CN117384135A - Compounds useful as CDK7 kinase inhibitors and uses thereof - Google Patents

Compounds useful as CDK7 kinase inhibitors and uses thereof Download PDF

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CN117384135A
CN117384135A CN202210788052.4A CN202210788052A CN117384135A CN 117384135 A CN117384135 A CN 117384135A CN 202210788052 A CN202210788052 A CN 202210788052A CN 117384135 A CN117384135 A CN 117384135A
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compound
cancer
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alkyl
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梁阿朋
朱健
李钧
陈少清
尹洲
吴豫生
董胜利
李美华
牛成山
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Deuracor Therapeutic Inc
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Priority to PCT/CN2023/105733 priority patent/WO2024008083A1/en
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Abstract

The present invention relates to compounds useful as inhibitors of CDK7 kinase and uses thereof. Specifically, the compound has a structure shown in a formula I, wherein the definition of each group and substituent is described in the specification. The compounds of the invention are useful as inhibitors of cyclin dependent kinase 7 (CDK 7) for the treatment or prophylaxis of proliferative diseases such as cancer, in particular for modulating and treating diseases associated with aberrant activity of cyclin dependent kinase 7 (CDK 7).

Description

Compounds useful as CDK7 kinase inhibitors and uses thereof
Technical Field
The present invention relates to the field of pharmaceutical technology, in particular to compounds useful as inhibitors of CDK7 kinase and their use in modulating CDK7 kinase activity or in the treatment of CDK 7-related disorders, in particular cancer.
Background
Cyclin-dependent kinases CDKs (Cyclin-dependent kinases) belong to the serine/threonine kinase family, which exert physiological functions by binding to the corresponding Cyclin (Cyclin) to form active dimeric complexes, causing cell growth and proliferation. It has now been found that over 20 CDKs fall into two broad categories according to their function: CDKs that regulate the cell cycle and CDKs that regulate the transcription of cells, wherein CDKs 1-6 and 14-18 are involved in the regulation of the cell cycle and CDKs 7-13 and 19-20 are involved in the regulation of the transcription of cells.
CDK7 is an important member of the CDKs family, the primary physiological function being the regulation of cell cycle and transcription. In the cell fluid, CDK7, together with cyclin H and Mat1, constitute CAK (CDKs activating kinase), and participate in the regulation of the cell cycle by phosphorylating CDK 1/2/4/6. In the nucleus, CDK7 is a component of the general transcription factor TF II H (Transcription factor II human), and is involved in the gene transcription process of cells by phosphorylating the CTD domain (carboxy-terminal domain) of RNA polymerase II (RNA polymerase II) in the most important initial stage of gene transcription. Since CDK7 has the dual functions of CAK and CTD phosphorylation, it plays an important role in cell proliferation, cell cycle and gene transcription processes.
Due to the dual unique functional role of CDK7 in transcription and cell cycle progression, its broad expression in various types of cancers can lead to a reduction in cell proliferation by down-regulating CDK7 activity. More importantly, it is now agreed that targeted transcription selectively limits the synthesis of mRNA involved in tumor growth without causing disruption of housekeeping gene (housekeeping genes) transcription. Thus, CDK7 is considered a viable, very promising target for tumor treatment, and has attracted considerable attention, with many small molecules, such as THZ1, THZ2, CT7001, SY-1365, etc., exhibiting very good tumor growth inhibiting effects in preclinical studies. Especially in the field of major diseases such as small cell lung cancer, triple negative breast cancer, pancreatic cancer and the like which are not satisfied with effective treatment means at present. Therefore, the development of specific CDK7 inhibitors is expected to be useful in the above clinically unmet fields.
Disclosure of Invention
The invention provides a novel compound with CDK7 kinase inhibitory activity and better pharmacodynamics and pharmacokinetics.
In a first aspect the present invention provides a compound for use as an inhibitor of CDK7 kinase, said compound being a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound or prodrug thereof,
wherein:
R 1 selected from the group consisting of:
R 2 selected from the group consisting of: H. CF (compact flash) 3 、Cl、Br、CH 3 、Cyclopropyl, phenyl;
R 3 is H;
or R is 2 And R is R 3 Forming a saturated or unsaturated 5-6 membered cycloalkyl group;
R 4 selected from the group consisting of:
X 1 、X 2 、X 3 、X 4 each independently selected from the group consisting of: NR (NR) 6 、CR 7 R 8 、O、S；
Each R is 6 、R 7 、R 8 Independently and separatelySelected from the group consisting of: H. C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S;
each m, n is independently selected from the group consisting of: 0. 1, 2, 3, 4, 5.
In another preferred embodiment, R 1 Selected from the group consisting of:
in another preferred embodiment, R 2 Is CF (CF) 3 。
In another preferred embodiment, X 1 、X 2 、X 3 、X 4 Each independently is CR 7 R 8 ；
Each R is 7 、R 8 Independently selected from the group consisting of: H. C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl.
In another preferred embodiment, R 1 Selected from the group consisting of:
R 2 selected from the group consisting of: H. CF (compact flash) 3 、Cl、Br、CH 3 、
R 3 H.
In another preferred embodiment, R 4 Selected from the group consisting of:
R 2 selected from the group consisting of: H. CF (compact flash) 3 、Cl。
In another preferred embodiment, the compound is selected from the group consisting of:
in another preferred embodiment, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt;
the inorganic acid salt is selected from the group consisting of: hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate;
the organic acid salt is selected from the group consisting of: formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, camphorsulfonate.
In a second aspect of the invention there is provided a pharmaceutical composition comprising one or more compounds of the first aspect of the invention in a prophylactically and/or therapeutically effective amount, together with a pharmaceutically acceptable carrier.
In a third aspect of the invention there is provided the use of a compound according to the first aspect of the invention for the manufacture of a medicament for use as a CDK7 kinase inhibitor.
In a fourth aspect of the invention there is provided the use of a compound according to the first aspect of the invention for the manufacture of a medicament for use in modulating CDK7 kinase activity or treating a CDK 7-related disorder.
In another preferred embodiment, the CDK 7-related disorder is selected from the group consisting of: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
In another preferred embodiment, the cancer is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, renal cancer, esophageal cancer, uterine cancer.
In another preferred embodiment, the lung cancer is selected from the group consisting of: small cell lung cancer, non-small cell lung cancer.
In another preferred embodiment, the breast cancer is a triple negative breast cancer.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The present inventors have conducted extensive and intensive studies and have unexpectedly found a class of compounds having a superior CDK7 kinase inhibitory activity. In addition, the compounds have excellent inhibitory activity against CDK7 kinase and have better pharmacodynamic/pharmacokinetic properties. On this basis, the present invention has been completed.
Terminology
The following terms used in this application (including the specification and claims) have the definitions set forth below, unless specified otherwise.
When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH 2 O-is equivalent to-OCH 2 -。
"alkyl (alone or in combinationAs part of other groups) "refers to monovalent straight or branched saturated hydrocarbon groups containing 1 to 12 carbon atoms consisting of carbon and hydrogen atoms only. Alkyl is preferably C1-C6 alkyl (i.e., containing 1, 2, 3, 4, 5, or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. In this application, alkyl is also intended to include substituted alkyl groups, i.e., one or more positions in the alkyl group are substituted, especially 1-4 substituents, and may be substituted at any position. "haloalkyl" refers to an alkyl group as defined herein wherein one or more hydrogens are replaced with the same or different halogens. Examples of haloalkyl groups include-CH 2 Cl、-CH 2 CF 3 、-CH 2 CCl 3 Perfluoroalkyl (e.g., -CF) 3 ) Etc.
"alkylene" refers to a divalent group of an alkyl group, e.g., -CH 2 -、-CH 2 CH 2 -and-CH 2 CH 2 CH 2 -。
"alkoxy (alone or as part of another group)" refers to an alkyl group having an alkyl O-structure to which an oxy group is attached, wherein the alkyl group has the definition as described above, preferably alkoxy is C1-C6 alkoxy. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, t-butoxy, and the like. "haloalkoxy" refers to a group of formula-OR, wherein R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2-trifluoroethoxy, and the like.
"thioalkyl" means that the carbon in the alkyl group is replaced with S, S (O) or S (O) 2.
"alkenyl (alone or as part of another group)" refers to an aliphatic group containing at least one double bond, typically having from 2 to 20 carbon atoms. In the present invention, "C2-C6 alkenyl" means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. In the present invention, alkenyl includes substituted alkenyl.
"alkenylene" refers to an alkenyl group having two points of attachment. For example, "vinylidene" means a group-ch=ch-. Alkenylene groups may also be in unsubstituted form or substituted form with one or more substituents.
"alkynyl" (alone or as part of another group) refers to a straight or branched hydrocarbon chain containing more than 2 carbon atoms and characterized by one or more triple bonds, typically having from 2 to 20 carbon atoms. In the present invention, "C2-6 alkynyl" refers to alkynyl groups having 2, 3, 4, 5 or 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of an alkynyl substituent. In the present invention, alkynyl also includes substituted alkynyl.
"alkynylene" refers to an alkynyl group having two points of attachment. For example, "ethynylene" means a group: -C≡C-. Alkynylene groups may also be unsubstituted or substituted with one or more substituents.
"aliphatic" refers to straight, branched, or cyclic hydrocarbon groups, including saturated and unsaturated groups, such as alkyl, alkenyl, and alkynyl groups.
"aromatic ring system" refers to a monocyclic, bicyclic, or polycyclic hydrocarbon ring system in which at least one ring is aromatic.
"aryl (alone or as part of another group)" refers to a monovalent group of an aromatic ring system. Representative aryl groups include all-aromatic ring systems such as phenyl, naphthyl, and anthracenyl; and ring systems in which an aromatic carbocyclic ring is fused to one or more non-aromatic carbocyclic rings, such as indanyl, phthalimidyl, naphthalimidyl, tetrahydronaphthyl, and the like. In the present invention, the aryl group is preferably a C6-C12 aryl group. In the present invention, aryl is also intended to include substituted aryl.
"arylalkyl" or "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced with an aryl group. Aralkyl includes groups in which one or more hydrogen atoms are replaced by an aryl group, with aryl and alkyl having the definitions described above. Examples of "arylalkyl" or "aralkyl" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, trityl and the like.
"aryloxy" refers to-O- (aryl) wherein the aryl moiety is as defined herein.
"heteroalkyl" refers to a substituted alkyl group having one or more backbone chain atoms selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. A range of values may be given, for example, C1-C6 heteroalkyl refers to the number of carbons in the chain, which includes 1 to 6 carbon atoms. For example-CH 2 OCH 2 CH 3 The group is referred to as "C3" heteroalkyl. The linkage to the remainder of the molecule may be through a heteroatom or carbon in the heteroalkyl chain. "heteroalkylene" refers to an optionally substituted divalent alkyl group having one or more backbone chain atoms selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, or combinations thereof.
"carbocyclic ring system" refers to a monocyclic, bicyclic, or polycyclic hydrocarbon ring system in which each ring is fully saturated or contains one or more units of unsaturation, but in which none of the rings is aromatic.
"carbocyclyl" refers to a monovalent group of a carbocyclic ring system. Examples include cycloalkyl (cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, etc.) and cycloalkenyl (e.g., cyclopentenyl, cyclohexenyl, cyclopentadienyl, etc.).
"cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of mono-or bicyclic rings having 3 to 12, preferably 3 to 10, more preferably 3 to 8 ring atoms. Cycloalkyl groups may be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
"Cycloalkoxy" refers to a group of formula-OR, wherein R is cycloalkyl as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. "cycloalkylalkyl" refers to- (cycloalkyl) -alkyl wherein cycloalkyl and alkyl are as disclosed herein. "cycloalkylalkyl" is bonded to the parent molecular structure through cycloalkyl.
"heteroaryl ring system" refers to a monocyclic (e.g., 5 or 6 membered), bicyclic (6-12 membered), or polycyclic ring system wherein at least one ring is both aromatic and contains at least one heteroatom (e.g., N, O or S); and wherein none of the other rings are heterocyclyl (as defined below). In certain instances, a ring that is aromatic and contains heteroatoms that contain 1, 2, 3, or 4 ring heteroatoms in the ring. At least one of the rings is heteroaromatic and the remaining rings may be saturated, partially unsaturated or fully unsaturated.
"heteroaryl" refers to a monocyclic (e.g., 5 or 6 membered), bicyclic (e.g., 8-10 membered) or tricyclic group of 5 to 12 ring atoms containing at least 1 aromatic ring containing 1, 2 or 3 ring heteroatoms selected from N, O or S, the remaining ring atoms being C, it being understood that the point of attachment of the heteroaryl group should be on the aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazolyl group, Azolyl, iso->Oxazolyl, thiazolyl, isothiazolyl, < ->Diazolyl, thiadiazolyl, pyrazinyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzo->Azolyl, benzo->Diazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, aza>Radical, diaza->A group, an acridinyl group, and the like. Heteroarylene refers to a heteroaryl group having two attachment sites.
"heterocyclic ring system" refers to monocyclic, bicyclic, and polycyclic ring systems wherein at least one ring is saturated or partially unsaturated (but not aromatic) and the ring contains at least one heteroatom. The heterocyclic ring system may be attached to a pendant group at any heteroatom or carbon atom that results in a stable structure and any ring atom may be optionally substituted.
"heterocyclyl" refers to a monovalent group of a heterocyclic ring system, typically a stable monocyclic (e.g., 3-8 membered, i.e., 3-, 4-, 5-, 6-, 7-, or 8-membered) or bicyclic (e.g., 5-12-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered) or polycyclic (e.g., 7-14-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered) ring structure, including fused-, spiro-, and/or bridged ring structures, which are saturated, partially unsaturated, and which contain carbon atoms and 1,2,3, or 4 heteroatoms independently selected from N, O and S. Representative heterocyclyl groups include those wherein (1) each ring is non-aromatic and at least one ring contains a heteroatom, e.g., tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl; (2) At least one ring is non-aromatic and comprises heteroatoms and at least one other ring is an aromatic carbocyclic ring, e.g., 1,2,3, 4-tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl; and (3) at least one ring is non-aromatic and comprises a heteroatom and at least one other ring is aromatic and comprises a heteroatom, for example, 3, 4-dihydro-1H-pyrano [4,3-c ] pyridine and 1,2,3, 4-tetrahydro-2, 6-naphthyridine. Heterocyclylene refers to a heterocyclic group having two attachment sites. In the present invention, the heterocyclylene is preferably bicyclic, in which one ring is heteroaryl and is attached to the other moiety in the formula via heteroaryl. In the present invention, the heterocyclic group is preferably a 5-6 membered monocyclic heterocyclic group or an 8-10 membered bicyclic heterocyclic group.
"heterocycloalkyl" refers to an alkyl group substituted with a heterocyclyl group, where heterocyclyl and alkyl are defined above.
"alkylamino" refers to a group having an alkyl-NR-structure wherein R is H, or alkyl, cycloalkyl, aryl, heteroaryl, and the like as described above.
"cycloalkylamine" refers to a group of formula-NRaRb wherein Ra is H, alkyl as defined herein, or cycloalkyl as defined herein, rb is cycloalkyl as defined herein, or Ra and Rb together with the N atom to which they are attached form a 3-10 membered N-containing monocyclic or bicyclic heterocyclic group, such as tetrahydropyrrolyl. As used herein, C3-C8 cycloalkylamine groups refer to amine groups containing 3 to 8 carbon atoms.
In the present invention, "ester" means having the structure-C (O) -O-R or R-C (O) -O-, wherein, R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, as defined above.
In the present invention, the term "amide" refers to a group with the structure-CONRR ', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine fragment.
In the present invention, the term "sulfonamide" refers to a compound having the structure-SO 2 A group of NRR ', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine fragment.
"Ketocarbonyl" refers to R-C (=O) -, where R is alkyl, cycloalkyl, etc., as described above.
When the substituent is a non-terminal substituent, it is a subunit of the corresponding group, e.g., alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl corresponds to heterocyclylene, alkoxy corresponds to alkyleneoxy, and the like.
In the present invention, each of the above-mentioned alkyl groups, alkoxy groups, cycloalkyl groups, heteroalkyl groups, aryl groups, heteroaryl groups, cycloheteroalkyl groups, alkenyl groups, alkyne groups, heterocycle groups, heterocyclic groups and the like may be substituted or unsubstituted.
In the present invention, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The specific substituents are those described in the foregoing for each of the examples or are those found in each of the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, which may be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., a single halogen substituent or a multiple halogen substituent, the latter such as trifluoromethyl or containing Cl) 3 Alkyl group of (c), cyano group, nitro group, oxo group (e.g., =o), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, alkynyl group, heterocycle, aromatic ring, OR group a 、SR a 、S(＝O)R e 、S(＝O) 2 R e 、P(＝O) 2 R e 、S(＝O) 2 OR e ，P(＝O) 2 OR e 、NR b R c 、NR b S(＝O) 2 R e 、NR b P(＝O) 2 R e 、S(＝O) 2 NR b R c 、P(＝O) 2 NR b R c 、C(＝O)OR d 、C(＝O)R a 、C(＝O)NR b R c 、OC(＝O)R a 、OC(＝O)NR b R c 、NR b C(＝O)OR e 、NR d C(＝O)NR b R c 、NR d S(＝O) 2 NR b R c 、NR d P(＝O) 2 NR b R c 、NR b C(＝O)R a Or NR b P(＝O) 2 R e Wherein R is a Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle or aromatic ring, R b 、R c And R is d Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R b And R is c Together with the N atom, may form a heterocyclic ring; r is R e Can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle or aromatic ring. Typical substituents described above, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring, may be optionally substituted. Such as (but not limited to): halogen, hydroxy, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, C1-C6 ureido, and the like.
"cyano" refers to a-CN group.
"nitro" means-NO 2 。
"hydroxy" refers to-OH.
"amino" means-NH 2 Or RNH-, wherein R is a ketocarbonyl group, a sulfonyl group, a sulfonamide group, R a -C(＝O)-、R a R b N-C (=o) -etc., wherein R a And R is b Alkyl, cycloalkyl, aryl, heteroaryl, and the like.
"halogen (halo)" refers to any halogen group, such as, -F, -Cl, -Br, or-I.
"deuterated" refers to a compound in which one hydrogen atom (H) or a plurality of hydrogen atoms (H) in the compound are replaced with deuterium atoms (D).
In the present invention, the term "plurality" independently means 2, 3, 4, 5.
The structural formula of the carbamate group is-NH-C (=O) -O-R, wherein R is alkyl, aryl or heteroaryl.
Active ingredient
As used herein, the term "compound of the invention" or "active ingredient of the invention" is used interchangeably to refer to a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (e.g., deuterated compound) or prodrug thereof. The term also includes racemates and optical isomers.
The compound of formula I has the following structure:
wherein R is 1 、R 2 、R 3 、R 4 Is defined as above.
In another preferred embodiment, R 1 、R 2 、R 3 、R 4 Each independently is a corresponding group in a particular compound described herein.
Salts which may be formed with the compounds of the present invention are also within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include salts thereof. The term "salt" as used herein refers to salts formed with inorganic or organic acids and bases in the acid or base form. Furthermore, when the compound of the present invention contains a basic moiety, it includes, but is not limited to, pyridine or imidazole, and an acidic moiety, including, but not limited to, carboxylic acids, the possible formation of zwitterions ("inner salts") are included within the term "salts". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during the preparation process. The compounds of the invention may form salts, for example, by reacting compound I with an amount of, for example, an equivalent of, an acid or base, salting out in a medium, or lyophilizing in aqueous solution.
The compounds of the present invention contain basic fragments, including but not limited to amine or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that may be salified include acetates (e.g., with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, mesylate, naphthalene sulfonate (e.g., 2-naphthalene sulfonate), nicotinate, nitrate, oxalate, pectate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluene sulfonate such as p-toluenesulfonate, dodecanoate, and the like.
Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, that may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hydrabamine (salts with N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and dipentyl sulfates), long chain halides (e.g., decyl, dodecyl, tetradecyl and tetradecyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenyl bromides), and the like.
Prodrugs and solvates (or solvates) of the compounds of the invention are also within the scope of coverage.
The term "prodrug" as used herein refers to a compound that undergoes chemical conversion by metabolic or chemical processes to produce a compound, salt, or solvate of the invention when used in the treatment of a related disorder. The compounds of the present invention include solvates, such as hydrates.
The compounds, salts or solvates of the present invention, may exist in tautomeric forms (e.g., amides and imine ethers). All of these tautomers are part of the present invention.
Stereoisomers of all compounds (e.g., those having asymmetric carbon atoms which may be present as a result of various substitutions), including enantiomeric and diastereoisomeric forms thereof, are contemplated as falling within the scope of the present invention. The compounds of the invention may be stereoisomers alone, which may not be present with other isomers (e.g., having particular activity as a pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures with all or a portion of the other stereoisomers. The chiral center of the present invention has two configurations, S or R, defined by the International Association of theory and application chemistry (IUPAC) 1974. The racemic forms can be resolved by physical methods, such as fractional crystallization, or by separation of crystals by derivatization into diastereomers, or by chiral column chromatography. Individual optical isomers may be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.
The compounds of the present invention are prepared, isolated and purified in sequence to give the compounds in an amount of 90% by weight or more, for example 95% or more and 99% or more ("very pure" compounds), as listed in the text description. Such "very pure" compounds of the invention are also included herein as part of the invention.
All configurational isomers of the compounds of the present invention are within the scope of coverage, whether in mixtures, pure or very pure form. The definition of compounds in the present invention includes both the cis (Z) and the trans (E) olefin isomers, as well as the cis and trans isomers of carbocycles and heterocycles.
Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
Specific functional groups and chemical term definitions are described in detail below. For the purposes of the present invention, chemical elements are described in conjunction with Periodic Table of the Elements, CAS version, handbook of Chemistry and Physics,75 th Ed.. The definition of specific functional groups is also described herein. Furthermore, the basic principles of organic chemistry and specific functional groups and reactivities are described in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999, which is incorporated by reference in its entirety.
Certain compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures thereof. In addition, an asymmetric carbon atom may represent a substituent such as an alkyl group. All isomers and mixtures thereof are encompassed by the present invention.
According to the invention, the mixture of isomers may contain various isomer ratios. For example, in a mixture of only two isomers, there may be a combination of: all ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomers are within the scope of the invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are within the scope of the present invention, as would be readily understood by one of ordinary skill in the art.
The present invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as original compounds. In practice it will often occur that one or more atoms are replaced by an atom of a different atomic weight or mass number than it is. Examples of isotopes that can be listed as compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, respectively, such as 2 H、 3 H、 13 C、 11 C、 14 C、 15 N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes or other isotopic atoms containing such compounds are within the scope of the present invention. Certain isotopically-labeled compounds of the present invention, e.g 3 H and 14 radioisotopes of C are also useful in, among other things, tissue distribution experiments of drugs and substrates. Tritium, i.e. tritium 3 H and carbon-14, i.e 14 C, their preparation and detection are relatively easy. Is the first choice in isotopes. In addition, heavier isotopic substitutions such as deuterium, i.e 2 H may be preferred in some cases because of its good metabolic stability, which may be advantageous in certain therapies, such as increasing half-life or decreasing dosage in vivo. Isotopically-labeled compounds can be prepared by conventional methods by using readily available isotopically-labeled reagents in place of non-isotopically-labeled reagents using the protocols disclosed in the examples.
If one is to design the synthesis of a particular enantiomer of a compound of the invention, it may be prepared by asymmetric synthesis or by derivatization with chiral auxiliary, separating the resulting diastereomeric mixture and removing the chiral auxiliary to give the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed therewith using an appropriate optically active acid or base, and then the resulting mixture can be separated by conventional means such as fractional crystallization or chromatography to give the pure enantiomer.
As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to extend their inclusion. In general, the term "substituted", whether appearing before or after the term "optional", in the formulas of the present invention includes substituents, means that the specified structural substituent is substituted for the hydrogen radical. When multiple of a particular structure are substituted at a position with multiple particular substituents, the substituents may be the same or different at each position. The term "substitution" as used herein includes all permissible organic compound substitutions. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any of the permissible organic compounds described hereinabove to supplement the valence state thereof. Furthermore, the present invention is not intended to be limited in any way to allow substitution of organic compounds. The present invention recognizes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds. The term "stable" as used herein refers to a compound that is stable for a period of time sufficient to maintain structural integrity of the compound, preferably for a period of time sufficient to be effective, as used herein for the purposes described above.
Metabolites of the compounds and pharmaceutically acceptable salts thereof, as well as prodrugs that can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof, are also encompassed by the claims of the present application.
Preparation method
The following schemes and examples describe methods for preparing compounds of formula I. The starting materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order of the steps of the reaction scheme may be altered to promote the reaction or to avoid unwanted side reaction products.
The following more particularly describes the preparation method of the compound of the formula I, but these specific methods do not limit the present invention. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present invention pertains.
Typically, in the preparation scheme, each reaction is carried out in a suitable solvent, typically under inert gas, at 0 to 150℃for a period of typically 2 to 24 hours.
The preparation method is preferably as follows:
The method comprises the following steps:
the first step: under the action of alkali in inert solvents (such as tetrahydrofuran, 1, 2-dichloroethane, N-dimethylformamide, dioxane, ethylene glycol dimethyl ether and the like), SM3 and SM2 react to obtain M1;
and a second step of: m1 is reacted with SM1 in an inert solvent (e.g., N-dimethylformamide, dioxane, ethanol, dimethylsulfoxide, etc.), under basic (e.g., potassium carbonate, potassium phosphate, triethylamine, etc.) conditions to form T (i.e., a compound of formula I).
In the above formulae, R 1 、R 2 、R 3 、R 4 As described above.
Unless otherwise indicated, all starting materials mentioned above may be purchased commercially or synthesized according to reported literature.
Pharmaceutical compositions and methods of administration
The pharmaceutical composition provided by the invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
The compounds of formula I may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode of administration and dosage of the original drug may remain unchanged, while the compound of formula I is administered simultaneously or subsequently. When the compound of formula I is administered simultaneously with one or more other drugs, it may be preferable to use a pharmaceutical composition containing one or more known drugs together with the compound of formula I. Drug combinations also include administration of the compound of formula I with one or more other known drugs over overlapping time periods. When a compound of formula I is administered in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of the compound of formula I alone.
Drugs or active ingredients that may be used in combination with the compounds of formula I include, but are not limited to: PD-1 inhibitors (e.g., nafimab, pemumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009, or biological analogues of the above, etc.), PD-L1 inhibitors (e.g., dewaruzumab, altezumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311, or biological analogues of the above, etc.), CD20 antibodies (e.g., rituximab, ab You Tuozhu monoclonal antibody, ofatumumab, tositumumab, etc.), CD47 antibodies (e.g., hu5F9-G4, CC-90002, NI-TTI, TTI-622, OSE-172, SRF-231, ALX-148, NI 1701, etc.), and the like SHR-1603, IBI188, IMM 01), ALK inhibitors (e.g., ceritinib, ai Leti, buntinib, loratidine, oxcartinib, PI3K inhibitors (e.g., idarubirist, dactolisib, taselisib, buparlisib, etc.), BTK inhibitors (e.g., ibrutinib, tirabrutinib, acalabrutinib, etc.), EGFR inhibitors (e.g., afatinib, gefitinib, erlotinib, lapatinib, dacatinib, icotinib, etc.), VEGFR inhibitors (e.g., sorafenib, pazopanib, revatinib, cabatinib, sunitinib, donafinib, etc.), HDAC inhibitors (e.g., givinostat, droxinostat, entinostat, daritinib, tacroline, etc.), CDK inhibitors (e.g., pamitinib, rapamicinib, abemaciclib, lerociclib, etc.), MEK inhibitors (e.g., semitinib (AZD 6244), sunitinib, trametinib (GSK 1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040, etc.), akt inhibitors (e.g., MK-2206, ipatasertib, capivasertib, afuresertib, uprosertib, etc.), mTOR inhibitors (e.g., vistuertib, etc.), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (e.g., ceritinib, oxatinib, linsitinib, BMS-754807, GSK1838705a, etc.), ER antagonists or degradation agents (e.g., tamoxifen, fulvestrant, etc.), aromatase inhibitors (e.g., letrozole, etc.), BCL2 or BCL-XL inhibitors (e.g., ABT-199, ABT-263, etc.), hedgehog inhibitors (e.g., vismodegib, cyclopamine, etc.), chemotherapeutic agents (e.g., cisplatin, etoposide, topotecan, etc.), PARP inhibitors (e.g., olaparib, veliparib, rucaparib, etc.), ATR/ATM inhibitors (e.g., ceralasertib, berzosertib, etc.), or combinations thereof.
Dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, pellicle, dripping pill, external liniment, controlled release or sustained release preparation, or nanometer preparation.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 10-1000mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g. ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed 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, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings 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 waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise 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 nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The methods of treatment of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: a pharmaceutically acceptable carrier is admixed with a compound of formula I according to the invention or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, thereby forming a pharmaceutical composition.
The invention also provides a treatment method, which comprises the following steps: administering a compound of formula I, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, or a pharmaceutical composition as described herein, to a subject in need thereof, for inhibiting CDK7.
Compared with the prior art, the invention has the following main advantages:
(1) The compounds of the present invention have excellent inhibitory ability against CDK7 kinase;
(2) The compound has lower toxic and side effects;
(3) The compound has better pharmacodynamics and pharmacokinetics.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions such as Sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
Examples
The technical scheme of the invention is further described below, but the protection scope of the invention is not limited to the scheme.
Example T-01
The compound synthesized by the invention:
the experimental procedure was as follows:
1. synthesis of intermediate SM1
The synthetic route is as follows:
1. synthesis of intermediate SM1
Compound 1 (5 g,1.0 eq), 4-Boc-aminopiperidine (5.5 g,1.2 eq), DIPEA (3 g,1.0 eq) and solvent DMF (50 ml) were mixed well in a 100ml round bottom flask and reacted for 1.5h at room temperature. TLC showed no starting material remaining, and the reaction was quenched with water and extracted with EA. The EA phase was separated and purified by column chromatography to obtain 4g of compound SM1.HPLC purity 97.6%. LC-MS [ M+1]:381.
2. synthesis of Compound T-01
The synthetic route is as follows:
1. synthesis of Compound 2
SM1 (288 mg,1.0 eq), 3-amino-2-butanol (100 mg,1.05 eq), triethylamine (115 mg,1.5 eq) and absolute ethanol (6 mL) were mixed well in a 100mL round bottom flask, and after three substitutions with nitrogen, the reaction was heated at 80℃for 22h under nitrogen protection. TLC showed no starting material remained and the reaction was directly purified by column chromatography to give 291mg of compound 2.LC-MS [ M+1]:434.
2. Synthesis of Compound T-01
Compound 2 (2910 mg,1.0 eq) was dissolved in solvent dichloromethane (3 mL) in a 100mL round bottom flask, TFA (254 mL,5.0 eq) was added and mixed well and reacted at room temperature for 24h. TLC showed no starting material remaining, and the reaction solution was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate, and extracted with EA. The EA phase was isolated and purified using prep plates to give 100mg of compound T-01.HPLC purity 99.2%. LC-MS [ M+1]:334.
referring to the procedure of example T-01, the following compounds were synthesized:
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test example 1 enzyme Activity test
Biological activity test experiments are performed on some of the compounds of the above examples and comparative examples.
The biological activity test experimental procedure is as follows:
test compound CDK7 kinase IC 50 Value detection (detection at tin-free herborist).
1. Compound preparation:
compound powder was dissolved in 100% dmso to prepare 10mM stock solution, the stock solution was further diluted to 0.5mM as the starting concentration, and serial 3-fold dilutions were made to obtain 10 compound solutions of different concentrations, compound and enzyme pre-incubation times were 0 min and 60 min, respectively, using multiplex well assays. By Staurosporine compound (structural formula is) As a positive control, the activity of the compound on CDK7 kinase was tested using the method of Mobility shift assay. / >
2. Kinase reaction process:
1) The compound solution and positive control were diluted 8.3-fold with double distilled water and added to 384-well plates at 2 uL/well each;
(2) 6nM CDK7/Cyclin H/MAT1 kinase solution was added to each of the compound wells and positive control wells;
(3) Incubating for 0 and 60 minutes at room temperature;
(4) Adding 2mM ATP and 2pM 5-FAM-CDK7 peptide substrate (5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK) solution;
(5) Incubating 384 well plates for 30 minutes at 25 ℃;
(6) 4uL of 120mM EDTA was added to stop the kinase reaction;
(7) Conversion was read with a Caliper/LabChip EZ Reader (Perkin Elmer);
(8) Curve fitting by GraphPad Prism 8 software to obtain IC 50 Numerical values.
By the above detection, IC of the inhibitory activity of the test sample against CDK7 kinase is obtained 50 (nM) values are shown in Table 1, where A.ltoreq.10 nM;10nM<B<500nM；C≥500nM。
From the table above, by in vitro biological activity screening, staurosporine (Staurosporine) is used as a reference substance, and the compound synthesized by the application has good inhibitory ability on CDK7 kinase, and is expected to be further developed into a medicament for regulating CDK7 kinase activity or treating CDK7 related diseases.
Test example 2 cell anti-proliferation assay
1. Experimental materials and apparatus:
ovarian cancer cells a2780, colorectal cancer cells WiDr were purchased from bei na-invasive biotechnology limited. DMEM medium (Bio-Channel), DMSO (dimethyl sulfoxide), MTT (thiazole blue), 0.25% edta-Tripsin (pancreatin digest), 1xPBS (phosphate buffer, PH 7.2), 96 well plates (Corning), fetal Bovine Serum (FBS), 10,000u/mL penicillin-G/streptomycin, high speed cryocentrifuge (EPPENDORF 5810R), enzyme linked immunosorbent assay (Tecan Spark).
2. Experiment preparation:
1. cell plating
A) Tumor cells were cultured in DMEM (high sugar, 10% FBS and 100U/mL penicillin-G/streptomycin) at 37℃under conditions of 5% CO2 and saturated humidity to 80-90% concentration.
B) Removing the culture medium in the 10cm dish;
c) The cells were rinsed once with 10ml of 1 xPBS;
d) Adding 4ml of 0.25% EDTA-Tripsin, placing into a 37 ℃ and 5% CO2 incubator, performing pancreatin digestion for 5 minutes, transferring into a 15ml centrifuge tube, centrifuging for 5 minutes with 200g, and discarding the supernatant to obtain cell sediment;
e) Resuspended in 4ml DMEM medium, counted and adjusted to 50,000 cells/ml.
F) The cell suspension was added to a 96-well plate at 100. Mu.L per well volume and incubated overnight at 37℃in a 5% CO2 incubator.
2. Treatment with a compound
Dilution of the Compounds
A) Preparing a test compound gradient dilution solution: test compounds were prepared as 1mM stock solution, then 1.5. Mu.l stock solution was dissolved in 1.5ml of DMSO-free medium, and 3-fold serial gradient dilutions were made in 0.1% DMSO medium for a total of 9 concentrations, and the compound concentrations after dilution were as follows:
333.33nM，111.11nM，37.03nM，12.35nM，4.15nM，1.37nM，0.46nM，0.15nM
b) After fully and uniformly mixing, respectively taking 100 mu L of culture compound solution to replace culture solution in a cell culture plate, wherein each concentration is 4 compound holes;
c) Cells were transferred to an incubator for 3 days.
3. MTT assay
A) Taking out the cell culture plate, and adding 5mg/ml MTT 10 mu L into a biosafety cabinet;
b) Placing the cell culture plate back into the incubator for further incubation for 3 hours;
c) The cell culture plate was removed from the culture, 100. Mu.L of isopropyl alcohol (0.4 mM HCl,0.1% NP-40) was added, and the mixture was shaken at room temperature for 30 minutes;
d) The absorbance was measured on a TECAN enzyme-linked immunosorbent assay (elisa) by selecting a wavelength of 570 nm.
4. Data analysis
The percent retention (%cell availability) was calculated using the following formula:
％Cell Viability＝100％×(Lum_Sample-Lum_LC)/(Lum_HC-Lum_LC)
Lum_HC 0.1% DMSO control cell reading
Lum_sample cell reading of added compounds
Lum_LC blank Medium reading
IC50 values were obtained by curve fitting with GraphPad Prism 8 software.
As shown in Table 2, wherein A.ltoreq.10 nM;10nM < B <500nM; c is more than or equal to 500nM.
As can be seen from Table 2, the compounds of the present invention have very good inhibitory effect on ovarian cancer cells A2780 and colorectal cancer cells WiDr.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (10)

1. A compound useful as a CDK7 kinase inhibitor, wherein the compound is a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, or prodrug thereof,
wherein:
R 1 selected from the group consisting of:
R 2 selected from the group consisting of: H. CF (compact flash) 3 、Cl、Br、CH 3 、Cyclopropyl, phenyl;
R 3 is H;
or R is 2 And R is R 3 Forming a saturated or unsaturated 5-6 membered cycloalkyl group;
R 4 selected from the group consisting of:
X 1 、X 2 、X 3 、X 4 each independently selected from the group consisting of: NR (NR) 6 、CR 7 R 8 、O、S；
Each R is 6 、R 7 、R 8 Independently selected from the group consisting of: H. C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylAn amine group, a 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O, S, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, S;
each m, n is independently selected from the group consisting of: 0. 1, 2, 3, 4, 5.
2. The compound of claim 1, wherein R 1 Selected from the group consisting of:
3. a compound according to claim 1 wherein,
R 1 selected from the group consisting of:
R 2 selected from the group consisting of: H. CF (compact flash) 3 、Cl、Br、CH 3 、
R 3 H.
4. A compound according to claim 1 wherein,
R 4 Selected from the group consisting of:
R 2 selected from the group consisting of: H. CF (compact flash) 3 、Cl。
5. The compound of claim 1, wherein the compound is selected from the group consisting of:
6. a pharmaceutical composition comprising one or more prophylactically and/or therapeutically effective amounts of a compound of claim 1, and a pharmaceutically acceptable carrier.
7. Use of a compound according to claim 1 for the manufacture of a medicament for use as a CDK7 kinase inhibitor.
8. Use of a compound according to claim 1 for the manufacture of a medicament for modulating CDK7 kinase activity or treating a CDK 7-related disorder.
9. The use according to claim 8, wherein the CDK 7-related disorder is selected from the group consisting of: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
10. The use of claim 9, wherein the cancer is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, renal cancer, esophageal cancer, uterine cancer.
CN202210788052.4A 2022-07-04 2022-07-04 Compounds useful as CDK7 kinase inhibitors and uses thereof Pending CN117384135A (en)

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