WO2022063212A1 - Pyrimidyl derivative, preparation method therefor and use thereof - Google Patents

Pyrimidyl derivative, preparation method therefor and use thereof Download PDF

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WO2022063212A1
WO2022063212A1 PCT/CN2021/120199 CN2021120199W WO2022063212A1 WO 2022063212 A1 WO2022063212 A1 WO 2022063212A1 CN 2021120199 W CN2021120199 W CN 2021120199W WO 2022063212 A1 WO2022063212 A1 WO 2022063212A1
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alkyl
cancer
halogenated
independently
cyano
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PCT/CN2021/120199
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French (fr)
Chinese (zh)
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邱关鹏
王永钢
邓代国
雷曾荣
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广州费米子科技有限责任公司
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Publication of WO2022063212A1 publication Critical patent/WO2022063212A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D247/00—Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00 - C07D245/00
    • C07D247/02—Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00 - C07D245/00 having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention relates to the technical field of medicine, in particular to a pyrimidine derivative, a preparation method and use thereof.
  • CDKs Cyclin-dependent kinases
  • CDKs 7-13 and 19-20 Almost all known CDKs are activated by (i) binding to cyclins and (ii) phosphorylating their T-loops by CDK-activating kinase (CAK).
  • CAK is a trimeric complex composed of CDK7, cyclin H, and the RING finger protein MAT1, which uniquely engages CDK7 in the regulation of transcription and cell cycle.
  • CDK7 is autophosphorylated at the Thr170 site of its T-loop and interacts with Activated by cyclin H binding.
  • CDK7 combines with cyclin H and MATI to form a trimeric cyclin-activated kinase (CDK), which exerts its function by participating in the regulation of other CDKs in the cell cycle by phosphorylation. These complexes control specific transitions between the two phases of the cell cycle, the M and S phases. CDK7 is involved in the regulation of temporal control and transcriptional activity of the cell cycle, and is involved in transcription initiation through the phosphorylation of the Rbpl subunit of RNA polymerase II (RNAPII). Uncontrolled cell proliferation and transcriptional dysregulation are hallmarks of cancer.
  • RNAPII RNA polymerase II
  • CDK7 Aberrant excess of CDK7 has been detected in multiple cancer types and is associated with aggressive clinicopathological features and poor prognosis.
  • CRC colorectal cancer
  • immunohistochemical analysis of gastric cancer specimens showed that CDK7 levels were elevated in 173 gastric cancer specimens and correlated with tumor grade.
  • CDK7 was significantly overexpressed in oral squamous cell carcinoma samples, indicating its utility as a prognostic marker; protein and mRNA levels of CDK7 were also upregulated in breast cancer tissue compared with adjacent normal breast tissue; High expression is associated with poor clinical outcomes in triple-negative breast cancer (TNBC) patients.
  • Selective targeting of CDK7 has the advantage of simultaneously inhibiting active transcription and cell cycle progression.
  • CDK7 is a promising target for the treatment of cancer, especially aggressive and refractory cancers. It is of great significance to provide selective CDK7 inhibitors for the treatment of cell proliferation disorders, such as cancer.
  • the pyrimidinyl derivatives can be used as selective CDK7 inhibitors to address the need for effective treatment of various cancers, especially cancers with dysregulated transcription.
  • ring A is a 4-6 membered saturated nitrogen-containing heterocyclic group, a -C 1 -C 3 alkylene group, a -4-6 membered saturated nitrogen-containing heterocyclic group or ring Q;
  • Ring A is substituted with 1 to 3 R 0 , each R 0 is independently selected from -H, C 1 -C 3 alkyl, hydroxy, halogen, -NH 2 and -NH-(C 1 -C 3 alkyl);
  • Ring Q is selected from the following groups:
  • R 1 is selected from -H, halogen, cyano, C 1 -C 3 haloalkyl, 3-5 membered saturated cycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkoxy;
  • R 2 and R 3 are each independently selected from -H, halogen, cyano, -C(O)NH(C 1 -C 4 alkyl), -C(O)N(C 1 -C 4 alkyl) 2 , 5-6 membered heteroaryl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl and C 1 -C 4 haloalkoxy;
  • X is selected from CH or N;
  • R 4 is selected from the following groups:
  • R 5 and R 6 are each independently selected from -H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl , 3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl and -(C 1 -C 3 alkyl)-5-12 membered heteroaryl;
  • R 5 and R 6 are not connected or connected into a 4-6 membered ring
  • Ring A is selected from 4-6 membered saturated nitrogen-containing heterocyclic group, -C 1 -C 3 alkylene-4-6 membered saturated nitrogen-containing heterocyclic group, R 4 is not
  • Ring A can also be selected from other cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.
  • ring A is selected from one of the following groups, and the H on ring A is substituted by 1 to 3 R 0 :
  • ring A is selected from one of the following groups, and the H on ring A is substituted by 1 to 3 R 0 :
  • each R 0 is independently selected from -H, methyl, ethyl, hydroxyl, -NH 2 and -NH-CH 3 .
  • R 1 is selected from -H, halogen, cyano, C 1 -C 3 haloalkyl, 3-5 membered saturated cycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkoxy.
  • R 1 can also be selected from other alkyl groups, cycloalkyl groups, alkoxy groups and their halogenated forms, and can also be selected from cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups bases and their halogenated forms.
  • R 1 is selected from C 1 -C 3 haloalkyl. Specifically, R 1 is -CF 3 .
  • R 2 , R 3 are each independently selected from -H, halogen, cyano, -C(O)NH(C 1 -C 4 alkyl), -C(O)N( C 1 -C 4 alkyl) 2 , 5-6 membered heteroaryl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl and C 1 -C 4 haloalkoxy base.
  • R 2 and R 3 can also be independently selected from other alkyl groups, cycloalkyl groups, alkoxy groups and their halogenated forms, and can also be selected from cycloalkyl groups, heterocyclic groups , aryl, heteroaryl and their halogenated forms.
  • R 2 is selected from -H, halogen or cyano. Specifically, R 2 is -H, -F or -CN.
  • R 3 is -H.
  • X is selected from CH and N.
  • X is selected from CH.
  • R 4 is selected from the following groups:
  • R 5 and R 6 are each independently selected from -H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl , 3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl and -(C 1 -C 3 alkyl)-5-12 membered heteroaryl;
  • R 5 and R 6 are not connected or connected into a 4-6 membered ring
  • Ring A is selected from 4-6 membered saturated nitrogen-containing heterocyclic group, -C 1 -C 3 alkylene-4-6 membered saturated nitrogen-containing heterocyclic group, R 4 is not
  • R 4 is
  • R 5 and R 6 are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl and 3-6 membered saturated cycloalkyl Saturated cycloalkyl;
  • R 5 and R 6 are not linked or linked into a 4-6 membered ring.
  • R 5 and R 6 are methyl groups.
  • R4 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 5 and R 6 are each independently selected from -H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl and 3 -6-membered saturated cycloalkyl;
  • R 5 and R 6 are not linked or linked into a 4-6 membered ring.
  • R 5 is methyl; R 6 is -H.
  • R4 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 5 and R 6 are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered Saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl and -(C 1 -C 3 alkyl)-5 -12-membered heteroaryl;
  • Ring A is selected from ring Q.
  • R 5 and R 6 are methyl groups.
  • R4 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 5 is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl, 6 -10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl and -(C 1 -C 3 alkyl)-5-12 membered heteroaryl ;
  • Ring A is selected from ring Q.
  • R 5 is methyl, propyl or phenyl.
  • R 5 and R 6 can also be independently selected from other alkyl groups, cycloalkyl groups, alkoxy groups and their halogenated forms, and can also be selected from cycloalkyl groups, heterocyclic groups , aryl, heteroaryl and their halogenated forms.
  • R5 and R6 are not linked or linked to other cycloalkyl, heterocyclyl, aryl or heteroaryl ring systems.
  • R 4 is
  • R 5 is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl, 6 -10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl or -(C 1 -C 3 alkyl)-5-12 membered heteroaryl .
  • R 1 is -CF 3 .
  • R 2 is -H, -F or -CN.
  • R3 is -H.
  • the pyrimidinyl derivative is selected from one of the following compounds:
  • pyrimidinyl derivative is selected from one of the following compounds:
  • the present invention also provides the preparation method of the described pyrimidine derivatives, comprising the following steps:
  • V is each independently selected from halogen; R 1 , R 2 , R 3 , R 4 , w, x and A are as defined in the specification.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned pyrimidine derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof derivatives or prodrugs, as well as pharmaceutically acceptable excipients, diluents or carriers.
  • the pharmaceutical composition further comprises a combined agent; the combined agent is selected from at least one of an anti-proliferative agent, an anti-cancer agent, an immunosuppressant and a pain relief agent.
  • the present invention also provides the pyrimidinyl derivatives as described above, their optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs or drugs as described above Use of the composition in the manufacture of a medicament for preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity.
  • the present invention relates to pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof, or containing the same
  • the present invention relates to a method of preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity, Including the administration of described pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof to a subject in need thereof or comprising its pharmaceutical composition.
  • the cancer associated with aberrant CDK7 activity is selected from the group consisting of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, stomach cancer, brain cancer, bile duct cancer, cervical cancer, endometrial cancer, head and neck cancer , bladder cancer, bone cancer, bowel cancer, kidney cancer, throat cancer, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T -ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer , one or more of soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer and uterine cancer.
  • CLL chronic lymphocytic leukemia
  • ALL acute
  • the present invention has one or more of the following beneficial effects:
  • the present invention provides a pyrimidine-based derivative, which can be used as a novel selective CDK7 inhibitor to induce apoptosis and/or inhibit transcription by inhibiting the abnormal activity of CDK7, relative to other cyclin-dependent kinase isoforms With high selectivity and high kinase inhibitory activity, it is used to treat subjects with proliferative diseases and address the need for effective treatment of various cancers, especially cancers with dysregulated transcription. Experimental studies show that the compounds of the present invention have good inhibitory activity and selectivity to CDK7.
  • optical isomer shall include one of all isomers or their mixtures, for example, double bonds, geometric isomers in rings (E, Z, cis ( cis), trans (trans)), optical isomers (R-type, S-type) produced by the presence of asymmetric carbon atoms in straight-chain alkyl groups and branched-chain alkyl groups, and mixtures thereof in any ratio. Racemic mixtures and all isomers resulting from tautomers are included in the present invention.
  • each compound structure can be different stereoisomers with the same molecular formula, among which stereoisomers also include enantiomers and diastereomers, and enantiomers are optical isomers Diastereomers are stereoisomers of achiral enantiomers, and different isomers with the same molecular formula as the compounds of the present invention are also within the protection scope of the present invention.
  • salts refers to compounds that can be converted by conventional methods into the corresponding salts which are chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and which are physiologically compatible with the receptor .
  • the salts may be acid and/or base salts of the compound with inorganic and/or organic acids and/or with inorganic and/or bases, including zwitterionic salts (inner salts), and also quaternary ammonium salts, such as alkanes base ammonium salt. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by appropriately mixing the compound of the present invention or its stereoisomer or solvate with a certain amount of acid or base.
  • the salt is preferably a water-soluble pharmaceutically acceptable non-toxic acid addition salt, exemplified by an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with an organic acid (such as acetic acid) , oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or by using other methods conventional in the art such as ion exchange.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acid such as acetic acid
  • oxalic acid maleic acid, tartaric acid, citric acid, succinic acid or malonic acid
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonic acid Salt, Glycerophosphate, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobate, Lactate, Laurate, Lauryl sulfonate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, bisulfate Hynaphate, pectate,
  • Additional pharmaceutically acceptable salts may also include salts derived from suitable bases, including alkali metal, alkaline earth metal, and ammonium salts, as appropriate.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Additional pharmaceutically acceptable salts include non-toxic formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate. Ammonium, quaternary ammonium and amine cations.
  • solvate may also be referred to as “solvate”, “solvate”, and refers to a compound containing a solvent, wherein the solvent molecule can include coordinate bonds, covalent bonds, van der Waals forces, ionic bonds, hydrogen bonds and other ways to combine with compound molecules.
  • prodrug refers to any compound that, when administered to an organism, produces a drug, ie, an active ingredient, as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and/or metabolic chemical reactions.
  • a prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.
  • Suitable examples include, but are not limited to: carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compounds, carbamates, azo compounds, phosphoramides, glucosides of compounds , ether, acetal and other forms.
  • atropisomer is a class of stereoisomers in which the atoms of the two isomers are arranged differently in space. Atropisomers exist due to restricted rotation caused by hindered rotation of the large group about the central bond.
  • isotopically labeled compound is equivalent to a compound described herein except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H , 13C , 11C , 14C , 15N , 18 , respectively O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs containing the above isotopes and/or other isotopes of other atoms are within the scope of the present invention.
  • alkyl refers to a saturated hydrocarbon group containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. Phrases containing this term, for example, "C 1 -C 3 alkyl” refers to an alkyl group containing 1 to 3 carbon atoms, each occurrence of which may independently be a C 1 alkyl, C 2 alkyl, C3 alkyl. Preferred alkyl groups are C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl and C 1 -C 3 alkyl.
  • Suitable examples include, but are not limited to: methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n - propyl, -CH2CH2CH ) 3 ), 2-propyl (i-Pr, i-propyl, -CH( CH3 ) 2 ).
  • alkylene refers to a divalent group formed by removal of another hydrogen from an alkyl group, and may be substituted or unsubstituted. In some embodiments, C1 - C4 alkylene, C2 - C4 alkylene, and C1 - C3 alkylene are preferred.
  • haloalkyl refers to the aforementioned alkyl groups, which are substituted with one or more halogen groups.
  • hydroxy refers to -OH.
  • cyano refers to -CN.
  • saturated cycloalkyl refers to a non-aromatic cyclic hydrocarbon group containing ring carbon atoms, which may be monocyclic or bridged. Phrases containing this term, for example, “4-7 membered saturated cycloalkyl” refers to a cycloalkyl group containing 4 to 7 ring carbon atoms, each occurrence of which may independently be C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl.
  • Preferred saturated cycloalkyls are 3-8 membered cycloalkyl, 3-7 membered cycloalkyl, 3-6 membered cycloalkyl and 5-6 membered cycloalkyl. Suitable examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • saturated nitrogen-containing heterocyclic group refers to a non-aromatic cyclic hydrocarbon group in which at least one ring carbon atom in the ring system is substituted by N;
  • saturated nitrogen-containing spirocyclic group refers to the ring system as a spiro ring structure A saturated nitrogen-containing heterocyclic group in which at least one ring carbon atom in the ring system is substituted by N.
  • Preferred saturated nitrogen-containing heterocyclic groups are 3-8 membered nitrogen-containing heterocyclic groups, 3-6 membered nitrogen-containing heterocyclic groups or 4-6 membered nitrogen-containing heterocyclic groups.
  • halogen refers to -F, -Cl, -Br or -I.
  • halo refers to the substitution of -F, -Cl, -Br or -I for -H in the corresponding group.
  • alkoxy refers to a group having an -O-alkyl group, ie an alkyl group as defined above is attached to the core structure via an oxygen atom. Phrases containing this term, for example, " C1 -C3alkoxy” means that the alkyl moiety contains 1 to 3 carbon atoms.
  • aryl refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing one hydrogen atom, which may be a single-ring aryl group, a condensed-ring aryl group or a polycyclic aryl group. For polycyclic groups, at least one is an aromatic ring system. Phrases containing this term, eg, "5-6 membered aryl” refer to groups whose aromatic ring systems contain 5-6 ring atoms. Preferred aryl groups are 6-10 membered aryl groups, which can be selected from phenyl and naphthyl as examples.
  • heteroaryl refers to an aryl group containing a heteroatom, which may be a monocyclic or fused cyclic group, and the heteroatom is independently selected from N, O, and S.
  • the heteroaryl group is preferably a 5-12 membered heteroaryl group, more preferably a 5-6 membered heteroaryl group.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinoline base, isoquinolyl, triazolyl, tetrahydropyrrolyl.
  • heteroaryl is typically a 5-6 membered monocyclic heteroaryl containing 1 or more heteroatoms independently selected from N, O and S.
  • 5-membered heteroaryl is an exemplary 5-membered heteroaryl group containing one heteroatom, examples including, but not limited to, pyrrolyl, furanyl, and thienyl; two heteroatoms containing Exemplary 5-membered heteroaryl groups include, but are not limited to, imidazolyl, pyrazolyl, oxazolinyl, isoxazolinyl, thiazolyl, and isothiazolyl; exemplary 5-membered Membered heteroaryl groups include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl; exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • heterocyclyl refers to a non-aromatic cyclic group in which one or more atoms constituting the ring are heteroatoms including, but not limited to, nitrogen, oxygen, sulfur, and the like, and the remainder is carbon.
  • Preferred heterocyclyl groups are 3-10 membered saturated heterocyclyl groups.
  • a heterocyclyl group may be monocyclic ("monocyclic heterocyclyl"), or a bicyclic, tricyclic or more cyclic heterocyclic system, which may include cycloheterocyclic (fused), bridged (bridged ring), or spiro ring systems (eg, bicyclic ring systems ("bicyclic heterocycloalkyl").
  • Heterocycloalkyl bicyclic ring systems may be in one or two and is saturated.
  • Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridyl, oxiranyl, and thiirane, or Stereoisomers thereof;
  • exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, propylene oxide, thietane, or isomers and stereoisomers thereof Constructs;
  • exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, Imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiofuranyl, dithiofuranyl, or is
  • Exemplary 6-membered heterocyclyl groups include but not limited to, piperidinyl, tetrahydropyranyl, cyclopentanyl sulfide, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or Isomers and stereoisomers thereof;
  • exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, and dicycloheptyl Azacycloheptyl, or its isomers and stereoisomers.
  • heterocycloalkyl typically a 5-6 membered unit containing 1 or more heteroatoms independently selected from N, O, and S Cyclic heterocyclyl.
  • heterocycloalkyl is a 4-6 membered heterocycloalkyl, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • linking substituents are described.
  • the Markush variables listed for that group should be understood to be the linking group.
  • the Markush group definition for that variable recites “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” respectively represents the linking An alkylene group or an arylene group.
  • the alkyl group represents the alkylene group to which it is attached, eg, the group " -C1 - C3 haloalkyl" Alkyl in should be understood to mean alkylene.
  • the present invention adopts traditional methods such as mass spectrometry and nuclear magnetic resonance to identify compounds, and each step and condition can refer to the routine operation steps and conditions in the art.
  • the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
  • the description mode "...independently” used in the present invention should be understood in a broad sense, meaning that the described individuals are independent of each other and can independently are the same or different specific groups.
  • the description mode "...independently” can either mean that in different groups, the specific options expressed between the same symbols do not affect each other; it can also mean that in the same group, between the same symbols The specific options expressed do not affect each other.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the present invention relates to the following embodiments.
  • the present invention relates to pyrimidinyl derivatives having the structure represented by general formula (I), their optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled Derivatives or Prodrugs:
  • ring A is a 4-6 membered saturated nitrogen-containing heterocyclic group, -C 1 -C 3 alkylene-4-6 membered saturated nitrogen-containing heterocyclic group or ring Q; ring A is substituted by 1 to 3 R 0 , R 0 is independently selected from -H, C 1 -C 3 alkyl, hydroxyl, halogen, -NH 2 or -NH-(C 1 -C 3 alkyl);
  • Ring Q is selected from the following groups:
  • R 1 is selected from -H, halogen, cyano, C 1 -C 3 haloalkyl, 3-5 membered saturated cycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 haloalkoxy;
  • R 2 and R 3 are each independently selected from -H, halogen, cyano, -C(O)NH(C 1 -C 4 alkyl), -C(O)N(C 1 -C 4 alkyl) 2 , 5-6 membered heteroaryl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy;
  • X is selected from CH or N;
  • R 4 is selected from the following groups:
  • R 5 and R 6 are each independently selected from -H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl , 3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl or -(C 1 -C 3 alkyl)-5-12 membered heteroaryl;
  • R 5 and R 6 are not connected or connected into a 4-6 membered ring
  • Ring A is selected from 4-6 membered saturated nitrogen-containing heterocyclic group, -C 1 -C 3 alkylene-4-6 membered saturated nitrogen-containing heterocyclic group, R 4 is not
  • the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof Derivatives or prodrugs characterized by,
  • R 5 and R 6 are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl or 3-6 membered saturated cycloalkyl Saturated cycloalkyl;
  • R 5 and R 6 are not linked or linked into a 4-6 membered ring.
  • the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof
  • R 5 and R 6 are each independently selected from -H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl or 3 -6-membered saturated cycloalkyl;
  • R 5 and R 6 are not linked or linked into a 4-6 membered ring.
  • the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof Derivatives or prodrugs characterized by,
  • R 5 is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl, 6 -10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl or -(C 1 -C 3 alkyl)-5-12 membered heteroaryl .
  • the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof
  • R 5 and R 6 are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered Saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl or -(C 1 -C 3 alkyl)-5 -12-membered heteroaryl;
  • Ring A is selected from ring Q.
  • the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof Derivatives or prodrugs characterized by,
  • R 5 is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl, 6 -10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl or -(C 1 -C 3 alkyl)-5-12 membered heteroaryl ;
  • Ring A is selected from ring Q.
  • the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof
  • the derivative or prodrug characterized in that R 1 is -CF 3 .
  • the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof
  • the derivative or prodrug characterized in that R 2 is -H, -F or -CN.
  • the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof
  • the derivative or prodrug characterized in that R 3 is -H.
  • the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof
  • the derivative or prodrug characterized in that ring A is selected from one of the following groups and the H on ring A is substituted by 1 to 3 R 0 :
  • the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof
  • the derivative or prodrug characterized in that ring A is selected from one of the following groups and the H on ring A is substituted by 1 to 3 R 0 :
  • the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof
  • the derivative or prodrug of wherein each R 0 is independently selected from -H, methyl, ethyl, hydroxyl, -NH 2 and -NH-CH 3 .
  • the present invention relates to compounds of general formula (a), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof:
  • R 5 and R 6 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
  • R 5' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R 6' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 9 and R 10 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
  • R 11 is selected from -H, -OR', -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl, -NHC(O)C 1-6 alkyl, -NHC(O) OC 1-6 alkyl, -NHC(O)NHC 1-6 alkyl and -NHC(O)N(C 1-6 alkyl) 2 ; wherein the C 1-6 alkyl is optionally replaced by 1-3 substituted with a substituent selected from hydroxyl, thiol, -OR' and -NR'R";
  • R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • n1, m2, n1, and n2 are each independently 0, 1, or 2;
  • p is selected from 0, 1, 2, 3, 4, 5 and 6;
  • t is selected from 1, 2, 3 and 4;
  • the present invention relates to the above-described compounds of formula (a), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
  • R 5 and R 6 are each independently selected from -H and C 1-4 alkyl
  • R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl
  • R 9 and R 10 are each independently selected from -H and C 1-4 alkyl
  • R 11 is selected from -H, -NR'R", -NHC(O)OC 1-4 alkyl, -NHC(O)NHC 1-4 alkyl and -NHC(O)N(C 1-4 alkyl ) 2 ; wherein the C 1-4 alkyl is optionally substituted by 1-3 substituents selected from hydroxyl, mercapto and -NR'R";
  • R' and R" are each independently selected from -H, C 1-4 alkyl and haloC 1-4 alkyl;
  • n1, m2, n1, and n2 are each independently 0, 1, or 2;
  • p is selected from 0, 1 and 2;
  • t is selected from 1 and 2;
  • the present invention relates to the above-described compounds of formula (a), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
  • R 5 and R 6 are each independently C 1-4 alkyl
  • R 8 is halogenated C 1-4 alkyl
  • R 9 and R 10 are each independently -H;
  • R 11 is selected from H and -NR'R"
  • R' and R" are each independently selected from -H and C 1-4 alkyl
  • n1, m2, n1 and n2 are each independently 1 or 2;
  • t is selected from 1 and 2;
  • the present invention relates to the above-described compounds of formula (a), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
  • R 5 and R 6 are each independently C 1-4 alkyl
  • R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
  • R 9 and R 10 are each independently -H;
  • R 11 is -NR'R"
  • R' and R" are each independently -H
  • n1, m2, n1 and n2 are each independently 1;
  • the present invention relates to compounds of general formula (b), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof,
  • R 5 and R 6 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
  • R 5' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R 6' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 11 is selected from -H, -OR', C 1-6 alkyl, halogenated C 1-6 alkyl, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl , -C(O)NHC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; wherein the C 1-6 alkyl is optionally , -OR' and -NR'R" substituents are substituted;
  • R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • n1, m2, n1, and n2 are each independently 0, 1, or 2;
  • t is selected from 1, 2, 3 and 4;
  • p is selected from 0, 1, 2, 3, 4, 5 and 6.
  • the present invention relates to the above-described compounds of general formula (b), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
  • R 5 and R 6 are each independently selected from -H and C 1-4 alkyl
  • R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl
  • R 11 is selected from -H, -C(O)OC 1-4 alkyl, -C(O)NHC 1-4 alkyl and -C(O)N(C 1-4 alkyl) 2 ; wherein said C 1-4 alkyl is optionally substituted by 1-3 substituents selected from hydroxyl, mercapto and -NR'R";
  • R' and R" are each independently selected from -H and C 1-6 alkyl
  • n1, m2, n1, and n2 are each independently 0, 1, or 2;
  • t is selected from 1 and 2;
  • p is selected from 0 and 1;
  • the present invention relates to the above-described compounds of general formula (b), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
  • R 5 and R 6 are each independently C 1-4 alkyl
  • R 8 is halogenated C 1-4 alkyl
  • R 11 is H or -C(O)OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups;
  • n1, m2, n1 and n2 are each independently 1 or 2;
  • t is selected from 1 and 2;
  • p is selected from 0 and 1;
  • the present invention relates to compounds of general formula (b-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or pro- Medicine,
  • R 5 and R 6 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
  • R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 11 is selected from -H, -OR', C 1-6 alkyl, halogenated C 1-6 alkyl, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl , -C(O)NHC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; wherein the C 1-6 alkyl is optionally , -OR' and -NR'R" substituents are substituted;
  • R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • n1, m2, n1, and n2 are each independently 0, 1, or 2.
  • the present invention relates to the above-mentioned compounds of general formula (b-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or A prodrug, which:
  • R 7 is selected from -H, halogen, cyano, C 1-4 alkyl and halogenated C 1-4 alkyl;
  • R 5 and R 6 are each independently selected from -H and C 1-4 alkyl
  • R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl
  • R 11 is selected from -H, -C(O)OC 1-4 alkyl, -C(O)NHC 1-4 alkyl and -C(O)N(C 1-4 alkyl) 2 ; wherein said C 1-4 alkyl is optionally substituted by 1-3 substituents selected from hydroxyl, mercapto and -NR'R";
  • R' and R" are each independently selected from -H and C 1-6 alkyl
  • n1, m2, n1, and n2 are each independently 0, 1, or 2.
  • the present invention relates to the above-mentioned compounds of general formula (b-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or A prodrug, which:
  • R is selected from -H , halogen and cyano
  • R 5 and R 6 are each independently C 1-4 alkyl
  • R 8 is halogenated C 1-4 alkyl
  • R 11 is H or -C(O)OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups;
  • n1, m2, n1 and n2 are each independently 1 or 2.
  • the present invention relates to the above-mentioned compounds of general formula (b-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or A prodrug, which:
  • R 7 is -H
  • R 5 and R 6 are each independently C 1-4 alkyl
  • R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
  • R 11 is -C(O)OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups;
  • n1, m2, n1, and n2 are each independently 1.
  • the present invention relates to compounds of general formula (b-2), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof ,
  • R 5 and R 6 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
  • R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 15 is C 1-6 alkyl, which is optionally substituted by 1-3 substituents selected from hydroxyl, mercapto, -OR' and -NR'R";
  • R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • n1, m2, n1, and n2 are each independently 0, 1, or 2.
  • the present invention relates to the above-described compounds of general formula (b-2), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives thereof, or A prodrug, which:
  • R 7 is selected from -H, halogen, cyano, C 1-4 alkyl and halogenated C 1-4 alkyl;
  • R 5 and R 6 are each independently selected from -H and C 1-4 alkyl
  • R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl
  • R 15 is C 1-4 alkyl, which is optionally substituted with 1-3 substituents selected from hydroxyl, mercapto and -NR'R";
  • R' and R" are each independently selected from -H and C 1-6 alkyl
  • n1, m2, n1, and n2 are each independently 0, 1, or 2.
  • the present invention relates to the above-described compounds of general formula (b-2), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives thereof, or A prodrug, which:
  • R is selected from -H , halogen and cyano
  • R 5 and R 6 are each independently C 1-4 alkyl
  • R 8 is halogenated C 1-4 alkyl
  • R 15 is C 1-4 alkyl; it is optionally substituted with 1-2 hydroxyl groups;
  • n1, m2, n1 and n2 are each independently 1 or 2.
  • the present invention relates to the above-described compounds of general formula (b-2), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives thereof, or A prodrug, which:
  • R 7 is -H
  • R 5 and R 6 are each independently C 1-4 alkyl
  • R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
  • R 11 is -C(O)OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups;
  • n1, m2, n1, and n2 are each independently 1.
  • the present invention relates to compounds of general formula (c), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof,
  • R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 13 and R 14 are each independently selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 15 is each independently selected from -H, halogen, -OR', cyano, C 1-6 alkyl, halogenated C 1-6 alkyl,
  • R 5' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R 6' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • s and q are each independently selected from 0, 1 and 2;
  • r is selected from 1, 2, 3 and 4;
  • the present invention relates to the above-described compounds of general formula (c), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
  • R 8 is halogenated C 1-6 alkyl
  • R 13 and R 14 are each independently selected from H and C 1-6 alkyl
  • R 15 is each independently selected from -H, halogen, cyano,
  • R 5' is selected from -H and C 1-6 alkyl
  • R 6' is selected from -H, cyano and C 1-6 alkyl
  • s and q are each independently selected from 0 and 1;
  • r is selected from 1 and 2;
  • the present invention relates to the above-described compounds of general formula (c), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
  • R 8 is halogenated C 1-4 alkyl
  • R 13 and R 14 are each independently C 1-4 alkyl
  • R 15 is each independently selected from -H, halogen, cyano and
  • R 5' is selected from -H and C 1-4 alkyl
  • R 6' is selected from -H, cyano and C 1-4 alkyl
  • s and q are each independently selected from 0 and 1;
  • r is selected from 1 and 2;
  • the present invention relates to the above-described compounds of general formula (c), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
  • R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
  • R 13 and R 14 are each independently C 1-4 alkyl
  • R 15 is selected from halogen and
  • R 5' is C 1-4 alkyl
  • R 6' is selected from -H and cyano
  • s and q are each independently 1;
  • r is selected from 1 and 2;
  • the present invention relates to compounds of general formula (c-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or pro- Medicine,
  • R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 13 and R 14 are each independently selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 15 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl, halogenated C 1-6 alkyl,
  • R 5' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 6' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • s and q are each independently selected from 0, 1 and 2.
  • the present invention relates to the above-mentioned compounds of general formula (c-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or A prodrug, which:
  • R 8 is halogenated C 1-4 alkyl
  • R 13 and R 14 are each independently selected from -H and C 1-4 alkyl
  • R 15 is selected from -H, halogen and cyano
  • R 5' is selected from -H and C 1-4 alkyl
  • R 6' is selected from -H, cyano and C 1-4 alkyl
  • s and q are each independently selected from 0 and 1.
  • the present invention relates to the above-mentioned compounds of general formula (c-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or A prodrug, which:
  • R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
  • R 13 and R 14 are each independently selected from -H and C 1-4 alkyl
  • R 15 is selected from -H and halogen
  • R 5' is C 1-4 alkyl
  • R 6' is selected from -H and cyano
  • s and q are each independently 1.
  • the pyrimidinyl derivative is selected from one of the following compounds:
  • the pyrimidinyl derivative is selected from one of the following compounds:
  • the present invention provides a method for preparing pyrimidine derivatives, which is characterized in that it comprises the following steps:
  • V is each independently selected from halogen; R 1 , R 2 , R 3 , R 4 , w, x and A are as defined in the specification.
  • the method of reacting the group w to form R4 comprises the steps of:
  • the group w is halogen, and the group w undergoes a substitution reaction with R 4 -H to form R 4 ;
  • the group w is -SR 5 , and the group w undergoes an oxidation reaction to form R 4 ;
  • the group w is -NO 2 , the group w undergoes a reduction reaction to generate -NH 2 , and -NH 2 undergoes a condensation reaction to form R 4 ;
  • R 1 , R 2 , R 3 , R 4 , w, x and A are as described in the specification defined.
  • the present invention relates to a pharmaceutical composition, characterized in that the pharmaceutical composition comprises the pyrimidinyl derivative according to the present invention, an optical isomer thereof, a pharmaceutically acceptable salt, a solvent compounds, atropisomers, isotopically-labeled derivatives or prodrugs, and pharmaceutically acceptable excipients, diluents or carriers.
  • the pharmaceutical composition further comprises a combined agent; the combined agent is selected from at least one of an antiproliferative agent, an anticancer agent, an immunosuppressant, and a pain relief agent.
  • the present invention relates to said pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof or said Use of a pharmaceutical composition in the preparation of a medicament for preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity.
  • the cancer associated with aberrant CDK7 activity is selected from the group consisting of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, gastric cancer, brain cancer, bile duct cancer, cervical cancer, endometrial cancer, head and neck cancer, Bladder cancer, bone cancer, bowel cancer, kidney cancer, throat cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia of leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine, esophageal, penile, prostate, skin, soft tissue sarcoma, spinal cord, testicular, thyroid and uterine cancers one or more.
  • the present invention relates to said pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof or said A pharmaceutical composition for preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity.
  • the cancer associated with aberrant CDK7 activity is selected from the group consisting of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, gastric cancer, brain cancer, bile duct cancer, cervical cancer, endometrial cancer, head and neck cancer, Bladder cancer, bone cancer, bowel cancer, kidney cancer, throat cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia of leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine, esophageal, penile, prostate, skin, soft tissue sarcoma, spinal cord, testicular, thyroid and uterine cancers one or more.
  • the present invention relates to a method of preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with aberrant CDK7 activity, Including the administration of the pyrimidinyl derivatives of the present invention, their optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs to subjects in need or the pharmaceutical composition.
  • the cancer associated with aberrant CDK7 activity is selected from the group consisting of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, gastric cancer, brain cancer, bile duct cancer, cervical cancer, endometrial cancer , head and neck cancer, bladder cancer, bone cancer, bowel cancer, kidney cancer, throat cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myelogenous leukemia , acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine, esophageal, penile, prostate, skin, soft tissue sarcoma, spinal cord, testicular, thyroid and One or more of uterine cancers.
  • Embodiments of the present invention also provide a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned pyrimidine derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers thereof , isotopically labeled derivatives or prodrugs, and pharmaceutically acceptable excipients, diluents or carriers.
  • the pharmaceutical composition further comprises a combined agent; the combined agent is selected from the group consisting of anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressive agents, and pain relief agents at least one of the agents.
  • the combination agent is one or more anticancer agents.
  • the combination agent is selected from small organic molecules, such as pharmaceutical compounds (eg, compounds approved by the US Food and Drug Administration) as provided in the Code of Federal Regulations (CFR) ), as well as peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA , nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.
  • pharmaceutical compounds eg, compounds approved by the US Food and Drug Administration
  • CFR Code of Federal Regulations
  • composition may also include a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides pyrimidinyl derivatives as described above, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof, or as described above
  • a pharmaceutical composition in the preparation of a medicament for preventing or treating a CDK7-mediated disease or condition.
  • the CDK7-mediated disease or disorder refers to a CDK7-mediated disease or disorder in mammals (especially humans).
  • the CDK7-mediated disease or disorder refers to aberrant CDK7 activity-related proliferative diseases (such as cancer), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, Autoimmune disease, infectious disease or allergic disease.
  • the cancer associated with abnormal CDK7 activity is selected from breast cancer (especially triple negative breast cancer), ovarian cancer, rectal cancer, liver cancer, lung cancer, stomach cancer, brain cancer, bile duct cancer, Cervical cancer, endometrial cancer, head and neck cancer, bladder cancer, bone cancer, bowel cancer, kidney cancer, laryngeal cancer, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine carcinoma, esophagus
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphoblastic leukemia
  • T-ALL T-cell acute lymphoblastic leukemia
  • CML chronic myeloid leukemia
  • AML acute
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC measurement was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6 mm).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • the known starting materials of the present invention can be synthesized by using or according to methods known in the art, or can be purchased from Titan Technology, Annagy Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and other companies.
  • Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature.
  • Room temperature is the most suitable reaction temperature, which is 20°C to 30°C.
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium
  • PE petroleum ether
  • Step 2 cis-(3-(((benzyloxy)carbonyl)amino)cyclohexyl)(methyl)carbamic acid benzyl ester 2c
  • Tetrahydrocyclopentadiene-2,5(1H,3H)-dione 3a (10 g, 72.38 mmol) was dissolved in dry ethyl acetate (300 mL) and the air was replaced with N2 3 times. Drop to 0° C., add 1 mol/L lithium aluminum tri-tert-butoxyhydride (217 ml, 217 mmol). After the addition was completed, the temperature was naturally raised to room temperature, and the mixture was stirred for 18 hours. Saturated ammonium chloride (300 ml) was added to the reaction solution to quench, and the layers were separated. The aqueous phase was extracted with ethyl acetate (300 mL ⁇ 2), and the organic phases were combined.
  • 2,3-Difluoronitrobenzene 4a (20 g, 0.126 mol) was dissolved in DMSO (200 mL), sodium methanethiolate (9.7 g, 0.138 mol) was added thereto, and the mixture was stirred at room temperature overnight. Water (600 mL) was added to the reaction solution to quench, and the organic phase was obtained by extraction with ethyl acetate (300 mL ⁇ 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to obtain a residue.
  • DMSO 200 mL
  • sodium methanethiolate 9.7 g, 0.138 mol
  • (2-Fluoro-6-nitrophenyl)(methyl)sulfane 4b (10 g, 0.0535 mol) was dissolved in dry tetrahydrofuran (170 mL) and the air was replaced with N2 3 times. Then it was lowered to -78°C, and 1.5 mol/L of vinylmagnesium bromide (169 mL, 0.254 mol) was added. After the addition was completed, the temperature was naturally warmed to room temperature and stirred for 3 hours. Saturated ammonium chloride (200 mL) was added to the reaction solution for quenching, followed by extraction with ethyl acetate (100 mL ⁇ 2), and the organic phases were combined.
  • Step 3 3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-7-(methylthio)-1H-indole (Intermediate 4)
  • 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (8.0 g, 37.29 mmol) was dissolved in dry 1,2-dichloroethane (30 mL) and the air was replaced with N2 3 times.
  • Anhydrous aluminum trichloride (4.98 g, 37.29 mmol) was added, then heated to 80°C and stirred for half an hour.
  • the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2), and the organic phases were combined.
  • the organic phase was washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product.
  • 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (8.0 g, 37.0 mmol) was dissolved in anhydrous dichloroethane (50 mL), and anhydrous aluminum trichloride (4.8 g, 36.0 mmol) was added ), N 2 was replaced 3 times. Then, the temperature was raised to 80°C, and the reaction was carried out for 30 minutes. 7-(Methylthio)-1H-indole 5b (2 g, 12.3 mmol) was added and reacted for 1 hour. Water (100 mL) and ethyl acetate (150 mL) were added, the layers were separated, and the organic phase was retained.
  • the aqueous phase was extracted with ethyl acetate (30 mL ⁇ 2), and the organic phases were combined.
  • the organic phase was washed with saturated brine (30 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product.
  • the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2), and the organic phases were combined.
  • the organic phase was washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a solid compound 1-(((methylsulfonyl)oxy)methyl)-5-azaspiro[ 2.4] Heptane-5-carboxylate tert-butyl ester 6c (1 g, 81.3% yield).
  • Step 2 6-((4-(7-(Dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2- Azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (Intermediate 7)
  • Heptane-2-carboxylate tert-butyl ester 7b (240mg, 0.43mmol) was dissolved in DMF (5mL), dimethylphosphine oxide (170mg, 2.15mmol), palladium acetate (20mg, 0.08mmol), phosphoric acid were added Potassium (184 mg, 0.86 mmol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (75 mg, 0.13 mmol) were reacted in a microwave at 150° C.
  • Step 2 6-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl) Amino)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (Intermediate 8)
  • Phenylphosphino)ferrocene]palladium dichloride (254 mg, 0.34 mmol), potassium phosphate (368 mg, 1.70 mmol) and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene ( 200 mg, 0.34 mmol), nitrogen protection, microwave reaction, reaction at 150 ° C for 1 hour. The temperature was lowered to room temperature, ethyl acetate was added, the mixture was washed with saturated brine, and the organic layers were combined.
  • the first step 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole 1B
  • the residual crude product was purified by Prep-HPLC (instrument: Gilson; Flow: 25 mL/min; mobile phase A: 0.1% NH 4 OH inwater, mobile phase B: CAN; the volume ratio of A to B was 45%) to obtain the compound 1 (2 mg, 10.27%) as a white solid.
  • the first step trans-N 1 -(4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)cyclohexane-1,3- Diamine 2A
  • the third step trans-(3-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) cyclohexyl) tert-butyl carbamate 2C
  • the first step 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 3A
  • the aqueous phase was extracted with dichloromethane (10 mL ⁇ 2), and the organic phases were combined.
  • the organic phase was washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate at room temperature, filtered, and concentrated to obtain a residue.
  • the second step trans-3-(2-((3-aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-bromo-1H-indole-6-methyl Nitrile 3B
  • the third step trans-(3-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) Cyclohexyl) tert-butyl carbamate 3C
  • the crude product 3B (140 mg, 0.29 mmol) was dissolved in tetrahydrofuran (3 ml), N,N-diisopropylethylamine (113 mg, 0.89 mmol) and di-tert-butyl dicarbonate (194 mg, 0.89 mmol) were added, The N2 was replaced 3 times, and the reaction was carried out at room temperature for one hour.
  • reaction solution was cooled to room temperature, water (10 mL) and ethyl acetate (10 mL) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2). The combined organic phases were washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated.
  • 2-Bromo-1-fluoro-3-nitrobenzene 7A (10 g, 45.67 mmol) was dissolved in dry tetrahydrofuran (30 mL) and the air was replaced 3 times with N 2 to -78 °C. 1.5 mol/L vinylmagnesium bromide (91 ml, 136.99 mmol) was added, and after the addition was completed, the temperature was naturally raised to room temperature and stirred for 3 hours. Saturated ammonium chloride (100 mL) was added to the reaction solution to quench, and then ethyl acetate (100 mL) was added to separate the layers.
  • the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 2), and the organic phases were combined.
  • the organic phase was washed with saturated brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate at room temperature, filtered and concentrated.
  • 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (3 g, 13.89 mmol) was dissolved in dry 1,2-dichloroethane (30 mL) and N 2 replaced air 3 times.
  • Anhydrous aluminum trichloride (1.9 g, 14.29 mmol) was added and heated to 85°C and stirred for half an hour.
  • dichloromethane (30 ml) and ice water (30 mL) were added to the reaction solution, and the layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL ⁇ 2). The combined organic phases were washed with saturated brine (20 mL ⁇ 2). Dry over anhydrous sodium sulfate at room temperature, filter, and concentrate.
  • the third step 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy) yl)methyl)-1H-indole 7D
  • the fifth step (S)-3-((4-(7-((dimethyl(oxo)- ⁇ 6 -sulfanylidene)amino)-6-fluoro-1-(((2-(trimethyl) Silyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 7F
  • reaction solution was cooled to room temperature, concentrated, water (10 mL) and ethyl acetate (15 ml) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2). The combined organic phases were washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 7 (S)-((6-Fluoro-3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-7 -yl)imino)dimethyl- ⁇ 6 -sulfoxide (compound 7)
  • the first step 3-(2-(((2s,3aR,5r,6aS)-5-aminooctahydrocyclopentadien-2-yl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl)-7-bromo-1H-indole-6-carbonitrile 11A
  • the third step ((2s,3aR,5r,6aS)-5-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-( Trifluoromethyl)pyrimidin-2-yl)amino)octahydrocyclopentadien-2-yl)carbamate tert-butyl ester 11C
  • the first step (2s,3aR,5r,6aS)-N2-(4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)octahydro cyclopentadiene-2,5-diamine 12A
  • Step 2 ((2s,3aR,5r,6aS)-5-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl) Amino) octahydrocyclopentadien-2-yl) tert-butyl carbamate 12B
  • the third step ((2s,3aR,5r,6aS)-5-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl) Pyrimidine-2-yl)amino)octahydrocyclopentadien-2-yl)carbamate tert-butyl ester 12C
  • the fourth step 3-(2-(((2s,3aR,5r,6aS)-5-aminooctahydrocyclopentadien-2-yl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl)-1H-indol-7-yl)dimethylphosphine oxide (compound 12)
  • Step 5 3-(2-(((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile (Compound 13)
  • the 2.2 g racemate 14C obtained above was subjected to chiral separation to obtain 1.0 g each of 14C-P1 (retention time: 1.45 min) and 14C-P2 (retention time: 1.74 min).
  • Step 4 (6-Fluoro-3-(2-(((S)-piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole- 7-yl)(imino)(methyl)- ⁇ 6 -sulfoxide (Compound 14-P1)
  • reaction solution was cooled to room temperature, concentrated and spin-dried to obtain an oily compound (S)-N-(6,6-dimethylpiperidin-3-yl)-4-(7-(methylthio)-1-((2 -(Trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine 15A (500 mg, 70% yield).
  • the fourth step (5S)-5-((4-(7-(N-cyano-S-methylsulfoxide)-1-((2-(trimethylsilyl)ethoxy) (yl)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl Ester 15D
  • Step 5 N-((3-(2-(((S)-6,6-dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) -1H-Indol-7-yl)(methyl)(oxo)- ⁇ 6 -sulfanylidene)cyanamide (Compound 15)
  • the first step 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-indole-6-carbonitrile 16A
  • the first step 1-(((4-(7-Bromo-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)- 5-Azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 17A
  • Step 2 1-(((4-(7-(dimethylphosphoryl)-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl) Amino)methyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 17B
  • reaction solution was cooled to room temperature, water (10 mL) and ethyl acetate (15 mL) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2). The combined organic phases were washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated.
  • the third step (3-(2-(((5-azaspiro[2.4]heptane-1-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6 -Fluoro-1H-indol-7-yl)dimethylphosphine oxide (compound 17)
  • the first step 1-(((4-(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl) -5-Azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 18A
  • Step 2 1-(((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl )amino)methyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 18B
  • reaction solution was cooled to room temperature, water (10 mL) and ethyl acetate (15 mL) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2).
  • the combined organic phases were washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated.
  • the third step 3-(2-(((5-azaspiro[2.4]heptan-1-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7- (Dimethylphosphoryl)-1H-indole-6-carbonitrile (Compound 18)
  • Heptane-2-carboxylate tert-butyl ester (Intermediate 7) (50 mg, 0.09 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (1 ml), and the reaction was stirred at room temperature for one hour. Concentration under reduced pressure gave crude brown oil. Ethyl acetate (10 ml) was added thereto, then a saturated solution of sodium carbonate was added to make it basic, and the layers were separated.
  • the first step 6-((4-(7-Bromo-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-aza Spiro[3.3]heptane-2-carboxylate tert-butyl ester 20A
  • Step 2 6-((4-(7-(dimethylphosphoryl)-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )-2-Azaspiro[3.3]heptane-2-carboxylate tert-butyl ester 20B
  • reaction solution was cooled to room temperature, water (10 mL) and ethyl acetate (15 mL) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2). The combined organic phases were washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated.
  • the third step (3-(2-((2-azaspiro[3.3]heptane-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H -Indol-7-yl)dimethylphosphine oxide (compound 20)
  • Dimethylphosphine oxide (compound 19) (100 mg, 0.22 mmol) was dissolved in toluene (6 mL), cesium carbonate (144 mg, 0.44 mmol) and ethylene carbonate (18 mg, 0.22 mmol) were added, and heated to 100 ° C for reaction 2 Hour. The reaction solution was concentrated and spin-dried, and then dichloromethane (15 mL) was added, followed by filtration. The filtrate was concentrated and spin-dried to obtain crude product.

Abstract

A pyrimidyl derivative, a preparation method therefor and the use thereof. The pyrimidyl derivative has a structure as represented by general formula (I). The pyrimidyl derivative can be used as a selective CDK7 inhibitor to address the effective treatment requirements of multiple cancers, especially transcription-dysregulated cancers. <img file="dest_path_image002.jpg" he="53.18" img-content="drawing" img-format="jpg" inline="yes" orientation="portrait" wi="106.89"/>

Description

嘧啶基衍生物、其制备方法及其用途Pyrimidine derivatives, methods for their preparation and uses thereof 技术领域technical field
本发明涉及医药技术领域，特别是一种嘧啶基衍生物、其制备方法及其用途。The present invention relates to the technical field of medicine, in particular to a pyrimidine derivative, a preparation method and use thereof.
背景技术Background technique
细胞周期蛋白依赖性激酶(CDKs)是调控转录(CDKs 7-13和19-20)或细胞周期进程(CDKs 1-6和14-18)的丝氨酸/苏氨酸蛋白激酶。几乎所有已知的CDKs都是通过(i)与细胞周期蛋白结合和(ii)CDK激活激酶(CAK)磷酸化其T-环而被激活。CAK是一种由CDK7、cyclin H和环指蛋白MAT1组成的三聚体复合物，使CDK7独特地参与转录和细胞周期的调控，CDK7在其T-环的Thr170位点发生自磷酸化并与cyclin H结合后被激活。另有研究表明，CDKs也是一类在癌细胞增殖和解除控制的致癌转录过程中起重要调控作用的激酶。CDK7与cyclin H和MATI结合形成三聚体细胞周期蛋白活化激酶(CDK)，通过磷酸化参与细胞周期调控其他CDKs来发挥其功能。这些复合物控制着细胞周期中M期和S期两个阶段之间的特定转变。CDK7涉及调控细胞周期的时间控制和转录活性，通过RNA聚合酶II(RNAPII)的Rbpl亚基磷酸化参与转录起始过程。不受控制的细胞增殖和转录失调是癌症的标志。CDK7异常过剩已在多种癌症类型中被检测到，并与侵袭性临床病理特征和不良预后相关。有研究证实，CDK7在肝细胞癌、胃癌和结直肠癌(CRC)中扩增。例如，胃癌标本免疫组化分析显示，173例胃癌标本CDK7水平升高，且与肿瘤分级相关。类似地，CDK7在口腔鳞状细胞癌样本中大量过表达，表明其作为预后标志物的效用；乳腺癌组织中与相邻的正常乳腺组织相比，CDK7的蛋白和mRNA水平也上调；CDK7的高表达与三阴性乳腺癌(TNBC)患者的不良临床结果有关。选择性靶向CDK7具有同时抑制活性转录和细胞周期进展的优势。Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that regulate transcription (CDKs 7-13 and 19-20) or cell cycle progression (CDKs 1-6 and 14-18). Almost all known CDKs are activated by (i) binding to cyclins and (ii) phosphorylating their T-loops by CDK-activating kinase (CAK). CAK is a trimeric complex composed of CDK7, cyclin H, and the RING finger protein MAT1, which uniquely engages CDK7 in the regulation of transcription and cell cycle. CDK7 is autophosphorylated at the Thr170 site of its T-loop and interacts with Activated by cyclin H binding. Other studies have shown that CDKs are also a class of kinases that play important regulatory roles in cancer cell proliferation and uncontrolled oncogenic transcription. CDK7 combines with cyclin H and MATI to form a trimeric cyclin-activated kinase (CDK), which exerts its function by participating in the regulation of other CDKs in the cell cycle by phosphorylation. These complexes control specific transitions between the two phases of the cell cycle, the M and S phases. CDK7 is involved in the regulation of temporal control and transcriptional activity of the cell cycle, and is involved in transcription initiation through the phosphorylation of the Rbpl subunit of RNA polymerase II (RNAPII). Uncontrolled cell proliferation and transcriptional dysregulation are hallmarks of cancer. Aberrant excess of CDK7 has been detected in multiple cancer types and is associated with aggressive clinicopathological features and poor prognosis. Studies have confirmed that CDK7 is amplified in hepatocellular carcinoma, gastric cancer, and colorectal cancer (CRC). For example, immunohistochemical analysis of gastric cancer specimens showed that CDK7 levels were elevated in 173 gastric cancer specimens and correlated with tumor grade. Similarly, CDK7 was significantly overexpressed in oral squamous cell carcinoma samples, indicating its utility as a prognostic marker; protein and mRNA levels of CDK7 were also upregulated in breast cancer tissue compared with adjacent normal breast tissue; High expression is associated with poor clinical outcomes in triple-negative breast cancer (TNBC) patients. Selective targeting of CDK7 has the advantage of simultaneously inhibiting active transcription and cell cycle progression.
因此，CDK7是治疗癌症，特别是侵袭性和难治性癌症的一个有希望的靶点。提供具有选择性的CDK7抑制剂，用于细胞增殖失调的治疗，如癌症，具有十分重要的意义。Therefore, CDK7 is a promising target for the treatment of cancer, especially aggressive and refractory cancers. It is of great significance to provide selective CDK7 inhibitors for the treatment of cell proliferation disorders, such as cancer.
本领域仍然需要对CDK7具有良好的抑制活性和选择性的化合物。There is still a need in the art for compounds with good inhibitory activity and selectivity for CDK7.
发明内容SUMMARY OF THE INVENTION
基于此，有必要提供一种嘧啶基衍生物。该嘧啶基衍生物可以作为具有选择性的CDK7抑制剂，解决多种癌症的有效治疗需求，尤其是转录失调的癌症。Based on this, it is necessary to provide a pyrimidinyl derivative. The pyrimidinyl derivatives can be used as selective CDK7 inhibitors to address the need for effective treatment of various cancers, especially cancers with dysregulated transcription.
具体技术方案如下：The specific technical solutions are as follows:
具有通式(I)所示结构的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药：Pyrimidyl derivatives having the structure represented by the general formula (I), their optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs:
Figure PCTCN2021120199-appb-000001
Figure PCTCN2021120199-appb-000001
其中，环A为4-6元饱和含氮杂环基、-C 1-C 3亚烷基、-4-6元饱和含氮杂环基或环Q； Wherein, ring A is a 4-6 membered saturated nitrogen-containing heterocyclic group, a -C 1 -C 3 alkylene group, a -4-6 membered saturated nitrogen-containing heterocyclic group or ring Q;
环A被1至3个R 0取代，R 0各自独立地选自-H、C 1-C 3烷基、羟基、卤素、-NH 2和-NH-(C 1-C 3烷基)； Ring A is substituted with 1 to 3 R 0 , each R 0 is independently selected from -H, C 1 -C 3 alkyl, hydroxy, halogen, -NH 2 and -NH-(C 1 -C 3 alkyl);
环Q选自如下基团：Ring Q is selected from the following groups:
Figure PCTCN2021120199-appb-000002
Figure PCTCN2021120199-appb-000002
R 1选自-H、卤素、氰基、C 1-C 3卤代烷基、3-5元饱和环烷基、C 1-C 3烷基、C 1-C 3烷氧基和C 1-C 3卤代烷氧基； R 1 is selected from -H, halogen, cyano, C 1 -C 3 haloalkyl, 3-5 membered saturated cycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkoxy;
R 2、R 3各自独立地选自-H、卤素、氰基、-C(O)NH(C 1-C 4烷基)、-C(O)N(C 1-C 4烷基) 2、5-6元杂芳基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基和C 1-C 4卤代烷氧基； R 2 and R 3 are each independently selected from -H, halogen, cyano, -C(O)NH(C 1 -C 4 alkyl), -C(O)N(C 1 -C 4 alkyl) 2 , 5-6 membered heteroaryl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl and C 1 -C 4 haloalkoxy;
X选自CH或N；X is selected from CH or N;
R 4选自如下基团： R 4 is selected from the following groups:
Figure PCTCN2021120199-appb-000003
Figure PCTCN2021120199-appb-000003
其中，R 5、R 6各自独立地选自-H、C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基、3-6元饱和环烷基、6-10元芳基、5-12元杂芳基、-(C 1-C 3烷基)-6-10元芳基和-(C 1-C 3烷基)-5-12元杂芳基； Wherein, R 5 and R 6 are each independently selected from -H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl , 3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl and -(C 1 -C 3 alkyl)-5-12 membered heteroaryl;
R 5和R 6不连接或连接成4-6元环； R 5 and R 6 are not connected or connected into a 4-6 membered ring;
条件是，当环A选自4-6元饱和含氮杂环基、-C 1-C 3亚烷基-4-6元饱和含氮杂环基时，R 4不为
Figure PCTCN2021120199-appb-000004
The condition is that when Ring A is selected from 4-6 membered saturated nitrogen-containing heterocyclic group, -C 1 -C 3 alkylene-4-6 membered saturated nitrogen-containing heterocyclic group, R 4 is not
Figure PCTCN2021120199-appb-000004
在另外一个具体的实施方案中，环A还可以选自其它环烷基、杂环基、芳基和杂芳基。In another specific embodiment, Ring A can also be selected from other cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.
作为优选地，环A选自如下基团中的一个，环A上的H被1至3个R 0取代：
Figure PCTCN2021120199-appb-000005
Figure PCTCN2021120199-appb-000006
Preferably, ring A is selected from one of the following groups, and the H on ring A is substituted by 1 to 3 R 0 :
Figure PCTCN2021120199-appb-000005
Figure PCTCN2021120199-appb-000006
在其中一个优选的实施例中，环A选自如下基团中的一个，环A上的H被1至3个R 0取代：
Figure PCTCN2021120199-appb-000007
In one of the preferred embodiments, ring A is selected from one of the following groups, and the H on ring A is substituted by 1 to 3 R 0 :
Figure PCTCN2021120199-appb-000007
在其中一个优选的实施例中，R 0各自独立地选自-H、甲基、乙基、羟基、-NH 2和-NH-CH 3。 In one of the preferred embodiments, each R 0 is independently selected from -H, methyl, ethyl, hydroxyl, -NH 2 and -NH-CH 3 .
在其中一个具体的实施方案中，R 1选自-H、卤素、氰基、C 1-C 3卤代烷基、3-5元饱和环烷基、C 1-C 3烷基、C 1-C 3烷氧基和C 1-C 3卤代烷氧基。 In one specific embodiment, R 1 is selected from -H, halogen, cyano, C 1 -C 3 haloalkyl, 3-5 membered saturated cycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkoxy.
在另外一个具体的实施方案中，R 1还可以选自其它烷基、环烷基、烷氧基和它们的卤代形式，也可以选自环烷基、杂环基、芳基、杂芳基和它们的卤代形式。 In another specific embodiment, R 1 can also be selected from other alkyl groups, cycloalkyl groups, alkoxy groups and their halogenated forms, and can also be selected from cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups bases and their halogenated forms.
作为优选地，R 1选自C 1-C 3卤代烷基。具体地，R 1为-CF 3。 Preferably, R 1 is selected from C 1 -C 3 haloalkyl. Specifically, R 1 is -CF 3 .
在其中一个具体的实施方案中，R 2、R 3各自独立地选自-H、卤素、氰基、-C(O)NH(C 1-C 4烷基)、-C(O)N(C 1-C 4烷基) 2、5-6元杂芳基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基和C 1-C 4卤代烷氧基。 In one specific embodiment, R 2 , R 3 are each independently selected from -H, halogen, cyano, -C(O)NH(C 1 -C 4 alkyl), -C(O)N( C 1 -C 4 alkyl) 2 , 5-6 membered heteroaryl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl and C 1 -C 4 haloalkoxy base.
在另外一个具体的实施方案中，R 2、R 3还可以各自独立地选自其它烷基、环烷基、烷氧基和它们的卤代形式，也可以选自环烷基、杂环基、芳基、杂芳基和它们的卤代形式。 In another specific embodiment, R 2 and R 3 can also be independently selected from other alkyl groups, cycloalkyl groups, alkoxy groups and their halogenated forms, and can also be selected from cycloalkyl groups, heterocyclic groups , aryl, heteroaryl and their halogenated forms.
作为优选地，R 2选自-H、卤素或氰基。具体地，R 2为-H、-F或-CN。 Preferably, R 2 is selected from -H, halogen or cyano. Specifically, R 2 is -H, -F or -CN.
作为优选地，R 3为-H。 Preferably, R 3 is -H.
在其中一个具体的实施方案中，X选自CH和N。作为优选地，X选自CH。In one specific embodiment, X is selected from CH and N. Preferably, X is selected from CH.
在另外一个具体的实施方案中，R 4选自如下基团： In another specific embodiment, R 4 is selected from the following groups:
Figure PCTCN2021120199-appb-000008
Figure PCTCN2021120199-appb-000008
其中，R 5、R 6各自独立地选自-H、C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基、3-6元饱和环烷基、6-10元芳基、5-12元杂芳基、-(C 1-C 3烷基)-6-10元芳基和-(C 1-C 3烷基)-5-12元杂芳基； Wherein, R 5 and R 6 are each independently selected from -H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl , 3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl and -(C 1 -C 3 alkyl)-5-12 membered heteroaryl;
R 5和R 6不连接或连接成4-6元环； R 5 and R 6 are not connected or connected into a 4-6 membered ring;
条件是，当环A选自4-6元饱和含氮杂环基、-C 1-C 3亚烷基-4-6元饱和含氮杂环基时，R 4 不为
Figure PCTCN2021120199-appb-000009
The condition is that when Ring A is selected from 4-6 membered saturated nitrogen-containing heterocyclic group, -C 1 -C 3 alkylene-4-6 membered saturated nitrogen-containing heterocyclic group, R 4 is not
Figure PCTCN2021120199-appb-000009
进一步地，在其中一个具体的实施方案中，R 4为
Figure PCTCN2021120199-appb-000010
Further, in one of the specific embodiments, R 4 is
Figure PCTCN2021120199-appb-000010
R 5、R 6各自独立地选自C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基和3-6元饱和环烷基； R 5 and R 6 are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl and 3-6 membered saturated cycloalkyl Saturated cycloalkyl;
R 5和R 6不连接或连接成4-6元环。 R 5 and R 6 are not linked or linked into a 4-6 membered ring.
更进一步地，R 5、R 6为甲基。 Furthermore, R 5 and R 6 are methyl groups.
在另一个具体的实施方案中，R 4为
Figure PCTCN2021120199-appb-000011
 In another specific embodiment, R4 is
Figure PCTCN2021120199-appb-000011
R 5、R 6各自独立地选自-H、C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基和3-6元饱和环烷基； R 5 and R 6 are each independently selected from -H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl and 3 -6-membered saturated cycloalkyl;
R 5和R 6不连接或连接成4-6元环。 R 5 and R 6 are not linked or linked into a 4-6 membered ring.
更进一步地，R 5为甲基；R 6为-H。 Further, R 5 is methyl; R 6 is -H.
在另一个具体的实施方案中，R 4为
Figure PCTCN2021120199-appb-000012
 In another specific embodiment, R4 is
Figure PCTCN2021120199-appb-000012
R 5、R 6各自独立地选自C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基、3-6元饱和环烷基、6-10元芳基、5-12元杂芳基、-(C 1-C 3烷基)-6-10元芳基和-(C 1-C 3烷基)-5-12元杂芳基； R 5 and R 6 are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered Saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl and -(C 1 -C 3 alkyl)-5 -12-membered heteroaryl;
环A选自环Q。Ring A is selected from ring Q.
更进一步地，R 5、R 6为甲基。 Furthermore, R 5 and R 6 are methyl groups.
在另一个具体的实施方案中，R 4为
Figure PCTCN2021120199-appb-000013
 In another specific embodiment, R4 is
Figure PCTCN2021120199-appb-000013
R 5选自C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基、3-6元饱和环烷基、6-10元芳基、5-12元杂芳基、-(C 1-C 3烷基)-6-10元芳基和-(C 1-C 3烷基)-5-12元杂芳基； R 5 is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl, 6 -10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl and -(C 1 -C 3 alkyl)-5-12 membered heteroaryl ;
环A选自环Q。Ring A is selected from ring Q.
更进一步地，R 5为甲基、
Figure PCTCN2021120199-appb-000014
丙基或苯基。 Further, R 5 is methyl,
Figure PCTCN2021120199-appb-000014
propyl or phenyl.
在另外一个具体的实施方案中，R 5、R 6还可以各自独立地选自其它烷基、环烷基、烷氧基和它们的卤代形式，也可以选自环烷基、杂环基、芳基、杂芳基和它们的卤代形式。R 5和R 6不连接或连接成其它环烷基、杂环基、芳基或杂芳基环系。 In another specific embodiment, R 5 and R 6 can also be independently selected from other alkyl groups, cycloalkyl groups, alkoxy groups and their halogenated forms, and can also be selected from cycloalkyl groups, heterocyclic groups , aryl, heteroaryl and their halogenated forms. R5 and R6 are not linked or linked to other cycloalkyl, heterocyclyl, aryl or heteroaryl ring systems.
在其中一个实施例中，R 4为
Figure PCTCN2021120199-appb-000015
In one embodiment, R 4 is
Figure PCTCN2021120199-appb-000015
R 5选自C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基、3-6元饱和环烷基、6-10元芳基、5-12元杂芳基、-(C 1-C 3烷基)-6-10元芳基或-(C 1-C 3烷基)-5-12元杂芳基。 R 5 is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl, 6 -10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl or -(C 1 -C 3 alkyl)-5-12 membered heteroaryl .
在其中一个实施例中，R 1为-CF 3。 In one of these embodiments, R 1 is -CF 3 .
在其中一个实施例中，R 2为-H、-F或-CN。 In one of these embodiments, R 2 is -H, -F or -CN.
在其中一个实施例中，R 3为-H。 In one of these embodiments, R3 is -H.
在其中一个实施例中，所述嘧啶基衍生物选自以下化合物中的一种：In one embodiment, the pyrimidinyl derivative is selected from one of the following compounds:
Figure PCTCN2021120199-appb-000016
Figure PCTCN2021120199-appb-000016
Figure PCTCN2021120199-appb-000017
Figure PCTCN2021120199-appb-000017
Figure PCTCN2021120199-appb-000018
Figure PCTCN2021120199-appb-000018
Figure PCTCN2021120199-appb-000019
Figure PCTCN2021120199-appb-000019
Figure PCTCN2021120199-appb-000020
Figure PCTCN2021120199-appb-000020
进一步，所述嘧啶基衍生物选自以下化合物中的一种：Further, the pyrimidinyl derivative is selected from one of the following compounds:
Figure PCTCN2021120199-appb-000021
Figure PCTCN2021120199-appb-000021
本发明还提供所述的嘧啶基衍生物的制备方法，包括如下步骤：The present invention also provides the preparation method of the described pyrimidine derivatives, comprising the following steps:
Figure PCTCN2021120199-appb-000022
Figure PCTCN2021120199-appb-000022
化合物a与化合物b进行取代反应，制备化合物c；Compound a is subjected to substitution reaction with compound b to prepare compound c;
化合物c与化合物d进行取代反应，制备化合物e；Compound c is subjected to substitution reaction with compound d to prepare compound e;
将基团w反应形成R 4； reacting group w to form R4 ;
其中，V各自独立地选自卤素；R 1、R 2、R 3、R 4、w、x和A如说明书中所定义。 wherein V is each independently selected from halogen; R 1 , R 2 , R 3 , R 4 , w, x and A are as defined in the specification.
本发明还提供一种药物组合物，所述药物组合物包含如上所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，以及药学上可接受的辅料、稀释剂或载体。The present invention also provides a pharmaceutical composition comprising the above-mentioned pyrimidine derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof derivatives or prodrugs, as well as pharmaceutically acceptable excipients, diluents or carriers.
在其中一个实施例中，所述药物组合物还包括联用药剂；所述联用药剂选自抗增殖剂、抗癌剂、免疫抑制剂和疼痛缓解剂中的至少一种。In one embodiment, the pharmaceutical composition further comprises a combined agent; the combined agent is selected from at least one of an anti-proliferative agent, an anti-cancer agent, an immunosuppressant and a pain relief agent.
本发明还提供如上所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药或如上所述的药物组合物在制备用于预防或治疗与异常的CDK7活性相关的癌症、良性赘生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病或感染性疾病的药物中的用途。The present invention also provides the pyrimidinyl derivatives as described above, their optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs or drugs as described above Use of the composition in the manufacture of a medicament for preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity.
在其中一个实施例中，本发明涉及嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药或包含其的药物组合物，其用于预防或治疗与异常的CDK7活性相关的癌症、良性赘生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病或感染性疾病。In one of these embodiments, the present invention relates to pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof, or containing the same A pharmaceutical composition for preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity.
其中一个实施例中，本发明涉及一种预防或治疗与异常的CDK7活性相关的癌症、良性赘生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病或感染性疾病的方法，包括向需要的受试者给药所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药或包含其的药物组合物。在其中一个实施例中，所述与异常的CDK7活性相关的癌症选自乳腺癌、卵巢癌、直肠癌、肝癌、肺癌、胃癌、脑癌、胆管癌、***、子宫内膜癌、头颈癌、膀胱癌、骨癌、肠癌、肾癌、喉癌、淋巴瘤、白血病、慢性淋巴细胞性白血病(CLL)、急性成淋巴细胞性白血病(ALL)、T细胞急性成淋巴细胞性白血病(T-ALL)、慢性骨髓性白血病(CML)、急性骨髓性白血病(AML)、多发性骨髓瘤、黑色素瘤、间皮瘤、骨髓瘤、神经内分泌癌、食管癌、***癌、***癌、皮肤癌、软组织肉瘤癌、脊髓癌、睾丸癌、甲状腺癌和子宫癌中的一种或几种。In one embodiment, the present invention relates to a method of preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity, Including the administration of described pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof to a subject in need thereof or comprising its pharmaceutical composition. In one embodiment, the cancer associated with aberrant CDK7 activity is selected from the group consisting of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, stomach cancer, brain cancer, bile duct cancer, cervical cancer, endometrial cancer, head and neck cancer , bladder cancer, bone cancer, bowel cancer, kidney cancer, throat cancer, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T -ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer , one or more of soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer and uterine cancer.
与现有技术相比较，本发明具有如下有益效果中的一种或多种：Compared with the prior art, the present invention has one or more of the following beneficial effects:
本发明提供了一种嘧啶基衍生物，其可以作为新型的选择性CDK7抑制剂，通过抑制CDK7的异常活性来诱导细胞凋亡和/或抑制转录，相对于其它细胞周期蛋白依赖性激酶亚型具有较高的选择性和较高的激酶抑制活性，用来治疗患有增殖性疾病的受试者，解决多种癌症的有效治疗需求，尤其是转录失调的癌症。经试验研究表明，本发明化合物对CDK7具有良好的抑制活性和选择性。The present invention provides a pyrimidine-based derivative, which can be used as a novel selective CDK7 inhibitor to induce apoptosis and/or inhibit transcription by inhibiting the abnormal activity of CDK7, relative to other cyclin-dependent kinase isoforms With high selectivity and high kinase inhibitory activity, it is used to treat subjects with proliferative diseases and address the need for effective treatment of various cancers, especially cancers with dysregulated transcription. Experimental studies show that the compounds of the present invention have good inhibitory activity and selectivity to CDK7.
具体实施方式detailed description
以下结合具体实施例对本发明的嘧啶基衍生物、其制备方法及其应用作进一步详细的说明。本发 明可以以许多不同的形式来实现，并不限于本文所描述的实施方式。相反地，提供这些实施方式的目的是使对本发明公开内容理解更加透彻全面。The pyrimidinyl derivatives of the present invention, their preparation methods and their applications will be described in further detail below with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that a thorough and complete understanding of the present disclosure is provided.
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施方案的目的，不是旨在于限制本发明。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terms used herein in the description of the present invention are for the purpose of describing specific embodiments only, and are not intended to limit the present invention.
术语“光学异构体”如果没有特殊说明，应包括所有异构体中的一种或它们的混合物，例如，双键、环中的几何异构体(E型、Z型、顺式的(cis)、反式的(trans))，直链烷基和支链烷基中由存在不对称碳原子等而产生的光学异构体(R型、S型)及它们任意比例的混合物。外消旋混合物以及所有的由互变异构体产生的异构体均包括在本发明中。另外，每种化合物结构均可以为具有相同分子式的不同立体异构体，其中的立体异构体还包括对映异构体和非对映异构体，对映异构体即为光学异构体，非对映异构体为不成手性对映的立体异构体，与本发明化合物具有相同分子式的不同异构体也在本发明的保护范围内。The term "optical isomer", unless otherwise specified, shall include one of all isomers or their mixtures, for example, double bonds, geometric isomers in rings (E, Z, cis ( cis), trans (trans)), optical isomers (R-type, S-type) produced by the presence of asymmetric carbon atoms in straight-chain alkyl groups and branched-chain alkyl groups, and mixtures thereof in any ratio. Racemic mixtures and all isomers resulting from tautomers are included in the present invention. In addition, each compound structure can be different stereoisomers with the same molecular formula, among which stereoisomers also include enantiomers and diastereomers, and enantiomers are optical isomers Diastereomers are stereoisomers of achiral enantiomers, and different isomers with the same molecular formula as the compounds of the present invention are also within the protection scope of the present invention.
术语“药学上可接受的盐”是指化合物可以通过传统的方法转化为相应的盐，其在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。该盐可以为化合物与无机和/或有机酸和/或与无机和/或碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将本发明的化合物或其立体异构体或溶剂合物与一定量的酸或碱适当混合而得到的。这些盐可能在溶液中形成沉淀，然后以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷却干燥制得。具体地，盐优选为水溶性的药学上可接受的无毒酸加成盐，实例为氨基与无机酸(如盐酸、氢溴酸、磷酸、硫酸以及高氯酸)或与有机酸(如乙酸、草酸、顺丁烯二酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐，或通过使用本领域中传统的其他方法(例如离子交换法)形成的盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘化物、2-羟基-乙烷磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对-甲苯磺酸盐、十一烷酸盐、戊酸盐等。适当时，另外的药学上可接受的盐还可以包括衍生自适当碱的盐，包括碱金属盐、碱土金属盐以及铵盐。代表性碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐等。适当时，另外的药学上可接受的盐包括使用如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根以及芳基磺酸根等平衡离子形成的无毒铵、季铵以及胺阳离子。The term "pharmaceutically acceptable salts" refers to compounds that can be converted by conventional methods into the corresponding salts which are chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and which are physiologically compatible with the receptor . The salts may be acid and/or base salts of the compound with inorganic and/or organic acids and/or with inorganic and/or bases, including zwitterionic salts (inner salts), and also quaternary ammonium salts, such as alkanes base ammonium salt. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by appropriately mixing the compound of the present invention or its stereoisomer or solvate with a certain amount of acid or base. These salts may form precipitates in solution and then be collected by filtration, or recovered after evaporation of the solvent, or by reaction in an aqueous medium followed by cooling and drying. Specifically, the salt is preferably a water-soluble pharmaceutically acceptable non-toxic acid addition salt, exemplified by an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with an organic acid (such as acetic acid) , oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or by using other methods conventional in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonic acid Salt, Glycerophosphate, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobate, Lactate, Laurate, Lauryl sulfonate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, bisulfate Hynaphate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, Tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Additional pharmaceutically acceptable salts may also include salts derived from suitable bases, including alkali metal, alkaline earth metal, and ammonium salts, as appropriate. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include non-toxic formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate. Ammonium, quaternary ammonium and amine cations.
术语“溶剂合物”也可以称为“溶剂化合物”、“溶剂化物”，指的是含有溶剂的化合物，其中溶剂分子可以以包括配位键、共价键、范德华力、离子键、氢键等方式与化合物分子相结合。The term "solvate" may also be referred to as "solvate", "solvate", and refers to a compound containing a solvent, wherein the solvent molecule can include coordinate bonds, covalent bonds, van der Waals forces, ionic bonds, hydrogen bonds and other ways to combine with compound molecules.
术语“前药”是指当被施用至生物体时由于自发化学反应、酶催化的化学反应、光解和/或代谢化学反应而产生药物，即活性成分的任何化合物。前药因此是治疗活性化合物的共价改性的类似物或潜在形式。合适的实例包括但不限于：化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。The term "prodrug" refers to any compound that, when administered to an organism, produces a drug, ie, an active ingredient, as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and/or metabolic chemical reactions. A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound. Suitable examples include, but are not limited to: carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compounds, carbamates, azo compounds, phosphoramides, glucosides of compounds , ether, acetal and other forms.
术语“阻转异构体”是一类立体异构体，其中两种异构体的原子空间排列不同。阻转异构体由于大基团围绕中心键的旋转受阻引起的受限制的旋转而存在。The term "atropisomer" is a class of stereoisomers in which the atoms of the two isomers are arranged differently in space. Atropisomers exist due to restricted rotation caused by hindered rotation of the large group about the central bond.
术语“同位素标记的化合物”等同于本发明所述的化合物，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。 The term "isotopically labeled compound" is equivalent to a compound described herein except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H , 13C , 11C , 14C , 15N , 18 , respectively O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs containing the above isotopes and/or other isotopes of other atoms are within the scope of the present invention.
术语“烷基”是指包含伯(正)碳原子、或仲碳原子、或叔碳原子、或季碳原子、或其组合的饱和烃基。包含该术语的短语，例如，“C 1-C 3烷基”是指包含1～3个碳原子的烷基，每次出现时，可以互相独立地为C 1烷基、C 2烷基、C 3烷基。优选的烷基为C 1-C 6烷基、C 1-C 5烷基、C 1-C 4烷基和C 1-C 3烷基。合适的实例包括但不限于：甲基(Me、-CH 3)、乙基(Et、-CH 2CH 3)、1-丙基(n-Pr、n-丙基、-CH 2CH 2CH 3)、2-丙基(i-Pr、i-丙基、-CH(CH 3) 2)。 The term "alkyl" refers to a saturated hydrocarbon group containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. Phrases containing this term, for example, "C 1 -C 3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms, each occurrence of which may independently be a C 1 alkyl, C 2 alkyl, C3 alkyl. Preferred alkyl groups are C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl and C 1 -C 3 alkyl. Suitable examples include, but are not limited to: methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n - propyl, -CH2CH2CH ) 3 ), 2-propyl (i-Pr, i-propyl, -CH( CH3 ) 2 ).
术语“亚烷基”是指是指除去烷基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C 1-C 4亚烷基、C 2-C 4亚烷基和C 1-C 3亚烷基是优选的。 The term "alkylene" refers to a divalent group formed by removal of another hydrogen from an alkyl group, and may be substituted or unsubstituted. In some embodiments, C1 - C4 alkylene, C2 - C4 alkylene, and C1 - C3 alkylene are preferred.
术语“卤代烷基”是指上述烷基，其被一个或多个卤素基团取代。The term "haloalkyl" refers to the aforementioned alkyl groups, which are substituted with one or more halogen groups.
术语“羟基”是指-OH。The term "hydroxy" refers to -OH.
术语“氰基”是指-CN。The term "cyano" refers to -CN.
术语“饱和环烷基”是指包含环碳原子的非芳香族环状烃基，可以为单环烷基或桥环烷基。包含该术语的短语，例如，“4-7元饱和环烷基”是指包含4～7个环碳原子的环烷基，每次出现时，可以互相独立地为C 4环烷基、C 5环烷基、C 6环烷基、C 7环烷基。优选的饱和环烷基为3-8元环烷基、3-7元环烷基、3-6元环烷基和5-6元环烷基。合适的实例包括但不限于：环丙基、环丁基、环戊基、环己基和环庚基。相应地，术语“饱和含氮杂环基”是指，环系中至少一个环碳原子被N取代的非芳香族环状烃基；术语“饱和含氮螺环基”是指环系为螺环结构且环系中至少一个环碳原子被N取代的饱和含氮杂环基。优选的饱和含氮杂环基为3-8元含氮杂环基、3-6元含氮杂环基或4-6元含氮杂环基。 The term "saturated cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group containing ring carbon atoms, which may be monocyclic or bridged. Phrases containing this term, for example, "4-7 membered saturated cycloalkyl" refers to a cycloalkyl group containing 4 to 7 ring carbon atoms, each occurrence of which may independently be C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl. Preferred saturated cycloalkyls are 3-8 membered cycloalkyl, 3-7 membered cycloalkyl, 3-6 membered cycloalkyl and 5-6 membered cycloalkyl. Suitable examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Correspondingly, the term "saturated nitrogen-containing heterocyclic group" refers to a non-aromatic cyclic hydrocarbon group in which at least one ring carbon atom in the ring system is substituted by N; the term "saturated nitrogen-containing spirocyclic group" refers to the ring system as a spiro ring structure A saturated nitrogen-containing heterocyclic group in which at least one ring carbon atom in the ring system is substituted by N. Preferred saturated nitrogen-containing heterocyclic groups are 3-8 membered nitrogen-containing heterocyclic groups, 3-6 membered nitrogen-containing heterocyclic groups or 4-6 membered nitrogen-containing heterocyclic groups.
术语“卤素”是指-F、-Cl、-Br或-I。相应地，“卤代”是指以-F、-Cl、-Br或-I替代相应基团中的-H。The term "halogen" refers to -F, -Cl, -Br or -I. Correspondingly, "halo" refers to the substitution of -F, -Cl, -Br or -I for -H in the corresponding group.
术语“烷氧基”是指具有-O-烷基的基团，即如上所定义的烷基经由氧原子连接至母核结构。包含该术语的短语，例如，“C 1-C 3烷氧基”是指烷基部分包含1～3个碳原子。 The term "alkoxy" refers to a group having an -O-alkyl group, ie an alkyl group as defined above is attached to the core structure via an oxygen atom. Phrases containing this term, for example, " C1 -C3alkoxy" means that the alkyl moiety contains 1 to 3 carbon atoms.
术语“芳基”是指在芳香环化合物的基础上除去一个氢原子衍生的芳族烃基，可以为单环芳基、稠环芳基或多环芳基。对于多环状基团，至少一个是芳族环系。包含该术语的短语，例如，“5-6元芳基”是指芳香环系包含5-6个环原子的基团。优选的芳基为6-10元芳基，作为实例可以选自苯基和萘基。The term "aryl" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing one hydrogen atom, which may be a single-ring aryl group, a condensed-ring aryl group or a polycyclic aryl group. For polycyclic groups, at least one is an aromatic ring system. Phrases containing this term, eg, "5-6 membered aryl" refer to groups whose aromatic ring systems contain 5-6 ring atoms. Preferred aryl groups are 6-10 membered aryl groups, which can be selected from phenyl and naphthyl as examples.
术语“杂芳基”是指含有杂原子的芳基，可为单环或稠合环状基团，并且所述杂原子独立地选自N、O和S。杂芳基优选为5-12元杂芳基，更优选为5-6元杂芳基。杂芳基的实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、***基、四氢吡咯基。在某一方案中，杂芳基典型地为含1个或多个独立选自N、O和S的杂原子的5-6元单环杂芳基。除非另外说明，“5-元杂芳基”为包含一个杂原子的示例性5-元杂芳基基团，实例包括但不限于，吡咯基、呋喃基以及噻吩基；包含两个杂原子的示例性5-元杂芳基基团包括但不限于，咪唑基、吡唑基、噁唑啉基、异噁唑啉基、噻唑基以及异噻唑基；包含三个杂原子的示例性5-元杂芳基基团包括但不限于，***基、噁二唑基以及噻二唑基；包含四个杂原子的示例性5-元杂芳基基团包括但不限于，四唑基。The term "heteroaryl" refers to an aryl group containing a heteroatom, which may be a monocyclic or fused cyclic group, and the heteroatom is independently selected from N, O, and S. The heteroaryl group is preferably a 5-12 membered heteroaryl group, more preferably a 5-6 membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinoline base, isoquinolyl, triazolyl, tetrahydropyrrolyl. In one embodiment, heteroaryl is typically a 5-6 membered monocyclic heteroaryl containing 1 or more heteroatoms independently selected from N, O and S. Unless otherwise specified, "5-membered heteroaryl" is an exemplary 5-membered heteroaryl group containing one heteroatom, examples including, but not limited to, pyrrolyl, furanyl, and thienyl; two heteroatoms containing Exemplary 5-membered heteroaryl groups include, but are not limited to, imidazolyl, pyrazolyl, oxazolinyl, isoxazolinyl, thiazolyl, and isothiazolyl; exemplary 5-membered Membered heteroaryl groups include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl; exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
术语“杂环基”是指构成环的一个或多个原子是杂原子且其余为碳的非芳香环状基团，所述的杂原子包括而不限于氮原子、氧原子和硫原子等。优选的杂环基为3-10元饱和杂环基。除非本说明书中另外特别指明，否则杂环基可以是单环的(“单环的杂环基”)，或者是双环、三环或更多环的杂环状体系，其可包括并环的(稠合的)、桥联的(桥环的)或螺的环***(例如二环***(“二环的杂环烷基”)。杂环烷基二环的环***可以在一个或两个环中包括一个或多个杂原子；并且是饱和的。示例性3-元杂环基基团包括但不限于，氮杂环丙基、环氧乙烷基以及硫杂环丙烷基，或者其立体异构体；示例性4-元杂环基基团包括但不限于，氮杂环丁烷基，环氧丙烷基，硫杂环丁烷基，或者其同分异构体和立体异构体；示例性5-元杂环基基团包括但不限于，四氢呋喃基，四氢噻吩基，吡咯烷基，噻唑烷基，异噻唑烷基，噁唑烷基，异噁唑烷基，咪唑烷基，吡唑烷基，二氧戊环基，氧杂硫呋喃基，二硫呋喃基，或者其同分异构体和立体异构体。示例性6-元杂环基基团包括但不限于，哌啶基，四氢吡喃基，硫化环戊烷基，吗啉基，硫代吗啉基，二噻烷基，二噁烷基，哌嗪基，三嗪烷基，或者其同分异构体和立体异构体；示例性7-元杂环基基团包括但不限于，氮杂环庚烷基，氧杂环庚烷基，硫杂环庚烷基，以及二氮杂环庚基，或者其同分异构体和立体异构体。在某一方案中，典型的含1个或多个独立选自N、O和S的杂原子的5-6元单环杂环基。方案中，“杂环烷基”为4-6元杂环烷基，其中杂原子选自N、O和S中的一种或多种，杂原子数为1、2或3个。The term "heterocyclyl" refers to a non-aromatic cyclic group in which one or more atoms constituting the ring are heteroatoms including, but not limited to, nitrogen, oxygen, sulfur, and the like, and the remainder is carbon. Preferred heterocyclyl groups are 3-10 membered saturated heterocyclyl groups. Unless specifically stated otherwise in this specification, a heterocyclyl group may be monocyclic ("monocyclic heterocyclyl"), or a bicyclic, tricyclic or more cyclic heterocyclic system, which may include cycloheterocyclic (fused), bridged (bridged ring), or spiro ring systems (eg, bicyclic ring systems ("bicyclic heterocycloalkyl"). Heterocycloalkyl bicyclic ring systems may be in one or two and is saturated. Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridyl, oxiranyl, and thiirane, or Stereoisomers thereof; exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, propylene oxide, thietane, or isomers and stereoisomers thereof Constructs; exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, Imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiofuranyl, dithiofuranyl, or isomers and stereoisomers thereof. Exemplary 6-membered heterocyclyl groups include but not limited to, piperidinyl, tetrahydropyranyl, cyclopentanyl sulfide, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or Isomers and stereoisomers thereof; exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, and dicycloheptyl Azacycloheptyl, or its isomers and stereoisomers. In one embodiment, typically a 5-6 membered unit containing 1 or more heteroatoms independently selected from N, O, and S Cyclic heterocyclyl. In the scheme, "heterocycloalkyl" is a 4-6 membered heterocycloalkyl, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列 举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。在一些具体的结构中，当烷基基团清楚地表示为连接基团时，则该烷基基团代表连接的亚烷基基团，例如，基团“-C 1-C 3卤代烷基”中的烷基应当理解为亚烷基。 In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the linking An alkylene group or an arylene group. In some specific structures, when an alkyl group is clearly represented as a linking group, then the alkyl group represents the alkylene group to which it is attached, eg, the group " -C1 - C3 haloalkyl" Alkyl in should be understood to mean alkylene.
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义，则以本文定义为准。应该理解，在本发明中使用的单数形式，如“一种”，包括复数指代，除非另有规定。Unless otherwise defined, all technical and scientific terms used herein have the standard meaning in the art to which the claimed subject matter belongs. If more than one definition exists for a term, the definitions herein prevail. It should be understood that singular forms such as "a" used in the present invention include plural referents unless stated otherwise.
此外，术语“包括”是开放性限定并非封闭式，即包括本发明所指明的内容，但并不排除其他方面的内容。In addition, the term "comprising" is an open definition rather than a closed one, that is, it includes the contents specified in the present invention, but does not exclude other aspects.
除非另有说明，本发明采用质谱、核磁等传统方法鉴定化合物，各步骤和条件可参照本领域常规的操作步骤和条件。Unless otherwise specified, the present invention adopts traditional methods such as mass spectrometry and nuclear magnetic resonance to identify compounds, and each step and condition can refer to the routine operation steps and conditions in the art.
除非另有指明，本发明采用分析化学、有机合成化学和光学的标准命名及标准实验室步骤和技术。在某些情况下，标准技术被用于化学合成、化学分析、发光器件性能检测。Unless otherwise indicated, the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“…独立地”应做广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“…独立地”既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响；也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless clearly stated otherwise, the description mode "...independently" used in the present invention should be understood in a broad sense, meaning that the described individuals are independent of each other and can independently are the same or different specific groups. In more detail, the description mode "...independently" can either mean that in different groups, the specific options expressed between the same symbols do not affect each other; it can also mean that in the same group, between the same symbols The specific options expressed do not affect each other.
本领域技术人员可以理解，根据本领域中使用的惯例，本申请描述基团的结构式中所使用的
Figure PCTCN2021120199-appb-000023
或“*”是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。 It can be understood by those skilled in the art that, according to the conventions used in the art, the formula used in the structural formula of the group described in this application
Figure PCTCN2021120199-appb-000023
Or "*" means that the corresponding group is connected to other fragments and groups in the compound through this site. On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明涉及如下实施方案。The present invention relates to the following embodiments.
在一个实施方案中，本发明涉及具有通式(I)所示结构的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药：In one embodiment, the present invention relates to pyrimidinyl derivatives having the structure represented by general formula (I), their optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled Derivatives or Prodrugs:
Figure PCTCN2021120199-appb-000024
Figure PCTCN2021120199-appb-000024
其中，环A为4-6元饱和含氮杂环基、-C 1-C 3亚烷基-4-6元饱和含氮杂环基或环Q；环A被1至3个R 0取代，R 0各自独立地选自-H、C 1-C 3烷基、羟基、卤素、-NH 2或-NH-(C 1-C 3烷基)； Wherein, ring A is a 4-6 membered saturated nitrogen-containing heterocyclic group, -C 1 -C 3 alkylene-4-6 membered saturated nitrogen-containing heterocyclic group or ring Q; ring A is substituted by 1 to 3 R 0 , R 0 is independently selected from -H, C 1 -C 3 alkyl, hydroxyl, halogen, -NH 2 or -NH-(C 1 -C 3 alkyl);
环Q选自如下基团：Ring Q is selected from the following groups:
Figure PCTCN2021120199-appb-000025
Figure PCTCN2021120199-appb-000025
R 1选自-H、卤素、氰基、C 1-C 3卤代烷基、3-5元饱和环烷基、C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3卤代烷氧基； R 1 is selected from -H, halogen, cyano, C 1 -C 3 haloalkyl, 3-5 membered saturated cycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 haloalkoxy;
R 2、R 3各自独立地选自-H、卤素、氰基、-C(O)NH(C 1-C 4烷基)、-C(O)N(C 1-C 4烷基) 2、5-6元杂芳基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基或C 1-C 4卤代烷氧基； R 2 and R 3 are each independently selected from -H, halogen, cyano, -C(O)NH(C 1 -C 4 alkyl), -C(O)N(C 1 -C 4 alkyl) 2 , 5-6 membered heteroaryl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy;
X选自CH或N；X is selected from CH or N;
R 4选自如下基团： R 4 is selected from the following groups:
Figure PCTCN2021120199-appb-000026
Figure PCTCN2021120199-appb-000026
其中，R 5、R 6各自独立地选自-H、C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基、3-6元饱和环烷基、6-10元芳基、5-12元杂芳基、-(C 1-C 3烷基)-6-10元芳基或-(C 1-C 3烷基)-5-12元杂芳基； Wherein, R 5 and R 6 are each independently selected from -H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl , 3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl or -(C 1 -C 3 alkyl)-5-12 membered heteroaryl;
R 5和R 6不连接或连接成4-6元环； R 5 and R 6 are not connected or connected into a 4-6 membered ring;
条件是，当环A选自4-6元饱和含氮杂环基、-C 1-C 3亚烷基-4-6元饱和含氮杂环基时，R 4不为
Figure PCTCN2021120199-appb-000027
Figure PCTCN2021120199-appb-000028
The condition is that when Ring A is selected from 4-6 membered saturated nitrogen-containing heterocyclic group, -C 1 -C 3 alkylene-4-6 membered saturated nitrogen-containing heterocyclic group, R 4 is not
Figure PCTCN2021120199-appb-000027
Figure PCTCN2021120199-appb-000028
在一个实施方案中，本发明涉及上述具有通式(I)所示结构的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof Derivatives or prodrugs characterized by,
R 4为
Figure PCTCN2021120199-appb-000029
 R4 is
Figure PCTCN2021120199-appb-000029
R 5、R 6各自独立地选自C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基或3-6元饱和环烷基； R 5 and R 6 are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl or 3-6 membered saturated cycloalkyl Saturated cycloalkyl;
R 5和R 6不连接或连接成4-6元环。 R 5 and R 6 are not linked or linked into a 4-6 membered ring.
在一个实施方案中，本发明涉及上述具有通式(I)所示结构的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，R 4为
Figure PCTCN2021120199-appb-000030
In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof The derivative or prodrug, characterized in that R 4 is
Figure PCTCN2021120199-appb-000030
R 5、R 6各自独立地选自-H、C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基或3-6元饱和环烷基； R 5 and R 6 are each independently selected from -H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl or 3 -6-membered saturated cycloalkyl;
R 5和R 6不连接或连接成4-6元环。 R 5 and R 6 are not linked or linked into a 4-6 membered ring.
在一个实施方案中，本发明涉及上述具有通式(I)所示结构的嘧啶基衍生物、其光学异构体、药学 上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof Derivatives or prodrugs characterized by,
R 4为
Figure PCTCN2021120199-appb-000031
 R4 is
Figure PCTCN2021120199-appb-000031
R 5选自C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基、3-6元饱和环烷基、6-10元芳基、5-12元杂芳基、-(C 1-C 3烷基)-6-10元芳基或-(C 1-C 3烷基)-5-12元杂芳基。 R 5 is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl, 6 -10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl or -(C 1 -C 3 alkyl)-5-12 membered heteroaryl .
在一个实施方案中，本发明涉及上述具有通式(I)所示结构的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，R 4为
Figure PCTCN2021120199-appb-000032
In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof The derivative or prodrug, characterized in that R 4 is
Figure PCTCN2021120199-appb-000032
R 5、R 6各自独立地选自C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基、3-6元饱和环烷基、6-10元芳基、5-12元杂芳基、-(C 1-C 3烷基)-6-10元芳基或-(C 1-C 3烷基)-5-12元杂芳基； R 5 and R 6 are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered Saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl or -(C 1 -C 3 alkyl)-5 -12-membered heteroaryl;
环A选自环Q。Ring A is selected from ring Q.
在一个实施方案中，本发明涉及上述具有通式(I)所示结构的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof Derivatives or prodrugs characterized by,
R 4为
Figure PCTCN2021120199-appb-000033
 R4 is
Figure PCTCN2021120199-appb-000033
R 5选自C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基、3-6元饱和环烷基、6-10元芳基、5-12元杂芳基、-(C 1-C 3烷基)-6-10元芳基或-(C 1-C 3烷基)-5-12元杂芳基； R 5 is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl, 6 -10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl or -(C 1 -C 3 alkyl)-5-12 membered heteroaryl ;
环A选自环Q。Ring A is selected from ring Q.
在一个实施方案中，本发明涉及上述具有通式(I)所示结构的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，R 1为-CF 3。 In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof The derivative or prodrug, characterized in that R 1 is -CF 3 .
在一个实施方案中，本发明涉及上述具有通式(I)所示结构的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，R 2为-H、-F或-CN。 In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof The derivative or prodrug, characterized in that R 2 is -H, -F or -CN.
在一个实施方案中，本发明涉及上述具有通式(I)所示结构的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，R 3为-H。 In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof The derivative or prodrug, characterized in that R 3 is -H.
在一个实施方案中，本发明涉及上述具有通式(I)所示结构的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，环A选自如下基团中的一个且环A上的H被1至3个R 0取代： In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof The derivative or prodrug, characterized in that ring A is selected from one of the following groups and the H on ring A is substituted by 1 to 3 R 0 :
Figure PCTCN2021120199-appb-000034
Figure PCTCN2021120199-appb-000034
在一个实施方案中，本发明涉及上述具有通式(I)所示结构的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，环A选自如下基 团中的一个且环A上的H被1至3个R 0取代： In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof The derivative or prodrug, characterized in that ring A is selected from one of the following groups and the H on ring A is substituted by 1 to 3 R 0 :
Figure PCTCN2021120199-appb-000035
Figure PCTCN2021120199-appb-000035
在一个实施方案中，本发明涉及上述具有通式(I)所示结构的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，R 0各自独立地选自-H、甲基、乙基、羟基、-NH 2和-NH-CH 3。 In one embodiment, the present invention relates to the above-mentioned pyrimidinyl derivatives having the structure represented by the general formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopic labels thereof The derivative or prodrug of , wherein each R 0 is independently selected from -H, methyl, ethyl, hydroxyl, -NH 2 and -NH-CH 3 .
在一个实施方案中，本发明涉及具有通式(a)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药：In one embodiment, the present invention relates to compounds of general formula (a), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof:
Figure PCTCN2021120199-appb-000036
Figure PCTCN2021120199-appb-000036
其中：in:
R 7各自独立地选自-H、卤素、氰基、-NR’R”、-OR’、C 1-6烷基、卤代C 1-6烷基、
Figure PCTCN2021120199-appb-000037
和-P(＝O)R 5R 6； R 7 is each independently selected from -H, halogen, cyano, -NR'R", -OR', C 1-6 alkyl, halogenated C 1-6 alkyl,
Figure PCTCN2021120199-appb-000037
and -P(=O)R 5 R 6 ;
R 5和R 6各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R 5 and R 6 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
R 5’选自-H、C 1-6烷基和卤代C 1-6烷基； R 5' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
R 6’选自-H、氰基、C 1-6烷基和卤代C 1-6烷基； R 6' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
R 8选自-H、卤素、氰基、-OR’、C 1-6烷基和卤代C 1-6烷基； R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
R 9和R 10各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R 9 and R 10 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
R 11选自-H、-OR’、-NR’R”、C 1-6烷基、卤代C 1-6烷基、-NHC(O)C 1-6烷基、-NHC(O)OC 1-6烷基、-NHC(O)NHC 1-6烷基和-NHC(O)N(C 1-6烷基) 2；其中所述C 1-6烷基任选被1-3个选自羟基、巯基、-OR’和-NR’R”的取代基取代； R 11 is selected from -H, -OR', -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl, -NHC(O)C 1-6 alkyl, -NHC(O) OC 1-6 alkyl, -NHC(O)NHC 1-6 alkyl and -NHC(O)N(C 1-6 alkyl) 2 ; wherein the C 1-6 alkyl is optionally replaced by 1-3 substituted with a substituent selected from hydroxyl, thiol, -OR' and -NR'R";
R’和R”各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
m1、m2、n1和n2各自独立地为0、1或2；m1, m2, n1, and n2 are each independently 0, 1, or 2;
p选自0、1、2、3、4、5和6；p is selected from 0, 1, 2, 3, 4, 5 and 6;
t选自1、2、3和4；t is selected from 1, 2, 3 and 4;
条件是R 7中至少一个为-P(＝O)R 5R 6。 Provided that at least one of R 7 is -P(=O)R 5 R 6 .
在一个实施方案中，本发明涉及上述具有通式(a)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-described compounds of formula (a), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
R 7各自独立地选自-H、卤素、氰基、C 1-4烷基、卤代C 1-4烷基和-P(＝O)R 5R 6； R 7 is each independently selected from -H, halogen, cyano, C 1-4 alkyl, haloC 1-4 alkyl and -P(=O)R 5 R 6 ;
R 5和R 6各自独立地选自-H和C 1-4烷基； R 5 and R 6 are each independently selected from -H and C 1-4 alkyl;
R 8选自卤素、氰基和卤代C 1-4烷基； R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl;
R 9和R 10各自独立地选自-H和C 1-4烷基； R 9 and R 10 are each independently selected from -H and C 1-4 alkyl;
R 11选自-H、-NR’R”、-NHC(O)OC 1-4烷基、-NHC(O)NHC 1-4烷基和-NHC(O)N(C 1-4烷基) 2；其中所述C 1-4烷基任选被1-3个选自羟基、巯基和-NR’R”的取代基取代； R 11 is selected from -H, -NR'R", -NHC(O)OC 1-4 alkyl, -NHC(O)NHC 1-4 alkyl and -NHC(O)N(C 1-4 alkyl ) 2 ; wherein the C 1-4 alkyl is optionally substituted by 1-3 substituents selected from hydroxyl, mercapto and -NR'R";
R’和R”各自独立地选自-H、C 1-4烷基和卤代C 1-4烷基； R' and R" are each independently selected from -H, C 1-4 alkyl and haloC 1-4 alkyl;
m1、m2、n1和n2各自独立地为0、1或2；m1, m2, n1, and n2 are each independently 0, 1, or 2;
p选自0、1和2；p is selected from 0, 1 and 2;
t选自1和2；t is selected from 1 and 2;
条件是R 7中至少一个为-P(＝O)R 5R 6。 Provided that at least one of R 7 is -P(=O)R 5 R 6 .
在一个实施方案中，本发明涉及上述具有通式(a)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-described compounds of formula (a), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
R 7各自独立地选自卤素、氰基和-P(＝O)R 5R 6； R 7 is each independently selected from halogen, cyano and -P(=O)R 5 R 6 ;
R 5和R 6各自独立地为C 1-4烷基； R 5 and R 6 are each independently C 1-4 alkyl;
R 8为卤代C 1-4烷基； R 8 is halogenated C 1-4 alkyl;
R 9和R 10各自独立地为-H； R 9 and R 10 are each independently -H;
R 11选自H和-NR’R”； R 11 is selected from H and -NR'R";
R’和R”各自独立地选自-H和C 1-4烷基； R' and R" are each independently selected from -H and C 1-4 alkyl;
m1、m2、n1和n2各自独立地为1或2；m1, m2, n1 and n2 are each independently 1 or 2;
p为0；p is 0;
t选自1和2；t is selected from 1 and 2;
条件是R 7中至少一个为-P(＝O)R 5R 6。 Provided that at least one of R 7 is -P(=O)R 5 R 6 .
在一个实施方案中，本发明涉及上述具有通式(a)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-described compounds of formula (a), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
R 7为-P(＝O)R 5R 6； R 7 is -P(=O)R 5 R 6 ;
R 5和R 6各自独立地为C 1-4烷基； R 5 and R 6 are each independently C 1-4 alkyl;
R 8为卤代C 1-4烷基，优选为-CF 3； R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
R 9和R 10各自独立地为-H； R 9 and R 10 are each independently -H;
R 11为-NR’R”； R 11 is -NR'R";
R’和R”各自独立地为-H；R' and R" are each independently -H;
m1、m2、n1和n2各自独立地为1；m1, m2, n1 and n2 are each independently 1;
p为0；p is 0;
t为1。t is 1.
在一个实施方案中，本发明涉及具有通式(b)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，In one embodiment, the present invention relates to compounds of general formula (b), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof,
Figure PCTCN2021120199-appb-000038
Figure PCTCN2021120199-appb-000038
其中，in,
R 7各自独立地选自-H、卤素、氰基、-OR’、-NR’R”、C 1-6烷基、卤代C 1-6烷基、
Figure PCTCN2021120199-appb-000039
和-P(＝O)R 5R 6； R 7 is each independently selected from -H, halogen, cyano, -OR', -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl,
Figure PCTCN2021120199-appb-000039
and -P(=O)R 5 R 6 ;
R 5和R 6各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R 5 and R 6 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
R 5’选自-H、C 1-6烷基和卤代C 1-6烷基； R 5' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
R 6’选自-H、氰基、C 1-6烷基和卤代C 1-6烷基； R 6' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
R 8选自-H、卤素、氰基、-OR’、C 1-6烷基和卤代C 1-6烷基； R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
R 11选自-H、-OR’、C 1-6烷基、卤代C 1-6烷基、-C(O)C 1-6烷基、-C(O)OC 1-6烷基、-C(O)NHC 1-6烷基和-C(O)N(C 1-6烷基) 2；其中所述C 1-6烷基任选被1-3个选自羟基、巯基、-OR’和-NR’R”的取代基取代； R 11 is selected from -H, -OR', C 1-6 alkyl, halogenated C 1-6 alkyl, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl , -C(O)NHC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; wherein the C 1-6 alkyl is optionally , -OR' and -NR'R" substituents are substituted;
R’和R”各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
m1、m2、n1和n2各自独立地为0、1或2；m1, m2, n1, and n2 are each independently 0, 1, or 2;
t选自1、2、3和4；t is selected from 1, 2, 3 and 4;
p选自0、1、2、3、4、5和6。p is selected from 0, 1, 2, 3, 4, 5 and 6.
在一个实施方案中，本发明涉及上述具有通式(b)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-described compounds of general formula (b), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
R 7各自独立地选自-H、卤素、氰基、C 1-4烷基、卤代C 1-4烷基和-P(＝O)R 5R 6； R 7 is each independently selected from -H, halogen, cyano, C 1-4 alkyl, haloC 1-4 alkyl and -P(=O)R 5 R 6 ;
R 5和R 6各自独立地选自-H和C 1-4烷基； R 5 and R 6 are each independently selected from -H and C 1-4 alkyl;
R 8选自卤素、氰基和卤代C 1-4烷基； R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl;
R 11选自-H、-C(O)OC 1-4烷基、-C(O)NHC 1-4烷基和-C(O)N(C 1-4烷基) 2；其中所述C 1-4烷基任选被1-3个选自羟基、巯基和-NR’R”的取代基取代； R 11 is selected from -H, -C(O)OC 1-4 alkyl, -C(O)NHC 1-4 alkyl and -C(O)N(C 1-4 alkyl) 2 ; wherein said C 1-4 alkyl is optionally substituted by 1-3 substituents selected from hydroxyl, mercapto and -NR'R";
R’和R”各自独立地选自-H和C 1-6烷基； R' and R" are each independently selected from -H and C 1-6 alkyl;
m1、m2、n1和n2各自独立地为0、1或2；m1, m2, n1, and n2 are each independently 0, 1, or 2;
t选自1和2；t is selected from 1 and 2;
p选自0和1；p is selected from 0 and 1;
条件是R 7中至少一个为-P(＝O)R 5R 6。 Provided that at least one of R 7 is -P(=O)R 5 R 6 .
在一个实施方案中，本发明涉及上述具有通式(b)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-described compounds of general formula (b), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
R 7各自独立地选自-H、卤素、氰基和-P(＝O)R 5R 6； R 7 is each independently selected from -H, halogen, cyano and -P(=O)R 5 R 6 ;
R 5和R 6各自独立地为C 1-4烷基； R 5 and R 6 are each independently C 1-4 alkyl;
R 8为卤代C 1-4烷基； R 8 is halogenated C 1-4 alkyl;
R 11为H或-C(O)OC 1-4烷基；其中所述C 1-4烷基任选被1-2个羟基取代； R 11 is H or -C(O)OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups;
m1、m2、n1和n2各自独立地为1或2；m1, m2, n1 and n2 are each independently 1 or 2;
t选自1和2；t is selected from 1 and 2;
p选自0和1；p is selected from 0 and 1;
条件是R 7中至少一个为-P(＝O)R 5R 6。 Provided that at least one of R 7 is -P(=O)R 5 R 6 .
在一个实施方案中，本发明涉及具有通式(b-1)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，In one embodiment, the present invention relates to compounds of general formula (b-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or pro- Medicine,
Figure PCTCN2021120199-appb-000040
Figure PCTCN2021120199-appb-000040
其中，in,
R 7选自-H、卤素、氰基、-OR’、-NR’R”、C 1-6烷基、卤代C 1-6烷基和-P(＝O)R 5R 6； R 7 is selected from -H, halogen, cyano, -OR', -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl and -P(=O)R 5 R 6 ;
R 5和R 6各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R 5 and R 6 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
R 8选自-H、卤素、氰基、-OR’、C 1-6烷基和卤代C 1-6烷基； R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
R 11选自-H、-OR’、C 1-6烷基、卤代C 1-6烷基、-C(O)C 1-6烷基、-C(O)OC 1-6烷基、-C(O)NHC 1-6烷基和-C(O)N(C 1-6烷基) 2；其中所述C 1-6烷基任选被1-3个选自羟基、巯基、-OR’和-NR’R”的取代基取代； R 11 is selected from -H, -OR', C 1-6 alkyl, halogenated C 1-6 alkyl, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl , -C(O)NHC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; wherein the C 1-6 alkyl is optionally , -OR' and -NR'R" substituents are substituted;
R’和R”各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
m1、m2、n1和n2各自独立地为0、1或2。m1, m2, n1, and n2 are each independently 0, 1, or 2.
在一个实施方案中，本发明涉及上述具有通式(b-1)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-mentioned compounds of general formula (b-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or A prodrug, which:
R 7选自-H、卤素、氰基、C 1-4烷基和卤代C 1-4烷基； R 7 is selected from -H, halogen, cyano, C 1-4 alkyl and halogenated C 1-4 alkyl;
R 5和R 6各自独立地选自-H和C 1-4烷基； R 5 and R 6 are each independently selected from -H and C 1-4 alkyl;
R 8选自卤素、氰基和卤代C 1-4烷基； R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl;
R 11选自-H、-C(O)OC 1-4烷基、-C(O)NHC 1-4烷基和-C(O)N(C 1-4烷基) 2；其中所述C 1-4烷基任选被1-3个选自羟基、巯基和-NR’R”的取代基取代； R 11 is selected from -H, -C(O)OC 1-4 alkyl, -C(O)NHC 1-4 alkyl and -C(O)N(C 1-4 alkyl) 2 ; wherein said C 1-4 alkyl is optionally substituted by 1-3 substituents selected from hydroxyl, mercapto and -NR'R";
R’和R”各自独立地选自-H和C 1-6烷基； R' and R" are each independently selected from -H and C 1-6 alkyl;
m1、m2、n1和n2各自独立地为0、1或2。m1, m2, n1, and n2 are each independently 0, 1, or 2.
在一个实施方案中，本发明涉及上述具有通式(b-1)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-mentioned compounds of general formula (b-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or A prodrug, which:
R 7选自-H、卤素和氰基； R is selected from -H , halogen and cyano;
R 5和R 6各自独立地为C 1-4烷基； R 5 and R 6 are each independently C 1-4 alkyl;
R 8为卤代C 1-4烷基； R 8 is halogenated C 1-4 alkyl;
R 11为H或-C(O)OC 1-4烷基；其中所述C 1-4烷基任选被1-2个羟基取代； R 11 is H or -C(O)OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups;
m1、m2、n1和n2各自独立地为1或2。m1, m2, n1 and n2 are each independently 1 or 2.
在一个实施方案中，本发明涉及上述具有通式(b-1)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-mentioned compounds of general formula (b-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or A prodrug, which:
R 7为-H； R 7 is -H;
R 5和R 6各自独立地为C 1-4烷基； R 5 and R 6 are each independently C 1-4 alkyl;
R 8为卤代C 1-4烷基，优选为-CF 3； R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
R 11为-C(O)OC 1-4烷基；其中所述C 1-4烷基任选被1-2个羟基取代； R 11 is -C(O)OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups;
m1、m2、n1和n2各自独立地为1。m1, m2, n1, and n2 are each independently 1.
在一个实施方案中，本发明涉及通式(b-2)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，In one embodiment, the present invention relates to compounds of general formula (b-2), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof ,
Figure PCTCN2021120199-appb-000041
Figure PCTCN2021120199-appb-000041
其中，in,
R 7选自-H、卤素、氰基、-OR’、-NR’R”、C 1-6烷基、卤代C 1-6烷基和-P(＝O)R 5R 6； R 7 is selected from -H, halogen, cyano, -OR', -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl and -P(=O)R 5 R 6 ;
R 5和R 6各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R 5 and R 6 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
R 8选自-H、卤素、氰基、-OR’、C 1-6烷基和卤代C 1-6烷基； R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
R 15为C 1-6烷基，其任选被1-3个选自羟基、巯基、-OR’和-NR’R”的取代基取代； R 15 is C 1-6 alkyl, which is optionally substituted by 1-3 substituents selected from hydroxyl, mercapto, -OR' and -NR'R";
R’和R”各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
m1、m2、n1和n2各自独立地为0、1或2。m1, m2, n1, and n2 are each independently 0, 1, or 2.
在一个实施方案中，本发明涉及上述具有通式(b-2)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-described compounds of general formula (b-2), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives thereof, or A prodrug, which:
R 7选自-H、卤素、氰基、C 1-4烷基和卤代C 1-4烷基； R 7 is selected from -H, halogen, cyano, C 1-4 alkyl and halogenated C 1-4 alkyl;
R 5和R 6各自独立地选自-H和C 1-4烷基； R 5 and R 6 are each independently selected from -H and C 1-4 alkyl;
R 8选自卤素、氰基和卤代C 1-4烷基； R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl;
R 15为C 1-4烷基，其任选被1-3个选自羟基、巯基和-NR’R”的取代基取代； R 15 is C 1-4 alkyl, which is optionally substituted with 1-3 substituents selected from hydroxyl, mercapto and -NR'R";
R’和R”各自独立地选自-H和C 1-6烷基； R' and R" are each independently selected from -H and C 1-6 alkyl;
m1、m2、n1和n2各自独立地为0、1或2。m1, m2, n1, and n2 are each independently 0, 1, or 2.
在一个实施方案中，本发明涉及上述具有通式(b-2)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-described compounds of general formula (b-2), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives thereof, or A prodrug, which:
R 7选自-H、卤素和氰基； R is selected from -H , halogen and cyano;
R 5和R 6各自独立地为C 1-4烷基； R 5 and R 6 are each independently C 1-4 alkyl;
R 8为卤代C 1-4烷基； R 8 is halogenated C 1-4 alkyl;
R 15为C 1-4烷基；其任选被1-2个羟基取代； R 15 is C 1-4 alkyl; it is optionally substituted with 1-2 hydroxyl groups;
m1、m2、n1和n2各自独立地为1或2。m1, m2, n1 and n2 are each independently 1 or 2.
在一个实施方案中，本发明涉及上述具有通式(b-2)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-described compounds of general formula (b-2), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives thereof, or A prodrug, which:
R 7为-H； R 7 is -H;
R 5和R 6各自独立地为C 1-4烷基； R 5 and R 6 are each independently C 1-4 alkyl;
R 8为卤代C 1-4烷基，优选为-CF 3； R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
R 11为-C(O)OC 1-4烷基；其中所述C 1-4烷基任选被1-2个羟基取代； R 11 is -C(O)OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups;
m1、m2、n1和n2各自独立地为1。m1, m2, n1, and n2 are each independently 1.
在一个实施方案中，本发明涉及具有通式(c)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，In one embodiment, the present invention relates to compounds of general formula (c), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof,
Figure PCTCN2021120199-appb-000042
Figure PCTCN2021120199-appb-000042
其中：in:
R 8选自-H、卤素、氰基、-OR’、C 1-6烷基和卤代C 1-6烷基； R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
R 13和R 14各自独立地选自H、C 1-6烷基和卤代C 1-6烷基； R 13 and R 14 are each independently selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
R 15各自独立地选自-H、卤素、-OR’、氰基、C 1-6烷基、卤代C 1-6烷基、
Figure PCTCN2021120199-appb-000043
Figure PCTCN2021120199-appb-000044
R 15 is each independently selected from -H, halogen, -OR', cyano, C 1-6 alkyl, halogenated C 1-6 alkyl,
Figure PCTCN2021120199-appb-000043
Figure PCTCN2021120199-appb-000044
R 5’选自-H、C 1-6烷基和卤代C 1-6烷基； R 5' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
R 6’选自-H、氰基、C 1-6烷基和卤代C 1-6烷基； R 6' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
R’选自-H、C 1-6烷基和卤代C 1-6烷基； R' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
s和q各自独立地选自0、1和2；s and q are each independently selected from 0, 1 and 2;
r选自1、2、3和4；r is selected from 1, 2, 3 and 4;
条件是至少一个R 15为
Figure PCTCN2021120199-appb-000045
provided that at least one R 15 is
Figure PCTCN2021120199-appb-000045
在一个实施方案中，本发明涉及上述具有通式(c)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-described compounds of general formula (c), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
R 8为卤代C 1-6烷基； R 8 is halogenated C 1-6 alkyl;
R 13和R 14各自独立地选自H和C 1-6烷基； R 13 and R 14 are each independently selected from H and C 1-6 alkyl;
R 15各自独立地选自-H、卤素、氰基、
Figure PCTCN2021120199-appb-000046
R 15 is each independently selected from -H, halogen, cyano,
Figure PCTCN2021120199-appb-000046
R 5’选自-H和C 1-6烷基； R 5' is selected from -H and C 1-6 alkyl;
R 6’选自-H、氰基和C 1-6烷基； R 6' is selected from -H, cyano and C 1-6 alkyl;
s和q各自独立地选自0和1；s and q are each independently selected from 0 and 1;
r选自1和2；r is selected from 1 and 2;
条件是至少一个R 15为
Figure PCTCN2021120199-appb-000047
provided that at least one R 15 is
Figure PCTCN2021120199-appb-000047
在一个实施方案中，本发明涉及上述具有通式(c)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-described compounds of general formula (c), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
R 8为卤代C 1-4烷基； R 8 is halogenated C 1-4 alkyl;
R 13和R 14各自独立地为C 1-4烷基； R 13 and R 14 are each independently C 1-4 alkyl;
R 15各自独立地选自-H、卤素、氰基和
Figure PCTCN2021120199-appb-000048
R 15 is each independently selected from -H, halogen, cyano and
Figure PCTCN2021120199-appb-000048
R 5’选自-H和C 1-4烷基； R 5' is selected from -H and C 1-4 alkyl;
R 6’选自-H、氰基和C 1-4烷基； R 6' is selected from -H, cyano and C 1-4 alkyl;
s和q各自独立地选自0和1；s and q are each independently selected from 0 and 1;
r选自1和2；r is selected from 1 and 2;
条件是至少一个R 15为
Figure PCTCN2021120199-appb-000049
provided that at least one R 15 is
Figure PCTCN2021120199-appb-000049
在一个实施方案中，本发明涉及上述具有通式(c)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-described compounds of general formula (c), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically-labeled derivatives or prodrugs thereof ,in:
R 8为卤代C 1-4烷基，优选为-CF 3； R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
R 13和R 14各自独立地为C 1-4烷基； R 13 and R 14 are each independently C 1-4 alkyl;
R 15选自卤素和
Figure PCTCN2021120199-appb-000050
R 15 is selected from halogen and
Figure PCTCN2021120199-appb-000050
R 5’为C 1-4烷基； R 5' is C 1-4 alkyl;
R 6’选自-H和氰基； R 6' is selected from -H and cyano;
s和q各自独立地为1；s and q are each independently 1;
r选自1和2；r is selected from 1 and 2;
条件是至少一个R 15为
Figure PCTCN2021120199-appb-000051
provided that at least one R 15 is
Figure PCTCN2021120199-appb-000051
在一个实施方案中，本发明涉及具有通式(c-1)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，In one embodiment, the present invention relates to compounds of general formula (c-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or pro- Medicine,
Figure PCTCN2021120199-appb-000052
Figure PCTCN2021120199-appb-000052
其中：in:
R 8选自-H、卤素、氰基、-OR’、C 1-6烷基和卤代C 1-6烷基； R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
R 13和R 14各自独立地选自H、C 1-6烷基和卤代C 1-6烷基； R 13 and R 14 are each independently selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
R 15选自-H、卤素、氰基、-OR’、C 1-6烷基、卤代C 1-6烷基、
Figure PCTCN2021120199-appb-000053
R 15 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl, halogenated C 1-6 alkyl,
Figure PCTCN2021120199-appb-000053
R 5’选自-H、氰基、C 1-6烷基和卤代C 1-6烷基； R 5' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
R 6’选自-H、氰基、C 1-6烷基和卤代C 1-6烷基； R 6' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
R’选自-H、C 1-6烷基和卤代C 1-6烷基； R' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
s和q各自独立地选自0、1和2。s and q are each independently selected from 0, 1 and 2.
在一个实施方案中，本发明涉及上述具有通式(c-1)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-mentioned compounds of general formula (c-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or A prodrug, which:
R 8为卤代C 1-4烷基； R 8 is halogenated C 1-4 alkyl;
R 13和R 14各自独立地选自-H和C 1-4烷基； R 13 and R 14 are each independently selected from -H and C 1-4 alkyl;
R 15选自-H、卤素和氰基； R 15 is selected from -H, halogen and cyano;
R 5’选自-H和C 1-4烷基； R 5' is selected from -H and C 1-4 alkyl;
R 6’选自-H、氰基和C 1-4烷基； R 6' is selected from -H, cyano and C 1-4 alkyl;
s和q各自独立地选自0和1。s and q are each independently selected from 0 and 1.
在一个实施方案中，本发明涉及上述具有通式(c-1)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：In one embodiment, the present invention relates to the above-mentioned compounds of general formula (c-1), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives thereof, or A prodrug, which:
R 8为卤代C 1-4烷基，优选为-CF 3； R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
R 13和R 14各自独立地选自-H和C 1-4烷基； R 13 and R 14 are each independently selected from -H and C 1-4 alkyl;
R 15选自-H和卤素； R 15 is selected from -H and halogen;
R 5’为C 1-4烷基； R 5' is C 1-4 alkyl;
R 6’选自-H和氰基； R 6' is selected from -H and cyano;
s和q各自独立地为1。s and q are each independently 1.
具体地，所述嘧啶基衍生物选自以下化合物中的一种：Specifically, the pyrimidinyl derivative is selected from one of the following compounds:
Figure PCTCN2021120199-appb-000054
Figure PCTCN2021120199-appb-000054
Figure PCTCN2021120199-appb-000055
Figure PCTCN2021120199-appb-000055
Figure PCTCN2021120199-appb-000056
Figure PCTCN2021120199-appb-000056
Figure PCTCN2021120199-appb-000057
Figure PCTCN2021120199-appb-000057
Figure PCTCN2021120199-appb-000058
Figure PCTCN2021120199-appb-000058
在一个实施方案中，所述嘧啶基衍生物选自以下化合物中的一种：In one embodiment, the pyrimidinyl derivative is selected from one of the following compounds:
Figure PCTCN2021120199-appb-000059
Figure PCTCN2021120199-appb-000059
在一个实施方案中，本发明提供嘧啶基衍生物的制备方法，其特征在于，包括如下步骤：In one embodiment, the present invention provides a method for preparing pyrimidine derivatives, which is characterized in that it comprises the following steps:
Figure PCTCN2021120199-appb-000060
Figure PCTCN2021120199-appb-000060
化合物a与化合物b进行取代反应，制备化合物c；Compound a is subjected to substitution reaction with compound b to prepare compound c;
化合物c与化合物d进行取代反应，制备化合物e；Compound c is subjected to substitution reaction with compound d to prepare compound e;
将基团w反应形成R 4； reacting group w to form R4 ;
其中，V各自独立地选自卤素；R 1、R 2、R 3、R 4、w、x和A如说明书中所定义。 wherein V is each independently selected from halogen; R 1 , R 2 , R 3 , R 4 , w, x and A are as defined in the specification.
在其中一个具体的实施方案中，将基团w反应形成R 4的方法包括如下步骤： In one specific embodiment, the method of reacting the group w to form R4 comprises the steps of:
基团w为卤素，基团w与R 4-H进行取代反应，形成R 4；或 The group w is halogen, and the group w undergoes a substitution reaction with R 4 -H to form R 4 ; or
基团w为-S-R 5，基团w进行氧化反应，形成R 4；或 The group w is -SR 5 , and the group w undergoes an oxidation reaction to form R 4 ; or
基团w为-NO 2，基团w进行还原反应生成-NH 2，-NH 2进行缩合反应，形成R 4；R 1、R 2、R 3、R 4、w、x和A如说明书中所定义。 The group w is -NO 2 , the group w undergoes a reduction reaction to generate -NH 2 , and -NH 2 undergoes a condensation reaction to form R 4 ; R 1 , R 2 , R 3 , R 4 , w, x and A are as described in the specification defined.
在一个实施方案中，本发明涉及一种药物组合物，其特征在于，所述药物组合物包含如本发明所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，以及药学上可接受的辅料、稀释剂或载体。In one embodiment, the present invention relates to a pharmaceutical composition, characterized in that the pharmaceutical composition comprises the pyrimidinyl derivative according to the present invention, an optical isomer thereof, a pharmaceutically acceptable salt, a solvent compounds, atropisomers, isotopically-labeled derivatives or prodrugs, and pharmaceutically acceptable excipients, diluents or carriers.
在一个实施方案中，所述药物组合物还包括联用药剂；所述联用药剂选自抗增殖剂、抗癌剂、免疫抑制剂和疼痛缓解剂中的至少一种。In one embodiment, the pharmaceutical composition further comprises a combined agent; the combined agent is selected from at least one of an antiproliferative agent, an anticancer agent, an immunosuppressant, and a pain relief agent.
在一个实施方案中，本发明涉及所述嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药或所述药物组合物在制备用于预防或治疗与异常的CDK7活性相关的癌症、良性赘生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病或感染性疾病的药物中的用途。In one embodiment, the present invention relates to said pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof or said Use of a pharmaceutical composition in the preparation of a medicament for preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity.
在一个实施方案中，所述与异常的CDK7活性相关的癌症选自乳腺癌、卵巢癌、直肠癌、肝癌、肺癌、胃癌、脑癌、胆管癌、***、子宫内膜癌、头颈癌、膀胱癌、骨癌、肠癌、肾癌、喉癌、淋巴瘤、白血病、慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、T细胞急性成淋巴细胞性白血病、慢性骨髓性白血病、急性骨髓性白血病、多发性骨髓瘤、黑色素瘤、间皮瘤、骨髓瘤、神经内分泌癌、食管癌、***癌、***癌、皮肤癌、软组织肉瘤癌、脊髓癌、睾丸癌、甲状腺癌和子宫癌中的一种或几种。In one embodiment, the cancer associated with aberrant CDK7 activity is selected from the group consisting of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, gastric cancer, brain cancer, bile duct cancer, cervical cancer, endometrial cancer, head and neck cancer, Bladder cancer, bone cancer, bowel cancer, kidney cancer, throat cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia of leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine, esophageal, penile, prostate, skin, soft tissue sarcoma, spinal cord, testicular, thyroid and uterine cancers one or more.
在一个实施方案中，本发明涉及所述嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药或所述药物组合物，其用于预防或治疗与异常的CDK7活性相关的癌症、良性赘生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病或感染性疾病。In one embodiment, the present invention relates to said pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof or said A pharmaceutical composition for preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity.
在一个实施方案中，所述与异常的CDK7活性相关的癌症选自乳腺癌、卵巢癌、直肠癌、肝癌、肺癌、胃癌、脑癌、胆管癌、***、子宫内膜癌、头颈癌、膀胱癌、骨癌、肠癌、肾癌、喉癌、淋巴瘤、白血病、慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、T细胞急性成淋巴细胞性白血病、慢性骨髓性白血病、急性骨髓性白血病、多发性骨髓瘤、黑色素瘤、间皮瘤、骨髓瘤、神经内分泌癌、食管癌、***癌、***癌、皮肤癌、软组织肉瘤癌、脊髓癌、睾丸癌、甲状腺癌和子宫癌中的一种 或几种。In one embodiment, the cancer associated with aberrant CDK7 activity is selected from the group consisting of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, gastric cancer, brain cancer, bile duct cancer, cervical cancer, endometrial cancer, head and neck cancer, Bladder cancer, bone cancer, bowel cancer, kidney cancer, throat cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia of leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine, esophageal, penile, prostate, skin, soft tissue sarcoma, spinal cord, testicular, thyroid and uterine cancers one or more.
在一个实施方案中，本发明涉及一种预防或治疗与异常的CDK7活性相关的癌症、良性赘生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病或感染性疾病的方法，包括向需要的受试者给药本发明所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药或所述药物组合物。In one embodiment, the present invention relates to a method of preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with aberrant CDK7 activity, Including the administration of the pyrimidinyl derivatives of the present invention, their optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs to subjects in need or the pharmaceutical composition.
在该治疗方法的一个实施方案中，所述与异常的CDK7活性相关的癌症选自乳腺癌、卵巢癌、直肠癌、肝癌、肺癌、胃癌、脑癌、胆管癌、***、子宫内膜癌、头颈癌、膀胱癌、骨癌、肠癌、肾癌、喉癌、淋巴瘤、白血病、慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、T细胞急性成淋巴细胞性白血病、慢性骨髓性白血病、急性骨髓性白血病、多发性骨髓瘤、黑色素瘤、间皮瘤、骨髓瘤、神经内分泌癌、食管癌、***癌、***癌、皮肤癌、软组织肉瘤癌、脊髓癌、睾丸癌、甲状腺癌和子宫癌中的一种或几种。In one embodiment of the method of treatment, the cancer associated with aberrant CDK7 activity is selected from the group consisting of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, gastric cancer, brain cancer, bile duct cancer, cervical cancer, endometrial cancer , head and neck cancer, bladder cancer, bone cancer, bowel cancer, kidney cancer, throat cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myelogenous leukemia , acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine, esophageal, penile, prostate, skin, soft tissue sarcoma, spinal cord, testicular, thyroid and One or more of uterine cancers.
本发明的实施例还提供一种药物组合物，所述药物组合物包含如上所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，以及药学上可接受的辅料、稀释剂或载体。Embodiments of the present invention also provide a pharmaceutical composition comprising the above-mentioned pyrimidine derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers thereof , isotopically labeled derivatives or prodrugs, and pharmaceutically acceptable excipients, diluents or carriers.
在其中一个具体的实施方案中，所述药物组合物还包括联用药剂；所述联用药剂选自抗增殖剂、抗癌剂、抗糖尿病剂、抗炎剂、免疫抑制剂、以及疼痛缓解剂中的至少一种。在某些实施方式中，所述联用药剂为一种或多种抗癌剂。所述联用药剂选自小有机分子，如药物化合物(例如《美国联邦法规(Code of Federal Regulations)》(CFR)中所提供的由美国食品和药物管理局(U.S.Foodand Drug Administration)批准的化合物)，以及肽、蛋白质、碳水化合物、单糖、低聚糖、多糖、核蛋白、粘蛋白、脂蛋白、合成多肽或蛋白质、与蛋白质连接的小分子、糖蛋白、类固醇、核酸、DNA、RNA、核苷酸、核苷、寡核苷酸、反义寡核苷酸、脂质、激素、维生素以及细胞等。In one specific embodiment, the pharmaceutical composition further comprises a combined agent; the combined agent is selected from the group consisting of anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressive agents, and pain relief agents at least one of the agents. In certain embodiments, the combination agent is one or more anticancer agents. The combination agent is selected from small organic molecules, such as pharmaceutical compounds (eg, compounds approved by the US Food and Drug Administration) as provided in the Code of Federal Regulations (CFR) ), as well as peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA , nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.
可以理解地，所述药物组合物还可以包括药学上可接受的载体或稀释剂。It is understood that the pharmaceutical composition may also include a pharmaceutically acceptable carrier or diluent.
本发明还提供如上所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，或如上所述的药物组合物在制备用于预防或治疗CDK7介导的疾病或病症的药物中的应用。具体地，所述CDK7介导的疾病或病症是指哺乳动物(尤其是人)中CDK7介导的疾病或病症。The present invention also provides pyrimidinyl derivatives as described above, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof, or as described above Use of a pharmaceutical composition in the preparation of a medicament for preventing or treating a CDK7-mediated disease or condition. Specifically, the CDK7-mediated disease or disorder refers to a CDK7-mediated disease or disorder in mammals (especially humans).
在其中一个具体的实施方案中，所述CDK7介导的疾病或病症是指异常的CDK7活性相关的增殖性疾病(如癌症)、良性赘生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病、感染性疾病或过敏性疾病。In one specific embodiment, the CDK7-mediated disease or disorder refers to aberrant CDK7 activity-related proliferative diseases (such as cancer), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, Autoimmune disease, infectious disease or allergic disease.
在其中一个具体的实施方案中，所述与异常的CDK7活性相关的癌症选自乳腺癌(尤 其是三阴乳腺癌)、卵巢癌、直肠癌、肝癌、肺癌、胃癌、脑癌、胆管癌、***、子宫内膜癌、头颈癌、膀胱癌、骨癌、肠癌、肾癌、喉癌、淋巴瘤、白血病、慢性淋巴细胞性白血病(CLL)、急性成淋巴细胞性白血病(ALL)、T细胞急性成淋巴细胞性白血病(T-ALL)、慢性骨髓性白血病(CML)、急性骨髓性白血病(AML)、多发性骨髓瘤、黑色素瘤、间皮瘤、骨髓瘤、神经内分泌癌、食管癌、***癌、***癌、皮肤癌、软组织肉瘤癌、脊髓癌、睾丸癌、甲状腺癌和子宫癌中的一种或几种。In one specific embodiment, the cancer associated with abnormal CDK7 activity is selected from breast cancer (especially triple negative breast cancer), ovarian cancer, rectal cancer, liver cancer, lung cancer, stomach cancer, brain cancer, bile duct cancer, Cervical cancer, endometrial cancer, head and neck cancer, bladder cancer, bone cancer, bowel cancer, kidney cancer, laryngeal cancer, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine carcinoma, esophagus One or more of cancer, penile cancer, prostate cancer, skin cancer, soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer and uterine cancer.
以下为具体的实施方案。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，可以由本领域技术人员通过传统的优化程序来确定。The following are specific embodiments. The experimental methods that do not specify specific conditions in the following examples can be determined by those skilled in the art through traditional optimization procedures according to conventional methods and conditions.
化合物的结构是通过核磁共振(NMR)和/或质谱(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 III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10&lt;&quot; 6 &gt; (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) ), the internal standard is tetramethylsilane (TMS).
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。The HPLC measurement was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm).
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～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ~ 0.20mm, and the size of the TLC separation and purification products is 0.4mm ~0.5mm.
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。The known starting materials of the present invention can be synthesized by using or according to methods known in the art, or can be purchased from Titan Technology, Annagy Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and other companies.
氮气氛是指反应瓶连接一个约1L容积的氮气气球。Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
实施例中无特殊说明，反应在氮气氛下进行。There is no special description in the examples, and the reaction is carried out under nitrogen atmosphere.
实施例中无特殊说明，溶液是指水溶液。There is no special description in the examples, and the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温。There is no special description in the examples, and the reaction temperature is room temperature.
室温为最适宜的反应温度，为20℃～30℃。Room temperature is the most suitable reaction temperature, which is 20°C to 30°C.
化学合成相关缩写：Abbreviations related to chemical synthesis:
Boc 2O：一缩二碳酸二叔丁基酯 Boc 2 O: di-tert-butyl dicarbonate
DIEA：N,N-二异丙基乙胺DIEA: N,N-Diisopropylethylamine
Xantphos：4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
Johnphos：2-(二叔丁基膦)联苯Johnphos: 2-(di-tert-butylphosphine)biphenyl
Pd(OAc) 2：醋酸钯 Pd(OAc) 2 : palladium acetate
Pd(PPh 3) 4：四(三苯基膦)钯 Pd(PPh 3 ) 4 : tetrakis(triphenylphosphine)palladium
Pd(Pd(PPh 3) 2Cl 2：双苯基磷二氯化钯 Pd(Pd(PPh 3 ) 2 Cl 2 : bisphenylphosphonium palladium dichloride
Pd(dppf)Cl 2：[1,1'-双(二苯基磷)二茂铁]二氯化钯 Pd(dppf)Cl 2 : [1,1'-bis(diphenylphosphonium)ferrocene]palladium dichloride
Pd 2(dba) 3：三(二亚苄基丙酮)二钯 Pd 2 (dba) 3 : tris(dibenzylideneacetone)dipalladium
Pd/C：钯炭催化剂Pd/C: Palladium on carbon catalyst
NaOtBu：叔丁醇钠NaOtBu: sodium tert-butoxide
PE：石油醚；PE: petroleum ether;
EA：乙酸乙酯；EA: ethyl acetate;
DMF：N,N-二甲基甲酰胺；DMF: N,N-dimethylformamide;
DCM：二氯甲烷；DCM: dichloromethane;
THF：四氢呋喃THF: Tetrahydrofuran
MeOH：甲醇MeOH: methanol
Prep-HPLC：高压制备液相色谱Prep-HPLC: High Pressure Preparative Liquid Chromatography
Rf：比移值；Rf: ratio shift value;
g：克g: grams
mg：毫克mg: milligrams
h：小时h: hours
rt：室温rt: room temperature
mol：摩尔mol: mole
mmol：毫摩尔mmol: millimoles
mL：毫升mL: milliliter
M：摩尔/升M: moles/liter
SEMCl：氯甲基三甲基硅乙基醚SEMCl: Chloromethyltrimethylsilyl ethyl ether
TFA：三氟乙酸TFA: trifluoroacetic acid
TFAA：三氟乙酸酐TFAA: trifluoroacetic anhydride
中间体1：7-溴-1H-吲哚-6-甲腈Intermediate 1: 7-Bromo-1H-indole-6-carbonitrile
Figure PCTCN2021120199-appb-000061
Figure PCTCN2021120199-appb-000061
第一步：7-溴-1H-吲哚-6-羧酸1bStep 1: 7-Bromo-1H-indole-6-carboxylic acid 1b
Figure PCTCN2021120199-appb-000062
Figure PCTCN2021120199-appb-000062
将乙烯基溴化镁(1mol/L，320mL)加入到200mL无水THF中，降温至-78℃，向其中慢慢滴加化合物2-溴-3-硝基苯甲酸1a(20g,81.3mmol)溶解在320mL无水THF的溶液。滴加完成后，升至室温搅拌过夜。反应液用150mL饱和NH4Cl溶液淬灭，用1mol/L的盐酸溶液调节pH至2左右，接着用EtOAc(3x200mL)萃取。有机相用饱和NaCl溶液洗涤，无水Na 2SO 4干燥，真空旋干得固体粗品。向粗品中加入适量DCM进行打浆纯化，得到棕色固体产品1b(16g，收率：82％)。 Vinylmagnesium bromide (1 mol/L, 320 mL) was added to 200 mL of anhydrous THF, cooled to -78°C, and the compound 2-bromo-3-nitrobenzoic acid 1a (20 g, 81.3 mmol) was slowly added dropwise thereto. ) dissolved in 320 mL of anhydrous THF. After the dropwise addition was completed, the mixture was warmed to room temperature and stirred overnight. The reaction solution was quenched with 150 mL of saturated NH 4 Cl solution, adjusted to pH about 2 with 1 mol/L hydrochloric acid solution, and then extracted with EtOAc (3×200 mL). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 , and dried in vacuo to obtain a solid crude product. An appropriate amount of DCM was added to the crude product for beating and purification to obtain a brown solid product 1b (16 g, yield: 82%).
MS m/z(ESI)：240.1[M+1]。MS m/z (ESI): 240.1 [M+1].
第二步：7-溴-1H-吲哚-6-羧酰胺1cStep 2: 7-Bromo-1H-indole-6-carboxamide 1c
Figure PCTCN2021120199-appb-000063
Figure PCTCN2021120199-appb-000063
将化合物1b(16g，66.9mmol)溶于150mL无水DMF中，降温至0℃，加入CDI(21.7g，134mmol)，0℃下搅拌1h。LC-MS监测化合物1b已消耗掉。接着向其中加入96mL氨水，继续在0℃下反应1h。反应液加水淬灭，用THF(3x100mL)萃取。有机相用饱和NaCl溶液洗涤，无水Na 2SO 4干燥，真空旋干。粗品通过硅胶柱(洗脱剂：二氯甲烷/甲醇＝70/1)纯化后得到黄色固体产品1c(11g，收率：69％)。 Compound 1b (16 g, 66.9 mmol) was dissolved in 150 mL of anhydrous DMF, cooled to 0 °C, CDI (21.7 g, 134 mmol) was added, and stirred at 0 °C for 1 h. LC-MS monitored that compound 1b was consumed. Then, 96 mL of ammonia water was added thereto, and the reaction was continued at 0° C. for 1 h. The reaction was quenched with water and extracted with THF (3×100 mL). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 and spun dry in vacuo. The crude product was purified by silica gel column (eluent: dichloromethane/methanol=70/1) to obtain product 1c (11 g, yield: 69%) as a yellow solid.
MS m/z(ESI)：239.1[M+1]。MS m/z (ESI): 239.1 [M+1].
第三步：7-溴-1H-吲哚-6-甲腈(中间体1)Step 3: 7-Bromo-1H-indole-6-carbonitrile (Intermediate 1)
Figure PCTCN2021120199-appb-000064
Figure PCTCN2021120199-appb-000064
将化合物1c(11g，46.2mmol)溶于50mL无水DCM中，降温至0℃。加入三乙胺(9.3g，92.4mmol)，搅拌5min，接着向其中缓慢滴加TFAA(三氟乙酸酐)(19.4g，92.4mmol)。添加完成后，反应液于0℃下搅拌1h。反应加水淬灭，接着用DCM萃取。有机相用饱和NaCl溶液洗涤，无水Na 2SO 4干燥，真空旋干得到粗品。粗品通过硅胶柱(洗脱剂：石油醚/乙酸乙酯＝15/1)纯化得浅黄色固体产品7-溴-1H-吲哚-6-甲腈(中间体1)(2.0g，收率：20％)。 Compound 1c (11 g, 46.2 mmol) was dissolved in 50 mL of anhydrous DCM and cooled to 0 °C. Triethylamine (9.3 g, 92.4 mmol) was added, stirred for 5 min, and then TFAA (trifluoroacetic anhydride) (19.4 g, 92.4 mmol) was slowly added dropwise thereto. After the addition was completed, the reaction solution was stirred at 0 °C for 1 h. The reaction was quenched with water, followed by extraction with DCM. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 , and dried in vacuo to obtain the crude product. The crude product was purified by silica gel column (eluent: petroleum ether/ethyl acetate=15/1) to obtain 7-bromo-1H-indole-6-carbonitrile (intermediate 1) as a light yellow solid product (2.0 g, yield : 20%).
1H-NMR(400MHz,CDCl 3)δ8.61(brs,1H),7.64(d,1H),7.48(t,1H),7.36(d,1H),6.72(dd,1H)。 1H-NMR (400 MHz, CDCl 3 ) δ 8.61 (brs, 1H), 7.64 (d, 1H), 7.48 (t, 1H), 7.36 (d, 1H), 6.72 (dd, 1H).
中间体2：顺式-N 1-甲基环己烷-1,3-二胺 Intermediate 2: cis-N 1 -methylcyclohexane-1,3-diamine
Figure PCTCN2021120199-appb-000065
Figure PCTCN2021120199-appb-000065
第一步：((1R,3S)-环己烷-1,3-二基)二氨基甲酸二苄酯2bThe first step: ((1R,3S)-cyclohexane-1,3-diyl)dibenzyl dicarbamate 2b
Figure PCTCN2021120199-appb-000066
Figure PCTCN2021120199-appb-000066
将化合物(1R,3S)-环己烷-1,3-二羧酸(2a)(5g，1eq)、DPPA(16g，2eq)和Et 3N(6g，2eq)在甲苯(25mL)中的混合物在60℃搅拌0.5h。然后在加入BnOH(6.4g，2eq)后，将最终混合物在100℃下再搅拌3小时。TLC显示原料已耗尽。将反应混合物通过添加10mL水稀释，有机层用乙酸乙酯(20ml×3)萃取，有机相用盐水洗涤，用无水硫酸钠干燥。减压浓缩有机相得到粗化合物。粗品通过硅胶柱色谱法纯化，用(MeOH/DCM＝0至5％)洗脱，得到((1R,3S)-环己烷-1,3-二基)二氨基甲酸二苄酯2b(3g，27％)。 Compound (1R,3S)-cyclohexane-1,3-dicarboxylic acid (2a) (5g, 1eq), DPPA (16g, 2eq) and Et3N (6g, 2eq) in toluene (25mL) The mixture was stirred at 60 °C for 0.5 h. Then after addition of BnOH (6.4 g, 2 eq), the final mixture was stirred at 100°C for an additional 3 hours. TLC showed starting material was consumed. The reaction mixture was diluted by adding 10 mL of water, the organic layer was extracted with ethyl acetate (20 ml×3), the organic phase was washed with brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude compound. The crude product was purified by silica gel column chromatography eluting with (MeOH/DCM = 0 to 5%) to give ((1R,3S)-cyclohexane-1,3-diyl)dicarbamate dibenzyl ester 2b (3 g , 27%).
1H NMR(400MHz,DMSO-D6)δ7.39–7.29(m,10H),7.26(s,1H),7.24(s,1H),5.00(s,4H),2.00–1.62(m,5H),1.35–0.93(m,5H)1H NMR (400MHz, DMSO-D6) δ7.39–7.29(m,10H), 7.26(s,1H), 7.24(s,1H), 5.00(s,4H), 2.00–1.62(m,5H), 1.35–0.93(m,5H)
第二步：顺式-(3-(((苄氧基)羰基)氨基)环己基)(甲基)氨基甲酸苄基酯2cStep 2: cis-(3-(((benzyloxy)carbonyl)amino)cyclohexyl)(methyl)carbamic acid benzyl ester 2c
Figure PCTCN2021120199-appb-000067
Figure PCTCN2021120199-appb-000067
在0℃下，向2b(380mg，1mmol)的DMF(5mL)混合物中加入NaH(40mg，1mmol)。将混合物在0℃下搅拌0.5h。加入CH 3I(142mg，1mmol)。将混合物在25℃搅拌2h。加入10mL水稀释反应混合物，将有机层用乙酸乙酯(20ml×3)萃取，将有机相用盐水洗涤，用无水硫酸钠干燥。将混合物在减压下浓缩得到粗品。通过硅胶上的柱色谱法纯化所述粗品，用(乙酸乙酯/石油醚＝0至50％)洗脱，得到顺式-(3-(((苄氧基)羰基)氨基)环己基)(甲基)氨基甲酸苄基酯(2c)(120mg)，为黄色油状物。 To a mixture of 2b (380 mg, 1 mmol) in DMF (5 mL) at 0 °C was added NaH (40 mg, 1 mmol). The mixture was stirred at 0 °C for 0.5 h. CH3I (142 mg, 1 mmol) was added. The mixture was stirred at 25 °C for 2 h. 10 mL of water was added to dilute the reaction mixture, the organic layer was extracted with ethyl acetate (20 ml×3), the organic phase was washed with brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography on silica gel eluting with (ethyl acetate/petroleum ether = 0 to 50%) to give cis-(3-(((benzyloxy)carbonyl)amino)cyclohexyl) Benzyl (methyl)carbamate (2c) (120 mg) as a yellow oil.
MS m/z(ESI):397.1[M+1]。MS m/z (ESI): 397.1 [M+1].
第三步：顺式-N 1-甲基环己烷-1,3-二胺(中间体2) The third step: cis-N 1 -methylcyclohexane-1,3-diamine (intermediate 2)
Figure PCTCN2021120199-appb-000068
Figure PCTCN2021120199-appb-000068
将Pd/C(32mg，0.1eq)加入到2c(120mg，1eq)的MeOH(5mL)溶液中，在室温搅拌2h。TLC显示原料消耗完后，将反应混合物过滤。将固体用MeOH(10ml×2)洗涤。减压浓缩滤液，得到化合物顺式-N 1-甲基环己烷-1,3-二胺(中间体2)(30mg，77.3％)，为浅黄色固体。 Pd/C (32 mg, 0.1 eq) was added to a solution of 2c (120 mg, 1 eq) in MeOH (5 mL) and stirred at room temperature for 2 h. After TLC showed that the starting material was consumed, the reaction mixture was filtered. The solid was washed with MeOH (10 ml x 2). The filtrate was concentrated under reduced pressure to give compound cis-N1 - methylcyclohexane-1,3-diamine (Intermediate 2) (30 mg, 77.3%) as a pale yellow solid.
中间体3：(2s,3as,5s,6as)-八氢并环戊二烯-2,5-二胺Intermediate 3: (2s,3as,5s,6as)-octahydrocyclopentadiene-2,5-diamine
Figure PCTCN2021120199-appb-000069
Figure PCTCN2021120199-appb-000069
第一步：(2r,3ar,5r,6ar)-八氢并环戊二烯-2,5-二醇3bThe first step: (2r,3ar,5r,6ar)-octahydrocyclopentadiene-2,5-diol 3b
Figure PCTCN2021120199-appb-000070
Figure PCTCN2021120199-appb-000070
将四氢并环戊二烯-2,5(1H,3H)-二酮3a(10g,72.38mmol)溶于干燥的乙酸乙酯(300mL)中并用N 2置换空气3次。降至0℃,加入1mol/L三叔丁氧基氢化锂铝(217ml，217mmol)。添加完成后自然升温至室温，搅拌18个小时。向反应液中加入饱和氯化铵(300ml)淬灭，分液，水相用乙酸乙酯(300mL×2)萃取，合并有机相。有机相用饱和食盐水(100mL×2)洗涤，室温无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝5:1)得到白色固体(2r,3ar,5r,6ar)-八氢并环戊二烯-2,5-二醇3b(6.2g,产率60.24％)。 Tetrahydrocyclopentadiene-2,5(1H,3H)-dione 3a (10 g, 72.38 mmol) was dissolved in dry ethyl acetate (300 mL) and the air was replaced with N2 3 times. Drop to 0° C., add 1 mol/L lithium aluminum tri-tert-butoxyhydride (217 ml, 217 mmol). After the addition was completed, the temperature was naturally raised to room temperature, and the mixture was stirred for 18 hours. Saturated ammonium chloride (300 ml) was added to the reaction solution to quench, and the layers were separated. The aqueous phase was extracted with ethyl acetate (300 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate at room temperature, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5:1) to obtain (2r,3ar,5r,6ar)-octahydrocyclopentadiene-2,5- as a white solid Diol 3b (6.2 g, 60.24% yield).
第二步：(2r,3ar,5r,6ar)-二甲磺酸八氢并环戊二烯-2,5-二基酯3cThe second step: (2r,3ar,5r,6ar)-dimethanesulfonic acid octahydrocyclopentadiene-2,5-diyl ester 3c
Figure PCTCN2021120199-appb-000071
Figure PCTCN2021120199-appb-000071
将(2r,3ar,5r,6ar)-八氢并环戊二烯-2,5-二醇3b(6.2g，43.6mmol)和三乙胺(17.65g，174.4mmol)溶于干燥的二氯甲烷(100mL)中并用N 2置换空气3次。0℃加入MsCl(12.49g，109mmol)，搅拌反应一个小时。向反应液中加入二氯甲烷(100ml)和冰水(100mL)，分液。水相用二氯甲烷(100mL×2)萃取，合并有机相。有机相用饱和食盐水(20mL×2)洗涤，室温用无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝3:1)得到淡白色固体状的化合物(2r,3ar,5r,6ar)-二甲磺酸八氢并环戊二烯-2,5-二基酯3c(5.8g,产率44.58％)。 (2r,3ar,5r,6ar)-octahydrocyclopentadiene-2,5-diol 3b (6.2 g, 43.6 mmol) and triethylamine (17.65 g, 174.4 mmol) were dissolved in dry dichloro in methane (100 mL) and replacing the air with N2 3 times. MsCl (12.49 g, 109 mmol) was added at 0°C and the reaction was stirred for one hour. Dichloromethane (100 ml) and ice water (100 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate at room temperature, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3:1) to obtain compound (2r, 3ar, 5r, 6ar)-dimethanesulfonic acid octahydrocyclocyclohexane as a pale white solid Pentadiene-2,5-diyl ester 3c (5.8 g, 44.58% yield).
第三步：(2s,3as,5s,6as)-2,5-二叠氮基八氢并环戊二烯3dThe third step: (2s,3as,5s,6as)-2,5-diazidooctahydrocyclopentadiene 3d
Figure PCTCN2021120199-appb-000072
Figure PCTCN2021120199-appb-000072
将(2r,3ar,5r,6ar)-二甲磺酸八氢并环戊二烯-2,5-二基酯3c(2.5g,8.38mmol)和叠氮钠(5.45g,83.79mmol)溶于N,N-二甲基甲酰胺(20ml)中,N 2置换3次，然后加热至80℃反应四个小时。向反应液中加入乙酸乙酯(60ml)和冰水(100mL)，分液。水相用乙酸乙酯(100mL×2)萃取，合并有机相。有机相用饱和食盐水(20mL×2)洗涤，室温用无水硫酸钠干燥，过滤，浓缩得到残留物。残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝10:1)得到淡黄色油状的化合物(2s,3as,5s,6as)-2,5-二叠氮基八氢并环戊二烯3d(1.6g,产率99％)。 (2r,3ar,5r,6ar)-dimethanesulfonic acid octahydrocyclopentadiene-2,5-diyl ester 3c (2.5 g, 8.38 mmol) and sodium azide (5.45 g, 83.79 mmol) were dissolved In N,N-dimethylformamide (20 ml), N 2 was replaced 3 times, then heated to 80 °C for four hours. Ethyl acetate (60 ml) and ice water (100 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate (100 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate at room temperature, filtered, and concentrated to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10:1) to obtain compound (2s,3as,5s,6as)-2,5-diazidoocta as a pale yellow oil Hydrocyclopentadiene 3d (1.6 g, 99% yield).
第四步：(2s,3as,5s,6as)-八氢并环戊二烯-2,5-二胺(中间体3)The fourth step: (2s,3as,5s,6as)-octahydrocyclopentadiene-2,5-diamine (intermediate 3)
Figure PCTCN2021120199-appb-000073
Figure PCTCN2021120199-appb-000073
将(2s,3as,5s,6as)-2,5-二叠氮基八氢并环戊二烯3d(1.6g,8.32mmol)溶于无水四氢呋喃(20mL)中，加入Pd/C(160mg),H 2置换3次，室温反应6个小时。过滤，减压浓缩得棕色油状残留物。残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝3:1)得到棕色油状的化合物(2s,3as,5s,6as)-八氢并环戊二烯-2,5-二胺(中间体3)(1.1g，产率94％)。 (2s,3as,5s,6as)-2,5-diazidooctahydrocyclopentadiene 3d (1.6g, 8.32mmol) was dissolved in anhydrous tetrahydrofuran (20mL), Pd/C (160mg) was added ), replaced by H 3 times, and reacted at room temperature for 6 hours. Filtration and concentration under reduced pressure gave a brown oily residue. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3:1) to obtain the compound (2s,3as,5s,6as)-octahydrocyclopentadiene-2 as a brown oil, 5-Diamine (Intermediate 3) (1.1 g, 94% yield).
中间体4：3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-7-(甲硫基)-1H-吲哚Intermediate 4: 3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-7-(methylthio)-1H-indole
Figure PCTCN2021120199-appb-000074
Figure PCTCN2021120199-appb-000074
第一步：(2-氟-6-硝基苯基)(甲基)硫烷4bStep 1: (2-Fluoro-6-nitrophenyl)(methyl)sulfane 4b
Figure PCTCN2021120199-appb-000075
Figure PCTCN2021120199-appb-000075
将2,3-二氟硝基苯4a(20g,0.126mol)溶于DMSO(200mL)中，向其中加入甲硫醇钠(9.7g,0.138mol)，室温搅拌过夜。向反应液中加入水(600mL)淬灭，用乙酸乙酯(300mL×2)萃取得到有机相。有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩旋干得到残留物。残留物通过硅胶柱(石油醚/乙酸乙酯(v/v)＝10/1)纯化后得到棕色油状化合物(2-氟-6-硝基苯基)(甲基)硫烷4b(12g,产率51％)。2,3-Difluoronitrobenzene 4a (20 g, 0.126 mol) was dissolved in DMSO (200 mL), sodium methanethiolate (9.7 g, 0.138 mol) was added thereto, and the mixture was stirred at room temperature overnight. Water (600 mL) was added to the reaction solution to quench, and the organic phase was obtained by extraction with ethyl acetate (300 mL×2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to obtain a residue. The residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v) = 10/1) to give brown oily compound (2-fluoro-6-nitrophenyl)(methyl)sulfane 4b (12 g, yield 51%).
MS m/z(ESI)：188.1[M+1]MS m/z(ESI): 188.1[M+1]
第二步：6-氟-7-(甲硫基)-1H-吲哚4cStep 2: 6-Fluoro-7-(methylthio)-1H-indole 4c
Figure PCTCN2021120199-appb-000076
Figure PCTCN2021120199-appb-000076
将(2-氟-6-硝基苯基)(甲基)硫烷4b(10g,0.0535mol)溶于干燥的四氢呋喃(170mL)中并用N 2置换空气3次。然后降至-78℃,加入1.5mol/L的乙烯基溴化镁(169mL，0.254mol)。添加完成后自然升温至室温并搅拌3个小时。向反应液中加入饱和氯化铵(200mL)淬灭，接着用乙酸乙酯(100mL×2)萃取，合并有机相。有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩旋干得到残留物。残留物过硅胶柱(石油醚/乙酸乙酯(v/v)＝10/1)纯化后得到棕色油状化合物6-氟-7-(甲硫基)-1H-吲哚4c(4.5g,产率46％)。 (2-Fluoro-6-nitrophenyl)(methyl)sulfane 4b (10 g, 0.0535 mol) was dissolved in dry tetrahydrofuran (170 mL) and the air was replaced with N2 3 times. Then it was lowered to -78°C, and 1.5 mol/L of vinylmagnesium bromide (169 mL, 0.254 mol) was added. After the addition was completed, the temperature was naturally warmed to room temperature and stirred for 3 hours. Saturated ammonium chloride (200 mL) was added to the reaction solution for quenching, followed by extraction with ethyl acetate (100 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to obtain a residue. The residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v)=10/1) to obtain 6-fluoro-7-(methylthio)-1H-indole 4c (4.5 g, yield) as a brown oily compound. rate 46%).
MS m/z(ESI)：182.1[M+1]MS m/z(ESI): 182.1[M+1]
第三步：3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-7-(甲硫基)-1H-吲哚(中间体4)Step 3: 3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-7-(methylthio)-1H-indole (Intermediate 4)
Figure PCTCN2021120199-appb-000077
Figure PCTCN2021120199-appb-000077
将2,4-二氯-5-(三氟甲基)嘧啶(8.0g，37.29mmol)溶于干燥的1,2-二氯乙烷(30mL)中并用N 2置换空气3次。加入无水三氯化铝(4.98g，37.29mmol)，然后加热至80℃搅拌半个小时。将6-氟-7-(甲硫基)-1H-吲哚4c(4.5g,24.86mmol)的1,2-二氯乙烷溶液(10ml)缓慢加入反应体系，保持80℃继续搅拌2个小时。降至室温，向反应液中加入二氯甲烷(30mL)、冰水(30mL)，分液，水相用二氯甲烷(20mL×2)萃取。合并有机相，有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩得到残留物。残留物通过硅胶柱(石油醚/乙酸乙酯(v/v)＝3/1)纯化后得到淡黄色固体化合物3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-7-(甲硫基)-1H-吲哚(中间体4)(4.8g,产率54％)。 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (8.0 g, 37.29 mmol) was dissolved in dry 1,2-dichloroethane (30 mL) and the air was replaced with N2 3 times. Anhydrous aluminum trichloride (4.98 g, 37.29 mmol) was added, then heated to 80°C and stirred for half an hour. A solution of 6-fluoro-7-(methylthio)-1H-indole 4c (4.5 g, 24.86 mmol) in 1,2-dichloroethane (10 ml) was slowly added to the reaction system, and kept stirring at 80 °C for 2 Hour. The temperature was lowered to room temperature, dichloromethane (30 mL) and ice water (30 mL) were added to the reaction solution, and the layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL×2). The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v)=3/1) to give a pale yellow solid compound 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl) -6-Fluoro-7-(methylthio)-1H-indole (Intermediate 4) (4.8 g, 54% yield).
MS m/z(ESI)：360.1[M-1]MS m/z(ESI): 360.1[M-1]
中间体5：3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(甲硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚Intermediate 5: 3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylthio)-1-((2-(trimethylsilyl)ethoxy yl)methyl)-1H-indole
Figure PCTCN2021120199-appb-000078
Figure PCTCN2021120199-appb-000078
第一步：7-(甲硫基)-1H-吲哚5bThe first step: 7-(methylthio)-1H-indole 5b
Figure PCTCN2021120199-appb-000079
Figure PCTCN2021120199-appb-000079
将7-溴-1H-吲哚5a(4.0g,20.4mmol)溶于二甲苯(15mL)中，加入硫代丁酸S-酸甲酯(12.0g,102mmol)、二氯化钯(1.0g,5.65mmol)、叔丁醇钾(8.5g,75.9mmol)、9,9-二甲基-4,5-双(二苯基膦)杂蒽(1.0g,5.65mmol),N 2置换3次，升温至140℃反应12个小时。加入水(50mL)和乙酸乙酯(150ml)，分液，保留有机相。水相再用乙酸乙酯(10mL×2)萃取，合并有机相。将有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品通过硅胶柱(石油醚/乙酸乙酯＝5/1)纯化后得到黄色油状化合物7-(甲硫基)-1H-吲哚5b(2.6g，产率79％)。 7-Bromo-1H-indole 5a (4.0 g, 20.4 mmol) was dissolved in xylene (15 mL), S-methyl thiobutyrate (12.0 g, 102 mmol), palladium dichloride (1.0 g) were added , 5.65mmol), potassium tert-butoxide (8.5g, 75.9mmol), 9,9-dimethyl-4,5-bis(diphenylphosphine)xanthene (1.0g, 5.65mmol), N 2 replacement 3 time, the temperature was raised to 140 °C for 12 hours. Water (50 mL) and ethyl acetate (150 mL) were added, the layers were separated, and the organic phase was retained. The aqueous phase was extracted with ethyl acetate (10 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column (petroleum ether/ethyl acetate=5/1) to obtain compound 7-(methylthio)-1H-indole 5b (2.6 g, yield 79%) as yellow oil.
MS m/z(ESI)：164.1[M+1]MS m/z(ESI): 164.1[M+1]
第二步：3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(甲硫基)-1H-吲哚5cStep 2: 3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylthio)-1H-indole 5c
Figure PCTCN2021120199-appb-000080
Figure PCTCN2021120199-appb-000080
将2,4-二氯-5-(三氟甲基)嘧啶(8.0g,37.0mmol)溶于无水二氯乙烷(50mL)中，加入无水三氯化铝(4.8g，36.0mmol)，N 2置换3次。然后升温至80℃，反应30分钟。加入7-(甲硫基)-1H-吲哚5b(2g,12.3mmol)，反应1个小时。加入水(100mL)和乙酸乙酯(150ml)，分液，保留有机相。水相用乙酸乙酯(30mL×2)萃取，合并有机相。将有机相用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品通过硅胶柱(石油醚/乙酸乙酯＝5/1)纯化后得到黄色固体化合物3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(甲硫基)-1H-吲哚5c(1.0g，产率24％)。 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (8.0 g, 37.0 mmol) was dissolved in anhydrous dichloroethane (50 mL), and anhydrous aluminum trichloride (4.8 g, 36.0 mmol) was added ), N 2 was replaced 3 times. Then, the temperature was raised to 80°C, and the reaction was carried out for 30 minutes. 7-(Methylthio)-1H-indole 5b (2 g, 12.3 mmol) was added and reacted for 1 hour. Water (100 mL) and ethyl acetate (150 mL) were added, the layers were separated, and the organic phase was retained. The aqueous phase was extracted with ethyl acetate (30 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column (petroleum ether/ethyl acetate=5/1) to obtain a yellow solid compound 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylthio) )-1H-indole 5c (1.0 g, 24% yield).
MS m/z(ESI)：344.1[M+1]MS m/z(ESI): 344.1[M+1]
第三步：3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(甲硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚(中间体5)The third step: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylthio)-1-((2-(trimethylsilyl)ethoxy yl)methyl)-1H-indole (Intermediate 5)
Figure PCTCN2021120199-appb-000081
Figure PCTCN2021120199-appb-000081
将3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(甲硫基)-1H-吲哚5c(1.0g,2.92mmol)溶于N,N-二甲基甲酰胺(10mL)中，N 2置换3次。然后降至0度，加入钠氢(180mg,4.38mmol)，反应30分钟。然后加入(2-(氯甲氧基)乙基)三甲基硅烷(540mg,4.10mmol)，升温至室温，反应4个小时。加入水(20mL) 和乙酸乙酯(15mL)，分液，保留有机相。水相再用乙酸乙酯(10mL×2)萃取，合并有机相。将有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品通过硅胶柱(石油醚/乙酸乙酯＝5/1)纯化后得到黄色油状化合物3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(甲硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚中间体5(600mg，产率43％)。 3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylthio)-1H-indole 5c (1.0 g, 2.92 mmol) was dissolved in N,N-di In methylformamide (10 mL), N 2 was replaced 3 times. Then it was lowered to 0 degrees, sodium hydrogen (180 mg, 4.38 mmol) was added, and the reaction was carried out for 30 minutes. Then (2-(chloromethoxy)ethyl)trimethylsilane (540 mg, 4.10 mmol) was added, the temperature was raised to room temperature, and the reaction was carried out for 4 hours. Water (20 mL) and ethyl acetate (15 mL) were added, the layers were separated, and the organic phase was retained. The aqueous phase was extracted with ethyl acetate (10 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column (petroleum ether/ethyl acetate=5/1) to obtain yellow oily compound 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylthio) )-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole Intermediate 5 (600 mg, 43% yield).
MS m/z(ESI)：474.1[M+1]MS m/z(ESI): 474.1[M+1]
中间体6：1-(氨甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯Intermediate 6: tert-butyl 1-(aminomethyl)-5-azaspiro[2.4]heptane-5-carboxylate
Figure PCTCN2021120199-appb-000082
Figure PCTCN2021120199-appb-000082
第一步：1-(羟甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯6bThe first step: 1-(hydroxymethyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 6b
Figure PCTCN2021120199-appb-000083
Figure PCTCN2021120199-appb-000083
将5-(叔丁氧羰基)-5-氮杂螺[2.4]庚烷-1-羧酸6a(900mg,3.73mmol)溶于无水四氢呋喃(20mL)中，N 2置换3次。降温至0℃，加入硼烷四氢呋喃(1mol/L)(7.5ml,7.5mmol),升温至室温，反应3个小时。加入水(20mL)和乙酸乙酯(15ml)，分液。水相用乙酸乙酯(10mL×2)萃取，合并有机相。将有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩得到油状的化合物1-(羟甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯6b(920mg，粗品)，直接用于下一步反应。 5-(tert-Butoxycarbonyl)-5-azaspiro[2.4]heptane-1-carboxylic acid 6a (900 mg, 3.73 mmol) was dissolved in dry tetrahydrofuran (20 mL) and replaced with N 3 times. The temperature was lowered to 0° C., borane tetrahydrofuran (1 mol/L) (7.5 ml, 7.5 mmol) was added, the temperature was raised to room temperature, and the reaction was carried out for 3 hours. Water (20 mL) and ethyl acetate (15 mL) were added to separate the layers. The aqueous phase was extracted with ethyl acetate (10 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an oily compound 1-(hydroxymethyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-Butyl ester 6b (920 mg, crude) was used directly in the next reaction.
MS m/z(ESI)：228.4[M+1]MS m/z(ESI): 228.4[M+1]
第二步：1-(((甲基磺酰基)氧基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯6cThe second step: 1-(((methylsulfonyl)oxy)methyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 6c
Figure PCTCN2021120199-appb-000084
Figure PCTCN2021120199-appb-000084
将1-(羟甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯6b(920mg,4.05mmol)溶于二氯甲烷(20mL)中，加入三乙胺(1.23g，12.16mmol)，N 2置换3次。降温至0℃，滴加甲基磺酰氯(923mg，8.1mmol),升温至室温，反应3个小时。加入水(20mL)和乙酸乙酯(15ml)，分液，水相用乙酸乙酯(10mL×2)萃取，合并有机相。有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩得到固体状的化合物1-(((甲基磺酰基)氧基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯6c(1g，产率81.3％)。 1-(Hydroxymethyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 6b (920 mg, 4.05 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.23 mmol) was added g, 12.16 mmol), replaced by N 3 times. The temperature was lowered to 0° C., methylsulfonyl chloride (923 mg, 8.1 mmol) was added dropwise, the temperature was raised to room temperature, and the reaction was carried out for 3 hours. Water (20 mL) and ethyl acetate (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a solid compound 1-(((methylsulfonyl)oxy)methyl)-5-azaspiro[ 2.4] Heptane-5-carboxylate tert-butyl ester 6c (1 g, 81.3% yield).
MS m/z(ESI)：306.4[M+1]MS m/z(ESI): 306.4[M+1]
第三步：1-(叠氮甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯6dThe third step: 1-(azidomethyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 6d
Figure PCTCN2021120199-appb-000085
Figure PCTCN2021120199-appb-000085
将1-(((甲基磺酰基)氧基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯6c(1g,3.97mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入叠氮化钠(774mg，11.9mmol)，N 2置换3次。升温至80℃，反应16个小时。加入水(20mL)和乙酸乙酯(15ml)，分液，水相用乙酸乙酯(10mL×2)萃取，合并有机相。有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩得到油状的化合物1-(叠氮甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯6d(900mg，粗品)，直接用于下一步反应。 1-(((methylsulfonyl)oxy)methyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 6c (1 g, 3.97 mmol) was dissolved in N,N-di To methylformamide (10 mL), sodium azide (774 mg, 11.9 mmol) was added and replaced with N 2 three times. The temperature was raised to 80°C, and the reaction was carried out for 16 hours. Water (20 mL) and ethyl acetate (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an oily compound 1-(azidomethyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-Butyl ester 6d (900 mg, crude) was used directly in the next reaction.
MS m/z(ESI)：253.3[M+1]MS m/z(ESI): 253.3[M+1]
第四步：1-(氨甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(中间体6)The fourth step: tert-butyl 1-(aminomethyl)-5-azaspiro[2.4]heptane-5-carboxylate (intermediate 6)
Figure PCTCN2021120199-appb-000086
Figure PCTCN2021120199-appb-000086
将1-(叠氮甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯6d(900mg,3.57mmol)溶于无水甲醇(20mL)中，加入10％钯炭(100mg)，氢气置换3次，室温反应5个小时。将反应混合物用硅藻土过滤，浓缩得到油状的化合物1-(氨甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯中间体6(800mg，产率99％)。1-(Azidomethyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 6d (900 mg, 3.57 mmol) was dissolved in anhydrous methanol (20 mL), and 10% palladium on carbon was added (100 mg), replaced by hydrogen 3 times, and reacted at room temperature for 5 hours. The reaction mixture was filtered through celite and concentrated to give compound 1-(aminomethyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester intermediate 6 (800 mg, 99% yield) as an oil ).
MS m/z(ESI)：227.4[M+1]MS m/z(ESI): 227.4[M+1]
中间体7：6-((4-(7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁基酯Intermediate 7: 6-((4-(7-(Dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2- Azaspiro[3.3]heptane-2-carboxylate tert-butyl ester
Figure PCTCN2021120199-appb-000087
Figure PCTCN2021120199-appb-000087
第一步：6-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁基酯7bThe first step: 6-((4-(7-Bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3] Heptane-2-carboxylate tert-butyl ester 7b
Figure PCTCN2021120199-appb-000088
Figure PCTCN2021120199-appb-000088
将7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚1B(450mg,1.19mmol)和6-氨基-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(303mg,1.43mmol)溶解在四氢呋喃(10mL)中，加入DIEA(462mg,3.57mmol)，氮气置换，升温至70℃，反应2小时。反应液降至室温，浓缩旋干得到残留物。该残留物通过反相柱(ACN:H2O＝5:95到95:5)纯化后得到黄色固体产物6-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁基酯7b(400mg，收率60％)。7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole 1B (450 mg, 1.19 mmol) and 6-amino-2-azaspiro[3.3 ] Heptane-2-carboxylate tert-butyl ester (303 mg, 1.43 mmol) was dissolved in tetrahydrofuran (10 mL), DIEA (462 mg, 3.57 mmol) was added, nitrogen was replaced, the temperature was raised to 70° C. and reacted for 2 hours. The reaction solution was cooled to room temperature, concentrated and spin-dried to obtain a residue. The residue was purified by reverse phase column (ACN:H2O=5:95 to 95:5) to give the product 6-(((4-(7-bromo-1H-indol-3-yl)-5-() as a yellow solid Trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester 7b (400 mg, 60% yield).
MS m/z(ESI)：552.1[M+1]MS m/z(ESI): 552.1[M+1]
第二步：6-((4-(7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁基酯(中间体7)Step 2: 6-((4-(7-(Dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2- Azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (Intermediate 7)
Figure PCTCN2021120199-appb-000089
Figure PCTCN2021120199-appb-000089
氮气保护下，将6-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁基酯7b(240mg，0.43mmol)溶解在DMF(5mL)中,加入二甲基氧化膦(170mg，2.15mmol)、醋酸钯(20mg，0.08mmol)、磷酸钾(184mg，0.86mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(75mg，0.13mmol)，微波中150℃反应1小时。降至室温，加入乙酸乙酯，用饱和的食盐水水洗涤。分离有几层，用无水硫酸钠干燥，然后浓缩得到残留物。残留物过硅胶柱(石油醚/乙酸乙酯(v/v)＝1/1)纯化后得到淡黄色固体化合物6-((4-(7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁基酯中间体7(110mg，收率47％)。Under nitrogen protection, 6-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3 ] Heptane-2-carboxylate tert-butyl ester 7b (240mg, 0.43mmol) was dissolved in DMF (5mL), dimethylphosphine oxide (170mg, 2.15mmol), palladium acetate (20mg, 0.08mmol), phosphoric acid were added Potassium (184 mg, 0.86 mmol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (75 mg, 0.13 mmol) were reacted in a microwave at 150° C. for 1 hour. The temperature was lowered to room temperature, ethyl acetate was added, and the mixture was washed with saturated brine. The layers were separated, dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v)=1/1) to obtain a pale yellow solid compound 6-((4-(7-(dimethylphosphoryl)-1H-indole) -3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester Intermediate 7 (110 mg, yield 47%).
MS m/z(ESI)：550.1[M+1]MS m/z(ESI): 550.1[M+1]
中间体8：6-((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁基酯Intermediate 8: 6-((4-(6-Cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl) Amino)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester
Figure PCTCN2021120199-appb-000090
Figure PCTCN2021120199-appb-000090
第一步：6-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁基酯8bThe first step: 6-((4-(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-nitrogen Heteraspiro[3.3]heptane-2-carboxylate tert-butyl ester 8b
Figure PCTCN2021120199-appb-000091
Figure PCTCN2021120199-appb-000091
将7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈3A(2.00g,5.0mmol)和6-氨基-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(1.30g,6.00mmol)溶解在异丙醇(40mL)中，加入DIEA(1.94g,15.0mmol)，氮气置换，升温至100℃，反应2小时。降至室温，直接浓缩，残留物通过反相柱(ACN:H2O＝5:95到95:5)纯化后得到固体化合物6-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁基酯8b(1.30g白色固体，收率45.1％)。7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 3A (2.00 g, 5.0 mmol) and 6-amino-2 - Azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (1.30 g, 6.00 mmol) was dissolved in isopropanol (40 mL), DIEA (1.94 g, 15.0 mmol) was added, nitrogen was replaced, and the temperature was raised to 100 ℃, the reaction was carried out for 2 hours. After cooling to room temperature, it was directly concentrated, and the residue was purified by reverse phase column (ACN:H2O=5:95 to 95:5) to obtain solid compound 6-((4-(7-bromo-6-cyano-1H-indone). dol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester 8b (1.30 g white solid, yield 45.1%).
MS m/z(ESI)：577.1[M+1]MS m/z(ESI): 577.1[M+1]
第二步：6-((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁基酯(中间体8)Step 2: 6-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl) Amino)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (Intermediate 8)
Figure PCTCN2021120199-appb-000092
Figure PCTCN2021120199-appb-000092
将6-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁 基酯8b(200mg，0.34mmol)溶解在DMF(10mL)中，加入二甲基氧化膦(135mg,1.73mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(254mg,0.34mmol)、磷酸钾(368mg,1.70mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(200mg,0.34mmol)，氮气保护，微波反应，于150℃反应1小时。降至室温，加入乙酸乙酯，用饱和的食盐水水洗，合并有机层。干燥有机层，然后浓缩，残留物通过硅胶柱(石油醚/乙酸乙酯(v/v)＝1/1)纯化后得到淡黄色固体化合物6-((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁基酯中间体8(112mg，产率56.3％)。6-((4-(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[ 3.3] Heptane-2-carboxylate tert-butyl ester 8b (200 mg, 0.34 mmol) was dissolved in DMF (10 mL), and dimethylphosphine oxide (135 mg, 1.73 mmol), [1,1'-bis(bis(bis(bis(bis(bis(bis(bis(bis(bis(bis))) were then added. Phenylphosphino)ferrocene]palladium dichloride (254 mg, 0.34 mmol), potassium phosphate (368 mg, 1.70 mmol) and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene ( 200 mg, 0.34 mmol), nitrogen protection, microwave reaction, reaction at 150 ° C for 1 hour. The temperature was lowered to room temperature, ethyl acetate was added, the mixture was washed with saturated brine, and the organic layers were combined. The organic layer was dried and then concentrated, and the residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v)=1/1) to obtain a pale yellow solid compound 6-((4-(6-cyano-7- (Dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-Butyl ester intermediate 8 (112 mg, 56.3% yield).
MS m/z(ESI)：575.1[M+1]MS m/z(ESI): 575.1[M+1]
实施例1Example 1
(S)-二甲基((3-(2-(哌啶-3-基氨基)-5-(三氟甲基)-嘧啶-4-基)-1H-吲哚-7-基)亚氨基)-λ 6-亚砜的制备(化合物1) (S)-Dimethyl((3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)-pyrimidin-4-yl)-1H-indol-7-yl)idene Preparation of amino)-λ 6 -sulfoxide (Compound 1)
Figure PCTCN2021120199-appb-000093
Figure PCTCN2021120199-appb-000093
第一步：7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚1BThe first step: 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole 1B
Figure PCTCN2021120199-appb-000094
Figure PCTCN2021120199-appb-000094
向2,4-二氯-5-(三氟甲基)嘧啶(3.98g,15.3mmol)的DCE(30mL)溶液中在氮气保护下添加三氯化铝(3.06g,22.95mmol)，由此产生的混合物在80℃下搅拌30分钟。反应混合物冷却到室温，加入7-溴-吲哚1A(3g、15.3mmol)。将得到的混合物在80℃下继续搅拌3h，随着时间的推移，溶液变红。然后将混合物倒入碎冰和乙酸乙酯中，分层分离。将合并的有机层用无水硫酸钠干燥，过滤，减压浓缩得到粗品残留物。粗品残留物经硅胶(乙酸乙酯/石油醚＝0～50％)洗脱后柱层析纯化，得到7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚1B(2.8g,48.59％)。To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3.98 g, 15.3 mmol) in DCE (30 mL) was added aluminum trichloride (3.06 g, 22.95 mmol) under nitrogen, thereby The resulting mixture was stirred at 80°C for 30 minutes. The reaction mixture was cooled to room temperature and 7-bromo-indole 1A (3 g, 15.3 mmol) was added. The resulting mixture was stirred for a further 3 h at 80°C, the solution turned red over time. The mixture was then poured into crushed ice and ethyl acetate and the layers were separated. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by column chromatography after eluting with silica gel (ethyl acetate/petroleum ether=0-50%) to obtain 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidine-4- base)-1H-indole 1B (2.8 g, 48.59%).
第二步：(S)-3-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-甲酸叔丁酯1CStep 2: (S)-3-((4-(7-Bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1- tert-Butyl formate 1C
Figure PCTCN2021120199-appb-000095
Figure PCTCN2021120199-appb-000095
将1B(500mg,1.33mmol)、DIEA(458.9mg,3.98mmol)、(S)-3-氨基哌啶-1-羧酸叔丁酯(319mg,1.59mmol)与DCM(30mL)的混合物在氮气保护下在25℃下搅拌18h。当TLC显示原料消耗后，加入40mL水稀释反应混合物，用100mLx3的乙酸乙酯萃取有机层，用盐水洗涤有机相，用无水硫酸钠干燥。将混合物减压浓缩得到粗品化合物。将粗品化合物用硅胶(乙酸乙酯/石油醚＝0-50％)洗脱得到(S)-3-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-甲酸叔丁酯1C(350mg,48.78％)。A mixture of 1B (500 mg, 1.33 mmol), DIEA (458.9 mg, 3.98 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (319 mg, 1.59 mmol) and DCM (30 mL) was mixed under nitrogen It was stirred at 25 °C for 18 h under protection. When TLC showed that the starting material was consumed, 40 mL of water was added to dilute the reaction mixture, the organic layer was extracted with 100 mL x 3 of ethyl acetate, the organic phase was washed with brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give the crude compound. The crude compound was eluted with silica gel (ethyl acetate/petroleum ether=0-50%) to give (S)-3-((4-(7-bromo-1H-indol-3-yl)-5-(tris Fluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 1C (350 mg, 48.78%).
第三步：(S)-3-((4-(7-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-氨基)哌啶-1-羧酸叔丁基酯1DThe third step: (S)-3-((4-(7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl) -5-(Trifluoromethyl)pyrimidine-2-amino)piperidine-1-carboxylate tert-butyl ester 1D
Figure PCTCN2021120199-appb-000096
Figure PCTCN2021120199-appb-000096
在0℃下向1C(150mg,0.277mmol)的THF(15mL)溶液中加入氢化钠(16.6mg,0.416mmol)，氮气气氛下搅拌30分钟。添加SEMCl(55.5mg,0.333mmol)。反应混合物在氮气气氛下在25℃下继续搅拌2h。加水稀释后用乙酸乙酯(2x100ml)萃取。有机相合并后用盐水清洗，干燥(Na 2SO 4)和减压浓缩。得到的粗品通过硅胶过滤提纯，用0％到50％的乙酸乙酯/石油醚洗脱，得到(S)-3-((4-(7-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯1D(107mg，57.48％)。 To a solution of 1C (150 mg, 0.277 mmol) in THF (15 mL) was added sodium hydride (16.6 mg, 0.416 mmol) at 0°C, followed by stirring under nitrogen atmosphere for 30 minutes. SEMCl (55.5 mg, 0.333 mmol) was added. The reaction mixture was stirred for a further 2 h at 25 °C under nitrogen atmosphere. After dilution with water, it was extracted with ethyl acetate (2x100ml). The combined organic phases were washed with brine, dried ( Na2SO4 ) and concentrated under reduced pressure. The resulting crude product was purified by filtration through silica gel eluting with 0% to 50% ethyl acetate/petroleum ether to give (S)-3-((4-(7-bromo-1-((2-(trimethyl) Silyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 1D (107 mg, 57.48%).
第四步：(S)-3-((4-(7-((二甲基(氧代)-λ 6-硫亚基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-烷基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-甲酸叔丁基酯1E The fourth step: (S)-3-((4-(7-((dimethyl(oxo)-λ 6 -sulfanylidene)amino)-1-((2-(trimethylsilyl) )ethoxy)methyl)-1H-indol-3-alkyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester 1E
Figure PCTCN2021120199-appb-000097
Figure PCTCN2021120199-appb-000097
将1D(107mg,0.159mmol)、Pd 2(dba)3(14.6mg,0.015mmol)、Johnphos(9.52mg,0.031mmol)、NaOtBu(46mg,0.478mmol)、亚氨基二甲基-λ 6-亚砜(29.7mg,0.319mmol)溶于1,4-二氧六环(10mL)中，在80℃和在氮气保护条件下搅拌4小时。当TLC显示原料消耗尽后，加入30mL水稀释反应混合物， 用50mLx3的乙酸乙酯提取有机层，用盐水洗涤有机相，用无水硫酸钠干燥。将混合物减压浓缩，得到粗品，硅胶柱层析纯化(乙酸乙酯/石油醚＝0-50％)，得到(S)-3-((4-(7-((二甲基(氧代)-λ 6-亚硫烷基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-甲酸叔丁基酯1E(58mg,53.23％)。 1D (107 mg, 0.159 mmol), Pd 2 (dba) 3 (14.6 mg, 0.015 mmol), Johnphos (9.52 mg, 0.031 mmol), NaOtBu (46 mg, 0.478 mmol), iminodimethyl-λ 6 -idene The sulfone (29.7 mg, 0.319 mmol) was dissolved in 1,4-dioxane (10 mL) and stirred at 80 °C under nitrogen for 4 h. When TLC showed that the starting material was consumed, 30 mL of water was added to dilute the reaction mixture, the organic layer was extracted with 50 mL x 3 of ethyl acetate, the organic phase was washed with brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-50%) to obtain (S)-3-((4-(7-((dimethyl(oxo) )-λ 6 -sulfinyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoro Methyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester 1E (58 mg, 53.23%).
第五步：(S)-二甲基((3-(2-(哌啶-3-基氨基)-5-(三氟甲基)-嘧啶-4-基)-1H-吲哚-7-基)亚氨基)-λ 6-亚砜的制备(化合物1) The fifth step: (S)-dimethyl((3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)-pyrimidin-4-yl)-1H-indole-7 Preparation of -yl)imino)-λ 6 -sulfoxide (Compound 1)
Figure PCTCN2021120199-appb-000098
Figure PCTCN2021120199-appb-000098
在1E(58mg,0.084mmol)的DCM(8ml)溶液中加入三氟乙酸(5mL)。反应混合物在室温下搅拌2小时。混合物在减压下浓缩。在残液中加入THF(8mL)和NH 4OH(4mL)，室温搅拌2h。残液用水(20mL)稀释，乙酸乙酯(2x40mL)提取。所得有机层用Na 2SO 4干燥，减压浓缩，得到残留粗品。用Prep-HPLC(仪器:Gilson；Flow:25mL/min；流动相A:0.1％NH 4OH inwater，流动相B:CAN；A与B的体积比为45％)对残留粗品进行纯化，得到化合物1(2mg,10.27％)白色固体。 To a solution of 1E (58 mg, 0.084 mmol) in DCM (8 ml) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. THF (8 mL) and NH 4 OH (4 mL) were added to the residue, and the mixture was stirred at room temperature for 2 h. The residue was diluted with water (20 mL) and extracted with ethyl acetate (2 x 40 mL). The resulting organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a residual crude product. The residual crude product was purified by Prep-HPLC (instrument: Gilson; Flow: 25 mL/min; mobile phase A: 0.1% NH 4 OH inwater, mobile phase B: CAN; the volume ratio of A to B was 45%) to obtain the compound 1 (2 mg, 10.27%) as a white solid.
MS m/z(ESI):453.1[M+1]；MS m/z(ESI): 453.1[M+1];
1H NMR(400MHz,DMSO-D6)δ11.37(d,1H),8.52(d,1H),7.92(dd,1H),7.66(d,2H),6.98(t,1H),6.84(d,1H),3.91(d,1H),3.27(s,6H),3.05(d,1H),2.79(d,1H),2.45(d,2H),2.03–1.87(m,1H),1.64(d,1H),1.56–1.37(m,2H)。1H NMR(400MHz, DMSO-D6)δ11.37(d,1H), 8.52(d,1H), 7.92(dd,1H), 7.66(d,2H), 6.98(t,1H), 6.84(d, 1H), 3.91(d, 1H), 3.27(s, 6H), 3.05(d, 1H), 2.79(d, 1H), 2.45(d, 2H), 2.03–1.87(m, 1H), 1.64(d , 1H), 1.56–1.37 (m, 2H).
实施例2Example 2
反式-(3-(2-((3-氨基环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦(化合物2)trans-(3-(2-((3-aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide ( Compound 2)
Figure PCTCN2021120199-appb-000099
Figure PCTCN2021120199-appb-000099
第一步：反式-N 1-(4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)环己烷-1,3-二胺2A The first step: trans-N 1 -(4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)cyclohexane-1,3- Diamine 2A
Figure PCTCN2021120199-appb-000100
Figure PCTCN2021120199-appb-000100
将1B(50mg，0.132mmol)、DIEA(51mg，0.398mmol)、反式-1,3-环己烷二胺(18.19mg，0.159mmol)在DCM(8ml)中的混合物在氮气气氛下于25℃搅拌18小时。TLC显示原料已消耗后，通过添加40mL水稀释反应混合物。有机层用乙酸乙酯(50ml×3)萃取，有机相用盐水洗涤，用无水硫酸钠干燥。将混合物在减压下浓缩得到粗制化合物，将其通过硅胶柱色谱法纯化，用(乙酸乙酯/石油醚＝0-50％)洗脱，得到反式-N 1-(4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)环己烷-1,3-二胺2A(55mg，91.18％)。 A mixture of 1B (50 mg, 0.132 mmol), DIEA (51 mg, 0.398 mmol), trans-1,3-cyclohexanediamine (18.19 mg, 0.159 mmol) in DCM (8 ml) was added under nitrogen at 25 °C was stirred for 18 hours. After TLC showed that the starting material had been consumed, the reaction mixture was diluted by adding 40 mL of water. The organic layer was extracted with ethyl acetate (50 ml×3), and the organic phase was washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography eluting with (ethyl acetate/petroleum ether=0-50%) to give trans-N1-(4-( 7 -Bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)cyclohexane-1,3-diamine 2A (55 mg, 91.18%).
第二步：反式-(3-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)环己基)氨基甲酸叔丁基酯2BThe second step: trans-(3-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclohexyl)carbamic acid tert-butyl ester 2B
Figure PCTCN2021120199-appb-000101
Figure PCTCN2021120199-appb-000101
在25℃下向2A(55mg，0.121mmol)和DIEA(46.9mg，0.363mmol)的DCM(10mL)溶液中加入Boc 2O(52.8mg，0.242mmol)。将反应混合物在氮气气氛下在25℃搅拌18小时。减压浓缩反应物。残 余物用水稀释，并用乙酸乙酯萃取(2×100ml)。有机相用盐水洗涤，无水硫酸钠干燥，浓缩，残余物通过硅胶柱色谱纯化，用(乙酸乙酯/石油醚＝0-50％)洗脱，得到反式-(3-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)环己基)氨基甲酸叔丁基酯2B(60mg，89.39％)。 To a solution of 2A (55 mg, 0.121 mmol) and DIEA (46.9 mg, 0.363 mmol) in DCM (10 mL) at 25 °C was added Boc2O (52.8 mg , 0.242 mmol). The reaction mixture was stirred at 25°C for 18 hours under nitrogen atmosphere. The reaction was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2 x 100 ml). The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography, eluting with (ethyl acetate/petroleum ether=0-50%) to give trans-(3-((4- (7-Bromo-lH-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclohexyl)carbamate tert-butyl ester 2B (60 mg, 89.39%).
第三步：反式-(3-((4-(7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)环己基)氨基甲酸叔丁基酯2CThe third step: trans-(3-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) cyclohexyl) tert-butyl carbamate 2C
Figure PCTCN2021120199-appb-000102
Figure PCTCN2021120199-appb-000102
将化合物2B(60mg，0.108mmol)、二甲基氧化膦(12.67mg，0.162mmol)、Pd(OAc) 2(2.4mg，0.01mmol)、K 3PO 4(68.92mg，0.324mmol)、Xantphos(6.2mg,0.01mmol)加入到DMF(8ml)溶液中，于150℃搅拌2h，并用氮气保护。TLC显示原料耗尽后，将反应混合物用10mL水稀释。有机层用乙酸乙酯(20ml×3)萃取，有机相用盐水洗涤，用无水硫酸钠干燥。减压浓缩，得到粗化合物。将其通过硅胶柱色谱纯化，用(乙酸乙酯/石油醚＝0-50％)洗脱，得到反式-(3-((4-(7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)环己基)氨基甲酸叔丁基酯2C(43mg，72.04％)。 Compound 2B (60 mg, 0.108 mmol), dimethylphosphine oxide (12.67 mg, 0.162 mmol), Pd(OAc) 2 (2.4 mg, 0.01 mmol), K 3 PO 4 (68.92 mg, 0.324 mmol), Xantphos ( 6.2 mg, 0.01 mmol) was added to DMF (8 ml) solution, stirred at 150 °C for 2 h, and protected with nitrogen. After TLC showed consumption of starting material, the reaction mixture was diluted with 10 mL of water. The organic layer was extracted with ethyl acetate (20 ml×3), and the organic phase was washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave crude compound. It was purified by silica gel column chromatography eluting with (ethyl acetate/petroleum ether=0-50%) to give trans-(3-((4-(7-(dimethylphosphoryl)-1H-indone) Indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclohexyl)carbamate tert-butyl ester 2C (43 mg, 72.04%).
第四步：反式-(3-(2-((3-氨基环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦(化合物2)The fourth step: trans-(3-(2-((3-aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylform phosphine oxide (compound 2)
Figure PCTCN2021120199-appb-000103
Figure PCTCN2021120199-appb-000103
将化合物2C(43mg，0.077mmol)和TFA(1ml)在DCM(8ml)中的混合物在25℃下在氮气保护下搅拌1h。TLC显示原料耗尽后，通过添加30mL水稀释反应混合物。有机层用乙酸乙酯(30ml×3)萃取，有机相用盐水洗涤，用无水硫酸钠干燥。将混合物在减压下浓缩得到粗品，通过在硅胶上进行柱色谱法来纯化，用(DCM/MeOH＝0-10％)洗脱，得到反式-(3-(2-((3-氨基环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦(化合物2)(20mg，56.8％)。A mixture of compound 2C (43 mg, 0.077 mmol) and TFA (1 ml) in DCM (8 ml) was stirred at 25 °C for 1 h under nitrogen protection. After TLC showed consumption of starting material, the reaction mixture was diluted by adding 30 mL of water. The organic layer was extracted with ethyl acetate (30 ml×3), and the organic phase was washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel eluting with (DCM/MeOH=0-10%) to give trans-(3-(2-((3-amino Cyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-lH-indol-7-yl)dimethylphosphine oxide (compound 2) (20 mg, 56.8%).
MS m/z(ESI):452.2[M+1]；MS m/z(ESI): 452.2[M+1];
1H NMR(400MHz,DMSO-D6)δ8.61(s,1H),8.29(s,1H),7.92(s,1H),7.50(dd,J＝13.1,7.5Hz, 1H),7.28(t,J＝6.8Hz,1H),4.38(s,1H),3.39(s,2H),2.12(s,1H),1.76(dd,J＝44.7,27.7Hz,12H),1.44(d,J＝38.8Hz,2H),1.25–1.11(m,2H)。 1 H NMR (400MHz, DMSO-D6) δ 8.61(s, 1H), 8.29(s, 1H), 7.92(s, 1H), 7.50(dd, J=13.1, 7.5Hz, 1H), 7.28(t , J=6.8Hz, 1H), 4.38(s, 1H), 3.39(s, 2H), 2.12(s, 1H), 1.76(dd, J=44.7, 27.7Hz, 12H), 1.44(d, J= 38.8Hz, 2H), 1.25–1.11 (m, 2H).
化合物2的拆分：化合物2(20mg)用Chiral-HPLC制备色谱分离纯化(
Figure PCTCN2021120199-appb-000104
5μm，流动相A：正己烷，流动相B：EtOH(0.1％DEA)，A与B的体积比为80:20，流速：1mL/min，分离时间20分钟)，获得化合物2A(7mg)和化合物2B(6mg)。 Resolution of compound 2: Compound 2 (20 mg) was separated and purified by Chiral-HPLC preparative chromatography (
Figure PCTCN2021120199-appb-000104
5 μm, mobile phase A: n-hexane, mobile phase B: EtOH (0.1% DEA), the volume ratio of A to B is 80:20, flow rate: 1 mL/min, separation time 20 minutes) to obtain compound 2A (7 mg) and Compound 2B (6 mg).
Figure PCTCN2021120199-appb-000105
Figure PCTCN2021120199-appb-000105
化合物2A：在色谱柱中保留时间8.57min；Compound 2A: retention time in chromatographic column 8.57min;
MS m/z(ESI):452.0[M+1]；MS m/z(ESI): 452.0[M+1];
化合物2B：在色谱柱中保留时间10.29min；Compound 2B: retention time in chromatographic column 10.29min;
MS m/z(ESI):452.1[M+1]。MS m/z(ESI): 452.1[M+1].
实施例3Example 3
反式-3-(2-((3-氨基环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈(化合物3)trans-3-(2-((3-aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6 -carbonitrile (compound 3)
Figure PCTCN2021120199-appb-000106
Figure PCTCN2021120199-appb-000106
第一步：7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈3AThe first step: 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 3A
Figure PCTCN2021120199-appb-000107
Figure PCTCN2021120199-appb-000107
将7-溴-1H-吲哚-6-甲腈中间体1(200mg,0.91mmol)、2,4-二氯-5-(三氟甲基)嘧啶(393mg，1.82mmol)溶于干燥的1,2-二氯乙烷(10mL)中并N2置换空气3次。加入无水三氯化铝(363mg，2.73mmol)并于封管中加热至110℃，搅拌9个小时。降至室温，向反应液中加入二氯甲烷(10ml)和冰水(10mL)，分液，水相用二氯甲烷(10mL×2)萃取，合并有机相。有机相用饱和食盐水(20mL×2)洗涤，室温无水硫酸钠干燥，过滤，浓缩得到残留物。将残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝3:1)得到淡黄色固体状的化合物7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈3A(70mg,产率19％)。7-Bromo-1H-indole-6-carbonitrile Intermediate 1 (200 mg, 0.91 mmol), 2,4-dichloro-5-(trifluoromethyl)pyrimidine (393 mg, 1.82 mmol) were dissolved in dry 1,2-Dichloroethane (10 mL) and N2 replaced the air 3 times. Anhydrous aluminum trichloride (363 mg, 2.73 mmol) was added and heated to 110°C in a sealed tube and stirred for 9 hours. The temperature was lowered to room temperature, dichloromethane (10 ml) and ice water (10 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with dichloromethane (10 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate at room temperature, filtered, and concentrated to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3:1) to obtain compound 7-bromo-3-(2-chloro-5-(trifluoromethyl) as a pale yellow solid yl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 3A (70 mg, 19% yield).
MS m/z(ESI)：400.8[M-1]。MS m/z (ESI): 400.8 [M-1].
第二步：反式-3-(2-((3-氨基环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-溴-1H-吲哚-6-甲腈3BThe second step: trans-3-(2-((3-aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-bromo-1H-indole-6-methyl Nitrile 3B
Figure PCTCN2021120199-appb-000108
Figure PCTCN2021120199-appb-000108
将7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈3A(70mg,0.18mmol)溶于无水四氢呋喃(3mL)中，加入反式-环己烷-1,3-二胺(114mg,1mmol)，N 2置换3次。升温至60℃，反应12个小时。降至室温，减压浓缩得类棕色油状物粗品，其为反式-3-(2-((3-氨基环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-溴-1H-吲哚-6-甲腈3B(140mg，粗品)。 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 3A (70 mg, 0.18 mmol) was dissolved in dry tetrahydrofuran (3 mL) ), trans-cyclohexane-1,3-diamine (114 mg, 1 mmol) was added, and N 2 was replaced 3 times. The temperature was raised to 60°C, and the reaction was carried out for 12 hours. Cooled to room temperature and concentrated under reduced pressure to give a crude brown oil, which is trans-3-(2-((3-aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 7-Bromo-1H-indole-6-carbonitrile 3B (140 mg, crude).
MS m/z(ESI)：479.3[M+1]。MS m/z (ESI): 479.3 [M+1].
第三步：反式-(3-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)环己基)氨基甲酸叔丁基酯3CThe third step: trans-(3-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) Cyclohexyl) tert-butyl carbamate 3C
Figure PCTCN2021120199-appb-000109
Figure PCTCN2021120199-appb-000109
将粗品3B(140mg,0.29mmol)溶于四氢呋喃(3ml)中，加入N,N-二异丙基乙胺(113mg，0.89mmol)和一缩二碳酸二叔丁酯(194mg，0.89mmol)，N 2置换3次，室温反应一个小时。将反应液浓缩，乙 酸乙酯溶解后用制备板分离提纯(石油醚/乙酸乙酯(v/v)＝3:1)，浓缩得淡黄色固体，其为反式-(3-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)环己基)氨基甲酸叔丁基酯3C(25mg，产率15％)。 The crude product 3B (140 mg, 0.29 mmol) was dissolved in tetrahydrofuran (3 ml), N,N-diisopropylethylamine (113 mg, 0.89 mmol) and di-tert-butyl dicarbonate (194 mg, 0.89 mmol) were added, The N2 was replaced 3 times, and the reaction was carried out at room temperature for one hour. The reaction solution was concentrated, dissolved in ethyl acetate, separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v)=3:1), and concentrated to obtain a light yellow solid, which was trans-(3-((4 -(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclohexyl)carbamate tert-butyl ester 3C (25 mg, yield 15%).
MS m/z(ESI)：579.4[M+1]。MS m/z (ESI): 579.4 [M+1].
第四步：反式-(3-((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)环己基)氨基甲酸叔丁基酯3DThe fourth step: trans-(3-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine- 2-yl)amino)cyclohexyl)carbamate tert-butyl ester 3D
Figure PCTCN2021120199-appb-000110
Figure PCTCN2021120199-appb-000110
将3C(25mg,0.04mmol)、磷酸三钾(46mg,0.22mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(23mg,0.04mmol)、醋酸钯(9mg,0.04mmol)、二甲基氧化膦(17mg,0.22mmol)溶于干燥N,N-二甲基甲酰胺(2mL)中，升至150℃反应2小时。将反应液冷却至室温，加入水(10mL)和乙酸乙酯(10ml)，分液，水相用乙酸乙酯(10mL×2)萃取。将合并的有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。所得残留物用制备板分离提纯(石油醚/乙酸乙酯(v/v)＝1：1，)得到类白色固体状的化合物，其为反式-(3-((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)环己基)氨基甲酸叔丁基酯3D(15mg，产率60％)。3C (25mg, 0.04mmol), Tripotassium Phosphate (46mg, 0.22mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (23mg, 0.04mmol), Palladium acetate (9mg , 0.04 mmol), and dimethyl phosphine oxide (17 mg, 0.22 mmol) were dissolved in dry N,N-dimethylformamide (2 mL), and the temperature was raised to 150° C. for 2 hours. The reaction solution was cooled to room temperature, water (10 mL) and ethyl acetate (10 mL) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v)=1:1,) to give the compound as an off-white solid, which was trans-(3-((4-(6-cyano) tert-butyl-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclohexyl)carbamate 3D (15 mg , the yield is 60%).
MS m/z(ESI)：577.3[M+1]。MS m/z (ESI): 577.3 [M+1].
第五步：反式-3-(2-((3-氨基环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈(化合物3)The fifth step: trans-3-(2-((3-aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H- Indole-6-carbonitrile (Compound 3)
Figure PCTCN2021120199-appb-000111
Figure PCTCN2021120199-appb-000111
将3D(15mg,0.026mmol)溶于二氯甲烷(1mL)中，加入三氟乙酸(0.5ml)，室温反应一个小时。将反应混合物减压浓缩，残留物加碳酸钠水溶液调制碱性。加入水(10mL)和乙酸乙酯(10ml)，分液，水相用乙酸乙酯(10mL×2)萃取。将合并的有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。将残留物用甲醇溶解并用制备板分离提纯(二氯甲烷/甲醇(v/v)＝8:1)得到白色固体状的化合物，其为反式-3-(2-((3-氨基环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈3D (15 mg, 0.026 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 ml) was added, and the reaction was carried out at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and the residue was made alkaline by adding an aqueous sodium carbonate solution. Water (10 mL) and ethyl acetate (10 mL) were added, the solution was separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in methanol and purified by preparative plate separation (dichloromethane/methanol (v/v)=8:1) to give the compound as a white solid, which was trans-3-(2-((3-amino ring Hexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile
(化合物3)(3mg，产率24％)。(Compound 3) (3 mg, 24% yield).
MS m/z(ESI)：477.0[M+1]；MS m/z(ESI): 477.0[M+1];
1H NMR(400MHz,CD 3OD)δ8.58(m,2H),8.17(s,1H),7.65(m,1H),4.59(m,1H),4.41(m,1H),2.14(s,3H),2.11(s,3H),1.90(m,1H),1.78(m,4H),1.52–1.40(m,1H),1.29(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 8.58(m, 2H), 8.17(s, 1H), 7.65(m, 1H), 4.59(m, 1H), 4.41(m, 1H), 2.14(s , 3H), 2.11 (s, 3H), 1.90 (m, 1H), 1.78 (m, 4H), 1.52–1.40 (m, 1H), 1.29 (m, 2H).
实施例4Example 4
顺式-3-(2-((3-氨基环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈(化合物4)cis-3-(2-((3-aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6 -carbonitrile (compound 4)
Figure PCTCN2021120199-appb-000112
Figure PCTCN2021120199-appb-000112
参照实施例3的合成方法，按照上面的步骤，以顺式-1,3-环己二胺盐酸盐为原料，合成得到化合物4。Referring to the synthesis method of Example 3, following the above steps, using cis-1,3-cyclohexanediamine hydrochloride as a raw material, compound 4 was synthesized.
MS m/z(ESI)：477.1[M+1]；MS m/z(ESI): 477.1[M+1];
1H NMR(400MHz,CD 3OD)δ8.53(m,2H),8.05(s,1H),7.51(s,1H),2.45(m,1H),2.22–2.15(m,1H),2.08(s,3H),2.05(s,3H),2.03–1.95(m,2H),1.65–1.43(m,2H),1.38–1.34(m,2H),1.33(s,2H)。 1 H NMR (400MHz, CD 3 OD) δ 8.53(m, 2H), 8.05(s, 1H), 7.51(s, 1H), 2.45(m, 1H), 2.22–2.15(m, 1H), 2.08 (s, 3H), 2.05 (s, 3H), 2.03–1.95 (m, 2H), 1.65–1.43 (m, 2H), 1.38–1.34 (m, 2H), 1.33 (s, 2H).
实施例5Example 5
顺式-(3-(2-((3-氨基环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦(化合物5)cis-(3-(2-((3-Aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide ( Compound 5)
Figure PCTCN2021120199-appb-000113
Figure PCTCN2021120199-appb-000113
参照实施例2的合成方法，按照上面的步骤，以顺式-1,3-环己二胺盐酸盐为原料，合成得到化合物5。Referring to the synthesis method of Example 2, following the above steps, using cis-1,3-cyclohexanediamine hydrochloride as a raw material, compound 5 was synthesized.
MS m/z(ESI)：452.1[M+1]；MS m/z(ESI): 452.1[M+1];
1H NMR(400MHz,CD 3OD)δ8.54(s,2H),7.96(s,1H),7.50(dd,1H),7.33(s,1H),4.11(m,1H),3.19(m,1H),2.45(m,1H),2.02(m,4H),1.93(s,3H),1.90(s,3H),1.59–1.29(m,4H)。 1 H NMR (400MHz, CD 3 OD) δ 8.54(s, 2H), 7.96(s, 1H), 7.50(dd, 1H), 7.33(s, 1H), 4.11(m, 1H), 3.19(m , 1H), 2.45 (m, 1H), 2.02 (m, 4H), 1.93 (s, 3H), 1.90 (s, 3H), 1.59–1.29 (m, 4H).
实施例6Example 6
顺式-二甲基(3-(2-((3-(甲基氨基)环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)氧化膦(化合物6)cis-dimethyl(3-(2-((3-(methylamino)cyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl ) phosphine oxide (compound 6)
Figure PCTCN2021120199-appb-000114
Figure PCTCN2021120199-appb-000114
参照实施例2的合成方法，按照上面的步骤，以中间体2为原料，合成得到化合物6。Referring to the synthesis method of Example 2, following the above steps, using intermediate 2 as a raw material, compound 6 was synthesized.
MS m/z(ESI)：466.0[M+1]；MS m/z(ESI): 466.0[M+1];
1H NMR(400MHz,CD 3OD)δ8.55(m,3H),7.96(s,1H),7.50(dd,1H),7.33(m,1H),4.08(m,1H),3.13(m,1H),2.78–2.62(m,3H),2.53(d,1H),2.15(m,2H),2.02(m,2H),1.93(s,3H),1.89(s,3 H),1.45–1.27(m,4H)。 1 H NMR (400MHz, CD 3 OD) δ 8.55(m, 3H), 7.96(s, 1H), 7.50(dd, 1H), 7.33(m, 1H), 4.08(m, 1H), 3.13(m ,1H),2.78–2.62(m,3H),2.53(d,1H),2.15(m,2H),2.02(m,2H),1.93(s,3H),1.89(s,3H),1.45 -1.27(m, 4H).
实施例7Example 7
(S)-((6-氟-3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)亚氨基)二甲基-λ 6-亚砜(化合物7) (S)-((6-Fluoro-3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)idene Amino)dimethyl-λ 6 -sulfoxide (Compound 7)
Figure PCTCN2021120199-appb-000115
Figure PCTCN2021120199-appb-000115
第一步：7-溴-6-氟-1H-吲哚7BStep 1: 7-Bromo-6-fluoro-1H-indole 7B
Figure PCTCN2021120199-appb-000116
Figure PCTCN2021120199-appb-000116
将2-溴-1-氟-3-硝基苯7A(10g,45.67mmol)溶于干燥的四氢呋喃(30mL)中并用N 2置换空气3次，降至-78℃。加入1.5mol/L乙烯基溴化镁(91ml，136.99mmol),添加完成后自然升温至室温搅拌3个小时。向反应液中加入饱和氯化铵(100ml)淬灭，然后加入乙酸乙酯(100mL)，分液。水相用乙酸乙酯(50mL×2)萃取，合并有机相。有机相用饱和食盐水(100mL×2)洗涤，室温无水硫酸钠干燥，过滤，浓缩。所得残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝30:1)得到棕色油状物7-溴-6-氟-1H-吲哚7B(2g,产率21％)。 2-Bromo-1-fluoro-3-nitrobenzene 7A (10 g, 45.67 mmol) was dissolved in dry tetrahydrofuran (30 mL) and the air was replaced 3 times with N 2 to -78 °C. 1.5 mol/L vinylmagnesium bromide (91 ml, 136.99 mmol) was added, and after the addition was completed, the temperature was naturally raised to room temperature and stirred for 3 hours. Saturated ammonium chloride (100 mL) was added to the reaction solution to quench, and then ethyl acetate (100 mL) was added to separate the layers. The aqueous phase was extracted with ethyl acetate (50 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate at room temperature, filtered and concentrated. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=30:1) to obtain 7-bromo-6-fluoro-1H-indole 7B (2 g, yield 21%) as a brown oily substance ).
MS m/z(ESI)：214.1[M+1]。MS m/z (ESI): 214.1 [M+1].
第二步：7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚7CStep 2: 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indole 7C
Figure PCTCN2021120199-appb-000117
Figure PCTCN2021120199-appb-000117
将2,4-二氯-5-(三氟甲基)嘧啶(3g，13.89mmol)溶于干燥的1,2-二氯乙烷(30mL)中并N 2置换空气3次。加入无水三氯化铝(1.9g，14.29mmol)并加热至85℃，搅拌半个小时。将7-溴-6-氟-1H-吲哚7B(2g,9.39mmol)的1,2-二氯乙烷溶液(10ml)缓慢加入反应体系中，保持85℃继续搅拌2个小时。降至室温后，向反应液中加入二氯甲烷(30ml)和冰水(30mL)，分液，水相用二氯甲烷(20mL×2)萃取。将合并的有机相用饱和食盐水(20mL×2)洗涤。在室温用无水硫酸钠干燥，过滤，浓缩。将所得残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝3:1)得到淡黄色固体状的化合物7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚7C(1.7g,产率46％)。 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (3 g, 13.89 mmol) was dissolved in dry 1,2-dichloroethane (30 mL) and N 2 replaced air 3 times. Anhydrous aluminum trichloride (1.9 g, 14.29 mmol) was added and heated to 85°C and stirred for half an hour. A solution of 7-bromo-6-fluoro-1H-indole 7B (2 g, 9.39 mmol) in 1,2-dichloroethane (10 ml) was slowly added to the reaction system, and stirring was continued at 85° C. for 2 hours. After cooling to room temperature, dichloromethane (30 ml) and ice water (30 mL) were added to the reaction solution, and the layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL×2). The combined organic phases were washed with saturated brine (20 mL×2). Dry over anhydrous sodium sulfate at room temperature, filter, and concentrate. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3:1) to obtain compound 7-bromo-3-(2-chloro-5-(trifluoro) as a pale yellow solid Methyl)pyrimidin-4-yl)-6-fluoro-lH-indole 7C (1.7 g, 46% yield).
MS m/z(ESI)：391.4[M-1]。MS m/z (ESI): 391.4 [M-1].
第三步：7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚7DThe third step: 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy) yl)methyl)-1H-indole 7D
Figure PCTCN2021120199-appb-000118
Figure PCTCN2021120199-appb-000118
将7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚7C(1.3g,3.3mmol)溶于N,N-二甲基甲酰胺(20ml)中，降温至0℃,N 2置换3次。然后加入氢化钠(60％)(160mg，3.98mmol)，反应一个小时。接着加入2-(三甲基甲硅烷基)乙氧甲基氯，室温继续反应两个小时。向反应液中加入乙酸乙酯(30ml)和冰水(30mL)，分液。水相用乙酸乙酯(20mL×2)萃取。将合并的有机相用饱和食盐水(20mL×2)洗涤，于室温用无水硫酸钠干燥，过滤，浓缩。将所得残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝10:1)得到淡黄色固体状的化合物7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚7D(500mg,产率29％)。 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indole 7C (1.3 g, 3.3 mmol) was dissolved in N,N-di In methylformamide (20 ml), the temperature was lowered to 0 °C, and N 2 was replaced 3 times. Then sodium hydride (60%) (160 mg, 3.98 mmol) was added and reacted for one hour. Next, 2-(trimethylsilyl)ethoxymethyl chloride was added, and the reaction was continued for two hours at room temperature. Ethyl acetate (30 ml) and ice water (30 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate at room temperature, filtered and concentrated. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10:1) to obtain compound 7-bromo-3-(2-chloro-5-(trifluoro) as a pale yellow solid Methyl)pyrimidin-4-yl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole 7D (500 mg, 29% yield).
MS m/z(ESI)：524.4[M+1]。MS m/z (ESI): 524.4 [M+1].
第四步：(S)-3-((4-(7-溴-6-氟-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯7EThe fourth step: (S)-3-((4-(7-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole- 3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 7E
Figure PCTCN2021120199-appb-000119
Figure PCTCN2021120199-appb-000119
将7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚7D(400mg,0.765mmol)溶于无水四氢呋喃(8mL)中，加入3-氨基哌啶-1-羧酸叔丁基酯(306mg,1.53mmol)和N,N-二异丙基乙胺(396mg,3.07mmol),N 2置换3次。升温至60℃，反应4个小时。降至室温，减压浓缩，将所得残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝3:1)得到淡黄色固体状的化合物7E(300mg，产率57％)。 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl base)-1H-indole 7D (400 mg, 0.765 mmol) was dissolved in dry tetrahydrofuran (8 mL), tert-butyl 3-aminopiperidine-1-carboxylate (306 mg, 1.53 mmol) and N,N- Diisopropylethylamine (396 mg, 3.07 mmol), replaced 3 times with N 2 . The temperature was raised to 60°C, and the reaction was carried out for 4 hours. It was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3:1) to obtain compound 7E (300 mg, yield 57%) as a pale yellow solid ).
第五步：(S)-3-((4-(7-((二甲基(氧代)-λ 6-硫亚基)氨基)-6-氟-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯7F The fifth step: (S)-3-((4-(7-((dimethyl(oxo)-λ 6 -sulfanylidene)amino)-6-fluoro-1-(((2-(trimethyl) Silyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 7F
Figure PCTCN2021120199-appb-000120
Figure PCTCN2021120199-appb-000120
将(S)-3-((4-(7-溴-6-氟-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯7E(50mg,0.074mmol)、三[二亚苄基丙酮]二钯(13.6mg,0.014mmol)、2-(二叔丁基膦)联苯(4.45mg,0.014mmol)、叔丁醇钠(14.3mg,0.14mmol)、二甲基亚氨基砜(20.8mg,0.223mmol)溶于干燥1.4-二氧六环(5mL)中，升至80℃反应2小时。将反应液冷却至室温，浓缩，加入水(10mL)和乙酸乙酯(15ml)，分液，水相用乙酸乙酯(10mL×2)萃取。将合并的有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。将所得残留物用制备板分离提纯(石油醚/乙酸乙酯(v/v)＝1：1，)得到类白色固体状的化合物，其为(S)-3-((4-(7-((二甲基(氧代)-λ 6-硫亚基)氨基)-6-氟-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯7F(46mg，产率90％)。 (S)-3-((4-(7-Bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl )-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 7E (50 mg, 0.074 mmol), tris[dibenzylideneacetone]dipalladium (13.6 mg) , 0.014mmol), 2-(di-tert-butylphosphine)biphenyl (4.45mg, 0.014mmol), sodium tert-butoxide (14.3mg, 0.14mmol), dimethylimidosulfone (20.8mg, 0.223mmol) dissolved in In dry 1.4-dioxane (5 mL), the temperature was raised to 80°C for 2 hours. The reaction solution was cooled to room temperature, concentrated, water (10 mL) and ethyl acetate (15 ml) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v)=1:1,) to obtain the compound as an off-white solid, which was (S)-3-((4-(7- ((Dimethyl(oxo)-λ 6 -sulfanylidene)amino)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole -3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 7F (46 mg, 90% yield).
MS m/z(ESI)：701.4[M+1]。MS m/z (ESI): 701.4 [M+1].
第六步：(S)-((6-氟-1-(羟甲基)-3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)亚氨基)二甲基-λ 6-亚砜7G The sixth step: (S)-((6-fluoro-1-(hydroxymethyl)-3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl )-1H-indol-7-yl)imino)dimethyl-λ 6 -sulfoxide 7G
Figure PCTCN2021120199-appb-000121
Figure PCTCN2021120199-appb-000121
将(S)-3-((4-(7-((二甲基(氧代)-λ 6-硫亚基)氨基)-6-氟-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯7F(46mg,0.065mmol)溶于二氯甲烷(3ml)和 三氟乙酸(3ml)中，室温搅拌反应一个小时。将反应混合物减压浓缩，得到棕色油状物粗品，其为(S)-((6-氟-1-(羟甲基)-3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)亚氨基)二甲基-λ 6-亚砜7G(24mg，产率73％)。 (S)-3-((4-(7-((Dimethyl(oxo)-λ 6 -sulfanylidene)amino)-6-fluoro-1-((2-(trimethylsilane yl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 7F (46 mg , 0.065 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (3 ml), and the reaction was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure to give crude brown oil as (S)-((6-fluoro-1-(hydroxymethyl)-3-(2-(piperidin-3-ylamino)-5- (Trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)imino)dimethyl-λ6 - sulfoxide 7G (24 mg, 73% yield).
第七步：(S)-((6-氟-3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)亚氨基)二甲基-λ 6-亚砜(化合物7) Step 7: (S)-((6-Fluoro-3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-7 -yl)imino)dimethyl-λ 6 -sulfoxide (compound 7)
Figure PCTCN2021120199-appb-000122
Figure PCTCN2021120199-appb-000122
将粗品(S)-((6-氟-1-(羟甲基)-3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)亚氨基)二甲基-λ 6-亚砜7G(24mg,0.047mmol)溶于四氢呋喃(3mL)中，加入氨水(1ml),室温反应三十分钟。将反应混合物减压浓缩，残留物加甲醇溶解，然后通过制备型HPLC制备分离提纯(仪器：Gilson.流量：25mL/min，流动相A：水中含有0.1％NH 4OH，流动相B：ACN,A:B(V/V)＝45％)得到白色固体状的化合物(S)-((6-氟-3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)亚氨基)二甲基-λ 6-亚砜，其为化合物7(6mg，产率26％)。 The crude (S)-((6-fluoro-1-(hydroxymethyl)-3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-Indol-7-yl)imino)dimethyl-λ 6 -sulfoxide 7G (24 mg, 0.047 mmol) was dissolved in tetrahydrofuran (3 mL), ammonia water (1 mL) was added, and the reaction was carried out at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol, and then preparatively separated and purified by preparative HPLC (apparatus: Gilson. Flow rate: 25 mL/min, mobile phase A: 0.1% NH 4 OH in water, mobile phase B: ACN, A:B(V/V)=45%) to give compound (S)-((6-fluoro-3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl) as white solid ) pyrimidin-4-yl)-1H-indol-7-yl)imino)dimethyl-λ6-sulfoxide, which was compound 7 ( 6 mg, 26% yield).
MS m/z(ESI)：471.1[M+1]；MS m/z(ESI): 471.1[M+1];
1H NMR(400MHz,DMSO-D6)δ11.46(s,1H),8.53(d,1H),7.95(ddd,1H),7.76–7.65(m,2H),6.96(dd,1H),3.91(m,1H),3.26(s,6H),3.05(d,1H),2.79(d,1H),2.44(m,2H),1.96(m,1H),1.64(m,1H),1.52–1.38(m,2H)。 1 H NMR (400MHz, DMSO-D6) δ 11.46 (s, 1H), 8.53 (d, 1H), 7.95 (ddd, 1H), 7.76–7.65 (m, 2H), 6.96 (dd, 1H), 3.91 (m, 1H), 3.26(s, 6H), 3.05(d, 1H), 2.79(d, 1H), 2.44(m, 2H), 1.96(m, 1H), 1.64(m, 1H), 1.52– 1.38 (m, 2H).
实施例8Example 8
反式-((3-(2-((3-氨基环己基)氨基)-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚-7-基)亚氨基)二甲基-λ 6-亚砜(化合物8) trans-((3-(2-((3-aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indol-7-yl)idene Amino)dimethyl-λ 6 -sulfoxide (compound 8)
Figure PCTCN2021120199-appb-000123
Figure PCTCN2021120199-appb-000123
参照实施例7的合成方法，按照上面的步骤，以反式-1,3-环己二胺为原料，合成得到化合物8。Referring to the synthesis method of Example 7, following the above steps, using trans-1,3-cyclohexanediamine as a raw material, compound 8 was synthesized.
MS m/z(ESI)：485.2[M+1]；MS m/z(ESI): 485.2[M+1];
1H NMR(400MHz,DMSO-D6)δ11.53(s,1H),8.56(d,1H),8.08–7.68(m,3H),6.97(m,1H),4.37(m,1H),3.27(s,6H),1.99(m,1H),1.72(m,6H),1.49–1.33(m,1H),1.25(m,1H)。 1 H NMR (400MHz, DMSO-D6) δ 11.53 (s, 1H), 8.56 (d, 1H), 8.08–7.68 (m, 3H), 6.97 (m, 1H), 4.37 (m, 1H), 3.27 (s, 6H), 1.99 (m, 1H), 1.72 (m, 6H), 1.49–1.33 (m, 1H), 1.25 (m, 1H).
实施例9Example 9
(S)-N-(3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)甲磺酰胺(化合物9)(S)-N-(3-(2-(Piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)methanesulfonamide ( Compound 9)
Figure PCTCN2021120199-appb-000124
Figure PCTCN2021120199-appb-000124
第一步：3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-硝基-1H-吲哚9BThe first step: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-nitro-1H-indole 9B
Figure PCTCN2021120199-appb-000125
Figure PCTCN2021120199-appb-000125
将三氯化铝(2.40g,18.0mmol)和2,4-二氯-5-(三氟甲基)嘧啶(7.90g,36.5mmol)溶解在DCE(50mL)中，氮气置换，升温至80℃，反应30分钟。然后加入7-硝基-1H-吲哚1(2.0g,12.3mmol),反应12小时。降至室温，向反应液里加入乙酸乙酯(200mL)，用饱和食盐水(200mL×3)洗涤。将所得有机相用无水硫酸钠干燥，过滤，浓缩。将所得残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:15～1:8)得到固体化合物3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-硝基-1H-吲哚9B(1.70g，产率40.4％)。Aluminum trichloride (2.40 g, 18.0 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (7.90 g, 36.5 mmol) were dissolved in DCE (50 mL), nitrogen was replaced, and the temperature was raised to 80 ℃, the reaction was carried out for 30 minutes. Then 7-nitro-1H-indole 1 (2.0 g, 12.3 mmol) was added, and the reaction was carried out for 12 hours. The temperature was lowered to room temperature, ethyl acetate (200 mL) was added to the reaction solution, and the mixture was washed with saturated brine (200 mL×3). The resulting organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:15～1:8) to obtain the solid compound 3-(2-chloro-5-(trifluoromethyl)pyrimidine) -4-yl)-7-nitro-1H-indole 9B (1.70 g, 40.4% yield).
MS m/z(ESI)：343.0[M+1]。MS m/z (ESI): 343.0 [M+1].
第二步：(S)-3-((4-(7-硝基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁酯9CThe second step: (S)-3-((4-(7-nitro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1 - tert-butyl carboxylate 9C
Figure PCTCN2021120199-appb-000126
Figure PCTCN2021120199-appb-000126
将3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-硝基-1H-吲哚9B(1.70g,4.95mmol)溶解在异丙醇(30mL)中，加入DIEA(1.60g,12.44mmol)和(S)-3-氨基哌啶-1-羧酸叔丁酯(1.20g,6.00mmol)，于100℃反应12小时。降至室温，浓缩。将所得残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:5～1:1)得到白色固体化合物(S)-3-((4-(7-硝基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁酯9C(900mg，产率36.4％)。3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-nitro-1H-indole 9B (1.70 g, 4.95 mmol) was dissolved in isopropanol (30 mL), DIEA (1.60 g, 12.44 mmol) and (S)-3-aminopiperidine-1-carboxylate tert-butyl ester (1.20 g, 6.00 mmol) were added, and the reaction was carried out at 100° C. for 12 hours. Cooled to room temperature and concentrated. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:5～1:1) to obtain a white solid compound (S)-3-((4-(7-nitro) -1H-Indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 9C (900 mg, 36.4% yield).
MS m/z(ESI)：507.1[M+1]。MS m/z (ESI): 507.1 [M+1].
第三步：(S)-3-((4-(7-氨基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁酯9DThe third step: (S)-3-((4-(7-amino-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1- tert-Butyl Carboxylate 9D
Figure PCTCN2021120199-appb-000127
Figure PCTCN2021120199-appb-000127
将(S)-3-((4-(7-硝基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁酯9C(900mg，1.77mmol)溶解在乙醇(10mL)和饱和的氯化铵水溶液(10mL)中，加入铁粉(5g,89.28mmol)，氮气保护，于80℃反应2小时。降至室温，过滤，浓缩。将所得残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:5～1:1)得到灰色固体化合物(S)-3-((4-(7-氨基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁酯9D(800mg)。(S)-3-((4-(7-Nitro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid Tert-butyl ester 9C (900 mg, 1.77 mmol) was dissolved in ethanol (10 mL) and saturated aqueous ammonium chloride solution (10 mL), iron powder (5 g, 89.28 mmol) was added, and the reaction was carried out at 80° C. for 2 hours under nitrogen protection. Cooled to room temperature, filtered and concentrated. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:5～1:1) to obtain gray solid compound (S)-3-((4-(7-amino- 1H-Indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 9D (800 mg).
MS m/z(ESI)：477.1[M+1]。MS m/z (ESI): 477.1 [M+1].
第四步：(S)-3-((4-(7-(甲基磺酰胺基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-甲酸叔丁酯9EThe fourth step: (S)-3-((4-(7-(methylsulfonamido)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) piperidine-1-carboxylate tert-butyl ester 9E
Figure PCTCN2021120199-appb-000128
Figure PCTCN2021120199-appb-000128
将(S)-3-((4-(7-氨基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁酯9D(300mg，0.63mmol)和三乙胺(127mg，1.26mmol)溶解在二氯甲烷(5mL)中，加入甲基磺酰氯(86mg,0.75mmol)，氮气保护，室温反应2小时。将反应液浓缩除去溶剂，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:2～1:1)得到油状化合物(S)-3-((4-(7-(甲基磺酰胺基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-甲酸叔丁酯9E(120mg)。(S)-3-((4-(7-Amino-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tertiary Butyl ester 9D (300 mg, 0.63 mmol) and triethylamine (127 mg, 1.26 mmol) were dissolved in dichloromethane (5 mL), methylsulfonyl chloride (86 mg, 0.75 mmol) was added, and the reaction was carried out at room temperature for 2 hours under nitrogen protection. The reaction solution was concentrated to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:2～1:1) to obtain an oily compound (S)-3-((4-( 7-(Methylsulfonamido)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester 9E (120 mg).
MS m/z(ESI)：555.1[M+1]。MS m/z (ESI): 555.1 [M+1].
第五步：(S)-N-(3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)甲磺酰胺(化合物9)The fifth step: (S)-N-(3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl) Methanesulfonamide (Compound 9)
Figure PCTCN2021120199-appb-000129
Figure PCTCN2021120199-appb-000129
将(S)-3-((4-(7-(甲基磺酰胺基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-甲酸叔丁酯9E(120mg,0.21mmol)溶于3N的盐酸甲醇溶液(2mL)中，室温反应2小时。将反应液浓缩旋干，将所得粗品经prep-HPLC(甲酸方法)纯化。冻干得白色固体状的化合物(S)-N-(3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)甲磺酰胺甲酸盐(化合物9)(69mg，产率70.4％)。(S)-3-((4-(7-(methylsulfonamido)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine -1-Carboxylic acid tert-butyl ester 9E (120 mg, 0.21 mmol) was dissolved in a 3N hydrochloric acid methanol solution (2 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated and spun dry, and the resulting crude product was purified by prep-HPLC (formic acid method). Freeze-dried compound (S)-N-(3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole- 7-yl)methanesulfonamide formate (compound 9) (69 mg, 70.4% yield).
MS m/z(ESI)：455.1[M+1]；MS m/z(ESI): 455.1[M+1];
1H-NMR(400MHz,DMSO-D6)δ11.77(s,1H),8.58(d,1H),8.31(s,1H),8.28-8.06(dd,1H),7.84(m,2H),7.16(m,2H),4.04(m,1H),3.17(m,1H),3.01(s,3H),2.97(m,1H),2.67-2.51(m,2H),2.02(m,1H),1.75(m,1H),1.60-1.46(m,2H)。 1 H-NMR (400MHz, DMSO-D6)δ11.77(s,1H), 8.58(d,1H), 8.31(s,1H), 8.28-8.06(dd,1H), 7.84(m,2H), 7.16(m, 2H), 4.04(m, 1H), 3.17(m, 1H), 3.01(s, 3H), 2.97(m, 1H), 2.67-2.51(m, 2H), 2.02(m, 1H) ,1.75(m,1H),1.60-1.46(m,2H).
实施例10Example 10
(S)-1-环丙基-N-(3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)甲磺酰胺(化合物10)(S)-1-Cyclopropyl-N-(3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-7- yl)methanesulfonamide (compound 10)
Figure PCTCN2021120199-appb-000130
Figure PCTCN2021120199-appb-000130
第一步：(S)-3-((4-(7-((环丙基甲基)磺酰胺基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-甲酸叔丁酯10AThe first step: (S)-3-((4-(7-((cyclopropylmethyl)sulfonamido)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine- 2-yl)amino)piperidine-1-carboxylate tert-butyl ester 10A
Figure PCTCN2021120199-appb-000131
Figure PCTCN2021120199-appb-000131
将(S)-3-((4-(7-氨基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁酯9D(140mg,0.29mmol)和三乙胺(90mg,0.87mmol)溶解在二氯甲烷(6mL)中，然后加入环丙基甲磺酰氯(89mg,0.58mmol)，室温搅拌2h。将反应液倒入水中，水相用乙酸乙酯萃取，合并的有机相经无水硫酸钠干燥、真空浓缩旋干得到粗品。粗品经prep-TLC纯化后得到(S)-3-((4-(7-((环丙基甲基)磺酰胺基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-甲酸叔丁酯10A(80mg，收率：45.8％，淡绿色固体)。(S)-3-((4-(7-Amino-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tertiary Butyl ester 9D (140 mg, 0.29 mmol) and triethylamine (90 mg, 0.87 mmol) were dissolved in dichloromethane (6 mL), then cyclopropylmethanesulfonyl chloride (89 mg, 0.58 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo and spun to dryness to obtain the crude product. The crude product was purified by prep-TLC to give (S)-3-((4-(7-((cyclopropylmethyl)sulfonamido)-1H-indol-3-yl)-5-(trifluoromethane) yl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester 10A (80 mg, yield: 45.8%, pale green solid).
LCMS(ESI)：595.0[M+1]。LCMS (ESI): 595.0 [M+1].
第二步：(S)-1-环丙基-N-(3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)甲磺酰胺(化合物10)The second step: (S)-1-cyclopropyl-N-(3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indium dol-7-yl)methanesulfonamide (compound 10)
Figure PCTCN2021120199-appb-000132
Figure PCTCN2021120199-appb-000132
将(S)-3-((4-(7-((环丙基甲基)磺酰胺基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-甲酸叔丁酯10A(80mg，0.13mmol)溶于HCl/二氧六环溶液(5mL)中，室温下反应1h，然后将反应液真空旋干，经prep-HPLC纯化后得到(S)-1-环丙基-N-(3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)甲磺酰胺(化合物10)(24mg，收率：36.1％，白色固体)。(S)-3-((4-(7-((cyclopropylmethyl)sulfonamido)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl ) Amino) piperidine-1-carboxylate tert-butyl ester 10A (80 mg, 0.13 mmol) was dissolved in HCl/dioxane solution (5 mL), reacted at room temperature for 1 h, and then the reaction solution was vacuum-dried, subjected to prep-HPLC After purification (S)-1-cyclopropyl-N-(3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole -7-yl)methanesulfonamide (compound 10) (24 mg, yield: 36.1%, white solid).
LC-MS(ESI)：495.1[M+1]；LC-MS (ESI): 495.1 [M+1];
1H-NMR(400MHz,DMSO-D6)δ11.73(s,1H),8.58(d,1H),8.36(s,1H),8.23-8.01(dd,1H),7.85(m,2H),7.20(m,1H),7.12(m,1H),4.07(m,1H),3.19(m,1H),3.10(d,2H),2.97(m,1H),2.67-2.51(m,2H),2.02(m,1H),1.75(m,1H),1.56(m,2H),1.00(m,1H),0.52(m,2H),0.24(m,2H)。 1 H-NMR (400MHz, DMSO-D6)δ11.73(s,1H), 8.58(d,1H), 8.36(s,1H), 8.23-8.01(dd,1H), 7.85(m,2H), 7.20(m, 1H), 7.12(m, 1H), 4.07(m, 1H), 3.19(m, 1H), 3.10(d, 2H), 2.97(m, 1H), 2.67-2.51(m, 2H) , 2.02(m, 1H), 1.75(m, 1H), 1.56(m, 2H), 1.00(m, 1H), 0.52(m, 2H), 0.24(m, 2H).
实施例11Example 11
3-(2-(((2s,3aR,5r,6aS)-5-氨基八氢并环戊二烯-2-基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈(化合物11)3-(2-(((2s,3aR,5r,6aS)-5-aminooctahydrocyclopentadien-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 7-(Dimethylphosphoryl)-1H-indole-6-carbonitrile (Compound 11)
Figure PCTCN2021120199-appb-000133
Figure PCTCN2021120199-appb-000133
第一步：3-(2-(((2s,3aR,5r,6aS)-5-氨基八氢并环戊二烯-2-基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-溴-1H-吲哚-6-甲腈11AThe first step: 3-(2-(((2s,3aR,5r,6aS)-5-aminooctahydrocyclopentadien-2-yl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl)-7-bromo-1H-indole-6-carbonitrile 11A
Figure PCTCN2021120199-appb-000134
Figure PCTCN2021120199-appb-000134
将7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈3A(300mg,0.74mmol)、(2s,3as,5s,6as)-八氢并环戊二烯-2,5-二胺(中间体3)(157mg,1.1mmol)和DIEA(289mg,2.24mmol)溶于干燥四氢呋喃(20mL)中，升至60℃反应16个小时。反应液冷却至室温，浓缩，残留物用制备板分离提纯(二氯甲烷/甲醇(v/v)＝10：1)得到淡黄色固体状的化合物3-(2-(((2s,3aR,5r,6aS)-5-氨基八氢并环戊二烯 -2-基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-溴-1H-吲哚-6-甲腈11A(1232mg，产率61％)。7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 3A (300 mg, 0.74 mmol), (2s,3as,5s ,6as)-octahydrocyclopentadiene-2,5-diamine (Intermediate 3) (157 mg, 1.1 mmol) and DIEA (289 mg, 2.24 mmol) were dissolved in dry tetrahydrofuran (20 mL) and warmed to 60 °C The reaction was carried out for 16 hours. The reaction solution was cooled to room temperature, concentrated, and the residue was separated and purified with a preparative plate (dichloromethane/methanol (v/v)=10:1) to obtain compound 3-(2-((((2s,3aR, 5r,6aS)-5-aminooctahydrocyclopentadien-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-bromo-1H-indole-6-methyl Nitrile 11A (1232 mg, 61% yield).
MS m/z(ESI)：505.7[M+1]MS m/z(ESI): 505.7[M+1]
第二步：((2s,3aR,5r,6aS)-5-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)八氢并环戊二烯-2-基)氨基甲酸叔丁基酯11BThe second step: ((2s,3aR,5r,6aS)-5-(((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine -2-yl)amino)octahydrocyclopentadien-2-yl)carbamate tert-butyl ester 11B
Figure PCTCN2021120199-appb-000135
Figure PCTCN2021120199-appb-000135
将3-(2-(((2s,3aR,5r,6aS)-5-氨基八氢并环戊二烯-2-基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-溴-1H-吲哚-6-甲腈11A(232mg,0.45mmol)和DIEA(178mg,1.38mmol)溶于四氢呋喃(10ml)中,加入一缩二碳酸二叔丁酯(150mg,0.68mmol)，室温搅拌反应一个小时。减压浓缩，残余物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)得到棕色固状物，其为((2s,3aR,5r,6aS)-5-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)八氢并环戊二烯-2-基)氨基甲酸叔丁基酯11B(132mg，产率47％)。3-(2-(((2s,3aR,5r,6aS)-5-aminooctahydrocyclopentadien-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) -7-Bromo-1H-indole-6-carbonitrile 11A (232 mg, 0.45 mmol) and DIEA (178 mg, 1.38 mmol) were dissolved in tetrahydrofuran (10 ml), and di-tert-butyl dicarbonate (150 mg, 0.68 mmol) was added. mmol), and the reaction was stirred at room temperature for one hour. It was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:1) to obtain a brown solid, which was ((2s,3aR,5r,6aS)-5- ((4-(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)octahydrocyclopentadiene-2- yl) tert-butyl carbamate 11B (132 mg, 47% yield).
MS m/z(ESI)：605.2[M+1]MS m/z(ESI): 605.2[M+1]
第三步：((2s,3aR,5r,6aS)-5-((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)八氢并环戊二烯-2-基)氨基甲酸叔丁基酯11CThe third step: ((2s,3aR,5r,6aS)-5-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-( Trifluoromethyl)pyrimidin-2-yl)amino)octahydrocyclopentadien-2-yl)carbamate tert-butyl ester 11C
Figure PCTCN2021120199-appb-000136
Figure PCTCN2021120199-appb-000136
将((2s,3aR,5r,6aS)-5-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)八氢并环戊二烯-2-基)氨基甲酸叔丁基酯11B(132mg,0.218mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(126mg,0.218mmol)、1,1'-双二苯基膦二茂铁二氯化钯(159mg,0.218mmol)、K 3PO 4(138mg,0.65mmol)和二甲基氧化膦(85mg,0.65mmol)溶于干燥的N,N-二甲基甲酰胺(8mL)中，升温至150℃，反应一个小时。减压浓缩，残留物通过制备板分离提纯(PE/EA(v/v)＝1：1得到黄色固体状的化合物((2s,3aR,5r,6aS)-5-((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)八氢并环戊二烯-2-基)氨基甲酸叔丁基酯11C(55mg，产率41％) ((2s,3aR,5r,6aS)-5-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine-2- (132 mg, 0.218 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxy Xanthene (126 mg, 0.218 mmol), 1,1'- bisdiphenylphosphinoferrocene palladium dichloride (159 mg, 0.218 mmol), K3PO4 (138 mg, 0.65 mmol) and dimethylphosphine oxide ( 85 mg, 0.65 mmol) was dissolved in dry N,N-dimethylformamide (8 mL), the temperature was raised to 150 °C, and the reaction was carried out for one hour. Concentrated under reduced pressure, the residue was separated and purified by preparative plate (PE/EA(v/v)=1:1 to obtain compound ((2s,3aR,5r,6aS)-5-((4-(6- Cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)octahydrocyclopentadien-2-yl ) tert-butyl carbamate 11C (55 mg, 41% yield)
MS m/z(ESI)：603.4[M+1]MS m/z(ESI): 603.4[M+1]
第四步：3-(2-(((2s,3aR,5r,6aS)-5-氨基八氢并环戊二烯-2-基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈(化合物11)The fourth step: 3-(2-(((2s,3aR,5r,6aS)-5-aminooctahydrocyclopentadien-2-yl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile (Compound 11)
Figure PCTCN2021120199-appb-000137
Figure PCTCN2021120199-appb-000137
将((2s,3aR,5r,6aS)-5-((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)八氢并环戊二烯-2-基)氨基甲酸叔丁基酯11C(55mg,0.091mmol)溶于DCM(3mL)和三氟乙酸(3mL)中，室温反应三个小时。减压浓缩，残留物通过制备板分离提纯(DCM/MeOH(v/v)＝10：1)得到白色固体状的化合物3-(2-(((2s,3aR,5r,6aS)-5-氨基八氢并环戊二烯-2-基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈化合物11(4mg，产率8.7％)。((2s,3aR,5r,6aS)-5-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethane 11C (55 mg, 0.091 mmol) was dissolved in DCM (3 mL) and trifluoroacetic acid (3 mL), The reaction was carried out at room temperature for three hours. Concentrated under reduced pressure, the residue was purified by preparative plate separation (DCM/MeOH(v/v)=10:1) to give compound 3-(2-(((2s,3aR,5r,6aS)-5- as a white solid Aminooctahydrocyclopentadien-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile Compound 11 (4 mg, 8.7% yield).
MS m/z(ESI)：503.0[M+1]MS m/z(ESI): 503.0[M+1]
1H NMR(400MHz,DMSO-D6)δ8.73–8.63(m,1H),8.59(d,1H),8.21(s,1H),7.96(d,1H),7.67(dd,1H),4.37(s,1H),3.42(m,2H),2.67(m,2H),2.05(s,3H),2.02(s,3H),1.78–1.67(m,6H),1.50(m,2H).1H NMR (400MHz, DMSO-D6) δ8.73–8.63(m,1H), 8.59(d,1H), 8.21(s,1H), 7.96(d,1H), 7.67(dd,1H), 4.37( s, 1H), 3.42(m, 2H), 2.67(m, 2H), 2.05(s, 3H), 2.02(s, 3H), 1.78–1.67(m, 6H), 1.50(m, 2H).
实施例12Example 12
(3-(2-(((2s,3aR,5r,6aS)-5-氨基八氢并环戊二烯-2-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基二甲基氧化膦(化合物12)(3-(2-(((2s,3aR,5r,6aS)-5-aminooctahydrocyclopentadien-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) -1H-Indol-7-yl)dimethyldimethylphosphine oxide (compound 12)
Figure PCTCN2021120199-appb-000138
Figure PCTCN2021120199-appb-000138
第一步：(2s,3aR,5r,6aS)-N2-(4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)八氢并环戊二烯-2,5-二胺12AThe first step: (2s,3aR,5r,6aS)-N2-(4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)octahydro cyclopentadiene-2,5-diamine 12A
Figure PCTCN2021120199-appb-000139
Figure PCTCN2021120199-appb-000139
将7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚1B(210mg,0.56mmol)和(2s,3as,5s,6as)-八氢并环戊二烯-2,5-二胺溶解在异丙醇(5mL)中，然后加入DIEA(217mg,1.68mmol)，氮气置换，于100℃下反应16小时。将反应液倒入水中，水相用乙酸乙酯萃取。合并的有机相经饱和食盐水洗涤，无水硫酸钠干燥，真空旋干得到粗品(2s,3aR,5r,6aS)-N2-(4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)八氢并环戊二烯-2,5-二胺12A(289mg)，粗品直接用于下一步反应。7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole 1B (210 mg, 0.56 mmol) and (2s,3as,5s,6as)-octa Hydrogenocyclopentadiene-2,5-diamine was dissolved in isopropanol (5 mL), then DIEA (217 mg, 1.68 mmol) was added, nitrogen was replaced, and the reaction was carried out at 100° C. for 16 hours. The reaction solution was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried in vacuo to obtain crude product (2s,3aR,5r,6aS)-N2-(4-(7-bromo-1H-indol-3-yl) -5-(trifluoromethyl)pyrimidin-2-yl)octahydrocyclopentadiene-2,5-diamine 12A (289 mg), the crude product was directly used in the next reaction.
LC-MS：480.1[M+H]+LC-MS: 480.1 [M+H]+
第二步：((2s,3aR,5r,6aS)-5-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)八氢并环戊二烯-2-基)氨基甲酸叔丁基酯12BStep 2: ((2s,3aR,5r,6aS)-5-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl) Amino) octahydrocyclopentadien-2-yl) tert-butyl carbamate 12B
Figure PCTCN2021120199-appb-000140
Figure PCTCN2021120199-appb-000140
将(2s,3aR,5r,6aS)-N2-(4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)八氢并环戊二烯-2,5-二胺12A(289mg,0.603mmol)溶解在二氯甲烷(10mL)中加入一缩二碳酸二叔丁酯(197mg,0.903mmol)和三乙胺(122mg,1.21mmol)，氮气置换后，室温下反应6小时。反应液真空旋除溶剂得到粗品。粗品经硅胶柱层析(乙酸乙酯/石油醚＝1/10)纯化后得到((2s,3aR,5r,6aS)-5-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)八氢并环戊二烯-2-基)氨基甲酸叔丁基酯12B(140mg，收率40％，黄色油状物)。(2s,3aR,5r,6aS)-N2-(4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)octahydrocyclopenta Diene-2,5-diamine 12A (289 mg, 0.603 mmol) was dissolved in dichloromethane (10 mL) and di-tert-butyl dicarbonate (197 mg, 0.903 mmol) and triethylamine (122 mg, 1.21 mmol) were added , after nitrogen replacement, the reaction was carried out at room temperature for 6 hours. The reaction solution was spun off to remove the solvent in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/10) to obtain ((2s,3aR,5r,6aS)-5-((4-(7-bromo-1H-indole-3- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)octahydrocyclopentadien-2-yl)carbamate tert-butyl ester 12B (140 mg, 40% yield, yellow oil) .
LC-MS：580.1[M+H]+LC-MS: 580.1 [M+H]+
第三步：((2s,3aR,5r,6aS)-5-((4-(7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)八氢并环戊二烯-2-基)氨基甲酸叔丁基酯12CThe third step: ((2s,3aR,5r,6aS)-5-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl) Pyrimidine-2-yl)amino)octahydrocyclopentadien-2-yl)carbamate tert-butyl ester 12C
Figure PCTCN2021120199-appb-000141
Figure PCTCN2021120199-appb-000141
将((2s,3aR,5r,6aS)-5-((4-(7-溴-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)八氢并环戊二烯-2-基)氨基甲酸叔丁基酯12B(140mg,0.242mmol)溶解在N,N-二甲基甲酰胺(5mL)中，加入二甲基氧化膦(94mg,1.21mmol)、磷酸钾(103mg,0.484mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(28mg,0.0484mmol)和1,1'-双二苯基膦二茂铁二氯化钯(35mg,0.0478mmol)，氮气置换后，微波150℃下反应1小时。将反应液倒入水中，水相用乙酸乙酯萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、真空旋除溶剂得到粗品。粗品经硅胶柱层析(甲醇：二氯甲烷＝1:15)分离纯化得到((2s,3aR,5r,6aS)-5-((4-(7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)八氢并环戊二烯-2-基氨基甲酸叔丁基酯12C(69mg，收率50％，黄色油状物)。((2s,3aR,5r,6aS)-5-((4-(7-bromo-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)octa tert-Butyl hydroisocyclopentadien-2-yl)carbamate 12B (140 mg, 0.242 mmol) was dissolved in N,N-dimethylformamide (5 mL), dimethylphosphine oxide (94 mg, 1.21 mmol) was added mmol), potassium phosphate (103 mg, 0.484 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (28 mg, 0.0484 mmol) and 1,1'-bisdiphenyl Phosphinoferrocene palladium dichloride (35 mg, 0.0478 mmol) was replaced with nitrogen and reacted at 150° C. for 1 hour in a microwave. The reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (methanol:dichloromethane=1:15) to obtain ((2s,3aR,5r,6aS)-5-((4-(7-(dimethylphosphoryl)-1H- Indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)octahydrocyclopentadien-2-ylcarbamate tert-butyl ester 12C (69 mg, 50% yield, yellow oil).
LC-MS：578.2[M+H] + LC-MS: 578.2 [M+H] +
第四步：3-(2-(((2s,3aR,5r,6aS)-5-氨基八氢并环戊二烯-2-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦(化合物12)The fourth step: 3-(2-(((2s,3aR,5r,6aS)-5-aminooctahydrocyclopentadien-2-yl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl)-1H-indol-7-yl)dimethylphosphine oxide (compound 12)
Figure PCTCN2021120199-appb-000142
Figure PCTCN2021120199-appb-000142
将((2s,3aR,5r,6aS)-5-((4-(7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)八氢并环戊二烯-2-基氨基甲酸叔丁基酯12C(69mg,0.12mmol)溶解在二氯甲烷(4mL)中，加入三氟乙酸(1mL)，室温下反应1小时。反应液真空旋除溶剂得到粗品。粗品经制备型HPLC纯化后冻干得到白色固体(化合物12)(14mg，收率25％)。((2s,3aR,5r,6aS)-5-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine-2 -yl)amino)octahydrocyclopentadien-2-ylcarbamate tert-butyl ester 12C (69 mg, 0.12 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature 1 hour. The reaction solution was vacuumed to remove the solvent to obtain the crude product. The crude product was purified by preparative HPLC and lyophilized to obtain a white solid (compound 12) (14 mg, yield 25%).
LC-MS：478.0[M+H] + LC-MS: 478.0 [M+H] +
1H NMR(400MHz,CD 3OD)δ8.56(d,1H),8.51(m,1H),7.95(s,1H),7.49(dd,1H),7.31(td,1H),4.52(m,1H),3.66(m,1H),2.88(m,2H),2.00-1.78(m,14H). 1H NMR (400MHz, CD3OD )δ8.56(d,1H), 8.51(m,1H), 7.95(s,1H), 7.49(dd,1H), 7.31(td,1H), 4.52(m, 1H), 3.66(m, 1H), 2.88(m, 2H), 2.00-1.78(m, 14H).
实施例13Example 13
3-(2-(((1R,3s,5S)-8-氮杂双环[3.2.1]辛烷-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈(化合物13)3-(2-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 7-(Dimethylphosphoryl)-1H-indole-6-carbonitrile (Compound 13)
Figure PCTCN2021120199-appb-000143
Figure PCTCN2021120199-appb-000143
第一步：(1R,3s,5S)-3-((叔丁氧羰基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸苄基酯13BThe first step: (1R,3s,5S)-3-((tert-butoxycarbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate benzyl ester 13B
Figure PCTCN2021120199-appb-000144
Figure PCTCN2021120199-appb-000144
将((1R,3s,5S)-8-氮杂双环[3.2.1]辛烷-3-基)氨基甲酸叔丁基酯13A(200mg,0.885mmol)溶于干燥的二氯甲烷(10mL)中并加入三乙胺(268mg，2.65mmol)，N 2置换空气3次。然后降至0℃,加入氯 甲酸苄酯(225mg，1.3mmol)。添完完成后自然升温至室温搅拌1个小时。向反应液中加入乙酸乙酯(100mL)，分液，水相用乙酸乙酯(50mL×2)萃取。将合并的有机相在室温用无水硫酸钠干燥，过滤，浓缩，残留物用TLC板提纯(石油醚/乙酸乙酯(v/v)＝2:1)得到(1R,3s,5S)-3-((叔丁氧羰基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸苄基酯13B(300mg,产率94％)。 ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate tert-butyl ester 13A (200 mg, 0.885 mmol) was dissolved in dry dichloromethane (10 mL) Triethylamine (268 mg, 2.65 mmol) was added to it, and N 2 replaced the air 3 times. It was then lowered to 0°C and benzyl chloroformate (225 mg, 1.3 mmol) was added. After the addition was completed, the temperature was naturally raised to room temperature and stirred for 1 hour. Ethyl acetate (100 mL) was added to the reaction solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate at room temperature, filtered, concentrated, and the residue was purified with a TLC plate (petroleum ether/ethyl acetate (v/v)=2:1) to give (1R,3s,5S)- 3-((tert-Butoxycarbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate benzyl ester 13B (300 mg, 94% yield).
MS m/z(ESI)：361[M+1]MS m/z(ESI): 361[M+1]
第二步：(1R,3s,5S)-3-氨基-8-氮杂双环[3.2.1]辛烷-8-羧酸苄基酯13CThe second step: (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate benzyl ester 13C
Figure PCTCN2021120199-appb-000145
Figure PCTCN2021120199-appb-000145
向(1R,3s,5S)-3-((叔丁氧羰基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸苄基酯13B(300mg,0.83mmol)中加入盐酸的乙酸乙酯溶液(5ml)，搅拌1个小时。向反应液中加入饱和碳酸氢钠(30ml)和水(30mL)，分液，水相用乙酸乙酯(20mL×2)萃取。将合并的有机相在室温用无水硫酸钠干燥，过滤，浓缩得到(1R,3s,5S)-3-氨基-8-氮杂双环[3.2.1]辛烷-8-羧酸苄基酯13C(140mg,产率64％)。To (1R,3s,5S)-3-((tert-butoxycarbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate benzyl ester 13B (300 mg, 0.83 mmol) was added A solution of hydrochloric acid in ethyl acetate (5 ml) was stirred for 1 hour. Saturated sodium bicarbonate (30 mL) and water (30 mL) were added to the reaction solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phases were dried over anhydrous sodium sulfate at room temperature, filtered, and concentrated to give (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester 13C (140 mg, 64% yield).
MS m/z(ESI)：261[M+1]MS m/z(ESI): 261[M+1]
第三步：(1R,3s,5S)-3-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸苄基酯13DThe third step: (1R,3s,5S)-3-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine-2- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate benzyl ester 13D
Figure PCTCN2021120199-appb-000146
Figure PCTCN2021120199-appb-000146
将(1R,3s,5S)-3-氨基-8-氮杂双环[3.2.1]辛烷-8-羧酸苄基酯13C(140mg,0.583mmol)和7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈(100mg，0.249mmol)溶于四氢呋喃(5ml)中，加入N,N-二异丙基乙胺(80mg，0.62mmol)，升温至60℃,N 2置换3次，反应两个小时。向反应液中加入乙酸乙酯(30ml)和水(30mL)，分液，水相用乙酸乙酯(20mL×2)萃取。将合并的有机相在室温用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝5:1)得到(1R,3s,5S)-3-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸苄基酯13D(60mg,产率28％)。 (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate benzyl ester 13C (140 mg, 0.583 mmol) and 7-bromo-3-(2- Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile (100mg, 0.249mmol) was dissolved in tetrahydrofuran (5ml) and N,N-diisopropylethyl acetate was added Amine (80 mg, 0.62 mmol), warmed to 60 °C, replaced by N 2 three times, and reacted for two hours. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phases were dried over anhydrous sodium sulfate at room temperature, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5:1) to give (1R,3s,5S) )-3-((4-(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-8-azabicyclo [3.2.1] Benzyl octane-8-carboxylate 13D (60 mg, 28% yield).
MS m/z(ESI)：625[M+1]MS m/z(ESI): 625[M+1]
第四步：(1R,3r,5S)-3-((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸苄基酯13EThe fourth step: (1R,3r,5S)-3-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl) yl)pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate benzyl ester 13E
Figure PCTCN2021120199-appb-000147
Figure PCTCN2021120199-appb-000147
将(1R,3s,5S)-3-((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸苄基酯13D(60mg,0.096mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(12mg，0.02mmol)、醋酸钯(5mg，0.02mmol)和磷酸钾(102mg，0.48mmol)溶于N,N-二甲基甲酰胺(8mL)中，加入二甲基氧化膦(37.5mg，0.48mmol)，N 2置换3次，升温至150℃，反应1个小时。降至室温，减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝2:1)得到(1R,3r,5S)-3-((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸苄基酯13E(10mg，产率17％)。 (1R,3s,5S)-3-((4-(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )-8-azabicyclo[3.2.1]octane-8-carboxylate benzyl ester 13D (60 mg, 0.096 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxy Xanthene (12 mg, 0.02 mmol), palladium acetate (5 mg, 0.02 mmol) and potassium phosphate (102 mg, 0.48 mmol) were dissolved in N,N-dimethylformamide (8 mL) and dimethylphosphine oxide (37.5 mmol) was added. mg, 0.48 mmol), replaced by N 2 three times, heated to 150 °C, and reacted for 1 hour. The temperature was lowered to room temperature, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2:1) to obtain (1R,3r,5S)-3-((4-(6 -Cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1 ] Benzyl octane-8-carboxylate 13E (10 mg, 17% yield).
MS m/z(ESI)：623[M+1]MS m/z(ESI): 623[M+1]
第五步：3-(2-(((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈(化合物13)Step 5: 3-(2-(((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile (Compound 13)
Figure PCTCN2021120199-appb-000148
Figure PCTCN2021120199-appb-000148
将(1R,3r,5S)-3-((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸苄基酯13E(10mg,0.016mmol)和钯炭(2mg)溶于乙酸乙酯(10mL)中，在氢气下反应2小时。将反应混合物过滤，浓缩，加入水(10mL)和乙酸乙酯(15ml)，分液，水相用乙酸乙酯(10mL×2)萃取。将合并的有机相用无水硫酸钠干燥，过滤，浓缩，残留物用制备板分离提纯(二氯甲烷/无水甲醇(v/v)＝10：1，)得到类白色固体状的化合物3-(2-(((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈(化合物13)(1mg，产率13％)。(1R,3r,5S)-3-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine -2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate benzyl ester 13E (10 mg, 0.016 mmol) and palladium on carbon (2 mg) were dissolved in ethyl acetate (10 mL) , and reacted under hydrogen for 2 hours. The reaction mixture was filtered, concentrated, water (10 mL) and ethyl acetate (15 ml) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a preparative plate (dichloromethane/anhydrous methanol (v/v)=10:1,) to obtain compound 3 as an off-white solid -(2-(((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7 -(Dimethylphosphoryl)-1H-indole-6-carbonitrile (Compound 13) (1 mg, 13% yield).
MS m/z(ESI)：489.1[M+1]MS m/z(ESI): 489.1[M+1]
实施例14Example 14
(6-氟-3-(2-(((S)-哌啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(亚氨基)(甲基)-λ 6-亚砜(化合物14-P1和化合物14-P2) (6-Fluoro-3-(2-(((S)-piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl) (Imino)(methyl)-λ 6 -sulfoxide (Compound 14-P1 and Compound 14-P2)
Figure PCTCN2021120199-appb-000149
Figure PCTCN2021120199-appb-000149
第一步：(S)-3-((4-(6-氟-7-(甲硫基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁酯14AThe first step: (S)-3-((4-(6-fluoro-7-(methylthio)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl )amino)piperidine-1-carboxylate tert-butyl ester 14A
Figure PCTCN2021120199-appb-000150
Figure PCTCN2021120199-appb-000150
将3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-7-(甲硫基)-1H-吲哚(中间体4)(4.8g,13.2mmol)溶于无水四氢呋喃(50mL)中，加入(S)-1-叔丁氧羰基-3氨基哌啶(3.36g,16.8mmol)、N,N-二异丙基乙胺(4.3g,33.6mmol),N2置换3次，升温至60℃，反应3个小时。降至室温，减压浓缩得棕色油状物。将所得残留物通过反相柱(ACN:H2O＝5:95到95:5)纯化后得到淡黄色固体状的化合物(S)-3-((4-(6-氟-7-(甲硫基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁酯14A(3.0g,产率43％)。3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-7-(methylthio)-1H-indole (Intermediate 4) (4.8 g, 13.2 mmol ) was dissolved in anhydrous tetrahydrofuran (50 mL), and (S)-1-tert-butoxycarbonyl-3-aminopiperidine (3.36 g, 16.8 mmol), N,N-diisopropylethylamine (4.3 g, 33.6 mmol) were added. mmol), N2 was replaced 3 times, the temperature was raised to 60 °C, and the reaction was carried out for 3 hours. It was cooled to room temperature and concentrated under reduced pressure to give a brown oil. The obtained residue was purified by reverse phase column (ACN:H2O=5:95 to 95:5) to give compound (S)-3-((4-(6-fluoro-7-(methylthio) as a pale yellow solid. yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 14A (3.0 g, 43% yield).
MS m/z(ESI)：526.1[M+1]MS m/z(ESI): 526.1[M+1]
第二步：(S)-3-((4-(6-氟-7-(甲硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯14BThe second step: (S)-3-((4-(6-fluoro-7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -Indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 14B
Figure PCTCN2021120199-appb-000151
Figure PCTCN2021120199-appb-000151
将(S)-3-((4-(6-氟-7-(甲硫基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁酯14A(3.0g,5.70mmol)溶于N,N-二甲基甲酰胺(20mL)中，降温0℃,N2置换3次。加入氢化钠(60％)(383 mg，9.57mmol)，反应半小时，然后加入2-(三甲基甲硅烷基)乙氧甲基氯(1.14g，6.84mmol)，室温继续反应两个小时。向反应液中加入乙酸乙酯(30mL)和冰水(30mL)，分液，水相用乙酸乙酯(20mL×2)萃取，合并有机相。有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩旋干。残留物通过硅胶柱(石油醚/乙酸乙酯(v/v)＝10/1)纯化后得到类白色固体状的化合物(S)-3-((4-(6-氟-7-(甲硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯14B(3.8g，产率100％)。(S)-3-((4-(6-Fluoro-7-(methylthio)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) Piperidine-1-carboxylate tert-butyl ester 14A (3.0 g, 5.70 mmol) was dissolved in N,N-dimethylformamide (20 mL), the temperature was lowered to 0°C, and N2 was replaced three times. Sodium hydride (60%) (383 mg, 9.57 mmol) was added to react for half an hour, then 2-(trimethylsilyl)ethoxymethyl chloride (1.14 g, 6.84 mmol) was added, and the reaction was continued for two hours at room temperature . Ethyl acetate (30 mL) and ice water (30 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried. The residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v)=10/1) to obtain compound (S)-3-((4-(6-fluoro-7-(methyl) as an off-white solid. Thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl) Amino)piperidine-1-carboxylate tert-butyl ester 14B (3.8 g, 100% yield).
MS m/z(ESI)：656.1[M+1]MS m/z(ESI): 656.1[M+1]
第三步：(3S)-3-((4-(6-氟-7-(S-甲基亚氨亚砜基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯14CThe third step: (3S)-3-((4-(6-fluoro-7-(S-methylsulfoxide)-1-((2-(trimethylsilyl)ethoxy) )methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 14C
Figure PCTCN2021120199-appb-000152
Figure PCTCN2021120199-appb-000152
将(S)-3-((4-(6-氟-7-(甲硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯14B(500mg,0.763mmol)、(二乙酰氧基碘)苯(983mg,3.05mmol)、碳酸铵(220mg,2.29mmol)溶于甲醇(5mL)中，反应0.5个小时。平行投8个该反应。合并反应液，室温浓缩旋干，残留物用制备板分离提纯(石油醚/乙酸乙酯(v/v)＝2/1)，得到白色固体化合物(3S)-3-((4-(6-氟-7-(S-甲基亚氨亚砜基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯14C(2.2g，产率55％)。(S)-3-((4-(6-Fluoro-7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole -3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 14B (500 mg, 0.763 mmol), (diacetoxyiodo)benzene ( 983 mg, 3.05 mmol) and ammonium carbonate (220 mg, 2.29 mmol) were dissolved in methanol (5 mL) and reacted for 0.5 hours. Roll 8 of this reaction in parallel. The reaction solutions were combined, concentrated and spun dry at room temperature, and the residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v)=2/1) to obtain a white solid compound (3S)-3-((4-(6 -Fluoro-7-(S-methylsulfoxide)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5 -(Trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 14C (2.2 g, 55% yield).
MS m/z(ESI)：687.1[M+1]MS m/z(ESI): 687.1[M+1]
将上述得到的2.2克消旋体14C进行手性拆分，分别得到14C-P1(保留时间：1.45min)和14C-P2(保留时间：1.74min)各1.0g。The 2.2 g racemate 14C obtained above was subjected to chiral separation to obtain 1.0 g each of 14C-P1 (retention time: 1.45 min) and 14C-P2 (retention time: 1.74 min).
手性拆分的具体条件如下表所示：The specific conditions for chiral resolution are shown in the following table:
Figure PCTCN2021120199-appb-000153
Figure PCTCN2021120199-appb-000153
Figure PCTCN2021120199-appb-000154
Figure PCTCN2021120199-appb-000154
第四步：(6-氟-3-(2-(((S)-哌啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(亚氨基)(甲基)-λ 6-亚砜(化合物14-P1) Step 4: (6-Fluoro-3-(2-(((S)-piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole- 7-yl)(imino)(methyl)-λ 6 -sulfoxide (Compound 14-P1)
Figure PCTCN2021120199-appb-000155
Figure PCTCN2021120199-appb-000155
将(3S)-3-((4-(6-氟-7-(S-甲基亚氨亚砜基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯14C-P1(1.0g,1.46mmol)溶于二氯甲烷(10mL)和三氟乙酸(5mL)中，室温搅拌反应一个小时，减压浓缩旋干。残留物溶于四氢呋喃(5mL)中，加入氨水(2mL)，室温反应三十分钟，减压浓缩旋干得粗品。粗品经制备型HPLC纯化后冻干得白色固体产品(6-氟-3-(2-(((S)-哌啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(亚氨基)(甲基)-λ 6-亚砜(化合物14-P1)(262mg，产率39％)。 (3S)-3-((4-(6-Fluoro-7-(S-methylsulfoxide)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 14C-P1 (1.0 g, 1.46 mmol) in solution In dichloromethane (10 mL) and trifluoroacetic acid (5 mL), the reaction was stirred at room temperature for one hour, concentrated under reduced pressure and spin-dried. The residue was dissolved in tetrahydrofuran (5 mL), ammonia water (2 mL) was added, the reaction was carried out at room temperature for 30 minutes, concentrated under reduced pressure and spin-dried to obtain the crude product. The crude product was purified by preparative HPLC and then lyophilized to give a white solid product (6-fluoro-3-(2-(((S)-piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl)-1H-indol-7-yl)(imino)(methyl) -λ6 -sulfoxide (compound 14-P1) (262 mg, 39% yield).
MS m/z(ESI)：457.1[M+1]MS m/z(ESI): 457.1[M+1]
1HNMR(400MHz,DMSO-D6)δ11.66(s,1H),8.72-8.40(m,2H),7.95-7.80(m,2H),7.19(q,1H),5.15(s,1H),3.90-3.80(m,1H),3.36(s,3H),3.10-3.00(m,1H),2.85-2.75(m,1H),2.48-2.38(m,2H),2.00-1.90(m,1H),1.70-1.60(m,1H),1.55-1.35(m,2H).1HNMR(400MHz,DMSO-D6)δ11.66(s,1H),8.72-8.40(m,2H),7.95-7.80(m,2H),7.19(q,1H),5.15(s,1H),3.90 -3.80(m, 1H), 3.36(s, 3H), 3.10-3.00(m, 1H), 2.85-2.75(m, 1H), 2.48-2.38(m, 2H), 2.00-1.90(m, 1H) ,1.70-1.60(m,1H),1.55-1.35(m,2H).
(6-氟-3-(2-(((S)-哌啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(亚氨基)(甲基)-λ 6-亚砜(化合物14-P2) (6-Fluoro-3-(2-(((S)-piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl) (Imino)(methyl)-λ 6 -sulfoxide (Compound 14-P2)
Figure PCTCN2021120199-appb-000156
Figure PCTCN2021120199-appb-000156
将(3S)-3-((4-(6-氟-7-(S-甲基亚氨亚砜基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯14C-P2(1.0g,1.46mmol)溶于二氯甲烷(10mL)和三氟乙酸(5mL)中，室温搅拌反应一个小时，减压浓缩旋干。残留物溶于四氢呋喃(5mL)中，加入氨水(2mL)，室温反应三十分钟。减压浓缩旋干反应混合物得粗品。粗品经制备型HPLC纯化后冻干得白色固体产品(6-氟-3-(2-(((S)-哌啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(亚氨基)(甲基)-λ 6-亚砜(化合物14-P2)(186mg，产率28％)。 (3S)-3-((4-(6-Fluoro-7-(S-methylsulfoxide)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 14C-P2 (1.0 g, 1.46 mmol) in solution In dichloromethane (10 mL) and trifluoroacetic acid (5 mL), the reaction was stirred at room temperature for one hour, concentrated under reduced pressure and spin-dried. The residue was dissolved in tetrahydrofuran (5 mL), ammonia water (2 mL) was added, and the reaction was carried out at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and spin-dried to obtain crude product. The crude product was purified by preparative HPLC and then lyophilized to give a white solid product (6-fluoro-3-(2-(((S)-piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl)-1H-indol-7-yl)(imino)(methyl)-λ 6 -sulfoxide (compound 14-P2) (186 mg, 28% yield).
MS m/z(ESI)：457.0[M+1]MS m/z(ESI): 457.0[M+1]
1HNMR(400MHz,CDCl 3)δ10.74(s,1H),8.58(m,1H),8.49(dd,1H),7.85(s,1H),7.11(t,1H),5.96(s,1H),4.13(m,1H),3.42(s,3H),3.22-3.19(m,1H),2.89-2.80(m,3H),1.95(m,1H),1.81(m,1H),1.69-1.60(m,2H). 1HNMR(400MHz, CDCl 3 )δ10.74(s,1H), 8.58(m,1H), 8.49(dd,1H), 7.85(s,1H), 7.11(t,1H), 5.96(s,1H) ,4.13(m,1H),3.42(s,3H),3.22-3.19(m,1H),2.89-2.80(m,3H),1.95(m,1H),1.81(m,1H),1.69-1.60 (m,2H).
实施例15Example 15
N-((3-(2-(((S)-6,6-二甲基哌啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(甲基)(氧代)-λ 6-硫亚基)氰胺(化合物15) N-((3-(2-(((S)-6,6-dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole Indol-7-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide (Compound 15)
Figure PCTCN2021120199-appb-000157
Figure PCTCN2021120199-appb-000157
第一步：(S)-N-(6,6-二甲基哌啶-3-基)-4-(7-(甲硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-胺15AThe first step: (S)-N-(6,6-dimethylpiperidin-3-yl)-4-(7-(methylthio)-1-((2-(trimethylsilyl) )ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine 15A
Figure PCTCN2021120199-appb-000158
Figure PCTCN2021120199-appb-000158
将3-(2-氯-5-(三氟甲基)嘧啶-4-基)-7-(甲硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚(中间体5)(600mg,1.27mmol)溶于异丙醇(10mL)中，加入(S)-6,6-二甲基哌啶-3-胺(420mg，3.81mmol)、N,N-二异丙基乙胺(670mg,4.87mmol)，氮气置换3次，升至90℃，反应15个小时。反应液冷却至室温，浓缩旋干得到油状化合物(S)-N-(6,6-二甲基哌啶-3-基)-4-(7-(甲硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-胺15A(500mg，产率70％)。3-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl (S)-1H-indole (Intermediate 5) (600 mg, 1.27 mmol) was dissolved in isopropanol (10 mL), (S)-6,6-dimethylpiperidin-3-amine (420 mg, 3.81 mmol) was added mmol), N,N-diisopropylethylamine (670 mg, 4.87 mmol), replaced with nitrogen three times, raised to 90° C., and reacted for 15 hours. The reaction solution was cooled to room temperature, concentrated and spin-dried to obtain an oily compound (S)-N-(6,6-dimethylpiperidin-3-yl)-4-(7-(methylthio)-1-((2 -(Trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine 15A (500 mg, 70% yield).
MS m/z(ESI)：566.3[M+1]MS m/z(ESI): 566.3[M+1]
第二步：(S)-2,2-二甲基-5-((4-(7-(甲硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯15BThe second step: (S)-2,2-dimethyl-5-((4-(7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl) yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 15B
Figure PCTCN2021120199-appb-000159
Figure PCTCN2021120199-appb-000159
将(S)-N-(6,6-二甲基哌啶-3-基)-4-(7-(甲硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-胺15A(500mg,0.88mmol)溶于二氯甲烷(10mL)中，加入三乙胺(300mg,2.66mmol)和一缩二碳酸二叔丁酯(347mg,1.76mmol),N2置换3次，室温反应1个小时。减压浓缩，残留物用制备板分离提纯(石油醚/乙酸乙酯(v/v)＝3/1)得到类白色固体化合物(S)-2,2-二甲基-5-((4-(7-(甲硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯15B(380mg，产率72％)。(S)-N-(6,6-Dimethylpiperidin-3-yl)-4-(7-(methylthio)-1-((2-(trimethylsilyl)ethoxy yl)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine 15A (500 mg, 0.88 mmol) was dissolved in dichloromethane (10 mL) and triethylamine was added (300 mg, 2.66 mmol) and di-tert-butyl dicarbonate (347 mg, 1.76 mmol), replaced by N2 three times, and reacted at room temperature for 1 hour. Concentrated under reduced pressure, the residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v)=3/1) to obtain an off-white solid compound (S)-2,2-dimethyl-5-((4 -(7-(Methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl) Pyrimidine-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 15B (380 mg, 72% yield).
MS m/z(ESI)：666.4[M+1]MS m/z(ESI): 666.4[M+1]
第三步：(5S)-2,2-二甲基-5-((4-(7-(S-甲基亚氨亚砜基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯15CThe third step: (5S)-2,2-dimethyl-5-((4-(7-(S-methylsulfoxide)-1-((2-(trimethylsilyl) )ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 15C
Figure PCTCN2021120199-appb-000160
Figure PCTCN2021120199-appb-000160
将(S)-2,2-二甲基-5-((4-(7-(甲硫基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯15B(380mg,0.571mmol)溶于甲醇(5mL)中，加入(二乙酰氧 基碘)苯(460mg,1.43mmol)和碳酸铵(170mg,1.97mmol)，空气氛围中反应半个小时。反应液直接用制备板分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)得到类白色固体化合物(5S)-2,2-二甲基-5-((4-(7-(S-甲基亚氨亚砜基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯15C(280mg，产率71％)。(S)-2,2-dimethyl-5-((4-(7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-Indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 15B (380 mg, 0.571 mmol) was dissolved in methanol (5 mL) In the solution, (diacetoxyiodo)benzene (460 mg, 1.43 mmol) and ammonium carbonate (170 mg, 1.97 mmol) were added, and the reaction was carried out in an air atmosphere for half an hour. The reaction solution was directly separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v)=1:1) to obtain an off-white solid compound (5S)-2,2-dimethyl-5-((4-(7 -(S-Methylsulfoxide)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoro Methyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 15C (280 mg, 71% yield).
MS m/z(ESI)：697.4[M+1]MS m/z(ESI): 697.4[M+1]
第四步：(5S)-5-((4-(7-(N-氰基-S-甲基亚氨亚砜基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2,2-二甲基哌啶-1-羧酸叔丁基酯15DThe fourth step: (5S)-5-((4-(7-(N-cyano-S-methylsulfoxide)-1-((2-(trimethylsilyl)ethoxy) (yl)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl Ester 15D
Figure PCTCN2021120199-appb-000161
Figure PCTCN2021120199-appb-000161
将(5S)-2,2-二甲基-5-((4-(7-(S-甲基亚氨亚砜基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯15C(50mg,0.07mmol)溶于二氯甲烷(5mL)中，加入氰化溴(15mg,0.14mmol)和4-二甲氨基吡啶(18mg,0.14mmol)，室温反应过夜。过滤反应液，减压浓缩，残留物用制备板分离提纯(石油醚/乙酸乙酯(v/v)＝2/1)得到白色固体化合物(5S)-5-((4-(7-(N-氰基-S-甲基亚氨亚砜基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2,2-二甲基哌啶-1-羧酸叔丁基酯15D(30mg，产率59％)。(5S)-2,2-dimethyl-5-((4-(7-(S-methylsulfoxide)-1-((2-(trimethylsilyl)ethoxy) (yl)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 15C (50 mg, 0.07 mmol) Dissolve in dichloromethane (5 mL), add bromine cyanide (15 mg, 0.14 mmol) and 4-dimethylaminopyridine (18 mg, 0.14 mmol), and react at room temperature overnight. The reaction solution was filtered, concentrated under reduced pressure, and the residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v)=2/1) to obtain a white solid compound (5S)-5-((4-(7-( N-cyano-S-methylsulfoxide)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5- (Trifluoromethyl)pyrimidin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylate tert-butyl ester 15D (30 mg, 59% yield).
MS m/z(ESI)：722.3[M+1]MS m/z(ESI): 722.3[M+1]
第五步：N-((3-(2-(((S)-6,6-二甲基哌啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(甲基)(氧代)-λ 6-硫亚基)氰胺(化合物15) Step 5: N-((3-(2-(((S)-6,6-dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) -1H-Indol-7-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide (Compound 15)
Figure PCTCN2021120199-appb-000162
Figure PCTCN2021120199-appb-000162
将(5S)-5-((4-(7-(N-氰基-S-甲基亚氨亚砜基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2,2-二甲基哌啶-1-羧酸叔丁基酯15D(30mg,0.04mmol)溶于二氯甲烷(2mL)和三氟乙酸(1mL)中，室温搅拌反应4小时。反应液浓缩旋干，残留物溶于四氢呋喃(2mL)中。加入氨水(1mL)，室温搅拌反应30分钟。浓缩旋干，残留物用制备板分离提纯(二氯甲烷/甲醇(v/v)＝10：1，)得到白色固体化合物N-((3-(2-(((S)-6,6-二甲基哌啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)(甲基)(氧代)-λ 6-硫亚基)氰胺(化合物15)(3.1mg，产率16％)。 (5S)-5-((4-(7-(N-cyano-S-methylsulfoxide)-1-((2-(trimethylsilyl)ethoxy)methyl ( 30 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL), and the reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated and spun dry, and the residue was dissolved in tetrahydrofuran (2 mL). Aqueous ammonia (1 mL) was added, and the reaction was stirred at room temperature for 30 minutes. Concentrated and spin-dried, the residue was separated and purified with a preparative plate (dichloromethane/methanol (v/v)=10:1,) to obtain a white solid compound N-((3-(2-((((S)-6,6) -Dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)(methyl)(oxo)-λ 6 - Sulfurylidene)cyanamide (Compound 15) (3.1 mg, 16% yield).
MS m/z(ESI)：492.1[M+1]MS m/z(ESI): 492.1[M+1]
1HNMR(400MHz,CD 3OD)δ8.84-8.59(m,2H),7.98(m,1H),7.91(d,1H),7.50(t,1H),4.09(m,1H),3.63(d,2H),3.25(m,2H),2.90(t,1H),2.02(m,1H),1.85-1.67(m,2H),1.59(m,1H),1.26(s,6H). 1HNMR(400MHz, CD 3 OD) δ8.84-8.59(m, 2H), 7.98(m, 1H), 7.91(d, 1H), 7.50(t, 1H), 4.09(m, 1H), 3.63(d ,2H),3.25(m,2H),2.90(t,1H),2.02(m,1H),1.85-1.67(m,2H),1.59(m,1H),1.26(s,6H).
实施例16Example 16
(S)-7-((二甲基(氧代)-λ 6-亚硫基)氨基)-3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈(化合物16) (S)-7-((Dimethyl(oxo)-λ 6 -thiosulfinyl)amino)-3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidine -4-yl)-1H-indole-6-carbonitrile (Compound 16)
Figure PCTCN2021120199-appb-000163
Figure PCTCN2021120199-appb-000163
第一步：7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-6-甲腈16AThe first step: 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-indole-6-carbonitrile 16A
Figure PCTCN2021120199-appb-000164
Figure PCTCN2021120199-appb-000164
将7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈3A(250mg,0.625mmol)溶于N,N-二甲基甲酰胺(8ml)中，降温至0℃,N2置换3次,加入氢化钠(60％)(50mg，1.25mmol)，反应一个小时。然后加入2-(三甲基甲硅烷基)乙氧甲基氯(208mg，1.25mmol)，室温继续反应两个小时。向反应液中加入乙酸乙酯(10ml)和冰水(10mL)，分液，水相用乙酸乙酯(10mL×2)萃取，合并有机相。有机相用饱和食盐水(10mL×2)洗涤，室温用无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝10:1)得到淡黄色固体状的化合物7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-6-甲腈16A(70mg,产率21％)。7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 3A (250 mg, 0.625 mmol) was dissolved in N,N-dicarbonitrile In methylformamide (8 ml), the temperature was lowered to 0° C., N2 was replaced three times, sodium hydride (60%) (50 mg, 1.25 mmol) was added, and the reaction was carried out for one hour. Then 2-(trimethylsilyl)ethoxymethyl chloride (208 mg, 1.25 mmol) was added and the reaction was continued for two hours at room temperature. Ethyl acetate (10 ml) and ice water (10 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate at room temperature, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10:1) to obtain compound 7-bromo-3-(2-chloro-5-(trifluoromethyl) as a pale yellow solid )pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile 16A (70 mg, 21% yield).
MS m/z(ESI)：531.8[M+1]MS m/z(ESI): 531.8[M+1]
第二步：(S)-3-((4-(7-溴-6-氰基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯16BThe second step: (S)-3-((4-(7-bromo-6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole -3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 16B
Figure PCTCN2021120199-appb-000165
Figure PCTCN2021120199-appb-000165
将7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-6-甲腈16A(70mg,0.132mmol)溶于无水四氢呋喃(5mL)中，加入3-氨基哌啶-1-羧酸叔丁基酯(53mg,0.264mmol)和N,N-二异丙基乙胺(52mg,0.4mmol),N2置换3次，升温至60℃，反应4个小时。降至室温，减压浓缩。残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝3:1)得到类白色固体状的化合物(S)-3-((4-(7-溴-6-氰基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯16B(60mg，产率65％)。7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -Indole-6-carbonitrile 16A (70 mg, 0.132 mmol) was dissolved in dry tetrahydrofuran (5 mL), tert-butyl 3-aminopiperidine-1-carboxylate (53 mg, 0.264 mmol) and N,N were added - Diisopropylethylamine (52 mg, 0.4 mmol), replaced by N2 3 times, heated to 60°C, and reacted for 4 hours. It was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3:1) to obtain compound (S)-3-((4-(7-bromo-6-cyano) as an off-white solid yl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) Piperidine-1-carboxylate tert-butyl ester 16B (60 mg, 65% yield).
MS m/z(ESI)：695.6[M+1]MS m/z(ESI): 695.6[M+1]
第三步：(S)-3-((4-(6-氰基-7-((二甲基(氧代)-λ 6-亚硫基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯16C The third step: (S)-3-((4-(6-cyano-7-((dimethyl(oxo)-λ 6 -sulfinyl)amino)-1-((2-(tri Methylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl Ester 16C
Figure PCTCN2021120199-appb-000166
Figure PCTCN2021120199-appb-000166
将(S)-3-((4-(7-溴-6-氰基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯16B(58mg,0.083mmol)、三[二亚苄基丙酮]二钯(15.3mg,0.016mmol)、2-(二叔丁基膦)联苯(9.5mg,0.032mmol)、叔丁醇钠(16mg,0.16mmol)和二甲基亚氨基亚砜(38.8mg,0.416mmol)溶于干燥1.4-二氧六环(5mL)中，升至80℃反应16个小时。将反应液冷却至室温，硅藻土过滤浓缩。残留物用制备板分离提纯(石油醚/乙酸乙酯(v/v)＝1：1，)得到淡黄色油状的化合物(S)-3-((4-(6-氰基-7-((二甲基(氧代)-λ 6-亚硫基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯16C(9mg，产率15％)。 (S)-3-((4-(7-Bromo-6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 16B (58 mg, 0.083 mmol), tris[dibenzylideneacetone]dipalladium (15.3 mg, 0.016 mmol), 2-(di-tert-butylphosphine)biphenyl (9.5 mg, 0.032 mmol), sodium tert-butoxide (16 mg, 0.16 mmol) and dimethylimidosulfoxide (38.8 mg, 0.416 mmol) Dissolve in dry 1.4-dioxane (5 mL), raise to 80°C and react for 16 hours. The reaction solution was cooled to room temperature, filtered through celite and concentrated. The residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v)=1:1,) to obtain compound (S)-3-((4-(6-cyano-7-() as a pale yellow oil. (Dimethyl(oxo) -λ6 -thiosulfinyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl) -5-(Trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 16C (9 mg, 15% yield).
MS m/z(ESI)：708.2[M+1]MS m/z(ESI): 708.2[M+1]
第四步：(S)-7-((二甲基(氧代)-λ 6-亚硫基)氨基)-1-(羟甲基)-3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈16D The fourth step: (S)-7-((dimethyl(oxo)-λ 6 -sulfinyl)amino)-1-(hydroxymethyl)-3-(2-(piperidin-3-yl) Amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 16D
Figure PCTCN2021120199-appb-000167
Figure PCTCN2021120199-appb-000167
将(S)-3-((4-(6-氰基-7-((二甲基(氧代)-λ 6-亚硫基)氨基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁基酯16C(9mg,0.013mmol)，溶于二氯甲烷(2ml)和三氟乙酸(0.5ml)中，室温搅拌反应一个小时。减压浓缩反应混合物得到粗品棕色油状物(S)-7-((二甲基(氧代)-λ 6-亚硫基)氨基)-1-(羟甲基)-3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈16D(12mg，粗品)，直接用于下一步反应。 (S)-3-((4-(6-cyano-7-((dimethyl(oxo)-λ 6 -sulfinyl)amino)-1-((2-(trimethylmethyl Silyl)ethoxy)methyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester 16C ( 9 mg, 0.013 mmol), dissolved in dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml), and the reaction was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure to give crude brown oil (S)-7-((dimethyl(oxo)-λ 6 -thiosulfinyl)amino)-1-(hydroxymethyl)-3-(2-( Piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 16D (12 mg, crude) was used directly in the next reaction.
MS m/z(ESI)：508.5[M+1]MS m/z(ESI): 508.5[M+1]
第五步：(S)-7-((二甲基(氧代)-λ 6-亚硫基)氨基)-3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈(化合物16) The fifth step: (S)-7-((dimethyl(oxo)-λ 6 -sulfinyl)amino)-3-(2-(piperidin-3-ylamino)-5-(trifluoro) Methyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile (Compound 16)
Figure PCTCN2021120199-appb-000168
Figure PCTCN2021120199-appb-000168
将粗品(S)-7-((二甲基(氧代)-λ 6-亚硫基)氨基)-1-(羟甲基)-3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈16D(12mg,0.023mmol)，溶于四氢呋喃(2mL)中，加入氨水(1ml),室温反应三十分钟。减压浓缩反应混合物。残留物中加甲醇溶解，通过制备板分离提纯(二氯甲烷/甲醇(v/v)＝7：1得到白色固体状的化合物(S)-7-((二甲基(氧代)-λ 6-亚硫基)氨基)-3-(2-(哌啶-3-基氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈(化合物16)(2mg，产率18％)。 The crude (S)-7-((dimethyl(oxo)-λ 6 -thiosulfinyl)amino)-1-(hydroxymethyl)-3-(2-(piperidin-3-ylamino) -5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 16D (12mg, 0.023mmol) was dissolved in tetrahydrofuran (2mL), ammonia water (1ml) was added, and the reaction was carried out at room temperature for three ten minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol, and separated and purified by a preparative plate (dichloromethane/methanol (v/v)=7:1 to obtain compound (S)-7-((dimethyl(oxo)-λ) as a white solid 6 -Sulfanyl)amino)-3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile (compound 16) (2 mg, 18% yield).
MS m/z(ESI)：478.0[M+1]MS m/z(ESI): 478.0[M+1]
1H NMR(400MHz,CD 3OD)δ8.58(s,1H),7.95(m,2H),7.44-7.14(m,1H),4.26(m,1H),3.63-3.48(m,2H),3.34(s,6H)2.94-2.89(m,2H),2.21-2.17(m,1H),2.02(m,1H),1.75-1.60(m,2H). 1H NMR (400MHz, CD 3 OD) δ8.58(s, 1H), 7.95(m, 2H), 7.44-7.14(m, 1H), 4.26(m, 1H), 3.63-3.48(m, 2H), 3.34(s,6H)2.94-2.89(m,2H),2.21-2.17(m,1H),2.02(m,1H),1.75-1.60(m,2H).
实施例17Example 17
(3-(2-(((5-氮杂螺[2.4]庚烷-1-基)甲基)氨基)-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚-7-基)二甲基氧化膦(化合物17)(3-(2-(((5-Azaspiro[2.4]heptan-1-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H -Indol-7-yl)dimethylphosphine oxide (compound 17)
Figure PCTCN2021120199-appb-000169
Figure PCTCN2021120199-appb-000169
第一步：1-(((4-(7-溴-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁基酯17AThe first step: 1-(((4-(7-Bromo-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)- 5-Azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 17A
Figure PCTCN2021120199-appb-000170
Figure PCTCN2021120199-appb-000170
将7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚7C(150mg,0.38mmol)溶于无水四氢呋喃(5mL)中，加入1-(氨甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(中间体6)(172mg,0.76mmol)、N,N-二异丙基乙胺(245mg,1.9mmol),N2置换3次，升温至60℃，反应4个小时。降至室温，减压浓缩，残留物用制备板分离提纯(石油醚/乙酸乙酯(v/v)＝3:1)得到类白色色固体状的化合物1-(((4-(7-溴-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁基酯17A(120mg，产率54％)。7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indole 7C (150 mg, 0.38 mmol) was dissolved in dry tetrahydrofuran (5 mL) 1-(aminomethyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester (Intermediate 6) (172 mg, 0.76 mmol), N,N-diisopropylethyl Amine (245 mg, 1.9 mmol), replaced by N2 three times, heated to 60 °C, and reacted for 4 hours. It was cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v)=3:1) to obtain compound 1-((((4-(7-) as an off-white solid. bromo-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-5-azaspiro[2.4]heptane-5-carboxy tert-Butyl acid 17A (120 mg, 54% yield).
MS m/z(ESI)：584.4[M+1]MS m/z(ESI): 584.4[M+1]
第二步：1-(((4-(7-(二甲基磷酰基)-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁基酯17BStep 2: 1-(((4-(7-(dimethylphosphoryl)-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl) Amino)methyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 17B
Figure PCTCN2021120199-appb-000171
Figure PCTCN2021120199-appb-000171
将1-((4-(7-溴-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁基酯17A(102mg,0.174mmol)、1,1'-双二苯基膦二茂铁二氯化钯(127mg,0.174mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(100mg,0.174mmol)、磷酸三钾(184mg,0.87mmol)和二甲基氧化膦(68mg,0.87mmol)溶于干燥N,N-二甲基甲酰胺(3mL)中，升至150℃反应1个小时。将反应液冷却至室温，加入水(10mL)和乙酸乙酯(15ml)，分液，水相用乙酸乙酯(10mL×2)萃取。将合并的有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用制备板分离提纯(石油醚/乙酸乙酯(v/v)＝1：1，)得到黄色固体状的化合物1-(((4-(7-(二甲基磷酰基)-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁基酯17B(20mg，产率20％)。1-((4-(7-Bromo-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-5-aza Spiro[2.4]heptane-5-carboxylate tert-butyl ester 17A (102 mg, 0.174 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (127 mg, 0.174 mmol), 4,5 -Bis(diphenylphosphine)-9,9-dimethylxanthene (100 mg, 0.174 mmol), tripotassium phosphate (184 mg, 0.87 mmol) and dimethylphosphine oxide (68 mg, 0.87 mmol) were dissolved in dry In N,N-dimethylformamide (3 mL), the temperature was raised to 150°C for 1 hour. The reaction solution was cooled to room temperature, water (10 mL) and ethyl acetate (15 mL) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v)=1:1,) to obtain compound 1-(((4-(7-(dimethylphosphoryl)-6 as a yellow solid -Fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl base ester 17B (20 mg, 20% yield).
MS m/z(ESI)：582.4[M+1]MS m/z(ESI): 582.4[M+1]
第三步：(3-(2-(((5-氮杂螺[2.4]庚烷-1-基)甲基)氨基)-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚-7-基)二甲基氧化膦(化合物17)The third step: (3-(2-(((5-azaspiro[2.4]heptane-1-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6 -Fluoro-1H-indol-7-yl)dimethylphosphine oxide (compound 17)
Figure PCTCN2021120199-appb-000172
Figure PCTCN2021120199-appb-000172
将1-(((4-(7-(二甲基磷酰基)-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁基酯17B(20mg,0.03mmol)溶于二氯甲烷(2ml)和三氟乙酸(1ml)中，于室温搅拌反应一个小时。将反应混合物减压浓缩，得到粗品棕色油状物。向其中加入乙酸乙酯(10ml)和碳酸钠饱和溶液调至碱性，分层，水相用乙酸乙酯(10ml)萃取。将合并的有机相用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用制备板分离提纯(二氯甲烷/甲醇(v/v)＝8：1，)得到白色固体状的化合物(3-(2-(((5-氮杂螺[2.4]庚烷-1-基)甲基)氨基)-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚-7-基)二甲基氧化膦(化合物17)(11mg，产率67％)。1-(((4-(7-(Dimethylphosphoryl)-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methane yl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 17B (20 mg, 0.03 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (1 ml), and the reaction was stirred at room temperature One hour. The reaction mixture was concentrated under reduced pressure to give a crude brown oil. Ethyl acetate (10 ml) and saturated sodium carbonate solution were added thereto to make basic, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 ml). The combined organic phases were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified with a preparative plate (dichloromethane/methanol (v/v)=8:1,) to obtain compound (3-(2-(((5-azaspiro[2.4]heptane-) as a white solid. 1-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indol-7-yl)dimethylphosphine oxide (compound 17) (11 mg, yield 67%).
MS m/z(ESI)：482.1[M+1]MS m/z(ESI): 482.1[M+1]
1H NMR(400MHz,CD 3OD)δ8.59(d,2H),7.95(s,1H),7.11-7.05(m,1H),3.60(m,1H),3.51-3.35(m,4H),3.27-3.11(m,1H),2.09–2.04(m,1H),1.97(s,3H),1.93(m,4H),1.58-1.49(m,1H),1.01-0.97(m,1H),0.73-0.70(m,1H). 1H NMR (400MHz, CD 3 OD) δ8.59(d, 2H), 7.95(s, 1H), 7.11-7.05(m, 1H), 3.60(m, 1H), 3.51-3.35(m, 4H), 3.27-3.11(m,1H), 2.09-2.04(m,1H), 1.97(s,3H), 1.93(m,4H), 1.58-1.49(m,1H), 1.01-0.97(m,1H), 0.73-0.70(m,1H).
实施例18Example 18
3-(2-(((5-氮杂螺[2.4]庚烷-1-基)甲基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈(化合物18)3-(2-(((5-azaspiro[2.4]heptan-1-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethyl) Phosphoryl)-1H-indole-6-carbonitrile (Compound 18)
Figure PCTCN2021120199-appb-000173
Figure PCTCN2021120199-appb-000173
第一步：1-(((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁基酯18AThe first step: 1-(((4-(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl) -5-Azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 18A
Figure PCTCN2021120199-appb-000174
Figure PCTCN2021120199-appb-000174
将7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-6-甲腈(230mg,0.575mmol)溶于无水四氢呋喃(2mL)中，加入1-(氨甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(中间体6)(260mg,1.15mmol)和三乙胺(121mg,1.19mmol),N2置换3次，升温至80℃，反应1.5个小时。降至室温，减压浓缩，残留物用制备板分离提纯(石油醚/乙酸乙酯(v/v)＝1：1)得到类白色固体状的化合物1-(((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁基酯18A(130mg，产率37％)。7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile (230 mg, 0.575 mmol) was dissolved in dry tetrahydrofuran (2 mL) 1-(aminomethyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester (Intermediate 6) (260 mg, 1.15 mmol) and triethylamine (121 mg, 1.19 mmol) were added , N2 was replaced 3 times, the temperature was raised to 80°C, and the reaction was carried out for 1.5 hours. It was cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) = 1:1) to obtain compound 1-(((4-(7-bromo as an off-white solid). -6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-5-azaspiro[2.4]heptane-5-carboxy tert-Butyl acid 18A (130 mg, 37% yield).
MS m/z(ESI)：591.4[M+1]MS m/z(ESI): 591.4[M+1]
第二步：1-(((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁基酯18BStep 2: 1-(((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl )amino)methyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 18B
Figure PCTCN2021120199-appb-000175
Figure PCTCN2021120199-appb-000175
将1-(((4-(7-溴-6-氰基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁基酯18A(123mg,0.21mmol)、1,1'-双二苯基膦二茂铁二氯化钯(149.7mg,0.208mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(120.5mg,0.208mmol)、磷酸三钾(98mg,1.04mmol)和二甲基氧化膦(81mg,1.04mmol)溶于干燥N,N-二甲基甲酰胺(2mL)中，升至150℃反应1个小时。将反应液冷却至室温，加入水(10mL)和乙酸乙酯(15ml)，分液，水相用乙酸乙酯(10mL×2)萃取。将合并的有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。将所得残留物用制备板分离提纯(石油醚/乙酸乙酯(v/v)＝1：1，)得到黄色固体状的化合物1-(((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁基酯18B(50mg，产率40％)。1-(((4-(7-Bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-5- Azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 18A (123 mg, 0.21 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (149.7 mg, 0.208 mmol), 4,5-Bis(diphenylphosphine)-9,9-dimethylxanthene (120.5mg, 0.208mmol), Tripotassium Phosphate (98mg, 1.04mmol) and Dimethylphosphine Oxide (81mg, 1.04mmol) ) was dissolved in dry N,N-dimethylformamide (2 mL), heated to 150°C and reacted for 1 hour. The reaction solution was cooled to room temperature, water (10 mL) and ethyl acetate (15 mL) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v)=1:1,) to obtain compound 1-(((4-(6-cyano-7-(di) as a yellow solid. Methylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-5-azaspiro[2.4]heptane-5-carboxy tert-Butyl acid 18B (50 mg, 40% yield).
MS m/z(ESI)：589.4[M+1]MS m/z(ESI): 589.4[M+1]
第三步：3-(2-(((5-氮杂螺[2.4]庚烷-1-基)甲基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈(化合物18)The third step: 3-(2-(((5-azaspiro[2.4]heptan-1-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7- (Dimethylphosphoryl)-1H-indole-6-carbonitrile (Compound 18)
Figure PCTCN2021120199-appb-000176
Figure PCTCN2021120199-appb-000176
将1-(((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)甲基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁基酯18B(50mg,0.086mmol)溶于二氯甲烷(2ml)和三氟乙酸(1ml)中，室温搅拌反应一个小时。将反应混合物减压浓缩，得到粗品棕色油状物。向其中加入乙酸乙酯(10ml)，然后加入碳酸钠饱和溶液调至碱性，分层，水相用乙酸乙酯(10ml)萃取。将合并的有机相用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。所得残留物用制备板分离提纯(二氯甲烷/甲醇(v/v)＝10：1，)得到白色固体状的化合物3-(2-(((5-氮杂螺[2.4]庚烷-1-基)甲基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈(化合物18)(10mg，产率24％)。1-((((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) Methyl)-5-azaspiro[2.4]heptane-5-carboxylate tert-butyl ester 18B (50mg, 0.086mmol) was dissolved in dichloromethane (2ml) and trifluoroacetic acid (1ml), and the reaction was stirred at room temperature One hour. The reaction mixture was concentrated under reduced pressure to give a crude brown oil. Ethyl acetate (10 ml) was added thereto, then a saturated solution of sodium carbonate was added to make it basic, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 ml). The combined organic phases were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified with a preparative plate (dichloromethane/methanol (v/v)=10:1,) to obtain the compound 3-(2-(((5-azaspiro[2.4]heptane-) as a white solid. 1-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile (compound 18) (10 mg , yield 24%).
MS m/z(ESI)：489.2[M+1]MS m/z(ESI): 489.2[M+1]
1H NMR(400MHz,CD 3OD)δ8.59(d,2H),7.95(s,1H),7.11-7.05(m,1H),3.60(m,1H),3.51-3.35(m,4H),3.27-3.11(m,1H),2.09–2.04(m,1H),1.97(s,3H),1.93(m,4H),1.58-1.49(m,1H),1.01-0.97(m,1H),0.73-0.70(m,1H). 1H NMR (400MHz, CD 3 OD) δ8.59(d, 2H), 7.95(s, 1H), 7.11-7.05(m, 1H), 3.60(m, 1H), 3.51-3.35(m, 4H), 3.27-3.11(m,1H), 2.09-2.04(m,1H), 1.97(s,3H), 1.93(m,4H), 1.58-1.49(m,1H), 1.01-0.97(m,1H), 0.73-0.70(m,1H).
实施例19Example 19
(3-(2-((2-氮杂螺[3.3]庚烷-6-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦(化合物19)(3-(2-((2-Azaspiro[3.3]heptan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl) Dimethylphosphine oxide (compound 19)
Figure PCTCN2021120199-appb-000177
Figure PCTCN2021120199-appb-000177
将6-((4-(7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(中间体7)(50mg,0.09mmol)溶于二氯甲烷(2ml)和三氟乙酸(1ml)中，于室温搅拌反应一个小时。减压浓缩，得到粗品棕色油状物。向其中加入乙酸乙酯(10ml)，然后加入碳酸钠饱和溶液调至碱性，分层。水相用乙酸乙酯(10ml)萃取。将合并的有机相用饱和食盐水(10mL×2)洗涤，无水硫 酸钠干燥，过滤，浓缩。残留物用制备板分离提纯(二氯甲烷/甲醇(v/v)＝8：1，)得到白色固体状的化合物(3-(2-((2-氮杂螺[3.3]庚烷-6-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦(化合物19)(16mg，产率39％)。6-((4-(7-(Dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro [3.3] Heptane-2-carboxylate tert-butyl ester (Intermediate 7) (50 mg, 0.09 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (1 ml), and the reaction was stirred at room temperature for one hour. Concentration under reduced pressure gave crude brown oil. Ethyl acetate (10 ml) was added thereto, then a saturated solution of sodium carbonate was added to make it basic, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 ml). The combined organic phases were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified with a preparative plate (dichloromethane/methanol (v/v)=8:1,) to obtain compound (3-(2-((2-azaspiro[3.3]heptane-6) as a white solid. -yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-lH-indol-7-yl)dimethylphosphine oxide (compound 19) (16 mg, 39% yield).
MS m/z(ESI)：450[M+1]MS m/z(ESI): 450[M+1]
1H NMR(400MHz,CD 3OD)δ8.53(s,2H),7.94(s,1H),7.52-7.47(m,1H),7.33(m,1H),4.43(m,1H),4.15-4.05(m,4H),2.81-2.76(m,2H),2.38-2.33(m,2H),1.93(s,3H),1.89(s,3H). 1 H NMR (400MHz, CD 3 OD) δ 8.53(s, 2H), 7.94(s, 1H), 7.52-7.47(m, 1H), 7.33(m, 1H), 4.43(m, 1H), 4.15 -4.05(m,4H),2.81-2.76(m,2H),2.38-2.33(m,2H),1.93(s,3H),1.89(s,3H).
实施例20Example 20
(3-(2-((2-氮杂螺[3.3]庚烷-6-基)氨基)-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚-7-基)二甲基氧化膦(化合物20)(3-(2-((2-Azaspiro[3.3]heptan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indole- 7-yl)dimethylphosphine oxide (compound 20)
Figure PCTCN2021120199-appb-000178
Figure PCTCN2021120199-appb-000178
第一步：6-((4-(7-溴-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁基酯20AThe first step: 6-((4-(7-Bromo-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-aza Spiro[3.3]heptane-2-carboxylate tert-butyl ester 20A
Figure PCTCN2021120199-appb-000179
Figure PCTCN2021120199-appb-000179
将7-溴-3-(2-氯-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚7C(300mg,0.76mmol)溶于无水四氢呋喃(5mL)中，加入6-氨基-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(243mg,1.15mmol)和N,N-二异丙基乙胺(490mg,3.8mmol),N 2置换3次，升温至60℃，反应4个小时。降至室温，减压浓缩，残留物用制备板分离提纯(石油醚/乙酸乙酯(v/v)＝3:1)得到类白色固体状的化合物20A(150mg，产率35％)。 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indole 7C (300 mg, 0.76 mmol) was dissolved in dry tetrahydrofuran (5 mL) 6-amino-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (243mg, 1.15mmol) and N,N-diisopropylethylamine (490mg, 3.8mmol), N 2 was replaced three times, the temperature was raised to 60°C, and the reaction was carried out for 4 hours. It was cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v)=3:1) to obtain compound 20A (150 mg, yield 35%) as an off-white solid.
MS m/z(ESI)：570.4[M+1]MS m/z(ESI): 570.4[M+1]
第二步：6-((4-(7-(二甲基磷酰基)-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯20BStep 2: 6-((4-(7-(dimethylphosphoryl)-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )-2-Azaspiro[3.3]heptane-2-carboxylate tert-butyl ester 20B
Figure PCTCN2021120199-appb-000180
Figure PCTCN2021120199-appb-000180
将6-((4-(7-溴-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁基酯20A(150mg,0.263mmol)、1,1'-双二苯基膦二茂铁二氯化钯(192mg,0.263mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(152mg,0.263mmol)、磷酸三钾(167mg,0.79mmol)和二甲基氧化膦(102mg,1.315mmol)溶于干燥N,N-二甲基甲酰胺(5mL)中，升至150℃反应1个小时。将反应液冷却至室温，加入水(10mL)和乙酸乙酯(15ml)，分液，水相用乙酸乙酯(10mL×2)萃取。合并的有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用制备板分离提纯(石油醚/乙酸乙酯(v/v)＝1：1，)得到黄色固体状的化合物6-((4-(7-(二甲基磷酰基)-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯20B(100mg，产率66％)。6-((4-(7-Bromo-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3 ] Heptane-2-carboxylate tert-butyl ester 20A (150mg, 0.263mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (192mg, 0.263mmol), 4,5-bis( Diphenylphosphine)-9,9-dimethylxanthene (152 mg, 0.263 mmol), tripotassium phosphate (167 mg, 0.79 mmol) and dimethylphosphine oxide (102 mg, 1.315 mmol) were dissolved in dry N,N -In dimethylformamide (5 mL), the temperature was raised to 150°C for 1 hour. The reaction solution was cooled to room temperature, water (10 mL) and ethyl acetate (15 mL) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v)=1:1,) to obtain compound 6-((4-(7-(dimethylphosphoryl)-6- as a yellow solid) Fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester 20B (100 mg , the yield is 66%).
MS m/z(ESI)：567.5[M+1]MS m/z(ESI): 567.5[M+1]
第三步：(3-(2-((2-氮杂螺[3.3]庚烷-6-基)氨基)-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚-7-基)二甲基氧化膦(化合物20)The third step: (3-(2-((2-azaspiro[3.3]heptane-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H -Indol-7-yl)dimethylphosphine oxide (compound 20)
Figure PCTCN2021120199-appb-000181
Figure PCTCN2021120199-appb-000181
将6-((4-(7-(二甲基磷酰基)-6-氟-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯20B(100mg,0.176mmol)溶于二氯甲烷(2ml)和三氟乙酸(1ml)中，于室温搅拌反应一个小时。减压浓缩，得到粗品棕色油状物。向其中加入乙酸乙酯(10ml)，然后加入碳酸钠饱和溶液调至碱性，分层。水相用乙酸乙酯(10ml)萃取。合并的有机相用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用制备板分离提纯(二氯甲烷/甲醇(v/v)＝10：1，)得到白色固体状的化合物(3-(2-((2-氮杂螺[3.3]庚烷-6-基)氨基)-5-(三氟甲基)嘧啶-4-基)-6-氟-1H-吲哚-7-基)二甲基氧化膦(化合物20)(27mg，产率33％)。6-((4-(7-(Dimethylphosphoryl)-6-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2 - Azaspiro[3.3]heptane-2-carboxylate tert-butyl ester 20B (100 mg, 0.176 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (1 ml) and the reaction was stirred at room temperature for one hour. Concentration under reduced pressure gave crude brown oil. Ethyl acetate (10 ml) was added thereto, then a saturated solution of sodium carbonate was added to make it basic, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 ml). The combined organic phases were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified with a preparative plate (dichloromethane/methanol (v/v)=10:1,) to obtain the compound (3-(2-((2-azaspiro[3.3]heptane-6) as a white solid. -yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indol-7-yl)dimethylphosphine oxide (compound 20) (27 mg, 33% yield) ).
MS m/z(ESI)：468.1[M+1]MS m/z(ESI): 468.1[M+1]
1H NMR(400MHz,CD 3OD)δ8.67-8.51(m,2H),7.94(s,1H),7.07(s,1H),4.39(m,1H),3.88–3.77(m,4H),2.71(m,2H),2.25(m,2H),1.97(s,3H),1.93(s,3H). 1H NMR (400MHz, CD 3 OD) δ8.67-8.51(m, 2H), 7.94(s, 1H), 7.07(s, 1H), 4.39(m, 1H), 3.88-3.77(m, 4H), 2.71(m, 2H), 2.25(m, 2H), 1.97(s, 3H), 1.93(s, 3H).
实施例21Example 21
6-((4-(7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸2-羟基-2-甲基丙基酯(化合物21)6-((4-(7-(Dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[ 3.3] Heptane-2-carboxylic acid 2-hydroxy-2-methylpropyl ester (Compound 21)
Figure PCTCN2021120199-appb-000182
Figure PCTCN2021120199-appb-000182
将化合物(3-(2-((2-氮杂螺[3.3]庚烷-6-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦(化合物19)(400mg，0.89mmol)溶于1,4-二氧六环(5mL)中，于搅拌下加入4,4-二甲基-1,3-二氧戊环-2-酮(200mg,1.78mmol)和碳酸铯(725mg,2.23mmol)，将混合物在50℃下搅拌16小时。反应结束后浓缩，通过制备型HPLC纯化，冻干得到白色固体化合物6-((4-(7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸2-羟基-2-甲基丙基酯(化合物21)(53mg，收率10％)。The compound (3-(2-((2-azaspiro[3.3]heptan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-7- base) dimethylphosphine oxide (compound 19) (400 mg, 0.89 mmol) was dissolved in 1,4-dioxane (5 mL), and 4,4-dimethyl-1,3-dioxane was added with stirring Pentacyclo-2-one (200 mg, 1.78 mmol) and cesium carbonate (725 mg, 2.23 mmol), the mixture was stirred at 50° C. for 16 hours. After the reaction, it was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound 6-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethane) yl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 2-hydroxy-2-methylpropyl ester (Compound 21) (53 mg, 10% yield).
MS m/z(ESI)：566.6[M+1]MS m/z(ESI): 566.6[M+1]
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),8.61-8.43(m,2H),8.20(t,1H),7.92(d,1H),7.51-7.48(m,1H),7.33-7.26(m,1H),4.51(s,1H),4.35-4.31(m,1H),3.99-3.90(m,4H),3.72(s,2H),2.58-2.56(m,2H),2.25(m,2H),1.83(s,3H),1.79(s,3H),1.07(s,6H). 1 H NMR(400MHz,DMSO-d6)δ11.55(s,1H),8.61-8.43(m,2H),8.20(t,1H),7.92(d,1H),7.51-7.48(m,1H) ,7.33-7.26(m,1H),4.51(s,1H),4.35-4.31(m,1H),3.99-3.90(m,4H),3.72(s,2H),2.58-2.56(m,2H) ,2.25(m,2H),1.83(s,3H),1.79(s,3H),1.07(s,6H).
实施例22Example 22
6-((4-(7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸2-羟乙基酯(化合物22)6-((4-(7-(Dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[ 3.3] Heptane-2-carboxylate 2-hydroxyethyl ester (Compound 22)
Figure PCTCN2021120199-appb-000183
Figure PCTCN2021120199-appb-000183
将(3-(2-((2-氮杂螺[3.3]庚烷-6-基)氨基)-5-(三氟甲基)嘧啶-4-基)-1H-吲哚-7-基)二甲基氧化膦(化合物19)(100mg,0.22mmol)溶于甲苯(6mL)中，加入碳酸铯(144mg,0.44mmol)和碳酸乙烯酯(18mg,0.22mmol)，加热至100℃反应2小时。将反应液浓缩旋干，然后加入二氯甲烷(15mL)，过滤。滤液浓缩旋干得到粗品。粗品经制备型HPLC纯化后冻干得白色固体化合物6-((4-(7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸2-羟乙基酯(化合物22)(12mg，收率10％)。(3-(2-((2-Azaspiro[3.3]heptan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl ) Dimethylphosphine oxide (compound 19) (100 mg, 0.22 mmol) was dissolved in toluene (6 mL), cesium carbonate (144 mg, 0.44 mmol) and ethylene carbonate (18 mg, 0.22 mmol) were added, and heated to 100 ° C for reaction 2 Hour. The reaction solution was concentrated and spin-dried, and then dichloromethane (15 mL) was added, followed by filtration. The filtrate was concentrated and spin-dried to obtain crude product. The crude product was purified by preparative HPLC and lyophilized to give a white solid compound 6-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine- 2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 2-hydroxyethyl ester (compound 22) (12 mg, 10% yield).
MS m/z(ESI)：538.3[M+1]MS m/z(ESI): 538.3[M+1]
1HNMR(400MHz,DMSO-D6)δ11.55(s,1H),8.58-8.43(m,2H),8.19(t,1H),7.91(d,1H),7.48(m,1H),7.32-7.26(m,1H),4.72(s,1H),4.35-4.33(m,1H),3.95-3.88(m,6H),3.52-3.51(m,2H),2.60-2.58(m,2H),2.23(m,2H),1.83(s,3H),1.79(s,3H). 1 HNMR(400MHz,DMSO-D6)δ11.55(s,1H),8.58-8.43(m,2H),8.19(t,1H),7.91(d,1H),7.48(m,1H),7.32- 7.26(m, 1H), 4.72(s, 1H), 4.35-4.33(m, 1H), 3.95-3.88(m, 6H), 3.52-3.51(m, 2H), 2.60-2.58(m, 2H), 2.23(m, 2H), 1.83(s, 3H), 1.79(s, 3H).
实施例23Example 23
3-(2-((2-氮杂螺[3.3]庚烷-6-基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈(化合物23)3-(2-((2-Azaspiro[3.3]heptan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)- 1H-Indole-6-carbonitrile (Compound 23)
Figure PCTCN2021120199-appb-000184
Figure PCTCN2021120199-appb-000184
将6-((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁基酯(中间体8)(670mg,1.16mmol)溶于二氯甲烷溶液(27mL)中，加入三氟乙酸(3mL)，室温反应2小时。浓缩反应液，残留物加入氨水调节至弱碱性，然后过反相柱(ACN:H2O＝5:95到95:5)纯化后得到3-(2-((2-氮杂螺[3.3]庚烷-6-基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈(化合物23)(420mg，产率76％)。6-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 2-Azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (Intermediate 8) (670 mg, 1.16 mmol) was dissolved in dichloromethane solution (27 mL), trifluoroacetic acid (3 mL) was added, room temperature React for 2 hours. The reaction solution was concentrated, the residue was adjusted to weakly alkaline by adding ammonia water, and then purified by reversed-phase column (ACN:H2O=5:95 to 95:5) to obtain 3-(2-((2-azaspiro[3.3] Heptan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile (compound 23) (420mg , the yield is 76%).
MS m/z(ESI)：475.1[M+1]MS m/z(ESI): 475.1[M+1]
1H NMR(400MHz,DMSO-D6)δ8.76(dd,1H),8.61(m,1H),8.52(m,1H),8.30(m,1H),8.19(d,1H),7.82-7.69(m,1H),4.33-4.24(m,1H),4.02(d,2H),3.91(d,2H),2.66-2.64(m,2H),2.33-2.20(m,2H),2.06(s,3H),2.02(s,3H). 1 H NMR (400MHz, DMSO-D6)δ8.76(dd,1H), 8.61(m,1H), 8.52(m,1H), 8.30(m,1H), 8.19(d,1H), 7.82-7.69 (m,1H),4.33-4.24(m,1H),4.02(d,2H),3.91(d,2H),2.66-2.64(m,2H),2.33-2.20(m,2H),2.06(s ,3H),2.02(s,3H).
实施例24Example 24
6-((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸2-羟乙基酯(化合物24)6-((4-(6-Cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2 - Azaspiro[3.3]heptane-2-carboxylic acid 2-hydroxyethyl ester (compound 24)
Figure PCTCN2021120199-appb-000185
Figure PCTCN2021120199-appb-000185
将3-(2-((2-氮杂螺[3.3]庚烷-6-基)氨基)-5-(三氟甲基)嘧啶-4-基)-7-(二甲基磷酰基)-1H-吲哚-6-甲腈(化合物23)(200mg,0.37mmol)溶于甲苯(15mL)中，加入碳酸铯(410mg,1.25mmol)和碳酸乙烯酯(73mg,0.83mmol)，油浴锅加热反应，于100℃反应2小时。浓缩反应液，然后加入二氯甲烷(15mL)，然后过滤，得到滤液，浓缩。所得残余物通过制备型HPLC纯化，冻干得白色固体化合物6-((4-(6-氰基-7-(二甲基磷酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸2-羟乙基酯(化合物24)(40mg，产率17％)。3-(2-((2-Azaspiro[3.3]heptan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl) -1H-Indole-6-carbonitrile (compound 23) (200 mg, 0.37 mmol) was dissolved in toluene (15 mL), cesium carbonate (410 mg, 1.25 mmol) and ethylene carbonate (73 mg, 0.83 mmol) were added, oil bath The pot was heated and reacted at 100°C for 2 hours. The reaction solution was concentrated, and then dichloromethane (15 mL) was added, followed by filtration to obtain a filtrate, which was concentrated. The resulting residue was purified by preparative HPLC and lyophilized to give a white solid compound 6-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-( Trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid 2-hydroxyethyl ester (compound 24) (40 mg, 17% yield).
MS m/z(ESI)：563.2[M+1]MS m/z(ESI): 563.2[M+1]
1H NMR(400MHz,DMSO-D6)δ12.12(s,1H),8.72-8.51(m,2H),8.29(d,1H),8.18(d,1H),7.75(dd,1H),4.74(s,1H),4.35-4.26(m,1H),3.98-3.88(m,6H),3.52(m,2H),2.60-2.55(m,2H),2.24(m,2H),2.05(s,3H),2.02(s,3H). 1 H NMR (400MHz, DMSO-D6) δ 12.12(s, 1H), 8.72-8.51(m, 2H), 8.29(d, 1H), 8.18(d, 1H), 7.75(dd, 1H), 4.74 (s,1H),4.35-4.26(m,1H),3.98-3.88(m,6H),3.52(m,2H),2.60-2.55(m,2H),2.24(m,2H),2.05(s ,3H),2.02(s,3H).
测试例：Test case:
测试例1、CDK激酶抑制活性的测定Test Example 1. Determination of CDK Kinase Inhibitory Activity
使用Caliper/LabChip EZ Reader(PerkinElmer，Waltham，MA)开发的每种CDK的激酶测定法测定本发明化合物对CDK7、CDK9、CDK12和CDK2活性的抑制作用。这些测定测量磷酸化肽底物的量，该磷酸化肽底物在27℃孵育期后，作为总肽的一部分产生，其含有以下成分：测试化合物(可变浓度从10μM降至0.508nM，在一系列3倍的系列稀释液中)、活性CDK激酶蛋白(具有下文列出的每种CDK的指示的细胞周期蛋白)、ATP(2mM)和底物肽(如下所列)，在下列缓冲液中：2-(N-吗啉代)乙磺酸盐(MES缓冲液，20mM)，pH 6.75，0.01％(v/v)吐温20清洁剂，0.05mg/mL牛血清白蛋白(BSA)。具体地，CDK7抑制测定使用CDK7/细胞周期蛋白H/MAT1复合物(6nM)和“5-FAMCDK7tide”肽底物(2μM，合成的荧光团标记的肽，具有以下序列：5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK(SEQ ID No.1)，其中“5-FAM”是指5-羧基荧光素)，且在上面列出的缓冲液组合物中含有6mM MgCl 2。此外， CDK9抑制测定使用CDK9/细胞周期蛋白T1复合物(8nM)和“5-FAM-CDK9tide”肽底物(2μM，合成的荧光团标记的肽，具有以下序列：5-FAM-GSRTPMY(SEQ ID No.2)-NH 2，5-FAM如上所定义且NH 2表示C-端酰胺)，且在上面列出的缓冲液组合物中含有10mM MgCl 2。CDK12抑制测定使用CDK12(aa686-1082)/细胞周期蛋白K复合物(50nM)和如上定义的“5-FAM-CDK9tide”(2μM)，且在上面列出的缓冲液组合物中含有2mM MgCl 2。此外，CDK2抑制测定使用CDK2/细胞周期蛋白E1复合物(0.5nM)和如上定义的“5-FAM-CDK7tide”(2μM)，且在上面列出的缓冲液组合物中含有2mM MgCl 2。选择每种CDK抑制试验在27℃下的孵育期，使得每次试验中产生的磷酸化肽产物相对于总肽浓度的比例对于未抑制的激酶约为20％(±5％)(对于CDK7，35分钟，对于CDK2，35分钟，对于CDK12，3小时，对于CDK9，15分钟)。在测试化合物滴定并导致肽产物形成抑制的情况下，这些数据拟合产生最佳拟合IC50值。 The inhibition of CDK7, CDK9, CDK12 and CDK2 activity by compounds of the invention was determined using a kinase assay for each CDK developed by the Caliper/LabChip EZ Reader (PerkinElmer, Waltham, MA). These assays measure the amount of phosphorylated peptide substrate produced as part of the total peptide following an incubation period at 27°C, containing the following components: test compound (variable concentrations from 10 μM to 0.508 nM, at in serial 3-fold serial dilutions), active CDK kinase protein (cyclins with the indicated cyclins for each CDK listed below), ATP (2 mM) and substrate peptides (listed below) in the following buffers Medium: 2-(N-morpholino)ethanesulfonate (MES buffer, 20 mM), pH 6.75, 0.01% (v/v) Tween 20 detergent, 0.05 mg/mL bovine serum albumin (BSA) . Specifically, the CDK7 inhibition assay used the CDK7/cyclin H/MAT1 complex (6 nM) and the "5-FAMCDK7tide" peptide substrate (2 μM, a synthetic fluorophore-labeled peptide with the following sequence: 5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK ( SEQ ID No. 1), wherein "5-FAM" refers to 5-carboxyfluorescein), with 6 mM MgCl2 in the buffer composition listed above. In addition, CDK9 inhibition assays used the CDK9/cyclin T1 complex (8 nM) and the "5-FAM-CDK9tide" peptide substrate (2 μM, a synthetic fluorophore-labeled peptide with the following sequence: 5-FAM-GSRTPMY (SEQ ID No. 2) -NH2 , 5-FAM is as defined above and NH2 represents C-terminal amide), and contains 10 mM MgCl2 in the buffer compositions listed above. The CDK12 inhibition assay used CDK12 (aa686-1082)/cyclin K complex (50 nM) and "5-FAM-CDK9tide" (2 μM) as defined above with 2 mM MgCl in the buffer composition listed above . In addition, CDK2 inhibition assays used CDK2/Cyclin El complex (0.5 nM) and "5-FAM-CDK7tide" (2 μM) as defined above with 2 mM MgCl2 in the buffer composition listed above. The incubation period at 27°C for each CDK inhibition assay was chosen such that the ratio of phosphorylated peptide product produced in each assay relative to the total peptide concentration was approximately 20% (±5%) for uninhibited kinase (for CDK7, 35 minutes, 35 minutes for CDK2, 3 hours for CDK12, 15 minutes for CDK9). Fitting of these data yields best-fit IC50 values where the test compound is titrated and results in inhibition of peptide product formation.
这些测定的结果如下表1所示，其中“A”代表计算的IC 50大于1nM小于或等于10nM；“B”表示计算的IC 50大于10nM小于或等于100nM；“C”表示计算的IC 50大于100nM小于或等于1000nM；“D”表示计算的IC 50大于1000nM；“NT”表示未在指定的测定中测试指定的化合物。 The results of these assays are shown in Table 1 below, where "A" represents a calculated IC50 greater than 1 nM and less than or equal to 10 nM; "B" represents a calculated IC50 greater than 10 nM and less than or equal to 100 nM; "C" represents a calculated IC50 greater than 100 nM 100 nM is less than or equal to 1000 nM; "D" indicates that the calculated IC50 is greater than 1000 nM; "NT" indicates that the indicated compound was not tested in the indicated assay.
表1.本发明的化合物对CDK2、CDK7、CDK9和CDK12的抑制活性。Table 1. Inhibitory activity of compounds of the invention on CDK2, CDK7, CDK9 and CDK12.
化合物compound CDK2CDK2 CDK7CDK7 CDK9CDK9 CDK12CDK12
11    AA      
22    AA      
2A2A DD AA DD DD
2B2B    BB      
33    BB      
44    BB      
55    AA      
66    BB      
77 DD AA DD CC
88    BB      
99 DD AA CC BB
1010 DD AA CC CC
1111 DD AA DD DD
1212 DD AA DD CC
1313    CC      
14-P114-P1 DD AA DD CC
14-P214-P2 DD AA DD CC
1515 DD AA DD DD
1616 DD AA DD CC
1717 DD AA DD DD
1818    BB      
1919 DD AA DD DD
2020 DD AA DD DD
21twenty one DD AA DD DD
22twenty two DD AA DD DD
23twenty three DD BB DD DD
24twenty four DD BB DD DD
以上的结果表明本发明的化合物对CDK7具有良好的抑制活性和选择性。The above results show that the compounds of the present invention have good inhibitory activity and selectivity to CDK7.
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity, all possible combinations of the technical features in the above-described embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be regarded as the scope described in this specification.
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。The above-mentioned embodiments only represent several embodiments of the present invention, and the descriptions thereof are specific and detailed, but should not be construed as a limitation on the scope of the invention patent. It should be pointed out that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can also be made, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.

Claims (45)

  1. 具有通式(I)所示结构的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药：Pyrimidyl derivatives having the structure represented by the general formula (I), their optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs:
    Figure PCTCN2021120199-appb-100001
    Figure PCTCN2021120199-appb-100001
    其中，环A为4-6元饱和含氮杂环基、-C 1-C 3亚烷基-4-6元饱和含氮杂环基或环Q；环A被1至3个R 0取代，R 0各自独立地选自-H、C 1-C 3烷基、羟基、卤素、-NH 2和-NH-(C 1-C 3烷基)； Wherein, ring A is a 4-6 membered saturated nitrogen-containing heterocyclic group, -C 1 -C 3 alkylene-4-6 membered saturated nitrogen-containing heterocyclic group or ring Q; ring A is substituted by 1 to 3 R 0 , R 0 are each independently selected from -H, C 1 -C 3 alkyl, hydroxyl, halogen, -NH 2 and -NH-(C 1 -C 3 alkyl);
    环Q选自如下基团：Ring Q is selected from the following groups:
    Figure PCTCN2021120199-appb-100002
    Figure PCTCN2021120199-appb-100002
    R 1选自-H、卤素、氰基、C 1-C 3卤代烷基、3-5元饱和环烷基、C 1-C 3烷基、C 1-C 3烷氧基和C 1-C 3卤代烷氧基； R 1 is selected from -H, halogen, cyano, C 1 -C 3 haloalkyl, 3-5 membered saturated cycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkoxy;
    R 2、R 3各自独立地选自-H、卤素、氰基、-C(O)NH(C 1-C 4烷基)、-C(O)N(C 1-C 4烷基) 2、5-6元杂芳基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基和C 1-C 4卤代烷氧基； R 2 and R 3 are each independently selected from -H, halogen, cyano, -C(O)NH(C 1 -C 4 alkyl), -C(O)N(C 1 -C 4 alkyl) 2 , 5-6 membered heteroaryl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl and C 1 -C 4 haloalkoxy;
    X选自CH和N；X is selected from CH and N;
    R 4选自如下基团： R 4 is selected from the following groups:
    Figure PCTCN2021120199-appb-100003
    Figure PCTCN2021120199-appb-100003
    其中，R 5、R 6各自独立地选自-H、C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基、3-6元饱和环烷基、6-10元芳基、5-12元杂芳基、-(C 1-C 3烷基)-6-10元芳基和-(C 1-C 3烷基)-5-12元杂芳基； Wherein, R 5 and R 6 are each independently selected from -H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl , 3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl and -(C 1 -C 3 alkyl)-5-12 membered heteroaryl;
    R 5和R 6不连接或连接成4-6元环； R 5 and R 6 are not connected or connected into a 4-6 membered ring;
    条件是，当环A选自4-6元饱和含氮杂环基和-C 1-C 3亚烷基-4-6元饱和含氮杂环基时，R 4不为
    Figure PCTCN2021120199-appb-100004
    Provided that when Ring A is selected from 4-6 membered saturated nitrogen-containing heterocyclic group and -C 1 -C 3 alkylene-4-6 membered saturated nitrogen-containing heterocyclic group, R 4 is not
    Figure PCTCN2021120199-appb-100004
  2. 根据权利要求1所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，The pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof according to claim 1, wherein:
    R 4为
    Figure PCTCN2021120199-appb-100005
     R4 is
    Figure PCTCN2021120199-appb-100005
    R 5、R 6各自独立地选自C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基和3-6元饱和环烷基； R 5 and R 6 are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl and 3-6 membered saturated cycloalkyl Saturated cycloalkyl;
    R 5和R 6不连接或连接成4-6元环。 R 5 and R 6 are not linked or linked into a 4-6 membered ring.
  3. 根据权利要求1所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，R 4为
    Figure PCTCN2021120199-appb-100006
    The pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof according to claim 1, wherein R 4 for
    Figure PCTCN2021120199-appb-100006
    R 5、R 6各自独立地选自-H、C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基和3-6元饱和环烷基； R 5 and R 6 are each independently selected from -H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl and 3 -6-membered saturated cycloalkyl;
    R 5和R 6不连接或连接成4-6元环。 R 5 and R 6 are not linked or linked into a 4-6 membered ring.
  4. 根据权利要求1所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，The pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof according to claim 1, wherein:
    R 4为
    Figure PCTCN2021120199-appb-100007
     R4 is
    Figure PCTCN2021120199-appb-100007
    R 5选自C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基、3-6元饱和环烷基、6-10元芳基、5-12元杂芳基、-(C 1-C 3烷基)-6-10元芳基和-(C 1-C 3烷基)-5-12元杂芳基。 R 5 is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl, 6 -10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl and -(C 1 -C 3 alkyl)-5-12 membered heteroaryl .
  5. 根据权利要求1所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，R 4为
    Figure PCTCN2021120199-appb-100008
    The pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof according to claim 1, wherein R 4 for
    Figure PCTCN2021120199-appb-100008
    R 5、R 6各自独立地选自C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基、3-6元饱和环烷基、6-10元芳基、5-12元杂芳基、-(C 1-C 3烷基)-6-10元芳基和-(C 1-C 3烷基)-5-12元杂芳基； R 5 and R 6 are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered Saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl and -(C 1 -C 3 alkyl)-5 -12-membered heteroaryl;
    环A选自环Q。Ring A is selected from ring Q.
  6. 根据权利要求1所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，The pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof according to claim 1, wherein:
    R 4为
    Figure PCTCN2021120199-appb-100009
     R4 is
    Figure PCTCN2021120199-appb-100009
    R 5选自C 1-C 4烷基、C 1-C 4卤代烷基、-(C 1-C 3烷基)-3-6元饱和环烷基、3-6元饱和环烷基、6-10元芳基、5-12元杂芳基、-(C 1-C 3烷基)-6-10元芳基和-(C 1-C 3烷基)-5-12元杂芳基； R 5 is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -(C 1 -C 3 alkyl)-3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl, 6 -10 membered aryl, 5-12 membered heteroaryl, -(C 1 -C 3 alkyl)-6-10 membered aryl and -(C 1 -C 3 alkyl)-5-12 membered heteroaryl ;
    环A选自环Q。Ring A is selected from ring Q.
  7. 根据权利要求1～6任一项所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，R 1为-CF 3。 The pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof according to any one of claims 1 to 6, wherein It is characterized in that R 1 is -CF 3 .
  8. 根据权利要求1～6任一项所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，R 2为-H、-F或-CN。 The pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof according to any one of claims 1 to 6, wherein Characterized in that R 2 is -H, -F or -CN.
  9. 根据权利要求1～6任一项所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，R 3为-H。 The pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof according to any one of claims 1 to 6, wherein characterized in that R 3 is -H.
  10. 根据权利要求1～6任一项所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，环A选自如下基团中的一个且环A上的H被1至3个R 0取代： The pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof according to any one of claims 1 to 6, wherein It is characterized in that ring A is selected from one of the following groups and the H on ring A is substituted by 1 to 3 R 0 :
    Figure PCTCN2021120199-appb-100010
    Figure PCTCN2021120199-appb-100010
  11. 根据权利要求10所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，环A选自如下基团中的一个且环A上的H被1至3个R 0取代： The pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof according to claim 10, wherein Ring A One of the following groups is selected and the H on ring A is substituted with 1 to 3 R 0 :
    Figure PCTCN2021120199-appb-100011
    Figure PCTCN2021120199-appb-100011
  12. 根据权利要求1～6任一项所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，R 0各自独立地选自-H、甲基、乙基、羟基、-NH 2和-NH-CH 3。 The pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof according to any one of claims 1 to 6, wherein It is characterized in that each R 0 is independently selected from -H, methyl, ethyl, hydroxyl, -NH 2 and -NH-CH 3 .
  13. 具有通式(a)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药：Compounds of general formula (a), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof:
    Figure PCTCN2021120199-appb-100012
    Figure PCTCN2021120199-appb-100012
    其中：in:
    R 7各自独立地选自-H、卤素、氰基、-NR’R”、-OR’、C 1-6烷基、卤代C 1-6烷基、
    Figure PCTCN2021120199-appb-100013
    和-P(＝O)R 5R 6；     R 7 is each independently selected from -H, halogen, cyano, -NR'R", -OR', C 1-6 alkyl, halogenated C 1-6 alkyl,
    Figure PCTCN2021120199-appb-100013
    and -P(=O)R 5 R 6 ;
    R 5和R 6各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R 5 and R 6 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
    R 5’选自-H、C 1-6烷基和卤代C 1-6烷基； R 5' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 6’选自-H、氰基、C 1-6烷基和卤代C 1-6烷基； R 6' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 8选自-H、卤素、氰基、-OR’、C 1-6烷基和卤代C 1-6烷基； R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 9和R 10各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R 9 and R 10 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
    R 11选自-H、-OR’、-NR’R”、C 1-6烷基、卤代C 1-6烷基、-NHC(O)C 1-6烷基、-NHC(O)OC 1-6烷基、-NHC(O)NHC 1-6烷基和-NHC(O)N(C 1-6烷基) 2；其中所述C 1-6烷基任选被1-3个选自羟基、巯基、-OR’和-NR’R”的取代基取代； R 11 is selected from -H, -OR', -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl, -NHC(O)C 1-6 alkyl, -NHC(O) OC 1-6 alkyl, -NHC(O)NHC 1-6 alkyl and -NHC(O)N(C 1-6 alkyl) 2 ; wherein the C 1-6 alkyl is optionally replaced by 1-3 substituted with a substituent selected from hydroxyl, thiol, -OR' and -NR'R";
    R’和R”各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    m1、m2、n1和n2各自独立地为0、1或2；m1, m2, n1, and n2 are each independently 0, 1, or 2;
    p选自0、1、2、3、4、5和6；p is selected from 0, 1, 2, 3, 4, 5 and 6;
    t选自1、2、3和4；t is selected from 1, 2, 3 and 4;
    条件是R 7中至少一个为-P(＝O)R 5R 6。 Provided that at least one of R 7 is -P(=O)R 5 R 6 .
  14. 根据权利要求13的通式(a)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：A compound of general formula (a), an optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically-labeled derivative or prodrug thereof according to claim 13, wherein:
    R 7各自独立地选自-H、卤素、氰基、C 1-4烷基、卤代C 1-4烷基和-P(＝O)R 5R 6； R 7 is each independently selected from -H, halogen, cyano, C 1-4 alkyl, haloC 1-4 alkyl and -P(=O)R 5 R 6 ;
    R 5和R 6各自独立地选自-H和C 1-4烷基； R 5 and R 6 are each independently selected from -H and C 1-4 alkyl;
    R 8选自卤素、氰基和卤代C 1-4烷基； R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl;
    R 9和R 10各自独立地选自-H和C 1-4烷基； R 9 and R 10 are each independently selected from -H and C 1-4 alkyl;
    R 11选自-H、-NR’R”、-NHC(O)OC 1-4烷基、-NHC(O)NHC 1-4烷基和-NHC(O)N(C 1-4烷基) 2；其中所述C 1-4烷基任选被1-3个选自羟基、巯基和-NR’R”的取代基取代； R 11 is selected from -H, -NR'R", -NHC(O)OC 1-4 alkyl, -NHC(O)NHC 1-4 alkyl and -NHC(O)N(C 1-4 alkyl ) 2 ; wherein the C 1-4 alkyl is optionally substituted by 1-3 substituents selected from hydroxyl, mercapto and -NR'R";
    R’和R”各自独立地选自-H、C 1-4烷基和卤代C 1-4烷基； R' and R" are each independently selected from -H, C 1-4 alkyl and haloC 1-4 alkyl;
    m1、m2、n1和n2各自独立地为0、1或2；m1, m2, n1, and n2 are each independently 0, 1, or 2;
    p选自0、1和2；p is selected from 0, 1 and 2;
    t选自1和2；t is selected from 1 and 2;
    条件是R 7中至少一个为-P(＝O)R 5R 6。 Provided that at least one of R 7 is -P(=O)R 5 R 6 .
  15. 根据权利要求13的通式(a)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：A compound of general formula (a), an optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically-labeled derivative or prodrug thereof according to claim 13, wherein:
    R 7各自独立地选自卤素、氰基和-P(＝O)R 5R 6； R 7 is each independently selected from halogen, cyano and -P(=O)R 5 R 6 ;
    R 5和R 6各自独立地为C 1-4烷基； R 5 and R 6 are each independently C 1-4 alkyl;
    R 8为卤代C 1-4烷基； R 8 is halogenated C 1-4 alkyl;
    R 9和R 10各自独立地为-H； R 9 and R 10 are each independently -H;
    R 11选自H和-NR’R”； R 11 is selected from H and -NR'R";
    R’和R”各自独立地选自-H和C 1-4烷基； R' and R" are each independently selected from -H and C 1-4 alkyl;
    m1、m2、n1和n2各自独立地为1或2；m1, m2, n1 and n2 are each independently 1 or 2;
    p为0；p is 0;
    t选自1和2；t is selected from 1 and 2;
    条件是R 7中至少一个为-P(＝O)R 5R 6。 Provided that at least one of R 7 is -P(=O)R 5 R 6 .
  16. 根据权利要求13的通式(a)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：A compound of general formula (a), an optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically-labeled derivative or prodrug thereof according to claim 13, wherein:
    R 7为-P(＝O)R 5R 6； R 7 is -P(=O)R 5 R 6 ;
    R 5和R 6各自独立地为C 1-4烷基； R 5 and R 6 are each independently C 1-4 alkyl;
    R 8为卤代C 1-4烷基，优选为-CF 3； R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
    R 9和R 10各自独立地为-H； R 9 and R 10 are each independently -H;
    R 11为-NR’R”； R 11 is -NR'R";
    R’和R”各自独立地为-H；R' and R" are each independently -H;
    m1、m2、n1和n2各自独立地为1；m1, m2, n1 and n2 are each independently 1;
    p为0；p is 0;
    t为1。t is 1.
  17. 通式(b)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，A compound of general formula (b), an optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically-labeled derivative or prodrug thereof,
    Figure PCTCN2021120199-appb-100014
    Figure PCTCN2021120199-appb-100014
    其中，in,
    R 7各自独立地选自-H、卤素、氰基、-OR’、-NR’R”、C 1-6烷基、卤代C 1-6烷基、
    Figure PCTCN2021120199-appb-100015
    和 -P(＝O)R 5R 6；     R 7 is each independently selected from -H, halogen, cyano, -OR', -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl,
    Figure PCTCN2021120199-appb-100015
    and -P(=O)R 5 R 6 ;
    R 5和R 6各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R 5 and R 6 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
    R 5’选自-H、C 1-6烷基和卤代C 1-6烷基； R 5' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 6’选自-H、氰基、C 1-6烷基和卤代C 1-6烷基； R 6' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 8选自-H、卤素、氰基、-OR’、C 1-6烷基和卤代C 1-6烷基； R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 11选自-H、-OR’、C 1-6烷基、卤代C 1-6烷基、-C(O)C 1-6烷基、-C(O)OC 1-6烷基、-C(O)NHC 1-6烷基和-C(O)N(C 1-6烷基) 2；其中所述C 1-6烷基任选被1-3个选自羟基、巯基、-OR’和-NR’R”的取代基取代； R 11 is selected from -H, -OR', C 1-6 alkyl, halogenated C 1-6 alkyl, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl , -C(O)NHC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; wherein the C 1-6 alkyl is optionally , -OR' and -NR'R" substituents are substituted;
    R’和R”各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    m1、m2、n1和n2各自独立地为0、1或2；m1, m2, n1, and n2 are each independently 0, 1, or 2;
    t选自1、2、3和4；t is selected from 1, 2, 3 and 4;
    p选自0、1、2、3、4、5和6。p is selected from 0, 1, 2, 3, 4, 5 and 6.
  18. 根据权利要求17的通式(b)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：A compound of general formula (b), an optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof according to claim 17, wherein:
    R 7各自独立地选自-H、卤素、氰基、C 1-4烷基、卤代C 1-4烷基和-P(＝O)R 5R 6； R 7 is each independently selected from -H, halogen, cyano, C 1-4 alkyl, haloC 1-4 alkyl and -P(=O)R 5 R 6 ;
    R 5和R 6各自独立地选自-H和C 1-4烷基； R 5 and R 6 are each independently selected from -H and C 1-4 alkyl;
    R 8选自卤素、氰基和卤代C 1-4烷基； R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl;
    R 11选自-H、-C(O)OC 1-4烷基、-C(O)NHC 1-4烷基和-C(O)N(C 1-4烷基) 2；其中所述C 1-4烷基任选被1-3个选自羟基、巯基和-NR’R”的取代基取代； R 11 is selected from -H, -C(O)OC 1-4 alkyl, -C(O)NHC 1-4 alkyl and -C(O)N(C 1-4 alkyl) 2 ; wherein said C 1-4 alkyl is optionally substituted by 1-3 substituents selected from hydroxyl, mercapto and -NR'R";
    R’和R”各自独立地选自-H和C 1-6烷基； R' and R" are each independently selected from -H and C 1-6 alkyl;
    m1、m2、n1和n2各自独立地为0、1或2；m1, m2, n1, and n2 are each independently 0, 1, or 2;
    t选自1和2；t is selected from 1 and 2;
    p选自0和1；p is selected from 0 and 1;
    条件是R 7中至少一个为-P(＝O)R 5R 6。 Provided that at least one of R 7 is -P(=O)R 5 R 6 .
  19. 根据权利要求17的通式(b)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：A compound of general formula (b), an optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof according to claim 17, wherein:
    R 7各自独立地选自-H、卤素、氰基和-P(＝O)R 5R 6； R 7 is each independently selected from -H, halogen, cyano and -P(=O)R 5 R 6 ;
    R 5和R 6各自独立地为C 1-4烷基； R 5 and R 6 are each independently C 1-4 alkyl;
    R 8为卤代C 1-4烷基； R 8 is halogenated C 1-4 alkyl;
    R 11为H或-C(O)OC 1-4烷基；其中所述C 1-4烷基任选被1-2个羟基取代； R 11 is H or -C(O)OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups;
    m1、m2、n1和n2各自独立地为1或2；m1, m2, n1 and n2 are each independently 1 or 2;
    t选自1和2；t is selected from 1 and 2;
    p选自0和1；p is selected from 0 and 1;
    条件是R 7中至少一个为-P(＝O)R 5R 6。 Provided that at least one of R 7 is -P(=O)R 5 R 6 .
  20. 通式(b-1)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，A compound of general formula (b-1), its optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug,
    Figure PCTCN2021120199-appb-100016
    Figure PCTCN2021120199-appb-100016
    其中，in,
    R 7选自-H、卤素、氰基、-OR’、-NR’R”、C 1-6烷基、卤代C 1-6烷基和-P(＝O)R 5R 6； R 7 is selected from -H, halogen, cyano, -OR', -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl and -P(=O)R 5 R 6 ;
    R 5和R 6各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R 5 and R 6 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
    R 8选自-H、卤素、氰基、-OR’、C 1-6烷基和卤代C 1-6烷基； R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 11选自-H、-OR’、C 1-6烷基、卤代C 1-6烷基、-C(O)C 1-6烷基、-C(O)OC 1-6烷基、-C(O)NHC 1-6烷基和-C(O)N(C 1-6烷基) 2；其中所述C 1-6烷基任选被1-3个选自羟基、巯基、-OR’和-NR’R”的取代基取代； R 11 is selected from -H, -OR', C 1-6 alkyl, halogenated C 1-6 alkyl, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl , -C(O)NHC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; wherein the C 1-6 alkyl is optionally , -OR' and -NR'R" substituents are substituted;
    R’和R”各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    m1、m2、n1和n2各自独立地为0、1或2。m1, m2, n1, and n2 are each independently 0, 1, or 2.
  21. 根据权利要求20的通式(b-1)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：The compound of general formula (b-1), its optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotope-labeled derivative or prodrug thereof according to claim 20, wherein:
    R 7选自-H、卤素、氰基、C 1-4烷基和卤代C 1-4烷基； R 7 is selected from -H, halogen, cyano, C 1-4 alkyl and halogenated C 1-4 alkyl;
    R 5和R 6各自独立地选自-H和C 1-4烷基； R 5 and R 6 are each independently selected from -H and C 1-4 alkyl;
    R 8选自卤素、氰基和卤代C 1-4烷基； R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl;
    R 11选自-H、-C(O)OC 1-4烷基、-C(O)NHC 1-4烷基和-C(O)N(C 1-4烷基) 2；其中所述C 1-4烷基任选被1-3个选自羟基、巯基和-NR’R”的取代基取代； R 11 is selected from -H, -C(O)OC 1-4 alkyl, -C(O)NHC 1-4 alkyl and -C(O)N(C 1-4 alkyl) 2 ; wherein said C 1-4 alkyl is optionally substituted by 1-3 substituents selected from hydroxyl, mercapto and -NR'R";
    R’和R”各自独立地选自-H和C 1-6烷基； R' and R" are each independently selected from -H and C 1-6 alkyl;
    m1、m2、n1和n2各自独立地为0、1或2。m1, m2, n1, and n2 are each independently 0, 1, or 2.
  22. 根据权利要求20的通式(b-1)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：The compound of general formula (b-1), its optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotope-labeled derivative or prodrug thereof according to claim 20, wherein:
    R 7选自-H、卤素和氰基； R is selected from -H , halogen and cyano;
    R 5和R 6各自独立地为C 1-4烷基； R 5 and R 6 are each independently C 1-4 alkyl;
    R 8为卤代C 1-4烷基； R 8 is halogenated C 1-4 alkyl;
    R 11为H或-C(O)OC 1-4烷基；其中所述C 1-4烷基任选被1-2个羟基取代； R 11 is H or -C(O)OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups;
    m1、m2、n1和n2各自独立地为1或2。m1, m2, n1 and n2 are each independently 1 or 2.
  23. 根据权利要求20的通式(b-1)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：The compound of general formula (b-1), its optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotope-labeled derivative or prodrug thereof according to claim 20, wherein:
    R 7为-H； R 7 is -H;
    R 5和R 6各自独立地为C 1-4烷基； R 5 and R 6 are each independently C 1-4 alkyl;
    R 8为卤代C 1-4烷基，优选为-CF 3； R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
    R 11为-C(O)OC 1-4烷基；其中所述C 1-4烷基任选被1-2个羟基取代； R 11 is -C(O)OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups;
    m1、m2、n1和n2各自独立地为1。m1, m2, n1, and n2 are each independently 1.
  24. 通式(b-2)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，A compound of general formula (b-2), an optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically-labeled derivative or prodrug thereof,
    Figure PCTCN2021120199-appb-100017
    Figure PCTCN2021120199-appb-100017
    其中，in,
    R 7选自-H、卤素、氰基、-OR’、-NR’R”、C 1-6烷基、卤代C 1-6烷基和-P(＝O)R 5R 6； R 7 is selected from -H, halogen, cyano, -OR', -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl and -P(=O)R 5 R 6 ;
    R 5和R 6各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R 5 and R 6 are each independently selected from -H, C 1-6 alkyl and haloC 1-6 alkyl;
    R 8选自-H、卤素、氰基、-OR’、C 1-6烷基和卤代C 1-6烷基； R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 15为C 1-6烷基，其任选被1-3个选自羟基、巯基、-OR’和-NR’R”的取代基取代； R 15 is C 1-6 alkyl, which is optionally substituted by 1-3 substituents selected from hydroxyl, mercapto, -OR' and -NR'R";
    R’和R”各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基； R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    m1、m2、n1和n2各自独立地为0、1或2。m1, m2, n1, and n2 are each independently 0, 1, or 2.
  25. 根据权利要求24的通式(b-2)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：The compound of general formula (b-2), its optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof according to claim 24, wherein:
    R 7选自-H、卤素、氰基、C 1-4烷基和卤代C 1-4烷基； R 7 is selected from -H, halogen, cyano, C 1-4 alkyl and halogenated C 1-4 alkyl;
    R 5和R 6各自独立地选自-H和C 1-4烷基； R 5 and R 6 are each independently selected from -H and C 1-4 alkyl;
    R 8选自卤素、氰基和卤代C 1-4烷基； R 8 is selected from halogen, cyano and halogenated C 1-4 alkyl;
    R 15为C 1-4烷基，其任选被1-3个选自羟基、巯基和-NR’R”的取代基取代； R 15 is C 1-4 alkyl, which is optionally substituted with 1-3 substituents selected from hydroxyl, mercapto and -NR'R";
    R’和R”各自独立地选自-H和C 1-6烷基； R' and R" are each independently selected from -H and C 1-6 alkyl;
    m1、m2、n1和n2各自独立地为0、1或2。m1, m2, n1, and n2 are each independently 0, 1, or 2.
  26. 根据权利要求24的通式(b-2)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：The compound of general formula (b-2), its optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof according to claim 24, wherein:
    R 7选自-H、卤素和氰基； R is selected from -H , halogen and cyano;
    R 5和R 6各自独立地为C 1-4烷基； R 5 and R 6 are each independently C 1-4 alkyl;
    R 8为卤代C 1-4烷基； R 8 is halogenated C 1-4 alkyl;
    R 15为C 1-4烷基；其任选被1-2个羟基取代； R 15 is C 1-4 alkyl; it is optionally substituted with 1-2 hydroxyl groups;
    m1、m2、n1和n2各自独立地为1或2。m1, m2, n1 and n2 are each independently 1 or 2.
  27. 根据权利要求24的通式(b-2)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：The compound of general formula (b-2), its optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof according to claim 24, wherein:
    R 7为-H； R 7 is -H;
    R 5和R 6各自独立地为C 1-4烷基； R 5 and R 6 are each independently C 1-4 alkyl;
    R 8为卤代C 1-4烷基，优选为-CF 3； R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
    R 11为-C(O)OC 1-4烷基；其中所述C 1-4烷基任选被1-2个羟基取代； R 11 is -C(O)OC 1-4 alkyl; wherein said C 1-4 alkyl is optionally substituted with 1-2 hydroxyl groups;
    m1、m2、n1和n2各自独立地为1。m1, m2, n1, and n2 are each independently 1.
  28. 通式(c)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，A compound of general formula (c), an optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically-labeled derivative or prodrug thereof,
    Figure PCTCN2021120199-appb-100018
    Figure PCTCN2021120199-appb-100018
    其中：in:
    R 8选自-H、卤素、氰基、-OR’、C 1-6烷基和卤代C 1-6烷基； R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 13和R 14各自独立地选自H、C 1-6烷基和卤代C 1-6烷基； R 13 and R 14 are each independently selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 15各自独立地选自-H、卤素、-OR’、氰基、C 1-6烷基、卤代C 1-6烷基、
    Figure PCTCN2021120199-appb-100019
    Figure PCTCN2021120199-appb-100020
    R 15 is each independently selected from -H, halogen, -OR', cyano, C 1-6 alkyl, halogenated C 1-6 alkyl,
    Figure PCTCN2021120199-appb-100019
    Figure PCTCN2021120199-appb-100020
    R 5’选自-H、C 1-6烷基和卤代C 1-6烷基； R 5' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 6’选自-H、氰基、C 1-6烷基和卤代C 1-6烷基； R 6' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R’选自-H、C 1-6烷基和卤代C 1-6烷基； R' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    s和q各自独立地选自0、1和2；s and q are each independently selected from 0, 1 and 2;
    r选自1、2、3和4；r is selected from 1, 2, 3 and 4;
    条件是至少一个R 15为
    Figure PCTCN2021120199-appb-100021
    provided that at least one R 15 is
    Figure PCTCN2021120199-appb-100021
  29. 根据权利要求28的通式(c)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：A compound of general formula (c), an optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof according to claim 28, wherein:
    R 8为卤代C 1-6烷基； R 8 is halogenated C 1-6 alkyl;
    R 13和R 14各自独立地选自H和C 1-6烷基； R 13 and R 14 are each independently selected from H and C 1-6 alkyl;
    R 15各自独立地选自-H、卤素、氰基、
    Figure PCTCN2021120199-appb-100022
    R 15 is each independently selected from -H, halogen, cyano,
    Figure PCTCN2021120199-appb-100022
    R 5’选自-H和C 1-6烷基； R 5' is selected from -H and C 1-6 alkyl;
    R 6’选自-H、氰基和C 1-6烷基； R 6' is selected from -H, cyano and C 1-6 alkyl;
    s和q各自独立地选自0和1；s and q are each independently selected from 0 and 1;
    r选自1和2；r is selected from 1 and 2;
    条件是至少一个R 15为
    Figure PCTCN2021120199-appb-100023
    provided that at least one R 15 is
    Figure PCTCN2021120199-appb-100023
  30. 根据权利要求28的通式(c)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：A compound of general formula (c), an optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof according to claim 28, wherein:
    R 8为卤代C 1-4烷基； R 8 is halogenated C 1-4 alkyl;
    R 13和R 14各自独立地为C 1-4烷基； R 13 and R 14 are each independently C 1-4 alkyl;
    R 15各自独立地选自-H、卤素、氰基和
    Figure PCTCN2021120199-appb-100024
    R 15 is each independently selected from -H, halogen, cyano and
    Figure PCTCN2021120199-appb-100024
    R 5’选自-H和C 1-4烷基； R 5' is selected from -H and C 1-4 alkyl;
    R 6’选自-H、氰基和C 1-4烷基； R 6' is selected from -H, cyano and C 1-4 alkyl;
    s和q各自独立地选自0和1；s and q are each independently selected from 0 and 1;
    r选自1和2；r is selected from 1 and 2;
    条件是至少一个R 15为
    Figure PCTCN2021120199-appb-100025
    provided that at least one R 15 is
    Figure PCTCN2021120199-appb-100025
  31. 根据权利要求28的通式(c)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：A compound of general formula (c), an optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof according to claim 28, wherein:
    R 8为卤代C 1-4烷基，优选为-CF 3； R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
    R 13和R 14各自独立地为C 1-4烷基； R 13 and R 14 are each independently C 1-4 alkyl;
    R 15选自卤素和
    Figure PCTCN2021120199-appb-100026
    R 15 is selected from halogen and
    Figure PCTCN2021120199-appb-100026
    R 5’为C 1-4烷基； R 5' is C 1-4 alkyl;
    R 6’选自-H和氰基； R 6' is selected from -H and cyano;
    s和q各自独立地为1；s and q are each independently 1;
    r选自1和2；r is selected from 1 and 2;
    条件是至少一个R 15为
    Figure PCTCN2021120199-appb-100027
    provided that at least one R 15 is
    Figure PCTCN2021120199-appb-100027
  32. 通式(c-1)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，A compound of general formula (c-1), its optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs,
    Figure PCTCN2021120199-appb-100028
    Figure PCTCN2021120199-appb-100028
    其中：in:
    R 8选自-H、卤素、氰基、-OR’、C 1-6烷基和卤代C 1-6烷基； R 8 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 13和R 14各自独立地选自H、C 1-6烷基和卤代C 1-6烷基； R 13 and R 14 are each independently selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 15选自-H、卤素、氰基、-OR’、C 1-6烷基、卤代C 1-6烷基、
    Figure PCTCN2021120199-appb-100029
    R 15 is selected from -H, halogen, cyano, -OR', C 1-6 alkyl, halogenated C 1-6 alkyl,
    Figure PCTCN2021120199-appb-100029
    R 5’选自-H、氰基、C 1-6烷基和卤代C 1-6烷基； R 5' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 6’选自-H、氰基、C 1-6烷基和卤代C 1-6烷基； R 6' is selected from -H, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R’选自-H、C 1-6烷基和卤代C 1-6烷基； R' is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    s和q各自独立地选自0、1和2。s and q are each independently selected from 0, 1 and 2.
  33. 根据权利要求32的通式(c-1)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转 异构体、同位素标记的衍生物或前药，其中：The compound of general formula (c-1), its optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof according to claim 32, wherein:
    R 8为卤代C 1-4烷基； R 8 is halogenated C 1-4 alkyl;
    R 13和R 14各自独立地选自-H和C 1-4烷基； R 13 and R 14 are each independently selected from -H and C 1-4 alkyl;
    R 15选自-H、卤素和氰基； R 15 is selected from -H, halogen and cyano;
    R 5’选自-H和C 1-4烷基； R 5' is selected from -H and C 1-4 alkyl;
    R 6’选自-H、氰基和C 1-4烷基； R 6' is selected from -H, cyano and C 1-4 alkyl;
    s和q各自独立地选自0和1。s and q are each independently selected from 0 and 1.
  34. 根据权利要求32的通式(c-1)的化合物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其中：The compound of general formula (c-1), its optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof according to claim 32, wherein:
    R 8为卤代C 1-4烷基，优选为-CF 3； R 8 is halogenated C 1-4 alkyl, preferably -CF 3 ;
    R 13和R 14各自独立地选自-H和C 1-4烷基； R 13 and R 14 are each independently selected from -H and C 1-4 alkyl;
    R 15选自-H和卤素； R 15 is selected from -H and halogen;
    R 5’为C 1-4烷基； R 5' is C 1-4 alkyl;
    R 6’选自-H和氰基； R 6' is selected from -H and cyano;
    s和q各自独立地为1。s and q are each independently 1.
  35. 根据权利要求1所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，所述嘧啶基衍生物选自以下化合物中的一种：The pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof according to claim 1, wherein the The pyrimidinyl derivative is selected from one of the following compounds:
    Figure PCTCN2021120199-appb-100030
    Figure PCTCN2021120199-appb-100030
    Figure PCTCN2021120199-appb-100031
    Figure PCTCN2021120199-appb-100031
    Figure PCTCN2021120199-appb-100032
    Figure PCTCN2021120199-appb-100032
    Figure PCTCN2021120199-appb-100033
    Figure PCTCN2021120199-appb-100033
    Figure PCTCN2021120199-appb-100034
    Figure PCTCN2021120199-appb-100034
  36. 根据权利要求1所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，其特征在于，所述嘧啶基衍生物选自以下化合物中的一种：The pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof according to claim 1, wherein the The pyrimidinyl derivative is selected from one of the following compounds:
    Figure PCTCN2021120199-appb-100035
    Figure PCTCN2021120199-appb-100035
  37. 权利要求1～36任一项所述的嘧啶基衍生物的制备方法，其特征在于，包括如下步骤：The preparation method of the pyrimidinyl derivative according to any one of claims 1 to 36, characterized in that, comprising the steps of:
    Figure PCTCN2021120199-appb-100036
    Figure PCTCN2021120199-appb-100036
    化合物a与化合物b进行取代反应，制备化合物c；Compound a is subjected to substitution reaction with compound b to prepare compound c;
    化合物c与化合物d进行取代反应，制备化合物e；Compound c is subjected to substitution reaction with compound d to prepare compound e;
    将基团w反应形成R 4； reacting group w to form R4 ;
    其中，V各自独立地选自卤素；wherein each V is independently selected from halogen;
    R 1、R 2、R 3、R 4、w、x和A如权利要求1中所定义。 R 1 , R 2 , R 3 , R 4 , w, x and A are as defined in claim 1 .
  38. 一种药物组合物，其特征在于，所述药物组合物包含如权利要求1～36中任一项所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药，以及药学上可接受的辅料、稀释剂或载体。A pharmaceutical composition, characterized in that the pharmaceutical composition comprises the pyrimidinyl derivative according to any one of claims 1 to 36, its optical isomer, pharmaceutically acceptable salt, and solvate , atropisomers, isotopically labeled derivatives or prodrugs, and pharmaceutically acceptable excipients, diluents or carriers.
  39. 根据权利要求38所述的药物组合物，其特征在于，所述药物组合物还包括联用药剂；所述联用药剂选自抗增殖剂、抗癌剂、免疫抑制剂和疼痛缓解剂中的至少一种。The pharmaceutical composition according to claim 38, characterized in that, the pharmaceutical composition further comprises a combined agent; the combined agent is selected from the group consisting of antiproliferative agents, anticancer agents, immunosuppressants and pain relief agents at least one.
  40. 权利要求1～36中任一项所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药或权利要求38～39中任一项所述的药物组合物在制备用于预防或治疗与异常的CDK7活性相关的癌症、良性赘生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病或感染性疾病的药物中的用途。The pyrimidinyl derivatives of any one of claims 1 to 36, their optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs or rights The pharmaceutical composition according to any one of claims 38 to 39 is prepared for the prevention or treatment of cancers, benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases associated with abnormal CDK7 activity or use in medicines for infectious diseases.
  41. 根据权利要求40所述的用途，其特征在于，所述与异常的CDK7活性相关的癌症选自乳腺癌、卵巢癌、直肠癌、肝癌、肺癌、胃癌、脑癌、胆管癌、***、子宫内膜癌、头颈癌、膀胱癌、骨癌、肠癌、肾癌、喉癌、淋巴瘤、白血病、慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、T细胞急性成淋巴细胞性白血病、慢性骨髓性白血病、急性骨髓性白血病、多发性骨髓瘤、黑色素瘤、间皮瘤、骨髓瘤、神经内分泌癌、食管癌、***癌、***癌、皮肤癌、软组织肉瘤癌、脊髓癌、睾丸癌、甲状腺癌和子宫癌中的一种或几种。The use according to claim 40, wherein the cancer associated with abnormal CDK7 activity is selected from the group consisting of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, stomach cancer, brain cancer, bile duct cancer, cervical cancer, uterine cancer Endometrial cancer, head and neck cancer, bladder cancer, bone cancer, bowel cancer, kidney cancer, laryngeal cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic Myeloid leukemia, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer, soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, One or more of thyroid cancer and uterine cancer.
  42. 权利要求1～36中任一项所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药或权利要求38～39中任一项所述的药物组合物，其用于预防或治疗与异常的CDK7活性相关的癌症、良性赘生物、血管生成、炎症性疾病、自身炎症性疾病、自身免疫性疾病或感染性疾病。The pyrimidinyl derivatives of any one of claims 1 to 36, their optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs or rights The pharmaceutical composition according to any one of claims 38 to 39, which is used for the prevention or treatment of cancer, benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases associated with abnormal CDK7 activity or infectious diseases.
  43. 根据权利要求42所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药或权利要求42所述的药物组合物，其特征在于，所述与异常的CDK7活性相关的癌症选自乳腺癌、卵巢癌、直肠癌、肝癌、肺癌、胃癌、脑癌、胆管癌、***、子宫内膜癌、头颈癌、膀胱癌、骨癌、肠癌、肾癌、喉癌、淋巴瘤、白血病、慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、T细胞急性成淋巴细胞性白血病、慢性骨髓性白血病、急性骨髓性白血病、多发性骨髓瘤、黑色素瘤、间皮瘤、骨髓瘤、神经内分泌癌、食管癌、***癌、***癌、皮肤癌、软组织肉瘤癌、脊髓癌、睾丸癌、甲状腺癌和子宫癌中的一种或几种。The pyrimidinyl derivative according to claim 42, its optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotope-labeled derivative or prodrug thereof, or the claimed 42 A pharmaceutical composition, characterized in that the cancer associated with abnormal CDK7 activity is selected from breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, stomach cancer, brain cancer, bile duct cancer, cervical cancer, endometrial cancer, head and neck cancer Cancer, bladder cancer, bone cancer, bowel cancer, kidney cancer, throat cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute Myeloid leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine, esophageal, penile, prostate, skin, soft tissue sarcoma, spinal cord, testicular, thyroid, and uterine cancers one or more of them.
  44. 一种预防或治疗与异常的CDK7活性相关的癌症、良性赘生物、血管生成、炎症性疾病、自 身炎症性疾病、自身免疫性疾病或感染性疾病的方法，包括向需要的受试者给药权利要求1～36中任一项所述的嘧啶基衍生物、其光学异构体、药学上可接受的盐、溶剂合物、阻转异构体、同位素标记的衍生物或前药或权利要求38～39中任一项所述的药物组合物。A method of preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease or infectious disease associated with abnormal CDK7 activity, comprising administering to a subject in need thereof The pyrimidinyl derivatives of any one of claims 1 to 36, their optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs or rights The pharmaceutical composition of any one of claims 38-39.
  45. 根据权利要求44所述的方法，其特征在于，所述与异常的CDK7活性相关的癌症选自乳腺癌、卵巢癌、直肠癌、肝癌、肺癌、胃癌、脑癌、胆管癌、***、子宫内膜癌、头颈癌、膀胱癌、骨癌、肠癌、肾癌、喉癌、淋巴瘤、白血病、慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、T细胞急性成淋巴细胞性白血病、慢性骨髓性白血病、急性骨髓性白血病、多发性骨髓瘤、黑色素瘤、间皮瘤、骨髓瘤、神经内分泌癌、食管癌、***癌、***癌、皮肤癌、软组织肉瘤癌、脊髓癌、睾丸癌、甲状腺癌和子宫癌中的一种或几种。The method of claim 44, wherein the cancer associated with abnormal CDK7 activity is selected from the group consisting of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, stomach cancer, brain cancer, bile duct cancer, cervical cancer, uterine cancer Endometrial cancer, head and neck cancer, bladder cancer, bone cancer, bowel cancer, kidney cancer, laryngeal cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic Myeloid leukemia, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer, soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, One or more of thyroid cancer and uterine cancer.
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