CN114907407A - Inhibitors of cyclin dependent kinase 7(CDK7) - Google Patents

Abstract

The invention provides CDK7 inhibitor compounds, in particular to a compound shown in a formula I or pharmaceutically acceptable salts thereof,

Description

Inhibitors of cyclin dependent kinase 7(CDK7)

The present invention claims priority from a prior application entitled "inhibitors of cyclin dependent kinase 7(CDK 7)" filed on 10/2/2021 with the chinese intellectual property office under patent application No. 202110187112.2. The entire contents of the above-mentioned prior application are incorporated herein by reference.

Technical Field

The invention belongs to the technical field of medicines, and relates to a CDK7 inhibitor compound or an optical isomer and a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same and application of the CDK7 inhibitor compound or the optical isomer and the pharmaceutically acceptable salt thereof as CDK7 inhibitors.

Background

Cyclin-dependent kinases (CDKs) are a group of serine/threonine protein kinases, CDKs drive the cell cycle through chemical action on serine/threonine proteins, and are important factors in cell cycle regulation in synergistic interaction with cyclins.

CDK7 is an important member of the CDKs family, and CDK7 exists as a heterotrimeric complex in the cytosol and is thought to function as a CDK 1/2-activated kinase (CAK), whereby phosphorylation of conserved residues in CDK1/2 by CDK7 is essential for full catalytic CDK activity and cell cycle progression. In the nucleus, CDK7 forms the kinase core of the RNA polymerase (RNAP) II general transcription factor complex and is responsible for phosphorylating the C-terminal domain (CTD) of RNAP II, a necessary step for gene transcription initiation. Because CDK7 has the dual functions of CAK and CTD phosphorylation, it plays important roles in cell proliferation, cell cycle and transcription.

According to the existing research, CDK7 has abnormal activity in various tumors such as liver cancer, cervical cancer, cholangiocarcinoma, ovarian cancer, pancreatic cancer, lung squamous cell carcinoma, gastric cancer, glioblastoma and the like, and the inhibition of the activity of CDK7 can effectively inhibit the proliferation and metastasis of tumor cells and promote the apoptosis of the tumor cells. More importantly, in some tumors with extremely high genetic complexity such as triple negative breast cancer and adult T-cell leukemia, inhibition of CDK7 activity can significantly induce apoptosis of tumor cells, suggesting a great potential of CDK7 inhibitors in tumor therapy.

Although some CDK7 small molecule inhibitors have been reported in the prior literature for treating cancer (such as patent documents WO2018013867a1, WO202093011a1, WO2019143719a1 and WO2019143730a1), there are still a large number of patients who cannot obtain satisfactory clinical treatment effects, and thus there is still a need for better and more effective clinical treatments and solutions. In view of the above, the invention creatively designs a series of compounds based on the prior art, provides a series of CDK7 inhibitors with novel structure, excellent drug effect, high bioavailability and good drug success, and is used for effectively treating diseases related to CDK7, including but not limited to tumors and the like.

Disclosure of Invention

The invention aims to provide a compound of CDK7 small-molecule inhibitor with high inhibition and high anti-tumor activity on CDK7 and application thereof.

In order to achieve the purpose, the invention adopts the following technical scheme:

a compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

selected from C ═ CH-NH, N-CH ═ CH, or N-CH ═ N;

x is selected from a chemical bond or NH;

R ₁ selected from CN, -O-C ₁ -C ₆ Alkyl, -S (═ O) ₂ -C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl or C ₃ -C ₈ Cycloalkyl radical, said C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^a Substitution; r ^a Selected from halogen, OH, NH ₂ Or C ₁ -C ₃ An alkyl group;

R ₂ selected from 5-10 membered heteroaryl, C ₃ -C ₈ Cycloalkyl or 3-10 membered heterocyclyl, said 5-10 membered heteroaryl, C ₃ -C ₈ Cycloalkyl or 3-10 membered heterocyclyl is optionally substituted by R ^b Substitution; r ^b Selected from halogen, CN, OH, NH ₂ 、-NH(C ₁ -C ₃ Alkyl), -N (C) ₁ -C ₃ Alkyl radical) ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^c Substitution; r ^c Selected from halogen, NH ₂ CN or OH;

R ₃ selected from H, halogen, C ₁ -C ₆ Alkyl, -P (═ O) (C) ₁ -C ₆ Alkyl radical) ₂ or-S (═ O) ₂ -C ₁ -C ₆ An alkyl group;

R ₄ selected from H, CN, halogen or C ₁ -C ₆ An alkyl group;

provided that when R is ₂ Is selected from

When the temperature of the water is higher than the set temperature,

selected from N-CH ═ CH or N-CH ═ N; or when R is ₂ Is selected from

When the temperature of the water is higher than the set temperature,

is selected from C ═ CH-NH and R ₁ Selected from-S (O) ₂ -C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or 5-10 membered heteroaryl, said 5-10 membered heteroaryl being optionally substituted with R ^a Substitution; r ^a Selected from halogen, OH, NH ₂ Or C ₁ -C ₃ An alkyl group.

In some embodiments of the present invention, the substrate is,

selected from C ═ CH-NH.

In some embodiments, R ₁ Selected from CN, -S (═ O) ₂ -C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl, said 5-10 membered heteroaryl or 3-10 membered heterocyclyl being optionally substituted with R ^a And (4) substitution.

In some embodiments, R ₁ Is selected from-S (═ O) ₂ -C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or 5-10 membered heteroaryl, said 5-10 membered heteroaryl being optionally substituted with R ^a And (4) substitution.

In some embodiments, R ₁ Is selected from-S (═ O) ₂ -C ₁ -C ₆ Alkyl or 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with R ^a And (4) substitution.

In some embodiments, R ₁ Is selected from-S (═ O) ₂ -C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Haloalkyl or pyrazolyl, said pyrazolyl orGround selecting quilt R ^a And (4) substitution.

In some embodiments, R ₁ Is selected from-S (═ O) ₂ -CH ₃ 、CF ₃ 、

In some embodiments, R ^a Selected from halogen or C ₁ -C ₃ An alkyl group.

In some embodiments, R ^a Is selected from C ₁ -C ₃ An alkyl group.

In some embodiments, R ₂ Selected from 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with R ^b Substitution; or

R ₂ Selected from the following groups:

the above-mentioned

Optionally substituted by R ^b And (4) substitution.

In some embodiments, R ₂ Selected from the following groups:

the above-mentioned

Optionally substituted by R ^b And (4) substitution.

In some embodiments, when R ₂ Selected from the group consisting of ^b SubstitutionIs/are as follows

When the temperature of the water is higher than the set temperature,

selected from N-CH ═ CH or N-CH ═ N; or when R is ₂ Selected from the group consisting of ^b Substituted by

When the temperature of the water is higher than the set temperature,

is selected from C ═ CH-NH and R ₁ Selected from-S (O) ₂ -C ₁ -C ₆ Alkyl or 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with R ^a Substitution; r ^a Selected from halogen, OH, NH ₂ Or C ₁ -C ₃ Alkyl radical

In some embodiments, when R ₂ Selected from the group consisting of ^b Substituted by

When the temperature of the water is higher than the set temperature,

selected from C ═ CH-NH and R ₁ Selected from 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with R ^a Substitution; r ^a Selected from halogen, OH, NH ₂ Or C ₁ -C ₃ An alkyl group.

In some embodiments, R ₂ Selected from 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with R ^b And (4) substitution.

In some embodiments, R ₂ Selected from pyrazolyl, furyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl or pyrazinyl, optionally substituted by R ^b And (4) substitution.

In some embodiments, R ₂ Selected from pyridyl or pyrazolyl groupsOptionally substituted by R ^b And (4) substitution.

In some embodiments, the R is ^b Selected from halogen, CN, OH, NH ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^c And (4) substitution.

In some embodiments, the R is ^b Selected from halogen, CN, OH, NH ₂ 、C ₁ -C ₆ Alkyl radical, said C ₁ -C ₆ Alkyl is optionally substituted by R ^c And (4) substitution.

In some embodiments, the R is ^b Is selected from NH ₂ Or C ₁ -C ₆ Alkyl radical, said C ₁ -C ₆ Alkyl is optionally substituted by R ^c And (4) substitution.

In some embodiments, the R is ^b Is selected from C ₁ -C ₆ Alkyl radical, said C ₁ -C ₆ Alkyl is optionally substituted by R ^c And (4) substitution.

In some embodiments, the R is ^c Selected from halogen or OH.

In some embodiments, R ₂ Selected from the following groups:

R ^d selected from H, halogen, CN, OH, NH ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^f Substitution; r ^f Selected from halogen, NH ₂ CN or OH.

In some embodiments, R ₂ Selected from the following groups:

R ^d selected from H, halogen, CN, OH, NH ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^f Substitution; r is ^f Selected from halogen, NH ₂ CN or OH.

In some embodiments, R ₂ Selected from the following groups:

R ^d selected from H, halogen, CN, OH, NH ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^f Substitution; r ^f Selected from halogen, NH ₂ CN or OH.

In some embodiments, the R is ^d Selected from H, NH ₂ 、C ₁ -C ₆ Alkyl radical, said C ₁ -C ₆ Alkyl is optionally substituted by R ^f And (4) substitution.

In some embodiments, the R is ^f Selected from halogen or OH.

In some embodiments, R ₂ Selected from the following groups:

in some embodiments, when R ₂ Is selected from

When the temperature of the water is higher than the set temperature,

selected from N-CH ═ CH or N-CH ═ N; or when R is ₂ Is selected from

When the temperature of the water is higher than the set temperature,

is selected from C ═ CH-NH and R ₁ Selected from-S (O) ₂ -C ₁ -C ₆ Alkyl or 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with R ^a Substitution; r ^a Selected from halogen, OH, NH ₂ Or C ₁ -C ₃ An alkyl group.

In some embodiments, R ₃ Is selected from H or-P (═ O) (C) ₁ -C ₆ Alkyl radical) ₂ 。

In some embodiments, R ₃ Is selected from H or-P (═ O) (C) ₁ -C ₃ Alkyl radical) ₂ 。

In some embodiments, R ₄ Selected from H or CN.

In some embodiments, R ₄ Is selected from CN.

In some embodiments, the compound of formula (I) is selected from a compound of formula (II) or a pharmaceutically acceptable salt thereof,

wherein R is ₁ 、R ₃ 、R ₄ X is as defined above;

R ₂ selected from 5-10 membered heteroaryl, optionally substituted with R ^b Substitution; r ^b Selected from halogen, CN, OH, NH ₂ 、-NH(C ₁ -C ₃ Alkyl), -N (C) ₁ -C ₃ Alkyl radical) ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substitutedBy R ^c Substitution; r ^c Selected from halogen, NH ₂ CN or OH;

or R ₂ Selected from the following groups:

R ^d selected from H, halogen, CN, OH, NH ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^f Substitution; r ^f Selected from halogen, NH ₂ CN or OH.

In some embodiments, R ₂ Selected from pyridyl or pyrazolyl optionally substituted by R ^b And (4) substitution.

In some embodiments, the R is ^b Selected from halogen, CN, OH, NH ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^c And (4) substitution.

In some embodiments, the R is ^b Selected from halogen, CN, OH, NH ₂ 、C ₁ -C ₆ Alkyl radical, said C ₁ -C ₆ Alkyl is optionally substituted by R ^c And (4) substitution.

In some embodiments, the R is ^b Is selected from C ₁ -C ₆ Alkyl radical, said C ₁ -C ₆ Alkyl is optionally substituted by R ^c And (4) substitution.

In some embodiments, the compound of formula (I) is selected from a compound of formula (III) or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,R ₁ 、R ₃ 、R ₄ x is as defined above;

R ₂ selected from 5-10 membered heteroaryl, C ₃ -C ₈ Cycloalkyl or 3-10 membered heterocyclyl, said 5-10 membered heteroaryl, C ₃ -C ₈ Cycloalkyl or 3-10 membered heterocyclyl is optionally substituted by R ^b Substitution; r ^b Selected from halogen, CN, OH, NH ₂ 、-NH(C ₁ -C ₃ Alkyl), -N (C) ₁ -C ₃ Alkyl radical) ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^c Substitution; r ^c Selected from halogen, NH ₂ CN or OH, but R ₂ The following groups are excluded:

in some embodiments, R ₂ Selected from 3-10 membered heterocyclyl, said 3-10 membered heterocyclyl being optionally substituted with R ^b And (4) substitution.

In some embodiments, R ₂ Selected from 6-10 membered heterocyclyl, said 6-10 membered heterocyclyl being optionally substituted with R ^b And (4) substitution.

In some embodiments, R ^b Selected from halogen, CN, OH, NH ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^c And (4) substitution.

In some embodiments, the R is ^b Selected from halogen, CN, OH, NH ₂ 、C ₁ -C ₆ Alkyl radical, said C ₁ -C ₆ Alkyl is optionally substituted by R ^c And (4) substitution.

In some embodiments, the R is ^b Is selected from C ₁ -C ₆ Alkyl radical, said C ₁ -C ₆ Alkyl is optionally substituted by R ^c And (4) substitution.

In some embodiments, X is selected from NH.

In some embodiments, the compound of formula (I) is selected from a compound of formula (IV) or a pharmaceutically acceptable salt thereof,

wherein R is ₄ Selected from CN, halogen or C ₁ -C ₆ An alkyl group; r ₁ 、R ₂ 、R ₃ And X is as defined above.

In some embodiments, X is selected from NH.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of a compound of formula (I), or a pharmaceutically acceptable salt thereof,

further, the invention also provides a pharmaceutical composition, which comprises the compound shown in the formula (I) or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.

Further, the invention relates to an application of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof in preparing a medicament for preventing or treating diseases related to CDK 7.

Further, the invention relates to a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and application of the compound in preventing or treating CDK7 related diseases.

Further, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of a CDK7 related disorder.

The present invention also relates to a method of treating a disease associated with CDK7, comprising administering to a subject a therapeutically effective amount of a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein.

Further, the diseases related to CDK7 described in the present invention include, but are not limited to, proliferative diseases, inflammatory diseases, autoimmune diseases.

Further, the proliferative disease is selected from cancer.

Definition and description of terms

Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present invention, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present invention as defined in the specification.

The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of the compounds described herein with non-toxic acids or bases, including salts of the compounds described herein with inorganic acids and bases, organic acids and bases.

The compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, enantiomers, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.

The enantiomers or enantiomerically pure compounds herein are illustrated by Maehr, J.chem.Ed.1985, 62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by wedge bonds and dashed bonds. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E, Z geometric isomer unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

The term "stereoisomer" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformers.

The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates; whereas in phenol the enol type predominates. The present invention encompasses all tautomeric forms of the compounds.

The term "pharmaceutical composition" denotes a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., ═ O), meaning that two hydrogen atoms are substituted, oxo does not occur on the aryl.

The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl is "optionally" substituted with halo, meaning that ethyl may be unsubstituted (CH) ₂ CH ₃ ) Monosubstituted (e.g. CH) ₂ CH ₂ F) To get moreOf generation (e.g. CHFCH) ₂ F、CH ₂ CHF ₂ Etc.) or completely substituted (CF) ₂ CF ₃ ). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.

The term "C ₁ -C ₁₀ Alkyl "is understood to mean a straight-chain or branched, saturated monovalent hydrocarbon radical having 1,2, 3, 4,5, 6,7,8, 9 or 10 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 2-dimethylbutyl, or the like. The term "C ₁ -C ₆ Alkyl "is understood to mean a straight-chain or branched, saturated monovalent hydrocarbon radical having 1,2, 3, 4,5, 6 carbon atoms. The term "C ₁ -C ₃ Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1,2, 3 carbon atoms.

The term "halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

The term "C ₆ -C ₁₀ Aryl "is to be understood as meaning a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partially aromatic character of 6,7,8, 9, 10 carbon atoms, in particular a ring having 6 carbon atoms (" C ₆ Aryl "), such as phenyl; or a ring having 9 carbon atoms ("C) ₉ Aryl group), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C) ₁₀ Aryl), such as tetralinyl, dihydronaphthyl, or naphthyl.

The term "C ₃ -C ₈ Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 8 carbon atoms. Examples of cycloalkyl radicals are cyclopropyl, cycloButyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or a bicyclic hydrocarbon group such as a decaline ring. According to the invention, the bicyclic hydrocarbon ring comprises a bridged, spiro or fused ring structure.

The term "3-to 10-membered heterocyclyl" is to be understood as a saturated or partially unsaturated monovalent monocyclic or bicyclic ring having 3 to 10 ring atoms, which contains 1 to 5, preferably 1 to 3 heteroatoms selected from N, O and S. The bicyclic hydrocarbon ring includes a bridged ring, a spiro ring or a fused ring structure. 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a partially saturated 6-membered ring such as tetrahydropyridinyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclyl group may be bicyclic, for example but not limited to a 5,5 membered ring, such as hexahydrocyclopenta [ c ]]Pyrrole-2 (1H) -cyclic rings, or 5,6 membered bicyclic rings, e.g. hexahydropyrrolo [1,2-a ]]Pyrazin-2 (1H) -yl or

The ring containing the nitrogen atom may be partially unsaturated, i.e. it may contain one or more double bonds, such as, but not limited to, pyrazolyl, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3, 4 [ ]]Thiadiazinyl, 4, 5-dihydrooxazolyl or 4H- [1,4 [ ]]A thiazinyl group; alternatively, it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl.

The term "5-to 10-membered heteroaryl" is to be understood as including such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems, in particular 5 or 6 or 9 or 10 ring atoms, and which contain 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in addition, may be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.

The term "treating" means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease condition, but has not yet been diagnosed as having the disease condition;

(ii) inhibiting the disease or disease state, i.e., arresting its development;

(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition.

The term "therapeutically effective amount" means an amount of a compound of the invention that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and disclosure of the invention.

The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of classes of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients enhance the handling characteristics of the pharmaceutical formulation, i.e., make the formulation more amenable to direct compression by increasing flowability and/or cohesiveness. Examples of typical "pharmaceutically acceptable carriers" suitable for use in the above formulations are: saccharides, starches, cellulose and its derivatives and the like which are commonly used as excipients in pharmaceutical preparations.

The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

The words "comprise", "comprises", "comprising" or "includes" and variations thereof such as "comprises" or "comprising" are to be understood in an open, non-exclusive sense, that is, to mean "including but not limited to".

The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like. In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated as tablets, pills, dragees, capsules, gels, slurries, suspensions and the like, for oral administration to a patient.

Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

In all methods of administration of the compounds described herein, the dose administered per day is from 0.01mg/kg body weight to 200mg/kg body weight.

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.

The chemical reactions of the embodiments of the present invention are carried out in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.

Detailed Description

The following examples illustrate the technical solutions of the present invention in detail, but the scope of the present invention includes but is not limited thereto.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). NMR shift in units of 10 ^-6 (ppm). Solvents for NMR measurement were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and an internal standard was Tetramethylsilane (TMS). ' IC ₅₀ "half inhibitory concentration" means the concentration at which half of the maximum inhibitory effect is achieved.

The acronyms are:

DCM: dichloromethane; mCPBA: m-chloroperoxybenzoic acid; DCE: ethylene dichloride; DIPEA and DIEA: n, N-diisopropylethylamine; NMP: n-methyl pyrrolidone; pd (OAc) ₂ : palladium acetate; xantphos: 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene; DMF: n, N-dimethylformamide; a dioxane: dioxane; (Boc) ₂ O: di-tert-butyl dicarbonate; et (Et) ₃ N and TEA: triethylamine; DMAP: 4-dimethylaminopyridine; ACN: acetonitrile; and (3) DBU: 1, 8-diazabicyclo [5.4.0]]Undec-7-ene; pd (dppf) Cl ₂ : [1,1' -bis (diphenylphosphino) ferrocene]Dichloro (phenyl) methanePalladium melting; THF: tetrahydrofuran; pd ₂ (dba) ₃ : tris (benzylidene acetone) dipalladium; XPhos: 2-dicyclohexylphosphonium-2 ',4',6' -triisopropylbiphenyl.

Example 1: (S) -7- (dimethylphosphoryl) -3- (2- ((6, 6-dimethylpiperidin-3-yl) amino) -5- (methylsulfonyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Step 1: 2, 4-dichloro-5- (methylsulfonyl) pyrimidine

2, 4-dichloro-5- (methylthio) pyrimidine (388mg,2mmol) was added to 5mL of dichloromethane, cooled to 0 ℃ in ice bath, m-chloroperoxybenzoic acid (865mg,5mmol) was slowly added thereto, and after the completion of the charge, the mixture was allowed to move to room temperature for reaction for 2 hours. After the reaction is finished, the title compound is obtained by column chromatography separation and purification.

Step 2: 7-bromo-3- (2-chloro-5- (methylsulfonyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

2, 4-dichloro-5- (methylsulfonyl) pyrimidine (230mg,1.02mmol) was dissolved in 5mL of dichloroethane, to which was added aluminum trichloride (340mg,5.1mmol), and stirred at 80 ℃ for half an hour. The reaction mixture was then cooled to room temperature, and 7-bromo-1H-indole-6-carbonitrile (112mg,0.51mmol) was added thereto, followed by further reaction at 80 ℃ for 12 hours. And after the reaction is finished, adding ice water for quenching, extracting by ethyl acetate, combining organic phases, drying by anhydrous sodium sulfate, filtering, concentrating, and separating and purifying the obtained residue by column chromatography to obtain the title compound.

And step 3: (S) -7-bromo-3- (2- (((6, 6-dimethylpiperidin-3-yl) amino) -5- (methylsulfonyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

7-bromo-3- (2-chloro-5- (methylsulfonyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (64mg,0.16mmol), (S) -6, 6-dimethylpiperidin-3-amine (31mg,0.24mmol), N, N-diisopropylethylamine (62mg,0.48mmol) was dissolved in 2mL of N-methylpyrrolidone and reacted at 130 ℃ for 1 hour. After the reaction is finished, water is added for quenching, ethyl acetate is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, filtration and concentration are carried out, and the obtained residue is separated and purified through column chromatography to obtain the title compound.

And 4, step 4: (S) -7- (dimethylphosphoryl) -3- (2- ((6, 6-dimethylpiperidin-3-yl) amino) -5- (methylsulfonyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

(S) -7-bromo-3- (2- (((6, 6-dimethylpiperidin-3-yl) amino) -5- (methylsulfonyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (30mg,0.06mmol), dimethylphosphine oxide (6mg,0.07mmol), palladium acetate (1.4mg,0.006mmol), potassium phosphate (19mg,0.09mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (3.5mg,0.006mmol) were dissolved in 1.5mL of N, N-dimethylformamide under an argon atmosphere at 150 ℃ for 2 hours.

DMSO-d6δ _H 12.15(s,1H),8.79-8.71(m,1.5H),8.68-8.62(m,1H),8.46-8.40(m,0.5H),8.07(s,1H),7.73-7.65(m,1H),3.92-3.77(m,1H),2.99(d,J＝6.1Hz,3H),2.92-2.85(m,1H),2.72-2.63(m,1H),2.05(s,3H),2.02(s,3H),1.87-1.75(m,1H),1.74-1.62(m,1H),1.56-1.46(m,1H),1.39-1.25(m,1H),1.10-1.02(m,6H).

LC/MS(m/z,MH ⁺ ):501.1

EXAMPLE 2 (S) -1- (2- (((6, 6-dimethylpiperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-5-carbonitrile

Step 1: 1- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-5-carbonitrile

2, 4-dichloro-5- (trifluoromethyl) pyrimidine (216mg,1mmol) was dissolved in 1.5mL of N, N-dimethylformamide, cooled on ice, followed by dissolving 5-cyanoindole (142mg,1mmol) in 1.5mL of N, N-dimethylformamide, cooled to 0 ℃ on ice, to which sodium hydride (36mg,1.2mmol) was slowly added, and the resulting solution was added dropwise to a solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine in N, N-dimethylformamide, and the dropwise addition was terminated at room temperature for 1 hour. After the reaction is finished, water is added for quenching, ethyl acetate is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, filtration and concentration are carried out, and the obtained residue is separated and purified through column chromatography to obtain the title compound.

Step 2: (S) -1- (2- (((6, 6-dimethylpiperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-5-carbonitrile

1- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-5-carbonitrile (85mg,0.264mmol), (S) -6, 6-dimethylpiperidin-3-amine (51mg,0.396mmol), N, N-diisopropylethylamine (102mg,0.792mmol) was dissolved in 2mL of N-methylpyrrolidone and reacted at 130 ℃ for 1 hour. After the reaction is finished, water is added for quenching, ethyl acetate is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, filtration and concentration are carried out, and the obtained residue is separated and purified through column chromatography to obtain the title compound.

DMSO-d6δ _H 8.86-8.80(m,1H),8.58(s,1H),8.45-8.41(m,1H),8.25-8.19(m,1H),7.78-7.71(m,1H),6.97-6.91(m,1H),4.32-4.24(m,1H),2.98-2.90(m,1H),2.87-2.78(m,1H),2.04-1.95(m,1H),1.95-1.87(m,1H),1.86-1.75(m,1H),1.56-1.45(m,1H),1.45-1.35(m,1H),1.13(s,3H),1.11(s,3H).

LC/MS(m/z,MH ⁺ ):415.1

EXAMPLE 3 (S) -3- (2- (((5-azaspiro [2.4] heptyl-7-yl ] amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile

Step 1: (S) -5-benzyl-5-azaspiro [2.4] heptane-7 amine hydrochloride

Tert-butyl (S) - (5-benzyl-5-azaspiro [2.4] heptan-7-yl) carbamate (160mg,0.53mmol) was added to 1mL of dichloromethane, and 2mL of 1, 4-dioxane was further added thereto, and the reaction was carried out at room temperature for 2 hours. After the reaction, the reaction solution was spin-dried and directly used in the next step.

Step 2: (S) -3- (2- (((5-benzyl-5-azaspiro [2.4] heptan-7-yl ] amino ] -5- (trifluoromethyl) pyrimidin-4-yl) -7-bromo-1H-indole-6-carbonitrile

(S) -5-benzyl-5-azaspiro [2.4] heptane-7 amine hydrochloride (91mg,0.45mmol), 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (120mg,0.3mmol), N, N-diisopropylethylamine (116mg,0.9mmol) were dissolved in 2mL of N-methylpyrrolidone and reacted at 130 ℃ for 1 hour. After the reaction is finished, water is added for quenching, ethyl acetate is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, filtration and concentration are carried out, and the obtained residue is separated and purified through column chromatography to obtain the title compound.

And step 3: (S) -3- (2- (((5-benzyl-5-azaspiro [2.4] heptan-7-yl ] amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile

(S) -3- (2- (((5-benzyl-5-azaspiro [2.4] heptan-7-yl ] amino ] -5- (trifluoromethyl) pyrimidin-4-yl) -7-bromo-1H-indole-6-carbonitrile (98mg,0.17mmol), dimethyl phosphine oxide (15mg,0.19mmol), palladium acetate (4mg,0.017mmol), potassium phosphate (54mg,0.26mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (10mg,0.017mmol) were dissolved in 1.5mL of N, N-dimethylformamide and reacted at 150 ℃ under argon atmosphere for 2 hours.

And 4, step 4: (S) -3- (2- (((5-azaspiro [2.4] heptan-7-yl ] amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile

(S) -3- (2- (((5-benzyl-5-azaspiro [2.4] heptan-7-yl ] amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (47mg,0.083mmol), di-tert-butyl dicarbonate (20mg,0.09mmol), palladium on carbon (4.7mg) was placed in 2mL of methanol, replacing gas with hydrogen for three times, reacting at room temperature for 12 hours, carrying out suction filtration after the reaction is finished, carrying out spin drying on the filtrate, dissolving the residue obtained by spin drying in 1mL of dichloromethane, then adding 1mL of trifluoroacetic acid into the dichloromethane, reacting at room temperature for 2 hours, adding a sodium bicarbonate solution into the solution after the reaction is finished, adjusting the solution to be neutral, extracting with ethyl acetate, combining organic phases, and carrying out spin drying to obtain the title compound.

DMSO-d6δ _H 8.80-8.73(m,0.5H),8.63-8.53(m,1H),8.45-8.39(m,0.5H),8.23-8.12(m,1H),8.06-7.94(m,0.5H),7.75-7.64(m,1H),7.25-7.17(m,0.5H),4.29-4.17(m,1H),3.75-3.57(m,1H),3.24-3.17(m,1H),3.04-2.96(m,1H),2.94-2.87(m,1H),2.69-2.56(m,1H),2.05(s,3H),2.02(s,3H),0.76-0.69(m,1H),0.68-0.58(m,1H),0.57-0.43(m,2H).

LC/MS(m/z,MH ⁺ ):475.1

Example 4: 3- (5- (trifluoromethyl) -2- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Step 1: 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

2, 4-dichloro-5- (trifluoromethyl) pyrimidine (2.27g,10.5mmol) was dissolved in 10mL1, 2-dichloroethane, and aluminum trichloride (4.67g,35mmol) was added thereto, and the mixture was stirred at 85 ℃ for one hour, then cooled to room temperature, and 6-cyanoindole (1g,7mmol) was added thereto, and reacted at 85 ℃ for 5 hours. After the reaction is finished, water is added for quenching, ethyl acetate is used for extraction, organic phases are combined and are dried by spinning, dichloromethane is used for washing, and suction filtration is carried out to obtain a filter cake which is the title compound.

Step 2: 3- (5- (trifluoromethyl) -2- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (40mg,0.12mmol), 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride (32mg,0.132mmol), N, N-diisopropylethylamine (32mg,0.24mmol) were dissolved in 2mL of N-methylpyrrolidone and reacted at 130 ℃ for 1 hour. After the reaction is finished, water is added for quenching, ethyl acetate is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, filtration and concentration are carried out, and the obtained residue is separated and purified through column chromatography to obtain the title compound.

DMSO-d6δ _H 8.83(s,1H),8.32-8.27(m,1H),8.12-8.09(m,1H),8.07-8.04(m,1H),7.56-7.51(m,1H),5.31(s,2H),4.44-4.31(m,4H).

LC/MS(m/z,MH ⁺ ):479.1

Example 5: 3- (2- (((1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Step 1: 4-Nitro-1H-pyrazole-1-carboxylic acid tert-butyl ester

4-Nitropyrazole (565mg,5mmol), triethylamine (1.01g,10mmol) and 4-dimethylaminopyridine (73mg,0.6mmol) were dissolved in 5mL of dichloromethane and di-tert-butyl dicarbonate (1.417mg,6.5mmol) was slowly added dropwise under ice-bath. After the addition, the reaction mixture was allowed to cool to room temperature for 2 hours. After the reaction is finished, water is added for quenching, ethyl acetate is used for extraction, organic phases are combined for spin drying, and the title compound is obtained through column chromatography separation and purification.

Step 2: 4-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester

Tert-butyl 4-nitro-1H-pyrazole-1-carboxylate (200mg,0.94mmol) and palladium on carbon (40mg) were placed in 3mL of methanol and reacted under a hydrogen atmosphere for 6 hours. After the reaction is finished, suction filtration is carried out, and filtrate is taken out and dried in a rotary manner to be directly used in the next step.

And step 3: 3- (2- (((1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (80mg,0.25mmol), tert-butyl 4-amino-1H-pyrazole-1-carboxylate (64mg,0.35mmol), N, N-diisopropylethylamine (97mg,0.75mmol) was dissolved in 2mL of N-methylpyrrolidone and reacted at 130 ℃ for 3 hours. After the reaction is finished, water is added for quenching, ethyl acetate is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, filtration and concentration are carried out, and the obtained residue is separated and purified through column chromatography to obtain the title compound.

DMSO-d6δ _H 12.61(s,1H),10.11(s,1H),8.81-8.72(m,1H),8.64-8.56(m,0.5H),8.21-8.02(m,2.5H),7.80(brs,2H),7.56–7.41(m,1H).

LC/MS(m/z,MH ⁺ ):370.1

Example 6: 3- (2- ((((1S, 3R) -3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Step 1: 3- (2- ((((1S, 3R) -3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

(1R, 3S) -cyclohexane-1, 3-diamine dihydrochloride (89mg,0.475mmol) was dissolved in 2.5mL of acetonitrile, DBU (400 mg of 1, 8-diazabicyclo [5.4.0] undec-7-ene) was added thereto, the mixture was stirred at 80 ℃ for half an hour, and 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (60mg,0.19mmol) was added thereto and reacted for one hour. And (4) after the reaction is finished, the solvent is dried in a spinning mode, and the title compound is obtained through column chromatography separation and purification.

DMSO-d6δH 8.63-8.53(m,1H),8.53-8.47(m,0.5H),8.40-8.36(m,0.5H),8.11-8.06(m,1H),8.03-7.95(m,2H),7.51-7.43(m,1H),3.92-3.83(m,1H),2.71-2.61(m,1H),2.09-1.99(m,1H),1.92-1.84(m,1H),1.77-1.70(m,2H),1.33-1.09(m,5H),1.01-0.90(m,1H).

LC/MS(m/z,MH ⁺ ):401.1

Example 7: 7- (dimethylphosphoryl) -3- (2- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Step 1: 7-bromo-3- (2- (((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Referring to the synthesis of compound258 step 3 in WO2018013867, 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile was prepared.

7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (100mg,0.25mmol),1- (4-amino-1H-pyrazol-1-yl) -2-methylpropan-2-ol (58mg,0.375mmol), N, N-diisopropylethylamine (97mg,0.75mmol) were dissolved in 2mL of N-methylpyrrolidone and reacted at 150 ℃ for 1 hour. After the reaction is finished, water is added for quenching, ethyl acetate is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, filtration and concentration are carried out, and the obtained residue is separated and purified through column chromatography to obtain the title compound.

Step 2: (7- (dimethylphosphoryl) -3- (2- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

7-bromo-3- (2- (((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (105mg,0.2mmol), dimethylphosphine oxide (17mg,0.22mmol), palladium acetate (4.5mg,0.02mmol), potassium phosphate (64mg,0.3mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (11.6mg,0.02mmol) were dissolved in 3mL of N, N-dimethylformamide and reacted at 150 ℃ for 2 hours under an argon atmosphere, and after completion of the reaction, water was added and quenched, ethyl acetate was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, the resulting residue was purified by column chromatography to give the title compound.

DMSO-d6δ _H 12.20(s,1H),10.25-10.09(m,1H),8.88-8.73(m,1.5H),8.40-8.32(m,0.5H),8.29-8.12(m,1H),8.02(s,0.5H),7.79(s,0.5H),7.77-7.65(m,1H),7.65-7.56(m,1H),4.74(s,0.5H),4.69(s,0.5H),4.02(s,1H),3.92(s,1H),2.08(s,3H),2.05(s,3H),1.08(s,3H),1.04(s,3H).

LC/MS(m/z,MH ⁺ ):518.1

Example 8: (S) -3- (2- (aza-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile

Step 1: (S) -3- ((3- (7-bromo-6-cyano-1H-indol-3-yl) -4- (trifluoromethyl) phenyl) amino) azepane-1-carboxylic acid tert-butyl ester

7-bromo-3- (5-chloro-2- (trifluoromethyl) phenyl) -1H-indole-6-carbonitrile (100mg,0.25mmol) was added to 2.5mL of N-methylpyrrolidinone, N-diisopropylethylamine (100mg,0.75mmol), (S) -3-aminoazepane-1-carboxylic acid tert-butyl ester (64.2mg,0.3mmol) was added, and the reaction was completed after heating to 100 ℃ and stirring for 2 hours. After cooling to room temperature, 20mL of purified water was added to the reaction mixture, followed by extraction twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by ethyl acetate and petroleum ether column chromatography to give the title compound.

Step 2: (S) -tert-butyl 3- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate and (S) -tert-butyl 3- ((4- (6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

Tert-butyl (S) -3- ((3- (7-bromo-6-cyano-1H-indol-3-yl) -4- (trifluoromethyl) phenyl) amino) azepane-1-carboxylate (115.6mg, 0.2mmol) was added to 16mL of ultra-dry N, N-dimethylformamide, and dimethylphosphine oxide (78mg,1.0mmol), palladium acetate (4.5mg,0.02mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (23mg,0.04mmol), potassium phosphate (23mg,0.022mmol), replaced three times with argon, and stirred at 150 ℃ for 6 hours under argon protection. After cooling, 50mL of purified water was added to the reaction solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography with ethyl acetate and petroleum ether to give the target compounds (S) -tert-butyl 3- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate and (S) -tert-butyl 3- ((4- (6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate.

And step 3: synthesis of (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile

Tert-butyl (S) -3- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (70mg, 0.12mmol) was added to 3mL of dichloromethane, the temperature was reduced to 0 ℃ in an ice-water bath with stirring by a magneton, 1mL of trifluoroacetic acid was added dropwise, and the temperature was raised to room temperature and 25 ℃ for reaction for 2 hours after the addition. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution into the reaction solution to adjust the pH value to be between 7 and 8, extracting with ethyl acetate, combining organic layers, drying with anhydrous sodium sulfate, and concentrating and drying under reduced pressure to obtain a crude product. 5mL of acetonitrile is added to the crude product, stirring is carried out for 30min, a white solid is insoluble, suction filtration is carried out, a filter cake is washed by 1mL of acetonitrile, and drying is carried out to obtain the title compound.

DMSO-d6δ _H 8.79-8.73(m,0.5H),8.65-8.56(m,1H),8.55-8.50(m,0.5H),8.23-8.15(m,1H),7.89-7.78(m,1H),7.75-7.65(m,1H),4.15-3.99(m,1H),3.09-2.97(m,1H),2.84-2.64(m,3H),2.06(s,3H),2.02(s,3H),1.96-1.85(m,1H),1.74-1.60(m,3H),1.60-1.43(m,2H).

LC/MS(m/z,MH ⁺ ):477.1

Example 9: (S) -3- (2- (aza-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Step 1: synthesis of (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Tert-butyl (S) -3- ((4- (6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (30mg,0.06mmol) was added to 2mL of dichloromethane, stirred with magnetons, cooled to about 0 ℃ in an ice-water bath, 0.7mL of trifluoroacetic acid was added dropwise, and after the dropwise addition was completed, the mixture was warmed to room temperature and 25 ℃ for reaction for 2 hours. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution into the reaction solution to adjust the pH value to be between 7 and 8, extracting by ethyl acetate, combining organic phases, washing the organic phases by saturated saline solution, drying by anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a crude product. The crude product was separated by preparative HPLC (Triart C18ExRS, acetonitrile/water gradient elution) and lyophilized to give the desired product as a white solid.

DMSO-d ₆ δ _H 8.65-8.54(m,1H),8.53-8.48(m,0.5H),8.36-8.31(m,0.5H),8.07(s,1H),8.04-7.98(m,1H),7.84-7.74(m,1H),7.52-7.44(m,1H),4.13-4.01(m,1H),3.08-2.99(m,1H),2.85-2.60(m,3H),1.97-1.82(m,3H),1.76-1.60(m,3H),1.60-1.45(m,2H).

LC/MS(m/z,MH ⁺ ):401.1

Example 10: 7- (dimethylphosphoryl) -3- (2- ((1-isopropylpiperidin-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Step 1: synthesis of 7-bromo-3- (5- (((1-isopropylpiperidin-4-yl) amino) -2- (trifluoromethyl) phenyl) -1H-indole-6-carbonitrile

7-bromo-3- (5-chloro-2- (trifluoromethyl) phenyl) -1H-indole-6-carbonitrile (100mg,0.25mmol) was added to 2.5mL N-methylpyrrolidinone, N-diisopropylethylamine (100mg,0.75mmol), 4-amino-1-isopropylpiperidine (43mg,0.3mmol) were added, and the reaction was completed after heating to 100 ℃ and stirring for 2 hours. After cooling to room temperature, 20mL of purified water was added to the reaction mixture, followed by extraction with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to give the title compound.

Step 2: synthesis of (7- (dimethylphosphoryl) -3- (2- ((1-isopropylpiperidin-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Adding (7-bromo-3- (5- (((1-isopropylpiperidin-4-yl) amino) -2- (trifluoromethyl) phenyl) -1H-indole-6-carbonitrile (110mg, 0.2mmol) to 16mL of ultra-dry N, N-dimethylformamide, adding dimethylphosphine oxide (78mg,1.0mmol), palladium acetate (4.5mg,0.02mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (23mg,0.04mmol), potassium phosphate (23mg,0.022mmol), displacing with argon three times, stirring at 150 ℃ for 6 hours under the protection of argon, after completion of the reaction, concentrating the reaction solution under reduced pressure to remove most of the solvent, purifying with an acetonitrile/water system through a reverse column to obtain a crude product, subjecting the crude product to preparative HPLC (Triart C18ExRS, acetonitrile/water gradient elution) and lyophilized to afford the title compound.

DMSO-d ₆ δ _H 12.13(s,1H),8.78-8.72(m,0.5H),8.66-8.56(m,1H),8.55-8.48(m,0.5H),8.25-8.15(m,1H),8.05-7.93(m,1H),7.74-7.63(m,1H),3.85-3.73(m,1H),2.87-2.75(m,2H),2.74-2.63(m,1H),2.23-2.10(m,2H),2.05(s,3H),2.02(s,3H),1.94-1.86(m,2H),1.60-1.47(m,2H),0.98(s,3H),0.96(s,3H).

LC/MS(m/z,MH ⁺ ):505.2

Example 11: (S) -3- (2- (((6, 6-dimethylpiperidin-3-yl) amino) -5- (1-methyl-1H-pyrazol-4-yl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Step 1: synthesis of 3- (5-bromo-2-chloropyrimidin-4-yl) -1H-indole-6-carbonitrile

5-bromo-2, 4-dichloropyrimidine (4.80g,21mmol) and anhydrous aluminium trichloride (3.75g,28mmol) were added to 90mL1, 2-dichloroethane, heated to 80 ℃ and stirred for 30 minutes, followed by addition of 6-cyanoindole (2.00g,14mmol) and continued reaction at 80 ℃ for 2 hours. The reaction was cooled to room temperature, 100mL of water and 100mL of ethyl acetate were added, stirring was continued thoroughly to precipitate a large amount of yellow solid, which was filtered off, the filter cake was washed with ethyl acetate and dried to give the title compound.

Step 2: synthesis of (S) -3- (5-bromo-2- ((6, 6-dimethylpiperidin-3-yl) amino) pyrimidin-4-yl) -1H-indole-6-carbonitrile

3- (5-bromo-2-chloropyrimidin-4-yl) -1H-indole-6-carbonitrile (500mg,1.50mmol) and (S) -6, 6-dimethylpiperidin-3-amine dihydrochloride (392mg,1.95mmol) were added to 5mL of N-methylpyrrolidone, followed by N, N-diisopropylethylamine (0.87mL,5.25mmol), and heated to 130 ℃ for reaction for 3 hours. The reaction solution was cooled to room temperature, then poured into 50mL of water, extracted with ethyl acetate, the organic layers were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to give the title compound.

And step 3: synthesis of ((S) -3- (2- (((6, 6-dimethylpiperidin-3-yl) amino) -5- (1-methyl-1H-pyrazol-4-yl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

(S) -3- (5-bromo-2- ((6, 6-dimethylpiperidin-3-yl) amino) pyrimidin-4-yl) -1H-indole-6-carbonitrile (80mg,0.19mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (47mg,0.22mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (14mg,0.02mmol) and potassium carbonate (52mg,0.38mmol) were added to 3mL of a mixed solvent of 1, 4-dioxane/water (V/V ═ 10:1), and the mixture was reacted for 3 hours while heating to 100 ℃ under protection of gas with inert gas substitution three times. After cooling the reaction solution, it was filtered and the filtrate was purified by preparative HPLC (Triart C18ExRS, acetonitrile/water gradient elution) to give the title compound.

DMSO-d6δ _H 8.50(s,1H),8.06(s,1H),7.98-7.93(m,1H),7.69(s,1H),7.43-7.31(m,2H),7.32(s,1H),7.00-6.90(m,1H),6.05-5.86(m,1H),3.85(s,3H),2.98-2.87(m,2H),2.70-2.58(m,2H),1.89-1.77(m,1H),1.71-1.62(m,1H),1.56-1.47(m,1H),1.38-1.30(m,1H),1.08(s,3H),1.05(s,3H).

LC/MS(m/z,MH ⁺ ):427.2

Example 12: (S) -3- (2- (((6, 6-dimethylpiperidin-3-yl) amino) -5- (1H-pyrazol-4-yl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

(S) -3- (5-bromo-2- ((6, 6-dimethylpiperidin-3-yl) amino) pyrimidin-4-yl) -1H-indole-6-carbonitrile (80mg,0.19mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylic acid tert-butyl ester (47mg,0.22mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (14mg,0.02mmol) and potassium carbonate (52mg,0.38mmol) were added to 3mL of a mixed solvent of 1, 4-dioxane/water (V/V ═ 10:1), and the mixture was reacted for 3 hours while being purged with inert gas three times and heated to 100 ℃ under gas protection. After cooling the reaction, filtration and purification of the filtrate by preparative HPLC (Triart C18ExRS, acetonitrile/water gradient) gave the title compound.

DMSO-d6δ _H 12.95(s,1H),11.85(s,1H),8.48(s,1H),8.08(s,1H),7.92(s,1H),7.66–7.47(m,2H),7.44–7.36(m,1H),7.29(s,1H),7.00–6.87(m,1H),3.89–3.67(m,1H),3.00–2.84(m,1H),2.72–2.59(m,1H),1.92–1.73(m,2H),1.73–1.60(m,1H),1.54–1.47(m,1H),1.40–1.29(m,1H),1.08(s,3H),1.06(s,3H).

LC/MS(m/z,MH ⁺ ):413.2

Example 13: 7- (dimethylphosphoryl) -3- (2- ((tetrahydro-2H-pyran-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Step 1: synthesis of 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.47g,6.79mmol) and anhydrous aluminum trichloride (1.20g,9.05mmol) were added to 18mL of 1, 2-dichloroethane, heated to 80 ℃ and stirred for 30 minutes, then 7-bromo-1H-indole-6-carbonitrile (1.00g,4.52mmol) was added and the reaction was continued at 80 ℃ for 4 hours. Cooling the reaction liquid to room temperature, adding 120mL of water, extracting with ethyl acetate, combining organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, adding a small amount of ethyl acetate, pulping, filtering, and drying to obtain the title compound.

Step 2: synthesis of 7-bromo-3- (2- (((tetrahydro-2H-pyran-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (200mg,0.50mmol) and 4-aminotetrahydropyran (65.7mg,0.65mmol) were added to 4mL of N-methylpyrrolidinone, followed by N, N-diisopropylethylamine (226mg,1.75mmol), and heated to 130 ℃ for 3 hours. The reaction solution was cooled to room temperature, then poured into 50mL of water, extracted with ethyl acetate, the organic layers were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to give the title compound.

And step 3: synthesis of 7- (dimethylphosphoryl) -3- (2- ((tetrahydro-2H-pyran-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

7-bromo-3- (2- (((tetrahydro-2H-pyran-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (70mg,0.15mmol), dimethylphosphine oxide (27mg,0.35mmol), palladium acetate (6.9mg,0.0075mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (8.7mg,0.015mmol) and potassium phosphate (64mg,0.30mmol) were added to 2mL of anhydrous N, N-dimethylformamide, heated to 150 ℃ for reaction for 2 hours, the reaction was cooled and poured into water, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, subjected to preparative HPLC (Triart C18ExRS, acetonitrile/water gradient elution) to afford the title compound.

DMSO-d6δ _H 12.15(s,1H),8.80-8.72(m,0.5H),8.67-8.58(m,1H),8.57-8.51(m,0.5H),8.24-8.16(m,1H),8.14-8.02(m,1H),7.80-7.66(m,1H),4.13-4.01(m,1H),3.95-3.85(m,2H),3.46-3.36(m,2H),2.06(s,3H),2.02(s,3H),1.93-1.81(m,2H),1.66-1.52(m,2H).

LC/MS(m/z,MH ⁺ ):464.2

Example 14: (S) -7- (dimethylphosphoryl) -3- (2- (pyrrolidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Step 1: synthesis of tert-butyl (S) -3- ((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) pyrrolidine-1-carboxylate

7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (131mg, 0.33mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (73mg, 0.39mmol), N, N-diisopropylethylamine (126mg, 0.98mmol) was added to N-methylpyrrolidinone (6mL), and the reaction was complete after stirring at 130 ℃ for 2H. And washing the reaction solution with water, extracting to obtain an organic phase, concentrating, and performing column chromatography to obtain the title compound.

Step 2: synthesis of tert-butyl (S) -3- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5 (trifluoromethyl) pyrimidin-2-yl) amino) pyrrolidine-1-carboxylate

Tert-butyl (S) -3- ((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) pyrrolidine-1-carboxylate (55mg, 0.1mmol), dimethylphosphine oxide (7.8mg, 0.1mmol), potassium phosphate (32mg, 0.15mmol), palladium acetate (2.24mg, 0.01mg), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (5.8mg, 0.01mmol) were added to N, N-dimethylformamide (6mL), and the reaction was completed after stirring at 150 ℃ for 2 hours. And washing the reaction solution with water, extracting to obtain an organic phase, concentrating, and performing column chromatography to obtain the title compound.

And step 3: synthesis of (S) -7- (dimethylphosphoryl) -3- (2- (pyrrolidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Tert-butyl (S) -3- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5 (trifluoromethyl) pyrimidin-2-yl) amino) pyrrolidine-1-carboxylate (40mg, 0.07mmol) was dissolved in a dichloromethane/trifluoroacetic acid system and the reaction was complete after stirring at room temperature for 2 hours. The title compound was obtained after concentration and column chromatography.

DMSO-d6δ _H 8.82-8.72(m,0.5H),8.70-8.50(m,1.5H),8.29-8.14(m,1.5H),8.11-8.00(m,0.5H),7.73-7.60(m,1H),4.53-4.31(m,1H),3.66-3.56(m,1H),3.52-3.45(m,1H)3.05-2.88(m,1H),2.84-2.70(m,1H),2.21-2.11(m,1H),2.05(s,3H),2.01(s,3H),1.79-1.67(m,1H).

LC/MS(m/z,MH ⁺ ):449.1

Example 15: 7- (dimethylphosphoryl) -3- (2- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Step 1: synthesis of 2- (4-bromopyridin-2-yl) propan-2-ol

A1M solution of methylmagnesium bromide in tetrahydrofuran (11.6mL, 11.57mmol) was placed in a three-necked flask under argon protection and cooled to-20 ℃. A solution of methyl 4-bromopicolinate (1g, 4.63mmol) in tetrahydrofuran (7.5mL) was added dropwise thereto, maintaining the temperature at-15 ℃ or lower. The reaction was completed after two hours of continued stirring. Quenching the reaction solution by using a saturated ammonium chloride solution, extracting by using ethyl acetate for three times, combining the filtrates, and carrying out column chromatography to obtain the title compound.

Step 2: synthesis of tert-butyl (2- (2-hydroxypropan-2-yl) pyridin-4-yl) carbamate

2- (4-Bromopyridin-2-yl) propan-2-ol (295mg, 1.37mmol), tert-butyl carbamate (161mg, 1.37mmol), cesium carbonate (895mg, 2.74mmol), 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (65mg, 0.14mmol), tris [ dibenzylideneacetone ] dipalladium (126mg, 0.14mmol) were added to 5mL1, 4-dioxane, argon was replaced, and the reaction was completed after stirring at 90 ℃ for 2 hours. The reaction was concentrated and subjected to column chromatography to give the title compound.

And step 3: synthesis of 2- (4-aminopyridin-2-yl) propan-2-ol

Tert-butyl (2- (2-hydroxypropan-2-yl) pyridin-4-yl) carbamate (100mg, 0.4mmol) was dissolved in methanol (1mL), a1, 4-dioxane solution (2mL) of hydrochloric acid was added, and the reaction was completed after stirring at room temperature for three hours. After extraction with saturated sodium bicarbonate water, the organic phase was concentrated to give the title compound.

And 4, step 4: synthesis of 7-bromo-3- (2- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (60mg, 0.15mmol), 2- (4-aminopyridin-2-yl) propan-2-ol (28mg, 0.18mmol), N, N-diisopropylethylamine (58mg, 0.45mmol) was added to 2mL of N-methylpyrrolidinone, and the reaction was complete after stirring at 130 ℃ for 2 hours. And washing the reaction solution with water, extracting to obtain an organic phase, concentrating, and performing column chromatography to obtain the title compound.

And 5: synthesis of 7- (dimethylphosphoryl) -3- (2- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

7-bromo-3- (2- ((2- (2-hydroxypropan-2-yl) pyridin-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (40mg, 0.08mmol), dimethylphosphine oxide (6mg, 0.08mmol), potassium phosphate (24mg, 0.12mmol), palladium acetate (1.7mg, 0.01mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (4.4mg, 0.01mmol) were added to N, N-dimethylformamide (2mL), and the reaction was completed after stirring at 150 ℃ for 2 hours. And washing the reaction solution with water, extracting to obtain an organic phase, concentrating, and performing column chromatography to obtain the title compound.

DMSO-d6δ _H 10.61(s,1H),12.25(s,1H),10.57(s,1H),8.93(s,1H),8.73(m,1H),8.40-8.24(m,2H),8.02-7.85(m,2H),7.74(s,1H),5.16(s,1H),1.43(s,5H),1.23(s,2H),0.00(s,3H).

LC/MS(m/z,MH ⁺ ):515.1

Example 16: (S) -4- (1H-benzo [ d ] imidazol-1-yl) -N- (6, 6-dimethylpiperidin-3-yl) -5- (trifluoromethyl) pyrimidin-2-amine

Step 1: synthesis of 1- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-benzo [ d ] imidazole

Benzimidazole (236mg,2.0mmol) was added to 2mL of anhydrous N, N-dimethylformamide, sodium hydride (96mg,2.4mmol) was added, and stirred for 10 minutes, followed by addition of a solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (434mg,2.0mmol) in N, N-dimethylformamide (2mL) and reaction at room temperature for 4 hours. The reaction was quenched by addition of water, extracted with ethyl acetate, the organic layers were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give the title compound.

Step 2: synthesis of (S) -4- (1H-benzo [ d ] imidazol-1-yl) -N- (6, 6-dimethylpiperidin-3-yl) -5- (trifluoromethyl) pyrimidin-2-amine

1- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-benzo [ d ] imidazole (50mg,0.17mmol) and (S) -6, 6-dimethylpiperidin-3-amine dihydrochloride (44mg,0.22mmol) were added to 2mL of N-methylpyrrolidinone, followed by N, N-diisopropylethylamine (76mg,0.59mmol), and heated to 130 ℃ for 2 hours. The reaction was cooled to room temperature, then poured into 20mL of water, extracted with ethyl acetate, the organic layers were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative HPLC (Triart C18ExRS, acetonitrile/water gradient elution) to give the title compound.

DMSO-d6δ _H 9.13(s,1H),8.65-8.58(m,1H),8.55-8.47(m,1H),7.84-7.76(m,1H),7.50-7.35(m,2H),7.31-7.20(m,1H),4.40-4.27(m,1H),3.00-2.89(m,1H),2.87-2.76(m,1H),2.02-1.88(m,1H),1.86-1.73(m,1H),1.58-1.48(m,1H),1.46-1.34(m,1H),1.13(s,3H),1.12(s,3H).

LC/MS(m/z,MH+):391.2

Experimental example 1 CDK kinase Activity inhibition experiment

The activity inhibition of the compounds on CDK2, CDK7, CDK6, CDK12 kinases was examined by the method of Caliper mobility shift assay. Compound final concentration tested was 10 μ M starting, 3-fold diluted 10 concentrations, and wells were re-plated. Using a dispenser Echo 550, 250nL of 100 fold final concentration of compound was transferred to the target plate 3573.

Adding 10 μ L of kinase solution with final concentration of 2.5nM CDK2/CycA2 onto kinase CDK2/CycA2, incubating at room temperature for 10 min, adding 15 μ L of mixed solution of ATP with final concentration of 17 μ M and 3 μ M substrate Peptide18, and reacting for 30 min;

adding 10 mu L of kinase solution with the final concentration of 10nM CDK7/CycH/MAT1 to kinase CDK7/CycH/MAT1, incubating at room temperature for 10 minutes, adding 15 mu L of ATP with the final concentration of 19.6 mu M and 3 mu M of substrate Peptide CTD3 mixed solution, and reacting for 120 minutes;

adding 10 μ L of kinase solution with final concentration of 10nM CDK6/CycT1 onto kinase CDK6/CycT1, incubating at room temperature for 10 min, adding 15 μ L of ATP with final concentration of 6.5 μ M and 3 μ M of substrate Peptide CTD3 mixed solution, and reacting for 30 min;

mu.L of kinase solution with a final concentration of 10nM CDK12 wt/CycK was added to kinase CDK12 wt/CycK, incubated at room temperature for 10 min, and 15. mu.L of mixed solution of ATP with a final concentration of 11.5. mu.M and 3. mu.M substrate Peptide C was added and reacted for 24 h.

(negative control wells contained 10. mu.L of kinase buffer and 250nL of 100% DMSO; positive control wells contained 10. mu.L of kinase solution and 250nL of 100% DMSO).

The kinase reaction was stopped by adding 30. mu.L of a termination assay solution containing EDTA. The conversion was read using a Caliper EZ Reader. And the conversion inhibition rate is (the positive control conversion rate mean value-the sample conversion rate%/(the positive control conversion rate mean value-the negative control conversion rate mean value%). wherein, the negative control hole represents the conversion rate reading of the hole without enzyme activity, the positive control hole represents the conversion rate reading of the hole without compound inhibition, the log value of the concentration is taken as an X axis, the percentage inhibition rate is taken as a Y axis, and an energy efficiency curve is fitted by adopting the log (inhibitor) of GraphPad Prism 5 of analysis software vs ₅₀ The value is obtained. Calculating the formula: y ═ Bottom + (Top-Bottom)/(1+10^ ((LogIC) ₅₀ -X)*HillSlope))。

And (3) test results: under the conditions of this experiment, the test compounds all had good inhibitory activity against CDK 7. Compounds of the examples of the present application have a higher selective inhibitory activity against CDK7 than CDK2 and/or CDK6 and/or CDK12, and the corresponding activity test results for the test compounds are detailed in table 1.

Kinase activity of compounds of table 1 against CDK7, CDK2, CDK6, CDK12

"-" indicates no testing was performed

Experimental example 2 detection of pharmacokinetic Properties of the Compound of the present invention

Test animals:

healthy adult BALB/c mice 3 female, each group 3, mice purchased from Beijing Wittingle laboratory animal technology, Inc., animal production license number: SCXK (Zhe) 2019-.

Preparing the medicine:

weighing a certain amount of medicine, dissolving in DMSO 5% + PG 20% + absolute ethyl alcohol 5% + solutol 10% + water 60%, preparing into 10mg/mL for intragastric administration.

The administration mode comprises the following steps:

and (3) intragastric administration group: BALB/c mice were fasted overnight and then gavaged at a dose of 10mg/kg and a volume of 1 mL/kg.

The operation method comprises the following steps:

after the mouse is subjected to intragastric administration, after 5min, 15min, 30min, 1h, 2h, 4h and 24h after administration, 40 mu L of orbital blood is collected, 5 mu LEDTA-K2 is subjected to anticoagulation at 12000rpm and 4 ℃, plasma is centrifugally separated for 5min, and the mouse is stored at the temperature of minus 20 ℃.

Determining the content of the compound to be tested in the plasma of the mouse after the drug with different concentrations is administered by gastric lavage: melting the sample at room temperature, and vortexing for 1 min; quantitatively transferring 15. mu.L to a 2ml 96-well plate, adding 150. mu.L of internal standard precipitant, and shaking (1200 rpm. multidot.3 min); centrifugation (4000rpm 15min) and transfer of 100. mu.L of supernatant into 1ml 96-well plates; blow-drying with nitrogen, adding 100. mu.L of the double solution (acetonitrile 1: 9), shaking (900 rpm. times.3 min), and analyzing 20. mu.L of the sample. LC/MS/MS conditions: mobile phase A, 0.1% aqueous formic acid, mobile phase B: 0.1% (v/v) formic acid in acetonitrile, column: ACE C ₁₈ 5 μm (3.0mm by 50mm), column temperature: at 35 ℃ and a flow rate of 0.5 mL/min.

And (3) test results:

under the conditions of the experiment, the tested compounds show better pharmacokinetic properties, and the results are shown in table 2.

TABLE 2 pharmacokinetic parameters following a single gavage administration of a Compound of the invention in mice

Claims (17)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

selected from C ═ CH-NH, N-CH ═ CH, or N-CH ═ N;

x is selected from a chemical bond or NH;

R ₁ selected from CN, -O-C ₁ -C ₆ Alkyl, -S (═ O) ₂ -C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl or C ₃ -C ₈ Cycloalkyl radical, said C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^a Substitution; r ^a Selected from halogen, OH, NH ₂ Or C ₁ -C ₃ An alkyl group;

R ₂ selected from 5-10 membered heteroaryl, C ₃ -C ₈ Cycloalkyl or 3-10 membered heterocyclyl, said 5-10 membered heteroaryl, C ₃ -C ₈ Cycloalkyl or 3-10 membered heterocyclyl is optionally substituted by R ^b Substitution; r ^b Selected from halogen, CN, OH, NH ₂ 、-NH(C ₁ -C ₃ Alkyl), -N (C) ₁ -C ₃ Alkyl radical) ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^c Substitution;R ^c selected from halogen, NH ₂ CN or OH;

R ₃ selected from H, halogen, C ₁ -C ₆ Alkyl, -P (═ O) (C) ₁ -C ₆ Alkyl radical) ₂ or-S (═ O) ₂ -C ₁ -C ₆ An alkyl group;

R ₄ selected from H, CN, halogen or C ₁ -C ₆ An alkyl group;

provided that when R is ₂ Is selected from

When the temperature of the water is higher than the set temperature,

selected from N-CH ═ CH or N-CH ═ N;

or when R is ₂ Is selected from

When the temperature of the water is higher than the set temperature,

is selected from C ═ CH-NH and R ₁ Selected from-S (O) ₂ -C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or 5-10 membered heteroaryl, said 5-10 membered heteroaryl being optionally substituted with R ^a Substitution; r ^a Selected from halogen, OH, NH ₂ Or C ₁ -C ₃ An alkyl group.

2. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein: r ₁ Selected from CN, -S (═ O) ₂ -C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl, said 5-10 membered heteroaryl or 3-10 membered heterocyclyl being optionally substituted with R ^a And (4) substitution.

3. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 2, wherein: r ₁ Is selected from-S (═ O) ₂ -C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or 5-10 membered heteroaryl, said 5-10 membered heteroaryl being optionally substituted with R ^a And (4) substitution.

4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-3, wherein: r ₂ Selected from 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with R ^b And (4) substitution.

5. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-4, wherein: said R is ^b Selected from halogen, CN, OH, NH ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^c And (4) substitution.

6. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-3, wherein: r ₂ Selected from the following groups:

R ^d selected from H, halogen, CN, OH, NH ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^f Substitution; r ^f Selected from halogen, NH ₂ CN or OH.

7. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 6, wherein: r ₂ Selected from the following groups:

R ^d selected from H, halogen, CN, OH, NH ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^f Substitution; r ^f Selected from halogen, NH ₂ CN or OH.

8. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein: r ₃ Is selected from H or-P (═ O) (C) ₁ -C ₆ Alkyl radical) ₂ 。

9. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-8, wherein: r ₄ Selected from H or CN.

10. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-9, wherein: x is selected from NH.

11. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-3 or 8-10, wherein: the compound shown in the formula (I) is selected from a compound shown in a formula (II) or a pharmaceutically acceptable salt thereof,

wherein R is ₁ 、R ₃ 、R ₄ X is as defined in any one of claims 1 to 3 or 8 to 10;

R ₂ selected from 5-10 membered heteroaryl, optionally substituted with R ^b Substitution; r ^b Selected from halogens、CN、OH、NH ₂ 、-NH(C ₁ -C ₃ Alkyl), -N (C) ₁ -C ₃ Alkyl radical) ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^c Substitution; r ^c Selected from halogen, NH ₂ CN or OH;

or R ₂ Selected from the following groups:

R ^d selected from H, halogen, CN, OH, NH ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^f Substitution; r ^f Selected from halogen, NH ₂ CN or OH.

12. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-3 or 8-10, wherein: the compound shown in the formula (I) is selected from a compound shown in a formula (III) or a pharmaceutically acceptable salt thereof,

wherein R is ₁ 、R ₃ 、R ₄ X is as defined in any one of claims 1 to 3 or 8 to 10;

R ₂ selected from 5-10 membered heteroaryl, C ₃ -C ₈ Cycloalkyl or 3-10 membered heterocyclyl, said 5-10 membered heteroaryl, C ₃ -C ₈ Cycloalkyl or 3-10 membered heterocyclyl is optionally substituted by R ^b Substitution; r ^b Selected from halogen, CN, OH, NH ₂ 、-NH(C ₁ -C ₃ Alkyl), -N (C) ₁ -C ₃ Alkyl radical) ₂ 、C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl radical, said C ₁ -C ₆ Alkyl or C ₃ -C ₈ Cycloalkyl is optionally substituted by R ^c Substitution; r ^c Selected from halogen, NH ₂ CN or OH, but R ₂ The following groups are excluded:

13. a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-8 or claim 10, wherein: the compound shown in the formula (I) is selected from a compound shown in a formula (IV) or a pharmaceutically acceptable salt thereof,

wherein R is ₄ Selected from CN, halogen or C ₁ -C ₆ An alkyl group; r ₁ 、R ₂ 、R ₃ X is as defined in any one of claims 1 to 8 or claim 10.

14. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein: the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof is selected from the following compounds or the pharmaceutically acceptable salts thereof,

15. a pharmaceutical composition comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

16. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15 in the manufacture of a medicament for the prevention or treatment of a disease associated with CDK 7.

17. Use according to claim 16, characterized in that: the CDK7 related diseases are selected from proliferative diseases, inflammatory diseases, autoimmune diseases.