WO2023246371A1 - Composé à petites molécules ayant une structure pyrimidothiophène et son utilisation - Google Patents

Composé à petites molécules ayant une structure pyrimidothiophène et son utilisation Download PDF

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WO2023246371A1
WO2023246371A1 PCT/CN2023/094038 CN2023094038W WO2023246371A1 WO 2023246371 A1 WO2023246371 A1 WO 2023246371A1 CN 2023094038 W CN2023094038 W CN 2023094038W WO 2023246371 A1 WO2023246371 A1 WO 2023246371A1
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compound
alkyl
add
reaction
synthesis
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Chinese (zh)
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樊梦阳
马大为
丁克
张红进
贾素云
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中国科学院基础医学与肿瘤研究所(筹)
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Publication of WO2023246371A1 publication Critical patent/WO2023246371A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • 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
    • 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
    • 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
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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 field of chemical drugs, and in particular to a class of small molecule compounds with a pyrimidothiophene structure and their applications.
  • the cyclin-dependent kinase family is a serine/threonine protein kinase that regulates transcription (CDK 7-13 and 19-20) or cell cycle progression (CDK 1-6 and 14-18 ).
  • CDK 7-13 and 19-20 serine/threonine protein kinase that regulates transcription
  • CDK 1-6 and 14-18 cell cycle progression
  • cell cycle dysregulation is a hallmark of cancer, and targeting cells
  • Drugs CDK4/6 inhibitors of cycle regulators have been launched and have achieved great success. Therefore, drugs targeting CDK family kinases are important tumor treatments.
  • CDK can combine with cyclin to form a heterodimer, in which CDK is the catalytic subunit and cyclin is the regulatory subunit.
  • Different cyclin-CDK complexes catalyze the phosphorylation of different substrates through CDK activity, thereby achieving different effects on the cell cycle.
  • the activity of CDK depends on the sequential expression of its positive regulatory subunit cyclin and the concentration of its negative regulatory subunit CKI (cyclin-dependent kinase inhibitor, CDK inhibitor).
  • CDK activity is also regulated by phosphorylation and dephosphorylation, as well as oncogenes and tumor suppressor genes.
  • CDK4/6 combines with cyclinD to promote the phosphorylation of retinoblastoma protein (Rb), and the activity of part of the transcription elongation factor E2F is released, which is used to synthesize a large amount of RNA and proteins to prepare for chromosome replication.
  • CDK2 combines with cyclinE to form the proteasome complex CDK2-cyclinE and is activated, which promotes further phosphorylation of Rb and induces the continued expression of the transcription factor E2F, thereby regulating cells to successfully pass through the G1 phase.
  • CDK2 After entering the S phase, CDK2 combines with cyclinA to form a complex CDK2-cyclinA, which participates in the S phase of the cell cycle and completes DNA replication. Subsequently, cyclinA/B and CDK1 form the CDK1-cyclinA/B complex, driving the cell cycle into the G2/M phase, synthesizing RNA and proteins to prepare for the formation of spindle fibers. Finally, the cells go through all the cell cycles of G1-S-G2-M in an orderly manner to complete cell mitosis. Almost all CDK activations occur through: (1) Binding to Cyclin; (2) T-Loop is phosphorylated by CDK Activating Kinase (CAK). CAK is a ternary complex consisting of CDK7, Cyclin H and RING-finger protein MAT1.
  • CDK7 The unique feature of CDK7 is that it is involved in the regulation of both transcription and cell cycle. It is ubiquitously expressed in various types of cancer, and its downregulation leads to reduced cell proliferation. CDK7 is considered a feasible cancer therapeutic target. High CDK7 expression has been detected in multiple cancer types and is associated with aggressive clinicopathological features and poor prognosis. CDK7 is amplified in hepatocellular carcinoma, gastric cancer, and colorectal cancer (CRC). Immunohistochemical analysis of 173 gastric cancer specimens showed that elevated CDK7 levels were related to tumor grade.
  • CDK7 protein is expressed in most oral squamous cells High expression in cell carcinoma specimens is associated with increased T stage and decreased disease-free survival rate, indicating that it can be used as a prognostic biomarker. CDK7 protein and mRNA levels are upregulated in cancerous breast tissue compared with adjacent normal breast tissue.
  • CDK2 is directly involved in cell cycle regulation and plays a key role.
  • the activity of CDK2 depends on the combination with cyclin E or cyclin A, regulating the transition of cells from G1 to S phase and the progression of S phase.
  • pan-CDK inhibitors have been discovered in the past decade.
  • first-generation CDK inhibitors exhibited strong side effects, which greatly hindered clinical development. Therefore, the development of drugs that can selectively inhibit the activity of CDK7 or CDK2 and exert pharmacological effects in the body is of great significance for the treatment of tumors.
  • the object of the present invention is to provide a small molecule compound with a pyrimidothiophene structure and its application.
  • a selective CDK7 or CDK2 inhibitor it can inhibit the kinase function of CDK in in vitro and in vivo experiments, and block The transcription of oncogenes and uncontrolled cell cycle progression achieve the effect of inhibiting tumor cell proliferation.
  • the first aspect of the present invention provides a compound represented by Formula I or Formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,
  • X is S or P
  • X’ and X are each independently CH or N;
  • Y and Y’ are each independently C or N;
  • Z and Z' are each independently CR z or N; wherein, R z is selected from: H, halogen, OH, NH 2 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2. Nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 One-membered heterocyclyl;
  • R 1 is selected from the following substituted or unsubstituted groups: C3-C10 cycloalkyl, -C1-C6 alkylene, C3-C10 cycloalkyl, 4-10 membered N-containing heterocyclyl, -C1-C6 alkylene Alkyl 4-10 membered N-containing heterocyclic group;
  • R 2 is selected from: H, halogen, OH, NH 2 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl;
  • R 4 and R' 4 are each independently selected from: None, hydrogen, halogen, OH, NH 2 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , nitro, Cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -COOC1-C6 alkyl, -OCOC1-C6 alkyl, -CONHC1-C6 alkyl, -CON(C1-C6 Alkyl) 2 , -NHC(O)C1-C6 alkyl, -NHC(O)OC1-C6 alkyl, -NHS(O) 2 C1-C6 alkyl, -S(O) 2 C1-C6 alkyl , -S(O)N(C1-C6 alkyl) 2 , -S(O) 2 N(C1-C6 alkyl
  • Rp 3 and R 5 are each independently selected from: H, halogen, OH, NH 2 , cyano, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, halogenated C1-C4 alkyl Oxygen;
  • R p-1 and R' p-1 are each independently selected from the following substituted or unsubstituted groups: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 ring Alkyl or 3-6 membered heterocyclyl; wherein, the substitution means substitution by one or more Ra;
  • L 1 is a substituted or unsubstituted C1-C6 alkyl group, wherein the substitution means substitution by one or more Ra;
  • Rn 1 and Rn 2 are each independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl; wherein, the substitution means by one or multiple Ra substitutions;
  • Ra is each independently selected from: halogen, OH, NH 2 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , Nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl , 3-6 membered heterocyclic group.
  • YR 4 is N.
  • X is P
  • Rp 1 and Rp 2 are each independently methyl, ethyl, or propyl.
  • R p-1 and R' p-1 are each independently methyl, ethyl, or propyl.
  • R' 1 is selected from the following substituted or unsubstituted groups: C1-C6 alkyl NRn 1 Rn 2 , C3-C10 cycloalkyl, -C1-C6 alkylene, C3-C10 cycloalkyl, 4- 10-membered N-containing heterocyclic group, -C1-C6 alkylene group, 4-10-membered N-containing heterocyclic group;
  • Rn 1 and Rn 2 are each independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl; wherein, the substitution means substitution by one or more Ra;
  • R' 2 is selected from: H, halogen, OH, NH 2 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , nitro, cyano, C1-C6 alkyl , C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl;
  • W is selected from: phenyl, naphthyl, 5-6 membered monocyclic heteroaryl or 8-10 membered fused bicyclic heteroaryl, benzo 5-10 membered heterocyclyl, 5-6 membered monocyclic heteroaryl And 5-10 membered heterocyclyl;
  • R' 5 and R' 6 are each independently selected from: hydrogen, halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, -N(R 5-1a R 5-1b ), phenyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, - NHC(O)R 5-2 , -NHC(O)OR 5-3 , -NHS(O) 2 R 5-4 , -C(O)N(R 5-5a R 5-5b ), -S( O) 2 R 5-6 , -S(O)(NH)R 5-7 , -S(O) 2 N(R 5-8a R 5-8b ) or -P(O)R 5-9a R 5 -9b ; or when R' 5 and R' 6 are connected to adjacent or the same ring atom, R 5' and R 6' together with the ring
  • R 5-1a , R 5-1b , R 5-2 , R 5-3 , R 5-4 , R 5-5a , R 5-5b , R 5-6 , R 5-7 , R 5-8a , R 5-8b , R 5-9a and R 5-9b are each independently selected from: hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; wherein, the C1-C6 alkyl, C3-C6 cycloalkyl The group is optionally substituted by one or more groups selected from the group consisting of: halogen, hydroxyl; or R 5-1a and R 5-1b , R 5-5a and R 5-5b , R 5-8a and R 5 -8b , R 5-9a and R 5-9b can together form a substituted or unsubstituted C3-C6 carbocyclic ring or a substituted or unsubstituted 4-6 membered heterocyclyl group with the atoms to which they are connected, where
  • Ra is each independently selected from: halogen, OH, NH 2 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , nitro, Cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- 6-membered heterocyclic group.
  • Rp 3 , Rp 4 , Rz and R' 4 are defined as above.
  • the W ring is selected from the following substituted or unsubstituted groups: phenyl, naphthyl, pyridyl, pyrimidine base, indolyl, isoindolyl, indazolyl, quinolyl, Wherein, the substitution refers to substitution by one or more Ra, and Ra is defined as above.
  • R' 5 and R' 6 are each independently selected from: hydrogen, halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, -NH 2 , -NHCH 3 , -NHCH(CH 3 ) 2 , -C(O)NH2, -C(O)NHCH 3 , -C(O)CH(CH 3 ) 2 , -P(O)(CH 3 ) 2 , -P(O)(CH 2 CH 3 ) 2 , -S(O) 2 NH 2 , -S(O ) 2 NHCH 3 , -NHC(O)O CH 3 , -S(O)(NH)CH 3 , -NHC(O)O CH 3 , -S(O)(NH)CH 3 , -NHC(O)CH 3 , -C(O)NH CH 2 CH 2 OH.
  • R 1 is selected from the following substituted or unsubstituted groups: C3-C10 cycloalkyl, -C1-C6 alkylene, C3-C10 cycloalkyl, 4-10 membered N-containing heterocycle group, -C1-C6 alkylene group, 4-10 membered N-containing heterocyclic group; wherein, the substitution means substitution by one or more Ra, and Ra is defined as above.
  • R 1 is selected from: substituted or unsubstituted 5-6 membered N-containing monocyclic heterocyclic groups (preferably azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, etc.) , substituted or unsubstituted 7-10 membered bicyclic or tricyclic (such as spirocyclic, fused ring, bridged ring) heterocyclic group, substituted or unsubstituted -(CH 2 ) 1-3 -(5-6 membered N-containing Monocyclic heterocyclyl (preferably azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, etc.), substituted or unsubstituted -(CH 2 ) 1-3 -(7-10 membered bicyclic or tricyclic Ring (such as spiro ring, fused ring, bridged ring) heterocyclyl), wherein the
  • R 1 is selected from: Among them, Rq is selected from: H, F, Cl.
  • R 1 is selected from:
  • R' 1 is selected from: C1-C6 alkyl NH 2 , C1-C6 alkyl NHC1-C6 alkyl, substituted or unsubstituted 5-6 membered N-containing monocyclic heterocyclic group (preferably azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, etc.), substituted or unsubstituted 7-10 membered bicyclic or tricyclic (such as spirocyclic, fused ring, bridged ring) heterocyclyl, substituted or untaken -(CH 2 ) 1-3 -(5-6 membered N-containing monocyclic heterocyclic group (preferably azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, etc.), substituted or Not taken -(CH 2 ) 1-3 -(7-10 membered bicyclic or tricyclic (such as spir
  • R'1 is selected from:
  • Y, Y', Z, Z', R 2 , R 4 , R' 4 , Rp 3 , R 5 , Rp 4 , L 1 , Rn 1 and Rn 2 are the specific ones in the embodiment.
  • the compound is selected from any one of the following compounds:
  • the compound is the compound shown in the embodiment.
  • a second aspect of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition includes the compound as described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further includes a drug selected from the following group: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab or biosimilars of the above drugs, etc.) , PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinumab Tocilizumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, itumomab, 90Y- itumomab, 90In- itumomab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172,
  • a method for preparing a pharmaceutical composition including the steps of: combining a pharmaceutically acceptable carrier with the compound described in the first aspect of the present invention or its stereoisomer or optical isomer. , pharmaceutically acceptable salts, prodrugs or solvates are mixed to form a pharmaceutical composition.
  • the compound of the present invention can be prepared into powders, tablets, granules, capsules, solutions, emulsions, suspensions, etc.
  • the third aspect of the present invention provides a compound as described in the first aspect, or a pharmaceutically acceptable salt thereof, immediately isomer, solvate or prodrug, or the use of the pharmaceutical composition as described in the second aspect in the preparation of anti-tumor drugs.
  • the tumor is selected from colorectal cancer, breast cancer, lung cancer, ovarian cancer or gastric cancer, preferably breast cancer.
  • Figure 1 shows the anti-proliferation curve of the compound of the present invention on the triple-negative breast cancer cell line MDA-MB-453.
  • Figure 2 shows the anti-proliferation curve of the compounds of the present invention on the ovarian cancer cell line OVCAR3.
  • Figure 3 shows the anti-tumor efficacy test of the compounds of the present invention on the nude mouse transplanted tumor model of the triple-negative breast cancer cell line MDA-MB-231.
  • 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 -.
  • the term "about” when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and between (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the term “contains” or “includes” can be open, semi-closed and closed. In other words, the term also includes “consisting essentially of,” or “consisting of.”
  • alkyl includes straight or branched chain alkyl groups.
  • C1-C8 alkyl represents a straight-chain or branched alkyl group with 1-8 carbon atoms, preferably C1-C6 alkyl, more preferably C1-C3 alkyl.
  • alkyl include but are not limited to methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.
  • alkenyl includes straight or branched chain alkenyl groups.
  • C2-C8 alkenyl refers to a linear or branched alkenyl group with 2-8 carbon atoms, preferably C2-C6 alkenyl, and more preferably C2-C4 alkenyl.
  • alkenyl include but are not limited to vinyl, Allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl or similar groups.
  • alkynyl includes straight or branched chain alkynyl groups.
  • C2-C8 alkynyl refers to a straight-chain or branched alkynyl group with 2-8 carbon atoms, preferably C2-C6 alkynyl, more preferably C2-C4 alkynyl
  • examples of alkynyl include but are not limited to ethynyl , propynyl, butynyl, pentynyl, hexynyl or similar groups.
  • cycloalkyl refers to a cyclic alkyl group containing a specific number of C atoms, such as "C3-C12 cycloalkyl” refers to a cyclic alkyl group having 3 to 12 (preferably 3, 4, 5, 6, 7 or 8) cycloalkyl carbon atoms. It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. Bicyclic forms, such as bridged or spirocyclic forms, are also possible. In the present invention, cycloalkyl is intended to include substituted cycloalkyl.
  • carbocyclyl refers to a saturated or partially saturated cyclic group containing a specified number of C atoms, such as "C3-C6 carbocyclyl” refers to a cyclic group having 3 to 6 (i.e., 3, 4, 5 , 6) Carbocyclic group of carbon atoms.
  • Bicyclic forms, such as bridged or spirocyclic forms, are also possible.
  • carbocyclyl is intended to include substituted carbocyclyl.
  • C1-C6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms; which has the formula C1-C6 alkyl-O- or -C1-C5 alkyl -O-C1-C5 alkyl (e.g., -CH 2 -O-CH 2 CH 3 , -CH 2 -O-(CH 2 ) 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 ) Structure, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc.
  • heterocyclyl refers to a saturated or partially saturated cyclic group having 1-3 heteroatoms selected from N, S and O
  • heterocyclyl refers to a cyclic group having 3 to 12-membered heterocyclyl.
  • the 3-12-membered heterocyclyl group is preferably a 3-8-membered heterocyclyl group, and more preferably is a 4-6-membered or 6-8-membered heterocyclyl group.
  • Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.
  • aryl refers to an aromatic cyclic group containing no heteroatoms in the ring, which aryl group may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring where it is attached to the parent structure
  • the ring is an aryl ring.
  • phenyl i.e. six-membered aromatic ring
  • naphthyl etc.
  • Aryl groups may be optionally substituted or unsubstituted.
  • heteroaryl refers to a cyclic aromatic group having 1-3 heteroatoms selected from the group consisting of N, S and O
  • heteroaryl refers to a cyclic aromatic group having 5-6 heteroatoms.
  • Heteroaryl can be a single ring (for example, 5-6 members) or a condensed ring (for example, 8-10 members).
  • Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridone, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1 ,2,4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, indolyl, isoindolyl, indazolyl, quinolyl, wait.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring.
  • Heteroaryl groups may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio , alkylamino, halogen, amino, nitro, Hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amide, sulfonamide, formyl, formamide, carboxyl and carboxylate Key et al.
  • halogen or "halogen atom” refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br.
  • -C1-C6 alkylene 4-10 membered N-containing heterocyclyl group refers to a C1-C6 alkylene group substituted by a 4-10 membered N-containing heterocyclyl group, preferably -C1-C3 alkylene
  • the base is a 4-6 membered N-containing heterocyclic group, for example, wait.
  • "-C1-C6 alkylene C3-C10 cycloalkyl” has a similar meaning.
  • 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.
  • substituted or unsubstituted the groups described in the present invention can be substituted with substituents selected from the following group: deuterium, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclyl, C3-C12 cycloalkyl, 5-12 membered heteroaryl , C6-C12 aryl.
  • substituents selected from the following group: deuterium, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclyl, C3-C12 cycloalkyl, 5-12 membered heteroaryl , C6-C12 aryl.
  • the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, containing asymmetric The R and S configurations of the center, the (Z) and (E) isomers of the double bond, etc. Therefore, individual stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformational isomers) are within the scope of the present invention.
  • tautomer means that structural isomers with different energies can exceed a low energy barrier and thereby convert into each other.
  • proton tautomers i.e., proton transfer
  • interconversion through proton migration such as 1H-indazole and 2H-indazole.
  • Valence tautomers involve interconversions through the recombination of some of the bonding electrons.
  • solvate refers to a complex in which a compound of the invention is coordinated with solvent molecules to form a complex in a specified proportion.
  • compounds of the present invention refers to compounds represented by Formula I, Formula I' or Formula II, and also includes pharmaceutically acceptable salts, stereoisomers, solvates or precursors of the compounds of Formula (A). medicine.
  • salts formed by the compounds in the present invention also belong to the scope of the present invention.
  • 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, it includes but is not limited to pyridine.
  • Zwitterions that may be formed when containing an acidic moiety, including but not limited to carboxylic acids, are included within the scope of the term "salt”.
  • Pharmaceutically acceptable (i.e., nontoxic, physiologically acceptable) 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, fumarate, glucoheptonate, glycerophosphate, hemisulfate, enanthate, caproate, hydrochloride, hydrobromide, hydroiodide, glycolate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salt, pectate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, sal
  • 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 of the compounds of the present invention are also within the scope of the invention.
  • the term "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 invention may be independent stereoisomers that do not exist simultaneously with other isomers (e.g., have a specific 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.
  • the racemic form can be resolved by physical means, For example, fractional crystallization, or separation and crystallization by derivatization into diastereoisomers, or separation by chiral column chromatography.
  • Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid followed by 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 solvates, which contain isotopes or other isotope 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 labeled in the usual manner by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents, using The protocols disclosed in the examples can be prepared.
  • 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.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 150°C, preferably 10°C to 100°C).
  • the reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.
  • the compounds of the present invention can be prepared by the following steps
  • the corresponding intermediate is obtained through a nucleophilic substitution reaction with an indole derivative under the action of aluminum trichloride or a Suzuki coupling reaction with a boronic acid derivative.
  • the resulting intermediate is a substitution reaction with the corresponding amine under the action of an organic base to obtain the corresponding product, and finally the I series target compounds are obtained by removing the protecting group;
  • the corresponding intermediate compound is obtained through a substitution reaction with the corresponding amine under the action of an organic base; the obtained intermediate is subjected to Suzuki coupling with a boronic acid derivative The reaction obtains the corresponding product, and finally the II series target compounds are obtained by removing the protecting group.
  • compositions and methods of administration are provided.
  • the compound of the present invention has excellent CDK kinase inhibitory activity
  • the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, as well as a pharmaceutical composition containing the compound of the present invention as the main active ingredient It can be used to prevent and/or treat (stabilize, alleviate or cure) CDK kinase related diseases such as tumors (such as colorectal cancer, breast cancer, lung cancer, ovarian cancer or gastric cancer).
  • the pharmaceutical composition of the present invention contains a compound of the present invention 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 10-200 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 filler 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.
  • the administration mode of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative administration modes include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
  • 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, in addition to the active compound, inert diluents conventionally employed in the art, such as water or other solvents.
  • Agents, 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, etc.
  • 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.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds (eg, CDK inhibitors).
  • other pharmaceutically acceptable compounds eg, CDK inhibitors.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (eg, CDK inhibitors).
  • one or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds may be used simultaneously, separately, or sequentially with the compound of the invention to prevent and/or treat CDK Diseases related to kinase activity or expression.
  • 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 20 to 500 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 compound of the present invention has a novel structure and has excellent CDK kinase inhibitory activity, especially CDK7 or CDK2;
  • the compounds of the present invention can be used as CDK kinase inhibitors, especially as highly selective inhibitors of CDK7 or CDK2.
  • the compound of the present invention has good pharmacokinetics and efficacy.
  • Trifluoroacetic acid (1 mL) was added to a solution (5 mL) of compound I-1-4 (110 mg, 210 ⁇ mol, 1 eq) in dichloromethane, and the mixture was stirred at room temperature for 5 hours. When the reaction is complete, the reaction solution is directly concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by pre-HPLC (FA) to obtain light yellow solid I-1 (25 mg).
  • Trifluoroacetic acid (1 mL) was added to a solution (5 mL) of compound I-2-1 (30 mg, 54 ⁇ mol, 1 eq) in dichloromethane, and the mixture was stirred at room temperature for 5 hours. When the reaction is complete, the reaction solution is directly concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by pre-HPLC (HCl) to obtain light yellow solid I-2 (10 mg).
  • Trifluoroacetic acid (1 mL) was added to a solution (5 mL) of compound I-3-1 (30 mg, 57 ⁇ mol, 1 eq) in dichloromethane, and the mixture was stirred at room temperature for 5 hours. When the reaction is complete, the reaction solution is directly concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by pre-HPLC (FA) to obtain light yellow solid I-3 (15 mg).
  • Trifluoroacetic acid (1 mL) was added to a solution (5 mL) of compound I-4-2 (30 mg, 57 ⁇ mol, 1 eq) in dichloromethane, and the mixture was stirred at room temperature for 5 hours. When the reaction is complete, the reaction solution is directly concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by pre-HPLC (FA) to obtain light yellow solid I-4 (12 mg).
  • Trifluoroacetic acid (0.3 mL) was added to a solution (3 mL) of compound I-5-2 (80 mg, 57 ⁇ mol, 1 eq) in dichloromethane, and the mixture was stirred at room temperature for 3 hours. When the reaction is complete, the reaction solution is directly concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by pre-HPLC (FA) to obtain light yellow solid I-5 (30 mg).
  • Trifluoroacetic acid (0.1 mL) was added to a solution (1 mL) of compound I-6-6 (30 mg, 51 ⁇ mol, 1 eq) in dichloromethane, and the mixture was stirred at room temperature for 5 hours. When the reaction is complete, the reaction solution is directly concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by pre-HPLC (HCl) to obtain light yellow solid I-6 (11 mg). LCMS(M+H):483.
  • Trifluoroacetic acid (0.1 mL) was added to a solution (1 mL) of compound I-7-8 (20 mg, 36 ⁇ mol, 1 eq) in dichloromethane, and the mixture was stirred at room temperature for 5 hours.
  • the reaction is complete, add 10 mL of methylene chloride to the reaction solution, wash with 10 mL of saturated sodium bicarbonate solution, and concentrate the organic phase under reduced pressure to obtain a crude product.
  • the crude product was separated and purified by pre-HPLC (HCl) to obtain light yellow solid I-7 (9 mg).
  • Compound I-35 was synthesized by referring to the synthetic route of compound I-1 in Example 1. Compound 4-fluoro-6-bromoindole was replaced with 6-bromoindole as the starting material. The obtained compound I-35 was a light yellow solid. (11 mg), LCMS (M+H): 444.
  • Compound I-36 was synthesized by referring to the synthetic route of compound I-1 in Example 1, replacing (S)-3-aminopiperidine-1-carboxylic compound with trans-(4-aminocyclohexyl)carbamic acid tert-butyl ester. Acid tert-butyl ester, the obtained compound I-36 was a light yellow solid (12 mg), LCMS (M+H): 440.
  • Compound I-37 was synthesized by referring to the synthetic route of compound I-1 in Example 1, except that (S)-3 was replaced with compound 3-(aminomethyl)-3-methyl-1-azetidinecarboxylic acid tert-butyl ester. -Aminopiperidine-1-carboxylic acid tert-butyl ester, the obtained compound I-37 was a light yellow solid (12 mg), LCMS (M+H): 426.
  • Compound I-38 was synthesized by referring to the synthetic route of compound I-1 in Example 1, except that compound (R)-2-aminomethyl-1-N-Boc-pyrrolidine was replaced with (S)-3-aminopiperidine- 1-tert-butylcarboxylate, the obtained compound 1-38 was a light yellow solid (8 mg), LCMS (M+H): 426.
  • Compound I-40 was synthesized by referring to the synthetic route of compound I-1 in Example 1, except that compound 3-(aminomethyl)-3-fluoro-1-azetidinecarboxylic acid tert-butyl ester was replaced with (S)-3- Aminopiperidine-1-carboxylic acid tert-butyl ester, the obtained compound I-40 was a light yellow solid (7 mg), LCMS (M+H): 430.
  • Compound I-41 was synthesized by referring to the synthetic route of compound I-1 in Example 1, except that compound 1-tert-butoxycarbonyl-3-(aminomethyl)pyrrolidine was replaced with (S)-3-aminopiperidine-1- Tert-butyl carboxylate, the obtained compound I-41 was a light yellow solid (11 mg), LCMS (M+H): 426.
  • Compound I-42 was synthesized by referring to the synthetic route of compound I-1 in Example 1, replacing (S)-3-aminopiperidine with compound ((1R,3S)-3-aminocyclopentyl)carbamate tert-butyl ester. -1-tert-butylcarboxylate, the obtained compound I-42 was a light yellow solid (13 mg), LCMS (M+H): 426.
  • Compound I-43 was synthesized by referring to the synthetic route of compound I-1 in Example 1, replacing (S)-3-aminopiperidine with compound ((1S,3S)-3-aminocyclopentyl)carbamate tert-butyl ester. -1-tert-butylcarboxylate, the obtained compound I-43 was a light yellow solid (14 mg), LCMS (M+H): 426.
  • reaction solution is cooled to room temperature, added to 20 mL of water, and then extracted with ethyl acetate (15 mL*3), combined the organic phases, washed with 20 mL saturated brine, and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain yellow oil II-30-1 (90 mg).
  • Compound I-44 was synthesized by referring to the synthetic route of compound I-7 in Example 1, replacing (S)-3-aminopiperidine-1 with compound (1S,3S)-3-aminocyclopentylcarbamate tert-butyl ester. -tert-butyl carboxylate, the obtained compound I-44 was a light yellow solid (10 mg), LCMS (M+H): 451.2.
  • Compound I-45 was synthesized by referring to the synthetic route of compound I-7 in Example 1, except that compound 5-amino-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester was replaced with (S)-3-aminopiperidine. -1-tert-butylcarboxylate, the obtained compound I-45 was a light yellow solid (9 mg), LCMS (M+H): 487.3.
  • Compound I-46 was synthesized by referring to the synthetic route of compound I-7 in Example 1, replacing (S)-3- with compound (3S,5S)-3-amino-5-fluoroperidine-1-carboxylic acid tert-butyl ester. Aminopiperidine-1-carboxylic acid tert-butyl ester, the obtained compound I-46 was a light yellow solid (13 mg), LCMS (M+H): 469.2.
  • compound I-47 was based on the synthetic route of compound I-7 in Example 1, except that compound (3S,5S)-3-amino-5-methylpiperidine-1-carboxylic acid tert-butyl ester was replaced with (S)-3. -Aminopiperidine-1-carboxylic acid tert-butyl ester, the obtained compound I-47 was a light yellow solid (11 mg), LCMS (M+H): 465.2.
  • Trifluoroacetic acid (0.2 mL) was added to a solution (2 mL) of compound I-1-3 (20 mg, 39 ⁇ mol, 1 eq) in dichloromethane, and the mixture was stirred at room temperature for 10 hours. When the reaction is complete, the reaction solution is directly concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by pre-HPLC (HCl) to obtain light yellow solid I-8 (10 mg). LCMS(M+H):428.
  • Test Example 1 Biochemical test of compounds inhibiting CDK7/cyclinH/MANT1 kinase protein activity
  • CDK7/cyclinH/MNAT1 kinase protein complex and its substrate peptide CDK7/9tide in 50mM HEPES Prepare a 2X solution in a buffer system consisting of pH 7.5, 0.01% BRIJ-35, 10mM MgCl 2 and 1mM EGTA.
  • Detection mixture is prepared from EDTA (30mM), Eu-anti-ADP antibody (6nM) and ADP tracer in TR-FRET dilution buffer.
  • the 10uL enzyme reaction system contains 20ng CDK7/cyclinH/MNAT1 kinase protein complex, 200uM substrate peptide CDK7/9tide and 150uM ATP.
  • the compound to be tested was diluted 3 times downward starting from the highest concentration of 10uM, for a total of 11 concentration points. Set up 2 multiple holes. Calculate the inhibition rate of each well based on the fluorescence reading, draw a dose-dependent curve, and calculate the half inhibitory concentration IC 50 of the tested compound. The results are shown in Table 1 below:
  • Test Example 2 Biochemical test of compounds inhibiting CDK2/cyclinE kinase protein activity
  • GST-tagged CDK2/cyclinE kinase protein complex and Eu-anti-GST were prepared into a 2X solution in a buffer system consisting of 50mM HEPES pH 7.5, 0.01% BRIJ-35, 10mM MgCl 2 and 1mM EGTA.
  • AlexaFluor-labeled Tracer is prepared as a 2X solution in Kinase buffer.
  • the final incubation system contained 2.5nM CDK2/cyclinE kinase protein complex, 2nM Eu-anti-GST and 100nM AlexaFluor-labeled Tracer.
  • the compound to be tested was diluted 3 times downward starting from the highest concentration of 10uM, for a total of 11 concentration points. Set up 2 multiple holes. Calculate the inhibition rate of each well based on the fluorescence reading, draw a dose-dependent curve, and calculate the half inhibitory concentration IC 50 of the tested compound. The results are as follows in Table 3:
  • Test Example 3 Test of anti-proliferative activity of compounds on triple-negative breast cancer cell line MDA-MB-453
  • MDA-MB-453 cells were seeded in a 96-well culture plate at a density of 4000 cells/well: the outer circle of cells was filled with 200uL PBS to prevent the rapid evaporation of the edge medium from causing excessive differences in the culture conditions of the inner plate wells.
  • the leftmost column of the 60 internal wells is a blank well, which is filled with an equal volume of PBS without adding cells.
  • the remaining 54 wells are plated with cells using a row gun. Each well is 100 uL and placed in a carbon dioxide incubator for 24 hours at 37°C. Use complete culture medium to dilute the compound stock solution, and add 50uL of drug solution of corresponding concentration to each well, with a final concentration of up to 10uM.
  • Test Example 4 Test of anti-proliferative activity of compounds on ovarian cancer cell line OVCAR3
  • OVCAR3 cells were seeded in a 96-well culture plate at a density of 2000 cells/well: the outer circle of cells was filled with 200uL PBS to prevent the rapid evaporation of the edge medium from causing excessive differences in the culture conditions of the inner plate wells.
  • the leftmost column of the 60 internal wells is a blank well, which is filled with an equal volume of PBS without adding cells.
  • the remaining 54 wells are plated with cells using a row gun. Each well is 100 uL and placed in a carbon dioxide incubator for 24 hours at 37°C. Use complete culture medium to dilute the compound stock solution, add 50uL of drug solution of corresponding concentration to each well, the final concentration is up to 10uM, and dilute 3 times downwards.
  • liver microsomes used in the experiment.
  • composition of the experimental incubation system is the composition of the experimental incubation system:
  • liver microsomes Take out the liver microsomes from the -80°C refrigerator, place them in a 37°C water bath constant-temperature oscillator to pre-incubate for 3 minutes, thaw and set aside for use.
  • Control group (without ⁇ -NADPH): Take 30 ⁇ L of the NCF control group as the 0min sample, add 180 ⁇ L of precipitant containing internal standard, and then add 30 ⁇ L of NADPH to obtain the 0min sample; add 30 ⁇ L of magnesium chloride to the remaining NCF group, incubate for 60 minutes, and then add 180 ⁇ L contains internal standard precipitating agent.
  • Sample group Take 30 ⁇ L of the sample group as the 0min sample, add 180 ⁇ L of precipitant containing internal standard, and then add 30 ⁇ L of NADPH to obtain the 0min sample; add 30 ⁇ L of NADPH to each tube of the remaining sample group, incubate for 5, 15, 30, and 60 min, then add 180 ⁇ L Contains internal standard precipitant.
  • Positive control group Take the PB solution, add the calculated liver microsomes of the corresponding species, then add the positive control working solution, vortex to mix, and divide into tubes. Add NADPH solution for incubation, and add 180 ⁇ L of precipitating agent at 5 and 15 min. Divide into two other tubes, first add the internal standard precipitant, and then add NADPH to obtain the 0min sample.
  • Test Example 6 Selectivity test of compounds inhibiting the activity of CDK family kinase proteins
  • I-7 has good selectivity for inhibiting CDK7; II-3 also has good inhibitory activity against CDK7, but it also inhibits multiple other CDK family kinase members, including CDK12, CDK13, CDK9, and CDK18. .
  • Animal dietary status The animals are not fasting before administration and can drink water freely.
  • Compound preparation method 0.5% CMC-Na was used for intragastric administration (G1 group), and 5% DMSO+30% PEG400+65% water for injection was used for intravenous injection (G2 group).
  • G1 group sampling time points 10min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after administration, a total of 8 points.
  • G2 group sampling time points 5min, 10min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after administration, a total of 9 points.
  • Sample collection On the day of the experiment, collect approximately 0.1 mL of whole blood samples at each set time point and place them in EDTA-K2 anticoagulant tubes.
  • Sample processing Within 30 minutes after collection, whole blood samples were centrifuged for 5 minutes at 4°C and 12,000 rpm, and the plasma was separated. The upper plasma samples were collected into sample tubes. The plasma samples were frozen and stored in a -10 ⁇ -30°C refrigerator within 30 minutes. And transfer to -60 ⁇ -90°C refrigerator within 24 hours.
  • IV* refers to the intravenous route
  • PO* refers to the intragastric route
  • Test Example 8 Anti-tumor efficacy test of the compound on the nude mouse transplanted tumor model of the triple-negative breast cancer cell line MDA-MB-231
  • a transplanted tumor model of the human triple-negative breast cancer cell line MDA-MB-231 was constructed on nude mice to evaluate the anti-tumor efficacy of compound I-46.
  • the specific steps are as follows:
  • MDA-MB-231 cells were cultured in DMEM culture medium containing 10% fetal bovine serum at 37°C and 5% CO2 in a cell culture incubator. After the cells were full grown, they were divided into bottles and passaged every 2 to 3 days. Tumor cells in the logarithmic growth phase are used for in vivo tumor seeding.

Abstract

La présente invention concerne un composé à petites molécules ayant une structure pyrimidothiophène, et son utilisation. Par inhibition de l'activité de la famille des kinases dépendantes des cyclines (CDK), le composé à petites molécules peut bloquer le processus de cycle cellulaire et empêcher la transcription d'oncogènes, ce qui permet d'inhiber la prolifération des cellules tumorales et d'atteindre l'objectif de traitement de tumeurs.
PCT/CN2023/094038 2022-06-24 2023-05-12 Composé à petites molécules ayant une structure pyrimidothiophène et son utilisation WO2023246371A1 (fr)

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