化合物10S-f(200mg,0.42mmol)、1-Boc-3-氮杂环丁酮10S-g(108mg,0.63mmol)和氯化锌(172mg,1.26mmol)依次溶于甲醇(7mL)中，再加入氰基硼氢化钠 (80mg,1.26mmol)。反应混合液在75℃下搅拌1小时。TLC监测反应完毕。反应混合液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物10S-h(250mg,收率94％)。MS m/z 630.6[M+H] +。
将化合物10S-h(250mg,0.40mmol)溶于甲醇(8mL)中，再加入HCl的二氧六环溶液(4.0M,1.5mL)。反应混合物在40℃下搅拌2小时。TLC监测反应完毕。反应混合物冷却至室温后减压浓缩。将所得混合物溶于少量甲醇中，用氨水中和，再减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝6:1,2％氨水)得到黄色固体化合物10S(173mg,收率82％)。 1H NMR(500MHz,CD 3OD)δ8.82(s,1H),7.19(d,J＝2.4Hz,1H),6.98(dd,J＝8.7,2.0Hz,1H),6.84(d,J＝8.8Hz,1H),5.98-5.89(m,1H),4.25(dd,J＝10.6,2.6Hz,1H),4.06-3.93(m,4H),3.79(d,J＝11.8Hz,1H),3.44-3.37(m,1H),3.14-3.08(m,1H),2.98-2.94(m,1H),2.90-2.85(m,1H),2.78-2.72(m,1H),2.48(s,3H),2.47-2.44(m,1H),2.35(s,3H),2.34-2.27(m,2H),2.24-2.16(m,1H),1.99-1.90(m,2H),1.88-1.77(m,3H),1.68-1.59(m,2H)ppm。MS m/z 530.4[M+H] +。
实施例12:化合物11S的制备
Figure PCTCN2021071144-appb-000031
将化合物10S(20mg,0.04mmol)和二异丙基乙基胺(7mg,0.06mmol)溶于二氯甲烷(4mL)中，0℃下缓慢滴加乙酰氯(3mg,0.04mmol)的二氯甲烷(1mL)稀释液。反应混合液在室温下搅拌1小时。反应完毕后，反应混合物减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物11S(20mg,收率93％)。 1H NMR(500MHz,CD 3OD)δ8.82(s,1H),7.19-7.17(m,1H),6.97(d,J＝8.6Hz,1H),6.84(d,J＝8.0Hz,1H),5.99-5.88(m,1H),4.31-4.22(m,2H),4.11(dd,J＝9.1,5.0Hz,1H),4.08-4.02(m,1H),4.01-3.96(m,1H),3.87(dd,J＝10.3,5.1Hz,1H),3.78(d,J＝12.1Hz,1H),3.27-3.21(m,1H),3.14-3.08(m,1H),3.03-2.97(m,1H),2.95-2.88(m,1H),2.78-2.71(m,1H),2.48(s,3H),2.35(s,3H),2.34-2.28(m,2H),2.25-2.18(m,1H),1.96-1.92(m,2H),1.90(s,3H),1.88-1.78(m,3H),1.68-1.60(m,2H)ppm。MS m/z572.7[M+H] +。
实施例13:化合物12S的制备
Figure PCTCN2021071144-appb-000032
将化合物10S(10mg,0.02mmol)、环丙基硼酸12S-a(3mg,0.04mmol)、醋酸铜(3mg,0.02mmol)、2,2'-联吡啶(3mg,0.081mmol)和碳酸钠(3mg,0.037mmol)溶于1,2-二氯乙烷(3mL)中,空气中敞口加热至70℃反应两小时。TLC监测反应完毕。将反应混合物经硅藻土过滤，滤液减压浓缩后得粗品。该得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物12S(1.7mg,收率16％)。MS m/z 570.6[M+H] +。
实施例14:化合物13S的制备
Figure PCTCN2021071144-appb-000033
将化合物10S-f(30mg,0.06mmol)、3-氧杂环丁酮13S-a(5mg,0.06mmol)和氯化锌(17mg,0.13mmol)依次溶于甲醇(5mL)中，再加入氰基硼氢化钠(12mg,0.19mmol)。反应混合液在75℃下搅拌1小时。TLC监测反应完毕。反应混合液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物13S(18mg,收率54％)。 1H NMR(500MHz,DMSO-d 6)δ9.88(s,1H),8.90(s,1H),7.17(s,1H),7.08(d,J＝7.5Hz,1H),6.84(d,J＝8.9Hz,1H),5.88-5.80(m,1H),4.62-4.52(m,2H),4.50-4.40(m,2H),4.24(dd,J＝10.5,2.6Hz,1H),3.94-3.85(m,1H),3.73(d,J＝11.8Hz,1H),3.50-3.40(m,1H),3.07-2.96(m,1H),2.81(dd,J＝19.5,10.4Hz,2H),2.67-2.56(m,1H),2.39(s,3H),2.28(s,3H),2.26-2.17(m,2H),2.09-2.00(m,1H),1.88(s,2H),1.76(s,2H),1.64(t,J＝10.6Hz,1H),1.60-1.51(m,2H)ppm。MS m/z 531.6[M+H] +。
实施例15:化合物14S的制备
Figure PCTCN2021071144-appb-000034
将化合物10S(20mg,0.04mmol)和二异丙基乙基胺(7mg,0.06mmol)溶于二氯甲烷(4mL)中，0℃下缓慢滴加甲磺酰氯(4mg,0.04mmol)的二氯甲烷(1mL)稀释液。反应混合液在室温下搅拌1小时。反应完毕后，反应混合物减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物14S(21mg,收率92％)。 1H NMR(500MHz,DMSO-d 6)δ9.88(s,1H),8.90(s,1H),7.18(d,J＝1.9Hz,1H),7.08(d,J＝8.2Hz,1H),6.85(d,J＝8.9Hz,1H),5.89-5.79(m,1H),4.24(dd,J＝10.6,2.6Hz,1H),3.94-3.71(m,6H),3.25-3.18(m,1H),3.01(s,3H),2.99-2.97(m,1H),2.87(dd,J＝20.6,10.5Hz,2H),2.64-2.57(m,1H),2.42(s,3H),2.29(s,3H),2.27-2.19(m,2H),2.14-2.06(m,1H),1.93-1.84(m,2H),1.81-1.68(m,3H),1.62-1.55(m,2H)ppm。MS m/z 608.8[M+H] +。
实施例16:化合物15S的制备
Figure PCTCN2021071144-appb-000035
化合物10S-f(15mg,0.03mmol)、3,3-二氟环丁酮15S-a(5mg,0.05mmol)和氯化锌(13mg,0.09mmol)依次溶于甲醇(4mL)中，再加入氰基硼氢化钠(6mg,0.09mmol)。反应混合液在80℃下搅拌1小时。TLC监测反应完毕。反应混合液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝30:1)得到黄色固体化合物15S(2mg,收率11％)。 1H NMR(500MHz,CDCl 3)δ8.71(s,1H),7.16(s,2H),6.97(d,J＝8.8Hz,1H),6.77(d,J＝8.6Hz,1H),5.89-5.80(m,1H),4.23(d,J＝10.3Hz,1H), 4.08-3.97(m,1H),3.78-3.65(m,1H),3.24-3.11(m,1H),3.04-2.92(m,1H),2.87-2.66(m,4H),2.54(s,3H),2.35(s,3H),2.33-2.26(m,2H),2.25-2.13(m,1H),2.00-1.90(m,2H),1.88-1.79(m,2H),1.68-1.51(m,6H)ppm。MS m/z 565.6[M+H] +。
实施例17:化合物16S的制备
Figure PCTCN2021071144-appb-000036
化合物10S-f(80mg,0.17mmol)、N-Boc-4-哌啶酮3S-a(50mg,0.25mmol)和氯化锌(69mg,0.51mmol)依次溶于甲醇(5mL)中，再加入氰基硼氢化钠(32mg,0.51mmol)。反应混合液在80℃下搅拌3小时。TLC监测反应完毕。反应混合液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝15:1)得到黄色固体化合物16S-a(91mg,收率82％)。MS m/z 658.7[M+H] +。
将化合物16S-a(91mg,0.14mmol)溶于甲醇(4mL)中，再加入HCl的二氧六环溶液(4.0M,1mL)。反应混合物在40℃下搅拌2小时。TLC监测反应完毕。反应混合物冷却至室温后减压浓缩。将所得混合物溶于少量甲醇中，用氨水中和，再减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝15:1,2％氨水)得到黄色固体化合物16S-b(58mg,收率75％)。MS m/z 558.6[M+H] +。
将化合物16S-b(20mg,0.04mmol)、16S-c(10mg,0.04mmol)和二异丙基乙基胺(9mg,0.07mmol)溶于N,N-二甲基甲酰胺(2mL)中，反应混合液在80℃下搅拌3小时。TLC监测反应完毕。反应混合液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝15:1)得到黄色固体化合物16S(16mg,收率70％)。 1H NMR(500MHz,CD 3OD)δ8.81(s,1H),7.17(d,J＝2.4Hz,1H),6.96(dd,J＝8.7,2.0Hz,1H),6.82(d,J＝8.9Hz,1H),5.97-5.89(m,1H),4.24(dd,J＝10.5,2.6Hz,1H),3.97(dd,J＝10.5,9.0Hz,1H),3.75(d,J＝11.7Hz,1H),3.14-2.98(m,7H),2.75-2.67(m,1H),2.47(s,3H),2.46-2.42(m,1H),2.39(t,J＝11.1Hz,2H),2.35(s,3H),2.33-2.27(m,3H),2.03(t,J＝10.7Hz,1H),1.96-1.78(m,6H),1.68-1.55(m,4H)ppm。MS m/z 640.8[M+H] +。
实施例18:化合物17S的制备
Figure PCTCN2021071144-appb-000037
将化合物16S-b(20mg,0.04mmol)和溴乙腈17S-a(5mg,0.04mmol)溶于四氢呋喃(2mL)中，反应混合液在室温下搅拌3小时。TLC监测反应完毕。反应混合液减压浓缩。所得粗品经制备型硅胶薄层色谱分离纯化(二氯甲烷:甲醇＝20:1)得到黄色固体化合物17S(12mg,收率56％)。 1H NMR(500MHz,DMSO-d 6)δ9.87(s,1H),8.90(s,1H),7.16(d,J＝2.0Hz,1H),7.07(d,J＝8.0Hz,1H),6.82(d,J＝8.9Hz,1H),5.90-5.77(m,1H),4.24(dd,J＝10.6,2.4Hz,1H),3.90(dd,J＝10.5,9.0Hz,1H),3.72-3.66(m,3H),3.01-2.89(m,3H),2.83(d,J＝11.2Hz,2H),2.58-2.52(m,1H),2.41(s,3H),2.35-2.31(m,1H),2.29(s,3H),2.26-2.20(m,3H),2.16(t,J＝10.8Hz,2H),1.93-1.84(m,3H),1.82-1.73(m,4H),1.62-1.54(m,2H),1.51-1.39(m,2H)ppm。MS m/z 597.8[M+H] +。
实施例19:化合物18S的制备
Figure PCTCN2021071144-appb-000038
化合物10S-f(15mg,0.03mmol)、环丁酮18S-a(3mg,0.05mmol)和氯化锌(13mg,0.09mmol)依次溶于甲醇(4mL)中，再加入氰基硼氢化钠(6mg,0.09mmol)。反应混合液在80℃下搅拌1小时。TLC监测反应完毕。反应混合液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝15:1)得到黄色固体化合物18S(11mg,收率66％)。 1H NMR(500MHz,DMSO-d 6)δ9.87(s,1H),8.90(s,1H),7.16(d,J＝2.0Hz,1H),7.07(d,J＝7.8Hz,1H),6.82(d,J＝8.9Hz,1H),5.87-5.78(m,1H),4.25(dd,J＝10.6,2.6Hz,1H),3.89(dd,J＝10.5,9.1Hz,1H),3.70(d,J＝11.6Hz,1H),2.99-2.92(m,1H),2.86(d,J＝11.7Hz,1H),2.81(d,J＝10.2Hz,1H),2.77-2.69(m,1H),2.59-2.52(m,1H),2.41(s,3H),2.29(s,3H),2.26-2.19(m,2H),2.02-1.73(m,8H),1.69-1.50(m,5H),1.27-1.22(m,1H)ppm。MS m/z 529.7[M+H] +。
实施例20:化合物19S的制备
Figure PCTCN2021071144-appb-000039
化合物19S-a(3.0g,12.61mmol)、19S-b(2.73g,12.61mmol)和氢氧化钾(2.12g,37.82mmol)溶于二甲亚砜(40mL)中，室温下搅拌3小时，再在60℃下搅拌3小时。反应完毕后，待反应混合物冷却后将其倒入冰水中，室温下搅拌1小时。混合物再经二氯甲烷萃取(3x40mL)、饱和食盐水洗涤、无水硫酸钠干燥，过滤后滤液减压浓缩。所得粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯:二氯甲烷＝15:1:1)得到黄色固体化合物19S-c(1.07g,收率20％)。
室温下向甲醇(6mL)中加入化合物19S-c(500mg,1.21mmol)和钯碳催化剂(10％,150mg)，该反应混合物在室温和1大气压的氢气氛围下搅拌1小时。TLC监测反应完成。反应混合物经过硅藻土过滤。滤液经减压浓缩得到粗品。随后该粗品经硅胶柱层析分离纯化(二氯甲烷:乙酸乙酯＝4:1)得到灰白色固体化合物19S-d(235mg,收率64％)。MS m/z 306.4[M+H] +。
将化合物19S-d(235mg,0.77mmol)和化合物Ib(257mg,0.77mmol)的甲苯(6mL)混合液置于封管中，加热至100℃搅拌5小时。TLC监测反应完毕，反应混合物冷却至室温后减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:乙酸乙酯＝2:1)得到黄色固体化合物19S-e(200mg,收率45％)。MS m/z 575.8[M+H] +。
将化合物19S-e(200mg,0.35mmol)溶于甲醇(2mL)中，再加入HCl的二氧六环溶液(4.0M,2mL)。反应混合物在40℃下搅拌2小时。TLC监测反应完毕。反应混合物冷却至室温后减压浓缩。将所得混合物溶于少量甲醇中，用氨水中和，再减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝15:1,2％氨水)得到黄色固体化合物19S-f(140mg,收率85％)。
化合物19S-f(20mg,0.04mmol)、19S-g(5mg,0.04mmol)和氯化锌(12mg,0.08mmol)依次溶于甲醇(5mL)中，再加入氰基硼氢化钠(8mg,0.13mmol)。反应混合液在75℃下搅拌1小时。TLC监测反应完毕。反应混合液减压浓缩。所得粗品经硅胶柱 层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物19S(10.44mg,收率43％)。 1H NMR(500MHz,CDCl 3)δ8.71(s,1H),7.13(s,1H),7.09(s,1H),6.77(s,2H),5.92-5.83(m,1H),4.19(dd,J＝10.5,2.7Hz,1H),4.03-3.95(m,1H),3.65(d,J＝11.2Hz,1H),3.22-3.15(m,2H),3.11-3.01(m,1H),2.99(d,J＝10.2Hz,1H),2.90-2.78(m,2H),2.54(s,3H),2.50-2.45(m,1H),2.44-2.37(m,3H),2.36(s,3H),2.32-2.22(m,4H),2.11-2.02(m,2H),2.01-1.71(m,10H)ppm。MS m/z 572.7[M+H] +。
实施例21:化合物20S的制备
Figure PCTCN2021071144-appb-000040
化合物19S-f(30mg,0.06mmol)、N-叔丁氧羰基-4-哌啶酮(13mg,0.06mmol)和氯化锌(17mg,0.13mmol)依次溶于甲醇(5mL)中，再加入氰基硼氢化钠(12mg,0.19mmol)。反应混合液在75℃下搅拌1小时。TLC监测反应完毕。反应混合液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物20S-b(25mg,收率60％)。MS m/z 658.3[M+H] +。
将化合物20S-b(25mg,0.04mmol)溶于甲醇(2mL)中，再加入HCl的二氧六环溶液(4.0M,1.5mL)。反应混合物在40℃下搅拌2小时。TLC监测反应完毕。反应混合物冷却至室温后减压浓缩。将所得混合物溶于少量甲醇中，用氨水中和，再减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝15:1,2％氨水)得到黄色固体化合物20S(12.8mg,收率60％)。 1H NMR(500MHz,CD 3OD)δ8.82(s,1H),7.17(d,J＝2.0Hz,1H),6.88-6.81(m,1H),6.69(d,J＝8.5Hz,1H),6.01-5.90(m,1H),4.23(dd,J＝10.5,2.6Hz,1H),3.99-3.91(m,1H),3.73(d,J＝11.5Hz,1H),3.41-3.35(m,3H),3.13-3.06(m,2H),3.01(d,J＝10.5Hz,1H),2.95-2.86(m,2H),2.79-2.72(m,1H),2.62-2.55(m,1H),2.47(s,3H),2.35(s,3H),2.33-2.23(m,2H),2.10-2.01(m,3H),2.01-1.88(m,2H),1.81(d,J＝4.8Hz,2H),1.75-1.65(m,2H),1.63-1.55(m,2H)ppm。MS m/z 558.6[M+H] +。
实施例22:化合物21S的制备
Figure PCTCN2021071144-appb-000041
化合物19S-f(20mg,0.04mmol)、化合物21S-a(6mg,0.04mmol)和氯化锌(12mg,0.08mmol)依次溶于甲醇(5mL)中，再加入氰基硼氢化钠(8mg,0.13mmol)。反应混合液在75℃下搅拌1小时。TLC监测反应完毕。反应混合液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物21S(15.30mg,收率60％)。 1H NMR(500MHz,CDCl 3)δ8.71(s,1H),7.15(s,1H),7.11(s,1H),6.86-6.72(m,2H),5.93-5.71(m,1H),4.74-4.65(m,1H),4.21(d,J＝9.6Hz,1H),4.06-3.96(m,1H),3.90(d,J＝12.8Hz,1H),3.76-3.68(m,1H),3.28-2.80(m,5H),2.69-2.55(m,2H),2.54(s,3H),2.35(s,3H),2.34-2.25(m,2H),2.10(s,3H),2.04-1.77(m,7H),1.78-1.54(m,5H)ppm。MS m/z 600.8[M+H] +。
实施例23:化合物1R的制备
Figure PCTCN2021071144-appb-000042
化合物1R-a采用专利WO2017101763中的方法合成。
将化合物1R-a(30mg,0.06mmol)、四氢吡喃酮1R-b(9mg,0.06mmol)和氯化锌(17mg,0.13mmol)依次溶于甲醇(5mL)中，再加入氰基硼氢化钠(12mg,0.19mmol)。反应混合液在75℃下搅拌1小时。TLC监测反应完毕。反应混合液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物1R(15mg,收率42％)。 1H NMR(500MHz,DMSO-d 6)δ9.88(s,1H),8.90(s,1H),7.16(d,J＝2.0Hz,1H),7.07(d,J＝7.7Hz,1H),6.82(d,J＝8.9Hz,1H),5.88-5.80(m,1H),4.24(dd,J＝10.5,2.4Hz,1H),4.02-3.85(m,3H),3.71(d,J＝11.7Hz,1H),3.33-3.23(m,2H),3.06-2.86(m,3H),2.63-2.54(m,2H),2.43(s,3H),2.29(s,3H),2.26-2.17(m,2H),2.01-1.85(m,4H),1.82-1.68(m,4H),1.65-1.52(m,2H),1.51-1.34(m,2H)ppm。MS m/z 559.8[M+H] +。
实施例24:化合物3R的制备
Figure PCTCN2021071144-appb-000043
化合物1R-a(30mg,0.06mmol)、1-Boc-4-哌啶酮3R-a(12mg,0.06mmol)和氯化锌(17mg,0.13mmol)依次溶于甲醇(5mL)中，再加入氰基硼氢化钠(12mg,0.19mmol)。反应混合液在75℃下搅拌1小时。TLC监测反应完毕。反应混合液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物3R-b(25mg,收率60％)。MS m/z 658.3[M+H] +。
将化合物3R-b(25mg,0.04mmol)溶于甲醇(2mL)中，再加入HCl的二氧六环溶液(4.0M,1.5mL)。反应混合物在40℃下搅拌2小时。TLC监测反应完毕。反应混合物冷却至室温后减压浓缩。将所得混合物溶于少量甲醇中，用氨水中和，再减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝15:1,2％氨水)得到黄色固体化合物3R(9mg,收率42％)。 1H NMR(500MHz,MeOD-d 4)δ8.72(s,1H),7.07(d,J＝2.0Hz,1H),6.86(dd,J＝9.0,2.0Hz,1H),6.73(d,J＝9.0Hz,1H),5.92-5.75(m,1H),4.14(dd,J＝10.5,2.6Hz,1H),3.98-3.82(m,1H),3.66(d,J＝11.6Hz,1H),3.16-3.06(m,2H),3.04-2.87(m,3H),2.66-2.55(m,3H),2.40(s,3H),2.36-2.31(m,1H),2.25(s,3H),2.24-2.15(m,2H),1.95(t,J＝21.3,10.6Hz,2H),1.92-1.78(m,4H),1.77-1.67(m,2H),1.61-1.49(m,2H),1.49-1.37(m,2H)ppm。MS m/z 558.6[M+H] +。
实施例25:化合物5R的制备
Figure PCTCN2021071144-appb-000044
将化合物1R-a(30mg,0.06mmol)，N-乙酰基-4-哌啶酮5R-a(9mg,0.06mmol)和氯化锌(17mg,0.13mmol)依次溶于甲醇(5mL)中，再加入氰基硼氢化钠(12mg,0.19mmol)。反应混合液在75℃下搅拌1小时。TLC监测反应完毕。反应混合液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到黄色固体化合物5R(14mg,收率37％)。 1H NMR(500MHz,CD3OD)δ8.81(s,1H),7.17(d,J＝2.4Hz,1H),6.96(dd,J＝8.7,1.9Hz,1H),6.82(d,J＝8.9Hz,1H),5.99-5.87(m,1H),4.53(d,J＝12.4Hz,1H),4.24(d,J＝9.8Hz,1H),4.05-3.92(m,2H),3.76(d,J＝10.7Hz,1H),3.15-2.95(m,4H),2.76-2.55(m,3H),2.54-2.50(m,1H),2.47(s,3H),2.35-2.26(m,5H),2.11-2.02(m,4H),2.02-1.88(m,4H),1.88-1.77(m,2H),1.70-1.58(m,2H)ppm,1.55-1.48(m,1H),1.43-1.36(m,1H)。MS m/z 600.8[M+H] +。
实施例26:
1)CDK2、CDK4、CDK6激酶活性抑制实验
采用Caliper迁移率变动检测技术(Caliper mobility shift assay)测定CDK2/CycA2,CDK4/CycD3和CDK6/cycD3蛋白激酶活性。将化合物用DMSO溶解后用激酶缓冲液稀释(CDK2/CycA2and CDK6/cycD3用50mM HEPES(pH 7.5),10mM MgCl2,0.0015％Brij-35,and 2mM dithiothreitol；CDK4/CycD3用20mM HEPES(pH 7.5),10mM MgCl2,0.01％Triton X-100,and 2mM dithiothreitol)，在384孔板中加入5μl的5倍反应终浓度的化合物(10％DMSO)。加入10μl的2.5倍酶溶液后在室温下孵育10分钟，再加入10μL的2.5倍底物溶液(相应酶和ATP浓度CDK2/CycA2 12nM,ATP Km 39μM；CDK4/CycD3 10nM,ATP Km 221μM；CDK6/cycD3 15nM,ATP Km 800μM)。28℃下各自孵育(60分钟CDK2,180分钟CDK4,60分钟CDK6)后加25μl终止液(100mM HEPES(pH 7.5),0.015％Brij-35，0.2％Coating Reagent#3，50mM EDTA)终止反应。Caliper EZ Reader II(Caliper Life Sciences)上读取转化率数据。把转化率转化成抑制率数据(％抑制率＝(max-转化率)/(max-min)*100)。其中max是指DMSO对照的转化率，min是指无酶活对照的转化率。以化合物浓度和抑制率为横纵坐标，绘制曲线，使用XLFit excel add-in version4.3.1软件拟合曲线并计算IC 50。部分代表性化合物的活性如表1所示。
2)TRKA激酶活性抑制实验
采用Caliper迁移率变动检测技术(Caliper mobility shift assay)测定TRKA蛋白激酶活性。将化合物用DMSO溶解，配置成10mM储液。配制1x激酶反应缓冲液，使用缓冲液梯度稀释化合物。受试化合物使用分液器Echo 550向目的板3573转移250nl100x终浓度的化合物。用1x激酶缓冲液配制2.5x终浓度的激酶溶液。在化合物孔和阳性对照孔分别加入10μL的2.5x终浓度的激酶溶液；在阴性对照孔中加10μL的1x激酶缓冲液。1000rpm离心30s，反应板振荡混匀后室温孵育10min。用1x激酶缓冲液配制5/3倍终浓度的ATP和激酶底物的混合溶液。加入15μL的5/3倍终浓度的ATP和底物的混合溶液，起始反应。将384孔板1000rpm离心30s，振荡混匀后，室温孵育相应的时间。加入30μL终止检测液停止激酶反应，1000rpm离心30s，振荡混匀，用Caliper EZ Reader读取转化率数据。把转化率转化成抑制率数据(％抑制率＝(max DMSO孔转化率-化合物样品转化率)/(max DMSO孔转化率-min阴性对照转化率)*100)。其中max是指DMSO对照的转化率，min是指无酶活对照的转化率。以化合物浓度和抑制率为横纵坐标，绘制曲线，使用XLFit excel add-in version4.3.1软件拟合曲线并计算IC 50。部分代表性化合物的活性如表1所示。
3)CDK5、CDK9、CDK16激酶活性抑制实验
采用ADP-Glo Kinase Assay测定CDK5/p35NCK，CDK9/CycT1和CDK16/CycY蛋白激酶活性。用100％DMSO将阳性药和待测化合物(10mM储液)25倍稀释，在96孔稀释板中进行4倍等比稀释，取1μL的化合物加入49μL的激酶反应缓冲液(1mM Tris,20mM MgCl 2,0.10％BSA,and 0.5mM DTT)中，在微孔板振荡器上震荡20min。转移2μL的2x激酶到384反应板中，加入1μL的待测化合物到384反应板中，1000rpm/min，离心1min，25℃孵育10min。转移1μL 4x底物混合物到384反应板中，1000rpm/min，离心1min，25℃孵育60min。转移4μL ADP-Glo到384反应板中 1000rpm/min，离心1min，25℃孵育40min。转移8μL Detection溶液到384反应板中1000rpm/min，离心1min，25℃孵育40min。使用Biotek多功能读板机读取RLU(Relative luminescence unit)信号。信号强度用于表征激酶的活性程度。化合物抑制率数据:％抑制率＝[1-(化合物RLU平均值-阳性对照RLU平均值)/(阴性对照RLU平均值-阳性对照RLU平均值)]*100。以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC 50值。部分代表性化合物的活性如表1所示。
表1 CDK2、CDK4、CDK6、CDK5、CDK9、CDK16和TRKA激酶活性抑制(IC 50，nM)
化合物 CDK2 CDK4 CDK6 CDK5 CDK9 CDK16 TRKA
Ref-A a ≥2000 <10 <20 <50 ≥300 ≥2000 ≥400
1S a <100 <10 <20        
1R <100 <10 <20 <100 <50 <100 <10
2S a <100 <10 <10 <50 <20 <100 <10
2R <100 <10 <10       <10
3S <100 <10 <10 <100 <20 <50 <10
3R <100 <10 <10        
4S <100 <10 <10 <100 <20 <100 <10
5S <100 <10 <10        
5R <100 <10 <20 <200 <50 <200 <10
6S <100 <10 <10        
7S <100 <10 <10 <100 <50 <100 <10
8S <500 <20 <100        
9S <500 <10 <50        
10S <100 <10 <10        
11S <100 <10 <20       <10
12S <100 <10 <10        
13S <100 <10 <20        
14S <100 <10 <20        
15S <1000 <50         <100
16S <500 <10          
17S <100 <10          
18S <500 <10          
19S <500 <100          
20S <500            
21S <500            
a化合物为盐酸盐
结果显示，本发明化合物具有与现有技术中的CDK4/6选择性抑制剂Palbociclib(Ref-A)具有相当的CDK4和CDK6抑制活性，同时对于CDK2、CDK5、CDK9、CDK16和TRKA激酶也有较强的抑制活性，是一种多靶点激酶抑制剂。
实施例27大鼠体内的药物动力学研究
仪器：Waters生产的XEVO TQ-S液质联用仪，所有的测定数据由Masslynx V4.1软件采集并处理，用Microsoft Excel计算和处理数据。用WinNonLin 8.0软件，采用统 计矩法进行药代动学参数计算。主要包括动力学参数T max、T 1/2、C max、AUC last等。色谱柱：ACQUITY UPLC BEH C18(2.1mm×50mm，1.7μm)；柱温40℃；流动相A为水(0.1％甲酸)，流动相B为乙腈，流速为0.350毫升/分钟，采用梯度洗脱，洗脱梯度为0.50min：10％B；1.50min：10％B；2.30min：95％B；2.31min：10％B；3.00min：stop。进样量：5μL。
动物：SD雄性大鼠3只，体重范围200-220g，购入后在实验动物中心实验室饲养2天后使用，给药前12小时及给药后4小时内禁食，试验期间自由饮水。大鼠灌胃后按既定的时间内点取血样。
溶媒：0.5％Methycellulose(含0.4％Tween 80和1％乙醇的水溶液)。灌胃给药溶液的配制：精密称量化合物，加入溶媒中，常温下超声5分钟使药品完全溶解，配制成0.3毫克/毫升的药液。
药物样品：本发明专利式(I)所示结构的代表性化合物，一般采取多个结构类似的样品(分子量相差在2个单位以上)，准确称量，一起给药(cassette PK)。这样可以同时筛选多个化合物，比较它们的口服吸收率。也采用单一给药来研究药物样品在大鼠体内的药物动力学。
灌胃给药后分别于0.25、0.5、1、2、4、9、12和24小时眼眶取血，置于肝素钠处理的试管中，离心后取上清液血浆用于LC-MS/MS分析。
准确称量化合物配制成不同的浓度，在质谱上进行定量分析，从而建立起标准曲线，然后测试上述血浆里化合物的浓度，得出不同时间点的化合物浓度。所有的测定数据由相关的软件采集并处理，采用统计矩法进行药代动学参数计算(主要包括动力学参数T max、T 1/2、C max、AUC last等)。部分代表性化合物的动力学参数如表2所示。
表2大鼠体内的药物动力学参数
Figure PCTCN2021071144-appb-000045
a该化合物为盐酸盐
结果显示，本发明化合物在大鼠中的口服吸收性能显著优于现有技术(WO2017101763)中的化合物7S(Ref-B)。
Ref-A和Ref-B的结构如下式所示：
Figure PCTCN2021071144-appb-000046
本发明的化合物除针对CDK4/CDK6具有抑制活性之外，对于其他CDK亚型(包括CDK2、CDK5、CDK9、CDK16)也具有良好的抑制活性，因此是一种pan-CDK抑制剂，同时对TRK激酶也具有良好的抑制活性。而现有技术中未记载该类化合物对于上述CDK亚型及TRK激酶具有抑制活性。
此外，相较于本领域中现有的作为CDK抑制剂的该类化合物，本发明的化合物还具有显著改进的药代动力学性能。在给药后，本发明化合物在大鼠体内的血浆峰浓度和暴露量明显提升，提示本发明化合物可以在更低的剂量下用药。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (19)

  1. 一种如下式(I)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物：
    Figure PCTCN2021071144-appb-100001
    “*”表示手性中心；
    X为氢、氘、卤素、C 1-4烷基、OR 1、NR 1R 2、或NR 1C(O)R 3；
    各个R各自独立为氢或C 1-4烷基；或当两个R同时连接到同一个碳原子上时，这两个R与其相连的碳原子可以任选共同形成羰基(C＝O)；
    G为NR f、O、S、S(O)、S(O) 2或CR gR g；
    p为0、1、2、或3；
    m和n各自独立为0、1、2、或3；前提条件是m和n不能同时为0；
    R 1和R 2各自独立为氢或C 1-4烷基；
    R 3为C 1-4烷基、C 2-4烯基、或C 2-4炔基；
    R f为氢、C 1-4烷基、C 1-4卤代烷基、氰基取代C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基、芳基、杂芳基、C(O)R 4、C(O)OR 1、C(O)NR 1R 2、S(O) 2R 4、或S(O) 2NR 1R 2；
    各个R g各自独立地选自下组：氢、卤素、或C 1-4烷基；或两个R g与其相连的碳原子共同形成羰基(C＝O)；或两个R g与其连接的碳原子一起形成3-至8-元环状结构，此环状结构任选地含有0、1或2个选自N、O、S的杂原子；
    R 4为C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基、芳基、或杂芳基；
    其中，各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR 1、SR 1、NR 1R 2、C(O)R 4、C(O)OR 1、C(O)NR 1R 2、NR 1C(O)R 4、或S(O) 2R 4，前提条件是所形成的化学结构是稳定的和有意义的；其中，R 1、R 2、R 4的定义如上所述；
    除非特别说明，上述的芳基为含有6-12个碳原子的芳香基团；杂芳基为5-至15-元杂芳香基团；环状结构为饱和的或不饱和的、含杂原子或不含杂原子的环状基团。
  2. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物，其特征在于，“*”表示手性中心；
    X为氢、氘、卤素、C 1-4烷基、OR 1、NR 1R 2、或NR 1C(O)R 3；
    各个R各自独立为氢或C 1-4烷基；或当两个R同时连接到同一个碳原子上时，这两个R与其相连的碳原子可以任选共同形成羰基(C＝O)；
    G为NR f、O、S、S(O)、S(O) 2或CR gR g；
    p为0、1、2、或3；
    m和n各自独立为1、2、或3；
    R 1和R 2各自独立为氢或C 1-4烷基；
    R 3为C 1-4烷基、C 2-4烯基、或C 2-4炔基；
    R f为氢、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基、芳基、杂芳基、C(O)R 4、C(O)OR 1、C(O)NR 1R 2，或S(O) 2R 4；
    各个R g各自独立地选自下组：氢、卤素、或C 1-4烷基；或两个R g与其相连的碳原子共同形成羰基(C＝O)；或两个R g与其连接的碳原子一起形成3-至8-元环状结构，此环状结构任选地含有0、1或2个选自N、O、S的杂原子；
    R 4为C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基、芳基、或杂芳基；
    其中，各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR 1、SR 1、NR 1R 2、C(O)R 4、C(O)OR 1、C(O)NR 1R 2、NR 1C(O)R 4、或S(O) 2R 4，前提条件是所形成的化学结构是稳定的和有意义的；其中，R 1、R 2、R 4的定义如上所述；
    除非特别说明，上述的芳基为含有6-12个碳原子的芳香基团；杂芳基为5-至15-元杂芳香基团；环状结构为饱和的或不饱和的、含杂原子或不含杂原子的环状基团。
  3. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物，其特征在于，式(I)为：
    Figure PCTCN2021071144-appb-100002
    “*”表示手性中心；
    X、R、G、p、m、和n的定义如权利要求1中所述。
  4. 如权利要求1-3任一所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物，其特征在于，X为氢、卤素、C 1-4烷基；R为氢，或两个R与其相连的碳原子共同形成羰基(C＝O)。
  5. 如权利要求1-4任一所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物，其特征在于，G为NR f、O、或CR gR g；m和n各自独立为1 或2；其中R f为氢、C 1-4烷基、C 1-4卤代烷基、C 3-8环烷基、4-至8-元杂环基、芳基、杂芳基、C(O)R 4、或S(O) 2R 4；其中R 4为C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基。
  6. 如权利要求1-5任一所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物，其特征在于，式(I)为：
    Figure PCTCN2021071144-appb-100003
    “*”表示手性中心；
    X为氢、卤素、C 1-4烷基；
    G为NR f、O、或CR gR g；m和n各自独立为1或2；其中R f为氢、C 1-4烷基、C 1-4卤代烷基、C 3-8环烷基、4-至8-元杂环基、芳基、杂芳基、C(O)R 4、或S(O) 2R 4；其中R 4为C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基。
  7. 如权利要求1-5任一所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物，其特征在于，式(I)为：
    Figure PCTCN2021071144-appb-100004
    “*”表示手性中心；
    X为氢、卤素、C 1-4烷基；
    G为NR f、O、或CR gR g；m和n各自独立为1或2；其中R f为氢、C 1-4烷基、C 1-4卤代烷基、C 3-8环烷基、4-至8-元杂环基、芳基、杂芳基、C(O)R 4、或S(O) 2R 4；其中R 4为C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基。
  8. 如权利要求6-7任一所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物，其特征在于，R f为氢、C 1-4烷基、C 1-4卤代烷基、氰基取代C 1-4烷基、C 3-8环烷基、C(O)R 4、或S(O) 2R 4；其中R 4为C 1-4烷基。
  9. 如权利要求5-7任一所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物，其特征在于，各个R g各自独立为氢或卤素。
  10. 如权利要求6或7所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物，其特征在于：
    式(IV)或式(V)中：
    “*”表示手性中心；
    X为氢、氟、或甲基；
    G为NR f、O、或CR gR g；m和n各自独立为1或2；其中R f为氢、甲基、乙基、CH 2CF 3、CH 2CN、环丙烷基、C(O)CH 3、或S(O) 2CH 3；各个R g各自独立为氢或氟。
  11. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物，其特征在于，所述的式(I)化合物为选自下组的化合物，或与与其对应的对映异构体的混合物：
    Figure PCTCN2021071144-appb-100005
    Figure PCTCN2021071144-appb-100006
    Figure PCTCN2021071144-appb-100007
    Figure PCTCN2021071144-appb-100008
  12. 如权利要求1-11任一所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物，其特征在于，所述的盐为盐酸盐。
  13. 一种药物组合物，其特征在于，所述的药物组合物包括有效量的如权利要求1-12所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物。
  14. 如权利要求1-12任一所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物，或如权利要求13所述的药物组合物的用途，其特征在于，用于：
    (a)制备治疗与激酶活性或表达量相关的疾病的药物；
    (b)制备激酶靶向抑制剂；和/或
    (c)体外非治疗性地抑制激酶的活性；
    其中，所述的激酶选自下组：CDK和/或TRK。
  15. 如权利要求1-12任一所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物，或如权利要求13所述的药物组合物的用途，其特征在于，可作为激酶抑制剂，或用于治疗与激酶高表达相关的疾病；其中，所述的激酶选自下组：CDK和/或TRK。
  16. 如权利要求15所述的用途，其特征在于，所述的疾病选自下组：DNA和RNA病毒感染、B细胞淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征、原发性血小板减少症、系统性巨细胞疾病、血液瘤、实体瘤、神经退行性疾病。
  17. 如权利要求15所述的用途，其特征在于，所述的疾病选自下组：过敏性哮喘、骨髓纤维化、类风湿性关节炎、炎症性疼痛、癌痛、艾滋病、孢疹病毒和流感病毒、分泌性乳腺癌、纤维肉瘤、唾液腺癌、肝癌、直肠癌、膀胱癌、咽喉癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、淋巴瘤、胃癌、多发性骨髓癌、脑瘤、肺癌、阿兹海默症、帕金森。
  18. 一种如权利要求1所述的化合物的制备方法，该方法包括步骤：
    Figure PCTCN2021071144-appb-100009
    在惰性溶剂中，用式Ia化合物与式Ib化合物反应，得到式I化合物。
  19. 如权利要求18所述的方法，其特征在于，所述的方法还包括步骤：
    Figure PCTCN2021071144-appb-100010
    (1)在惰性溶剂中，用式1-A3化合物进行脱保护，得到式1-A3-a化合物；
    (2)在惰性溶剂中，用式1-A3-a化合物与式1-A3-b化合物进行还原胺化反应，得到式1-A4化合物；
    (3)在惰性溶剂中，用式1-A4化合物进行还原反应，得到式Ia化合物。
PCT/CN2021/071144 2020-01-10 2021-01-11 作为激酶抑制剂的多环化合物 WO2021139817A1 (zh)

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