WO2022063212A1 - Dérivé de pyrimidyle, son procédé de préparation et son utilisation - Google Patents

Dérivé de pyrimidyle, son procédé de préparation et son utilisation Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cancer
halogenated
independently
cyano
Prior art date
Application number
PCT/CN2021/120199
Other languages
English (en)
Chinese (zh)
Inventor
邱关鹏
王永钢
邓代国
雷曾荣
Original Assignee
广州费米子科技有限责任公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广州费米子科技有限责任公司 filed Critical 广州费米子科技有限责任公司
Publication of WO2022063212A1 publication Critical patent/WO2022063212A1/fr

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • 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

L'invention concerne un dérivé de pyrimidyle, son procédé de préparation et son utilisation. Le dérivé de pyrimidyle a une structure telle que représentée par la formule générale (I). Le dérivé de pyrimidyle peut être utilisé en tant qu'inhibiteur sélectif de CDK7 pour répondre aux exigences de traitement efficaces de cancers multiples, en particulier de cancers avec dérégulation de la transcription.
PCT/CN2021/120199 2020-09-24 2021-09-24 Dérivé de pyrimidyle, son procédé de préparation et son utilisation WO2022063212A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202011014563.8 2020-09-24
CN202011014563 2020-09-24
CN202110613442 2021-06-02
CN202110613442.3 2021-06-02

Publications (1)

Publication Number Publication Date
WO2022063212A1 true WO2022063212A1 (fr) 2022-03-31

Family

ID=80790205

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/120199 WO2022063212A1 (fr) 2020-09-24 2021-09-24 Dérivé de pyrimidyle, son procédé de préparation et son utilisation

Country Status (3)

Country Link
CN (1) CN114249712A (fr)
TW (1) TW202214600A (fr)
WO (1) WO2022063212A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023040998A1 (fr) * 2021-09-17 2023-03-23 Taizhou Eoc Pharma Co., Ltd. Inhibiteur de kinase dépendante des cyclines
CN116082337A (zh) * 2023-03-16 2023-05-09 英矽智能科技(上海)有限公司 炔基取代的杂环化合物，其制法与医药上的用途

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115093397B (zh) * 2022-06-07 2023-09-05 自贡市第三人民医院 一种用于治疗肿瘤的化合物、合成方法及应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089913A1 (fr) * 2003-04-11 2004-10-21 Novartis Ag Derives de 2-aminopyrimidine et leur application en medecine
WO2017120429A1 (fr) * 2016-01-07 2017-07-13 CS Pharmasciences, Inc. Inhibiteurs sélectifs de mutants cliniquement importants de la tyrosine kinase de l'egfr
WO2018013867A1 (fr) * 2016-07-13 2018-01-18 Marineau Jason J Inhibiteurs de la kinase 7 dépendante des cyclines (cdk7)
WO2019035866A1 (fr) * 2017-08-15 2019-02-21 The Brigham & Women's Hospital, Inc. Compositions et méthodes de traitement du complexe de la sclérose tubéreuse
WO2020093006A1 (fr) * 2018-11-01 2020-05-07 Syros Pharmaceuticals, Inc. Méthodes de traitement du cancer chez des patients identifiés par biomarqueurs avec des inhibiteurs non covalents de la kinase cycline-dépendante 7 (cdk7)
CN112661745A (zh) * 2020-07-24 2021-04-16 浙江同源康医药股份有限公司 用作cdk7激酶抑制剂的化合物及其应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089913A1 (fr) * 2003-04-11 2004-10-21 Novartis Ag Derives de 2-aminopyrimidine et leur application en medecine
WO2017120429A1 (fr) * 2016-01-07 2017-07-13 CS Pharmasciences, Inc. Inhibiteurs sélectifs de mutants cliniquement importants de la tyrosine kinase de l'egfr
WO2018013867A1 (fr) * 2016-07-13 2018-01-18 Marineau Jason J Inhibiteurs de la kinase 7 dépendante des cyclines (cdk7)
WO2019035866A1 (fr) * 2017-08-15 2019-02-21 The Brigham & Women's Hospital, Inc. Compositions et méthodes de traitement du complexe de la sclérose tubéreuse
WO2020093006A1 (fr) * 2018-11-01 2020-05-07 Syros Pharmaceuticals, Inc. Méthodes de traitement du cancer chez des patients identifiés par biomarqueurs avec des inhibiteurs non covalents de la kinase cycline-dépendante 7 (cdk7)
WO2020093011A1 (fr) * 2018-11-01 2020-05-07 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
CN112661745A (zh) * 2020-07-24 2021-04-16 浙江同源康医药股份有限公司 用作cdk7激酶抑制剂的化合物及其应用

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023040998A1 (fr) * 2021-09-17 2023-03-23 Taizhou Eoc Pharma Co., Ltd. Inhibiteur de kinase dépendante des cyclines
CN116082337A (zh) * 2023-03-16 2023-05-09 英矽智能科技(上海)有限公司 炔基取代的杂环化合物，其制法与医药上的用途

Also Published As

Publication number Publication date
TW202214600A (zh) 2022-04-16
CN114249712A (zh) 2022-03-29

Similar Documents

Publication Publication Date Title
WO2019037678A1 (fr) Dérivé de pyrazolo[3,4-d]pyrimidin-3-one, composition pharmaceutique et utilisation associée
EP3173412B1 (fr) Dérivé 7h-pyrrolo[2,3-d]pyrimidine 2,4-disubstituté, procédé de préparation et utilisation médicinale de ce dernier
JP6035423B2 (ja) 新規な縮合ピリミジン化合物又はその塩
WO2022063212A1 (fr) Dérivé de pyrimidyle, son procédé de préparation et son utilisation
WO2021143701A1 (fr) Composé hétérocyclique de pyrimidine-4(3h)-cétone, son procédé de préparation et son utilisation en médecine et en pharmacologie
WO2016026445A1 (fr) Composés indazole utilisés comme inhibiteurs de la fgfr kinase, préparation et utilisation associées
JP2019518059A (ja) ＰＩ３Ｋβ阻害剤としてのアザベンゾイミダゾール誘導体
WO2016173557A1 (fr) Composé ayant une activité d'inhibition de kinase, procédé de préparation et utilisations
WO2017084640A1 (fr) Composé hétérocyclique azoté, procédé de préparation associé, et application dans l'inhibition de l'activité kinase
WO2022222964A1 (fr) Dérivé de pyridine et son utilisation en médecine
WO2021139775A1 (fr) Composé de pyridone et son application
WO2022170952A1 (fr) Dérivé de pyridazinone polycyclique servant d'inhibiteur de sos1, son procédé de préparation et son utilisation
WO2018010514A1 (fr) Composé hétérocyclique utilisé en tant qu'inhibiteur de fgfr
CN110167941A (zh) 取代的稠合杂芳基化合物作为激酶抑制剂及其应用
WO2016192630A1 (fr) Composé présentant une activité inhibitrice de kinase, son procédé de préparation, et utilisation de celui-ci
JP2020536113A (ja) 上皮成長因子受容体阻害剤
CN107108634B (zh) 作为PI3Kβ抑制剂的咪唑并哒嗪衍生物
WO2018228275A1 (fr) Composé hétérocyclique utilisé en tant qu'inhibiteur de mnk
WO2021083383A1 (fr) Composé cyclique fusionné contenant de l'azote en tant que régulateur de sting, son procédé de préparation et son utilisation
JP6586463B2 (ja) ＰＩ３Ｋβ阻害剤としての複素環連結イミダゾピリダジン誘導体
WO2020259703A1 (fr) Composé de pyrazolopyrimidine, son procédé de préparation et ses applications
WO2023036252A1 (fr) Dérivé de pyrrolopyrimidine ou de pyrrolopyridine et son utilisation médicale
WO2022222911A1 (fr) Composé pyrimidone et son utilisation
JP2019518032A (ja) Ｐｉ３ｋ ｂｅｔａ阻害薬としての二環式ピリジン、ピラジンおよびピリミジン誘導体
CN105163733B (zh) 作为激酶抑制剂的呋喃酮化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21871581

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21871581

Country of ref document: EP

Kind code of ref document: A1