CN117430597A - Compounds useful as CDK4 kinase inhibitors and uses thereof - Google Patents

Compounds useful as CDK4 kinase inhibitors and uses thereof Download PDF

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CN117430597A
CN117430597A CN202210833627.XA CN202210833627A CN117430597A CN 117430597 A CN117430597 A CN 117430597A CN 202210833627 A CN202210833627 A CN 202210833627A CN 117430597 A CN117430597 A CN 117430597A
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compound
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alkyl
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梁阿朋
王凯
陈少清
吴豫生
李钧
尹洲
李美华
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Deuracor Therapeutic Inc
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Priority to PCT/CN2023/107308 priority patent/WO2024012543A1/en
Priority to CN202380018443.0A priority patent/CN118632847A/en
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Abstract

The present invention relates to compounds useful as inhibitors of CDK4 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 Kinases (CDKs) for the treatment or prophylaxis of proliferative diseases such as cancer, in particular for the modulation and treatment of diseases associated with aberrant activity of cyclin dependent kinases (CDKs 4).

Description

Compounds useful as CDK4 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 CDK4 kinase and their use in modulating CDK4 kinase activity or treating CDK4 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. CDK inhibitors have now been shown to be useful in the treatment of cancer.
CDK4 and CDK6 are involved in regulating the cell cycle from G1 to S phase after binding to Cyclin D. Abnormalities in the cyclin D-CDK4/6-Rb pathway have been reported to be associated with drug resistance progression in endocrine therapy. Currently, a variety of CDK4/6 inhibitors, such as palbociclib, ribociclib, abemaciclib, have been marketed in combination with endocrine therapy for the treatment of advanced or metastatic breast cancer that is Hormone Receptor (HR) positive, human epidermal growth factor 2 (HER 2) negative. However, hematological toxicity such as neutropenia and/or toxic side effects of the gastrointestinal tract often occur during treatment with CDK4/6 inhibitors, resulting in withdrawal or interstitial administration, severely affecting the efficacy and compliance of the drug. Currently, there are research data showing that cyclin D3-CDK6 activity may be associated with these side effects. In view of the current side effects of CDK4/6 dual-target inhibitors, development of a selective CDK4 inhibitor may have better safety and efficacy.
Disclosure of Invention
The invention provides a novel compound with CDK4 kinase inhibitory activity and better pharmacodynamics and pharmacokinetics.
In a first aspect the present invention provides a compound for use as a CDK4 kinase inhibitor, said compound being a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound or prodrug thereof,
Wherein:
x is selected from the group consisting of: n, CR 5 ；
R 1 Selected from the group consisting of: H. methyl, CF 3 F, cl, br, ethyl, isopropyl, cyclopropyl;
R 2 selected from the group consisting of:
R 3 selected from the group consisting of:
R 4 selected from the group consisting of:
each R is 5 Independently selected from the group consisting of: H. hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C10 aryl; the substitution means substitution with one or more substituents selected from the group consisting of: deuterium, halogen, hydroxy, amino, C1-C6 alkylamino, C1-C6 alkoxy;
each m is independently selected from the group consisting of: 0. 1, 2, 3 and 4.
In another preferred embodiment, R 2 Selected from the group consisting of:
R 5 as defined above.
In another preferred embodiment, R 3 Is that
R 5 M is as defined above.
In another preferred embodiment, R 4 Selected from the group consisting of:
R 5 m is as defined above.
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 a prophylactically and/or therapeutically effective amount of a compound according to the first aspect of the invention, 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 CDK4 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 CDK4 kinase activity or treating a CDK 4-related disorder.
In another preferred embodiment, the CDK 4-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, liposarcoma.
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 CDK4 kinase inhibitory activity. In addition, the compounds have excellent inhibitory activity against CDK4 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 as part of another group)" refers to a monovalent straight or branched chain saturated hydrocarbon group containing 1 to 12 carbon atoms consisting of only carbon and hydrogen atoms. Alkyl is preferably C1-C6 alkyl (i.e., containing 1, 2, 3, 4, 5, or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butylButyl, 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. It is possible to give a range of values, 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 means having twoHeteroaryl groups at the 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.
"Heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein heterocyclyl and alkyl are as 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 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, heteroaryl and the like.
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:
R 1 、R 2 、R 3 、R 4 x is defined as above.
In another preferred embodiment, R 1 、R 2 、R 3 、R 4 X are each independently a specific group corresponding to a specific compound of the present invention.
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 due to its good metabolic stabilityThere are advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore, may be preferred in certain situations. 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 protection, 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: in a solvent (such as dioxane// water or toluene/water), under the action of a catalyst, SM1 and S1/S1' react at 70-120 ℃ to generate SM2;
and a second step of: in a solvent (dichloromethane, 1, 2-dichloroethane), oxidizing reaction is carried out under the action of an oxidant (m-chloroperoxybenzoic acid (m-CPBA), potassium persulfate and the like) to obtain a product SM3.
And a third step of: in a solvent, SM3 and S2 react under alkaline conditions to obtain a product T.
In the above formulae, R 1 、R 2 、R 3 、R 4 And X is 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 ofCompatible 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 CDK4.
Compared with the prior art, the invention has the following main advantages:
(1) The compound has excellent inhibitory capacity on CDK4 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 1
The compound synthesized by the invention:
the experimental procedure was as follows:
synthesis of Compound T-01
The synthetic route is as follows:
1. synthesis of Compound SM2
SM 1 (300.0 mg,1.0 e.q.), phenylboronic acid (154.8 mg,1.5 e.q.), potassium carbonate (233.7 mg,2.0 e.q.) and Pd (dppf) Cl 2 (18.6 mg,0.03 e.q.) was added sequentially to a 25mL three-port reaction flask, dioxane and water mixed solvent (v/v=10:1) were added under nitrogen protection, N2 was replaced three times, and the temperature was raised to reflux reaction. TLC showed no starting material remained and the reaction was complete. Cooling to room temperature, filtering with diatomite, washing with proper amount of ethyl acetate, directly concentrating the organic phase, separating and purifying by silica gel chromatography to obtain white solid SM2, LCMS: [ M+H ]] + = 352.50, yield 97%.
2. Synthesis of Compound SM3
Compound SM2 (290 mg,1.0 e.q.) was added to a 50mL three-necked flask, and 15mL of dichloromethane was added to dissolve the solution85% m-CPBA (335.1 mg,2.0 e.q.) was added and reacted at room temperature under nitrogen. TLC showed no starting material remained and the reaction was complete. Suction filtration, washing a filter cake with a proper amount of dichloromethane, concentrating the filtrate, and separating and purifying by silica gel column chromatography to obtain white solid SM3, LCMS: [ M+H ]] + ＝384.60，[2M+Na] + =789.90, hplc purity 99% yield 75.9%.
3. Synthesis of Compound T-01
Compound SM3 (210 mg,1.0 e.q.), (3 s,4 r) -4-aminooxahex-3-ol hydrochloride (126 mg,1.5 e.q.)) and DIPEA (283 mg,4.0 e.q.)) were added sequentially to a 25mL three-necked flask, DMSO was added, and the temperature was raised to 50 ℃ under nitrogen protection for reaction. TLC showed no starting material remained and the reaction was complete. The reaction solution was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give T-01 as pale white solid, lcms: [ M+H ]] + ＝421.5,[2M+Na] + =864.0, hplc purity 99.9% yield 52.2%.
1 H NMR(400MHz,Chloroform-d)δ8.59(s,1H),7.43(t,J＝8.0Hz,2H),7.35(t,J＝8.0Hz,1H),7.22(d,J＝8.0Hz,2H),5.89(t,J＝8.0Hz,1H),5.34(s,1H),4.09(dd,J＝12.0,4.0Hz,1H),4.01(dd,J＝12.0,4.0Hz,1H),3.95(s,1H),3.65(m,1H),3.50(td,J＝12.0,4.0Hz,1H),3.23(t,J＝12.0Hz,1H),2.29(m,2H),2.20(s,3H),2.13–1.98(m,3H),1.92–1.80(m,2H),1.62(m,3H)。
Referring to the synthetic method of example 1, the following compounds were synthesized:
example 2
The compound synthesized by the invention:
the experimental procedure was as follows:
2. synthesis of Compound T-09
The synthetic route is as follows:
synthesis of Compound T-09
Compound SM1 (100 mg,1.0 e.q.) 5- [ (4-methylpiperazin-1-yl) methyl]Pyridine-2-amine (53.2 mg,1.0 e.q.) and LiHDMS in THF (1.0M, 0.52mL,2.0 e.q.) were added to 2mL of toluene and reacted under nitrogen at 90℃for 1 hour by microwave heating. After the reaction was completed, the mixture was cooled to room temperature, the separated liquid was extracted with saturated sodium chloride and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and then purified by preparative chromatography to give 40mg of compound T-09, lcms: [ M+H ]] + =514.3, hplc purity 97.29% yield 30.1%.
1 H NMR(400MHz,Chloroform-d)δ8.85(s,1H),8.49(s,1H),8.33(d,J＝8.0Hz,1H),8.26(d,J＝4.0Hz,1H),7.71(dd,J＝8.0,4.0Hz,1H),7.45(d,J＝4.0Hz,1H),6.41(d,J＝4.0Hz,1H),5.97(p,J＝8.0Hz,1H),3.96(s,3H),3.51(s,2H),2.55(s,4H),2.42(s,3H),2.35(s,3H),2.25(s,4H),2.10–2.01(m,2H),1.94–1.82(m,2H),1.73–1.60(m,3H)。
Referring to the synthetic method of example 2, the following compounds were synthesized:
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:
1. kinase activity assay:
test compounds for CDK4, CDK6 kinase IC 50 And (5) detecting a value.
Information on (one) reagent
(II) device information
Apparatus and method for controlling the operation of a device Branding Goods number
Incubator Thermo Scientific -
Shaker QILINBEIER -
EZ Reader PerkinElmer 122919
Liquid Handler Labcyte Inc. Echo 550
Liquid Handler TECAN EVO200
(III) study design
(1) Compound preparation:
(1) test compounds were formulated as 0.5mM DMSO solutions, while the positive control drug Palbociclib (Palbociclib) was also formulated as 0.5mM DMSO solutions.
(2) Three-fold dilution gave 10 solutions of the compound at different concentrations.
(2) Enzyme assay was performed:
(1) as shown below, a 1.3 Xenzyme solution comprising enzyme, substrate and cofactor was prepared.
(2) mu.L of 1.3 Xenzyme solution was added to each well and incubated for 30 minutes at room temperature.
(3) The reaction was started by adding 5 μl of 4x ATP solution, each test well contained the ingredients in the list, and the final volume was 20 μl.
(4) Incubation was carried out for 150 minutes, and then the reaction was stopped by adding 75. Mu.L of buffer (containing 0.5M EDTA).
(5) The data from each test well was read with EZ for analysis.
(3) Data analysis:
the percentage of inhibition was calculated using the read Conversion Rate (CR) according to the following formula:
DMSO-treated wells were used as positive controls (positive controls) and wells without enzyme were used as negative controls (negative controls).
Percent inhibition = 100-100 x ((CRPC-CRSample)/(CRPC-CRNC)).
By the above detection, IC of the test sample for inhibiting CDK4 and CDK6 kinase is obtained 50 The (nM) values are shown in Table 1.
TABLE 1
From the above table, through in vitro biological activity screening, palbociclib is used as a reference substance, and the compound synthesized by the application has good inhibition capability on CDK4 kinase, and CDK4 and CDK6 kinase activities have good selectivity, so that side effects such as hematology and the like caused by inhibition on CDK6 are likely to be reduced greatly. Is expected to be further developed into medicines for regulating CDK4 kinase activity or treating CDK4 related diseases.
Test example 2 cell anti-proliferation assay
1. Experimental materials and apparatus:
human breast cancer cell MCF-7, ovarian cancer cell A2780.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 at 37℃with 5% CO 2 And saturated humidity, in DMEM (high sugar, 10% FBS and 100U/mL penicillin-G/streptomycin) 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) 4ml of 0.25% EDTA-Tripsin was added and the mixture was placed at 37℃with 5% CO 2 Performing pancreatin digestion on the incubator for 5 minutes, transferring the incubator to a 15ml centrifuge tube, centrifuging the incubator for 5 minutes at 200g, and discarding the supernatant to obtain a cell precipitate;
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 a volume of 100. Mu.L per well at 37℃with 5% CO 2 Culturing overnight in an incubator.
2. Treatment with a compound
Dilution of the Compounds
A) Preparing a test compound gradient dilution solution: test compounds were formulated as 1mM stock solutions. Then, 1.5. Mu.l stock solution was dissolved in 1.5ml of DMSO-free medium, and 3-fold serial gradient dilution was performed with 0.1% DMSO medium for a total of 9 concentrations, and the compound concentration after dilution was 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 5 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
Curve fitting by GraphPad Prism 8 software to obtain IC 50 Numerical value (unit nM).
As shown in table 2.
TABLE 2
Compounds of formula (I) MCF-7 A2780
T-02 116
T-04 137.8
T-11 238 636.7
Experimental example 3 preclinical rat pharmacokinetic test
1. Experimental materials and apparatus:
healthy adult SD rats, male, 6-8 weeks old, weight 200-300 grams purchased from XX company. EDTA-Na2 anticoagulant. Analytical balances, animal weight scales, magnetic stirrers, refrigerated centrifuges, single-pass manual pipettors, and the like.
2. The experimental process comprises the following steps:
1. pharmaceutical formulation
Precisely weighing about 10mg of sample to be measured, adding 5% of converted DMSO for dissolution, adding 10 percent of solutol HS-15 and 85% of physiological saline, carrying out ultrasonic treatment, and carrying out vortex mixing to obtain a solution with the concentration of 1 mg/mL; is prepared fresh before use.
Aspirate 0.2mL of sample into a 1.5mL centrifuge tube and store at-80℃for dosing solution concentration analysis.
2. Animal preparation
Animals are kept in a rat cage, and fasted (not less than 10 h) is started in the day before the test, but water is not forbidden; the day of the test was weighed separately and marked on the tail. Blank blood was collected separately prior to dosing. The blood collection mode adopts tail vein blood collection.
3. Administration of drugs
Route of administration: stomach (p.o.)
Dosage of administration: 10mg/kg
Dosing volume: 10mL/kg
The operation flow is as follows: the rat is caught by the left hand with the anti-biting glove, the rat is erected, the 16-gauge stomach-filling needle is inserted from the throat of the mouth, the needle is inserted under the condition that no obvious resistance is felt by a heuristic, and then the medicine is injected into the stomach.
4. Sample collection
The tested animals respectively collect 0.1ml of whole blood before and after the administration for 0.5h,1h,2h,4h,6h,8h,12h and 24h in EDTA-Na2 anticoagulant tube, mix them up and down for 3-4 times, centrifuge for 5min at 4 ℃ and separate plasma at 10000g, and store at-80 ℃ to be tested. The blood collection mode adopts tail vein blood collection.
Specifically, the rat is fixed on the fixer, so that the tail of the rat can be completely exposed, the tail of the rat is wiped by alcohol, the skin on the surface of the rat absorbs the alcohol, the obvious effect of vein diastole is achieved, proper veins are selected from two sides, and a needle is inserted at about one third of the position away from the tail tip. The syringe adopts insulin syringe, and the syringe needle inclined plane upwards advances the needle, and the back horse is parallel after feeling puncture skin, and it is little to feel that the syringe needle slides resistance in the vein, has the back blood in the syringe. I.e., into the vein, about 0.1-0.2ml of whole blood is withdrawn. After the needle is pulled out, the hemostatic is pressed.
3. Sample analysis:
preparation of a standard curve: respectively sucking 25 mu L of rat blank plasma into a centrifuge tube, adding 25 mu L of prepared standard series solution (prepared by methanol), adding 200 mu L of internal standard solution (prepared by methanol), mixing by vortex for 2min, and centrifuging at 4 ℃ for 10min at 10000 g.
Unknown plasma sample treatment: 25 mu L of rat drug-containing plasma is respectively sucked, 25 mu L of methanol and 200 mu L of internal standard solution are sequentially added, vortex mixing is carried out for 2min, and centrifugation is carried out for 10min at 10000g at 4 ℃. The supernatant was taken for LC/MS/MS detection.
4. Data processing
And establishing a quantitative detection method of the compound to be detected by utilizing a Shimadzu liquid phase and a Triple Quad TM 6500+AB mass spectrum. The concentration of the original drug in the plasma was measured. Drawing a blood concentration-time curve, and calculating main pharmacokinetic parameters by adopting a non-atrioventricular model in winnonlin Phoenix software.
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 CDK4 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:
x is selected from the group consisting of: n, CR 5 ；
R 1 Selected from the group consisting of: H. methyl, CF 3 F, cl, br, ethyl, isopropyl, cyclopropyl;
R 2 selected from the group consisting of:
R 3 selected from the group consisting of:
R 4 selected from the group consisting of:
each R is 5 Independently selected from the group consisting of: H. hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C10 aryl; the substitution means substitution with one or more substituents selected from the group consisting of: deuterium, halogen, hydroxy, amino, C1-C6 alkylamino, C1-C6 alkoxy;
each m is independently selected from the group consisting of: 0. 1, 2, 3 and 4.
2. The compound of claim 1, wherein R 2 Selected from the group consisting of:
R 5 as defined in claim 1.
3. The compound of claim 1, wherein R 3 Is that
R 5 M is as defined in claim 1.
4. A compound according to claim 1 wherein,
R 4 selected from the group consisting of:
R 5 m is as defined in claim 1Meaning.
5. The compound of claim 1, wherein the compound is selected from the group consisting of:
6. the compound of claim 1, wherein 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.
7. A pharmaceutical composition comprising a prophylactically and/or therapeutically effective amount of a compound of claim 1, and a pharmaceutically acceptable carrier.
8. Use of a compound according to claim 1 for the manufacture of a medicament for use as a CDK4 kinase inhibitor.
9. Use of a compound according to claim 1 for the manufacture of a medicament for modulating CDK4 kinase activity or treating a CDK 4-related disorder.
10. The use according to claim 9, wherein the CDK 4-related disorder is selected from the group consisting of: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
CN202210833627.XA 2022-07-14 2022-07-14 Compounds useful as CDK4 kinase inhibitors and uses thereof Pending CN117430597A (en)

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