WO2024008083A1 - 用作cdk7激酶抑制剂的化合物及其应用 - Google Patents

用作cdk7激酶抑制剂的化合物及其应用 Download PDF

Info

Publication number
WO2024008083A1
WO2024008083A1 PCT/CN2023/105733 CN2023105733W WO2024008083A1 WO 2024008083 A1 WO2024008083 A1 WO 2024008083A1 CN 2023105733 W CN2023105733 W CN 2023105733W WO 2024008083 A1 WO2024008083 A1 WO 2024008083A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
cancer
cdk7
present
Prior art date
Application number
PCT/CN2023/105733
Other languages
English (en)
French (fr)
Inventor
梁阿朋
朱健
李钧
陈少清
尹洲
吴豫生
董胜利
李美华
牛成山
Original Assignee
浙江同源康医药股份有限公司
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 浙江同源康医药股份有限公司 filed Critical 浙江同源康医药股份有限公司
Publication of WO2024008083A1 publication Critical patent/WO2024008083A1/zh

Links

Classifications

    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • 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
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • C07D401/02—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 two hetero rings
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/02—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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to the field of medical technology, and in particular to compounds used as CDK7 kinase inhibitors and their application in regulating CDK7 kinase activity or treating CDK7-related diseases, especially cancer.
  • CDKs Cyclin-dependent kinases
  • CDK7 is an important member of the CDKs family, and its main physiological function is to regulate cell cycle and transcription.
  • CDK7, cyclin H and Mat1 form CAK (CDKs activating kinase), which participates in the regulation of the cell cycle by phosphorylating CDK1/2/4/6.
  • CDK7 Due to CDK7's dual unique functions in transcription and cell cycle progression, it is widely expressed in various types of cancer. Down-regulating CDK7 activity can lead to a reduction in cell proliferation. More importantly, it is now agreed that targeted transcription can selectively limit the synthesis of mRNAs involved in tumor growth without causing disruption of transcription of housekeeping genes. Therefore, CDK7 is considered a feasible and very promising tumor treatment target, which has attracted widespread attention. Many small molecules, such as THZ1, THZ2, CT7001, SY-1365, etc., have shown very good performance in preclinical studies. Effectively inhibit tumor growth. Especially in the areas of major unmet diseases that currently lack effective treatments, such as small cell lung cancer, triple-negative breast cancer, and pancreatic cancer. Therefore, the development of specific CDK7 inhibitors is expected to be used in the above clinical unmet areas.
  • the present invention provides a new compound with CDK7 kinase inhibitory activity and better pharmacodynamics and pharmacokinetic properties.
  • a first aspect of the present invention provides a compound used as a CDK7 kinase inhibitor.
  • the compound is a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof. , solvates, isotopic compounds or prodrugs,
  • R 1 is selected from the following group:
  • R 2 is selected from the following group: H, CF 3 , Cl, Br, CH 3 , cyclopropyl, phenyl;
  • R 3 is H
  • R 2 and R 3 form a saturated or unsaturated 5-6 membered cycloalkyl group
  • R 4 is selected from the following group:
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from the following group: NR 6 , CR 7 R 8 , O, S;
  • Each R 6 , R 7 , R 8 is independently selected from the following group: H, C1-C6 alkyl, halogenated C1-C6 alkyl, containing 1, 2 or 3 heteroatoms selected from N, O, S C1-C6 heteroalkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, containing 1, 2 or 3 selected from N, O , 3-8-membered heterocycloalkyl group with S heteroatom, C6-C10 aryl group, 5-10-membered heteroaryl group with 1, 2 or 3 heteroatoms selected from N, O, S;
  • Each m, n is independently selected from the following group: 0, 1, 2, 3, 4, 5.
  • (R 6 )n is the -CH 2 - substituent contained in () m when m is not 0.
  • R 1 is selected from the following group:
  • R 2 is CF 3 .
  • X 1 , X 2 , X 3 and X 4 are each independently CR 7 R 8 ;
  • Each R 7 and R 8 is independently selected from the following group: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, and halogenated C3-C6 cycloalkyl.
  • R 1 is selected from the following group:
  • R 2 is selected from the following group: H, CF 3 , Cl, Br, CH 3 ,
  • R3 is H.
  • R 4 is selected from the following group:
  • R 2 is selected from the group consisting of: H, CF 3 , Cl.
  • the compound is selected from the following group:
  • the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt
  • the inorganic acid salt is selected from the following group: hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, acid phosphate;
  • the organic acid salt is selected from the following group: formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumaric acid Salt, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, picric acid Salt, glutamate, ascorbate, camphorate, camphorsulfonate.
  • a second aspect of the invention provides a pharmaceutical composition containing one or more preventive and/or therapeutic An effective amount of the compound described in the first aspect of the invention, and a pharmaceutically acceptable carrier.
  • a third aspect of the present invention provides a use of the compound described in the first aspect of the present invention for the preparation of a drug used as a CDK7 kinase inhibitor.
  • a fourth aspect of the present invention provides a use of the compound described in the first aspect of the present invention for preparing a medicament for regulating CDK7 kinase activity or treating CDK7-related diseases.
  • the CDK7-related disease is selected from the following group: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.
  • the cancer is selected from the following group: lung cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, kidney cancer, esophageal cancer, Uterine cancer.
  • the lung cancer is selected from the group consisting of small cell lung cancer and non-small cell lung cancer.
  • the breast cancer is triple-negative breast cancer.
  • the inventor unexpectedly discovered a class of compounds with better CDK7 kinase inhibitory activity.
  • the compound has excellent inhibitory activity against CDK7 kinase and better pharmacodynamic/pharmacokinetic properties.
  • the present invention was completed.
  • substituents When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes substituents that are chemically equivalent when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
  • Alkyl refers to a monovalent straight or branched chain saturated hydrocarbon group containing 1 to 12 carbon atoms consisting solely of carbon and hydrogen atoms. Alkyl is preferably C1-C6 alkyl (i.e. containing 1, 2, 3, 4, 5 or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
  • alkyl is also intended to include substituted alkyl, that is, one or more positions in the alkyl are substituted, especially 1 to 4 substituents, which may be substituted at any position.
  • Haloalkyl refers to an alkyl group as defined herein in which one or more hydrogens are replaced by the same or different halogens. Examples of haloalkyl groups include -CH 2 Cl, -CH 2 CF 3 , -CH 2 CCl 3 , perfluoroalkyl (eg, -CF 3 ), and the like.
  • Alkylene refers to a divalent alkyl group , such as -CH2- , -CH2CH2- , and -CH2CH2CH2- .
  • Alkoxy refers to an alkyl group having an oxygen group attached thereto, which has an alkyl O-structure, wherein the alkyl group has the definition as above.
  • alkoxy The base is C1 ⁇ C6 alkoxy group.
  • Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, etc.
  • Haloalkoxy refers to a group of the formula -OR, where R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.
  • Thioalkyl means that the carbon in the alkyl group is replaced by S, S(O) or S(O)2.
  • alkenyl refers to an aliphatic group containing at least one double bond, typically having from 2 to 20 carbon atoms.
  • C2-C6 alkenyl refers to an alkenyl group containing 2, 3, 4, 5 or 6 carbon atoms.
  • Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
  • alkenyl includes substituted alkenyl.
  • Alkenylene refers to an alkenyl group having two points of attachment.
  • Alkenylene may also be in unsubstituted form or substituted form with one or more substituents.
  • Alkynyl (alone or as part of another group) means a straight or branched hydrocarbon chain containing more than 2 carbon atoms and characterized by one or more triple bonds, usually having from 2 to 20 carbon atoms .
  • C2-6 alkynyl refers to an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.
  • Alkynyl groups include, but are not limited to, ethynyl, propargyl and 3-hexynyl. One of the triple bonded carbons may optionally be the point of attachment for the alkynyl substituent.
  • alkynyl also includes substituted alkynyl.
  • Alkynylene refers to an alkynyl group having two points of attachment.
  • ethynylene represents the group: -C ⁇ C-.
  • Alkynylene groups may also be unsubstituted or substituted with one or more substituents.
  • Aliphatic group refers to a straight chain, branched chain or cyclic hydrocarbon group, including saturated and unsaturated groups, such as alkyl, alkenyl and alkynyl groups.
  • Aromatic ring system refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which at least one ring is aromatic.
  • Aryl refers to a monovalent group of an aromatic ring system.
  • Representative aryl groups include fully aromatic ring systems, such as phenyl, naphthyl, and anthracenyl; and ring systems in which an aromatic carbocyclic ring is fused to one or more nonaromatic carbocyclic rings, such as indanyl, phthalate, Formimide group, naphthyl imide group or tetrahydronaphthyl group, etc.
  • the aryl group is preferably a C6-C12 aryl group.
  • aryl is also intended to include substituted aryl.
  • Arylalkyl or “aralkyl” refers to an alkyl moiety in which the alkyl hydrogen atoms are replaced by aryl groups.
  • Arane Groups include groups in which one or more hydrogen atoms are substituted by an aryl group, aryl and alkyl being as defined above.
  • Examples of “arylalkyl” or “aralkyl” include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, diphenylmethyl, trityl, and the like.
  • Aryloxy refers to -O-(aryl), where the aryl portion is as defined herein.
  • Heteroalkyl refers to a substituted alkyl group having one or more backbone chain atoms selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges may be given, for example, C1-C6 heteroalkyl refers to the number of carbons in the chain, which includes 1 to 6 carbon atoms. For example, the -CH 2 OCH 2 CH 3 group is called a "C3" heteroalkyl group. The connection to the rest of the molecule can be through a heteroatom or carbon in the heteroalkyl chain.
  • Heteroalkylene refers to an optionally substituted divalent alkyl group having one or more backbone chain atoms selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, or combinations thereof.
  • Carbocyclic ring system means a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which each ring is fully saturated or contains one or more unsaturated units, but none of the rings is aromatic.
  • Carbocyclyl refers to a monovalent group of a carbocyclic ring system. Examples include cycloalkyl (cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, etc.) and cycloalkenyl (eg, cyclopentenyl, cyclohexenyl, cyclopentadienyl, etc.).
  • Cycloalkyl refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring having 3 to 12, preferably 3 to 10, more preferably 3 to 8 ring atoms. Cycloalkyl groups may be optionally substituted with one or more substituents, where each substituent is independently hydroxyl, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Cycloalkoxy refers to a group of the formula -OR, where R is cycloalkyl as defined herein.
  • exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Cycloalkylalkyl refers to a -(cycloalkyl)-alkyl group in which the cycloalkyl and alkyl groups are as disclosed herein.
  • Cycloalkylalkyl is bonded to the parent molecular structure through a cycloalkyl group.
  • Heteroaromatic ring system refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (6-12-membered), or polycyclic ring system in which at least one ring is both aromatic and contains at least one heteroatom (e.g., N, O or S); and none of the other rings is heterocyclyl (as defined below).
  • a heteroatom-containing ring that is aromatic contains 1, 2, 3, or 4 ring heteroatoms in the ring. At least one of its rings is heteroaromatic, and the remaining rings may be saturated, partially unsaturated or completely unsaturated.
  • Heteroaryl refers to a monocyclic (eg, 5- or 6-membered), bicyclic (eg, 8-10-membered), or tricyclic group of 5 to 12 ring atoms, which contains at least 1 cyclic group containing 1, 2, or For aromatic rings with 3 ring heteroatoms selected from N, O or S and the remaining ring atoms being C, it should be clear that the point of attachment of the heteroaryl group should be located on the aromatic ring.
  • heteroaryl groups include, but are not limited to: imidazolyl, Azolyl, iso Azolyl, thiazolyl, isothiazolyl, Diazolyl, thiadiazolyl, pyrazinyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolyl, isoquinolyl, benzofuranyl, Benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzo Azolyl, benzo diazolyl, benzothiazolyl, benzothiadiazole base, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinazinyl, naphthyridinyl, pteridinyl,
  • Heterocyclic system refers to monocyclic, bicyclic and polycyclic systems in which at least one ring is saturated or partially unsaturated (but not aromatic) and the ring contains at least one heteroatom. Heterocyclic systems can be attached to any heteroatom or pendant group at a carbon atom, which results in a stable structure and any ring atom can be optionally substituted.
  • Heterocyclyl refers to a monovalent group of a heterocyclic system, usually a stable monocyclic ring (such as 3-8 members, that is, 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered) or two-membered ring.
  • Ring (such as 5-12 yuan, that is, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan, 11 yuan or 12 yuan) or multi-ring (such as 7-14 yuan, that is, 7 yuan, 8 yuan , 9-membered, 10-membered, 11-membered, 12-membered, 13-membered or 14), including fused ring, spiro ring and/or bridged ring structure, which is saturated, partially unsaturated, and contains carbon atoms and 1 , 2, 3 or 4 heteroatoms independently selected from N, O and S.
  • fused ring such as 5-12 yuan, that is, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan, 11 yuan or 12 yuan
  • multi-ring such as 7-14 y
  • heterocyclyl groups include ring systems in which (1) each ring is nonaromatic and at least one ring contains a heteroatom, for example, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, Pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepinyl, oxazepinyl, thiazolidinyl Azepinyl, morpholinyl and quinuclidinyl; (2) at least one ring is non-aromatic and contains heteroatoms and at least one other ring is an aromatic carbocyclic ring, for example, 1,2,3,4-tetrakis Hydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl; and (3) at least one ring is non-aro
  • Heterocyclylene refers to a heterocyclyl group with two attachment sites.
  • the heterocyclylene group is a bicyclic ring, one of which is a heteroaryl group, and is connected to other parts of the general formula through the heteroaryl group.
  • the heterocyclylene group is a 5-6 membered monocyclic heterocyclylene group or an 8-10 membered bicyclic heterocyclylene group.
  • Heterocycloalkyl refers to an alkyl group substituted by a heterocyclyl group, wherein heterocyclyl and alkyl are as defined above.
  • Alkylamino group refers to a group having an alkyl-NR- structure, wherein R is H, or an alkyl group, cycloalkyl group, aryl group, heteroaryl group, etc. as described above.
  • Cycloalkylamine refers to a group of the formula -NRaRb, wherein Ra is H, alkyl as defined herein, or cycloalkyl as defined herein, and Rb is cycloalkyl as defined herein, or Ra and Rb together with the N atom to which they are connected form a 3-10 membered N-containing monocyclic or bicyclic heterocyclic group, such as tetrahydropyrrolyl.
  • C3-C8 cycloalkylamino refers to an amine group containing 3-8 carbon atoms.
  • ester group means having a -C(O)-O-R or R-C(O)-O- structure, where R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl , heterocyclyl, as defined above.
  • amide group refers to a group with the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl radical, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' are mutually exclusive in the dialkylamine moiety Same or different.
  • sulfonamido refers to a group with the structure -SO 2 NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted Cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.
  • an alkyl group corresponds to an alkylene group
  • a cycloalkyl group corresponds to a cycloalkylene group
  • a heterocyclyl group corresponds to a heterocyclylene group
  • an alkoxy group corresponds to Alkyleneoxy etc.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • Specific substituents are the substituents described accordingly in the foregoing text, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic rings may be optionally substituted.
  • the substituents are for example (but not limited to): halogen, hydroxyl, cyano group, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1 -C6 urea group, etc.
  • Cyano refers to the -CN group.
  • Niro refers to -NO 2 .
  • Halo refers to any halogen group, for example, -F, -Cl, -Br or -I.
  • Deuterated compound refers to a compound obtained by replacing one hydrogen atom (H) or multiple hydrogen atoms (H) with a deuterium atom (D).
  • compound of the invention or “active ingredient of the invention” are used interchangeably and refer to a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (e.g., deuterated compound) or prodrug.
  • the term also includes racemates, optical isomers.
  • the compound of formula I has the following structure:
  • R 1 , R 2 , R 3 and R 4 are defined as above.
  • R 1 , R 2 , R 3 and R 4 are each independently the corresponding group in the specific compound described in the present invention.
  • salts formed by the compounds in the present invention also belong to the scope of the present invention. Unless otherwise stated, compounds in the present invention are understood to include salts thereof.
  • the term "salt” as used herein refers to an acidic or basic salt formed from an inorganic or organic acid and a base.
  • the compound of the present invention contains a basic moiety, which includes but is not limited to pyridine or imidazole, and when it contains an acidic moiety, including but is not limited to carboxylic acid, the zwitterion (“inner salt”) that may be formed is included in Within the scope of the term "salt”.
  • salts are preferred, although other salts are also useful, for example, in isolation or purification steps during preparation.
  • the compounds of the present invention may form salts, for example, compound I can be obtained by reacting with a certain amount of, for example, an equivalent amount of acid or base, salting out in a medium, or by freeze-drying in an aqueous solution.
  • the compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (eg, with acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, and benzoates.
  • benzenesulfonate hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethanesulfonate, Corydalis salt, glucoheptonate, glycerophosphate, hemisulfate, enanthate, caproate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate (e.g., 2-hydroxyethanesulfonate ethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectate , persulfate, phenylpropionate (such as 3-phenylpropionate
  • Certain compounds of the invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical salts formed with bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (such as organic amines), such as benzathine and dicyclohexylamine.
  • Hypamine salt with N,N-bis(dehydroabidyl)ethylenediamine
  • N-methyl-D-glucamine N-methyl-D-glucamide
  • tert-butyl Amines and salts formed with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl ester and dipentyl ester), long chain halides (such as decyl, dodecyl, tetradecyl and tetradecyl chlorides, bromides and iodide), aralkyl halides (such as benzyl and phenyl bromide), etc.
  • small halides such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl
  • dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl este
  • Prodrugs and solvates (or solvates) of the compounds of the present invention are also within the scope of the invention.
  • prodrug here refers to a compound that undergoes chemical transformation through metabolism or chemical processes to produce the compound, salt, or solvate of the present invention when treating related diseases.
  • Compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All such tautomers are part of the present invention.
  • All stereoisomers of the compounds are contemplated by the present invention.
  • the compounds of the present invention may exist independently as stereoisomers without other isomers (e.g., having a particular activity as a pure or substantially pure optical isomer), or they may be mixtures, e.g. Racemates, or mixtures with all other stereoisomers or portions thereof.
  • the chiral center of the present invention has two configurations: S or R, which are defined as recommended by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974.
  • Racemic forms can be resolved by physical methods, such as fractional crystallization, or by fractional crystallization by derivatization to diastereoisomers, or by chiral column chromatography. Individual optical isomers can be synthesized by appropriate Methods for obtaining the racemate include but are not limited to traditional methods, such as salt formation with an optically active acid and then recrystallization.
  • the weight content of the compounds in the present invention obtained by sequential preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), as described in the text List. Such "very pure” compounds of the invention are here also included as part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, elimination Spin mixtures and other mixtures.
  • asymmetric carbon atoms can represent substituents, such as alkyl groups. All isomers, as well as mixtures thereof, are included in the present invention.
  • the mixture of isomers may contain the isomers in various ratios.
  • a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: All ratios of isomers 2, 99:1, or 100:0 are within the scope of the invention. Similar ratios, as well as ratios for more complex mixtures of isomers that are readily understood by those of ordinary skill in the art, are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. In practice, however, it often occurs that one or more atoms are replaced by atoms with a different atomic weight or mass number.
  • isotopes of compounds that may be included in the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O respectively. , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solutions Agents containing isotopes or other isotopic atoms of the above compounds are within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention such as radioactive isotopes of 3 H and 14 C, are also included and are useful in tissue distribution experiments of drugs and substrates. Tritium, or 3H , and carbon-14, or 14C , are relatively easy to prepare and detect. It is the first choice among isotopes.
  • heavier isotope substitutions such as deuterium, i.e.
  • Isotopically labeled compounds can be prepared by general methods by replacing readily available isotopically labeled reagents with non-isotopic reagents, using the protocols disclosed in the Examples.
  • a synthesis of a specific enantiomer of the compound of the present invention it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, and the resulting diastereomeric mixture is separated and then the chiral auxiliary is removed. Pure enantiomer.
  • a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation, crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
  • the compounds of the present invention may be provided with any number of substituents or functional groups to broaden their encompassing scope.
  • substituents or functional groups in general, whether the term “substituted” appears before or after the term “optional”, the general formula of the substituent included in the formulation of the present invention means that the substituent of the specified structure is used in place of the hydrogen radical. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents may be the same or different at each position.
  • substitution as used herein includes all permissible substitutions of organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents or any of the permissible organic compounds described above to supplement their valence. Furthermore, this invention is not intended to be limited in any way to the permitted substituted organic compounds.
  • the present invention considers that combinations of substituents and variable groups are excellent in the treatment of diseases in the form of stable compounds.
  • stable refers to a compound that is stable, detectable over a long enough period of time to maintain the structural integrity of the compound, and preferably effective over a long enough period of time, and is used herein for the above purposes.
  • the preparation methods of the compound of formula I of the present invention are described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art. Such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • each reaction is usually carried out under the protection of inert gas, in an appropriate solvent, at 0 to 150°C, and the reaction time is usually 2-24 hours.
  • the preferred preparation method is as follows:
  • Step 1 In an inert solvent (such as tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, dioxane, ethylene glycol dimethyl ether, etc.), under the action of alkali, SM3 React with SM2 to obtain M1;
  • an inert solvent such as tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, dioxane, ethylene glycol dimethyl ether, etc.
  • Step 2 In an inert solvent (such as N,N-dimethylformamide, dioxane, ethanol, dimethyl sulfoxide, etc.), alkaline (such as potassium carbonate, potassium phosphate, triethylamine, etc.) Under the conditions, M1 reacts with SM1 to generate T (i.e. compound of formula I).
  • an inert solvent such as N,N-dimethylformamide, dioxane, ethanol, dimethyl sulfoxide, etc.
  • alkaline such as potassium carbonate, potassium phosphate, triethylamine, etc.
  • R 1 , R 2 , R 3 and R 4 are as described above.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition of the present invention is used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular diseases, infections, immune diseases, and metabolic diseases.
  • the compounds of formula I may be used in combination with other drugs known to treat or ameliorate similar conditions.
  • the original administration method and dosage of the drug can remain unchanged, while formula I is taken simultaneously or subsequently.
  • compound of When the compound of formula I is taken simultaneously with one or several other drugs, a pharmaceutical composition containing one or several known drugs and the compound of formula I can be preferably used.
  • Drug combinations also include administration of a compound of formula I with one or more other known drugs for overlapping periods of time. When a compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than that of the compound alone.
  • Drugs or active ingredients that can be combined with the compound of formula I include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB- A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, A Tecilizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab) monoclonal antibodies, obinutuzumab, ofatumumab, tositumomab, itumomab, etc.), CD
  • the dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injections, tablets, capsules, aerosols, suppositories, films, pills, external liniments, controlled-release or sustained-release types, or nano-preparations.
  • the pharmaceutical composition of the present invention contains a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.
  • the “safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, it contains 10-1000 mg of the compound of the present invention/dose.
  • the "dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting Agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • administration mode of the compounds or pharmaceutical compositions of the present invention is not particularly limited.
  • Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl mono
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils,
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions may contain, in addition to the active compound, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the treatment method of the present invention can be administered alone or in combination with other treatment methods or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage.
  • a mammal such as a human
  • the daily dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
  • the invention also provides a preparation method of a pharmaceutical composition, which includes the steps of: adding pharmaceutically acceptable
  • the carrier is mixed with the compound of formula I of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate to form a pharmaceutical composition.
  • the present invention also provides a treatment method, which includes the steps of: administering the compound of formula I described in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, to a subject in need of treatment, or administering
  • the pharmaceutical composition of the present invention is used to inhibit CDK7.
  • the present invention has the following main advantages:
  • the compound of the present invention has excellent inhibitory ability against CDK7 kinase
  • the compound of the present invention has lower toxic and side effects
  • the compounds of the present invention have better pharmacodynamics and pharmacokinetic properties.
  • compound 1 (10g, 1.0eq), dimethylhydroxylamine hydrochloride (6.7g, 1.3eq), N,N-diisopropylethylamine (23mL, 2.6eq), solvent DMF ( 120ml), mix evenly, replace with nitrogen three times, protect with nitrogen, stir for 10 minutes in an ice bath, add HATU (22g, 1.1eq), and react at room temperature overnight. TLC showed that there was no remaining raw material. The reaction solution was quenched with water, stirred with petroleum ether in an ice bath, filtered with suction to obtain a filter cake, and dried at 60°C to obtain 10.2 g of compound 2.
  • Test compound CDK7 kinase IC 50 value detection (detected in Wuxi Baiaode Company).
  • the inhibitory activity IC 50 (nM) value of the test sample against CDK7 kinase was obtained as shown in Table 1, where A ⁇ 10nM; 10nM ⁇ B ⁇ 500nM; C ⁇ 500nM.
  • the compounds synthesized in this application have good inhibitory capabilities on CDK7 kinase, and are expected to be further developed to regulate CDK7 kinase. Drugs that activate or treat CDK7-related diseases.
  • Ovarian cancer cell A2780 and colorectal cancer cell WiDr were purchased from Beijing Beina Chuanglian Biotechnology Co., Ltd.
  • DMEM medium Bio-Channel
  • DMSO dimethyl sulfoxide
  • MTT thiazolyl blue
  • 0.25% EDTA-Tripsin trypsin digestion solution
  • 1xPBS phosphate buffer saline, PH7.2
  • 96 wells Plate Corning
  • FBS fetal bovine serum
  • penicillin-G/streptomycin high-speed refrigerated centrifuge
  • EPPENDORF 5810R enzyme-linked immunoassay detector
  • Tumor cells were cultured in DMEM (high sugar, containing 10% FBS and 100 U/mL penicillin-G/streptomycin) at 37°C, 5% CO2 and saturated humidity to 80-90% density.
  • DMEM high sugar, containing 10% FBS and 100 U/mL penicillin-G/streptomycin
  • concentration of the compound after dilution is as follows:
  • %Cell Viability 100% ⁇ (Lum_Sample-Lum_LC)/(Lum_HC-Lum_LC)
  • Lum_HC 0.1% DMSO control cell readings
  • Lum_LC Blank medium reading
  • the IC50 value was obtained by curve fitting using GraphPad Prism 8 software.
  • the compounds of the present invention have very good inhibitory effects on ovarian cancer cells A2780 and colorectal cancer cells WiDr.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种用作CDK7激酶抑制剂的化合物及其应用。其具有式I所示结构，可用作细胞周期蛋白依赖性激酶7(CDK7)的抑制剂，用于增殖性疾病(如癌症)的治疗或预防，尤其是用于调节和治疗细胞周期蛋白依赖性激酶7(CDK7)的异常活性所导致的相关疾病。

Description

用作CDK7激酶抑制剂的化合物及其应用 技术领域
本发明涉及医药技术领域，具体涉及用作CDK7激酶抑制剂的化合物，及其在调节CDK7激酶活性或治疗CDK7相关疾病，尤其癌症方面的应用。
背景技术
细胞周期蛋白依赖性激酶CDKs(Cyclin-dependent kinases)属于丝氨酸/苏氨酸激酶家族，其通过与相应的细胞周期蛋白(Cyclins)结合形成活性的二聚体复合物发挥生理功能，引起细胞的生长和增值。目前已发现20多种CDKs，按照其功能分为两大类：调控细胞周期的CDKs和调控细胞转录的CDKs，其中CDKs 1-6和14-18参与细胞周期的调控，CDKs 7-13和19-20参与细胞的转录调控。
CDK7是CDKs家族的重要成员，主要的生理功能是调控细胞周期和转录。在细胞液中，CDK7与cyclin H和Mat1一起组成CAK(CDKs activating kinase)，通过磷酸化CDK1/2/4/6，参与细胞周期的调控。在细胞核内，CDK7作为通用转录因子TFⅡH(Transcription factorⅡhuman)的组成部分，在基因转录最重要的起始阶段，通过磷酸化RNA聚合酶Ⅱ(RNA polymeraseⅡ)的CTD结构域(carboxy-terminal domain)，参与细胞的基因转录过程。由于CDK7具有CAK和CTD磷酸化的双重功能，所以，其在细胞增殖、细胞周期和基因转录过程中都发挥着重要的作用。
由于CDK7在转录和细胞周期进程中的双重独特作用功能，其在各种类型的癌症中广泛表达，通过下调CDK7的活性可以导致细胞增殖的减少。更重要的是，现在人们一致认为，靶向转录可选择性的限制参与肿瘤生长的mRNA的合成，而不会导致管家基因(housekeeping genes)转录的中断。因此，CDK7被认为是一个可行的、非常有前途的肿瘤治疗靶点，引起了广泛关注，其中很多小分子，如THZ1、THZ2、CT7001、SY-1365等，在临床前的研究中表现出非常好地抑制肿瘤生长的效果。尤其是在小细胞肺癌、三阴乳腺癌、胰腺癌等目前缺乏有效治疗手段的未满足的重大疾病领域。因此，开发特异性的CDK7抑制剂有望用于以上临床未满足领域。
发明内容
本发明提供了一种新的具有CDK7激酶抑制活性的、具有更好药效学、药代动力学性能的化合物。
本发明的第一方面，提供了一种用作CDK7激酶抑制剂的化合物，所述化合物为式I化合物、或其药学上可接受的盐、立体异构体、互变异构体、水合物、溶剂化物、同位素化合物或前药，
其中：
R1选自下组：
R2选自下组：H、CF3、Cl、Br、CH3、环丙基、苯基；
R3为H；
或者R2与R3形成饱和或不饱和的5-6元环烷基；
R4选自下组：
X1、X2、X3、X4各自独立地选自下组：NR6、CR7R8、O、S；
各R6、R7、R8独立地选自下组：H、C1-C6烷基、卤代C1-C6烷基、含1、2或3个选自N、O、S的杂原子的C1-C6杂烷基、C3-C6环烷基、卤代C3-C6环烷基、C1-C6烷胺基、C3-C6环烷胺基、含1、2或3个选自N、O、S的杂原子的3-8元杂环烷基、C6-C10芳基、含1、2或3个选自N、O、S的杂原子的5-10元杂芳基；
各m、n独立地选自下组：0、1、2、3、4、5。
在另一优选例中，中，(R6)n为m不为0时，()m中所含-CH2-的取代基。
在另一优选例中，R1选自下组：
在另一优选例中，R2为CF3。
在另一优选例中，X1、X2、X3、X4各自独立地为CR7R8；
各R7、R8独立地选自下组：H、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基。
在另一优选例中，R1选自下组：
R2选自下组：H、CF3、Cl、Br、CH3、
R3为H。
在另一优选例中，R4选自下组：
R2选自下组：H、CF3、Cl。
在另一优选例中，所述化合物选自下组：



在另一优选例中，所述药学上可接受的盐为无机酸盐或有机酸盐；
所述无机酸盐选自下组：盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐；
所述有机酸盐选自下组：甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、水杨酸盐、苦味酸盐、谷氨酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐。
本发明的第二方面，提供了一种药物组合物，含有一种或多种预防和/或治疗 有效量的本发明第一方面所述的化合物，以及药学上可接受的载体。
本发明的第三方面，提供了一种本发明第一方面所述的化合物的用途，用于制备用作CDK7激酶抑制剂的药物。
本发明的第四方面，提供了一种本发明第一方面所述的化合物的用途，用于制备用于调节CDK7激酶活性或治疗CDK7相关疾病的药物。
在另一优选例中，所述CDK7相关疾病选自下组：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
在另一优选例中，所述癌症选自下组：肺癌、乳腺癌、前列腺癌、结直肠癌、肝癌、胰腺癌、卵巢癌、白血病、神经母细胞瘤、胃癌、肾癌、食管癌、子宫癌。
在另一优选例中，所述肺癌选自下组：小细胞肺癌、非小细胞肺癌。
在另一优选例中，所述乳腺癌为三阴乳腺癌。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究，意外地发现了一类具有较好的CDK7激酶抑制活性的化合物。此外，所述化合物对CDK7激酶具有优异的抑制活性，并且具有更好药效学/药代动力学性能。在此基础上，完成了本发明。
术语
除非特别说明，否则在本申请中(包括说明书和权利要求书)所用的以下术语具有下面所给出的定义。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH2O-等同于-OCH2-。
“烷基(单独或作为其他基团的一部分)”指的是仅由碳和氢原子组成的含有1至12个碳原子的单价直链或支链饱和烃基团。烷基优先选地为C1-C6烷基 (即包含1、2、3、4、5或6个碳原子)。烷基基团的实例包括但不限于甲基、乙基、丙基、异丙基、异丁基、仲丁基、叔丁基、戊基、正己基、辛基、十二烷基等。本申请中，烷基还意在包含取代烷基，即烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。“卤代烷基”指的是其中一个或多个氢被相同或不同的卤素代替的本文所定义的烷基。卤代烷基的实例包括-CH2Cl、-CH2CF3、-CH2CCl3、全氟烷基(例如，-CF3)等。
“亚烷基”是指烷基的二价基团，例如-CH2-、-CH2CH2-和-CH2CH2CH2-。
“烷氧基(单独或作为其他基团的一部分)”是指其上连接有氧基的烷基，其具有烷基O-结构，其中，烷基具有如上所述的定义优选地，烷氧基为C1～C6烷氧基。烷氧基包括但不限于甲氧基、乙氧基、丙氧基、叔丁氧基等。“卤代烷氧基”指的是式-OR基团，其中R是本文所定义的卤代烷基基团。卤代烷氧基基团的实例包括但不限于三氟甲氧基、二氟甲氧基、2,2,2-三氟乙氧基等。
“硫代烷基”是指烷基中的碳被S、S(O)或S(O)2所取代。
“烯基(单独或作为其他基团的一部分)”是指含有至少一个双键的脂族基团，通常具有为2至20个碳原子。本发明中，“C2-C6烯基”是指含有2、3、4、5或6个碳原子的烯基。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。本发明中，烯基包括取代的烯基。
“亚烯基”是指具有两个连接点的烯基。例如，“亚乙烯基”表示基团-CH＝CH-。亚烯基也可是未取代的形式或具有一个或多个取代基的取代形式。
“炔基(单独或作为其他基团的一部分)”是指含有2个以上碳原子且特征为具有一个或多个三键的直链或支链烃链，通常具有为2至20个碳原子。本发明中，“C2-6炔基”是指具有2、3、4、5或6个碳原子的炔基。炔基包括但不限于是乙炔基、炔丙基和3-己炔基。三键碳中的一个可以任选地为炔基取代基的连接点。本发明中，炔基还包括取代炔基。
“亚炔基”是指具有两个连接点的炔基。例如“亚乙炔基”表示基团：-C≡C-。亚炔基也可是未取代的形式或具有一个或多个取代基的取代形式。
“脂族基团”是指直链、支链或环状烃基，包括饱和及不饱和基团，如烷基、烯基和炔基。
“芳环系统”是指单环、双环或多环烃环系统，其中至少一个环是芳族的。
“芳基(单独或作为其他基团的一部分)”是指芳环系统的一价基团。代表性芳基包括全芳环系统，如苯基、萘基和蒽基；及其中芳族碳环与一个或多个非芳族碳环稠合的环系统，如茚满基、邻苯二甲酰亚胺基、萘基亚胺基或四氢萘基等等。本发明中，芳基优选地为C6-C12芳基。本发明中，芳基还意在包含取代芳基。
“芳基烷基”或“芳烷基”是指其中烷基氢原子被芳基取代的烷基部分。芳烷 基包括其中一个或以上氢原子被芳基取代的基团，芳基和烷基具有如上所述的定义。“芳基烷基”或“芳烷基”的实例包括苄基、2-苯基乙基、3-苯基丙基、9-芴基、二苯甲基和三苯甲基等。
“芳氧基”是指-O-(芳基)，其中芳基部分如本文所定义。
“杂烷基”是指被取代的烷基，其具有一个或多个选自除碳以外的原子的骨架链原子，例如，氧、氮、硫、磷或其组合。可以给出数值范围，例如，C1-C6杂烷基是指链中的碳数目，其包括1至6个碳原子。例如-CH2OCH2CH3基团被称为“C3”杂烷基。与分子其余部分的连接可以通过杂烷基链中的杂原子或碳。“杂亚烷基”是指任选被取代的二价烷基，其具有一个或多个选自除碳以外的原子的骨架链原子，例如，氧、氮、硫、磷或其组合。
“碳环系统”是指单环、二环或多环烃环系统，其中每个环是完全饱和的或含有一个或多个不饱和单元，但其中环都不是芳族的。
“碳环基”是指碳环系统的一价基团。例如包括环烷基(环戊基、环丁基、环丙基、环己基等)和环烯基(例如，环戊烯基、环己烯基、环戊二烯基等)。
“环烷基”指的是由单-或二环组成的单价饱和碳环基团，其具有3-12个、优选3-10个、更优选3-8个环原子。环烷基可以任选地被一个或多个取代基所取代，其中各取代基独立地为羟基、烷基、烷氧基、卤素、卤代烷基、氨基、单烷基氨基或二烷基氨基。环烷基基团的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基等。
“环烷氧基”指的是式-OR基团，其中R为如本文所定义的环烷基。示例性的环烷基氧基包括环丙基氧基、环丁基氧基、环戊基氧基、环己基氧基等。“环烷基烷基”是指其中环烷基和烷基如本文所公开的-(环烷基)-烷基。“环烷基烷基”通过环烷基与母体分子结构键合。
“杂芳环系统”是指单环(如5或6元)、双环(6-12元)或多环系统，其中至少一个环既为芳族的又包含至少一个杂原子(例如，N、O或S)；且其中其它环都不是杂环基(如下所定义)。在某些情况下，作为芳族的且包含杂原子的环在所述环中含有1、2、3或4个环杂原子。其至少有一个环是杂芳族的，其余环可以是饱和、部分不饱和或完全不饱和环。
“杂芳基”指的是5至12个环原子的单环(如5或6元)、二环(如8-10元)或三环基团，其含有至少1个包含1、2或3个选自N、O或S的环杂原子、剩余的环原子是C的芳环，应当清楚地是，杂芳基的连接点应当位于芳环上。杂芳基基团的实例包括但不限于：咪唑基、唑基、异唑基、噻唑基、异噻唑基、二唑基、噻二唑基、吡嗪基、噻吩基、呋喃基、吡喃基、吡啶基、吡咯基、吡唑基、嘧啶基、喹啉基、异喹啉基、苯并呋喃基、苯并呋喃基、苯并噻吩基、苯并噻喃基、苯并咪唑基、苯并唑基、苯并二唑基、苯并噻唑基、苯并噻二唑 基、苯并吡喃基、吲哚基、异吲哚基、三唑基、三嗪基、喹喔啉基、嘌呤基、喹唑啉基、喹嗪基、萘啶基、蝶啶基、咔唑基、氮杂基、二氮杂基、吖啶基等。亚杂芳基是指具有两个连接位点的杂芳基。
“杂环系统”是指单环、双环和多环系统，其中至少一个环是饱和的或部分不饱和的(但非芳族的)且该环包含至少一个杂原子。杂环系统可连接至任何杂原子或碳原子处的侧基，这产生了稳定的结构并且任一环原子可任选地被取代。
“杂环基”是指杂环系统的一价基团，通常指稳定的单环(如3-8元，即3元、4元、5元、6元、7元或8元)或二环(如5-12元，即5元、6元、7元、8元、9元、10元、11元或12元)或元多环(如7-14元，即7元、8元、9元、10元、11元、12元、13元或14)，包括稠环、螺环和/或桥环结构，其为饱和的、部分不饱和的，且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子。代表性杂环基包括以下环系统，其中(1)每个环为非芳族的且至少一个环包含杂原子，例如，四氢呋喃基、四氢吡喃基、四氢噻吩基、吡咯烷基、吡咯烷酮基、哌啶基、吡咯啉基、十氢喹啉基、噁唑烷基、哌嗪基、二噁烷基、二氧戊环基、二吖庚因基、噁吖庚因基、噻吖庚因基、吗啉基和奎宁环基；(2)至少一个环是非芳族的且包含杂原子并且至少一个其它环是芳族碳环，例如，1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基；及(3)至少一个环是非芳族的且包含杂原子并且至少一个其它环是芳族的且包含杂原子，例如，3,4-二氢-1H-吡喃并[4,3-c]吡啶和1,2,3,4-四氢-2,6-二氮杂萘。亚杂环基是指具有两个连接位点的杂环基。本发明中，优选地亚杂环基为双环，其中一个环为杂芳基，且通过杂芳基与通式中的其他部分相连。本发明中，优选地亚杂环基为5-6元单环亚杂环基或8-10元双环亚杂环基。
“杂环烷基”是指被杂环基取代的烷基，其中，杂环基和烷基的定义如上所述。
“烷胺基”是指具有烷基-NR-结构的基团，其中，R为H、或如上所述的烷基、环烷基、芳基、杂芳基等。
“环烷胺基”指的是式-NRaRb基团，其中，Ra为H、如本文所定义的烷基或如本文所定义的环烷基，Rb为如本文所定义的环烷基，或者Ra和Rb与其连接的N原子一起形成3-10元含N单环或双环杂环基，如四氢吡咯基。如本发明所用，C3～C8环烷胺基是指含有3-8个碳原子的胺基。
在本发明中，“酯基”是指具有-C(O)-O-R或R-C(O)-O-结构，其中，R独立地代表氢、烷基、环烷基、芳基、杂芳基、杂环基，如上文所定义。
在本发明中，术语“酰胺基”是指带有结构-CONRR'的基团，其中，R和R'可以独立地代表氢、烷基或取代的烷基、环烷基或取代的环烷基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相 同或不同。
在本发明中，术语“磺酰胺基”是指带有结构-SO2NRR'的基团，其中R和R'可以独立地代表氢、烷基或取代的烷基、环烷基或取代的环烷基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。
“酮羰基”是指R-C(＝O)-，其中R为如上所述的烷基、环烷基等。
当取代基为非末端取代基时，其为相应基团的亚基，例如烷基对应于亚烷基、环烷基对应亚环烷基、杂环基对亚杂环基、烷氧基对应亚烷氧基等。
在本发明中，上述的烷基、烷氧基、环烷基、杂烷基、芳基、杂芳基、环杂烷基、烯基、炔烃、杂环、杂环基等中各基团可以是取代的或未取代的。
本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。典型的取代包括但不限于一个或多个以下基团：如氢、氘、卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl3的烷基)、氰基、硝基、氧代(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、炔基、杂环、芳环、ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe，P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe、NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)Ra、或NRbP(＝O)2Re，其中，Ra可以独立表示氢、氘、烷基、环烷基、烯基、炔基、杂环或芳环，Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者Rb和Rc与N原子一起可以形成杂环；Re可以独立表示氢、烷基、环烷基、烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。所述取代基例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。
“氰基”是指-CN基团。
“硝基”是指-NO2。
“羟基”是指-OH。
“氨基”是指-NH2或RNH-，其中R为酮羰基、磺酰基、磺酰胺基、Ra-C(＝O)-、RaRbN-C(＝O)-等，其中Ra和Rb为烷基、环烷基、芳基或杂芳基等。
“卤素(卤代)”是指任何卤素的基团，例如，-F、-Cl、-Br或-I。
“氘代物”指的是化合物中一个氢原子(H)或多个氢原子(H)被氘原子(D)取代后所得到的化合物。
在本发明中，术语“多个”独立指2、3、4、5个。
所述氨甲酸酯基的结构式为-NH-C(＝O)-O-R，其中R为烷基、芳基、杂芳基。
活性成分
如本文所用，术语“本发明的化合物”或“本发明的活性成分”可互换使用，指式I化合物、或其药学上可接受的盐、水合物、溶剂化物、同位素化合物(如氘代化合物)或前药。该术语还包括外消旋体、光学异构体。
所述的式I化合物具有如下结构：
其中，R1、R2、R3、R4的定义如上所述。
在另一优选例中，R1、R2、R3、R4各自独立地为本发明所述具体化合物中的对应基团。
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索 酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物(或溶剂化物)也在涵盖的范围之内。
此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立地立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的 方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements，CAS version，Handbook of Chemistry and Physics，75th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”，Thomas Sorrell，University Science Books，Sausalito:1999，也有说明，其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢、碳、氮、氧、磷、硫、氟和氯同位素，分别如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶 剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如3H和14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即3H和碳-14，即14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。
制备方法
以下方案和实例中描述了制备式I的化合物的方法。原料和中间体从商业来源购买，由已知步骤制备，或以其他方式说明。在某些情况下，可以改变执行反应方案的步骤的顺序，以促进反应或避免不需要的副反应产物。
下面更具体地描述本发明式I结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。
通常，在制备流程中，各反应通常惰性气体保护下，适当溶剂中，在0到150℃下进行，反应时间通常为2-24小时。
优选地制备方法如下：
方法一：
第一步：在惰性溶剂(如四氢呋喃、1,2-二氯乙烷、N,N-二甲基甲酰胺、二氧六环、乙二醇二甲醚等)中，碱作用下，SM3和SM2反应得到M1；
第二步：在惰性溶剂(如N,N-二甲基甲酰胺、二氧六环、乙醇、二甲基亚砜等)中，碱性(如碳酸钾、磷酸钾、三乙胺等)条件下，M1与SM1反应，生成T(即式I化合物)。
上述各式中，R1、R2、R3、R4如上所述。
如无特别说明，上述起始原料均可通过商业途径购买或按照已报道的文献合成。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗以下疾病：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
通式I所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I 的化合物。当式I化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药的剂量低。
可以与通式I所述化合物进行药物联用的药物或活性成分包括但不局限为：PD-1抑制剂(如纳武单抗、派姆单抗、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如德瓦鲁单抗、阿特珠单抗、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、托西莫单抗、替伊莫单抗等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Dactolisib、Taselisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、Acalabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞伐替尼、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Droxinostat、恩替诺特、达西司特、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、AS-703026、PD184352(CI-1040)等)、Akt抑制剂(如MK-2206、Ipatasertib、Capivasertib、Afuresertib、Uprosertib等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)、IGF-1R抑制剂(如Ceritinib、奥卡替尼、linsitinib、BMS-754807、GSK1838705A等)、ER拮抗剂或降解剂(如他莫昔芬、氟维司群等)、芳香化酶抑制剂(如来曲唑等)、BCL2或BCL-XL抑制剂(如ABT-199、ABT-263等)、Hedgehog抑制剂(如vismodegib、cyclopamine等)、化疗药物(如cisplatin、etoposide、topotecan等)、PARP抑制剂(如Olaparib、Veliparib、Rucaparib等)、ATR/ATM抑制 剂(如Ceralasertib、Berzosertib等)或其组合。
本发明药物组合物的剂型包括(但并不限于)：注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠， 或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受 的载体与本发明所述通式I化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述式I化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明所述的药物组合物，用于抑制CDK7。
与现有技术相比，本发明具有以下主要优点：
(1)本发明化合物对CDK7激酶具有优良的抑制能力；
(2)本发明化合物具有更低的毒副作用；
(3)本发明化合物更好的药效学、药代动力学性能。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例
下面对本发明的技术方案作进一步的说明，但本发明的保护范围不限于此。
实施例T-01
本发明合成的化合物：
实验过程如下：
一、中间体SM1的合成
合成路线如下：
1、中间体SM1的合成
在100ml圆底烧瓶中将化合物1(5g，1.0eq)，4-Boc-氨基哌啶(5.5g，1.2eq)，DIPEA(3g，1.0eq)，溶剂DMF(50ml)混合均匀后，室温反应1.5h。TLC显示无原料剩余，反应液加水淬灭后用EA萃取。EA相用柱层析分离纯化两种位置异构体，得到4g的化合物SM1。HPLC纯度97.6％。LC-MS[M+1]：381。
二、化合物T-01的合成
合成路线如下：
1、化合物2的合成
在100mL圆底烧瓶中将SM1(288mg，1.0eq)，3-氨基-2-丁醇(100mg，1.05eq)，三乙胺(115mg，1.5eq)，溶剂无水乙醇(6ml)混合均匀后，用氮气置换三次后，氮气保护，80℃加热反应22h。TLC显示无原料剩余，反应液直接用柱层析分离纯化，得到291mg的化合物2。LC-MS[M+1]：434。
2、化合物T-01的合成
在100mL圆底烧瓶中将化合物2(291mg，1.0eq)，用溶剂二氯甲烷(3ml)溶解后，加入TFA(294ml，5.0eq)混合均匀，室温反应24h。TLC显示无原料剩余，反应液用饱和碳酸氢钠水溶液调PH为7-8后，用EA萃取。EA相用制备板分离纯化，得到100mg的化合物T-01。HPLC纯度99.2％。LC-MS[M+1]：334。
参照实施例T-01的方法，合成了如下化合物：



实施例T-47
本发明合成的化合物：
一、中间体SM2的合成
合成路线如下：
1、化合物2的合成
在500mL圆底烧瓶中将化合物1(20g，1.0eq)，二甲羟胺盐酸盐(13.6g，1.3eq)，N,N-二异丙基乙胺(45.2mL，2.6eq)，溶剂DMF(240ml)混合均匀后，用氮气置换三次后，氮气保护，冰浴下搅拌10min后，加入HATU(44g,1.1eq)，室温反应过夜。TLC显示无原料剩余，反应液加水淬灭，冰浴下加石油醚搅拌，抽滤得滤饼，60℃烘干得到18.7g的化合物2，白色固体。1H NMR(400MHz,Chloroform-d)δ5.18(s,1H),4.62(s,1H),3.70(s,3H),3.14(s,3H),1.37(s,9H),1.24(d,J＝6.9Hz,3H).
2、化合物3的合成
在1L圆底烧瓶中加入化合物2(18.7g，1.0eq)，用氮气置换三次后，氮 气保护，加入超干THF(560ml)溶解，降温至-20℃，滴加3M甲基氯化镁(270ml,10.0eq),加毕后室温反应3h。TLC显示无原料剩余，冰浴下加饱和氯化铵溶液淬灭反应，加水，EA萃取3次，EA相用饱和氯化钠溶液洗，无水硫酸钠干燥，用柱层析分离纯化，得到14.1g化合物3。1H NMR(400MHz,Chloroform-d)δ5.20(s,1H),4.24(p,J＝7.1,6.4Hz,1H),2.14(s,3H),1.37(s,9H),1.28(d,J＝7.2Hz,3H).
3、化合物4的合成
在1L圆底烧瓶中加入化合物3(14.1g，1.0eq)，用氮气置换三次后，氮气保护，加入超干THF(425ml)溶解，降温至-20℃，滴加3M甲基氯化镁(252ml,10.0eq),加毕后室温反应过夜。TLC显示无原料剩余，冰浴下加饱和氯化铵溶液淬灭反应，加水，EA萃取3次，EA相用饱和氯化钠溶液洗，无水硫酸钠干燥，用柱层析分离纯化，得到5.0g化合物4。1H NMR(400MHz,Chloroform-d)δ4.62(s,1H),3.54(d,J＝8.0Hz,1H),1.32(s,9H),1.16(s,3H),1.11(s,3H),1.06(d,J＝6.9Hz,3H).
3、化合物SM2的合成
在100mL圆底烧瓶中将化合物4(5g，1.0eq)，用溶剂乙酸乙酯(50ml)溶解后，加入4M HCl in Dioxane(50ml)，室温反应3h。TLC显示无原料剩余，直接蒸干反应液，得到3.4g化合物SM2。1H NMR(400MHz,Methanol-d4)δ3.15(q,J＝6.9Hz,1H),1.28(s,3H),1.26(d,J＝6.8Hz,3H),1.19(s,3H).
二、化合物T-47的合成
合成路线如下：
1、化合物2的合成
在100mL圆底烧瓶中将化合物SM1(375mg，1.0eq)，用溶剂无水乙醇(8ml) 溶解后，依次加入三乙胺(207ul，1.5eq)，SM2(300mg,1.5eq),室温反应过夜。TLC显示无原料剩余，加水，EA萃取2次，EA相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，用柱层析分离纯化，得到300mg化合物2。LC-MS[M+1]：448。
2、化合物T-47的合成
在100mL圆底烧瓶中将化合物2(300mg，1.0eq)，用溶剂二氯甲烷(8ml)溶解后，加入三氟乙酸(2ml)，室温反应过夜。TLC显示无原料剩余，加饱和碳酸氢钠溶液，EA萃取2次，EA相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，用柱层析分离纯化，得到200mg化合物T-47，纯度99.7％。1H NMR(400MHz,Methanol-d4)δ8.02(s,1H),4.64(s,1H),4.29(t,J＝6.7Hz,1H),4.15(d,J＝10.5Hz,1H),3.48(dd,J＝12.2,4.0Hz,1H),3.27(q,J＝4.2Hz,1H),3.02–2.85(m,2H),2.17–1.98(m,2H),1.93–1.76(m,1H),1.68(ddt,J＝18.4,11.6,5.9Hz,1H),1.26(s,3H),1.21(d,J＝5.1Hz,6H).
参照实施例T-47的方法，合成了如下化合物：

实施例T-48/T-49
本发明合成的化合物：
一、中间体SM2的合成
合成路线如下：
1、化合物2的合成
在250mL圆底烧瓶中将化合物1(5g，1.0eq)，二甲羟胺盐酸盐(3.4g，1.3eq)，N,N-二异丙基乙胺(11.3mL，2.6eq)，溶剂DMF(60ml)混合均匀后，用氮气置换三次后，氮气保护，冰浴下搅拌10min后，加入HATU(11g,1.1eq)，室温反应过夜。TLC显示无原料剩余，反应液加水淬灭，冰浴下加石油醚搅拌，抽滤得滤饼，60℃烘干得到2.91g的化合物2，LCMS[M+1]:233.1。
2、化合物3的合成
在250mL圆底烧瓶中加入化合物2(1g，1.0eq)，用氮气置换三次后，氮气保护，加入超干THF(30ml)溶解，降温至-20℃，滴加3M甲基溴化镁(14.3ml,10.0eq),加毕后室温反应3h。TLC显示无原料剩余，冰浴下加饱和氯化铵溶液淬灭反应，加水，EA萃取3次，EA相用饱和氯化钠溶液洗，无水硫酸钠干燥，用柱层析分离纯化，得到609mg化合物3，LCMS[M+1]:188.1。
3、化合物SM2的合成
在100mL圆底烧瓶中加入化合物3(363mg，1.0eq)，用氮气置换三次后，氮气保护，加入超干THF(16ml)溶解，降温至0℃，加入四氢铝锂(369mg,5.0eq),60℃反应4h。TLC显示无原料剩余，冰浴至0℃后加水淬灭反应，EA稀释后抽滤得到154mg化合物SM2，LCMS[M+1]:104.1。
二、化合物T-48/T-49的合成
合成路线如下：
1、化合物2/3的合成
在50mL圆底烧瓶中将化合物SM1(189mg，1.0eq)，用溶剂无水乙醇(4ml)溶解后，依次加入三乙胺(100ul，1.5eq)，SM2(154mg,3.0eq),80℃反应过夜。TLC显示无原料剩余，用柱层析分离纯化，得到63mg化合物2,LCMS[M+1]：448.5，和对应的旋光异构体化合物3，LCMS[M+1]：448.5。
2、化合物T-48的合成
在50mL圆底烧瓶中将化合物2(63mg，1.0eq)，用溶剂二氯甲烷(1ml)溶解后，加入三氟乙酸(100ul)，室温反应过夜。TLC显示无原料剩余，加饱和碳酸氢钠溶液，DCM萃取3次，DCM相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，用制备板分离纯化，得到12mg化合物T-48，LCMS[M+1]:348.1,纯度93.5％。1H NMR(400MHz,MeOD)δ8.08(s,1H),4.37–4.32(m,1H),4.07–3.97(m,1H),3.82–3.74(m,1H),3.38(dd,J＝12.1,3.7Hz,1H),2.91(s,3H),2.86(s,1H),2.10(dd,J＝15.0,7.5Hz,1H),1.99(s,2H),1.74–1.67(m,1H),1.57(dd,J＝20.1,9.7Hz,2H),1.13(d,J＝6.8Hz,3H),1.10(d,J＝6.2Hz,3H).
3、化合物T-49的合成
在50mL圆底烧瓶中将化合物3(28mg，1.0eq)，用溶剂二氯甲烷(500ul)溶解后，加入三氟乙酸(500ul)，室温反应过夜。TLC显示无原料剩余，加饱和碳酸氢钠溶液，DCM萃取3次，DCM相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，用制备板分离纯化，得到7mg化合物T-49，LCMS[M+1]:348.1,纯度97.2％。1H NMR(400MHz,MeOD)δ8.10(s,1H),4.55(s,1H),4.33(s,1H),4.09–4.06(m,1H),3.77(dd,J＝8.0,6.4Hz,1H),3.38(dd,J＝12.1,3.1Hz,1H),2.90(dd,J＝15.3,4.0Hz,1H),2.86(s,3H),2.81(s,1H),1.98(dd,J＝24.9,9.9Hz,2H),1.74(ddd,J＝14.7,12.9,7.5Hz,1H),1.65–1.53(m,1H),1.23(d,J＝6.6Hz,3H),1.01(d,J＝6.2Hz,3H).
实施例T-51
本发明合成的化合物：
一、中间体SM2的合成
合成路线如下：
1、化合物2的合成
在100mL圆底烧瓶中加入化合物1(250mg，1.0eq)，用氮气置换三次后，氮气保护，加入超干THF(10ml)溶解，降温至-20℃，滴加3M环丙基溴化镁(14.4ml,10.0eq),加毕后室温反应7.5h。TLC显示无原料剩余，冰浴下加饱和氯化铵溶液淬灭反应，加水，EA萃取3次，EA相用饱和氯化钠溶液洗，无水硫酸钠干燥，得到400mg化合物2,LCMS[M+1]:216.1。
2、化合物SM2的合成
在50mL圆底烧瓶中将化合物2(400mg，1.0eq)，用溶剂二氯甲烷(5ml)溶解后，加入三氟乙酸(3ml)，室温反应过夜。TLC显示无原料剩余，直接蒸干反应液，得到420mg化合物SM2，LCMS[M+1]:116.1。
二、化合物T-51的合成
合成路线如下：
1、化合物2的合成
在50mL圆底烧瓶中将化合物SM1(200mg，1.0eq)，用溶剂无水乙醇(2ml，10v)溶解后，依次加入三乙胺(1ml，10.0eq)，SM2(166mg,1.0eq),70℃反应过夜。TLC显示无原料剩余，加水，EA萃取3次，EA相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，用柱层析分离纯化，得到300mg化合物2。LCMS[M+1]:460.2。
2、化合物T-51的合成
在50mL圆底烧瓶中将化合物2(100mg，1.0eq)，用溶剂乙酸乙酯(2ml)溶解后，加入4M HCl in Dioxane(1ml)，室温反应5h。TLC显示无原料剩余， 加饱和碳酸氢钠溶液调pH，EA萃取3次，EA相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，用制备板分离纯化，得到35mg化合物T-51，LCMS[M+1]:360.1纯度98.7％。1H NMR(400MHz,MeOD)δ7.75(s,1H),3.77(d,J＝3.8Hz,1H),2.83(d,J＝12.3Hz,1H),2.70(d,J＝9.0Hz,1H),2.53–2.43(m,1H),2.40(dd,J＝12.1,6.8Hz,1H),1.81(s,1H),1.64(d,J＝3.9Hz,1H),1.52–1.28(m,3H),1.14–1.07(m,3H),0.73–0.61(m,2H),0.33–0.19(m,2H),0.13(dd,J＝9.7,4.4Hz,1H),0.08–-0.04(m,1H).
实施例T-52
本发明合成的化合物：
一、中间体SM2的合成
合成路线如下：
1、化合物2的合成
在250mL圆底烧瓶中将化合物1(10g，1.0eq)，二甲羟胺盐酸盐(6.7g，1.3eq)，N,N-二异丙基乙胺(23mL，2.6eq)，溶剂DMF(120ml)混合均匀后，用氮气置换三次后，氮气保护，冰浴下搅拌10min后，加入HATU(22g,1.1eq)，室温反应过夜。TLC显示无原料剩余，反应液加水淬灭，冰浴下加石油醚搅拌，抽滤得滤饼，60℃烘干得到10.2g的化合物2。1H NMR(400MHz,CDCl3)δ5.24(d,J＝6.0Hz,1H),4.66(s,1H),3.75(s,3H),3.19(s,3H),1.41(s,9H),1.29(d,J＝6.9Hz,3H).
2、化合物3的合成
在500mL圆底烧瓶中加入化合物2(10g，1.0eq)，用氮气置换三次后，氮气保护，加入超干THF(204ml)溶解，降温至-20℃，滴加3M甲基溴化镁(6ml，10.0eq),加毕后室温反应过夜。TLC显示无原料剩余，冰浴下加饱和氯化铵溶液淬灭反应，加水，EA萃取3次，EA相用饱和氯化钠溶液洗，无水硫酸钠干燥， 用柱层析分离纯化，得到7g化合物3。1H NMR(400MHz,CDCl3)δ5.28(s,1H),4.40–4.22(m,1H),2.21(s,3H),1.44(s,9H),1.35(d,J＝7.2Hz,3H).
3、化合物4的合成
在100mL圆底烧瓶中加入化合物3(300mg，1.0eq)，用氮气置换三次后，氮气保护，加入超干THF(6ml)溶解，降温至-20℃，滴加3M环丙基氯化镁(16ml,10.0eq),加毕后室温反应过夜。TLC显示无原料剩余，冰浴下加饱和氯化铵溶液淬灭反应，加水，EA萃取3次，EA相用饱和氯化钠溶液洗，无水硫酸钠干燥，得到472mg化合物4，LCMS[M+1]:230.3。
3、化合物SM2的合成
在50mL圆底烧瓶中将化合物4(472mg，1.0eq)，用溶剂二氯甲烷(5ml)溶解后，加入三氟乙酸(1.5ml)，室温反应3h。TLC显示无原料剩余，直接蒸干反应液，得到674mg化合物SM2,LCMS[M+1]:130.2。
二、化合物T-52的合成
合成路线如下：
1、化合物2的合成
在50mL圆底烧瓶中将化合物SM1(304mg，1.0eq)，用溶剂无水乙醇(6ml)溶解后，依次加入三乙胺(550ul，5.0eq)，SM2(207mg,2.0eq),80℃反应过夜。TLC显示无原料剩余，用柱层析分离纯化，得到129mg化合物2。LC-MS[M+1]：474.2。
2、化合物T-52的合成
在50mL圆底烧瓶中将化合物2(129mg，1.0eq)，用溶剂二氯甲烷(1.5ml)溶解后，加入三氟乙酸(0.2ul)，室温反应过夜。TLC显示无原料剩余，加饱和碳酸氢钠溶液，DCM萃取3次，DCM相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，用制备板分离纯化，得到22mg化合物T-52，LCMS[M+1]:374.2,纯度97.0％。1H NMR(400MHz,MeOD)δ7.91(s,1H),4.02(ddd,J＝13.5,9.4,3.8Hz,1H),3.51–3.43(m, 2H),3.39(dd,J＝12.2,3.4Hz,1H),3.19–3.13(m,1H),2.92–2.76(m,2H),2.18(q,J＝6.6Hz,2H),1.96(ddd,J＝14.9,12.6,8.5Hz,2H),1.73(dt,J＝14.5,10.7Hz,1H),1.67–1.58(m,1H),1.56(s,3H),1.24(d,J＝6.8Hz,3H),0.84–0.74(m,2H).
试验例1酶活性试验
下面对上述实施例部分化合物及对比例进行生物活性测试实验。
生物活性测试实验过程如下：
受试化合物CDK7激酶IC50值检测(在无锡佰翱得公司检测)。
1、化合物配制：
将化合物粉末溶解在100％DMSO中，配制成10mM储存液，将储存液进一步稀释成0.5mM作为起始浓度，并连续3倍稀释，从而获得10个不同浓度的化合物溶液，使用复孔检测，化合物和酶预孵育时间分别为0分钟和60分钟。以Staurosporine化合物(结构式为)作为阳性对照，使用Mobility shift assay的方法，检测该化合物在CDK7激酶上的活性。
2、激酶反应过程：
1)化合物溶液及阳性对照用双蒸水稀释8.3倍后加至384孔板，每个浓度2uL/孔；
(2)在化合物孔和阳性对照孔分别加6nM CDK7/Cyclin H/MAT1激酶溶液；
(3)室温孵育0和60分钟；
(4)加入2mM ATP和2pM 5-FAM-CDK7肽底物(5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK)溶液；
(5)将384孔板25℃孵育30分钟；
(6)加入4uL 120mM EDTA停止激酶反应；
(7)用Caliper/LabChip EZ Reader(Perkin Elmer)读取转化率；
(8)通过GraphPad Prism 8软件进行曲线拟合得到IC50数值。
通过上述检测，得到受试样品对CDK7激酶的抑制活性IC50(nM)值如表1所示，其中A≤10nM；10nM<B<500nM；C≥500nM。
表1
从上表可知，通过体外生物活性筛选，以星形孢菌素(Staurosporine)为对照品，本申请所合成的化合物对CDK7激酶均有很好的抑制能力，有望进一步开发成为用于调节CDK7激酶活性或治疗CDK7相关疾病方面的药物。
试验例2细胞抗增殖实验
一、实验材料和设备：
卵巢癌细胞A2780，结直肠癌细胞WiDr购于北京北纳创联生物科技有限公司。DMEM培养基(Bio-Channel)，DMSO(二甲基亚砜),MTT(噻唑蓝)，0.25％EDTA-Tripsin(胰酶消化液),1xPBS(磷酸盐缓冲液，PH7.2)，96孔板(Corning),胎牛血清(FBS)，10,000U/mL青霉素-G/链霉素,高速冷冻离心机(EPPENDORF 5810R)，酶联免疫检测仪(Tecan Spark)。
二、实验准备：
1、细胞铺板
A)肿瘤细胞在37℃，5％CO2及饱和湿度的条件下，在DMEM(高糖，含10％FBS和100U/mL青霉素-G/链霉素)中培养至80-90％密集度。
B)去除10cm培养皿中的培养基；
C)用10ml 1xPBS润洗细胞一遍；
D)加4ml 0.25％EDTA-Tripsin放入37℃，5％CO2培养箱胰酶消化5分钟， 转移到15ml离心管，200g离心5分钟，弃上清得到细胞沉淀；
E)用4ml DMEM培养基重悬，计数并调整到50,000细胞/ml。
F)将细胞悬液加入96孔板每孔体积100μL，在37℃,5％CO2培养箱中培养过夜。
2、化合物处理
化合物稀释
A)配制受测化合物梯度稀释溶液：将受测化合物配置成1mM的储备液，然后用1.5μl储液溶解于1.5ml无DMSO培养液中，再以0.1％DMSO培养液进行3倍连续梯度稀释，共9个浓度，稀释后化合物浓度如下：
333.33nM，111.11nM，37.03nM，12.35nM，4.15nM，1.37nM，0.46nM，0.15nM
B)充分混匀后分别取100μL培养化合物溶液替代细胞培养板中的培养液，每个浓度4个复孔；
C)将细胞转移至培养箱孵育3天。
3、MTT检测
A)取出细胞培养板在生物安全柜中加入5mg/ml MTT 10μL；
B)把细胞培养板放回培养箱继续孵育3小时；
C)取出细胞培养板去除培养液，加入异丙醇(含0.4mM HCl，0.1％NP-40)100μL，室温摇床30分钟；
D)在TECAN酶联免疫检测仪上选择570nm波长测定吸光度值。
4、数据分析
使用如下公式计算存率(％Cell Viability):
％Cell Viability＝100％×(Lum_Sample-Lum_LC)/(Lum_HC-Lum_LC)
Lum_HC:0.1％DMSO对照组细胞读数
Lum_Sample:加入化合物的细胞读数
Lum_LC:空白培养基读数
通过GraphPad Prism 8软件进行曲线拟合得到IC50数值。
如表2所示，其中A≤20nM；20nM<B≤500nM；C＞500nM。
表2
由表2可以看出，本发明化合物对卵巢癌细胞A2780，结直肠癌细胞WiDr均有非常好的抑制作用。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种用作CDK7激酶抑制剂的化合物，其特征在于，所述化合物为式I化合物、或其药学上可接受的盐、立体异构体、互变异构体、水合物、溶剂化物、同位素化合物或前药，
    其中：
    R1选自下组：
    R2选自下组：H、CF3、Cl、Br、CH3、环丙基、苯基；
    R3为H；
    或者R2与R3形成饱和或不饱和的5-6元环烷基；
    R4选自下组：
    X1、X2、X3、X4各自独立地选自下组：NR6、CR7R8、O、S；
    各R6、R7、R8独立地选自下组：H、C1-C6烷基、卤代C1-C6烷基、含1、2或3个选自N、O、S的杂原子的C1-C6杂烷基、C3-C6环烷基、卤代C3-C6环烷基、C1-C6烷胺基、C3-C6环烷胺基、含1、2或3个选自N、O、S的杂原子的3-8元杂环烷基、C6-C10芳基、含1、2或3个选自N、O、S的杂原子的5-10元杂芳基；
    各m、n独立地选自下组：0、1、2、3、4、5。
  2. 如权利要求1所述的化合物，其特征在于，R1选自下组：
  3. 如权利要求1所述的化合物，其特征在于，
    R1选自下组：
    R2选自下组：H、CF3、Cl、Br、CH3、
    R3为H。
  4. 如权利要求1所述的化合物，其特征在于，
    R4选自下组：
    R2选自下组：H、CF3、Cl。
  5. 如权利要求1所述的化合物，其特征在于，所述化合物选自下组：



  6. 一种药物组合物，其特征在于，含有一种或多种预防和/或治疗有效量的权利要求1所述的化合物，以及药学上可接受的载体。
  7. 一种权利要求1所述的化合物的用途，其特征在于，用于制备用作CDK7激酶抑制剂的药物。
  8. 一种权利要求1所述的化合物的用途，其特征在于，用于制备用于调节CDK7激酶活性或治疗CDK7相关疾病的药物。
  9. 如权利要求8所述的用途，其特征在于，所述CDK7相关疾病选自下组：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
  10. 如权利要求9所述的用途，其特征在于，所述癌症选自下组：肺癌、乳腺癌、前列腺癌、结直肠癌、肝癌、胰腺癌、卵巢癌、白血病、神经母细胞瘤、胃癌、肾癌、食管癌、子宫癌。
PCT/CN2023/105733 2022-07-04 2023-07-04 用作cdk7激酶抑制剂的化合物及其应用 WO2024008083A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210788052.4 2022-07-04
CN202210788052.4A CN117384135A (zh) 2022-07-04 2022-07-04 用作cdk7激酶抑制剂的化合物及其应用

Publications (1)

Publication Number Publication Date
WO2024008083A1 true WO2024008083A1 (zh) 2024-01-11

Family

ID=89436089

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/105733 WO2024008083A1 (zh) 2022-07-04 2023-07-04 用作cdk7激酶抑制剂的化合物及其应用

Country Status (2)

Country Link
CN (1) CN117384135A (zh)
WO (1) WO2024008083A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101568529A (zh) * 2006-12-22 2009-10-28 诺瓦提斯公司 作为cdk抑制剂、用于治疗癌症、炎症和病毒感染的杂芳基-杂芳基化合物
CN105849099A (zh) * 2013-10-18 2016-08-10 达纳-法伯癌症研究所股份有限公司 周期蛋白依赖性激酶7(cdk7)的多环抑制剂
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
CN113677346A (zh) * 2018-11-01 2021-11-19 希洛斯医药品股份有限公司 周期蛋白依赖性激酶7(cdk7)的抑制剂

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101568529A (zh) * 2006-12-22 2009-10-28 诺瓦提斯公司 作为cdk抑制剂、用于治疗癌症、炎症和病毒感染的杂芳基-杂芳基化合物
CN105849099A (zh) * 2013-10-18 2016-08-10 达纳-法伯癌症研究所股份有限公司 周期蛋白依赖性激酶7(cdk7)的多环抑制剂
CN113677346A (zh) * 2018-11-01 2021-11-19 希洛斯医药品股份有限公司 周期蛋白依赖性激酶7(cdk7)的抑制剂
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
CN113717157A (zh) * 2020-07-24 2021-11-30 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

Also Published As

Publication number Publication date
CN117384135A (zh) 2024-01-12

Similar Documents

Publication Publication Date Title
WO2022017533A1 (zh) 用作cdk7激酶抑制剂的化合物及其应用
WO2021078285A1 (zh) 环烷基类和杂环烷基类抑制剂及其制备方法和应用
WO2021143693A1 (zh) 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用
TW202128691A (zh) Ｋｒａｓ 突變蛋白抑制劑
WO2021228161A1 (zh) 烷氧基烷基取代杂环基类抑制剂及其制备方法和应用
CN115335379A (zh) 含螺环的喹唑啉化合物
RU2633694C2 (ru) Дейтерированный фениламинопиримидин и фармацевтическая композиция, содержащая такое соединение
WO2021249563A1 (zh) 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用
TWI832539B (zh) 用作ｃｄｋ７激酶抑制劑的化合物及其應用
WO2022161480A1 (zh) 取代双环并芳杂环胺类抑制剂及其制备方法和应用
CN115043842A (zh) 胺基取代双环类抑制剂及其制备方法和应用
WO2021098859A1 (zh) 氮杂七元环类抑制剂及其制备方法和应用
CN114835703A (zh) 取代嘧啶并吡啶酮类抑制剂及其制备方法和应用
CN113105448A (zh) 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用
US20230095530A1 (en) Compound used as ret kinase inhibitor and application thereof
EP4253374A1 (en) Deuterated 2-arylheterocycle-3-oxo-2,3-dihydropyridazine-4-carboxamide inhibitor and preparation method therefor and application thereof
WO2022143695A1 (zh) 磺酰胺类抑制剂及其制备方法和应用
WO2024008083A1 (zh) 用作cdk7激酶抑制剂的化合物及其应用
EP4155304A1 (en) Compound used as ret kinase inhibitor and application thereof
WO2022135591A1 (zh) 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用
CN115215844A (zh) 取代嘧啶并环类抑制剂及其制备方法和应用
CN114380805A (zh) 取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用
CN115215869A (zh) 取代三环类抑制剂及其制备方法和应用
WO2024012543A1 (zh) 用作cdk4激酶抑制剂的化合物及其应用
CN113354630B (zh) 一种5,6-二氢苯并[h]喹唑啉类化合物及其应用

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: 23834850

Country of ref document: EP

Kind code of ref document: A1