WO2024088296A1 - 哌啶并嘧啶类衍生物、其制备方法及其在医药上的应用 - Google Patents

哌啶并嘧啶类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2024088296A1
WO2024088296A1 PCT/CN2023/126415 CN2023126415W WO2024088296A1 WO 2024088296 A1 WO2024088296 A1 WO 2024088296A1 CN 2023126415 W CN2023126415 W CN 2023126415W WO 2024088296 A1 WO2024088296 A1 WO 2024088296A1
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Prior art keywords
alkyl
pharmaceutically acceptable
compound
acceptable salt
membered
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English (en)
French (fr)
Inventor
朱国栋
胡涛
陈美君
霍书华
李娇
李云飞
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Tuojie Biotech Shanghai Co Ltd
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Tuojie Biotech Shanghai Co Ltd
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Priority to KR1020257015228A priority Critical patent/KR20250091232A/ko
Priority to CN202380066883.3A priority patent/CN119894886A/zh
Priority to JP2025523071A priority patent/JP2025536384A/ja
Priority to EP23881873.6A priority patent/EP4610256A4/en
Priority to AU2023370363A priority patent/AU2023370363A1/en
Publication of WO2024088296A1 publication Critical patent/WO2024088296A1/zh
Priority to MX2025004676A priority patent/MX2025004676A/es
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a piperidopyrimidine derivative, a preparation method thereof, and its application in medicine.
  • the present disclosure relates to a pyrimidine derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a CDK7 inhibitor in treating diseases or conditions related to CDK7 activity.
  • Cyclin kinases are an important category of kinases and play an important role in the division and proliferation of cancer cells and the transcriptional regulation of oncogenes.
  • CDKs Cyclin kinases
  • Cyclin-dependent kinase 7 is a special member of the CDK family and has dual functions in cell division regulation and transcription regulation.
  • CDK7 binds to cyclin H and MAT1 to form a trimeric cyclin-activated kinase (CAK), which regulates the cell cycle by phosphorylating the relevant CDKs (including CDK1, CDK2, CDK4, CDK6) that control the cell cycle to activate the activity of the corresponding CDK kinase.
  • CDK7 also participates in the auxiliary regulation of transcription as a component of common transcription factor II H (TFIIH). It is involved in the transcription initiation process through the phosphorylation of the Rbp1 subunit of RNA polymerase II (RNAPII), and then regulates the elongation of transcription through the phosphorylation of the CDK9 complex.
  • TKIIH common transcription factor II H
  • CDK7 inhibitors that inhibit both transcription and cell cycle progression are theoretically feasible targets for cancer treatment.
  • CDK7 inhibitors include WO2016058544, WO2018013867, WO2019143719, WO2019143730, WO2019099298, WO2020093006 and WO2020093011, WO2022064009A, etc.
  • the purpose of the present disclosure is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
  • the G 1 is N or CR 1a ;
  • R 1 , R 2 , R 3 and R 1a are each independently selected from hydrogen, deuterium, cyano, hydroxyl, C 1-6 alkyl or halogen (e.g., fluorine, chlorine, bromine, iodine), and at least one of them is not hydrogen or deuterium;
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl or 3 to 6 membered cycloalkyl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or 3 to 6 membered cycloalkyl are optionally substituted with one or more substituents independently selected from RA , said RA is selected from deuterium, halogen, hydroxyl, cyano or 3 to 6 membered cycloalkyl;
  • the L1 is selected from a chemical bond or a C1-6 alkylene group, the C1-6 alkylene group is optionally substituted by one or more substituents independently selected from RB , the RB is selected from deuterium, halogen, hydroxyl, C1-6 alkoxy, amino, oxo, or two RBs connected to the same carbon atom form a 3-6-membered cycloalkyl group or a 3-7-membered heterocyclic group with the carbon atom to which they are connected, the heterocyclic group contains at least one heteroatom selected from N, O or S;
  • the ring A is selected from a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 5- to 12-membered heteroaryl group, or a 3- to 12-membered heterocyclyl group;
  • the C 1-6 alkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 5- to 12-membered heteroaryl, 3- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from RC , wherein RC is selected from deuterium, halogen, C 1-6 alkoxy, hydroxy, amino, oxo, C 2-6 alkynyl, C 2-6 alkenyl, cyano, C 1-6 hydroxyalkyl, 3- to 12-membered heterocyclyl, C 1-6 alkyl, C 3-6 cycloalkyl , 6- to 10-membered aryl, or 5- to 12-membered heteroaryl;
  • R 11 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6-membered cycloalkyl, 3 to 12-membered heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, said C 1-6 alkyl, C 1-6 alkoxy, 3 to 6-membered cycloalkyl, 3 to 12-membered heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, optionally substituted with one or more substituents independently selected from RD , said RD is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 6-membered cycloalkyl;
  • the ring B is selected from a 5- to 12-membered heteroaryl group or a 6- to 12-membered aryl group;
  • the R' is selected from hydrogen, cyano, C 1-6 alkyl, 3 to 6-membered cycloalkyl, 3 to 12-membered heterocyclyl, the C 1-6 alkyl, 3 to 6-membered cycloalkyl, 3 to 12-membered heterocyclyl is optionally substituted by one or more substituents independently selected from RE , the RE is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 6-membered cycloalkyl, 3 to 7-membered heterocyclyl;
  • the m is selected from 0 or 1;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • the o is selected from 0, 1, 2, 3 or 4.
  • Another aspect of the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof,
  • L 2 is selected from -NH- or -O-;
  • the B ring is selected from a 5- to 12-membered heteroaryl group or a 6- to 12-membered aryl group;
  • the L 3 is selected from C 0-6 alkylene, the C 0-6 alkylene is optionally substituted by one or more substituents independently selected from R I , the R I is selected from deuterium, halogen, oxo, hydroxyl, amino or C 1-6 alkyl;
  • the R 25 and R 26 are each independently selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, or R 25 and R 26 and the nitrogen atom to which they are attached form a 4-7 membered nitrogen-containing heterocyclic ring, wherein the 4-7 membered nitrogen-containing heterocyclic ring is optionally substituted by one or more substituents independently selected from R J , wherein R J is selected from halogen, hydroxyl, cyano, nitro or amino;
  • the y is selected from 0, 1, 2, 3 or 4;
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , L 1 , Ring A, R 10 and n are respectively as defined in claim 1 , with the proviso that said R 4 and R 5 are not hydrogen atoms at the same time.
  • the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein L 2 is -NH-.
  • the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein L 2 is -O-.
  • the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein L 3 is -CH 2 CH 2 -.
  • the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein, wherein, ring B is phenyl or pyridyl.
  • the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl.
  • the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein:
  • the R 27 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyl C 1-6 alkyl, C 2-6 alkynyl, 3 to 6 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, 5 to 12 membered aryl or heteroaryl.
  • the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein the R 27 is independently selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkynyl.
  • the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein the R 27 is independently selected from chlorine, fluorine, trifluoromethyl or ethynyl.
  • the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 25 and R 26 are each independently selected from hydrogen or C 1-6 alkyl.
  • the present disclosure provides a compound of formula (I) or (VI) or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen, deuterium, halogen, or C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula (I) or (VI) or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl.
  • R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen or deuterium.
  • R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen or deuterium, and R 4 is methyl.
  • L 1 is a chemical bond.
  • the present disclosure provides a compound represented by formula (I) or (VI) or a pharmaceutically acceptable salt thereof, wherein L1 is selected from C1-6 alkylene, and the C1-6 alkylene is optionally substituted by one or more substituents independently selected from RB , wherein RB is selected from deuterium, halogen, hydroxyl, and C1-6 alkoxy.
  • the present disclosure provides a compound represented by formula (I) or (VI) or a pharmaceutically acceptable salt thereof, wherein L1 is a methylene group, and the methylene group is optionally substituted by one or more substituents independently selected from RB , wherein RB is selected from deuterium, halogen, hydroxyl, and C1-6 alkoxy.
  • the present disclosure provides a compound of formula (I) or (VI) or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from a pyrazole ring, an imidazole ring, a tetrahydropyran ring, a pyrimidine ring or a cyclohexyl ring.
  • the present disclosure provides a compound of formula (I) or (VI) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from deuterium, cyano, C 2-6 alkynyl, -SC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, and the C 2-6 alkynyl, -SC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl is optionally substituted with one or more substituents independently selected from RC , wherein RC is selected from deuterium, halogen, C 1-6 alkoxy, hydroxyl, amino, oxo, and C 2-6 alkynyl.
  • the present disclosure provides a compound represented by formula (I) or (VI) or a pharmaceutically acceptable salt thereof, wherein
  • the compound of formula (VI) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof,
  • the L2 is selected from -NH- or -O-;
  • the ring B is selected from a 5- to 6-membered heteroaryl group or a 5- to 6-membered aryl group;
  • the L3 is selected from C1-3 alkylene (e.g., methylene, ethylene, propylene), the C1-3 alkylene is optionally substituted by one or more substituents independently selected from R1 , the R1 is selected from deuterium, halogen, oxo, hydroxyl, amino or C1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl);
  • R 25 and R 26 are each independently selected from hydrogen, C 1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl), and the C 1-6 alkyl is optionally substituted with one or more deuterium;
  • C 1-6 alkyl e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl
  • Said R 27 is each independently selected from deuterium, halogen, hydroxyl, carboxyl, C 1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl), halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylene-3 to 6-membered cycloalkyl (e.g., cyclopropyl, cyclobutyl), 3 to 6-membered cycloalkyl (e.g., cyclopropyl, cyclobutyl), -S- 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -NH-C 1-6 alkyl, -NH(C 1-6 alkyl) 2 ;
  • C 1-6 alkyl e.g.,
  • the y is selected from 0, 1, 2, 3 or 4;
  • R 4 is C 1-6 alkyl
  • R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl;
  • the L 1 is selected from a linker, or the L 1 is selected from a C 1-6 alkylene group (e.g., methylene, ethylene, propylene), or the L 1 is selected from a C 1-6 alkylene group, and the C 1-6 alkylene group is substituted by one or more substituents independently selected from RB , wherein RB is selected from deuterium, halogen, hydroxyl, C 1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl) or oxo;
  • RB is selected from deuterium, halogen, hydroxyl, C 1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl) or oxo;
  • the ring A is selected from a 5- to 6-membered aryl group, a 5- to 6-membered heteroaryl group, or a 3- to 7-membered heterocyclic group;
  • the C2-6 alkynyl, -SC1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 5- to 12-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from RC , wherein RC is selected from deuterium, halogen, C1-6 alkoxy, C1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl)), hydroxy, amino, oxo, C2-6 alkynyl;
  • the n is selected from 0, 1, 2 or 3.
  • the compound of formula (VI) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (VI-1) or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein L 2 is -NH-.
  • the present disclosure provides a compound of formula (VI-1) or (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from pyridyl or phenyl, and the R 27 is each independently selected from deuterium, halogen, hydroxyl, carboxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylene-3 to 6 membered cycloalkyl.
  • the present disclosure provides a compound of formula (VI-1) or (VI-2) or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl, and each of R 27 is independently selected from deuterium, halogen, hydroxyl, carboxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylene-3 to 6 membered cycloalkyl.
  • the present disclosure provides a compound represented by formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is phenyl, and the R 27 is independently selected from deuterium.
  • the present disclosure provides a compound represented by formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is phenyl, and the R 27 is independently selected from halogen.
  • the present disclosure provides a compound represented by formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is phenyl, and the R 27 is independently selected from a C 1-6 alkyl group.
  • the present disclosure provides a compound of formula (VI-1) or (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is a phenyl group, and the R 27 is independently selected from a methyl group or an ethyl group.
  • the present disclosure provides a compound represented by formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is phenyl, and the R 27 is each independently selected from methylene-cyclopropyl.
  • the present disclosure provides a compound represented by formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is phenyl, and the R 27 is independently selected from cyclopropyl.
  • the present disclosure provides a compound of formula (VI-1) or (VI-2) or a pharmaceutically acceptable salt thereof, wherein L3 is selected from a methylene group, and the methylene group is optionally substituted with one or more substituents independently selected from R1 , wherein R1 is selected from deuterium, halogen, oxo, hydroxyl, amino or C1-6 alkyl (for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl).
  • the compound of formula (VI-1) or formula (VI-2) provided by the present disclosure or its pharmaceutically acceptable With salt said L 3 is selected from ethylene, and said ethylene is optionally substituted by one or more substituents independently selected from R I , and said R I is selected from deuterium, halogen, oxo, hydroxyl, amino or C 1-6 alkyl (for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl).
  • the present disclosure provides a compound of formula (VI-1) or (VI-2) or a pharmaceutically acceptable salt thereof, wherein L3 is selected from propylene, and the propylene is optionally substituted with one or more substituents independently selected from R1 , wherein R1 is selected from deuterium, halogen, oxo, hydroxyl, amino or C1-6 alkyl (for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl).
  • the compound of formula (VI) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (VI-1-A) or formula (VI-1-B) or a pharmaceutically acceptable salt thereof,
  • R 5 , R 6 , R 7 , R 8 , R 9 , L 1 , Ring A, R 10 , n, R 25 , R 26 , R 27 and y are compounds represented by formula (VI-1-A) or formula (VI-1-B) or pharmaceutically acceptable salts thereof.
  • the compound represented by formula (VI) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound represented by formula (VI-1-A) or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L 1 is a connecting bond.
  • the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is selected from C1-6 alkylene, or L1 is selected from C1-6 alkylene, and the C1-6 alkylene is substituted with one or more substituents independently selected from RB , and RB is selected from deuterium, C1-6 alkyl or oxo.
  • the compounds of formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof provided by the present disclosure wherein L 1 is selected from C 1-6 alkylene, specifically methylene or ethylene.
  • the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is selected from C1-6 alkylene, and the C1-6 alkylene is substituted by one or more substituents independently selected from RB , and RB is selected from deuterium, methyl, ethyl or propyl.
  • the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is selected from C1-6 alkylene, and the C1-6 alkylene is substituted with one or more substituents independently selected from RB , and RB is selected from deuterium.
  • the present disclosure provides formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) The compound or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from C 1-6 alkylene, and the C 1-6 alkylene is substituted by one or more substituents independently selected from RB , and RB is selected from methyl.
  • the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is selected from C1-6 alkylene, and the C1-6 alkylene is substituted with one or more substituents independently selected from RB , and RB is selected from oxo.
  • the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L 1 is selected from methylene, or L 1 is selected from methylene, and the methylene is substituted by one or more substituents independently selected from RB , and RB is selected from deuterium or C 1-6 alkyl (e.g., methyl, ethyl).
  • the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L is selected from methylene, or L is selected from methylene, and the methylene is substituted with one or more substituents independently selected from RB , and RB is selected from deuterium or methyl.
  • the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is selected from methylene, and the methylene is substituted with one or more substituents independently selected from RB , and RB is selected from oxo.
  • the present disclosure provides compounds of formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen or deuterium.
  • the compounds of formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof provided by the present disclosure wherein ring A is selected from pyrazolyl, imidazolyl, pyridinyl, phenyl, tetrahydropyranyl, pyrimidinyl, and cyclohexyl.
  • the C 1-6 alkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl is optionally substituted by one or more substituents independently selected from RC , wherein RC is selected from deuterium, halogen, C 1-6 alkoxy, C 1-6 alkyl, hydroxy, amino, oxo, C 2-6 alkynyl;
  • the n is selected from 1, 2 or 3.
  • the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from C 1-6 alkyl;
  • the n is selected from 1, 2 or 3.
  • the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from methyl, ethyl or propyl;
  • the n is selected from 1, 2 or 3.
  • the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from methyl;
  • the n is selected from 1, 2 or 3.
  • the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from C 1-6 alkylene-3 to 6-membered cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl);
  • the n is selected from 1, 2 or 3.
  • the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from methylene-cyclopropyl;
  • the n is selected from 1, 2 or 3.
  • the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from a 3- to 6-membered cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl);
  • the n is selected from 1, 2 or 3.
  • the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from cyclopropyl;
  • the n is selected from 1, 2 or 3.
  • the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from phenyl, and the phenyl is optionally substituted with one or more substituents independently selected from RC , wherein RC is selected from deuterium, halogen, C 1-6 alkoxy, C 1-6 alkyl, hydroxyl, amino, oxo, C 2-6 alkynyl;
  • the n is selected from 1, 2 or 3.
  • the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from a 5- to 6-membered heteroaryl group (e.g., pyridine, imidazole, pyrazole, thiazole, oxazole), and the 5- to 6-membered heteroaryl group is optionally substituted by one or more substituents independently selected from RC , wherein RC is selected from deuterium, halogen, C 1-6 alkoxy, C 1-6 alkyl, hydroxy, amino, oxo, C 2-6 alkynyl;
  • R 10 is selected from a 5- to 6-membered heteroaryl group (e.g., pyridine, imidazole, pyrazole, thiazole, oxazole), and the 5- to 6-membered heteroaryl group is optionally substituted by one or more substituents independently selected from RC , wherein
  • the n is selected from 1, 2 or 3.
  • the present disclosure provides compounds of formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 10 is selected from (C ⁇ O)NH 2 , and n is selected from 1, 2 or 3.
  • the present disclosure provides formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1- B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from a 5- to 10-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by one or more substituents independently selected from RC , wherein RC is selected from deuterium, halogen, C 1-6 alkoxy, C 1-6 alkyl, hydroxy, amino, oxo, C 2-6 alkynyl,
  • the n is selected from 1, 2 or 3.
  • the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from a 5- to 10-membered bridged-heterocyclic group, wherein the bridged-heterocyclic group is optionally substituted by one or more substituents independently selected from RC , wherein RC is selected from deuterium, halogen, C 1-6 alkoxy, C 1-6 alkyl, hydroxyl, amino, oxo, C 2-6 alkynyl, and the heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
  • the n is selected from 1, 2 or 3.
  • the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein Selected from
  • the present disclosure provides compounds of formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 27 is independently selected from deuterium, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkylene-3 to 6 membered cycloalkyl, 3 to 6 membered cycloalkyl, halogenated C 1-6 alkoxy, -NH-C 1-6 alkyl, -NH(C 1-6 alkyl) 2 .
  • the present disclosure provides compounds of formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 27 is independently selected from halogen or C 1-6 alkyl.
  • the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 27 is independently selected from fluorine or chlorine;
  • the present disclosure provides compounds of formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 27 is independently selected from methyl.
  • R 25 and R 26 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl are optionally substituted with one or more deuterium.
  • the present disclosure provides compounds of formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 25 and R 26 are each independently selected from hydrogen, methyl, and ethyl, and the methyl and ethyl groups are optionally substituted with one or more deuterium groups.
  • the present disclosure provides compounds of formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 25 and R 26 are each independently selected from methyl, and the methyl is optionally substituted with one or more deuterium.
  • the present disclosure provides a compound as shown below or a pharmaceutically acceptable salt thereof, which is selected from:
  • Another aspect of the present disclosure provides a compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table A, an isotope substitution.
  • the isotope substitution is a deuterium atom substitution.
  • the present disclosure also provides a pharmaceutical composition, comprising at least one compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table A, an isotope-substituted compound, or a compound or a pharmaceutically acceptable salt thereof prepared by the aforementioned method and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising at least one compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table A, an isotope-substituted compound, or a compound or a pharmaceutically acceptable salt thereof prepared by the aforementioned method and a pharmaceutically acceptable excipient.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.
  • the present disclosure provides the compounds represented by the aforementioned formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or their pharmaceutically acceptable salts and the compounds in Table a, isotope substitutions, or the compounds or their pharmaceutically acceptable salts prepared by the aforementioned methods and the use of the aforementioned pharmaceutical compositions in the preparation of drugs for treating or preventing diseases or conditions associated with abnormal activity of serine/threonine kinases.
  • the present disclosure provides the compounds represented by the aforementioned formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or their pharmaceutically acceptable salts and the compounds in Table a, isotopic substitutions, or the compounds or their pharmaceutically acceptable salts prepared by the aforementioned methods and the use of the aforementioned pharmaceutical compositions in the preparation of drugs for treating and/or preventing diseases or conditions associated with abnormal activity of CDK7.
  • the disease or disorder associated with abnormal activity of CDK7 is selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease or an infectious disease.
  • the present disclosure provides the compounds represented by the aforementioned formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or their pharmaceutically acceptable salts and the compounds in Table a, isotopic substitutions, or the compounds or their pharmaceutically acceptable salts prepared by the aforementioned methods and the use of the aforementioned pharmaceutical compositions in the preparation of drugs for treating and/or preventing diseases or conditions, wherein the diseases or conditions are selected from proliferative diseases, inflammatory diseases, autoinflammatory diseases, autoimmune diseases or infectious diseases.
  • the disease or disorder is a proliferative disease.
  • the proliferative disease is cancer.
  • the cancer is selected from the group consisting of a hematological tumor and a solid tumor.
  • the blood tumor is selected from leukemia, specifically including: chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), etc.).
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphocytic leukemia
  • T-ALL T-cell acute lymphocytic leukemia
  • CML chronic myeloid leukemia
  • AML acute myeloid leukemia
  • the solid tumor is selected from breast cancer, colon cancer, lung cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, osteoma, neuroblastoma, cervical cancer, ovarian cancer, gastric cancer, and liver cancer.
  • the breast cancer is triple-negative breast cancer.
  • the breast cancer is ER/PR+HER2- breast cancer.
  • the breast cancer is ER/PR+HER2- breast cancer that is resistant to CDK4/6 inhibitors.
  • the CDK4/6 inhibitor is Palbociclib.
  • the lung cancer is non-small cell lung cancer.
  • the lung cancer is small cell lung cancer.
  • the intestinal cancer is colon cancer.
  • the intestinal cancer is rectal cancer.
  • the present disclosure provides a method for treating and/or preventing a disease or condition associated with abnormal activity of serine/threonine kinase in a patient, comprising administering to the patient a therapeutically effective amount of a compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table A, an isotopic substitution, or a compound or a pharmaceutically acceptable salt thereof prepared by the aforementioned method and the aforementioned pharmaceutical composition.
  • a compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table A an isotopic substitution, or a compound or a pharmaceutically acceptable salt thereof prepared by the aforementioned method and the aforementioned pharmaceutical composition.
  • the present disclosure provides a method for treating and/or preventing a disease or condition associated with abnormal activity of CDK7 in a patient, comprising administering to the patient a therapeutically effective amount of a compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table a, an isotopic substitution, or a compound or a pharmaceutically acceptable salt thereof prepared by the aforementioned method and the aforementioned pharmaceutical composition.
  • a compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table a an isotopic substitution, or a compound or a pharmaceutically acceptable salt thereof prepared by the aforementioned method and the aforementioned pharmaceutical composition.
  • the disease or disorder associated with abnormal activity of CDK7 is selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease or an infectious disease.
  • Another aspect of the present disclosure provides a method for treating and/or preventing a disease or condition in a patient, wherein the patient is administered a therapeutically effective amount of a compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table a, an isotope-substituted product thereof, or a compound or a pharmaceutically acceptable salt thereof and a pharmaceutical composition prepared by the aforementioned method, wherein the disease or condition is selected from proliferative diseases, inflammatory diseases, Autoinflammatory disease, autoimmune disease or infectious disease; in an optional embodiment, the disease or disorder is a proliferative disease.
  • a compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table a an isotope-substituted product thereof, or a compound or a pharmaceutically acceptable salt thereof and
  • the proliferative disease is cancer.
  • the cancer is selected from the group consisting of a hematological tumor and a solid tumor.
  • the blood tumor is selected from leukemia, specifically including: chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), etc.).
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphocytic leukemia
  • T-ALL T-cell acute lymphocytic leukemia
  • CML chronic myeloid leukemia
  • AML acute myeloid leukemia
  • the solid tumor is selected from breast cancer, colon cancer, lung cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, osteoma, neuroblastoma, cervical cancer, ovarian cancer, gastric cancer, and liver cancer.
  • the breast cancer is triple-negative breast cancer.
  • the breast cancer is ER/PR+HER2- breast cancer.
  • the breast cancer is ER/PR+HER2- breast cancer that is resistant to CDK4/6 inhibitors.
  • the CDK4/6 inhibitor is Palbociclib.
  • the lung cancer is non-small cell lung cancer.
  • the lung cancer is small cell lung cancer.
  • the intestinal cancer is colon cancer.
  • the intestinal cancer is rectal cancer.
  • the present disclosure provides a compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table A, an isotope-substituted product, or the use of the compound prepared by the aforementioned method as a drug.
  • the compound of formula (VI) or a pharmaceutically acceptable salt thereof provided in the present disclosure can be prepared by referring to the method of patent WO2022064009A1.
  • the compound of formula (VI) provided in the present disclosure is split into two fragments during the synthesis process, namely A and B.
  • the present disclosure provides a method for preparing a compound represented by formula (VI-1-A) or a pharmaceutically acceptable salt thereof, or an isotope substituted product thereof, comprising the steps of condensing a compound represented by formula (VI-1-A-01) or a pharmaceutically acceptable salt thereof with a compound represented by formula (VI-1-A-02) or a pharmaceutically acceptable salt thereof under the action of carbonyldiimidazole, phosgene or triphosgene,
  • R 5 , R 6 , R 7 , R 8 , R 9 , L 1 , Ring A, R 10 , n, R 25 , R 26 , R 27 and y are as defined above.
  • the condensation reaction occurs in an alkaline environment, which is provided by an inorganic base (sodium hydroxide) or an organic base (such as triethylamine, pyridine, piperidine or N,N-diisopropylethylamine), and the solvent in which the reaction occurs is a common solvent (such as DMF, DCM or DMSO).
  • an inorganic base sodium hydroxide
  • an organic base such as triethylamine, pyridine, piperidine or N,N-diisopropylethylamine
  • the solvent in which the reaction occurs is a common solvent (such as DMF, DCM or DMSO).
  • the present disclosure provides a method for preparing a compound represented by formula (VI-1-B) or a pharmaceutically acceptable salt thereof, or an isotope substituted product thereof, comprising the steps of condensing a compound represented by formula (VI-1-B-01) or a pharmaceutically acceptable salt thereof with a compound represented by formula (VI-1-A-02) or a pharmaceutically acceptable salt thereof under the action of carbonyldiimidazole, phosgene or triphosgene,
  • R 5 , R 6 , R 7 , R 8 , R 9 , L 1 , Ring A, R 10 , n, R 25 , R 26 , R 27 and y are as defined above.
  • the condensation reaction occurs in an alkaline environment, which is provided by an inorganic base (sodium hydroxide) or an organic base (such as triethylamine, pyridine, piperidine or N,N-diisopropylethylamine), and the solvent in which the reaction occurs is a common solvent (such as DMF, DCM or DMSO).
  • an inorganic base sodium hydroxide
  • an organic base such as triethylamine, pyridine, piperidine or N,N-diisopropylethylamine
  • the solvent in which the reaction occurs is a common solvent (such as DMF, DCM or DMSO).
  • the pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts.
  • the compounds described in the present disclosure can react with acidic or basic substances to form corresponding salts.
  • the present disclosure provides a compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table a, wherein the isotope substitute has excellent selectivity for CDK7 enzyme activity, and in an optional embodiment, the IC 50 is less than 100 nM, in an optional embodiment, the IC 50 is less than 50 nM, in an optional embodiment, the IC 50 is less than 30 nM, and in an optional embodiment, the IC 50 is less than 15 nM.
  • the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms.
  • the present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomers.
  • the present invention also provides a kind of isomers or diastereomers enriched mixture, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included in the scope of the present disclosure.
  • the compounds containing asymmetric carbon atoms of the present disclosure can be isolated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents.
  • Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamates are generated from amines).
  • the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations.
  • tautomer or “tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also referred to as prototransfer tautomers
  • proton migration such as keto-enol and imine-enamine, lactam-lactim isomerization. Lactam-lactim equilibrium examples are between A and B as shown below.
  • the present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl , respectively.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10% deuterium incorporation) that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%).
  • Examples of compounds having an abundance of deuterium greater than the natural abundance of deuterium may be at least 1000 times greater than the natural abundance of deuterium, at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium.
  • Deuterium can be present in an amount of 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more.
  • the present disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds of formula (I) with reference to relevant literature.
  • deuterated starting materials can be used when preparing deuterated forms of compounds of formula (I), or they can be synthesized using deuterated reagents using conventional techniques, and deuterated reagents include but are not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • Optionally or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur.
  • C 1-6 alkyl optionally substituted with halogen or cyano means that halogen or cyano may but need not be present, and the description includes instances where the alkyl is substituted with halogen or cyano and instances where the alkyl is not substituted with halogen and cyano.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • “Pharmaceutically acceptable excipients” include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or livestock animals.
  • an "effective amount” or “therapeutically effective amount” includes an amount sufficient to improve or prevent the symptoms or symptoms of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • C1-6alkyl indicates that the alkyl group has 1 to 6 carbon atoms, and specifically may be an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkyl refers to a non-branched or branched saturated hydrocarbon chain.
  • the alkyl group has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or 1 to 4 carbon atoms (i.e., C 1-4 alkyl).
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2 - pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
  • butyl includes n-butyl (i.e., -( CH2 ) 3CH3 ), sec-butyl (i.e., -CH( CH3 ) CH2CH3 ), isobutyl ( i.e.
  • alkenyl refers to an alkyl group having at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkenyl).
  • alkenyl include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond, having 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl).
  • alkynyl examples include ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl.
  • cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated cyclic alkyl having a monocyclic or polycyclic ring (including fused, bridged and spirocyclic ring systems).
  • cycloalkyl includes cycloalkenyl (i.e., the cyclic group has at least one double bond).
  • the cyclic alkyl used herein has 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 7 ring carbon atoms (i.e., C 3-7 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl).
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, cyclohexenyl, cyclohexadienyl.
  • the cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.
  • heterocyclyl or “heterocycloalkyl” refers to a saturated or unsaturated cycloalkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, sulfur and phosphorus.
  • heterocycloalkyl includes heterocycloalkenyl (i.e., a heterocyclyl having at least one double bond), bridged-heterocyclyl, fused heterocyclyl and spiral-heterocyclyl.
  • the heterocyclyl group can be a monocyclic or polycyclic ring, wherein the polycyclic ring can be fused, bridged or spiral.
  • any non-aromatic ring containing at least one heteroatom is considered to be a heterocyclyl, regardless of connection (i.e., it can be combined by carbon atoms or heteroatoms).
  • heterocyclyl is intended to include any non-aromatic ring containing at least one heteroatom, which ring can be fused to an aryl or heteroaryl ring, regardless of the connection to the rest of the molecule.
  • the heterocyclyl group has 3 to 20 ring atoms (i.e., 3 to 20-membered heterocyclyl), 3 to 12 ring atoms (i.e., 3 to 12-membered heterocyclyl), 3 to 10 ring atoms (i.e., 3 to 10-membered heterocyclyl), 3 to 8 ring atoms (i.e., 3 to 8-membered heterocyclyl), 3 to 7 ring atoms (i.e., 3 to 7-membered heterocyclyl), 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclyl); has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, and the ring heteroatoms are independently selected from nitrogen, sulfur, phosphorus or oxygen.
  • the ring heteroatoms are independently selected from nitrogen, sulfur, phosphorus or oxygen.
  • heterocyclic groups include pyrrolidinyl, imidazolidinyl, oxetanyl, dioxolanyl, azetidinyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.
  • bridged-heterocyclyl refers to a 4- to 10-membered cyclic moiety that is connected to one or more (e.g., 1 or 2) 4- to 10-membered cyclic moieties having at least one heteroatom at two non-adjacent atoms of the heterocyclyl, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, and phosphorus.
  • bridged-heterocyclyl includes bicyclic and tricyclic ring systems.
  • spiro-heterocyclyl refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, wherein the one or more additional The ring is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclyl, wherein a single atom of the one or more additional rings is also an atom of the 3- to 10-membered heterocyclyl.
  • spiro-heterocyclyl rings include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl.
  • fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl, wherein the heterocyclyl may be bound through any ring of the fused system.
  • heterocyclyl examples include:
  • heterocyclyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated ⁇ electron system, preferably 6- to 12-membered, such as phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 6 to 12 members, more preferably 5 or 6 members.
  • Non-limiting examples include: imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazine, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • alkoxy refers to the group “alkyl-O-,” wherein alkyl is as defined above. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • cycloalkyloxy and “heterocyclyloxy” are defined in the same manner as the above-mentioned “alkoxy”.
  • haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • a residue when a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached.
  • Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two or three halogen groups, which may be, but need not be, the same halogen. Examples of haloalkyl groups include difluoromethyl ( -CHF2 ) and trifluoromethyl ( -CF3 ).
  • haloalkoxy refers to an alkoxy group as defined above wherein one or more hydrogen atoms are replaced by a halogen.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, the alkyl group being as defined above.
  • hydroxy refers to an -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • MS was determined using Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC-MS (Manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), Waters ACQuity UPLC-QD/SQD (Manufacturer: Waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • HPLC preparation was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.
  • the average kinase inhibition rate and IC50 value were determined using NovoStar microplate reader (BMG, Germany).
  • the known starting materials disclosed in the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, J&K, Accela ChemBio Inc, Shanghai Bid Pharmaceuticals, Darui Chemicals and other companies.
  • the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.
  • Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Clear Blue QL-500 hydrogen generator or a HC2-SS hydrogenator.
  • the hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.
  • Microwave reactions were performed using a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, 20°C to 30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: petroleum ether/ethyl acetate/methanol, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • TFA trifluoroacetic acid
  • DCM dichloromethane
  • m-CPBA m-chloroperbenzoic acid
  • EtONa sodium ethoxide
  • Boc tert-butyloxycarbonyl
  • MeOH methanol
  • HBTU benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • TsOH p-toluenesulfonic acid
  • EtOAc ethyl acetate
  • t-BuOH tert-butyl alcohol
  • PdCl 2 (TPP) 2 dichlorobis(triphenylphosphine)palladium
  • XantPhos 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene
  • Pd 2 dba 3 trisdibenzylideneacetone dipalladium
  • PdCl 2 (TPP) 2 dichlorobis
  • EtONa ((0.456 mL, 5.822 mmol) was added to a solution of compound 1h (400 mg, 1.164 mmol) in EtOH (30 mL). The reaction temperature was gradually raised to 85°C and stirred for 5 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product 1i. At room temperature, the crude product 1i was added to a mixed solution of EtOH (15 mL) and H 2 O (15 mL), and NaOH (118 mg, 2.95 mmol) was added. The mixture was stirred for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product.
  • m-CPBA (10.3 g, 50.7 mmol) was added to a solution of compound 1m (5.00 g, 17.0 mmol) in DCM (100 mL), and the mixture was stirred for 2 hours.
  • the reaction mixture was warmed to room temperature and stirred for 10 hours.
  • the mixture was cooled to 0°C, and Na 2 SO 3 (10%, 40 mL) was added to the reaction mixture.
  • the mixture was extracted with DCM (30 mL x 3). The organic phases were combined and washed once with saturated brine (50 mL), dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • reaction solution was concentrated under reduced pressure to obtain crude product 1, which was separated and purified by preparative HPLC (chromatographic column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [(NH 4 HCO 3 )-CH 3 CN]; B%: 65%-90%) to obtain compound 1-1 (17.4 mg, 0.036 mmol, 9.18%) and compound 1-2 (17.0 mg, 0.035 mmol, 9.50%).
  • preparative HPLC chromatographic column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [(NH 4 HCO 3 )-CH 3 CN]; B%: 65%-90%) to obtain compound 1-1 (17.4 mg, 0.036 mmol, 9.18%) and compound 1-2 (17.0 mg, 0.035 mmol, 9.50%).
  • reaction solution was concentrated under reduced pressure to obtain crude product 2, which was separated and purified by preparative HPLC (chromatographic column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(NH 4 HCO 3 )-ACN]; B%: 10%-40%) to obtain compound 2 (11.8 mg, 25.2 ⁇ mol, yield 10.8%).
  • reaction solution was concentrated under reduced pressure to obtain crude product 3, which was separated and purified by preparative HPLC (chromatographic column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 10%-40%) to obtain compound 3 (44.4 mg, 98.9 ⁇ mol, yield 42.6%).
  • reaction solution was separated and purified by preparative HPLC (chromatographic column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(NH 4 HCO 3 )-ACN]; B%: 10%-40%, 8 min) to obtain compound 4h (9 mg, yield 6%).
  • CDI (213.2 mg, 1.32 mmol) was added to a DMF (3 mL) solution containing 2a (108 mg, 0.66 mmol), and the mixture was stirred at room temperature for 5 min.
  • Et 3 N (0.27 mL, 1.97 mmol) and compound 10d (114.3 mg, 0.46 mmol) were added in sequence, and the mixture was reacted overnight at room temperature.
  • the reaction solution was separated and purified by preparative HPLC (chromatographic column: Waters Xbridge Prep OBD C18 150*40 mm*10 um; mobile phase: [water(NH 4 HCO 3 )-ACN]) to obtain compound 10 (80 mg, yield: 27.7%).
  • CD 3 I (2.75 g, 19.0 mmol) was slowly added to a DMF (15.0 mL) solution of compound 14a (1.99 g, 15.8 mmol) and cesium carbonate (10.3 g, 31.7 mmol), and stirred at room temperature for 2 hours.
  • the reaction solution was extracted, dried, and concentrated to obtain a crude product, which was separated by column chromatography to obtain compound 14b (1.04 g, 7.26 mmol, yield: 45%).
  • urea (11.6 mL, 193.5 mmol) was added to a solution of 15f (14 g, 48.4 mmol) in anhydrous MeOH (200 mL), activated 4AMS (10 g) was added, the temperature was raised to reflux, and stirred overnight.
  • the reaction solution was extracted with ethyl acetate (100 mL ⁇ 2), washed with saturated brine, the organic phase was dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by C18 reverse silica gel column chromatography to obtain compound 15g (8 g, 28 mmol).
  • compound 15i 240 mg, 0.83 mmol
  • compound 15j 108 mg, 1.0 mmol
  • Xantphos-G3-Pd 79 mg, 0.08 mmol
  • Cs 2 CO 3 325 mg, 1.25 mmol
  • the reaction solution was concentrated to obtain a crude product.
  • the crude product was purified by silica gel chromatography with rapid column chromatography using 1-5% ethyl acetate in petroleum ether as the eluent to obtain compound 15k (100 mg, 33.4%).
  • compound 17 (10 mg, 0.023 mmol) was obtained from compound 15i (80 mg, 0.278 mmol) through three steps of reaction.
  • reaction solution was extracted with DCM/MeOH (9:1, 500 mL ⁇ 2), washed with saturated brine, the organic phase was dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography with rapid column chromatography, the eluent being 1-10% ethyl acetate in petroleum ether, to obtain compound 18c (60 mg, yield: 56.8%).
  • di-tert-butyl dicarbonate 69 mg, 0.32 mmol
  • DMAP 2 mg
  • saturated Na 2 CO 3 solution 1 mL
  • reaction mixture was extracted with ethyl acetate (100 mL ⁇ 2), washed with saturated brine, the organic phase was dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography with rapid column chromatography using 1-20% ethyl acetate in petroleum ether as the eluent to obtain compound 18e (70 mg, yield: 86.3%).
  • Test Example 1 Test of the inhibitory activity of the disclosed compounds on ovarian cancer cells (OVCAR3)
  • Ovarian cancer cells OVCAR3 were cultured in RPMI 1640 with 10% FBS in a cell culture incubator at 37%, 5% CO 2. On the first day, cells were plated in 96-well plates at a cell density of 2500 cells/well and cultured overnight in an incubator. Compound treatment was performed on the second day, with the highest concentration of compound treatment being 10uM, 3-fold dilution, 9 concentrations, and a final concentration of DMSO of 0.1%. After the cells were cultured in the incubator for 5 days, the cell viability was tested using the Celltiter Glo assay kit (Promega), and the test method was consistent with the operating method provided by the kit. GraphPad Prism 8 was used to process the data and calculate IC 50 .
  • X logarithmic value of compound concentration
  • Y % inhibition.
  • Test Example 2 Test of the inhibitory activity of the disclosed compounds on tumor cells
  • Breast cancer cells MCF7 (ATCC#HTB-22) and T47D (ATCC#HTB-133), pancreatic cancer cells PANC-1 (ATCC#CRL-1469) were purchased from ATCC.
  • Breast cancer cells MDA-MB-231 (Kebai#CBP60382), HCC1806 (Kebai#CBP60373) and MDA-MB-468 (Kebai#CBP60387), colorectal cancer cells HCT-116 (Kebai#CBP60028), leukemia cells OCI-AML-3 (Kebai#CBP60817) and MV-4-11 (Kebai#CBP60522) were purchased from Nanjing Kebai Biotechnology Co., Ltd.
  • OCI-AML-3 used RPMI 1640 medium with 20% FBS; HCC1806 and T47D used RPMI 1640 medium with 10% FBS; MCF7, MDA-MB-231, MDA-MB-468 and PANC-1 used DMEM medium with 10% FBS; MV-4-11 used IMDM medium with 20% FBS; HCT-116 used MC’5A medium with 10% FBS.
  • Palbociclib-resistant cells were constructed on MCF7 parental cells and labeled as MCF7Palbo-R.
  • the culture conditions were consistent with the parental cells. All tumor cells were cultured in a cell culture incubator at 37°C and 5% CO 2.
  • the cells were seeded according to the cell density (600 cells/well for MDA-MB-231; 500 cells/well for MDA-MB-468, PANC-1, HCT-116; 200 cells/well for MCF7, HCC1806; 800 cells/well for MCF7 Palbo-R; 3000 cells/well for OCI-AML-3&MV-4-11) and cultured in an incubator overnight. Compound treatment was performed the next day.
  • the highest concentration of compound treatment was 10 ⁇ M, 3-fold dilution, 9 concentrations, two replicates for each concentration, and the final concentration of DMSO was 0.1%.
  • the cells continued to be cultured in the incubator.
  • MDA-MB-231, PANC-1, MDA-MB-468, OCI-AML-3, and MV-4-11 were treated with drugs for 5 days;
  • HCC1806, MCF7, MCF7Palbo-R, and HCT116 were treated with drugs for 7 days.
  • Cell viability was tested using the Celltiter Glo assay kit (Promega), and the test method was consistent with the operation method provided by the kit.
  • the multi-function microplate reader Envision was used for reading.
  • GraphPad Prism 8 was used to process the data and calculate IC 50 .
  • X logarithmic value of compound concentration
  • Y % inhibition.
  • Test Example 3 Test of the inhibitory activity of the disclosed compounds on CDK kinase
  • ADP-Glo kinase assay is used to test CDK kinase activity.
  • the compound was diluted in a 384-well plate using Echo, with a starting concentration of 10uM, 3-fold gradient dilution, 10 concentration points, two replicates for each concentration, and a final DMSO concentration of 1% in the assay system.
  • CDK kinase solution prepared with assay buffer (final concentrations of 16.5nM CDK1/CyclinB, 1nM CDK2/CyclinE1, 16.3nM CDK4/CyclinD1, 11.5nM CDK5/p25, 15.7nM CDK6/CyclinD3, 80nM CDK7/Cyclin H/MAT1, 15.3nM CDK9/Cyclin T1, 150nM CDK12/CyclinK) was added, and the enzyme and compound were pre-incubated at room temperature for 10 minutes.
  • X logarithmic value of compound concentration
  • Y % inhibition.
  • reaction solution 30 ⁇ L aliquots were taken from the reaction solution at 0.5, 5, 10, 15, 20 and 30 minutes, respectively.
  • the reaction was terminated by adding 5 volumes of cold acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide), centrifuged, and 100 ⁇ L of the supernatant was mixed with 100 ⁇ L ultrapure H 2 O and then used for LC-MS/MS analysis.
  • IS cold acetonitrile containing IS
  • the slope value, k was determined from the linear regression of the natural logarithm of the parent drug remaining percentage versus the incubation time curve.
  • Tables 7 and 8 show that compared with Example 2 and Janssen-01, more original drug residues were detected at various time points during the incubation of human liver microparticles, the elimination half-life was significantly longer, and the clearance rate was significantly slower, indicating that the metabolism was more stable.

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Abstract

本公开涉及哌啶并嘧啶类衍生物、其制备方法及其在医药上的应用。具体而言，本公开涉及一种通式(I)所示的哌啶并嘧啶类衍生物、其制备方法及含有该衍生物的药物组合物，以及其作为CDK7抑制剂在治疗CDK7的异常活性相关的疾病或病症中的用途。其中通式(I)中各基团如说明书中所定义。

Description

哌啶并嘧啶类衍生物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种哌啶并嘧啶类衍生物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的嘧啶类衍生物、其制备方法及含有该衍生物的药物组合物，以及其作为CDK7抑制剂在治疗CDK7活性相关的疾病或病症的用途。
背景技术
细胞周期蛋白激酶(CDK)是激酶中的一个重要类别，并且在癌细胞的分裂增殖和致癌基因转录调控中具有重要的作用，目前发现的细胞周期蛋白激酶(CDK)具有超过20个亚型，由于CDK家族成员激酶结构域的序列和结构相似性，因此对各个亚型进行选择性地精准调控是一个重要挑战。
细胞周期蛋白依赖性激酶7(CDK7)是一种CDK家族的特殊成员，在细胞分裂调控和转录调控中具有双重功能。CDK7与细胞周期蛋白H和MAT1结合形成三聚化细胞周期蛋白活化激酶(CAK)，该激酶通过对细胞周期控制的相关CDK(包括CDK1,CDK2,CDK4,CDK6)进行磷酸化来激活相应CDK激酶的活性完成对细胞周期的调控。CDK7也作为常见转录因子II H(TFIIH)的组成部分参与转录的辅助调节，它通过RNA聚合酶II(RNAPII)的Rbp1亚单位的磷酸化牵涉转录起始过程，然后通过对CDK9复合物的磷酸化可以调控转录的延伸。
癌症的重要特征是细胞增殖不受控制和转录失调，因此同时抑制转录和细胞周期进程的CDK7抑制剂是治疗癌症理论上比较可行的作用靶点，目前尚未有该靶点选择性调控的药物上市。我们设想发展一种高选择性的CDK7抑制剂来治疗CDK7活性相关的疾病。
公开的CDK7抑制剂专利申请包括WO2016058544、WO2018013867、WO2019143719、WO2019143730、WO2019099298、WO2020093006和WO2020093011、WO2022064009A等。
发明内容
本公开的目的在于提供一种式(I)所示的化合物或其可药用盐：
其中，所述G1为N或CR1a；
所述R1、R2、R3和R1a各自独立地选自氢、氘、氰基、羟基、C1-6烷基或卤素(例如，氟、氯、溴、碘)，且至少有一个不为氢或氘；
所述R4、R5、R6、R7、R8、R9各自独立地选自氢、氘、卤素、C1-6烷基、氰基、C2-6烯基、C2-6炔基或3至6元环烷基，所述C1-6烷基、C2-6烯基、C2-6炔基或3至6元环烷基任选被一个或多个独立地选自RA的取代基取代，所述RA选自氘、卤素、羟基、氰基或3至6元环烷基；
所述L1选自化学键或C1-6亚烷基，所述C1-6亚烷基任选被一个或多个独立地选自RB的取代基取代，所述RB选自氘、卤素、羟基、C1-6烷氧基、氨基、氧代，或者，连接在同一个碳原子上的两个RB与共同连接的碳原子成3至6元环烷基或3至7元的杂环基，所述杂环基至少含有一个选自N，O或S的杂原子；
所述环A选自3至6元环烷基、6至10元芳基、5至12元的杂芳基或3至12元的杂环基；
所述R10各自独立地选自氘、氰基、卤素、羟基、氨基、C2-6炔基、C2-6烯基、-S-C1-6烷基、C1-6烷氧基、氧代、C1-6烷基、3至6元环烷基、6至10元芳基、5至12元的杂芳基、3到12元的杂环基、-NH-(C＝O)-C1-6烷基、-NH-(C＝O)-C3-6环烷基、-NH(C＝O)-OC1-6烷基、-NH(C＝O)-OC3-6环烷基、-O(C＝O)NHC1-6烷基、-O(C＝O)NH-C3-6环烷基、-(C＝O)NH-C1-6烷基、-(C＝O)-NH-C3-6环烷基、-(C＝O)-C1-6烷基、-(C＝O)-C3-6环烷基、-SO2-C1-6烷基、-SO2-C3-6环烷基、-SO2-NH2、-SO2-NH-C1-6烷基、-SO2-NH-C3-6环烷基、-SO2-N(C1-6烷基)2、-SO2-NH(C3- 6环烷基)2、-S(O)(NH)-C1-6烷基、-S(O)(NH)-C3-6环烷基，
所述C1-6烷基、3元到6元环烷基、6至10元芳基、5到12元的杂芳基、3到12元杂环基任选被一个或多个独立地选自RC的取代基取代，所述RC选自氘、卤素、C1-6烷氧基、羟基、氨基、氧代、C2-6炔基、C2-6烯基、氰基、C1-6羟烷基、3到12元的杂环基、C1-6烷基、C3-6环烷基、6至10元芳基或5到12元的杂芳基；
所述R11选自氢、氘、卤素、氰基、C1-6烷基、C1-6烷氧基、3至6元环烷基、3到12元杂环基、C2-6烯基、C2-6炔基，所述C1-6烷基、C1-6烷氧基、3至6元环烷基、3到12元杂环基、C2-6烯基、C2-6炔基、任选被一个或多个独立地选自RD的取代基取代，所述RD选自氢、氘、卤素、氰基、羟基、炔基、C1-6烷氧基、C1-6羟烷基、3至6元环烷基；
所述环B选自5至12元的杂芳基或6至12元的芳基；
所述R'选自氢、氰基、C1-6烷基、3至6元环烷基、3到12元杂环基，所述C1-6烷基、3至6元环烷基、3到12元杂环基任选被一个或多个独立地选自RE的取代基取代，所述RE选自氢、氘、卤素、氰基、羟基、炔基、C1-6烷氧基、C1-6羟烷基、3至6元环烷基、3至7元杂环基；
所述m选自0或1；
所述n选自0、1、2、3、4或5；
所述o选自0、1、2、3或4。
本公开另一方面提供一种式(VI)所示的化合物或其可药用盐，
其中，所述，L2选自-NH-或-O-；
所述B环选自5至12元的杂芳基或6至12元的芳基；
所述L3选自C0-6亚烷基，所述C0-6亚烷基任选被一个或多个独立地选自RI的取代基取代，所述RI选自氘、卤素、氧代、羟基、氨基或C1-6烷基；
所述R25和R26各自独立地选自氢、C1-6烷基、卤代C1-6烷基，或R25和R26与其连接的氮原子形成4至7元的含氮杂环，所述4至7元的含氮杂环任选被一个或多个独立地选自RJ的取代基取代，所述RJ选自卤素、羟基、氰基、硝基或氨基；
所述R27各自独立地选自氘、卤素、羟基、羧基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C2-6烯基、C2-6炔基、3至6元环烷基、-S-C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、-NH-C1-6烷基、-NH(C1-6烷基)2、-(C＝O)-NH2、烷基-(C＝O)-NH-C1-6烷基、-(C＝O)-NH-(C1-6烷基)2、-(C＝O)C1-6烷基、-NH-(C＝O)C1-6烷基；
所述y选自0、1、2、3或4；
所述R4、R5、R6、R7、R8、R9、L1、环A、R10和n分别如权利要求1中定义，前提是所述R4、R5不同时为氢。
可选的实施方案中，本公开提供的式(VI)所示的化合物或其可药用盐，其中，L2为-NH-。
可选的实施方案中，本公开提供的式(VI)所示的化合物或其可药用盐，其中，L2为-O-。
可选的实施方案中，本公开提供的式(VI)所示的化合物或其可药用盐，其中，L3为-CH2CH2-。
可选的实施方案中，本公开提供的式(VI)所示的化合物或其可药用盐，其中，其中，环B为苯基或吡啶基。
可选的实施方案中，本公开提供的式(VI)所示的化合物或其可药用盐，其中，环B为苯基。
可选的实施方案中，本公开提供的式(VI)所示的化合物或其可药用盐，其中， 所述R27各自独立地选自氢、氘、卤素、氰基、羟基、羧基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C2-6炔基、3至6元环烷基、3至12元杂环烷基、5-12元芳基或杂芳基。
可选的实施方案中，本公开提供的式(VI)所示的化合物或其可药用盐，其中，所述R27各自独立地选自卤素、C1-6烷基、卤代C1-6烷基、C2-6炔基。
可选的实施方案中，本公开提供的式(VI)所示的化合物或其可药用盐，其中，所述R27各自独立地选自氯、氟、三氟甲基或乙炔基。
可选的实施方案中，本公开提供的式(VI)所示的化合物或其可药用盐，其中，所述R25和R26各自独立地选自氢或C1-6烷基。
可选的实施方案中，本公开提供的式(I)、(VI)所示的化合物或其可药用盐，其中，所述R4、R5、R6、R7、R8、R9各自独立地选自氢、氘、卤素或C1-6烷基。
可选的实施方案中，本公开提供的式(I)、(VI)所示的化合物或其可药用盐，所述R4为甲基。
可选的实施方案中，本公开提供的式(I)、(VI)所示的化合物或其可药用盐，所述R5、R6、R7、R8、R9各自独立地选自氢或氘。
可选的实施方案中，本公开提供的式(I)、(VI)所示的化合物或其可药用盐，所述R5、R6、R7、R8、R9各自独立地选自氢或氘，所述R4为甲基。
可选的实施方案中，本公开提供的式(I)、(VI)所示的化合物或其可药用盐，所述L1为化学键。
可选的实施方案中，本公开提供的式(I)、(VI)所示的化合物或其可药用盐，所述L1选自C1-6亚烷基，所述C1-6亚烷基任选被一个或多个独立地选自RB的取代基取代，所述RB选自氘、卤素、羟基、C1-6烷氧基。
可选的实施方案中，本公开提供的式(I)、(VI)所示的化合物或其可药用盐，所述L1为亚甲基，所述亚甲基任选被一个或多个独立地选自RB的取代基取代，所述RB选自氘、卤素、羟基、C1-6烷氧基。
可选的实施方案中，本公开提供的式(I)、(VI)所示的化合物或其可药用盐，所述环A选自吡唑环、咪唑环、四氢吡喃环、嘧啶环或环己基。
可选的实施方案中，本公开提供的式(I)、(VI)所示的化合物或其可药用盐，所述R10选自氘、氰基、C2-6炔基、-S-C1-6烷基、C1-6烷氧基、C1-6烷基，所述C2-6炔基、-S-C1-6烷基、C1-6烷氧基、C1-6烷基任选被一个或多个独立地选自RC的取代基取代，所述RC选自氘、卤素、C1-6烷氧基、羟基、氨基、氧代、C2-6炔基。
可选的实施方案中，本公开提供的式(I)、(VI)所示的化合物或其可药用盐，所述
选自
一些实施方案中，本公开提供的式(VI)所示的化合物或其可药用盐，其为式(VI-1)或式(VI-2)所示的化合物或其可药用盐，
所述L2选自-NH-或-O-；
所述环B选自5至6元的杂芳基或5至6元芳基；
所述L3选自C1-3亚烷基(例如：亚甲基、亚乙基、亚丙基)，所述C1-3亚烷基任选被一个或多个独立地选自RI的取代基取代，所述RI选自氘、卤素、氧代、羟基、氨基或C1-6烷基(例如：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基)；
所述R25和R26各自独立地选自氢、C1-6烷基(例如：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基)，所述C1-6烷基任选被一个或多个氘取代；
所述R27各自独立地选自氘、卤素、羟基、羧基、C1-6烷基(例如：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基)、卤代C1-6烷基、羟基C1-6烷基、C2-6烯基、C2-6炔基、C1-6亚烷基-3至6元环烷基(例如环丙基、环丁基)、3至6元环烷基(例如环丙基、环丁基)、-S-C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、-NH-C1-6烷基、-NH(C1-6烷基)2；
所述y选自0、1、2、3或4；
所述R4为C1-6烷基；
所述R5、R6、R7、R8、R9各自独立地选自氢、氘、卤素或C1-6烷基；
所述L1选自连接键，或所述L1选自C1-6亚烷基(例如：亚甲基、亚乙基、亚丙基)，或所述L1选自C1-6亚烷基，所述C1-6亚烷基被一个或多个独立地选自RB的取代基取代，所述RB选自氘、卤素、羟基、C1-6烷基(例如：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基)或氧代；
所述环A选自5至6元芳基、5至6元杂芳基或3至7元杂环基；
所述R10选自氘、氰基、C2-6炔基、-S-C1-6烷基、C1-6烷氧基、C1-6烷基(例如：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基)、C1-6亚烷基-3至6元环烷基、3至6元环烷基、5至6元芳基、5至6元杂芳基、5至12元杂环烷基、-NH(C＝O)-OC1-6烷基、-(C＝O)NH-C1-6烷基或(C＝O)NH2；
所述C2-6炔基、-S-C1-6烷基、C1-6烷氧基、C1-6烷基、5至6元芳基、5至6元杂芳基、5至12元杂环烷基任选被一个或多个独立地选自RC的取代基取代，所述RC选自氘、卤素、C1-6烷氧基、C1-6烷基(例如：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基))、羟基、氨基、氧代、C2-6炔基；
所述n选自0、1、2或3。
一些实施方案中，本公开提供的式(VI)所示的化合物或其可药用盐，其为式(VI-1)所示的化合物或其可药用盐。
一些实施方案中，本公开提供的式(VI-1)或式(VI-2)所示的化合物或其可药用盐，所述L2为-NH-。
一些实施方案中，本公开提供的式(VI-1)或式(VI-2)所示的化合物或其可药用盐，所述环B选自吡啶基或苯基，所述R27各自独立地选自氘、卤素、羟基、羧基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6亚烷基-3至6元环烷基。
一些实施方案中，本公开提供的式(VI-1)或式(VI-2)所示的化合物或其可药用盐，所述环B为苯基，所述R27各自独立地选自氘、卤素、羟基、羧基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6亚烷基-3至6元环烷基。
一些实施方案中，本公开提供的式(VI-1)或式(VI-2)所示的化合物或其可药用盐，所述环B为苯基，所述R27各自独立地选自氘。
一些实施方案中，本公开提供的式(VI-1)或式(VI-2)所示的化合物或其可药用盐，所述环B为苯基，所述R27各自独立地选自卤素。
一些实施方案中，本公开提供的式(VI-1)或式(VI-2)所示的化合物或其可药用盐，所述环B为苯基，所述R27各自独立地选自C1-6烷基。
一些实施方案中，本公开提供的式(VI-1)或式(VI-2)所示的化合物或其可药用盐，所述环B为苯基，所述R27各自独立地选自甲基或乙基。
一些实施方案中，本公开提供的式(VI-1)或式(VI-2)所示的化合物或其可药用盐，所述环B为苯基，所述R27各自独立地选自亚甲基-环丙基。
一些实施方案中，本公开提供的式(VI-1)或式(VI-2)所示的化合物或其可药用盐，所述环B为苯基，所述R27各自独立地选自环丙基。
一些实施方案中，本公开提供的式(VI-1)或式(VI-2)所示的化合物或其可药用盐，所述L3选自亚甲基，所述亚甲基任选被一个或多个独立地选自RI的取代基取代，所述RI选自氘、卤素、氧代、羟基、氨基或C1-6烷基(例如：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基)。
一些实施方案中，本公开提供的式(VI-1)或式(VI-2)所示的化合物或其可药 用盐，所述L3选自亚乙基，所述亚乙基任选被一个或多个独立地选自RI的取代基取代，所述RI选自氘、卤素、氧代、羟基、氨基或C1-6烷基(例如：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基)。
一些实施方案中，本公开提供的式(VI-1)或式(VI-2)所示的化合物或其可药用盐，所述L3选自亚丙基，所述亚丙基任选被一个或多个独立地选自RI的取代基取代，所述RI选自氘、卤素、氧代、羟基、氨基或C1-6烷基(例如：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基)。
一些实施方案中，本公开提供的式(VI)所示的化合物或其可药用盐，其为式(VI-1-A)或式(VI-1-B)所示的化合物或其可药用盐，
所述R5、R6、R7、R8、R9、L1、环A、R10、n、R25、R26、R27和y分别如式(VI-1-A)或式(VI-1-B)所示的化合物或其可药用盐。
可选的实施方案中，本公开提供的式(VI)所示的化合物或其可药用盐，其为式(VI-1-A)所示的化合物或其可药用盐。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述L1为连接键。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述L1选自C1-6亚烷基，或所述L1选自C1-6亚烷基，所述C1-6亚烷基被一个或多个独立地选自RB的取代基取代，所述RB选自氘、C1-6烷基或氧代。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述L1选自C1-6亚烷基，具体可选择亚甲基或亚乙基。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述L1选自C1-6亚烷基，所述C1-6亚烷基被一个或多个独立地选自RB的取代基取代，所述RB选自氘、甲基、乙基或丙基。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述L1选自C1-6亚烷基，所述C1-6亚烷基被一个或多个独立地选自RB的取代基取代，所述RB选自氘。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B) 所示的化合物或其可药用盐，所述L1选自C1-6亚烷基，所述C1-6亚烷基被一个或多个独立地选自RB的取代基取代，所述RB选自甲基。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述L1选自C1-6亚烷基，所述C1-6亚烷基被一个或多个独立地选自RB的取代基取代，所述RB选自氧代。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述L1选自亚甲基，或所述L1选自亚甲基，所述亚甲基被一个或多个独立地选自RB的取代基取代，所述RB选自氘或C1-6烷基(例如，甲基、乙基)。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述L1选自亚甲基，或所述L1选自亚甲基，所述亚甲基被一个或多个独立地选自RB的取代基取代，所述RB选自氘或甲基。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述L1选自亚甲基，所述亚甲基被一个或多个独立地选自RB的取代基取代，所述RB选自氧代。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R5、R6、R7、R8、R9各自独立地选自氢或氘。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述环A选自吡唑基、咪唑基、吡啶基、苯基、四氢吡喃基、嘧啶基、环己基。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R10选自氘、C1-6烷基、C1-6亚烷基-3至6元环烷基、5至6元芳基、5至6元杂芳基、-NH(C＝O)-OC1-6烷基或-(C＝O)NH-C1-6烷基或(C＝O)NH2；
所述C1-6烷基、5至6元芳基、5至6元杂芳基任选被一个或多个独立地选自RC的取代基取代，所述RC选自氘、卤素、C1-6烷氧基、C1-6烷基、羟基、氨基、氧代、C2-6炔基；
所述n选自1、2或3。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R10选自C1-6烷基；
所述n选自1、2或3。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R10选自甲基、乙基或丙基；
所述n选自1、2或3。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R10选自甲基；
所述n选自1、2或3。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R10选自C1-6亚烷基-3至6元环烷基(例如环丙基、环丁基、环戊基、环己基)；
所述n选自1、2或3。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R10选自亚甲基-环丙基；
所述n选自1、2或3。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R10选自3至6元环烷基(例如环丙基、环丁基、环戊基、环己基)；
所述n选自1、2或3。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R10选自环丙基；
所述n选自1、2或3。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R10选自苯基，所述苯基任选被一个或多个独立地选自RC的取代基取代，所述RC选自氘、卤素、C1-6烷氧基、C1-6烷基、羟基、氨基、氧代、C2-6炔基；
所述n选自1、2或3。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R10选自5至6元杂芳基(例如：吡啶、咪唑、吡唑、噻唑、噁唑)，所述5至6元杂芳基任选被一个或多个独立地选自RC的取代基取代，所述RC选自氘、卤素、C1-6烷氧基、C1-6烷基、羟基、氨基、氧代、C2-6炔基；
所述n选自1、2或3。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R10选自-NH(C＝O)-OC1-6烷基(例如：甲基、乙基、正丙基、异丙基、正丁基、叔丁基)，所述n选自1、2或3。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R10选自-(C＝O)NH-C1-6烷基(例如：甲基、乙基、正丙基、异丙基、正丁基、叔丁基)，所述n选自1、2或3。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R10选自(C＝O)NH2，所述n选自1、2或3。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1- B)所示的化合物或其可药用盐，所述R10选自5至10元的杂环烷基，所述杂环烷基任选被一个或多个独立地选自RC的取代基取代，所述RC选自氘、卤素、C1-6烷氧基、C1-6烷基、羟基、氨基、氧代、C2-6炔基，
所述n选自1、2或3。
可选的实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R10选自5至10元的桥连-杂环基，所述桥连-杂环基任选被一个或多个独立地选自RC的取代基取代，所述RC选自氘、卤素、C1-6烷氧基、C1-6烷基、羟基、氨基、氧代、C2-6炔基，所述杂环基含有1、2或3个独立选自氮、氧、硫的杂原子；
所述n选自1、2或3。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述选自
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R27各自独立地选自氘、卤素、C1-6烷基、卤代C1-6烷基、C2-6炔基、C1-6亚烷基-3至6元环烷基、3至6元环烷基、卤代C1-6烷氧基、-NH-C1-6烷基、-NH(C1-6烷基)2。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R27各自独立地选自卤素或C1-6烷基。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R27各自独立地选自氟或氯；
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R27各自独立地选自甲基。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R25和R26各自独立地选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基，所述甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基任选被一个或多个氘取代。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R25和R26各自独立地选自氢、甲基、乙基，所述甲基、乙基任选被一个或多个氘取代。
一些实施方案中，本公开提供的式(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐，所述R25和R26各自独立地选自甲基，所述甲基任选被一个或多个氘取代。
本公开提供如下所示的化合物或其可药用盐，其选自：
表a










本公开另一方面提供一种式(I)(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐及表a化合物，同位素取代物。在可选的实施方案中，所述的同位素取代物为氘原子取代。
本公开中还提供了一种药物组合物，包括至少一种式(I)(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐及表a化合物，同位素取代物，或由前述方法制备获得化合物或其可药用盐以及药学上可接受的赋形剂。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用盐。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用盐。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述化合物或其可药用盐。在某些实施方案中，所述的药物组合物含有1％-99％的前述化合物或其可药用盐。在某些实施方案中，所述的药物组合物含有2％-98％的前述化合物或其可药用盐。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。
本公开另一方面提供前述式(I)(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐及表a化合物，同位素取代物，或由前述方法制备获得化合物或其可药用盐以及前述药物组合物在制备治疗或预防与丝氨酸/苏氨酸激酶的异常活性相关的疾病或病症的药物中的用途。
本公开另一方面提供前述式(I)(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐及表a化合物，同位素取代物，或由前述方法制备获得化合物或其可药用盐以及前述药物组合物在制备治疗和/或预防与CDK7的异常活性相关的疾病或病症的药物中的用途。
可选的实施方案中，所述与CDK7的异常活性相关的疾病或病症选自增殖性疾病、炎性疾病、自身炎性疾病、自身免疫性疾病或传染性疾病。
本公开另一方面提供前述式(I)、(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐及表a化合物，同位素取代物，或由前述方法制备获得化合物或其可药用盐以及前述药物组合物在制备治疗和/或预防疾病或病症的药物中的用途，所述的疾病或病症选自增殖性疾病、炎性疾病、自身炎性疾病、自身免疫性疾病或传染性疾病。
可选的实施方案中，所述的疾病或病症为增殖性疾病。
可选的实施方案中，所述增殖性疾病为癌症。
可选的实施方案中，所述癌症选自血液瘤和实体瘤。
可选的实施方案中，所述血液瘤选自白血病，具体包括：慢性淋巴细胞白血病(CLL)、急性淋巴细胞白血病(ALL)、T-细胞急性淋巴细胞白血病(T-ALL)、慢性髓性白血病(CML)、急性髓系白血病(AML)等)。
可选的实施方案中，所述实体瘤选自乳腺癌、肠癌、肺癌、胰腺癌、前列腺癌、尤文氏肉瘤、骨瘤、成神经细胞瘤、宫颈癌、卵巢癌、胃癌、肝癌。
可选的实施方案中，所述乳腺癌是三阴性乳腺癌。
可选的实施方案中，所述乳腺癌是ER/PR+HER2-乳腺癌。
可选的实施方案中，所述乳腺癌是对CDK4/6抑制剂耐药的ER/PR+HER2-乳腺癌。
可选的实施方案中，所述CDK4/6抑制剂是Palbociclib。
可选的实施方案中，所述肺癌是非小细胞肺癌。
可选的实施方案中，所述肺癌是小细胞肺癌。
可选的实施方案中，所述肠癌是结肠癌。
可选的实施方案中，所述肠癌是直肠癌。
本公开另一方面提供一种治疗和/或预防患者与丝氨酸/苏氨酸激酶的异常活性相关的疾病或病症的方法，给与患者治疗有效量的式(I)、(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐及表a化合物，同位素取代物，或由前述方法制备获得化合物或其可药用盐以及前述药物组合物。
本公开另一方面提供一种治疗和/或预防患者与CDK7的异常活性相关的疾病或病症的方法，给与患者治疗有效量的式(I)、(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐及表a化合物，同位素取代物，或由前述方法制备获得化合物或其可药用盐以及前述药物组合物。
可选的实施方案中，所述与CDK7的异常活性相关的疾病或病症选自增殖性疾病、炎性疾病、自身炎性疾病、自身免疫性疾病或传染性疾病。
本公开另一方面提供一种治疗和/或预防患者疾病或病症的方法，给与患者治疗有效量的式(I)、(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐及表a化合物，同位素取代物，或由前述方法制备获得化合物或其可药用盐以及前述药物组合物，所述的疾病或病症选自增殖性疾病、炎性疾病、 自身炎性疾病、自身免疫性即便或传染性疾病；可选的实施方案中，所述的疾病或病症为增殖性疾病。
可选的实施方案中，所述增殖性疾病为癌症。
可选的实施方案中，所述癌症选自血液瘤和实体瘤。
可选的实施方案中，所述血液瘤选自白血病，具体包括：慢性淋巴细胞白血病(CLL)、急性淋巴细胞白血病(ALL)、T-细胞急性淋巴细胞白血病(T-ALL)、慢性髓性白血病(CML)、急性髓系白血病(AML)等)。
可选的实施方案中，所述实体瘤选自乳腺癌、肠癌、肺癌、胰腺癌、前列腺癌、尤文氏肉瘤、骨瘤、成神经细胞瘤、宫颈癌、卵巢癌、胃癌、肝癌。
可选的实施方案中，所述乳腺癌是三阴性乳腺癌。
可选的实施方案中，所述乳腺癌是ER/PR+HER2-乳腺癌。
可选的实施方案中，所述乳腺癌是对CDK4/6抑制剂耐药的ER/PR+HER2-乳腺癌。
可选的实施方案中，所述CDK4/6抑制剂是Palbociclib。
可选的实施方案中，所述肺癌是非小细胞肺癌。
可选的实施方案中，所述肺癌是小细胞肺癌。
可选的实施方案中，所述肠癌是结肠癌。
可选的实施方案中，所述肠癌是直肠癌。
本公开另一方面提供一种式(I)、(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐及表a化合物，同位素取代物，或由前述方法制备获得化合物用做药物的用途。
本公开提供的化合物或其可药用盐可采用领域内通用的合成方法制备，以下提供示例性的方法：
本公开提供的式(VI)所述化合物或其可药用盐，可以参考专利WO2022064009A1方法制备。
本公开提供的式(VI)所述化合物，合成的过程中拆分成2个片段，分别是A和B，
本公开提供一种式(VI-1-A)所示的化合物或其可药用盐，或其同位素取代物的制备方法，包括式(VI-1-A-01)或其可药用盐在羰基二咪唑、光气或三光气的作用下，与式(VI-1-A-02)或其可药用盐发生缩合反应的步骤，
所述R5、R6、R7、R8、R9、L1、环A、R10、n、R25、R26、R27和y分别如前述定义。
可选的实施方案中，所述缩合反应在碱性环境中发生，所述碱性环境由无机碱(氢氧化钠)或有机碱(例如三乙胺、吡啶、哌啶或N,N-二异丙基乙胺)提供，反应发生的溶剂为常用溶剂(例如DMF、DCM或DMSO)。
本公开提供一种式(VI-1-B)所示的化合物或其可药用盐，或其同位素取代物的制备方法，包括式(VI-1-B-01)或其可药用盐在羰基二咪唑、光气或三光气的作用下，与式(VI-1-A-02)或其可药用盐发生缩合反应的步骤，
所述R5、R6、R7、R8、R9、L1、环A、R10、n、R25、R26、R27和y分别如前述定义。
可选的实施方案中，所述缩合反应在碱性环境中发生，所述碱性环境由无机碱(氢氧化钠)或有机碱(例如三乙胺、吡啶、哌啶或N,N-二异丙基乙胺)提供，反应发生的溶剂为常用溶剂(例如DMF、DCM或DMSO)。
本公开中所述化合物可药用盐选自无机盐或有机盐，本公开所述化合物可与酸性或碱性物质反应成相应盐。
本公开提供一种式(I)、(VI)、(VI-1)、(VI-2)、(VI-1-A)、(VI-1-B)所示的化合物或其可药用盐及表a化合物，同位素取代物对CDK7酶活性有优异的选自性，可选的实施方案中，IC50小于100nM，可选的实施方案中，IC50小于50nM，可选的实施方案中，IC50小于30nM，可选的实施方案中，IC50小于15nM。
本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异 构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本公开某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本公开所述化合物的化学结构中，键表示未指定构型，即如果化学结构中存在手性异构体，键可以为或者同时包含两种构型。
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
本公开中的所有化合物可以被画成A型或B型。所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少 5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取代的C1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
术语解释：
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本公开中所述“有效量”或“有效治疗量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
前缀“Cu-v”表示后面的基团具有从u到v个碳原子。例如，“C1-6烷基”表示烷基具有1至6个碳原子，具体可以是具有1、2、3、4、5或6个碳原子的烷基。
术语“烷基”是指非支化或者支化的饱和烃链。本文中使用的烷基具有1至20个碳原子(即，C1-20烷基)、1至8个碳原子(即，C1-8烷基)、1至6个碳原子(即，C1- 6烷基)，或者1至4个碳原子(即，C1-4烷基)。烷基的实例包括甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基、3-己基，和3-甲基戊基。当具有特定碳原子数的烷基残基通过化学名称命名或由分子式确定时，可以包括具有该碳原子数目的所有位置的异构体；因此，例如，“丁基”包括正丁基(即，-(CH2)3CH3)、仲丁基(即，-CH(CH3)CH2CH3)、异丁基(即，-CH2CH(CH3)2)和叔丁基(即，-C(CH3)3)；以及“丙基”包括正丙基(即，-(CH2)2CH3)和异丙基(即，-CH(CH3)2)。
术语“烯基”是指至少含有一个碳-碳双键的烷基，具有2至20个碳原子(即， C2-20烯基)、2至8个碳原子(即，C2-8烯基)、2至6个碳原子(即，C2-6烯基)，或者2至4个碳原子(即，C2-4烯基)。烯基的实例包括乙烯基、丙烯基、丁二烯基(包括1,2-丁二烯基和1,3-丁二烯基)。
术语“炔基”是指至少含有一个碳-碳三键的烷基，具有2至20个碳原子(即，C2-20炔基)、2至8个碳原子(即，C2-8炔基)、2至6个碳原子(即，C2-6炔基)，或者2至4个碳原子(即，C2-4炔基)。“炔基”的实施例包括乙炔基、丙炔基(例如1-丙炔基、2-丙炔基)、3-丁炔基、戊炔基、己炔基及1-甲基戊-2-炔基。
术语“环烷基”或“碳环”是指饱和的或者部分不饱和的环状烷基，其具有单环或者多环(包括稠合的、桥连的和螺环环系)。所述术语“环烷基”包括环烯基(即所述环状基团具有至少一个双键)。本文中使用的环状烷基具有3至20个环碳原子(即，C3-20环烷基)、3至12个环碳原子(即，C3-12环烷基)、3至10个环碳原子(即，C3-10环烷基)、3至8个环碳原子(即，C3-8环烷基)、或者3至7个环碳原子(即，C3-7环烷基)、或者3至6个环碳原子(即，C3-6环烷基)。环烷基的实例包括环丙基、环丁基、环戊基，和环己基、环己烯基、环己二烯基。所述环烷基环可以稠合于芳基或杂芳基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。
术语“杂环基”或“杂环烷基(Heterocycloalkyl)”指具有一个或多个独立地选自氮、氧、硫和磷的环杂原子的饱和或不饱和环烷基。术语“杂环烷基”包括杂环烯基(即具有至少一个双键的杂环基)、桥连-杂环基、稠合杂环基和螺-杂环基。杂环基可以是单环或多环，其中多环可以是稠合的、桥连的或螺环的。含有至少一个杂原子的任何非芳族环都被认为是杂环基，与连接无关(即，可以通过碳原子或杂原子结合)。此外，术语杂环基旨在包含任何含有至少一个杂原子的非芳族环，所述环可以与芳基或杂芳基环稠合，而与分子其余部分的连接无关。本文中使用的杂环基具有3至20个环原子(即，3至20元杂环基)、3至12个环原子(即，3至12元杂环基)、3至10个环原子(即，3至10元杂环基)、3至8个环原子(即，3至8元杂环基)、3至7个环原子(即，3至7元杂环基)、3至6个环原子(即，3至6元杂环基)；具有1至5个环杂原子、1至4个环杂原子、1至3个环杂原子、1至2个环杂原子，或者1个环杂原子，所述环杂原子独立地选自氮、硫、磷或者氧。杂环基的实例包括吡咯烷基、咪唑烷基、氧杂环丁烷基、二氧戊环基、氮杂环丁烷基、四氢呋喃基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基。
本文中使用的术语“桥连-杂环基”是指4至10元环状部分，其在杂环基的两个不相邻原子处与一个或者多个(例如，1或者2)具有至少一个杂原子的4至10元环状部分连接，其中各杂原子独立地选自氮、氧、硫和磷。本文中使用的“桥连-杂环基”包括二环和三环环系。此外，本文中使用的所述术语“螺-杂环基”是指其中3至10元的杂环基具有一个或者多个另外的环的环系，其中所述一个或者多个另外的 环为3至10元的环烷基或者3至10元的杂环基，其中所述一个或者多个另外的环的单一原子也为所述3至10元的杂环基的原子。螺-杂环基环的实例包括二环和三环环系，例如2-氧杂-7-氮杂螺[3.5]壬基、2-氧杂-6-氮杂螺[3.4]辛基，和6-氧杂-1-氮杂螺[3.3]庚基。稠合杂环基环的实例包括但不限于1,2,3,4-四氢异喹啉基，4,5,6,7-四氢噻吩并[2,3-c]吡啶基，二氢吲哚基和异二氢吲哚基，其中杂环基可以通过稠合体系的任一环结合。
“杂环基”非限制性实例包括：
等。
所述杂环基环可以稠合于芳基或杂芳基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
等。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：

术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为6至12元，更优选为5元或6元。例如。其非限制性实例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪，等等。
所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
术语“烷氧基”是指基团“烷基-O-”，其中烷基的定义如上所述。烷氧基的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基，和1,2-二甲基丁氧基。
术语“环烷基氧基”、“杂环基氧基”的定义同上述“烷氧基”定义方式。
术语“卤代烷基”是指如上定义的无支链或支链的烷基，其中一个或多个氢原子被卤素代替。例如，当一个残基取代有多于一个卤素，其可通过使用对应于连接的卤素部分的数目的前缀来提及。二卤代烷基和三卤代烷基是指取代有两个或三个卤素基团的烷基，它们可为，但不必须为，相同的卤素。卤代烷基的实例包括二氟甲基(-CHF2)和三氟甲基(-CF3)。
术语“卤代烷氧基”是指如上所定义的烷氧基，其中一个或者多个氢原子被卤素替代。
术语“羟烷基”是指被一个或者多个羟基取代的烷基，烷基如上述定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“氧代”指＝O取代基。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪或Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，J&K，韶远化学科技(Accela ChemBio Inc)、上海毕得医药，达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，D：石油醚/乙酸乙酯/甲醇，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
下述实验中所用缩写代表的含义如下:
TFA:三氟乙酸；DCM:二氯甲烷；m-CPBA:间氯过氧苯甲酸；EtONa：乙醇钠；Boc：叔丁氧羰基；MeOH：甲醇；HBTU：苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯；TsOH：对甲苯磺酸；EtOAc：乙酸乙酯；t-BuOH：叔丁醇；PdCl2(TPP)2:二氯双(三苯基膦)合钯；XantPhos:4,5-双(二苯基膦)-9,9-二甲基氧杂蒽；Pd2dba3:三二亚苄基丙酮二钯；PdCl2(TPP)2:二氯双(三苯基膦)合钯；XantPhos:4,5-双(二苯基膦)-9,9-二甲基氧杂蒽；Pd2dba3:三二亚苄基丙酮二钯；DMF:N,N-二甲基甲酰胺；CDI：N,N-羰基二咪唑；ACN:乙腈；DMP：戴斯-马丁氧化剂；DMAP：4-二甲氨基吡啶。
实施例1
((3S,4S)-3-(3-乙炔基苯基)-1-甲基哌啶-4-基)((R)-6-甲基-2-(((1-甲基-1H-吡唑-3-基)甲基)氨基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基)甲酮；((3R,4R)-3-(3-乙炔基苯基)-1-甲基哌啶-4-基)((R)-6-甲基-2-(((1-甲基-1H-吡唑-3-基)甲基)氨基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基)甲酮

第一步
化合物1c的制备
在N2氛围下，向溶有化合物1a(40.0g,99.2mmol)和1b(32.6g,149mmol)的1，4-二氧六环(400mL)加入Na2CO3(198mL，1M，198mmol)及Pd(PPh3)2Cl2(6.96g，9.92mmol)。在N2氛围下升温至90℃，搅拌12小时，反应液过滤，向滤液中加入水(150mL)，EtOAc(600mL)萃取，合并有机相并用Na2SO4干燥，过滤，滤液减压浓缩得到粗品。粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：10-30％乙酸乙酯的石油醚，得到化合物1c(90.0mg,收率98.1％)。
1H NMR(400MHz,DMSO-d6)δ7.11-6.97(m,1H),6.57(d,J＝8.0Hz,1H),6.41(s,1H),6.34(d,J＝7.2Hz,1H),5.15(s,2H),4.09(s,2H),3.92(q,J＝7.2Hz, 2H),2.44(s,2H),1.49(s,9H),0.92(t,J＝7.2Hz,3H)。
第二步
化合物1d的制备
在室温和N2氛围下，向盛有EtOH(400mL)的反应瓶中加入化合物1c(35.0g,101mmol)，Pd/C(10％，24.0g)，H2置换三次，在H2(50psi)氛围下，反应液在50℃下搅拌12小时。反应液过滤，滤液浓缩得到粗品1d(30.0g,86.1mmol,92.6％)。
第三步
化合物1e的制备
在0℃下，向溶有1d(10.0g,28.7mmol)的CH3CN(100mL)溶液中加入TsOH(11.0mL,71.7mmol)的水溶液(7mL)，反应液搅拌0.5小时，反应液维持在0℃，并向其中加入NaNO2(2.30mL，43.0mmol)的水溶液，缓慢滴加KI(2.35mL，43.0mmol)的水溶液(7.0mL)，滴加完毕后，升温至室温，搅拌16小时，反应液加水后经EtOAc(300mL x 3)萃取，有机相用Na2SO4干燥，过滤，滤液减压浓缩得到粗品。
粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：10-30％乙酸乙酯的石油醚，得到化合物1e(8.0g,17.4mmol,收率60.7％)。
第四步
化合物1f的制备
在N2氛围下，向DMF(60mL)中加入化合物1e(3.00g，6.53mmol)，三甲基硅基乙炔(21.4mL,150mmol)，CuI(0.111mL，3.26mmol)和Pd(DTBPF)Cl2(2.13g，3.266mmol)，反应液升温至110℃并搅拌12小时，向反应液中加入水(260mL)，EtOAc(50mL x 3)萃取，合并有机相并用Na2SO4干燥，过滤，滤液减压浓缩得到粗品，粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-5％乙酸乙酯的石油醚，得到化合物1f(2.06g，2.88mmol，收率44.1％)。
第五步
化合物1g的制备
在N2氛围下，向溶有化合物1f(1.00g，2.33mmol)的EtOAc(20mL)溶液中加入HCl/EtOAc(15mL)，室温下搅拌2小时，反应液减压浓缩得到粗品1g(900mg)，将粗品1g溶入DCM(60mL)，并向其加入NaOAc(0.305mL，3.28mmol)，甲醛(399mg,4.92mmol)，室温下搅拌1小时，加入NaBH(OAc)3(1440.2mg，6.83mmol)。在室温下反应，搅拌12小时，反应液经10％NaHCO3(20mL)洗一次，Na2SO4干燥，过滤，滤液减压浓缩得到粗品。
粗品经制备级HPLC(色谱柱:Waters Xbridge BEH C18 250*50mm*10um； 流动相:[水(NH4HCO3)-CH3CN]；B％:65％-90％)分离纯化，得到化合物1h(400mg,1.07mmol，收率39.2％)。
MS m/z(ESI):344.2[M+H]+。
第六步
中间体1j的制备
在室温下，将溶有化合物1h(400mg，1.164mmol)的EtOH(30mL)溶液中加入EtONa((0.456mL,5.822mmol)。反应也逐渐升温至85℃，搅拌5小时，反应液减压浓缩得到粗品1i。在室温下，将粗品1i加入EtOH(15mL)和H2O(15mL)的混合溶液中，加入NaOH(118mg，2.95mmol)，搅拌12小时，反应液减压浓缩，得到粗品，粗品经制备级HPLC(色谱柱:Phenomenex Luna C18 75*30mm*3um；流动相:[水(FA)-CH3CN]；B％:65％-90％)分离纯化，得到化合物1j(150mg,0.555mmol,37.6％)。
MS m/z(ESI):244.2[M+H]+。
第七步
化合物1l的制备
在室温下，向化合物1k(11.0g，51.6mmol，1.00eq)的DMF(50mL)溶液中，缓慢滴加DMF-DMA(12.3g，103mmol，13.7mL，2.00eq)，反应液升温至90℃，搅拌18小时，向反应液中加入水(150mL)，EtOAc(100mL x 3)萃取.合并有机相并用Na2SO4干燥，过滤，滤液减压浓缩得到粗品1l(12g)。
MS m/z(ESI):269.1[M+H]+。
第八步
化合物1m的制备
在室温下，向溶有化合物1l(12.0g，44.7mmol)和2-甲基异硫脲硫酸盐(24.9g，89.4mmol，2.00eq)的EtOH(200mL)中缓慢加入EtONa(6.69g,98.4mmol)，反应液升温至90℃，搅拌12小时，降至室温，加入H2O(150mL)，EtOAc(60mL x 5)萃取，合并有机相并用Na2SO4干燥，过滤，滤液减压浓缩得到粗品。粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：10-30％乙酸乙酯的石油醚，得到化合物1m(6.20g,21.0mmol,收率46.9％)。
MS m/z(ESI):296.1[M+H]+。
第九步
中间体1n的制备
在0℃下，向化合物1m(5.00g，17.0mmol)的DCM(100mL)溶液中加入m-CPBA(10.3g，50.7mmol)，搅拌2小时，反应液升至室温，搅拌10小时。降温至0℃，向反应液中加入Na2SO3(10％，40mL)，DCM(30mL x 3)萃取，合并有机相并饱和食盐水(50mL)洗一次，Na2SO4干燥，过滤，滤液减压浓缩得到粗品。
粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：10-30％乙酸乙酯的石油醚，得到化合物1n(2.7g,8.25mmol,收率48.7％)。
MS m/z(ESI):328.1[M+H]+。
1H NMR(400MHz,CDCl3)δ8.59(s,1H),5.08,5.02(m,1H),4.82(s,1H),4.33-4.27(m,1H),3.29(s,3H),3.13-3.06(m,1H),2.67-2.63(m,1H),1.45(s,9H),1.05-1.03(m,3H)。
化合物1n经手性柱拆分(色谱柱：Chiralcel OD-3,150×4.6mm I.D.,3um),流动相:A:超临界CO2流体B:甲醇(0.1％IPAm,v/v)，得到1n-1和1n-2。
化合物1n-1(保留时间2.770分钟)
MS m/z(ESI):328.1[M+H]+。
1H NMR(400MHz,CDCl3)δ8.59(s,1H),5.08-5.03(m,1H),4.82(br s,1H),4.32-4.27(m,1H),3.29(s,3H),3.13-3.06(m,1H),2.67-2.63(m,1H),1.43(s,9H),1.05-1.03(m,3H)
化合物1n-2(保留时间2.469分钟)。
第十步
中间体1p的制备
在室温下，向化合物1n-1的(140mg，0.428mmol)的t-BuOH(2mL)溶液中加入1o(380mg，3.42mmol)。反应液升温至100℃，搅拌12小时，反应液减压浓缩得到粗品，粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-5％乙酸乙酯的石油醚，得到化合物1p(100mg,0.279mmol,45.7％)。
MS m/z(ESI):359.1[M+H]+。
第十一步
化合物1的制备
在室温下，向化合物1p(100mg,0.279mmol)的DCM溶液中加入TFA(0.8mL,10.8mmol)，搅拌1小时。反应液减压浓缩至干得到粗品1q(96.0mg,0.186mmol,66.6％)。
MS(ESI):m/z＝259.1[M+H]+。
在室温下，将中间体1j(90.0mg,0.37mmol)加入到DMF(3mL)中，向反应液中加入HBTU(421mg,1.11mmol),DIEA(0.31mL,1.85mmol)和粗品1q(95.6mg,0.370mmol)，室温下搅拌12小时，反应液减压浓缩得到粗品1，粗品经制备级HPLC(色谱柱:Phenomenex Luna C18 75*30mm*3um；流动相:[(NH4HCO3)-CH3CN]；B％:65％-90％)分离纯化，得到化合物1-1(17.4mg，0.036mmol，9.18％)和化合物1-2(17.0mg，0.035mmol，9.50％)。
化合物1-1
MS(ESI):m/z＝484.3[M+H]+。
1H NMR(400MHz,CD3OD):δ:8.06-7.90(m,1H),7.56-7.17(m,4H),6.93-6.87(m,1H),6.95-6.16(m,1H),4.64-4.44(m,4H),3.88-3.84(m,3H),3.57-3.35(m,2H),3.17-2.86(m,4H),2.80-2.50(m,3H),2.45-2.22(m,5H),2.18-2.04(m,1H),1.96-1.87(m,1H),1.03-0.78(m,3H)。
化合物1-2
MSm/z(ESI):484.3[M+H]+。
1H NMR(400MHz,CD3OD):δ:8.06-7.92(m,1H),7.55-7.17(m,5H),6.25-6.15(m,1H),4.73-4.51(m,4H),3.90-3.83(m,4H),3.46-3.45(m,1H),3.04-2.71(m,6H),2.45-2.25(m,5H),2.17-1.86(m,3H),1.15-0.06(m,3H)。
实施例2
(R)-N-((S)-2-(二甲基氨基)-1-苯基乙基)-6-甲基-2-(((1-甲基-1H-吡唑-3-基)-甲基)氨基)-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺
第一步
化合物2制备
将化合物2a(57.2mg，348μmol)和N,N-碳酰二咪唑(75.3mg，464μmol)溶于四氢呋喃中，向溶液中加入三乙胺(1.16mmol,162μL)后室温搅拌0.5小时。向反应液中加入化合物1q(60.0mg，232μmol，化合物的合成实施例1中已描述)并置于室温搅拌12小时。反应液减压浓缩得到粗品2，粗品经制备级HPLC(色谱柱:Waters Xbridge Prep OBD C18 150*40mm*10um；流动相:[water(NH4HCO3)-ACN]；B％:10％-40％)分离纯化得到化合物2(11.8mg,25.2μmol，收率10.8％)。
MS m/z(ESI):449.3[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ:8.10(s,1H),7.53(d,J＝2.0Hz,1H),7.39-7.25(m,4H),7.23-7.10(m,2H),6.78(d,J＝7.6Hz,1H),6.10(d,J＝2.0Hz,1H),4.93-4.83(m,1H),4.72-4.55(m,2H),4.47-4.34(m,2H),3.96(d,J＝18.4Hz,1H),3.77 (s,3H),2.77(dd,J＝5.4,15.2Hz,1H),2.69-2.59(m,1H),2.42(d,J＝15.2Hz,1H),2.34(dd,J＝5.9,12.0Hz,1H),2.17(s,6H),0.94(d,J＝6.8Hz,3H)。
实施例3
(S)-N-((S)-2-(二甲基氨基)-1-苯基乙基)-6-甲基-2-(((1-甲基-1H-吡唑-3-基)-甲基)氨基)-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺
第一步
化合物3a制备
在室温下，向化合物1n-2(200mg,0.611mmol)的t-BuOH(2mL)溶液中加入1o(543mg,4.89mmol)。反应液升温至100℃，搅拌12小时，反应液减压浓缩得到粗品，粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-5％乙酸乙酯的石油醚，得到化合物3a(150mg，0.418mmol,收率68.51％)。
MS m/z(ESI):359.2[M+H]+。
第二步
化合物3制备
在室温下，向化合物3a(150mg,0.139mmol)的DCM溶液中加入TFA(1mL)，搅拌1小时。反应液减压浓缩至干得到粗品3b(80.0mg,0.135mmol)。
MS m/z(ESI):259.1[M+H]+。
将化合物2a(0.102mL,0.609mmol)和N,N-碳酰二咪唑(75.3mg,465μmol)溶于四氢呋喃中，向溶液中加入三乙胺(118mg,1.16mmol,162μL)后室温搅拌0.5小时。向反应液中加入化合物3b(60.0mg，232μmol)并置于室温搅拌12小时。反应液减压浓缩得到粗品3，粗品经制备级HPLC(色谱柱:Waters Xbridge Prep OBD C18 150*40mm*10um；流动相:[water(NH4HCO3)-ACN]；B％:10％-40％)分离纯化得到化合物3(44.4mg,98.9μmol,收率42.6％)。
MS m/z(ESI):449.3[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ:8.09(s,1H),7.53(d,J＝2.0Hz,1H),7.34- 7.30(m,2H),7.30-7.25(m,2H),7.22-7.12(m,2H),6.77(d,J＝7.2Hz,1H),6.10(d,J＝2.0Hz,1H),4.93-4.82(m,1H),4.70-4.59(m,2H),4.45-4.37(m,2H),3.93(d,J＝18.0Hz,1H),3.76(s,3H),2.80-2.60(m,2H),2.34(dd,J＝6.0,12.0Hz,2H),2.17(s,6H),0.95(d,J＝6.8Hz,3H)。
实施例4
8-氟-3-甲基-7-(((1-甲基-1H-吡唑-3-基)甲基)氨基)-3，4-二氢-2，6-萘啶-2(1H)-基)((3R,4R)-1-甲基-3-苯基哌啶-4-基)甲酮
第一步
化合物4b制备
将化合物4a(5g,23.7mmol)溶解到四氢呋喃中并冷却到-78℃，向溶液中逐滴加入正丁基锂(11.4mL,28.5mmol)，并在-78℃温度下搅拌2小时。缓慢加入饱和氯化铵溶液淬灭反应，后经萃取、干燥、浓缩后得到粗产品。该粗产品经正相分离后得到标题化合物4b(4.5g,产率79％)。
第二步
化合物4c制备
将化合物4b(4.5g,18.873mmol)溶于N,N-二甲基甲酰胺中，并加入PdCl2(TPP)2(0.28g,0.47mmol),碘化亚铜(90mg,0.47mmol)，三乙胺(6.5mL, 47.2mmol)和丙炔(22.6mL，22.6mmol)。反应液在氮气氛下室温搅拌2小时。反应液经萃取，浓缩，干燥后得到粗品，粗品经正相纯化得到4c(2.6g，产率69％)。
第三步
化合物4d制备
将化合物4c(2.6g,13.2mmol)溶于甲苯中，随后加入对甲苯磺酸(450mg,2.6mmol)和叔丁胺(7mL，65.8mmol)。反应液在90℃下反应12小时。反应液经萃取，浓缩，干燥后得到粗品，粗品经正相纯化得到4d(1.3g，产率50％)。
MS m/z(ESI):197.1[M+H]+。
第四步
化合物4e制备
将化合物4d溶于乙腈中，随后加入溴化苄。反应液在80℃下反应12小时。冷却至室温，向反应液中加入乙醚。经过滤，洗涤，干燥后得到粗品4e，该粗品可直接用作下一步反应。
MS m/z(ESI):287.1[M+H]+。
第五步
化合物4f制备
将化合物4e溶于甲醇中，后缓慢加入硼氢化钠固体。反应液在室温下搅拌30分钟。反应液经萃取，浓缩，干燥后得到粗品，粗品经正相纯化得到4f(0.4g，产率30％)。
MS m/z(ESI):291.1[M+H]+。
第六步
化合物4g制备
将化合物4f(130mg,0.45mmol)溶于1,2-二氯乙烷中，随后加入碳酸钾。反应液加热回流3小时。经过滤，浓缩后得到油状粗品。粗品溶于甲醇中，并加热回流1小时。反应液减压浓缩得到粗品，该粗品经正相纯化得到化合物4g(70mg,78％)。
MS m/z(ESI):201.1[M+H]+。
第七步
化合物4h制备
1-甲基-3-苯基六氢吡啶-4-甲酸(76.5mg,0.35mmol)和O-苯并三氮唑-四甲基脲六氟磷酸盐(396.9mg,1.05mmol)溶于N,N-二甲基甲酰胺中，搅拌10分钟后加入N,N-二异丙基乙胺(193μL,1.05mmol)和化合物4g。反应液经制备级HPLC(色谱柱:Waters Xbridge Prep OBD C18 150*40mm*10um；流动相:[water(NH4HCO3)-ACN]；B％:10％-40％,8min)分离纯化得到化合物4h(9mg,产率6％)。
MS m/z(ESI):402.1[M+H]+。
第八步
化合物4制备
氮气氛下，依次将化合物4h(9mg,0.022mmol)、1-甲基-1-乙烯基乙氮烷甲胺(4.98mg,0.045mmol)、XantPhos(0.65mg,0.001mmol)、Pd2dba3(1.02mg,0.001mmol)、磷酸钾(14.26mg,0.067mmol)溶于二氧六环中，微波120℃条件下反应1小时。反应液冷却至室温，过滤，收集滤液，减压浓缩后正相分离后得到标题化合物4(2mg,产率18％)。
MS m/z(ESI)478.2[M+H]+。
实施例5
(R)-N-((S)-2-(二甲基氨基)-1-苯基乙基)-6-甲基-2-(((R)-1-苯基乙基)氨基)-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺
第一步
化合物5b制备
向微波管中加入t-BuOH(2mL)、化合物1n-1(100mg,0.31mmol)和5a(0.39mL,3.05mmol)，氮气保护下微波反应8小时。浓缩反应液得到粗品，粗品经反相柱色谱分离(0-100％水/乙腈)得目标化合物5b(89mg,收率79％)。
MS m/z(ESI):369.3[M+H]+。
第二步
化合物5c制备
将化合物5b(89mg,0.24mmol)溶于DCM(1.0mL)，向其中缓慢滴加TFA(0.18mL,2.4mmol)，在室温下搅拌7小时，加水稀释，加K2CO3中和，DCM萃取，合并有机相，无水Na2SO4干燥，过滤，滤液旋干得目标化合物5c粗品，直接用于下一步反应。
MS m/z(ESI):269.2[M+H]+。
第三步
化合物5制备
将2a(30mg,0.18mmol)溶于DMF(0.5mL)，向其中加CDI(60mg,0.37mmol)，室温搅拌5分钟，依次加入Et3N(76μL,0.55mmol)和化合物5b(34.3mg,0.13mmol)，室温反应过夜。反应液经制备级HPLC(色谱柱:Waters Xbridge Prep OBD C18 150*40mm*10um；流动相:[water(NH4HCO3)-ACN])分离纯化得到化合物5(20mg，收率23.9％)。
MS m/z(ESI):459.4[M+H]+。
1H NMR(400MHz,CD3OD)：δ8.02(s,1H),7.42-7.34(m,6H),7.32-7.24(m,3H),7.20-7.14(m,1H),5.26(dd,J＝11.4,4.0Hz,1H),5.11(q,J＝6.9Hz,1H),4.79-4.68(m,2H),4.07(d,J＝18.3Hz,1H),3.37-3.33(m,1H),3.06(dd,J＝13.0,4.1Hz,1H),2.84(dd,J＝15.6,5.6Hz,1H),2.73(s,6H),2.48(d,16H),1.50(d,J＝7.0Hz,3H),1.01(d,7.2Hz,3H)。
实施例6
(R)-N-((S)-2-(二甲基氨基)-1-苯基乙基)-6-甲基-2-(((S)-1-(吡啶-2-基)乙基)氨基)-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺

第一步
化合物6b制备
向盛有t-BuOH(2.0mL)的微波管中加入化合物1n-1(100mg,0.31mmol)和6a(0.37mL,3.05mmol)，氮气保护下微波反应5小时，浓缩反应液，反相柱色谱分离(0-100％水/乙腈)得目标化合物6b(97.9mg,收率86.8％)。
MS m/z(ESI):370.3[M+H]+。
第二步
化合物6c制备
将化合物6b(97.9mg,0.27mmol)溶于DCM(1.0mL)，向其中缓慢滴加TFA(0.19mL,2.6mmol)，室温下搅拌7小时，加水稀释，加K2CO3中和，DCM萃取，合并有机相，无水Na2SO4干燥，过滤，滤液旋干得目标化合物6c粗品，粗品直接用于下一步反应。
MS m/z(ESI):270.2[M+H]+。
第三步
化合物6制备
将2a(30mg,0.18mmol)溶于DMF(0.5mL)中，向其中加CDI(60mg,0.37mmol)，室温搅拌5分钟，依次加入Et3N(76μL,0.55mmol)和化合物6c(34.4mg,0.13mmol)，室温下反应过夜。反应液经制备级HPLC(色谱柱:Waters Xbridge Prep OBD C18 150*40mm*10um；流动相:[water(NH4HCO3)-ACN])分离纯化得到化合物6(40mg，收率47.7％)。
MS m/z(ESI):460.3[M+H]+。
1H NMR(400MHz,DMSO-d6)：1H NMR(400MHz,)δ8.50(d,J＝4.4Hz,1H),8.08(s,1H),7.71(td,J＝7.7,1.8Hz,1H),7.41-7.38(m,2H),7.36-7.26(m,4H),7.23-7.18(m,2H),6.83(d,J＝7.7Hz,1H),5.12(p,J＝7.1Hz,1H),4.92-4.84(m,1H),4.68-4.48(m,2H),3.94(d,J＝18.8Hz,1H),2.77-2.64(m,2H),2.44-2.35(m,2H),2.19(s,6H),1.45(d,J＝7.0Hz,3H),0.93(d,J＝6.7Hz,3H)。
实施例7
(R)-2-((2，3-二氢-1H-茚-2-基)-氨基)-N-((S)-2-(二甲基氨基)-1-苯基乙基)-6-甲基-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺
化合物7的制备参考实施例5的合成方法。由起始原料1(100mg,0.31mmol)和7a(414.5mg,2.44mmol)经三步反应得到化合物7(35mg，收率：40.7％)。粗品化合物7经制备级HPLC(色谱柱:Waters Xbridge Prep OBD C18 150*40mm*10um；流动相:[water(NH4HCO3)-ACN])分离纯化得到。
MS m/z(ESI):471.4[M+H]+。
1H NMR(400MHz,CD3OD):δ8.09(s,1H),7.42-7.35(m,4H),7.32-7.27(m,1H),7.22-7.16(m,2H),7.15-7.10(m,2H),5.27(dd,J＝11.4,4.0Hz,1H),4.82-4.64(m,3H),4.17(d,J＝18.2Hz,1H),3.35-3.32(m,2H),3.28(s,1H),3.07(dd,J＝13.0,4.1Hz,1H),2.93-2.85(m,3H),2.73(s,6H),2.53(d,15.6Hz,1H),1.07(d,J＝6.8Hz,3H)。
实施例8
(R)-N-((S)-2-(乙基(甲基)氨基)-1-苯基乙基)-6-甲基-2-(((1-甲基-1H-吡唑-3-基)甲基)氨基)-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺
第一步
化合物8c的制备
向溶有8a(1g,3.51mmol)的DCM(30mL)中，加入HBTU(1.33g,3.51mmol)和K2CO3(1.45g,10.52mmol)，室温下反应0.5小时，向反应液中加8b(0.5g,5.26mmol)，40℃反应过夜。反应结束冷却至室温后过滤，反应也浓缩得到粗品，粗品经柱层析分离(0-100％石油醚/乙酸乙酯)得目标化合物8c(973mg,收率85.1％)。
MS m/z(ESI):327.2[M+H]+。
第二步
化合物8d制备
将化合物8c(973mg,2.98mmol)溶于乙酸乙酯(10mL)中，氮气保护下，加入10％Pd/C(300mg)，H2置换3次，在H2氛围下，室温反应6小时，硅藻土过滤，滤液浓缩得粗品化合物8d，粗品直接用于下一步反应。
MS m/z(ESI):193.2[M+H]+。
第三步
化合物8e制备
氮气保护下，向干燥的三口烧瓶中依次加入THF(6.0mL)和LiAlH4(4.7mL,1M，THF)，将反应液置于-78℃的干冰-乙醇浴中，向其中缓慢滴加化合物8d(400 mg,2.08mmol)的THF(2mL)，滴加完毕后回流反应过夜。待反应液冷却至室温后，置于冰浴条件下，向反应液中依次加0.5mL水，15％NaOH溶液(0.2mL)。无水Na2SO4干燥，过滤，滤液减压浓缩的粗品，粗品经反相柱色谱分离(0-100％水/乙腈)得黄色液体8e(177mg，收率：47.7％)。
MS m/z(ESI):179.2[M+H]+。
第四步
化合物8制备
将化合物8e(30mg,0.17mmol)溶于DMF(0.5mL)中，向其中加CDI(54.6mg,0.34mmol)，室温搅拌5分钟，加入Et3N(7μL,0.51mmol)和化合物5d(30.4mg,0.12mmol)，室温下反应过夜。反应液经制备级HPLC(色谱柱:Waters Xbridge Prep OBD C18 150*40mm*10um；流动相:[water(NH4HCO3)-ACN])分离纯化得到化合物8(20mg，收率：25.7％)。
MS m/z(ESI):463.4[M+H]+。
1H NMR(400MHz,)δ8.08(s,1H),7.49-7.36(m,6H),7.32-7.29(m,1H),6.19(d,J＝2.2Hz,1H),5.41-5.34(m,1H),4.82-4.73(m,2H),4.53(s,2H),4.14(d,J＝18.2Hz,1H),3.82(s,3H),3.57-3.47(m,1H),3.28-3.09(m,3H),2.90-2.86(s,4H),2.54-2.50(m,1H),1.32(t,J＝7.3Hz,3H),1.06(d,J＝7.0Hz,3H)。
实施例9
(R)-N-((S)-2-(二甲基氨基)-1-苯基乙基)-6-甲基-2(((S)-1-苯基乙基)氨基)-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺

化合物9的制备参考化合物5的合成方法。由起始原料1n-1(100mg,0.306mmol)经三步反应得到化合物9(12mg,0.026mmol)。
MS m/z(ESI):471.4[M+H]+。
1H NMR(400MHz,CD3OD):δ8.03(s,1H),7.37-7.25(m,8H),7.24-7.14(m,2H),5.13(q,J＝7.0Hz,1H),5.01(dd,J＝10.7,4.4Hz,1H),4.77-4.69(m,1H),4.66(d,J＝18.3Hz,1H),4.11(d,J＝18.3Hz,1H),2.91-2.78(m,2H),2.48(dd,J＝15.5,1.7Hz,1H),2.41(dd,J＝12.8,4.5Hz,1H),2.30(s,6H),1.51(d,J＝7.0Hz,3H),1.02(d,J＝6.8Hz,3H)。
实施例10
N-((S)-2-(二甲基氨基)-1-苯基乙基)-6-甲基-2-((四氢-2H-吡喃-4-基)氨基)-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺

第一步
化合物10c制备
氮气保护下，向溶有10b(1.09g,7.42mmol)的DMF(3.0mL)溶液中，依次加入DIPEA(1.63mL,9.89mmol)和10a(500mg,4.94mmol)，室温下反应48小时，反应液浓缩，粗品经反相柱色谱分离(流动相:[water(NH4OH)-ACN])得目标化合物10c(400mg,收率56.5％)。
MS m/z(ESI):144.2[M+H]+。
第二步
化合物10d制备
将化合物10c(346.8mg,2.42mmol)和化合物1l(500mg,1.86mmol)溶于EtOH(10mL)，向其中加EtONa(279mg,4.1mmol)，升温至50℃，反应过夜，反应液冷却至室温，加水稀释，DCM萃取3次，合并有机相，有机相用无水Na2SO4干燥，过滤，滤液浓缩，反相柱色谱分离(流动相:[water(NH4OH)-ACN])得目标化合物10d(258mg,收率：39.7％)。
MS m/z(ESI):349.2[M+H]+。
第三步
化合物10e制备
将化合物10d(258mg,0.74mmol)溶于1，4-二氧六环和MeOH(4mL,3：1)的混合溶液中，向其中缓慢滴加盐酸二氧六环溶液(1.8mL,4M)，室温下反应过夜，加水稀释，K2CO3溶液中和，DCM萃取3次，合并有机相，有机相用无Na2SO 4干燥，过滤，滤液旋干得粗品化合物10d，粗品直接用于下一步反应。
MS m/z(ESI):249.2[M+H]+。
第四步
化合物10制备
将向溶有2a(108mg,0.66mmol)的DMF(3mL)溶液中，加入CDI(213.2mg,1.32mmol)，室温下搅拌5min,依次加入Et3N(0.27mL,1.97mmol)和化合物10d(114.3mg,0.46mmol)，室温下反应过夜。反应液经制备级HPLC(色谱柱:Waters Xbridge Prep OBD C18 150*40mm*10um；流动相:[water(NH4HCO3)-ACN])分离纯化得到化合物10(80mg，收率：27.7％)。
MS m/z(ESI):439.3[M+H]+。
手性柱拆分后(色谱柱DAICEL ChiralPak IC(250×30mm,10μm)，流动相:A:超临界CO2流体,B:乙醇(0.1％NH3H2O))；得到化合物10-1和10-2，结构如下：
化合物10-1(保留时间3.43分钟)
MS m/z(ESI):439.3[M+H]+。
1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.24-7.13(m,5H),5.68(s,1H),4.86(d,J＝8.0Hz,1H),4.81-4.66(m,2H),4.53(d,J＝17.9Hz,1H),4.10(d,J＝17.8Hz,1H),3.99-3.89(m,3H),3.57-3.40(m,2H),2.84(dd,J＝15.8,5.8Hz,1H),2.53(t,J＝11.7Hz,1H),2.37-2.27(m,2H),2.21(s,6H),2.04-1.88(m,2H),1.52-1.44(m,2H),1.01(d,J＝6.8Hz,3H)。
化合物10-2(保留时间6.29分钟)
MS m/z(ESI):439.3[M+H]+。
1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.27-7.18(s,5H),5.95(s,1H),4.97(s,1H),4.83-4.72(m,1H),4.71-4.62(m,1H),4.55(d,J＝18.2Hz,1H),4.06(d,J＝18.2Hz,1H),4.06-3.89(m,3H),3.51-3.41(m,2H),2.91-2.83(m,1H),2.65(t,J＝11.8Hz,1H),2.39-2.32(m,3H),2.24(s,6H),1.98-1.94(m,2H),1.49-1.45(m,2H),0.99(d,J＝6.8Hz,3H)。
实施例11
(R)-N-((R)-2-(二甲基氨基)-1-苯基乙基)-6-甲基-2-(((1-甲基-1H-吡唑-3-基)-甲基)氨基)-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺
第一步
化合物11制备
将化合物11a(9.08mg,0.055mmol)和CDI(18mg,0.111mmol)溶于DMF(2mL)中，向溶液中加入Et3N(0.023mL,0.166mmol)后室温搅拌0.5小时。向反应液中加入化合物1q(10mg,0.039mmol)并置于室温搅拌12小时。反应液经制备级HPLC分离纯化得到化合物11(5.0mg,0.011mmol)。
MS m/z(ESI):449.38[M+H]+。
1H NMR(400MHz,CD3OD):δ8.05(s,1H),7.52-7.17(m,6H),6.16(s,1H),5.31(d,J＝7.8Hz,1H),4.78-4.58(m,2H),4.50(s,2H),4.16(d,J＝18.4Hz,1H),3.80(s,3H),3.52-3.36(m,1H),3.28(s,1H),3.23-3.12(m,1H),2.81(s,7H),2.49(d,J＝15.6Hz,1H),1.05(d,J＝6.8Hz,3H)。
实施例12
(R)-N-((S)-2-(六氘代二甲基氨基)-1-苯基乙基)-6-甲基-2-(((1-甲基-1H-吡唑-3-基)-甲基)氨基)-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺

第一步
化合物12c制备
在室温下，将12a(500mg,1.753mmol)和HBTU(1329mg,3.5mmol)溶于DCM(7mL)中，搅拌5分钟,加入K2CO3(726mg,5.26mmol)和12b(134.4mg,2.63mmol)。反应置于室温搅拌12小时。反应液经萃取,浓缩,干燥得到粗品。粗品经柱层析分离纯化得到化合物12c(900mg，2.83mmol)。
MS m/z(ESI):319.2[M+H]+。
第二步
化合物12d制备
在氢气氛围下，将10％的钯Pd/C加入化合物12c(900mg,2.83mmol)的乙酸乙酯(15mL)溶液中。室温下搅拌2小时。反应液经过滤，浓缩得到粗品12d(260mg)。该粗品可直接用于下一步反应(260mg)。
MS m/z(ESI):185.1[M+H]+
第三步
化合物12e制备
氮气氛下，将LiAlH4(82.0mg,2.17mmol)加入到无水THF(5.0mL)。冷却到-78℃后，逐滴加入化合物12d的THF溶液，搅拌30分钟。随后将反应液升温至50℃，反应2小时，加入氯化铵溶液淬灭。经萃取，浓缩，干燥得到粗产品。粗品经制备级HPLC分离纯化得到化合物12e(40.0mg，产率21％)。
MS m/z(ESI):171.1[M+H]+
第四步
化合物12制备
将化合物12e(20.0mg,0.094mmol)和CDI(30mg,0.188mmol)溶于DMF(1.0mL)中，向溶液中加入Et3N(0.039mL,0.282mmol)后室温搅拌0.5小时。向反应液中加入化合物1q(24.3mg,0.094mmol)，室温下搅拌12小时。反应液经 制备级HPLC分离纯化得到化合物12(5.0mg，0.011mmol)。
MS m/z(ESI):455.4[M+H]+。
1H NMR(400MHz,DMSO-d6):δ8.10(s,1H),7.53(s,1H),7.38-7.27(m,4H),7.24-7.16(m,2H),6.86(d,J＝7.8Hz,1H),6.09(s,1H),4.93-4.84(m,1H),4.73-4.55(m,2H),4.47-4.33(m,2H),3.97(d,J＝18.6Hz,1H),3.76(s,3H),2.81-2.71(m,2H),2.45-2.39(m,2H),0.93(d,J＝6.7Hz,3H)。
实施例13
(R)-N-((S)-1-(3-氯代苯基)-2-(二甲基氨基)乙基)-6-甲基-2-(((1-甲基-1H-吡唑-3-基)甲基)氨基)5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺
第一步
化合物13b的制备
向NaBH4的THF溶液中加入化合物13a(300mg,1.616mmol)，并将反应液冷却到0℃。逐滴加入I2(451mg,1.78mmol)的THF溶液，加样结束后，室温下反应2小时。反应结束后，加入KOH水溶液淬灭反应。经萃取，干燥，浓缩得到粗产物13b，该粗产物直接用于下一步反应。
MS m/z(ESI):172.01[M+H]+。
第二步
化合物13c的制备
将二碳酸二叔丁酯(698.3mg,3.2mmol)和Et3N(485.7mg,4.8mmol)加入到粗产物13b的DCM溶液中，室温搅拌过夜。反应液经萃取，干燥，浓缩得到粗 产物，该粗产物经柱层析分离得到目标化合物13c(170mg,0.627mmol)。
MS m/z(ESI):294.09[M+Na]+。
第三步
化合物13d的制备
将DMP(212.07mg,0.5mmol)加入到化合物13c的DCM溶液中，室温搅拌2小时。反应液经粗层析纯化得到目标化合物13d(40mg,0.148mmol)。
第四步
化合物13e的制备
将二甲胺盐酸盐(57.08mg,0.7mmol)加入到化合物3d(40.4mg,0.15mmol)的甲醇溶液中。室温搅拌2小时后缓慢加入NaBH3CN(18.9mg,0.3mmol)，室温下搅拌过夜。反应液直接经反相柱层析分离得到化合物13e(12mg,0.04mmol)。
MS m/z(ESI):299.17[M+H]+。
第五步
化合物13f的制备
向化合物13e(12mg,0.04mmol)的DCM(5.0mL)溶液中加入过量的TFA(1.0mL)，室温搅拌1小时。反应液经减压浓缩得到粗产物，该粗产物直接用于下一步反应。
MS m/z(ESI):199.02[M+H]+。
第六步
化合物13的制备
将化合物13f(11.89mg,0.06mmol)和CDI(19.5mg,0.12mmol)溶于DMF(2.0mL)中，向溶液中加入Et3N(0.18mmol)后室温搅拌0.5小时。向反应液中加入化合物1q(15.5mg,0.06mmol)并置于室温搅拌12小时。反应液经制备级HPLC分离纯化得到化合物13(2.0mg,0.004mmol)。
MS m/z(ESI):483.28[M+H]+。
1H NMR(400MHz,CD3OD)δ8.44(s,1H),8.10(s,1H),7.49-7.42(m,2H),7.40-7.28(m,3H),6.19(d,J＝2.3Hz,1H),5.24(dd,J＝11.2,4.1Hz,1H),4.80-4.69(m,2H),4.54(s,2H),4.18(d,J＝18.2Hz,1H),3.84(s,3H),3.25(d,J＝12.0Hz,1H),3.10-3.00(m,1H),2.95-2.85(m,1H),2.72(s,6H),2.54(dd,J＝15.6,1.9Hz,1H),2.03(q,J＝6.4Hz,1H),1.12-1.04(m,3H)。
实施例14
(R)-N-((S)-2-(二甲基氨基)-1-苯基乙基)-6-甲基-2-(((1-三氘代甲基-1H-吡唑-3-基)甲基)氨基)-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺
第一步
化合物14b的制备
向化合物14a(1.99g,15.8mmol)和碳酸铯(10.3g,31.7mmol)的DMF(15.0mL)溶液中缓慢加入CD3I(2.75g,19.0mmol)，室温下搅拌2小时。反应液经萃取，干燥，浓缩得到粗产物，粗产物经柱层析分离得到化合物14b(1.04g，7.26mmol，产率：45％)。
MS m/z(ESI):144.07[M+H]+。
第二步
化合物14c的制备
将化合物14b(1.04g，7.26mmol)溶于氨水中，室温搅拌4小时。反应液经减压干燥得到粗产物14c，粗产物直接用作下一步反应。
MS m/z(ESI):129.00[M+H]+。
第三步
化合物14d的制备
氮气氛下，将LiAlH4(212.5mg,5.6mmol)加入到无水THF(5.0ml)。冷却到-78℃后，逐滴加入化合物14c(2.8mmol)的THF溶液，并置于该温度下搅拌30分钟。随后将反应液置于50℃下反应12小时。反应结束后，加入氯化铵溶液淬灭。经萃取、浓缩、干燥得到粗产品14d，粗产物直接用作下一步反应。
MS m/z(ESI):114.99[M+H]+。
化合物14的制备
参考实施例5的合成，由化合物14d经三步反应合成制备14(2mg,0.0044mmol)。
MS m/z(ESI):452.37[M+H]+。
实施例15
(R)-N-((S)-2-(二甲基氨基)-1-苯基乙基)-6-甲基-2-((2-甲基吡啶-4-基)氨基)-5，8-二氢吡啶并[3,4,-d]嘧啶-7(6H)-甲酰胺
第一步
化合物15c的合成
在室温下，将化合物15a(50.0g,412.6mmol),化合物15b(67.3mL,474.5mmol)溶解到DCM中(500mL)，分批次缓慢加入NaBH(OAc)3(174g,825mmol)，室温搅拌过夜。反应液用DCM/MeOH(9:1,500×2mL)萃取，用饱和食盐水洗，有机相用Na2SO4干燥，过滤，滤液减压浓缩得到粗品化合物15c(80g,249mmol)。
MS m/z(ESI):250.3[M+H]+
第二步
化合物15e的合成
在室温下，将化合物15c(80.0g,249mmol),化合物15d(31.7mL,320.8mmol) 溶解到DCM中(1L)，分批次缓慢加入NaBH(OAc)3(203g,962mmol)，室温搅拌反应2天。反应液用DCM/MeOH(9:1,500mL×2)萃取，用饱和食盐水洗，有机相用Na2SO4干燥，过滤，滤液减压浓缩得到粗品，粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-10％乙酸乙酯的石油醚，得到化合物15e(40g,249mmol)。
MS m/z(ESI):336.3[M+H]+
第三步
化合物15f的合成
在室温下，将化合物15e(40.0g,119.2mmol)溶于溶解到甲苯中(200mL)，分批次缓慢加入t-BuOK(33.5g,298mmol)，室温搅拌反应过夜。反应液用乙酸乙酯(100mL×2)萃取，用饱和食盐水洗，有机相用Na2SO4干燥，过滤，滤液减压浓缩得到粗品，粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-10％乙酸乙酯的石油醚，得到化合物15f(14g,48.4mmol)。
MS m/z(ESI):262.2[M+H]+。
第四步
化合物15g的合成
在室温下，向溶有15f(14g,48.4mmol)的无水MeOH(200mL)溶液加入尿素(11.6mL,193.5mmol)，加入活化的4AMS(10g)，升温至回流，搅拌过夜。反应液用乙酸乙酯(100mL×2)萃取，用饱和食盐水洗，有机相用Na2SO4干燥，过滤，滤液减压浓缩得到粗品，粗品通过C18反向硅胶柱层析纯化，得到化合物15g(8g,28mmol)。
MS m/z(ESI):272.2[M+H]+。
第五步
化合物15h的合成
在室温下，将化合物15g(8g,28mmol)溶于POCl3(30mL)中，反应液回流搅拌过夜。将反应液浓缩得到粗品。粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-20％乙酸乙酯的石油醚，得到化合物15h(6g,18.6mmol)为白色固体。
MS m/z(ESI):308.2[M+H]+
第六步
化合物15i的合成
在室温下，将15h(6g,18.6mmol),氨水(8.0mL)溶解到EtOH(100mL)，加入活化的Zn(15g)，反应液加热回流搅拌过夜。反应液用乙酸乙酯(100mL×2)萃取，用饱和食盐水洗，有机相用Na2SO4干燥，过滤，滤液减压浓缩得到粗品，粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-10％乙酸乙酯的石油醚，得到化合物15i(3.5g,12.2mmol)为棕黄色固体。
MS m/z(ESI):288.1[M+H]+。
第七步
化合物15k的合成
在室温下，向溶有化合物15i(240mg,0.83mmol),化合物15j(108mg,1.0mmol),Xantphos-G3-Pd(79mg,0.08mmol)和Cs2CO3(325mg,1.25mmol)的二氧六环(5.0mL)，反应在氮气保护下加热至100℃搅拌4小时。将反应液浓缩得到粗品。粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-5％乙酸乙酯的石油醚，得到化合物15k(100mg,33.4％)。
MS m/z(ESI):360.3[M+H]+。
第八步
化合物15l的合成
在室温下，向溶有化合物15k(100mg,0.28mmol)的MeOH(5.0mL)加入10％Pd/C(50mg)，反应在氢气氛下室温搅拌过夜。将反应液浓缩得到粗品。粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-5％乙酸乙酯的石油醚，得到化合物15l(60mg,收率：84.5％)。
MS m/z(ESI):256.3[M+H]+
第九步
化合物15的合成
在室温下，将溶有15l(30mg,0.12mmol)，化合物2a(20mg,0.12mmol)的DMF(1.0mL)溶液，加入CDI(38mg,0.24mmol),Et3N(0.05mL,0.36mmol)，反应液在室温下搅拌过夜。反应液用乙酸乙酯(10mL×3)萃取，有机相用Na2SO4干燥，过滤，滤液减压浓缩得到粗品。粗品通过HPLC纯化得到化合物15(20mg48.3％)。
MS m/z(ESI):446.5[M+H]+。
1H NMR(400MHz,CD3OD):δ8.54(s,2H),8.41(s,1H),8.25(d,J＝6.7Hz,1H),7.97(dd,J＝6.7,2.3Hz,1H),7.92(d,J＝2.2Hz,1H),7.51-7.46(m,2H),7.43-7.37(m,2H),7.34-7.29(m,1H),5.43(dd,J＝12.1,4.0Hz,1H),5.05-4.97(m,1H),4.91-4.82(m,1H),4.33(d,J＝18.6Hz,1H),3.71-3.58(m,1H),3.39-3.33(m,1H),3.02-2.88(m,7H),2.66(d,J＝16.1,1.5Hz,1H),2.59(s,3H),1.09(d,J＝6.8Hz,3H)。
实施例16
(R)-2-((1-(环丙基甲基)-1H-吡唑-4-基)氨基)-N-((S)-2-(二甲基氨基)-1-苯基乙基)-6-甲基-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺
第一步
化合物16c的合成
在室温下，将溶有化合物16a(1.0g,8.84mmol)，化合物16b(1.0mL)和Cs2CO3(5.7g,17.68mmol)的DMF(10mL)溶液室温搅拌过夜。将反应液浓缩得到粗品。粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-5％乙酸乙酯的石油醚，得到化合物16c(1.0g,收率：67.6％)。
第二步
化合物16d的合成
在室温下，向溶有化合物16c(1.0g,6.0mmol)的MeOH(20mL)加入Pd/C(100mg)，反应在氢气氛下室温搅拌过夜。将反应液浓缩得到粗品。粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-5％乙酸乙酯的石油醚，得到化合物16d(800mg,收率：97.5％)。
MS m/z(ESI):138.3[M+H]+。
化合物16的合成参考化合物15。由化合物16d(33.9mg,0.25mmol),经三步反应纯化后得到16(20.8mg,0.044mmol)
MS m/z(ESI):475.4[M+H]+。
1H NMR(400MHz,CD3OD)δ8.17(s,1H),8.00(s,1H),7.61(s,1H),7.45-7.32(m,4H),7.28-7.23(m,1H),5.17(dd,J＝11.0,4.3Hz,1H),4.88-4.72(m,2H),4.22(d,J＝18.3Hz,1H),3.94(d,J＝7.0Hz,2H),3.11(t,J＝12.9,11.0Hz,1H),3.01-2.83(m,1H),2.78-2.71(m,1H),2.61-2.48(m,7H),1.33-1.21(m,1H),1.06(d,J＝6.8Hz,3H),0.66-0.53(m,2H),0.48-0.35(m,2H)。
实施例17
(R)-N-((S)-2-(二甲基氨基)-1-苯基乙基)-6-甲基-2-((1-甲基-1H-吡唑-4-基)氨基)-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺
参考化合物15的制备方法，由化合物15i(80mg,0.278mmol)经三步反应得到化合物17(10mg,0.023mmol)。
MS m/z(ESI):435.4[M+H]+。
实施例18
(R)-6-甲基-2-(((1-甲基-1H-吡唑-3-基)甲基)氨基)-N-((S)-2-(甲基氨基)-1-苯基乙基)-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺
第一步
化合物18b的合成
在室温下，将化合物18a(1.1g,3.86mmol)溶于硼烷/四氢呋喃(20mL,20mmol),搅拌过夜。淬灭反应液后，浓缩得到粗品。粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-5％乙酸乙酯的石油醚，得到化合物18b(700mg,收率：66.9％)。
MS m/z(ESI):272.3[M+H]+。
第二步
化合物18c的合成
在室温下，向溶有化合物18a(300mg,1.1mmol)的DCM(5.0mL)加入DMP(930mg,2.2mmol)，室温搅拌过1小时。淬灭反应液后用乙酸乙酯(100mL×2)萃取，用饱和食盐水洗，有机相用Na2SO4干燥，过滤，滤液减压浓缩得到粗品，粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-20％乙酸乙酯的石油醚，得到化合物18c(100mg,收率：33.6％)。
MS m/z(ESI):270.3[M+H]+。
第三步
化合物18d的合成
在室温下，将化合物18c(100mg,0.37mmol),甲胺盐酸盐(50mg,0.74mmol)溶解到DCM中(5mL)，分批次缓慢加入NaBH(OAc)3(235mg,1.1mmol)，室温搅拌反应过夜。反应液用DCM/MeOH(9:1,500mL×2)萃取，用饱和食盐水洗，有机相用Na2SO4干燥，过滤，滤液减压浓缩得到粗品，粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-10％乙酸乙酯的石油醚，得到化合物18c(60mg,收率：56.8％)。
MS m/z(ESI):285.3[M+H]+。
第四步
化合物18e的合成
在室温下，向溶有化合物18c(60mg,0.21mmol)的DCM(5.0mL)加入二碳酸二叔丁酯(69mg,0.32mmol)，DMAP(2mg)和饱和Na2CO3溶液(1mL)，室温搅拌过1小时。应液后用乙酸乙酯(100mL×2)萃取，用饱和食盐水洗，有机相用Na2SO4干燥，过滤，滤液减压浓缩得到粗品，粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-20％乙酸乙酯的石油醚，得到化合物18e(70mg,收率：86.3％)。
MS m/z(ESI):385.4[M+H]+。
第五步
化合物18f的合成
在室温下，向溶有化合物18e(70mg,0.18mmol)的MeOH(10mL)加入10％Pd/C(30mg)，反应在氢气氛下室温搅拌过夜。将反应液浓缩得到粗品。粗品通过硅胶色谱法快速柱层析纯化，淋洗剂为：1-5％乙酸乙酯的石油醚，得到化合物18f(30mg,收率：65.8％)。
MS m/z(ESI):251.5[M+H]+。
化合物18参考实施例11的合成，经成脲和脱Boc两步反应得到化合物18(22mg,0.049mmol)。
MS m/z(ESI):251.5[M+H]+。
1H NMR(400MHz,CD3OD)δ8.09(s,1H),7.48-7.46(m,1H),7.41-7.34(m,4H),7.32-7.26(m,1H),6.19(d,J＝2.3Hz,1H),5.22-5.12(m,1H),4.81-4.68(m,2H),4.54(s,2H),4.17(d,J＝18.3Hz,1H),3.84(s,3H),3.25-3.13(m,2H),2.95-2.85(m,1H),2.61(s,3H),2.53(d,J＝15.8,1.6Hz,1H),1.07(d,J＝6.8Hz,3H)。
实施例19
(R)-N-((S)-2-六氘代二甲基氨基-1-苯基乙基)-6-甲基-2-(((S)-1-(吡啶-2-基)乙基)氨基)-5，8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酰胺
化合物19(15mg,0.032mmol)参考实施例6的合成。
MS m/z(ESI):465.4[M+H]+。
1H NMR(400MHz,CDCl3)：δ8.49(d,J＝4.4Hz,1H),7.99(s,1H),7.56(td,J＝7.7,1.8Hz,1H),7.26-7.15(m,6H),7.11-7.02(m,1H),6.11-5.86(m,2H),5.19-5.10(m,1H),4.81-4.75(m,1H),4.70-4.65(m,1H),4.58-4.53(d,J＝18.1Hz,1H),4.08(d,J＝18.1Hz,1H),2.85(dd,J＝15.4,5.5Hz,1H),2.70-2.65(m,1H),2.42-2.32(m,2H),1.49(d,J＝6.8Hz,3H),0.97(d,J＝6.7Hz,3H)。
生物学评价
以下结合测试例进一步描述解释本公开，但这些实施例并非意味着限制本公开的范围。
测试例1
测试例1.本公开化合物对卵巢癌细胞(OVCAR3)抑制活性测试
1.1实验材料和仪器(见表1)
表1实验材料和仪器
1.2实验步骤
卵巢癌细胞OVCAR3使用10％FBS的RPMI 1640培养在37％，5％CO2的细胞培养箱中培养。第一天，细胞铺板在96-孔板中，铺板细胞浓度为2500个细胞/孔，在培养箱中培养过夜。第二天进行化合物处理，化合物处理最高浓度为10uM,3倍稀释，9个浓度,DMSO的终浓度为0.1％。细胞继续在培养箱中培养5天后，使用Celltiter Glo assay kit(Promega)测试细胞活力，测试方法与试剂盒提供的操作方法保持一致。使用GraphPad Prism 8处理数据并计算IC50。
计算公式Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。
X:化合物浓度的对数值；Y:％抑制。
表2.本公开化合物对OVCAR3的IC50(nM)

本公开实施例2、5-10、12-17、19化合物的活性优于实施例18。
测试例2
测试例2.本公开化合物对肿瘤细胞抑制活性测试
2.1实验材料和仪器(见表3)
表3实验材料和仪器
2.2实验步骤
乳腺癌细胞MCF7(ATCC#HTB-22)和T47D(ATCC#HTB-133)、胰腺癌细胞PANC-1(ATCC#CRL-1469)购自ATCC。乳腺癌细胞MDA-MB-231(科佰#CBP60382)、HCC1806(科佰#CBP60373)和MDA-MB-468(科佰#CBP60387)、结直肠癌细胞HCT-116(科佰#CBP60028)、白血病细胞OCI-AML-3(科佰#CBP60817)和MV-4-11(科佰#CBP60522)购自南京科佰生物科技有限公司。
OCI-AML-3使用20％FBS的RPMI 1640培养基；HCC1806、T47D使用10％FBS的RPMI 1640培养基；MCF7、MDA-MB-231、MDA-MB-468及PANC-1使用10％FBS的DMEM培养基；MV-4-11使用20％FBS的IMDM培养基；HCT-116使用10％FBS的MC’5A培养基。
在MCF7亲本细胞上构建Palbociclib耐药的细胞，标记为MCF7Palbo-R，培养条件与亲本细胞一致。所有的肿瘤细胞均在37℃，5％CO2的细胞培养箱中培养。在384-孔板中，按照细胞密度(600cells/well for MDA-MB-231；500cells/well for MDA-MB-468、PANC-1、HCT-116；200cells/well for MCF7、HCC1806；800cells/well for MCF7 Palbo-R；3000cells/well for OCI-AML-3&MV-4-11)进行种板，在培养箱中培养过夜。第二天进行化合物处理，化合物处理最高浓度为10μM,3倍稀释，9个浓度,每个浓度两复孔，DMSO的终浓度为0.1％。细胞在培养箱中继续培养， 其中MDA-MB-231、PANC-1、MDA-MB-468、OCI-AML-3、MV-4-11药物处理5天；HCC1806、MCF7、MCF7Palbo-R及HCT116药物处理7天，使用Celltiter Glo assay kit(Promega)测试细胞活力，测试方法与试剂盒提供的操作方法保持一致。使用多功能微孔板酶标仪Envision进行读数。使用GraphPad Prism 8处理数据并计算IC50。
计算公式Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。
X:化合物浓度的对数值；Y:％抑制。
表4.本公开化合物对测试肿瘤细胞的IC50(nM)
表5.本公开化合物对测试肿瘤细胞的IC50(nM)
表4和5中数据说明实施例2、6、12和19在多种肿瘤细胞系上均体现出高的抑制活性。
测试3
测试例3.本公开化合物对CDK激酶的抑制活性测试
3.1实验步骤
ADP-Glo kinase assay用于CDK激酶活性测试。用Echo将化合物在384孔板中进行稀释，起始浓度为10uM，3倍梯度稀释，10个浓度点，每个浓度两复孔，最终assay体系中DMSO浓度为1％。加入2.5uL用assay buffer配置的CDK激酶溶液(终浓度为16.5nM CDK1/CyclinB、1nM CDK2/CyclinE1、16.3nM CDK4/CyclinD1、11.5nM CDK5/p25、15.7nM CDK6/CyclinD3、80nM CDK7/Cyclin H/MAT1、15.3nM CDK9/Cyclin T1、150nM CDK12/CyclinK)，酶和化合物在室温预孵育10分钟。加入2.5uL用assay buffer配置的ATP(浓度为Km)&substrate溶液(20uM ATP&0.1mg/mL Histone H1 Protein for CDK1/CyclinB、15uM ATP&0.1mg/mL Histone H1 Protein for CDK2/CyclinE1、200uM ATP&0.2mg/mL DYRKtide peptide for CDK4/CyclinD1、10uM ATP&0.1mg/mL Histone H1 Protein for CDK5/p25、200uM ATP&0.1mg/mL Histone H1 Protein for CDK6/CyclinD3、70uM ATP&0.2mg/mL MBP for CDK7/Cyclin H/MAT1、60uM ATP&0.2mg/mL PDKtide for CDK9/Cyclin T1、20uM ATP&80uM pS7-CTD peptide for  CDK12/CyclinK)，混合均匀后在室温孵育，CDK1/4/9/12/13孵育120分钟，CDK2/5/6/7孵育60分钟。加入4uL ADP-Glo reagents，室温孵育40分钟。加入8uL kinase detection reagents，室温孵育40分钟。使用多功能微孔板酶标仪Envision进行读数。使用GraphPad Prism 8处理数据并计算IC50。
计算公式Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。
X:化合物浓度的对数值；Y:％抑制。
表6.本公开化合物对CDK激酶的抑制活性(IC50，nM)
表6中数据说明实施例2和6在CDK2/CDK7的选择性上显著好于Janssen-01。
Janssen-01参考WO2022064009A中提供的方法制备。
测试4
测试例4.人肝微粒体代谢研究
取222.5μL人肝微粒体(蛋白浓度：1mg/mL)，25μL NADPH(10nM)添加到孵化板中，预热10分钟。加入2.5μL对照化合物和测试化合物(100μM)。
分别在0.5、5、10、15、20和30分钟时从反应溶液中取出30μL等分试样。通过添加5倍体积的含有IS(100nM阿普唑仑、200nM咖啡因和100nM甲苯磺丁脲)的冷乙腈终止反应，离心，取100μL上清液与100μL超纯H2O混合，然后用于LC-MS/MS分析。
斜率值k由母体药物剩余百分比与孵育时间曲线的自然对数的线性回归确定。
体外半衰期(体外T1/2)由斜率值确定：
T1/2＝-(0.693/k)
使用以下等式(重复测定的平均值)将体外T1/2(分钟)转换为体外内在清除率(体外CLint，单位为μL/min/mg蛋白质)：
表7测试化合物在人肝微粒孵育过程中不同时间点的残留
表8测试化合物在人肝微粒中的代谢清除半衰期和清除率
表7和8说明实施例2和Janssen-01相比，在人肝微粒孵育过程中在各时间点的检测的原药残留更多，清除半衰期明显更长，清除速率明显更慢，说明代谢更稳定。

Claims (38)

  1. 一种式(I)所示的化合物或其可药用盐，
    其中，所述G1为N或CR1a；
    所述R1、R2、R3和R1a各自独立地选自氢、氘、氰基、羟基、C1-6烷基或卤素(例如，氟、氯、溴、碘)，且至少有一个不为氢或氘；
    所述R4、R5、R6、R7、R8、R9各自独立地选自氢、氘、卤素、C1-6烷基、氰基、C2-6烯基、C2-6炔基或3至6元环烷基，所述C1-6烷基、C2-6烯基、C2-6炔基或3至6元环烷基任选被一个或多个独立地选自RA的取代基取代，所述RA选自氘、卤素、羟基、氰基或3至6元环烷基；
    所述L1选自化学键或C1-6亚烷基，所述C1-6亚烷基任选被一个或多个独立地选自RB的取代基取代，所述RB选自氘、卤素、羟基、C1-6烷氧基、氨基、氧代，或者，连接在同一个碳原子上的两个RB与共同连接的碳原子成3至6元环烷基或3至7元的杂环基，所述杂环基至少含有一个选自N，O或S的杂原子；
    所述环A选自3至6元环烷基、6至10元芳基、5至12元的杂芳基或3至12元的杂环基；
    所述R10各自独立地选自氘、氰基、卤素、羟基、氨基、C2-6炔基、C2-6烯基、-S-C1-6烷基、C1-6烷氧基、氧代、C1-6烷基、3至6元环烷基、6至10元芳基、5至12元的杂芳基、3到12元的杂环基、-NH-(C＝O)-C1-6烷基、-NH-(C＝O)-C3-6环烷基、-NH(C＝O)-OC1-6烷基、-NH(C＝O)-OC3-6环烷基、-O(C＝O)NHC1-6烷基、-O(C＝O)NH-C3-6环烷基、-(C＝O)NH-C1-6烷基、-(C＝O)-NH-C3-6环烷基、-(C＝O)-C1- 6烷基、-(C＝O)-C3-6环烷基、-SO2-C1-6烷基、-SO2-C3-6环烷基、-SO2-NH2、-SO2-NH-C1-6烷基、-SO2-NH-C3-6环烷基、-SO2-N(C1-6烷基)2、-SO2-NH(C3-6环烷基)2、-S(O)(NH)-C1-6烷基、-S(O)(NH)-C3-6环烷基，
    所述C1-6烷基、3元到6元环烷基、6至10元芳基、5到12元的杂芳基、3到12元杂环基任选被一个或多个独立地选自RC的取代基取代，所述RC选自氘、卤素、C1-6烷氧基、羟基、氨基、氧代、C2-6炔基、C2-6烯基、氰基、C1-6羟烷基、3到12元的杂环基、C1-6烷基、C3-6环烷基、6至10元芳基或5到12元的杂芳基；
    所述R11选自氢、氘、卤素、氰基、C1-6烷基、C1-6烷氧基、3至6元环烷基、3到12元杂环基、C2-6烯基、C2-6炔基，所述C1-6烷基、C1-6烷氧基、3至6元环 烷基、3到12元杂环基、C2-6烯基、C2-6炔基、任选被一个或多个独立地选自RD的取代基取代，所述RD选自氢、氘、卤素、氰基、羟基、炔基、C1-6烷氧基、C1- 6羟烷基、3至6元环烷基；
    所述环B选自5至12元的杂芳基或6至12元的芳基；
    所述R'选自氢、氰基、C1-6烷基、3至6元环烷基、3到12元杂环基，所述C1- 6烷基、3至6元环烷基、3到12元杂环基任选被一个或多个独立地选自RE的取代基取代，所述RE选自氢、氘、卤素、氰基、羟基、炔基、C1-6烷氧基、C1-6羟烷基、3至6元环烷基、3至7元杂环基；
    所述m选自0或1；
    所述n选自0、1、2、3、4或5；
    所述o选自0、1、2、3或4。
  2. 一种式(VI)所示的化合物或其可药用盐，
    其中，所述，L2选自-NH-或-O-；
    所述B环选自5至12元的杂芳基或6至12元的芳基；
    所述L3选自C0-6亚烷基，所述C0-6亚烷基任选被一个或多个独立地选自RI的取代基取代，所述RI选自氘、卤素、氧代、羟基、氨基或C1-6烷基；
    所述R25和R26各自独立地选自氢、C1-6烷基、卤代C1-6烷基，或R25和R26与其连接的氮原子形成4至7元的含氮杂环，所述4至7元的含氮杂环任选被一个或多个独立地选自RJ的取代基取代，所述RJ选自卤素、羟基、氰基、硝基或氨基；
    所述R27各自独立地选自氘、卤素、羟基、羧基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C2-6烯基、C2-6炔基、3至6元环烷基、-S-C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、-NH-C1-6烷基、-NH(C1-6烷基)2、-(C＝O)-NH2、烷基-(C＝O)-NH-C1-6烷基、-(C＝O)-NH-(C1-6烷基)2、-(C＝O)C1-6烷基、-NH-(C＝O)C1-6烷基；
    所述y选自0、1、2、3或4；
    所述R4、R5、R6、R7、R8、R9、L1、环A、R10和n分别如权利要求1中定义，前提是所述R4、R5不同时为氢。
  3. 根据权利要求2所述的式(VI)所示的化合物或其可药用盐，其中，L2为-NH-。
  4. 根据权利要求2所述的式(VI)所示的化合物或其可药用盐，其中，L2为-O-。
  5. 根据权利要求2至4任一项所述的式(VI)所示的化合物或其可药用盐，其 中，L3为-CH2CH2-。
  6. 根据权利要求2至5任一项所述的式(VI)所示的化合物或其可药用盐，其中，环B为苯基或吡啶基，优选苯基。
  7. 根据权利要求2至6任一项所述的式(VI)所示的化合物或其可药用盐，其中，所述R27各自独立地选自氢、氘、卤素、氰基、羟基、羧基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C2-6炔基、3至6元环烷基、3至12元杂环烷基、5-12元芳基或杂芳基；优选卤素、C1-6烷基、卤代C1-6烷基、C2-6炔基；最优选氯、氟、三氟甲基或乙炔基。
  8. 根据权利要求根据权利要求2至7任一项所述的式(VI)所示的化合物或其可药用盐，其中，所述R25和R26各自独立地选自氢或C1-6烷基。
  9. 根据权利要求1至8任一项所述的化合物或其可药用盐，所述R4、R5、R6、R7、R8、R9各自独立地选自氢、氘、卤素或C1-6烷基。
  10. 根据权利要求9所述的化合物或其可药用盐，所述R4为甲基。
  11. 根据权利要求10所述的化合物或其可药用盐，所述R5、R6、R7、R8、R9各自独立地选自氢或氘。
  12. 根据权利要求1至11任一项所述的化合物或其可药用盐，所述L1为化学键。
  13. 根据权利要求1至12任一项所述的化合物或其可药用盐，所述L1选自C1-6亚烷基，所述C1-6亚烷基任选被一个或多个独立地选自RB的取代基取代，所述RB选自氘、卤素、羟基、C1-6烷氧基；优选地，所述L1为亚甲基，所述亚甲基任选被一个或多个独立地选自RB的取代基取代，所述RB选自氘、卤素、羟基、C1-6烷氧基。
  14. 根据权利要求1至13任一项所述的化合物或其可药用盐，所述环A选自吡唑环、咪唑环、四氢吡喃环、嘧啶环或环己基。
  15. 根据权利要求1至14任一项所述的化合物或其可药用盐，所述R10选自氘、氰基、C2-6炔基、-S-C1-6烷基、C1-6烷氧基、C1-6烷基，所述C2-6炔基、-S-C1-6烷基、C1-6烷氧基、C1-6烷基任选被一个或多个独立地选自RC的取代基取代，所述RC选自氘、卤素、C1-6烷氧基、羟基、氨基、氧代、C2-6炔基。
  16. 根据权利要求1至15任一项所述的化合物或其可药用盐，所述选自
  17. 根据权利要求2所述的式(VI)所示的化合物或其可药用盐，其为式(VI-1)或式(VI-2)所示的化合物或其可药用盐，优选式(VI-1)所示的化合物或其可药用盐，
    所述L2选自-NH-或-O-；
    所述环B选自5至6元的杂芳基或5至6元芳基；
    所述L3选自C1-3亚烷基(例如亚甲基)，所述C1-3亚烷基任选被一个或多个独立地选自RI的取代基取代，所述RI选自氘、卤素、氧代、羟基、氨基或C1-6烷基；
    所述R25和R26各自独立地选自氢、C1-6烷基(例如甲基、乙基)，所述C1-6烷基任选被一个或多个氘取代；
    所述R27各自独立地选自氘、卤素、羟基、羧基、C1-6烷基(例如甲基)、卤代C1-6烷基、羟基C1-6烷基、C2-6烯基、C2-6炔基、C1-6亚烷基-3至6元环烷基、3至6元环烷基、-S-C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、-NH-C1-6烷基、-NH(C1- 6烷基)2；
    所述y选自0、1、2、3或4；
    所述R4为C1-6烷基；
    所述R5、R6、R7、R8、R9各自独立地选自氢、氘、卤素或C1-6烷基；
    所述L1选自连接键，或所述L1选自C1-6亚烷基(例如亚甲基)，所述C1-6亚烷基被一个或多个独立地选自RB的取代基取代，所述RB选自氘、卤素、羟基、C1-6烷基(例如甲基)或氧代；
    所述环A选自5至6元芳基、5至6元杂芳基或3至7元杂环基；
    所述R10选自氘、氰基、C2-6炔基、-S-C1-6烷基、C1-6烷氧基、C1-6烷基(例如甲基)、C1-6亚烷基-3至6元环烷基、3至6元环烷基、5至6元芳基、5至6元杂芳基、5至12元杂环烷基、-NH(C＝O)-OC1-6烷基、-(C＝O)NH-C1-6烷基或(C＝O)NH2；
    所述C2-6炔基、-S-C1-6烷基、C1-6烷氧基、C1-6烷基、5至6元芳基、5至6元杂芳基、5至12元杂环烷基任选被一个或多个独立地选自RC的取代基取代，所述RC选自氘、卤素、C1-6烷氧基、C1-6烷基(例如甲基)、羟基、氨基、氧代、C2-6炔基；
    所述n选自0、1、2或3。
  18. 根据权利要求17所述的化合物或其可药用盐，所述L2为-NH-。
  19. 根据权利要求17或18任一项所述的化合物或其可药用盐，所述环B选自吡啶基或苯基，优选苯基，所述R27各自独立地选自氘、卤素、羟基、羧基、C1- 6烷基、C2-6烯基、C2-6炔基、C1-6亚烷基-3至6元环烷基或3至6元环烷基。
  20. 根据权利要求17至19任一项所述的化合物或其可药用盐，其为式(VI-1-A)或式(VI-1-B)所示的化合物或其可药用盐，优选式(VI-1-A)所示的化合物或其可药用盐，
    所述R5、R6、R7、R8、R9、L1、环A、R10、n、R25、R26、R27和y分别如权利要求17中定义。
  21. 根据权利要求17至20任一项所述的化合物或其可药用盐，所述L1为连接键。
  22. 根据权利要求17至20任一项所述的化合物或其可药用盐，所述L1选自C1-6亚烷基，或所述L1选自C1-6亚烷基，所述C1-6亚烷基被一个或多个独立地选自RB的取代基取代，所述RB选自氘、C1-6烷基(例如甲基)或氧代。
  23. 根据权利要求22所述的化合物或其可药用盐，所述L1选自亚甲基，或所述L1选自亚甲基，所述亚甲基被一个或多个独立地选自RB的取代基取代，所述RB选自氘或C1-6烷基(例如甲基)。
  24. 根据权利要求22所述的化合物或其可药用盐，所述L1选自亚甲基，所述亚甲基被一个或多个独立地选自RB的取代基取代，所述RB选自氧代。
  25. 根据权利要求17至24任一项所述的化合物或其可药用盐，所述R5、R6、R7、R8、R9各自独立地选自氢或氘。
  26. 根据权利要求17至25任一项所述的化合物或其可药用盐，所述环A选自吡唑基、咪唑基、吡啶基、苯基、四氢吡喃基、嘧啶基、环己基。
  27. 根据权利要求17至26任一项所述的化合物或其可药用盐，所述R10选自氘、C1-6烷基、C1-6亚烷基-3至6元环烷基、3至6元环烷基、5至6元芳基、5至6元杂芳基、5至12元杂环烷基、-NH(C＝O)-OC1-6烷基或-(C＝O)NH-C1-6烷基或(C＝O)NH2；
    所述C1-6烷基、5至6元芳基、5至6元杂芳基任选被一个或多个独立地选自RC的取代基取代，所述RC选自氘、卤素、C1-6烷氧基、C1-6烷基、羟基、氨基、氧代、C2-6炔基；
    所述n选自1、2或3；
    优选地，所述R10选自甲基、亚甲基-环丙基、环丙基，所述甲基、亚甲基-环丙基、环丙基任选被一个或多个独立地选自RC的取代基取代，所述RC选自氘。
  28. 根据权利要求17至27任一项所述的化合物或其可药用盐，所述选自
  29. 根据权利要求17至28任一项所述的化合物或其可药用盐，所述R27各自独立地选自氘、卤素、C1-6烷基、卤代C1-6烷基、C2-6炔基、C1-6亚烷基-3至6元环烷基、卤代C1-6烷氧基、-NH-C1-6烷基、-NH(C1-6烷基)2，优选地，所述R27各自独立地选自卤素或C1-6烷基，最优选氟、氯或甲基。
  30. 根据权利要求1至29任一项所述的化合物或其可药用盐，其选自：





  31. 一种根据权利要求1至29任一项所述的化合物的同位素取代物，优选地，所述的同位素取代物为氘原子取代。
  32. 一种制备根据权利要求20至31任一项所述的式(VI-1-A)或式(VI-1-B)所示的化合物或其可药用盐，或其同位素取代物的方法，包括式(VI-1-A-01)或其可药用盐，或(VI-1-B-01)或其可药用盐，在羰基二咪唑、光气或三光气的作用下，与式(VI-1-A-02)或其可药用盐发生缩合反应的步骤，
    所述R5、R6、R7、R8、R9、L1、环A、R10、n、R25、R26、R27和y分别如权利要求17中定义。
  33. 一种药物组合物，包含根据权利要求1至30任一项所述的化合物或其可药用盐，或权利要求31所述的同位素取代物及药学上可接受的赋形剂。
  34. 根据权利要求1至30任一项所述的化合物或其可药用盐，或权利要求31所述的同位素取代物或根据权利要求33所述的药物组合物在制备治疗和/或预防与丝氨酸/苏氨酸激酶的异常活性相关的疾病或病症的药物中的用途。
  35. 根据权利要求1至30任一项所述的化合物或其可药用盐，或权利要求31所述的同位素取代物或根据权利要求33所述的药物组合物在制备治疗和/或预防与CDK7的异常活性相关的疾病或病症的药物中的用途；优选地，所述与 CDK7的异常活性相关的疾病或病症选自增殖性疾病、炎性疾病、自身炎性疾病、自身免疫性疾病或传染性疾病。
  36. 根据根据权利要求1至30任一项所述的化合物或其可药用盐，或权利要求31所述的同位素取代物或根据权利要求33所述的药物组合物在制备治疗和/或预防疾病或病症的药物中的用途，所述的疾病或病症选自增殖性疾病、炎性疾病、自身炎性疾病、自身免疫性疾病或传染性疾病。
  37. 根据权利要求35或36任一项所述的用途，所述增殖性疾病为癌症；优选地，所述癌症选自血液瘤和实体瘤，所述血液瘤选自慢性淋巴细胞白血病、急性淋巴细胞白血病、T-细胞急性淋巴细胞白血病、慢性髓性白血病、急性髓系白血病，所述实体瘤选自乳腺癌、肠癌、肺癌、胰腺癌、前列腺癌、尤文氏肉瘤、骨瘤、成神经细胞瘤、宫颈癌、卵巢癌、胃癌、肝癌。
  38. 根据权利要求37所述的用途，所述乳腺癌是三阴性乳腺癌或ER/PR+HER2-乳腺癌，优选地，所述ER/PR+HER2-乳腺癌是对CDK4/6抑制剂耐药的ER/PR+HER2-乳腺癌；所述肺癌选自非小细胞肺癌或小细胞肺癌；所述肠癌选自结肠癌或直肠癌。
PCT/CN2023/126415 2022-10-25 2023-10-25 哌啶并嘧啶类衍生物、其制备方法及其在医药上的应用 Ceased WO2024088296A1 (zh)

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