Dihydroisoquinolinone and isoindolinone derivatives and their uses

Abstract

The present invention relates to a kinase inhibitor, which comprises a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof. The present invention also provides a method and use of using the inhibitor to treat diseases related to CDK9 and / or its mutation activity.

Description

Technical Field

[0001] The present invention relates to the pharmaceutical field, in particular to a compound containing a dihydroisoquinolinone / isoindolone structure and a pyrimidine / pyridine structure and a preparation method thereof, and a method and use thereof for treating and / or preventing diseases. Background Art

[0002] The cyclin-dependent kinase (CDK) protein family consists of members that are key regulators of the cell division cycle (cell cycle CDKs), members that participate in gene transcription regulation (transcription CDKs), and members with other functions. CDKs require activation of associations with regulatory cyclin subunits. CDK1 / cyclin B, CDK2 / cyclin A, CDK2 / cyclin E, CDK4 / cyclin D, and CDK6 / cyclin D in the cell cycle CDKs are successively activated to drive cells into and through the cell division cycle. CDK9 / cyclin T and CDK7 / cyclin H in the transcription CDKs regulate the activity of RNA polymerase II through phosphorylation of the carboxyl terminal domain (CTD). Positive transcription factor b (P-TEFb) is a heterodimer of CDK9 and one of the four cyclin partners (cyclin T1, cyclin K, cyclin T2a or T2b).

[0003] CDK9 (NCBI GenBank Gene ID 1025) is exclusively involved in transcriptional regulation, whereas CDK7 is additionally involved in cell cycle regulation as a CDK-activating kinase (CAK).

[0004] The transcription of gene by RNA polymerase II is initiated by the assembly of pre-initiation complex in promoter region and phosphorylation of Ser5 and Ser7 of CTD by CDK7 / cyclin H. For most genes, RNA polymerase II stops mRNA transcription after it moves 20-40 nucleotides along DNA template. This promoter proximal pause of RNA polymerase II is mediated by negative elongation factor, and is considered to be the main control mechanism (Cho et al., Cell Cycle 9, 1697, 2010) that regulates the expression of various stimuli of rapid induction. P-TEFb is crucially involved in overcoming the promoter proximal pause of RNA polymerase II, and phosphorylation and inactivation of Ser2 of CTD and negative elongation factor are converted into a prolific extension state.

[0005] The activity of P-TEFb itself is regulated by multiple mechanisms. About half of the P-TEFb of the cells exists in the form of an inactivation complex with 7SK small nuclear RNA (7SKsnRNA), La-related protein 7 (LARP7 / PIP7S) and hexamethylenebisacetamide induced protein 1 / 2 (HEXIM1 / 2, He et al., Mol Cell 29, 588, 2008)). The remaining half of P-TEFb exists in the form of an active complex containing bromodomain protein Brd4 (Yang et al., Mol Cell 19, 535, 2005). Brd4 recruits P-TEFb to the chromatin region prepared for gene transcription by interacting with acetylated histones. By interacting alternately with positive regulators and negative regulators, P-TEFb is maintained in a functional balance: the P-TEFb representative combined with the 7SK snRNA complex can release the reservoir of active P-TEFb according to the needs of cell transcription and cell proliferation. In addition, the activity of P-TEFb is regulated by post-transcriptional modifications including phosphorylation / dephosphorylation, ubiquitination, and acetylation.

[0006] Dysregulated activity of the CDK9 kinase activity of the P-TEFb heterodimer is associated with a variety of human pathological conditions such as hyperproliferative diseases (eg cancer), virus-induced infectious diseases or cardiovascular diseases.

[0007] Cancer is considered to be a hyperproliferative disorder mediated by an imbalance between proliferation and cell death (apoptosis). High levels of anti-apoptotic Bcl-2-family proteins are found in various human tumors, which lead to prolonged tumor cell survival and treatment resistance. Inhibition of P-TEFb kinase activity is manifested by reduced transcriptional activity of RNA polymerase II, resulting in a reduction in short-lived anti-apoptotic proteins (especially Mcl-1 and XIAP), restoring the ability of tumor cells to undergo apoptosis. A variety of other proteins associated with the transformed tumor phenotype (e.g., Myc, NF-kB response gene transcripts, mitotic kinases) are either short-lived proteins or are encoded by short-lived transcripts (which are sensitive to the reduced activity of RNA polymerase II mediated by P-TEFb inhibition).

[0008] There is no research on the drug resistance of CDK9 inhibitors. The present invention obtains a cell line resistant to CDK9 inhibitors by long-term administration, and finds that the compound of the present invention can inhibit the cell line resistant to CDK9 inhibitors after long-term use. Further protein expression of CDK9 mutant proteins in drug-resistant cell lines was performed, and it was found through detection that the compound of the present invention can overcome the drug-resistant mutation of CDK9.

[0009] In addition, many viruses rely on the transcriptional machinery of host cells to transcribe their own genomes. In the case of HIV-1, RNA polymerase II is recruited to the promoter region in the viral LTR. Viral transcription activator (Tat) protein binds to nascent viral transcripts and overcomes the promoter proximal RNA polymerase II pause caused by the recruitment of P-TEFb, which in turn promotes transcriptional elongation. In addition, Tat protein increases the active P-TEFb part by replacing the P-TEFb inhibitor protein HEXIM1 / 2 in the 7SK snRNA complex. The latest data show that inhibiting the kinase activity of P-TEFb is sufficient to block HIV-1 replication at a kinase inhibitor concentration that is non-cytotoxic to host cells (reviewed in Wang & Fischer, Trends Pharmacol Sci 29, 302, 2008). Similarly, recruitment of P-TEFb by viral proteins has been reported for other viruses, such as the B-cell cancer-associated Epstein-Barr virus, in which the nuclear antigen EBNA2 interacts with P-TEFb (Bark-Jones et al., Oncogene 25, 1775, 2006), and human T-lymphotropic virus type 1 (HTLV-1), in which the transcription activator Tax recruits P-TEFb (Zhou et al., J Virol 80, 4781, 2006).

[0010] Cardiac hypertrophy is an adaptive response of the heart to mechanical overload and pressure (hemodynamic pressure, such as hypertension, myocardial infarction), which can lead to heart failure and death in the long term. Cardiac hypertrophy is manifested as transcriptional activity and RNA polymerase II CTD phosphorylation increased in myocardial cells. It was found that P-TEFb was activated by dissociation from the inactivated 7SK snRNA / HEXIM1 / 2 complex. These findings show that pharmacological inhibition of P-TEFb kinase activity can be used as a therapeutic method for treating cardiac hypertrophy (reviewed in Dey et al., Cell Cycle 6, 1856, 2007).

[0011] In summary, multiple lines of evidence suggest that selective inhibition of the CDK9 kinase activity of the P-TEFb heterodimer (=CDK9 and one of the four cyclin partners (cyclin T1, cyclin K, cyclin T2a or T2b)) represents a new approach for the treatment of diseases such as cancer, viral diseases and / or cardiac diseases. CDK9 belongs to a family of at least 13 closely related kinases, of which a subset of cell cycle CDKs fulfill multiple roles in regulating cell proliferation. Therefore, co-inhibition of cell cycle CDKs (e.g. CDK1 / cyclin B, CDK2 / cyclin A, CDK2 / cyclin E, CDK4 / cyclin D, CDK6 / cyclin D) and CDK9 is expected to affect normally proliferating tissues, such as the intestinal mucosa, lymphoid and hematopoietic organs and reproductive organs. In order to maximize the therapeutic range of CDK9 kinase inhibition, molecules with high selectivity for CDK9 are therefore needed.

[0012] In general, although various CDK inhibitors are known, there remains a need for selective CDK9 inhibitors for treating diseases such as hyperproliferative diseases, viral diseases and / or cardiac disorders that offer one or more advantages over compounds known in the prior art. Summary of the invention

[0013] The present invention relates to a kinase inhibitor, which comprises a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,

[0014]

[0015] wherein A is selected from cyclohexyl, phenyl, pyridyl and piperidyl;

[0016] X is CH or N;

[0017] Z is -NH- or -NH-C(=O)-;

[0018] n is 0 or 1;

[0019] R 1 is selected from hydrogen, halogen, cyano, (C1-C6)alkyl, and (C1-C6)haloalkyl;

[0020] R 2 are selected from hydrogen and (C1-C6) alkyl, or two R 2 Together they form a (C3-C6)cycloalkyl group;

[0021] m is an integer selected from 1 to 3, and each R 3each independently selected from hydrogen, -NH-(C1-C3)alkyl-(C1-C3)alkoxy, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)alkylamido, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonylamino, aminosulfonyl, (C1-C6)alkylaminosulfonyl, heterocyclic sulfonyl optionally substituted by (C1-C6)alkyl, carboxyl (C1-C3) )alkyl, aminosulfonyl(C1-C3)alkyl, (C1-C3)alkylsulfonyl(C1-C3)alkyl, (C1-C3)alkylsulfonyl(C3-C6)cycloalkyl, heterocyclylaminoacyl wherein a heteroatom is optionally substituted by a (C1-C6)alkyl group, heterocyclyl wherein a heteroatom is optionally substituted by a (C1-C6)alkyl group, -S(=O)(=NH)(C1-C3)alkyl, and -(C1-C3)alkyl-S(=O)(=NH)(C1-C3)alkyl;

[0022] R 4 is selected from hydrogen and (C1-C6)alkyl.

[0023] In a preferred embodiment, the present invention relates to a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,

[0024]

[0025] Where X, n, R 1 , R 2 , R 3 , and R 4 As defined above.

[0026] In this embodiment, X is preferably N; in another embodiment, R 3 Preferred is -NH-(C1-C3)alkyl-(C1-C3)alkoxy or carboxy(C1-C3)alkyl.

[0027] In another preferred embodiment, the present invention relates to a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,

[0028]

[0029] Wherein, Y is CH or N; X, m, n, R 1 , R 2 , R 3 , and R 4 As defined above.

[0030] In a more preferred aspect, X is N; in another preferred aspect, Y is CH.

[0031] In another preferred aspect, each R 3 Each is independently selected from halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfonylamino, aminosulfonyl, (C1-C6) alkylaminosulfonyl, heterocyclylsulfonyl optionally substituted by (C1-C6) alkyl with a heteroatom, aminosulfonyl(C1-C3) alkyl, (C1-C3) alkylsulfonyl(C1-C3) alkyl, (C1-C3) alkylsulfonyl(C3-C6) cycloalkyl, heterocyclylaminoacyl optionally substituted by (C1-C6) alkyl with a heteroatom, heterocyclyl optionally substituted by (C1-C6) alkyl with a heteroatom, -S(=O)(=NH)(C1-C3) alkyl, and -(C1-C3) alkyl-S(=O)(=NH)(C1-C3) alkyl.

[0032] In another preferred embodiment, the present invention relates to a compound of formula (Ic) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,

[0033]

[0034] Where X, n, R 1 , R 2 , R 3 and R 4 As defined above.

[0035] In a more preferred aspect, R 3 It is a (C1-C6) alkylacylamino group.

[0036] In another preferred embodiment, the present invention relates to a compound of formula (Id) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,

[0037]

[0038] Where X, n, R 1 , R 2 , R 3 and R 4 As defined above.

[0039] In this embodiment, X is preferably N; in a more preferred aspect, R 3 It is a (C1-C6) alkylsulfonyl group.

[0040] In another aspect, the present application also relates to a pharmaceutical composition comprising the kinase inhibitor of the present invention and a pharmaceutically acceptable diluent or carrier.

[0041] In other aspects, the present application relates to the use of the kinase inhibitor of the present invention in the preparation of a medicament for treating hyperproliferative diseases, virus-induced infectious diseases and cardiovascular diseases.

[0042] In another aspect, the present application also relates to methods of using the kinase inhibitors of the present invention to treat hyperproliferative diseases, virus-induced infectious diseases and cardiovascular diseases. DETAILED DESCRIPTION

[0043] definition

[0044] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the invention belongs. In the specification, unless the context clearly indicates otherwise, the singular also includes the plural. All publications, patent applications, patents or other references mentioned herein are incorporated herein by reference. In the event of a conflict, this specification (including definitions) shall prevail. In addition, materials, methods and embodiments are illustrative only and are not intended to limit the scope of the invention.

[0045] Unless otherwise indicated, the present invention adopts conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology within the technical scope of the art. Unless specific definitions are provided, the nomenclature and laboratory operations and techniques related to chemical processes such as analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are known to those skilled in the art. In general, the aforementioned techniques and steps can be implemented by conventional methods well known in the art and described in various general and more specific literatures, which are cited and discussed in this specification.

[0046] The term "alkyl" refers to an aliphatic hydrocarbon group, which can be a branched or straight chain alkyl. According to the structure, the alkyl can be a monovalent group or a divalent group (i.e., an alkylidene group). In the present invention, the alkyl is preferably an alkyl having 1 to 8 carbon atoms, more preferably a "low alkyl" having 1 to 6 carbon atoms, and even more preferably an alkyl having 1 to 3 carbon atoms. Typical alkyls include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. It should be understood that the "alkyl" mentioned herein includes the alkyl of all possible configurations and conformations, such as the "propyl" mentioned herein includes n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl and tert-butyl, and "pentyl" includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and penta-3-yl, etc.

[0047] The term "alkoxy" refers to -O-alkyl, wherein alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.

[0048] The term "alkoxyalkyl" means an alkyl group, as defined herein, substituted with an alkoxy group, as defined herein.

[0049] The term "cycloalkyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen. Cycloalkyl includes a group having 3-12 ring atoms. According to the structure, cycloalkyl can be a monovalent group or a divalent group (e.g., cycloalkylidene). In the present invention, cycloalkyl is preferably a cycloalkyl having 3-8 carbon atoms, more preferably a "low cycloalkyl" having 3-6 carbon atoms. The example of cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and adamantyl.

[0050] The term "alkyl (cycloalkyl)" or "cycloalkylalkyl" refers to an alkyl group, as defined herein, substituted with a cycloalkyl group, as defined herein. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0051] The term "aromatic" refers to a planar ring having a delocalized π electron system and containing 4n+2 π electrons, where n is an integer. The aromatic ring may be composed of five, six, seven, eight, nine or more than nine atoms. The aromatic group may be optionally substituted. The term "aromatic" includes carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

[0052] The term "aryl" as used herein means that each of the atoms constituting the ring in the aromatic ring is a carbon atom. The aryl ring can be composed of five, six, seven, eight, nine or more than nine atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl. Depending on the structure, the aryl group can be a monovalent group or a divalent group (i.e., an arylene group).

[0053] The term "aryloxy" refers to an -O-aryl group wherein aryl is as defined herein.

[0054] The term "heteroaryl" refers to an aromatic group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. The N-containing "heteroaryl" part refers to an aromatic group in which at least one skeletal atom on the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monovalent group or a divalent group (i.e., a sub-heteroaryl group). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl and furopyridinyl, etc.

[0055] The term "heteroalkyl" as used herein refers to an alkyl group as defined herein where one or more of the backbone chain atoms is a heteroatom, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or a combination thereof. The heteroatom(s) may be located at any position within the heteroalkyl group or at a position where the heteroalkyl group is attached to the rest of the molecule.

[0056] The term "heterocycloalkyl" or "heterocyclic group" as used herein refers to a non-aromatic ring in which one or more atoms constituting the ring are heteroatoms selected from nitrogen, oxygen and sulfur. The heterocycloalkyl ring can be a monocyclic or polycyclic ring consisting of three, four, five, six, seven, eight, nine or more atoms. The heterocycloalkyl ring can be optionally substituted. Examples of heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimides, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1,3-dioxins, 1,3-dioxanes, 1,4-dioxins, 1,4-dioxanes, piperazines, 1,3-oxathiacyclohexanes, 1,4-oxathiacyclohexanes, 1,4-oxathiacyclohexanes, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbital Acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolane. Depending on the structure, the heterocycloalkyl group can be a monovalent group or a divalent group (i.e., a heterocycloalkylene group).

[0057] The term "alkyl(heterocycloalkyl)" or "heterocycloalkylalkyl" means an alkyl group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0058] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0059] The terms "haloalkyl", "haloalkoxy" and "haloheteroalkyl" include structures of alkyl, alkoxy or heteroalkyl, wherein at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from each other.

[0060] The term "hydroxy" refers to an -OH group.

[0061] The term "cyano" refers to a -CN group.

[0062] The term "carboxyl" refers to the group -COOH.

[0063] The term "ester group" refers to a chemical moiety having the formula -COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon), and heterocyclyl (attached through a ring carbon).

[0064] The term "amino" refers to -NH 2 Group.

[0065] The term "aminoacyl" refers to -CO-NH 2 Group.

[0066] The term "alkylaminoacyl" means a -CO-NH-R group wherein R is alkyl as defined herein.

[0067] The term "amido" or "amido" refers to -NR-CO-R', wherein R and R' are each independently hydrogen or alkyl.

[0068] The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups, specifically the group -NRR', wherein R and R' are each independently selected from hydrogen or lower alkyl, provided that -NRR' is not -NH 2 "Alkylamino" includes groups wherein -NH 2 A group of a compound having at least one alkyl group attached to the nitrogen of the compound. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like. "Dialkylamino" includes groups in which -NH 2 A group wherein the nitrogen of the amino group is connected to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.

[0069] The term "cycloalkylamino" refers to an amino substituent further substituted with one or two cycloalkyl groups as defined herein.

[0070] The term "heterocycloalkylamino" means an amino group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0071] The term "alkylaminoalkyl" means an alkyl group, as defined herein, substituted with an alkylamino group, as defined herein.

[0072] The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups.

[0073] The term "aminoalkoxy" refers to an alkoxy substituent further substituted with one or more amino groups.

[0074] The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more hydroxy groups.

[0075] The term "cyanoalkyl" refers to an alkyl substituent further substituted with one or more cyano groups.

[0076] The term "carboxyalkyl" refers to an alkyl substituent further substituted with one or more carboxy groups.

[0077] The term "acyl" refers to a monovalent atomic group remaining after removing the hydroxyl group from an organic or inorganic oxygen-containing acid, and has the general formula RM(O)-, wherein M is usually C.

[0078] The term "carbonyl" refers to an organic functional group consisting of two atoms, carbon and oxygen, connected by a double bond (C=O).

[0079] The term "alkanoyl" or "alkylcarbonyl" refers to a carbonyl group further substituted with an alkyl group. Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, hexanoyl, and the like.

[0080] The term "sulfone" or "sulfonyl" refers to the functional group of a sulfonic acid that has lost its hydroxyl group, specifically -S(=O) 2 -group.

[0081] The term "aminosulfonyl" or "aminosulfonyl" refers to -S(=O) 2 -NH 2 Group.

[0082] The term "alkylsulfonyl" or "alkylsulfonyl" refers to a -S(=O) 2 -R, wherein R is an alkyl group.

[0083] The term "alkylsulfonylamino" or "alkylsulfonylamino", and "cycloalkylsulfonylamino" or "cycloalkylsulfonylamino" refers to an amino group, as defined herein, substituted with an alkylsulfonyl or cycloalkylsulfonyl group, as defined herein, i.e., -NH-S(=O) 2 -R, wherein R is alkyl and cycloalkyl respectively.

[0084] The terms "cycloalkylsulfonyl" and "cycloalkylsulfonyl" refer to -S(=O) 2 -R, wherein R is a cycloalkyl group.

[0085] The term "optionally" refers to one or more events described later that may or may not occur, and includes both events that occur and events that do not occur. The term "optionally substituted" or "substituted" refers to that the group mentioned may be substituted by one or more additional groups, and the additional groups are each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic radical, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methylsulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc. Wherein, amino protecting group is preferably selected from pivaloyl, tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl, etc.

[0086] The term "pharmaceutically acceptable salt" herein refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the free acid or free base form of the purified compound with a suitable base or acid, respectively.

[0087] "Solvate" or "solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap fixed molar ratios of solvent molecules in a crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one molecule of the substance, wherein the water remains in its molecular state as H 2 O.

[0088] The "metabolites" of the compounds disclosed herein are derivatives of the compounds formed when the compounds are metabolized. The term "active metabolite" refers to the biologically active derivatives of the compounds formed when the compounds are metabolized. The term "metabolized" as used herein refers to the sum of processes in which a specific substance is changed by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Therefore, enzymes can produce specific structural changes to compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while diphosphotransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Further information on metabolism can be obtained from "The Pharmacological Basis of Therapeutics", Ninth Edition, McGraw-Hill (1996). The metabolites of the compounds disclosed herein can be identified by administering the compounds to a host and analyzing tissue samples from the host, or by incubating the compounds with hepatocytes in vitro and analyzing the resulting compounds. Both methods are known in the art. In some embodiments, the metabolites of the compounds are formed by oxidation processes and correspond to the corresponding hydroxyl-containing compounds. In some embodiments, the compound is metabolized to a pharmaceutically active metabolite.

[0089] As used herein, the term "modulate" refers to interacting directly or indirectly with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0090] The term "prodrug" or "prodrug" refers to a derivative that may not have pharmacological activity, but in some cases, can be administered orally or parenterally and thereafter metabolized in vivo to form a pharmacologically active compound of the present invention. Non-limiting examples of prodrugs include esters, carbonates, half-esters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, nitrogen-containing compounds, phosphoramides, glycosides, ethers, acetals, ketals, and the like.

[0091] "Effective amount" refers to the amount of a drug or pharmaceutical preparation that will elicit a biological or medical response in a tissue, system, animal or human being, such as that being studied by a researcher or physician. In addition, the term "therapeutically effective amount" refers to any amount that results in improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduced rate of progression of a disease or disorder, compared to a corresponding subject not receiving that amount. Also included within the scope of the term is an amount that is effective to enhance normal physiological function.

[0092] As used herein, the term "treat" refers to the alleviation of at least one symptom of a disease, disorder, or condition. The term includes administering and / or applying one or more compounds described herein to a subject to provide management or treatment of a condition. "Treatment" for the purposes of this disclosure may, but need not, provide a cure; rather, it is meant that "treatment" may be a form of management of a condition. When the compounds described herein are used to treat harmful proliferating cells (including cancer), "treatment" includes partial or complete destruction of the harmful proliferating cells, but minimal destruction of normal cells. The desired treatment mechanism for harmful rapidly proliferating cells (including cancer cells) is apoptosis at the cellular level.

[0093] As used herein, the term "prevention" includes co-preventing or slowing the onset of clinically significant disease development or preventing or slowing the onset of a preclinically significant disease stage in an at-risk individual. This includes prophylactic treatment of an individual at risk of developing a disease.

[0094] The term "subject" or "patient" includes organisms that can suffer from a disorder or a disorder associated with reduced or insufficient programmed cell death (apoptosis) or can otherwise benefit from the administration of the compounds of the invention, such as humans and non-human animals. Preferred humans include human patients suffering from or prone to suffering from a disorder or related condition as described herein. The term "non-human animal" includes vertebrates, such as mammals, such as non-human primates, sheep, cattle, dogs, cats, and rodents such as mice, as well as non-mammals, such as chickens, amphibians, reptiles, etc.

[0095] The GI used in this paper 50 It refers to the drug concentration required to inhibit 50% of cell growth, that is, the drug concentration at which the growth of 50% of cells (such as cancer cells) is inhibited or controlled.

[0096] IC used in this article 50 It refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximal effect in the assay measuring the effect.

[0097] The EC used in this paper 50 It refers to the dose, concentration or amount of a test compound which elicits a dose-dependent response of 50% of the maximal expression of a specific response induced, stimulated or potentiated by the particular test compound.

[0098] The term "associated with CDK9 and / or its mutations" or "disorders mediated by CDK9 and / or its mutations" shall include diseases associated with or involving CDK9 and / or its mutations activity (such as overactivity of CDK9 and / or its mutations), as well as conditions associated with these diseases. Examples of "associated with CDK9 and / or its mutations" or "disorders mediated by CDK9 and / or its mutations" include disorders caused by increased CDK9 and / or its mutations activity caused by mutations in genes that regulate CDK9 and / or its mutations activity (such as LARP7, HEXIM1 / 2 or 7sksnRNA), disorders caused by increased CDK9 and / or its mutations activity caused by activation of the CDK9 / cyclin T / RNA polymerase II complex by viral proteins (such as HIVTAT or HTLV-TAX), or disorders caused by increased CDK9 and / or its mutations activity caused by activation of mitogenic signal transduction pathways.

[0099] The term "overactivity of CDK9" refers to an increase in the enzymatic activity of CDK9 and / or mutations thereof compared to normal, non-diseased cells, or it refers to an increase in CDK9 activity that leads to undesirable cell proliferation or to reduced or insufficient programmed cell death (apoptosis), or a mutation that leads to constitutive activation of CDK9.

[0100] The term "hyperproliferative disorder" includes disorders involving undesired or uncontrolled cell proliferation, and it includes disorders involving reduced or insufficient programmed cell death (apoptosis).

[0101] Kinase inhibitors of the present invention

[0102] The present invention relates to a kinase inhibitor, which comprises a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,

[0103]

[0104] wherein A is selected from cyclohexyl, phenyl, pyridyl and piperidyl;

[0105] n is 0 or 1;

[0106] X is CH or N;

[0107] Z is -NH- or -NH-C(=O)-;

[0108] R 1 is selected from hydrogen, halogen, cyano, (C1-C6)alkyl, and (C1-C6)haloalkyl;

[0109] R 2 are selected from hydrogen and (C1-C6) alkyl, or two R 2Together they form a (C3-C6)cycloalkyl group;

[0110] m is an integer selected from 1 to 3, and each R 3 each independently selected from hydrogen, -NH-(C1-C3)alkyl-(C1-C3)alkoxy, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)alkylamido, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonylamino, aminosulfonyl, (C1-C6)alkylaminosulfonyl, heterocyclic sulfonyl optionally substituted by (C1-C6)alkyl, carboxyl (C1-C3) )alkyl, aminosulfonyl(C1-C3)alkyl, (C1-C3)alkylsulfonyl(C1-C3)alkyl, (C1-C3)alkylsulfonyl(C3-C6)cycloalkyl, heterocyclylaminoacyl wherein a heteroatom is optionally substituted by a (C1-C6)alkyl group, heterocyclyl wherein a heteroatom is optionally substituted by a (C1-C6)alkyl group, -S(=O)(=NH)(C1-C3)alkyl, and -(C1-C3)alkyl-S(=O)(=NH)(C1-C3)alkyl;

[0111] R 4 is selected from hydrogen and (C1-C6)alkyl.

[0112] In a preferred embodiment, the present invention relates to a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,

[0113]

[0114] Where X, n, R 1 , R 2 , R 3 , and R 4 As defined above.

[0115] In this embodiment, X is preferably N; in another embodiment, R 3 Preferred is -NH-(C1-C3)alkyl-(C1-C3)alkoxy or carboxy(C1-C3)alkyl.

[0116] In another preferred embodiment, the present invention relates to a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,

[0117]

[0118] Wherein, Y is CH or N; X, m, n, R 1 , R 2 , R 3 , and R 4 As defined above.

[0119] In a more preferred aspect, X is N; in another preferred aspect, Y is CH.

[0120] In another preferred aspect, each R 3 Each is independently selected from halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfonylamino, aminosulfonyl, (C1-C6) alkylaminosulfonyl, heterocyclylsulfonyl optionally substituted by (C1-C6) alkyl with a heteroatom, aminosulfonyl(C1-C3) alkyl, (C1-C3) alkylsulfonyl(C1-C3) alkyl, (C1-C3) alkylsulfonyl(C3-C6) cycloalkyl, heterocyclylaminoacyl optionally substituted by (C1-C6) alkyl with a heteroatom, heterocyclyl optionally substituted by (C1-C6) alkyl with a heteroatom, -S(=O)(=NH)(C1-C3) alkyl, and -(C1-C3) alkyl-S(=O)(=NH)(C1-C3) alkyl.

[0121] In another preferred embodiment, the present invention relates to a compound of formula (Ic) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,

[0122]

[0123] Where X, n, R 1 , R 2 , R 3 and R 4 As defined above.

[0124] In a more preferred aspect, R 3 It is a (C1-C6) alkylacylamino group.

[0125] In another preferred embodiment, the present invention relates to a compound of formula (Id) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,

[0126] Where X, n, R 1 , R 2 , R 3 and R 4 As defined above.

[0127] In this embodiment, X is preferably N; in a more preferred aspect, R 3 It is a (C1-C6) alkylsulfonyl group.

[0128] In an exemplary embodiment of the present invention, R 1It is preferably selected from hydrogen, chlorine, fluorine, cyano, (C1-C3) alkyl (more preferably methyl), and (C1-C3) haloalkyl (more preferably trifluoromethyl).

[0129] In another exemplary embodiment, R 2 Preferably selected from hydrogen, (C1-C3) alkyl (more preferably methyl), or two R 2 Together they form a cyclopropyl or cyclobutyl group.

[0130] In other exemplary embodiments, each R 3 Each is independently selected from hydrogen, (2-methoxy)ethylamino, chlorine, fluorine, methyl, methoxy, trifluoromethyl, acetamido, methylsulfonyl, methylsulfonylamino, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, morpholinosulfonyl, carboxymethyl, aminosulfonylmethyl, methylsulfonylmethyl, methylsulfonylcyclopropyl, (N-methylpiperidin-4-yl)aminoacyl, N-methylpiperazin-1-yl, N-ethylpiperazin-1-yl, N-isopropylpiperazin-1-yl, homopiperazin-1-yl, -S(=O)(=NH)methyl, and -methyl-S(=O)(=NH)methyl.

[0131] In another exemplary embodiment, R 4 It is preferably selected from hydrogen and (C1-C3)alkyl (more preferably methyl).

[0132] Described herein are novel kinase inhibitors. Also described herein are pharmaceutically acceptable salts, solvates, esters, acids, metabolites and prodrugs of the compounds.

[0133] The compounds of the present invention may exist in free form, such as free base or free acid or zwitter ion form, or may exist in the form of a salt. The salt may be any salt, an organic or inorganic addition salt, in particular any physiologically acceptable organic or inorganic addition salt commonly used in pharmacy.

[0134] Salts which are preferred for the purposes of the present invention are physiologically acceptable salts of the compounds according to the invention. However, salts which are themselves unsuitable for pharmaceutical applications but which can be used, for example, for isolating or purifying the compounds according to the invention are also included.

[0135] The term "pharmaceutically acceptable salt" refers to the relatively non-toxic inorganic or organic acid addition salts of compounds of the present invention, see, for example, SM Berge et al., "Pharmaceutical Salts, J. Pharm. Sci. 1977, 66, 1-19.

[0136] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, such as salts of the following acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid; or salts with organic acids, such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectin salts of ester acid, persulfuric acid, 3-phenylpropionic acid, picric acid, t-valeric acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.

[0137] Pharmaceutically acceptable salts of the compounds of the invention also include salts of common bases, such as and preferably alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, N-methylglucamine, dimethylglucamine, ethylglucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, tris(hydroxymethyl)aminomethane, aminopropylene glycol, Sovak's base and 1-amino-2,3,4-butanetriol.

[0138] The present invention includes all possible salts of the compounds of the present invention, either as a single salt or as any mixture of said salts in any ratio.

[0139] Solvate is a term used for the purposes of the present invention for those forms of the compounds of the invention which form complexes with solvent molecules by coordination in the solid or liquid state. Hydrates are a special form of solvates in which coordination occurs with water. Hydrates are preferred as solvates within the scope of the present invention.

[0140] Furthermore, the present invention also includes prodrugs of the compounds of the present invention. The term "prodrug" includes compounds which themselves may be biologically active or inert but which are converted (eg by metabolism or hydrolysis) into compounds of the present invention during their residence time in the body.

[0141] Furthermore, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as individual polymorphs or as mixtures of more than one polymorph in any ratio.

[0142] In the present specification, the structural formula of the compound represents a specific isomer for convenience in some cases, but the present invention includes all isomers such as geometric isomers, optical isomers based on asymmetric carbon atoms, stereoisomers, tautomers and the like.

[0143] The compounds with chirality to which the present invention relates may be in any configuration or in a mixed racemate. When the compounds used according to the present invention contain more than one chiral center, they may exist in diastereomeric forms. The diastereomeric isomer compounds may be separated by methods known to those skilled in the art (e.g., chromatography or crystallization), and the individual enantiomers may be separated as described above. The present invention includes the use of a variety of diastereomeric compounds used according to the present invention and mixtures thereof. The compounds used in the present invention may exist in different tautomeric forms or in different geometric isomeric forms, and the present invention includes the use of individual tautomers and / or geometric isomers of the compounds used according to the present invention and mixtures thereof. The compounds used in the present invention may exist in zwitterionic form. The present invention includes the use of individual zwitterionic forms of the compounds used according to the present invention and mixtures thereof.

[0144] Screening and characterizing pharmaceutically acceptable salts, polymorphs and / or solvates can be accomplished using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectrum, microscopy, elemental analysis. The various spectral techniques used include but are not limited to Raman, FTIR, UVIS and NMR (liquid and solid state). Various microscopic techniques include but are not limited to IR microscopy and Raman (Raman) microscopy.

[0145] Therefore, the present invention includes all possible salts, polymorphs, metabolites, hydrates, solvates, or prodrugs (e.g., esters) of the compounds of the present invention, as a single salt, polymorph, metabolite, hydrate, solvate, or prodrug, or as a mixture of more than one salt, polymorph, metabolite, hydrate, solvate, prodrug in any ratio.

[0146] Treatments and uses

[0147] Another subject of the present invention is a method and use of the kinase inhibitors according to the invention for the treatment and / or prevention of disorders, preferably disorders associated with or mediated by the activity of CDK9 and its mutations, in particular hyperproliferative disorders, virus-induced infectious diseases and / or cardiovascular diseases, more preferably hyperproliferative disorders.

[0148] The compounds of the present invention can be used to inhibit the activity or expression of CDK9 and its mutations. Therefore, the compounds of formula (I), (Ia), (Ib), (Ic) or (Id) are valuable as therapeutic agents. In one embodiment, the present invention provides a method for treating a condition associated with or mediated by CDK9 and its mutation activity in a patient in need of treatment, comprising administering to the patient an effective amount of a compound of formula (I), (Ia), (Ib), (Ic) or (Id) as defined above. In certain embodiments, the condition associated with CDK9 and its mutation activity is a hyperproliferative condition, a virus-induced infectious disease and / or a cardiovascular disease, more preferably a hyperproliferative condition, particularly cancer, more preferably leukemia, liver cancer, ovarian cancer, cervical cancer, colorectal cancer, gastrointestinal stromal tumor, or lymphoma.

[0149] In the context of the present invention, hyperproliferative disorders include, but are not limited to, e.g., psoriasis, keloids and other hyperplasias affecting the skin, endometriosis, skeletal disorders, angiogenic disorders or angioproliferative disorders, pulmonary hypertension, fibrotic disorders, mesangial cell proliferative disorders, colon polyps, polycystic kidney disease, benign prostatic hyperplasia, and solid tumors such as breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastases, lymphomas, sarcomas and leukemias.

[0150] Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ, canine or feline breast cancer.

[0151] Examples of respiratory tract cancers include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenoma, pleuropulmonary blastoma, and mesothelioma.

[0152] Examples of brain cancers include, but are not limited to, brainstem and hypothalamic gliomas, cerebellar and cerebral astrocytomas, glioblastomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.

[0153] Reproductive organ cancers include, but are not limited to, prostate cancer, testicular cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, and uterine sarcoma.

[0154] Digestive tract cancers include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, stomach cancer, pancreatic cancer, rectal cancer, small intestine cancer, salivary gland cancer, and anal gland cancer.

[0155] Urethral cancers include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urethral cancer, and hereditary and sporadic papillary renal cancer.

[0156] Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0157] Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (liver cell carcinoma with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

[0158] Examples of skin cancer include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, non-melanoma skin cancer, and mast cell tumor.

[0159] Head and neck cancers include, but are not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer, oral cancer, squamous cell carcinoma, and oral melanoma.

[0160] Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and lymphomas of the central nervous system.

[0161] Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, malignant histiocytosis, fibrosarcoma, angiosarcoma, hemangiopericytoma, and leiomyosarcoma.

[0162] Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia.

[0163] A preferred subject matter of the present invention is for use in the treatment and / or prevention of lung cancer (especially non-small cell lung cancer), prostate cancer (especially hormone-independent human prostate cancer), cervical cancer (including multidrug-resistant human cervical cancer), colorectal cancer, melanoma, ovarian cancer or leukemia (especially acute myeloid leukemia).

[0164] Fibrotic proliferative disorders (i.e., abnormal formation of extracellular matrix) that can be treated with the compounds and methods of the invention include pulmonary fibrosis, atherosclerosis, restenosis, cirrhosis of the liver, and mesangial cell proliferative disorders, including renal diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy.

[0165] Other conditions in humans or other mammals that may be treated by the compounds of the invention include tumor growth, retinopathies (including diabetic retinopathy, ischemic retinal vein occlusion, retinopathy of prematurity, and age-related macular degeneration), rheumatoid arthritis, psoriasis, and bullous disorders associated with subepidermal blister formation (including bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis).

[0166] The compounds of the invention can also be used for the prophylaxis and treatment of diseases of the respiratory tract and lungs, diseases of the gastrointestinal tract, and diseases of the bladder and bile duct.

[0167] The above-mentioned conditions have been well characterized in humans, but similar etiologies also exist in other animals, including mammals, and can be treated by administering the pharmaceutical compositions of the invention.

[0168] In another aspect of the invention, the compounds of the invention can be used in a method for the prophylaxis and / or treatment of infectious diseases, particularly virus-induced infectious diseases. These diseases include, but are not limited to, retroviruses, hepadnaviruses, herpesviruses, flaviviruses, and / or adenoviruses that cause virus-induced infectious diseases, including opportunistic diseases. In other preferred embodiments of the method, the retrovirus is selected from lentiviruses or oncoviruses, wherein the lentivirus is selected from HIV-1, HIV-2, FIV, BIV, SIV, SHIV, CAEV, VMV, or EIAV, preferably HIV-1 or HIV-2; and wherein the oncovirus is selected from HTLV-I, HTLV-II, or BLV. In other preferred embodiments of the method, the hepadnavirus is selected from HBV, GSHV, or WHV, preferably HBV; the herpesvirus is selected from HSV I, HSV II, EBV, VZV, HCMV, or HHV8, preferably HCMV; and the flavivirus is selected from HCV, West Nile virus, or yellow fever virus.

[0169] The compounds of the present invention can also be used to prevent and / or treat cardiovascular diseases, such as cardiac hypertrophy, congenital heart disease in adults, aneurysms, stable angina, unstable angina, angina pectoris, angioedema, aortic stenosis, aortic aneurysm, arrhythmia, arrhythmic right ventricular dysplasia, arteriosclerosis, arteriovenous malformation, atrial fibrillation, Behcet's syndrome, bradycardia, cardiac tamponade, cardiac enlargement, congestive cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, prevention of cardiovascular and cerebrovascular diseases, carotid stenosis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes, Epstein anomaly, Eisenmenger complex, cholesterol embolism, bacterial endocarditis, fibromuscular dysplasia, congenital heart defects, heart disease, congestive heart failure, heart valve disease, heart failure, epidural hematoma, subdural hematoma, Hippel-Lindau disease, congestion, hypertension, pulmonary hypertension, hypertrophic growth, left Ventricular hypertrophy, Right ventricular hypertrophy, Hypoplastic left heart syndrome, Hypotension, Intermittent claudication, Ischemic heart disease, Klippel-Trenaunay-Weber syndrome, Dorsolateral medullary syndrome, Long QT syndrome, Mitral valve prolapse, Moyamoya disease, Mucocutaneous lymph node syndrome, Myocardial infarction, Myocardial ischemia, Myocarditis, Pericarditis, Peripheral vascular disease, Phlebitis, Polyarteritis nodosa, Pulmonary atresia, Raynaud's disease, Restenosis, Sneddon syndrome, Stenosis, Superior vena cava syndrome, Syndrome X, Tachycardia, Takayasu's arteritis, Hereditary hemorrhagic telangiectasia, Telangiectasia, Temporal arteritis, Tetralogy of Fallot, Thromboangiitis obliterans, Thrombosis, Thromboembolism, Tricuspid atresia, Varicose veins, Vascular disease, Vasculitis, Vasospasm, Ventricular fibrillation, Williams syndrome, Peripheral vascular disease, Varicose veins and leg ulcers, Deep vein thrombosis of the lower extremities, Wolff-Parkinson-White syndrome.

[0170] The compounds of the invention are preferably used for the prevention and / or treatment of cardiac hypertrophy, congenital heart disease in adults, aneurysms, angina, angina pectoris, arrhythmias, cardiovascular disease prevention, cardiomyopathy, congestive heart failure, myocardial infarction, pulmonary hypertension, hypertrophic growth, restenosis, stenosis, thrombosis and atherosclerosis.

[0171] Another subject of the present invention is the use of the kinase inhibitors of the general formula (I), (Ia), (Ib), (Ic) or (Id) according to the invention for the preparation of medicaments.

[0172] A further subject of the present invention is the use of the kinase inhibitors of the general formula (I), (Ia), (Ib), (Ic) or (Id) according to the invention for the preparation of medicaments for the treatment and / or prevention of disorders, in particular the disorders mentioned above.

[0173] Pharmaceutical composition

[0174] Another aspect of the present invention relates to a drug conjugate comprising a kinase inhibitor of the present invention and a pharmaceutically acceptable diluent or carrier, and optionally one or more other active ingredients.

[0175] Another aspect of the present invention relates to a pharmaceutical composition comprising a kinase inhibitor of the general formula (I), (Ia), (Ib), (Ic) or (Id) of the present invention in combination with an inert, non-toxic, pharmaceutically suitable adjuvant.

[0176] Another aspect of the present invention relates to the use of the pharmaceutical composition according to the invention for the treatment and / or prevention of disorders, in particular the disorders mentioned above.

[0177] Another aspect of the present invention relates to the use of the pharmaceutical composition of the present invention for treating and / or preventing lung cancer (especially non-small cell lung cancer), prostate cancer (especially hormone-independent human prostate cancer), cervical cancer (including multidrug-resistant human cervical cancer), colorectal cancer, melanoma, ovarian cancer or leukemia (especially acute myeloid leukemia).

[0178] The compounds of the invention can be administered as a single dose or in combination with one or more other therapeutic agents, wherein the combination does not induce unacceptable side effects. The drug conjugates include administration of a single pharmaceutical dosage formulation comprising the compound of the invention and one or more other therapeutic agents, as well as administration of the compound of the invention and various other therapeutic agents in their own separate pharmaceutical dosage formulations. For example, the compound of formula (I), (Ia), (Ib), (Ic) or (Id) and the therapeutic agent can be administered together to the patient in a single oral dosage composition such as a tablet or capsule, or each agent can be administered in a separate dosage formulation.

[0179] When separate dosage formulations are used, the compound of the invention and one or more other therapeutic agents may be administered at substantially the same time (eg, simultaneously) or at separately staggered times (eg, sequentially).

[0180] In particular, the compounds of the present invention can be used in fixed combination or alone with other anti-tumor agents, such as alkylating agents, antimetabolites, anti-tumor agents derived from plants, hormone therapeutic agents, topoisomerase inhibitors, camptothecin derivatives, kinase inhibitors, targeted drugs, antibodies, interferons and / or biological response modifiers, anti-angiogenic compounds and other anti-tumor drugs. In this regard, the following is a non-limiting list of examples of second agents that can be used in combination with the compounds of the present invention: 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoic acid, hexamethylmelamine, aminodimethanone, amrubicin, amsacrine, anastrozole, aglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, leucovorin, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, simulleukin, cetuximab, chlorambucil, chlormadinone, nitrogen mustard, cisplatin, cladribine, clodronic acid, cloralbine, cleritase, cyclophosphamide, cyproterone acetate, cytarabine, dacarbazine, actinomycin, darbepoetin alfa , dasatinib, daunorubicin, decitabine, degarelix, denileukin, denosumab, deserelin, dibromospironium chloride, docetaxel, doxifluridine, doxorubicin, doxorubicin + estrone, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, epirubicin, cyclothiocarb, epoetin alfa, epoetin beta, epoetin platinum, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, Formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutathione, goserelin, histamine dihydrochloride, histrelin, hydroxyurea, iodine-125 particles, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon α, interferon β, interferon γ, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, levofloxacin, lentinan, letrozole, leuprolide, levofloxacin Imidazole, lisuride, lobaplatin, lomustine, lonidamine, masoprofen, medroxyprogesterone, megestrol, melphalan, mesandrostane, mercaptopurine, methotrexate, methoxsalen, methyl aminolevulinate, methyltestosterone, mifamide, miltefosine, miplatin, dibromomannitol, mitoguanidine, dibromodulanol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, diamine nitrazepam, ofatumumab, omeprazole, oprelleukin, oxaliplatin, p53 gene therapy,Paclitaxel, palifermin, palladium-103 particles, pamidronate, panitumumab, pazopanib, pegaspargase, pegylated epoetin (methoxypegylated epoetin), pegfilgrastin, peginterferon α-2b, pemetrexed, pentazocine, pentostatin, pyromycin, perfosfamide, bixibanib, pirarubicin, plerixafor, plicamycin, polyglucosamine, estradiol polyphosphate, versicolor polysaccharide K, porfimer sodium, pralatrexate, prednimustine, procarbazine, quinagolide, radium 223 chloride, raloxifene, raltitrexed, ranimustine, razoxane, refametinib, regorafenib, risedronate, rituximab, romidepeptide, romiplostim, sargramostim, sipuleucel-T, sizoran, sobuzosim, glycine Sodium bisulfite, sorafenib, streptozotocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasonamine, teisleukin, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thiabendazole, thiothiazide, thymosalicylic acid, thioguanine, tocilizumab, topotecan, toremifene, tosifen Momostat, trabectedin, trastuzumab, sulsulfuron, tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90 glass microspheres, nestatin, nestatin ester, zoledronic acid, and daunorubicin.

[0181] The compounds of the invention may also be used in cancer treatment in conjunction with radiation therapy and / or surgical intervention.

[0182] The compounds of the present invention can work systemically and / or locally. For this reason, they can be administered in an appropriate manner, for example, by oral route, parenteral route, pulmonary route, nasal route, sublingual route, lingual route, buccal route, rectal route, dermal route, transdermal route, conjunctival route or ear route, or in the form of an implant or stent.

[0183] For these administration routes, the compounds of the present invention can be administered in appropriate administration forms.

[0184] Suitable for oral administration are dosage forms which act as described in the prior art and deliver the compounds of the invention rapidly and / or in an improved manner, comprising the compounds of the invention in crystalline and / or amorphous and / or dissolved form, such as tablets (coated or uncoated, for example with an enteric coating, or with a coating which delays dissolution or is insoluble and controls the release of the compounds of the invention), tablets which disintegrate rapidly in the mouth, or films / flaky tablets, films / lyophilisates, capsules (for example hard capsules or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

[0185] Parenteral administration can be carried out which avoids an absorption step (e.g. intravenous administration, intraarterial administration, intracardial administration, intraspinal administration or intraperitoneal administration) or includes absorption (e.g. intramuscular administration, subcutaneous administration, intradermal administration, transdermal administration or intraperitoneal administration). Administration forms suitable for parenteral administration are especially preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

[0186] Examples of suitable other routes of administration are pharmaceutical forms for inhalation (especially powder inhalers, nebulizers), nasal drops / solutions / sprays; tablets, films / flasks or capsules for lingual, sublingual or buccal administration, suppositories, preparations for the eyes or ears, vaginal capsules, aqueous suspensions (lotions, vibrating mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. plasters), emulsions, pastes, foams, dusting powders, implants or stents.

[0187] The compounds of the invention can be converted into the administration forms described. This can be done in a manner known in the art by mixing with inert, non-toxic, pharmaceutically suitable adjuvants. These adjuvants include, in particular, carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g. sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinyl pyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants, such as ascorbic acid), colorants (e.g. inorganic pigments, such as iron oxide) and taste and / or odor masking agents.

[0188] The invention furthermore provides medicaments comprising at least one compound according to the invention, generally together with one or more inert, nontoxic, pharmaceutically suitable adjuvants, and their use for the purposes mentioned above.

[0189] Regardless of the selected administration route, the kinase inhibitor of the present invention and / or the pharmaceutical composition of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0190] Actual dosage levels and time courses of administration of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient and is not toxic to said patient.

[0191] Preparation of compounds

[0192] The compounds of the present invention can be synthesized using standard synthesis techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions given herein can be varied according to the art. As further guidance, the following synthetic methods can also be utilized.

[0193] The reactions can be used sequentially to provide compounds described herein; or they can be used to synthesize fragments that are subsequently added by methods described herein and / or known in the art.

[0194] The starting materials for synthesizing the compounds described herein can be synthesized or can be obtained from commercial sources. The compounds described herein and other related compounds with different substituents can be synthesized using techniques and raw materials known to those skilled in the art. The general method for preparing the compounds disclosed herein can be from reactions known in the art, and the reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various parts into the molecules provided herein.

[0195] If desired, the reaction products can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. These products can be characterized using conventional methods, including physical constants and spectral data.

[0196] Non-limiting examples of synthetic schemes for preparing compounds of formula (I) are described below.

[0197] Example

[0198] The following specific non-limiting examples are to be interpreted as merely illustrative and not limiting the present invention in any way. Although no further detailed description is required, it is believed that one skilled in the art can fully utilize the present disclosure based on the description herein.

[0199] Example 1: Synthesis of 6-(2-(((4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2-hydro)-one

[0200]

[0201] Tert-butyl ((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)carbamate (A2): Compound A1 (10.0 g, 46.7 mmol), 2-bromoethyl methyl ether (5.2 g, 37.4 mmol) and potassium carbonate (12.9 g, 93.4 mmol) were added to acetonitrile (150 mL), and the reaction was stirred at 80 ° C for 16 hours. The reaction was monitored by TLC. A small amount of raw materials remained, and the reaction was stopped. The reaction solution was cooled to room temperature, filtered, and the filtrate was dried by spin drying, mixed with silica gel, and silica gel column chromatography (eluent system: DCM / MeOH=100:1→40:1→20:1) was performed to obtain 6.3 g of yellow-white solid A2 with a yield of 50%.

[0202] (1r,4r)-N1-(2-methoxyethyl)cyclohexane-1,4-diamine hydrochloride (A3): Compound A2 (6 g, 22.0 mmol) was dissolved in HCl-EA (80 mL) and the reaction was stirred at room temperature for 2 hours. A large amount of solid precipitated. The reaction solution was filtered and the filter cake was dried to obtain 5.1 g of white solid (dihydrochloride) A3, with a yield of 94.8%.

[0203] 6-(2-Chloropyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2-hydrogen)-one (A6): A4 (81 mg, 0.54 mmol, 1.5 eq) was dissolved in 1,4-dioxane (10 mL), followed by the addition of A5 (100 mg, 0.36 mmol, 1.0 equiv.), potassium carbonate (99 mg, 0.72 mmol, 2 equiv.) and Pd(PPh 3 ) 4 (41 mg, 0.036 mmol, 0.1 eq), stirred at 95°C for 4 hours, TLC showed that the reaction was complete. Crude silica gel was added to the reaction system, and the mixture was separated by column chromatography (eluent system: DCM / EA=3:1) to obtain compound A6 (60 mg, 64%).

[0204] 6-(2-(((4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2-hydro)-one (1): Compound A6 (50 mg, 0.19 mmol, 1.0 equiv.), A3 (56 mg, 0.22 mmol, 1.2 equiv.), DIEA (73 mg, 0.57 mmol, 3.0 equiv.) and DMSO (2 mL) were added to a bottle and stirred at 125°C overnight. LC-MS showed that the starting material had been consumed. Water was added, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column (eluent system: DCM / MeOH=30:1) to obtain the target compound 1 (white solid, 30 mg, 40%). MS: (M+1) 396.2.1 H NMR (500MHz, DMSO-d6) δ8.37(s,1H),8.08–7.97(m,3H),7.94(d,J=8.0Hz,1H),7.15(t,J=6.5Hz,2H),3.74(s,1H),3.41(s ,4H),3.26(s,3H),2.98(t,J=6.6Hz,2H),2.75(d,J=5.7Hz,2H),2.46(s,1H),1.95(s,4H),1.35-1.27(m,2H),1.16(s,2H).

[0205] Unless otherwise specified, the following Examples 2-25 were synthesized in a manner similar to that of Example 1.

[0206] Example 2: 6-(5-chloro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2-hydro)-one compound 2

[0207]

[0208] MS (ESI) m / z (M+1)+: 430.2.

[0209] Example 3: 6-(5-fluoro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 3

[0210]

[0211] MS (ESI) m / z (M+1)+: 414.22.

[0212] Example 4: 6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-2-methyl-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 4

[0213]

[0214] MS (ESI) m / z (M+1)+: 410.26.

[0215] Example 5: 5-(2-(((1r,4r))-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)isoindolin-1-one compound 5

[0216]

[0217] MS (ESI) m / z (M+1)+: 382.22.

[0218] Example 6: 6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)-5-methylpyridin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 6

[0219]

[0220] The synthesis of compound 6 was accomplished by using a procedure similar to that described in Example 1, substituting 4-bromo-2-fluoro-5-methylpyridine for 2,4-dichloropyrimidine. MS (ESI) m / z (M+1)+: 437.29.

[0221] Example 7: 6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)-5-methylpyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 7

[0222]

[0223] MS (ESI) m / z (M+1)+: 410.26.

[0224] Example 8: 6-(5-chloro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyridin-4-yl)-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 8

[0225]

[0226] The synthesis of Example 8 compound was accomplished by using procedures similar to those described in Example 6. MS (ESI) m / z (M+1)+: 429.21.

[0227] Example 9: 2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)-4-(1-oxa-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidine-5-carbonitrile Compound 9

[0228]

[0229] MS (ESI) m / z (M+1)+: 421.24.

[0230] Example 10: 6-(5-chloro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyridin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 10

[0231]

[0232] The synthesis of Example 10 compound was accomplished by using procedures similar to those described in Example 6. MS (ESI) m / z (M+1)+: 457.24.

[0233] Example 11: 6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 11

[0234]

[0235] MS (ESI) m / z (M+1)+: 424.27.

[0236] Example 12: 6'-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1'-one Compound 12

[0237]

[0238] MS (ESI) m / z (M+1)+: 422.26.

[0239] Example 13: 4,4-diethyl-6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 13

[0240]

[0241] MS (ESI) m / z (M+1)+: 452.30.

[0242] Example 14: 4,4-diisopropyl-6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 14

[0243]

[0244] MS (ESI) m / z (M+1)+: 480.33.

[0245] Example 15: 6-(5-chloro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 15

[0246]

[0247] MS (ESI) m / z (M+1)+: 458.23.

[0248] Example 16: 6-(5-fluoro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 16

[0249]

[0250] MS (ESI) m / z (M+1)+: 442.26.

[0251] Example 17: 6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)-5-methylpyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 17

[0252]

[0253] MS (ESI) m / z (M+1)+: 438.29.

[0254] Example 18: 6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-2,4,4-trimethyl-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 18

[0255]

[0256] MS (ESI) m / z (M+1)+: 424.27.

[0257] Example 19: 6-(5-chloro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-2,4,4-trimethyl-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 19

[0258]

[0259] MS (ESI) m / z (M+1)+: 472.25.

[0260] Example 20: 5-(5-fluoro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one Compound 20

[0261]

[0262] MS (ESI) m / z (M+1)+: 428.25.

[0263] Example 21: 5-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one Compound 21

[0264]

[0265] MS (ESI) m / z (M+1)+: 410.26.

[0266] Example 22: 5-(5-chloro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one Compound 22

[0267]

[0268] MS (ESI) m / z (M+1)+: 444.22.

[0269] Example 23: 5-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-2,3,3-trimethylisoindolin-1-one Compound 23

[0270]

[0271] MS (ESI) m / z (M+1)+: 424.27.

[0272] Example 24: 5-(5-chloro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-2,3,3-trimethylisoindolin-1-one Compound 24

[0273]

[0274] MS (ESI) m / z (M+1)+: 458.23.

[0275] Example 25: 6'-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinoline]-1'-one Compound 25

[0276]

[0277] MS (ESI) m / z (M+1)+: 436.27.

[0278] Example 26: Synthesis of 3-((4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)benzenesulfonamide Compound 26

[0279]

[0280] 4,4-Dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (A8): Compound A7 (1.0 g, 3.93 mmol), biboronic acid pinacol ester (1.2 g, 4.72 mmol, 1.2 equiv.), potassium acetate (0.77 g, 7.86 mmol, 2 equiv.) and PdCl 2 (dppf) (0.32 g, 0.39 mmol, 0.1 equiv.) was added to 1,4-dioxane (20 mL), and the reaction was stirred at 100°C for 5 hours. The reaction was monitored by TLC, and no starting material remained, so the reaction was stopped. The reaction solution was cooled to room temperature, mixed with silica gel, and chromatographed on a silica gel column (eluent system: DCM / EA=3:1) to obtain a reddish brown solid A8 (0.9 g, 76%).

[0281] 6-(2-Chloropyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2-hydrogen)-one (A9): A8 (300 mg, 0.99 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL), followed by the addition of A4 (178 mg, 1.19 mmol, 1.2 equiv.), potassium carbonate (0.27 g, 1.98 mmol, 2 equiv.) and Pd(PPh 3 ) 4 (0.11 g, 0.099 mmol, 0.1 eq), stirred at 95°C for 4 hours, TLC showed that the reaction was complete. Crude silica gel was added to the reaction system, and the mixture was separated by column chromatography (eluent system: DCM / EA=3:1) to obtain the target compound A9 (130 mg, 45%).

[0282] 3-((4-(4,4-Dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)benzenesulfonamide (26): To a flask were added compound A9 (50 mg, 0.17 mmol, 1.0 equiv.), 4-aminobenzenesulfonanilide (30 mg, 0.17 mmol, 1.0 equiv.), p-toluenesulfonic acid (29 mg, 0.17 mmol, 1.0 equiv.) and sec-butanol (2 mL), and the mixture was stirred overnight at 120 °C. It was filtered, and the filter cake was washed with a small amount of methanol and methyl tert-butyl ether to obtain a pale yellow solid. The solid was transferred to a vial, saturated sodium bicarbonate solution was added and stirred, and finally filtered. The solid was washed with methanol and methyl tert-butyl ether to obtain the target compound 26 (white solid, 30 mg, 41%). MS: (M+1): 424.14. 1H NMR (500 MHz, DMSO-d 6 ) δ 10.08 (s, 1H), 8.65 (d, J = 5.2 Hz, 1H), 8.54 (s, 1H), 8.20 - 8.18 (m, 2H), 8.10 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.97–7.94 (m, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.52–7.44 (m, 2H), 7.31 (s, 2H), 3.23 (d, J = 3.0 Hz, 2H), 1.37 (s, 6H).

[0283] Examples 27 - 95, 99 - 101 below were synthesized by a method similar to that of Example 26 unless otherwise specified.

[0284] Example 27: (3-((4-(4,4-Dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)phenyl)methanesulfonamide Compound 27

[0285]

[0286] MS (ESI) m / z (M+1)+: 438.16.

[0287] Example 28: 4,4-Dimethyl-6-(2-((3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 28

[0288]

[0289] MS (ESI) m / z (M+1)+: 437.16.

[0290] Example 29: 3-((4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)-N,N-dimethylbenzenesulfonamide Compound 29

[0291]

[0292] MS (ESI) m / z (M+1)+: 452.18.

[0293] Example 30: 4,4-dimethyl-6-(2-((3-(morpholinosulfonyl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 30

[0294]

[0295] MS (ESI) m / z (M+1)+: 494.19.

[0296] Example 31: 3-((4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide Compound 31

[0297]

[0298] MS (ESI) m / z (M+1)+: 438.16.

[0299] Example 32: 4,4-dimethyl-6-(2-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 32

[0300]

[0301] MS (ESI) m / z (M+1)+: 423.15.

[0302] Example 33: 3-((4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)benzamide Compound 33

[0303]

[0304] MS (ESI) m / z (M+1)+: 485.27.

[0305] Example 34: N-(5-((4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)-2-fluorophenyl)methanesulfonamide Compound 34

[0306]

[0307] MS (ESI) m / z (M+1)+: 456.15.

[0308] Example 35: Synthesis of 6-(2-((3-(1,4-homopiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 35

[0309]

[0310] MS (ESI) m / z (M+1)+: 443.26.

[0311] Example 36: 6-(2-((4-fluoro-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 36

[0312]

[0313] MS (ESI) m / z (M+1)+: 455.16.

[0314] Example 37: 4,4-dimethyl-6-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 37

[0315]

[0316] MS (ESI) m / z (M+1)+: 433.26.

[0317] Example 38: 4,4-dimethyl-6-(2-((3-(S-methylsulfonylimino)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 38

[0318]

[0319] MS (ESI) m / z (M+1)+: 422.17.

[0320] Example 39: 4,4-dimethyl-6-(2-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 39

[0321]

[0322] MS (ESI) m / z (M+1)+: 423.15.

[0323] Example 40: 4,4-dimethyl-6-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 40

[0324]

[0325] MS (ESI) m / z (M+1)+: 443.26.

[0326] Example 41: 5-((4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)-2-fluoro-N-(1-methylpiperidin-4-yl)benzamide Compound 41

[0327]

[0328] MS (ESI) m / z (M+1)+: 503.26.

[0329] Example 42: 4,4-dimethyl-6-(2-((4-methyl-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 42

[0330]

[0331] MS (ESI) m / z (M+1)+: 451.18.

[0332] Example 43: 6-(2-((2,4-difluoro-5-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 43

[0333]

[0334] MS (ESI) m / z (M+1)+: 473.15.

[0335] Example 44: 4,4-dimethyl-6-(2-((3-((methylsulfonyl)methyl)-4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 44

[0336]

[0337] MS (ESI) m / z (M+1)+: 505.15.

[0338] Example 45: 6-(2-((4-methoxy-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 45

[0339]

[0340] MS (ESI) m / z (M+1)+: 467.18.

[0341] Example 46: 6-(2-((4-fluoro-3-((methylsulfonyl)methyl)phenyl)amino)pyridin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 46

[0342]

[0343] MS (ESI) m / z (M+1)+: 454.16.

[0344] Example 47: 4,4-dimethyl-6-(2-((2-((methylsulfonyl)methyl)pyridin-4-yl)amino)pyridin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 47

[0345]

[0346] MS (ESI) m / z (M+1)+: 437.16.

[0347] Example 48: 5-(2-((4-fluoro-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one Compound 48

[0348]

[0349] MS (ESI) m / z (M+1)+: 441.14.

[0350] Example 49: 3,3-Dimethyl-5-(2-((4-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)isoindolin-1-one Compound 49

[0351]

[0352] MS (ESI) m / z (M+1)+: 423.15.

[0353] Example 50: 5-(5-fluoro-2-((4-fluoro-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one Compound 50

[0354]

[0355] MS (ESI) m / z (M+1)+: 459.13.

[0356] Example 51: 5-(5-chloro-2-((4-fluoro-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one Compound 51

[0357]

[0358] MS (ESI) m / z (M+1)+: 475.10.

[0359] Example 52: 5-(5-chloro-2-((2,4-difluoro-5-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one Compound 52

[0360]

[0361] MS (ESI) m / z (M+1)+: 493.09.

[0362] Example 53: 5-(2-((2,4-difluoro-5-((methylsulfonyl)methyl)phenyl)amino)-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindolin-1-one Compound 53

[0363]

[0364] MS (ESI) m / z (M+1)+: 477.12.

[0365] Example 54: 5-(5-chloro-2-((4-methyl-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one Compound 54

[0366]

[0367] MS (ESI) m / z (M+1)+: 471.13.

[0368] Example 55: 5-(5-fluoro-2-((4-methyl-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one Compound 55

[0369]

[0370] MS (ESI) m / z (M+1)+: 455.16.

[0371] Example 56: 4,4-dimethyl-6-(2-((2-((methylsulfonyl)methyl)pyridin-4-yl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 56

[0372]

[0373] MS (ESI) m / z (M+1)+: 438.16.

[0374] Example 57: 4,4-dimethyl-6-(2-((4-((methylsulfonyl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 57

[0375]

[0376] MS (ESI) m / z (M+1)+: 438.16.

[0377] Example 58: 4,4-dimethyl-6-(2-((4-((S-methylsulfonylimino)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 58

[0378]

[0379] MS (ESI) m / z (M+1)+: 437.18.

[0380] Example 59: 4,4-dimethyl-6-(2-((4-(1-(methylsulfonyl)cyclopropyl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 59

[0381]

[0382] MS (ESI) m / z (M+1)+: 463.18.

[0383] Example 60: 6-(5-chloro-2-((4-(1-(methylsulfonyl)cyclopropyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 60

[0384]

[0385] MS (ESI) m / z (M+1)+: 497.14.

[0386] Example 61: 6-(5-fluoro-2-((4-(1-(methylsulfonyl)cyclopropyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 61

[0387]

[0388] MS (ESI) m / z (M+1)+: 481.17.

[0389] Example 62: 6-(5-chloro-2-((4-fluoro-3-(1-(methylsulfonyl)cyclopropyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 62

[0390]

[0391] MS (ESI) m / z (M+1)+: 515.13.

[0392] Example 63: 6-(5-fluoro-2-((4-fluoro-3-(1-(methylsulfonyl)cyclopropyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 63

[0393]

[0394] MS (ESI) m / z (M+1)+: 499.16.

[0395] Example 64: 6-(5-chloro-2-((2,4-difluoro-5-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 64

[0396]

[0397] MS (ESI) m / z (M+1)+: 507.11.

[0398] Example 65: 6-(2-((4-fluoro-3-(1-(methylsulfonyl)cyclopropyl)phenyl)amino)pyrimidin-4-yl)-2,4,4-trimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 65

[0399]

[0400] MS (ESI) m / z (M+1)+: 495.19.

[0401] Example 66: 6-(5-chloro-2-((4-fluoro-3-(1-(methylsulfonyl)cyclopropyl)phenyl)amino)pyrimidin-4-yl)-2,4,4-trimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 66

[0402]

[0403] MS (ESI) m / z (M+1)+: 529.15.

[0404] Example 67: 6-(5-fluoro-2-((4-fluoro-3-(1-(methylsulfonyl)cyclopropyl)phenyl)amino)pyrimidin-4-yl)-2,4,4-trimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 67

[0405]

[0406] MS (ESI) m / z (M+1)+: 513.18.

[0407] Example 68: 6-(5-chloro-2-((3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 68

[0408]

[0409] MS (ESI) m / z (M+1)+: 477.22.

[0410] Example 69: 6-(5-Fluoro-2-((3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 69

[0411]

[0412] MS (ESI) m / z (M+1)+: 461.25.

[0413] Example 70: 4,4-dimethyl-6-(5-methyl-2-((3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 70

[0414]

[0415] MS (ESI) m / z (M+1)+: 457.27.

[0416] Example 71: 6-(5-Fluoro-2-((4-methyl-3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 71

[0417]

[0418] MS (ESI) m / z (M+1)+: 475.26.

[0419] Example 72: 6-(5-Fluoro-2-((4-fluoro-3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 72

[0420]

[0421] MS (ESI) m / z (M+1)+: 479.24.

[0422] Example 73: 6-(5-fluoro-2-((3-fluoro-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 73

[0423]

[0424] MS (ESI) m / z (M+1)+: 479.24.

[0425] Example 74: 6-(5-chloro-2-((4-methyl-3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 74

[0426]

[0427] MS (ESI) m / z (M+1)+: 491.23.

[0428] Example 75: 6-(5-chloro-2-((4-fluoro-3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 75

[0429]

[0430] MS (ESI) m / z (M+1)+: 495.21.

[0431] Example 76: 6-(5-chloro-2-((3-(4-ethylpiperazin-1-yl)-4-fluorophenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 76

[0432]

[0433] MS (ESI) m / z (M+1)+: 509.22.

[0434] Example 77: 6-(5-chloro-2-((4-fluoro-3-(4-isopropylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 77

[0435]

[0436] MS (ESI) m / z (M+1)+: 523.24.

[0437] Example 78: 6-(5-chloro-2-((3-(4-isopropylpiperazin-1-yl)-4-methylphenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 78

[0438]

[0439] MS (ESI) m / z (M+1)+: 519.26.

[0440] Example 79: 6-(2-((3-(4-ethylpiperazin-1-yl)-4-fluorophenyl)amino)5-fluoropyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 79

[0441]

[0442] MS (ESI) m / z (M+1)+: 493.25.

[0443] Example 80: 6-(5-Fluoro-2-((4-fluoro-3-(4-isopropylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 80

[0444]

[0445] MS (ESI) m / z (M+1)+: 507.27.

[0446] Example 81: 6-(2-((4-fluoro-3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 81

[0447]

[0448] MS (ESI) m / z (M+1)+: 461.25.

[0449] Example 82: 4,4-methyl-6-(2-((4-methyl-3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-dihydroisoquinolin-1(2H)-one Compound 82

[0450]

[0451] MS (ESI) m / z (M+1)+: 457.27.

[0452] Example 83: 6-(5-fluoro-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2-hydro)-one Compound 83

[0453]

[0454] MS (ESI) m / z (M+1)+: 461.25.

[0455] Example 84: 6-(2-((3-(4-ethylpiperazin-1-yl)-4-fluorophenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 84

[0456]

[0457] MS (ESI) m / z (M+1)+: 475.26.

[0458] Example 85: 6-(2-((4-fluoro-3-(4-isopropylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 85

[0459]

[0460] MS (ESI) m / z (M+1)+: 489.28.

[0461] Example 86: 6-(2-((3-(4-ethylpiperazin-1-yl)-4-methylphenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 86

[0462]

[0463] MS (ESI) m / z (M+1)+: 471.29.

[0464] Example 87: 6-(2-((3-(4-isopropylpiperazin-1-yl)-4-methylphenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 87

[0465]

[0466] MS (ESI) m / z (M+1)+: 485.30.

[0467] Example 88: 6-(5-chloro-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 88

[0468]

[0469] MS (ESI) m / z (M+1)+: 477.22.

[0470] Example 89: 6-(5-fluoro-2-((4-((methylsulfonyl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 89

[0471]

[0472] MS (ESI) m / z (M+1)+: 456.15.

[0473] Example 90: 6-(5-chloro-2-((4-((methylsulfonyl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 90

[0474]

[0475] MS (ESI) m / z (M+1)+: 472.12.

[0476] Example 91: 4,4-dimethyl-6-(5-methyl-2-((4-((methylsulfonyl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 91

[0477]

[0478] MS (ESI) m / z (M+1)+: 452.18.

[0479] Example 92: 4,4-dimethyl-6-(2-((4-((methylsulfonyl)methyl)pyridin-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Compound 92

[0480]

[0481] MS (ESI) m / z (M+1)+: 506.15.

[0482] Example 93: 6-(5-fluoro-2-((4-((S-methylsulfonylimino)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 93

[0483]

[0484] MS (ESI) m / z (M+1)+: 455.17.

[0485] Example 94: 6-(5-chloro-2-((4-((S-methylsulfonylimino)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 94

[0486]

[0487] MS (ESI) m / z (M+1)+: 471.14.

[0488] Example 95: 4,4-dimethyl-6-(5-methyl-2-((4-((S-methylsulfonylimino)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one Compound 95

[0489]

[0490] MS (ESI) m / z (M+1)+: 451.19.

[0491] Example 96: (1S,3R)-3-acetamide-N-(5-chloro-4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-2-yl)cyclohexyl-1-carboxamide Compound 96

[0492]

[0493] Tert-butyl ((1R,3S)-3-((4-bromo-5-chloropyridin-2-yl)carbamoyl)cyclohexyl)carbamate (A11): Compound A10 (1.0 g, 4.11 mmol) was dissolved in dichloromethane, and then 1-chloro-N,N,2-trimethylpropenamine (0.82 g, 6.17 mmol, 1.5 equiv.) was added dropwise under ice bath, and the reaction mixture was stirred at 0°C for 30 minutes. Then, a tetrahydrofuran solution of 2-amino-4-bromo-5-chloropyridine (0.68 g, 3.28 mmol, 0.8 equiv.) and pyridine (0.32 g, 4.11 mmol, 1 equiv.) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC, and no starting material remained, and the reaction was stopped. Saturated sodium carbonate solution was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, mixed with silica gel, and purified by column chromatography (eluent system: PE / EA=3:1) to obtain white solid A11 (1.2 g, 68%).

[0494] Tert-butyl ((1R,3S)-3-((5-chloro-4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate (A12): A11 (800 mg, 1.85 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL), followed by the addition of A8 (613 mg, 2.03 mmol, 1.1 equiv.), potassium carbonate (0.51 g, 3.7 mmol, 2 equiv.) and Pd(PPh 3 ) 4 (0.21 g, 0.185 mmol, 0.1 eq), stirred at 100°C for 4 hours, TLC showed that the reaction was complete. Crude silica gel was added to the reaction system, and the sample was separated by column chromatography (eluent system: DCM / EA=3:1) to obtain the target compound A12 (585 mg, 60%).

[0495] (1S,3R)-3-acetamide-N-(5-chloro-4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-2-yl)cyclohexyl-1-carboxamide (96): Compound A12 (100 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added dropwise, and the mixture was stirred at room temperature for half an hour. After concentration, the residue was neutralized with saturated sodium bicarbonate to pH = 10, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a light yellow oil, which was used directly in the next step (60 mg). The product obtained in the previous step was dissolved in dichloromethane, triethylamine (21 mg, 0.21 mmol) was added, and acetyl chloride (16 mg, 0.21 mmol) was added dropwise under ice bath. TLC showed that the reaction was complete, and the reaction was stopped. The mixture was concentrated and purified by column chromatography (eluent system: DCM / MeOH=30:1) to obtain the target compound 96 (white solid, 30 mg, 46%). MS: (M+1) 469.20. 1H NMR (500MHz, DMSO-d6) δ 10.74 (s, 1H), 8.49 (s, 1H), 8.18 (s, 1H), 8.08 (d, J=3.1 Hz, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.50 (d, J=1.7 Hz, 1H), 7.44 (dd, J=7.9,1.7Hz,1H),3.60-3.51(m,1H),3.23(d,J=3.0Hz,2H),2.64-2.60(m,1H),1. 88(d,J=12.4Hz,1H),1.77(s,6H),1.31-1.24(m,9H),1.07(q,J=11.3,10.8Hz,1H).

[0496] Unless otherwise specified, the following Examples 97, 98, 102, and 107 were synthesized using a method similar to that of Example 96.

[0497] Example 97: (1S, 3R)-3-acetamide-N-(5-chloro-4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)cyclohexyl-1-carboxamide Compound 97

[0498]

[0499] MS (ESI) m / z (M+1)+: 470.20.

[0500] Example 98: (1S, 3R)-3-acetamide-N-(4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methylpyrimidin-2-yl)cyclohexyl-1-carboxamide Compound 98

[0501]

[0502] MS(ESI) m / z (M+1)+: 450.25。

[0503] Example 99: 6-(5-chloro-2-((4-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroxyquinolin-1(2H)-one Compound 99

[0504]

[0505] MS(ESI) m / z (M+1)+: 471.12。

[0506] Example 100: 6-(5-fluoro-2-((4-((((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroxyquinolin-1(2H)-one Compound 100

[0507]

[0508] MS(ESI) m / z (M+1)+: 455.15。

[0509] Example 101: 5-(2-((2,4-difluoro-5-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindol-1-one Compound 101

[0510]

[0511] MS(ESI) m / z (M+1)+: 459.13。

[0512] Example 102: (1S,3R)-3-acetamido-N-(5-chloro-4-(3,3-dimethyl-1-oxoindolin-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide Compound 102

[0513]

[0514] MS(ESI) m / z (M+1)+: 455.18。

[0515] Example 103: (S)-4,4-dimethyl-6-(2-((1-(methyl)piperidin-3-yl)amino)pyrimidin-4-yl)-3,4-dihydroxyquinolin-1(2H)-one Compound 103

[0516]

[0517] (S)-tert-Butyl 3-((4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (A14): A9 (100 mg, 0.35 mmol), A13 (105 mg, 0.52 mmol) and DIEA (90 mg, 0.7 mmol) were dissolved in sec-butanol (2 mL), and the mixture was reacted at 130°C overnight. LCMS showed that the reaction was complete. Coarse silica gel was added to the reaction system and A14 (70 mg, 44%) was separated by column chromatography.

[0518] (S)-4,4-Dimethyl-6-(2-(piperidin-3-ylamino)pyrimidin-4-yl)-3,4-dihydroxyquinolin-1(2H)-one (A15): A14 (70 mg) was dissolved in DCM (3 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature. LCMS showed that the reaction was complete. The mixture was neutralized with saturated sodium bicarbonate to alkalinity, and extracted with ethyl acetate. The organic phase was dried and concentrated, and the residue was separated by column chromatography to obtain A15 (38 mg, 73%).

[0519] (S)-4,4-Dimethyl-6-(2-((1-(methyl)piperidin-3-yl)amino)pyrimidin-4-yl)-3,4-dihydroxyquinolin-1(2H)-one (103): A15 (38 mg, 0.11 mmol) was dissolved in DCM (2 mL), and methanesulfonyl chloride (18 mg, 0.16 mmol) was added under ice bath. LCMS showed that the reaction was complete. The mixture was concentrated and the residue was separated by column chromatography to obtain 103 (22 mg, 48%). 1 H NMR (500MHz, DMSO-d6) δ8.43(d,J=5.1Hz,1H),8.11–7.94(m,4H),7.32(d,J=7.3Hz,1H),7.27(d,J=5.2Hz,1H),3.99–3.94(m,1H),3.47(s,1H),3 .21-3.20(m,2H),2.87(s,3H),2.75(td,J=11.3,2.8Hz,1H),2.56(t,J=1 0.3Hz,1H),1.97–1.85(m,2H),1.62–1.51(m,2H),1.34(d,J=6.0Hz,6H).

[0520] Unless otherwise specified, the following Examples 104-106 were synthesized in a manner similar to that of Example 103.

[0521] Example 104: (R)-4,4-dimethyl-6-(2-(((1-(methyl)piperidin-3-yl)amino)pyrimidin-4-yl)-3,4-dihydroxyquinolin-1(2-hydrogen)-one Compound 104

[0522]

[0523] MS (ESI) m / z (M+1)+: 430.19.

[0524] Example 105: 4,4-dimethyl-6-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-3,4-dihydroxyquinolin-1(2H)-one Compound 105

[0525]

[0526] MS (ESI) m / z (M+1)+: 430.19.

[0527] Example 106: 2-(1R,4R)-4-((4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyrimidin-2-yl)amino)cyclohexyl)acetic acid Compound 106

[0528]

[0529] MS (ESI) m / z (M+1)+: 409.22.

[0530] Example 107: (R)-N-(5-chloro-4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroxyquinolin-6-yl)pyridin-2-yl)piperidine-3-carboxamide Compound 107

[0531]

[0532] MS (ESI) m / z (M+1)+: 413.17.

[0533] Example 108: Effects of CDK9 inhibitors on cancer cell growth

[0534] We evaluated the selectivity of compounds in inhibiting cancer cell proliferation by testing the effects of CDK9 inhibitors on the growth of cancer cells.

[0535] In this embodiment, acute myeloid leukemia cell lines OCI-AML-3, MV4-11, MOLM13, MOLM14, histiocytic lymphoma U-937, human chronic myeloid leukemia cells K562, human colorectal cancer cells HCT116, DLD1, human ovarian granulosa tumor cells COV434, human liver cancer cell line HepG2, lymphoma cells WSU-DLCL2, cervical cancer cells HeLa, gastrointestinal stromal tumor GIST-T1 (all of the above cells were purchased from Nanjing Kebai), MOLM13 resistant strain MOLM13 BR1 obtained by long-term treatment with CDK9 inhibitor BAY1251152 (purchased from China MCE), and HepG2 resistant strain HepG2 KI C20-1 obtained by knocking in CRISPR Cas9 technology were selected. The specific construction method is as follows: HepG2 cells are transfected with guide RNA-PX459 plasmid was then used to obtain HepG2 CDK9 KI cells through puromycin selection and BAY1251152 screening. HepG2 KI C20-1 monoclonal cells were then obtained through monoclonal screening, which contained CDK9 resistance mutations as detected by sequencing.

[0536] In the examples, different concentrations (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137 μM, 0.0411 μM, 0.123 μM, 0.370 μM, 1.11 μM, 3.33 μM, 10 μM) of the compounds of the present invention and control compounds Dinaciclib, JSH-009 and BAY1251152 (all purchased from MCE, China) were added to the above cells, incubated for 72 hours, and then cultured with Cell (Promega, USA) Chemiluminescent Cell Viability Assay Kit, which detects the number of living cells by quantitatively measuring ATP in living cells, and calculates GI based on this 50 , the results are shown in Tables 1-3.

[0537] Through detection, it was found that the compounds of the present invention have a strong inhibitory effect on different cancer cell lines. As shown in Table 1 and its continuation, the inhibitory effect is comparable to that of the control compound pan-CDK inhibitor Dinaciclib and the selective CDK9 inhibitor JSH-009. The antiproliferative activity of most compounds on cells is comparable to or even better than that of the selective CDK9 inhibitor BAY1251152. In addition, a drug-resistant strain was obtained by treating acute myeloid leukemia cells MOLM13 with BAY1251152. Table 2 shows a strong antiproliferative effect against the drug-resistant strain. Therefore, the compounds of the present invention show an inhibitory effect of overcoming drug resistance. As shown in Table 3, the test results on the drug-resistant strain of liver cancer cell HepG2 show that the compounds of the present invention can still overcome drug resistance, while BAY1251152 has obvious drug resistance.

[0538] Table 1

[0539] <![CDATA[GI 50 / μM]]> U937 AML3 WSU-DLCL2 HeLa GIST-T1 Dinaciclib 0.005 0.004 0.013 0.0165 0.015 JSH-009 0.016 0.018 0.034 Compound 11 0.02 0.037 0.023 0.039 Compound 20 0.006 0.007 0.004 0.011 Compound 21 0.013 0.014 0.012 0.014 Compound 26 0.004 0.005 0.007 0.035 Compound 27 0.006 0.008 0.013 0.04 Compound 28 0.002 0.002 Compound 29 0.186 0.153 Compound 31 0.016 0.023 Compound 32 0.007 0.012 Compound 33 0.063 0.048 Compound 34 0.007 0.008 Compound 35 0.023 0.033 Compound 39 0.0077 0.022 Compound 40 0.0046 0.005 Compound 41 0.013 0.023 Compound 42 <0.0015 0.003

[0540] Table 1 (continued)

[0541]

[0542]

[0543] Table 2

[0544] <![CDATA[GI 50 (nM)]]> MOLM13 MOLM13 BR1 Compound 11 27.26 40.48 Compound 13 6.099 10.03 Compound 14 7.085 8.259 Compound 26 3.483 6.143 Compound 27 6.659 23.09 Compound 82 0.8445 1.705 Compound 35 1.689 Compound 37 3.052 Compound 40 4.387 Compound 42 8.449 Compound 73 1.64 0.345 Compound 80 11.59 12.3 Compound 96 5.6 BAY1251152 37.95 1188

[0545] Table 3

[0546] GI50(nM) HepG2 HepG2 CDK9 KI C20-1 Compound 35 87.42 138.5 Compound 37 27.77 74.8 BAY1251152 36.07 >1000

[0547] Example 109: Detection of the binding activity of compounds to CDK9

[0548] The split luciferase system plasmid was constructed using molecular cloning technology. The N-terminal domain (NLuc) and C-terminal domain (CLuc) of luciferase were cloned and inserted into the vector PCDNA3 to construct NLuc-PCDNA3 and CLuc-PCDNA3 vectors, and multiple cloning sites were retained at both ends of the sequence. CDC37 and CDK9 were then cloned into the corresponding vectors to construct C37-CL and CDK9-NL vectors. The C37-CL plasmid sequence is shown in SEQ ID NO.1. The CDK9-NL plasmid sequence is shown in SEQ ID NO.2.

[0549] HEK-293T (purchased from ATCC, USA) was inoculated in a 10 cm cell culture dish and waited for the cell density to reach 70% for use. 2 μg C37-CL (SEQ ID NO.1) and 2 μg CDK9-NL plasmid (SEQ ID NO.2) were added to 1 mL Opti-MEM (Cat. No. 2120763, purchased from Gibco, USA), and then 6 μL of transfection reagent (Cat. No.: 20200918, purchased from Hanheng Bio, China) was added and mixed for use. The mixed transfection complex was added to a 10 cm cell culture dish and incubated at 37°C and 5% CO 2 Culture for 24 hours. After 24 hours, use trypsin to digest the HEK-293T cells. After counting, the transfected cells are plated into a 96-well white Corning cell culture plate (purchased from Corning, USA), inoculated with 100 μL, and the density is 5000 / well. After 12 hours, aspirate the culture medium in the 96-well plate, add 100 μL of culture medium containing the corresponding concentration of the test compound, and continue to culture for 12 hours. After 12 hours, add 20 μL of Luciferase-Glo (purchased from Promega, USA) detection reagent to each well. After mixing, use an enzyme reader to detect the fluorescence value. Calculate the relative activity IC according to the following formula 50 Value: relative activity = (fluorescence value of the drug to be tested - background value) / (fluorescence value of the DMSO group - background value) × 100%. The test results show that the compounds of the present invention have a strong binding effect with CDK9.

[0550] Table 4

[0551] <![CDATA[Binding activity to CDK9 in HEK-293T cells (IC 50 : μM)]]> Compound 11 0.06 Compound 12 0.098 Compound 20 0.036 Compound 21 0.044 Compound 26 0.016 Compound 27 0.019 Compound 28 0.015 Compound 31 0.129 Compound 32 0.049 Compound 34 0.05 Compound 35 0.3 Compound 36 0.19 Compound 37 0.049 Compound 39 0.087 Compound 40 0.067 Compound 41 0.114 Compound 42 0.09

[0552] Example 110: In vitro assay for inhibition of CDK9 protein enzyme activity

[0553] The DMSO-diluted compounds and control compounds Dinaciclib, JSH-009, BAY-1211152, and AZD4573 (all purchased from MCE, China) were mixed with the detected CDK9 / CyclinT1 protein (Invitrogen, USA), CDK9-L156F mut / CyclinT1 mutant protein (the mutation is consistent with the mutation in HepG2 KI C20-1, constructed as described in Example 108), and incubated at room temperature for 30 minutes; Kinase Peptide Substrate Mixture (Invitrogen, USA) was added and mixed with 4×ATP, and the mixed system was transferred to a 384-well white opaque plate and reacted at room temperature for 1 hour; 5 μL Development Solution (Invitrogen, USA) was added and reacted at room temperature for 1 hour, and finally Stop Reagent (Invitrogen, USA) was added to terminate the reaction, and the fluorescence value was read using an MD SpectraMax I3X microplate reader (Molecular Devices, USA). Based on the fluorescence values ​​read, Prism 5.0 (GraphPad Software, San Diego, CA) was used to plot and calculate the IC values ​​of the compounds of the present invention for the tested CDK9 / CyclinT1 protein and CDK9 mutant protein CDK9-L156F mut / CyclinT1. 50 The values ​​are shown in Tables 5 and 6 below. The results show that the compounds of the present invention have a strong inhibitory effect on CDK9 and its mutations, and are superior to or equivalent to the control compound in the wild-type CDK9 / CyclinT1 protein, and the inhibitory effect on the CDK9 mutant protein CDK9-L156Fmut / CyclinT1 is significantly better than the control compound BAY1251152.

[0554] Table 5

[0555]

[0556]

[0557] Table 6

[0558]

[0559] The present invention provides a CDK9 kinase inhibitor, which can be used to inhibit the activity of CDK9 and / or its mutant kinases and treat or prevent diseases related to or mediated by the activity of CDK9 and / or its mutants. Therefore, it can be prepared into a corresponding drug, which is suitable for industrial application.

[0560] Although the present invention is described in detail herein, the present invention is not limited thereto. Those skilled in the art may make modifications based on the principles of the present invention. Therefore, all modifications made in accordance with the principles of the present invention should be understood to fall within the protection scope of the present invention. Sequence Listing <110> Hefei Institutes of Physical Science, Chinese Academy of Sciences <120> Dihydroisoquinolinone and isoindolinone derivatives and their uses <130> CGCNL212070W <150> CN202011308146.4 <151> 2020-11-20 <160> 2 <170> SIPOSequenceListing 1.0 <210> 1 <211> 6856 <212> DNA <213> Artificial Sequence <400> 1 gacggatcgg gagatctccc gatcccctat ggtgcactct cagtacaatc tgctctgatg 60 ccgcatagtt aagccagtat ctgctccctg cttgtgtgtt ggaggtcgct gagtagtgcg 120 cgagcaaaat ttaagctaca acaaggcaag gcttgaccga caattgcatg aagaatctgc 180 ttagggttag gcgttttgcg ctgcttcgcg atgtacgggc cagatatacg cgttgacatt 240 gattattgac tagttattaa tagtaatcaa ttacggggtc attagttcat agcccatata 300 tggagttccg cgttacataa cttacggtaa atggcccgcc tggctgaccg cccaacgacc 360 cccgcccatt gacgtcaata atgacgtatg ttcccatagt aacgccaata gggactttcc 420 attgacgtca atgggtggag tatttacggt aaactgccca cttggcagta catcaagtgt 480 atcatatgcc aagtacgcccc cctattgacg tcaatgacgg taaatggccc gcctggcatt 540 atgcccagta catgacctta tgggactttc ctacttggca gtacatctac gtattagtca 600 tcgctattac catggtgatg cggttttggc agtacatcaa tgggcgtgga tagcggtttg 660 actcacgggg atttccaagt ctccacccca ttgacgtcaa tgggagtttg ttttggcacc 720 aaaatcaacg ggactttcca aaatgtcgta acaactccgc cccattgacg caaatgggcg 780 gtaggcgtgt acggtgggag gtctatataa gcagagctct ctggctaact agagaaccca 840 ctgcttactg gcttatcgaa attaatacga ctcactatag ggagaccacaa gctggctagc 900 gccaccatgg tggactacag cgtgtgggac cacattgagg tgtctgatga tgaagacgag 960 acgcacccca acatcgacac ggccagtctc ttccgctggc ggcatcaggc ccgggtggaa 1020 1080 cgcaaggtgg ccgagtgcca gaggaactg aaggagctgg aggtggccga gggcggcaag 1140 gcagagctgg agcgcctgca ggccgaggca cagcagctgc gcaaggag gcggagctgg 1200 1260 ctcagcaaag acggcttcag caagagcatg gtaaatacca agcccgagaa gacggaggag 1320 gactcagagg aggtgaggga gcagaaacac aagaccttcg tggaaaaata cgagaaacag 1380 atcaagcact ttggcatgct tcgccgctgg gatgacagcc aaaagtacct gtcagacaac 1440 gtccacctgg tgtgcgagga gacagccaat tacctggtca tttggtgcat tgacctagag 1500 gtgggaga aatgtgcact catggagcag gtggcccacc agaaatcgt catgcaattt 1560 atcctggagc tggccaagag cctaaaggtg gacccccggg cctgcttccg gcagttcttc 1620 actaagatta agacagccga tcgccaagtac atggagggct tcaacgacga gctggaagcc 1680 ttcaaggagc gtgtgcgggg ccgtgccaag ctgcgcatcg agaaggccat gaaggagtac 1740 gaggagg agcgcaagaa gcggctcggc cccggcggcc tggaccccgt cgaggtctac 1800 gagtccctcc ctgaggaact ccagaagtgc ttcgatgtga aggacgtgca gatgctgcag gacgccatca gcaagatgga ccccaccgac gcaaagtacc acatgcagcg ctgcattgac tctggcctct gggtccccaa ctctaaggcc agcgaggcca agggggaga ggaggcaggt cctggggacc cattactgga agctgttccc aagacggggcg atgagaagga tgtcagtgtg aagcttggta ccgagctcgg atccggtggc ggaggggagcg gtggcggagg gagcggcggc 2100 2160. cgcaagcccg acgtcgtcca gattgtccgc aactacaacg cctaccttcg ggccagcgac gatctgccta agatgttcat cgagtccgac cctgggttct tttccaacgc tattgtcgag ggagctaaga agttccctaa caccgagttc gtgaaggtga agggcctcca cttcagccag gaggacgctc cagatgaaat gggtaagtac atcaagagct tcgtggagcg cgtgctgaag aacgagcaga gtctagaggc tgactacaaa gaccatgacg gtgattataa agatcatgac atcgactaca aggatgacga tgacaagtga gtttaaaccc gctgatcagc ctcgactgtg ccttctagtt gccagccatc tgttgtttgc ccctccccg tgccttcctt gaccctgga 2520 ggtgccactc ccactgtcct ttcctaataa aatgaggaaa ttgcatcgca ttgtctgagt 2580 aggtgtcatt ctattctggg gggtggggtg gggcaggaca gcaaggggga ggattgggaa 2640 gacaatagca ggcatgctgg ggatgcggtg ggctctatgg cttctgaggc ggaaagaacc 2700 agctggggct ctagggggta tccccacgcg ccctgtagcg gcgcattaag cgcggcgggt 2760 gtggtggtta cgcgcagcgt gaccgctaca cttgccagcg cctacgcc cgctcctttc 2820 gctttcttc cttcctttct cgccacgttc gccggctttc cccgtcaagc tctaaatcgg 2880 gggctccctt tagggttccg atttagtgct ttacggcacc tcgaccccaa aaaacttgat 2940 tagggtgatg gttcacgtag tgggccatcg ccctgataga cggttttcg ccctttgacg 3000 ttggagtcca cgttctttaa tagtggactc ttgttccaaa ctggaacaac actcaaccct 3060 atctcggtct attctttga tttataaggg atttgccga ttcggccta ttggttaaaa 3120 aatgagctga tttaacaaaa atttaacgcg aattaattct gtggaatgtg tgtcagttag 3180 gttgtggaaa gtccccaggc tccccagcag gcagaagtat gcaaagcatg catctcaatt 3240 agtcagcaac caggtgtgga aagtccccag gctccccagc aggcagaagt atgcaaagca 3300 tgcatctcaa ttagtcagca accatagtcc cgcccctaac tccgcccatc ccgcccctaa 3360 ctccgcccag ttccgcccat tctccgcccc atggctgact aatttttttt atttatgcag 3420 aggccgaggc cgcctctgcc tctgagctat tccagaagta gtgaggaggc ttttttggag 3480 gcctaggctt ttgcaaaaag ctcccgggag cttgtatatc cattttcgga tctgatcaag 3540 agacaggatg aggatcgttt cgcatgattg aacaagatgg attgcacgca ggttctccgg 3600 ccgcttgggt ggagaggcta ttcggctatg actgggcaca acagacaatc ggctgctctg 3660 atgccgccgt gttccggctg tcagcgcagg ggcgcccggt tctttttgtc aagaccgacc 3720 tgtccggtgc cctgaatgaa ctgcaggacg aggcagcgcg gctatcgtgg ctggccacga 3780 cgggcgttcc ttgcgcagct gtgctcgacg ttgtcactga agcgggaagg gactggctgc 3840 tattgggcga agtgccgggg caggatctcc tgtcatctca ccttgctcct gccgagaaag 3900 tatccatcat ggctgatgca atgcggcggc tgcatacgct tgatccggct acctgcccat 3960 tcgaccacca agcgaaacat cgcatcgagc gagcacgtac tcggatggaa gccggtcttg 4020 tcgatcagga tgatctggac gaagagcatc aggggctcgc gccagccgaa ctgttcgcca 4080 ggctcaaggc gcgcatgccc gacggcgagg atctcgtcgt gacccatggc gatgcctgct 4140 tgccgaatat catggtggaa aatggccgct tttctggatt catcgactgt ggccggctgg 4200 gtgtggcgga ccgctatcag gacatagcgt tggctacccg tgatattgct gaagagcttg 4260 gcggcgaatg ggctgaccgc ttcctcgtgc tttacggtat cgccgctccc gattcgcagc 4320 gcatcgcctt ctatcgcctt cttgacgagt tcttctgagc gggactctgg ggttcgaaat 4380 gaccgaccaa gcgacgccca acctgccatc acgagatttc gattccaccg ccgccttcta 4440 tgaaaggttg ggcttcggaa tcgttttccg ggacgccggc tggatgatcc tccagcgcgg 4500 ggatctcatg ctggagttct tcgcccaccc caacttgttt attgcagctt ataatggtta 4560 caaataaagc aatagcatca caaatttcac aaataaagca tttttttcac tgcattctag 4620 ttgtggtttg tccaaactca tcaatgtatc ttatcatgtc tgtataccgt cgacctctag 4680 ctagagcttg gcgtaatcat ggtcatagct gtttcctgtg tgaaattgtt atccgctcac 4740 aattccacac aacatacgag ccggaagcat aaagtgtaaa gcctggggtg cctaatgagt 4800 gagctaactc acattaattg cgttgcgctc actgcccgct ttccagtcgg gaaacctgtc 4860 gtgccagctg cattaatgaa tcggccaacg cgcggggaga ggcggtttgc gtattgggcg 4920 ctcttccgct tcctcgctca ctgactcgct gcgctcggtc gttcggctgc ggcgagcggt 4980 atcagctcac tcaaaggcgg taatacggtt atccacagaa tcaggggata acgcaggaaa 5040 gaacatgtga gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg cgttgctggc 5100 gtttttccat aggctccgcc cccctgacga gcatcacaaa aatcgacgct caagtcagag 5160 gtggcgaaac ccgacaggac tataaagata ccaggcgttt ccccctggaa gctccctcgt 5220 gcgctctcct gttccgaccc tgccgcttac cggatacctg tccgcctttc tcccttcggg 5280 aagcgtggcg ctttctcata gctcacgctg taggtatctc agttcggtgt aggtcgttcg 5340 ctccaagctg ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg ccttatccgg 5400 taactatcgt cttgagtcca acccggtaag acacgactta tcgccactgg cagcagccac 5460 tggtaacagg attagcagag cgaggtatgt aggcggtgct acagagttct tgaagtggtg 5520 gcctaactac ggctacacta gaagaacagt atttggtatc tgcgctctgc tgaagccagt 5580 taccttcgga aaaagagttg gtagctcttg atccggcaaa caaaccaccg ctggtagcgg 5640 ttttttgtt tgcaagcagc agattacgcg cagaaaaaaa ggatctcaag aagatccttt 5700 gatctttct acggggtctg acgctcagtg gaacgaaaac tcacgttaag ggattttggt 5760 catgagatta tcaaaaagga tcttcaccta gatcctttta attaaaaat gaagttttaa 5820 atcaatctaa agtatatatg agtaaacttg gtctgacagt taccaatgct taatcagtga 5880 ggcacctatc tcagcgatct gtctatttcg ttcatccata gttgcctgac tccccgtcgt 5940 gtagataact acgatacggg agggcttacc atctggcccc agtgctgcaa tgataccgcg 6000 agacccacgc tcaccggctc cagattatc agcaataaac cagccagccg gaagggccga 6060 gcgcagaagt ggtcctgcaa ctttatccgc ctccatccag tctattaatt gttgccggga 6120 agctagta agtagttcgc cagttaatag tttgcgcaac gttgttgcca ttgctacagg 6180. catcgtggtg tcacgctcgt cgtttggtat ggcttcattc agctccggtt cccaacgatc 6240 aaggcgagtt acatgatccc ccatgttgtg caaaaaagcg gttagctcct tcggtcctcc 6300. gatcgttgtc agaagtaagt tggccgcagt gttatcactc atggttatgg cagcactgca 6360. taattctctt actgtcatgc catccgtaag atgcttttct gtgactggtg agtactcaac caagtcattc tgagaatagt gtatgcggcg accgagttgc tcttgcccgg cgtcaatacg ggataatacc gcgccacata gcagaacttt aaaagtgctc atcattggaa aacgttcttc ggggcgaaaa ctctcaagga tcttaccgct gttgagatcc agttcgatgt aacccactcg 6600. 6660. tgcacccaac tgatcttcag catcttttac tttcaccagc gtttctgggt gagcaaaaac aggaaggca aatgccgca aaaagggat aagggcgaca cggaatgtt gaatactcat actcttcctt tttcaatatt attgaagcat ttatcagggt tattgtctca tgagcggata catatttga tgtatttaga aaaataaaca aataggggtt ccgcgcacat ttccccgaaa agtgccacct gacgtc 6856 <210> 2 <211> 7338 <212> DNA <213> Artificial Sequence <400> 2 gacggatcgg gagatctccc gatcccctat ggtgcactct cagtacaatc tgctctgatg 60 ccgcatagtt aagccagtat ctgctccctg cttgtgtgtt ggaggtcgct gagtagtgcg 120 cgagcaaaat ttaagctaca acaaggcaag gcttgaccga caattgcatg aagaatctgc 180 ttagggttag gcgttttgcg ctgcttcgcg atgtacgggc cagatatacg cgttgacatt 240 gattattgac tagttattaa tagtaatcaa ttacggggtc attagttcat agcccatata 300 tggagttccg cgttacataa cttacggtaa atggcccgcc tggctgaccg cccaacgacc 360 cccgcccatt gacgtcaata atgacgtatg ttcccatagt aacgccaata gggactttcc 420 attgacgtca atgggtggag tatttacggt aaactgccca cttggcagta catcaagtgt 480 atcatatgcc aagtacgccc cctattgacg tcaatgacgg taaatggccc gcctggcatt 540 atgcccagta catgacctta tgggactttc ctacttggca gtacatctac gtattagtca 600 tcgctattac catggtgatg cggttttggc agtacatcaa tgggcgtgga tagcggtttg 660 actcacgggg atttccaagt ctccacccca ttgacgtcaa tgggagtttg ttttggcacc 720 aaaatcaacg ggactttcca aaatgtcgta acaactccgc cccattgacg caaatgggcg 780 gtaggcgtgt acggtgggag gtctatataa gcagagctct ctggctaact agagaaccca 840 ctgcttactg gcttatcgaa attaatacga ctcactatag ggagaccacaa gctggctagc 900 gccaccatgg cttccaaggt gtacgacccc gagcaacgca aacgcatgat cactgggcct 960 cagtggtggg ctcgctgcaa gcaatgaac gtgctggact ccttcatcaa ctactatgat 1020 tccgagaagc acgccgagaa cgccgtgatt tttctgcatg gtaacgctgc ctccagctac 1080 ctgtggaggc acgtcgtgcc tcacatcgag cccgtggcta gatgcatcat ccctgatctg 1140 atcggaatgg gtaagtccgg caagagcggg aatggctcat atcgcctcct ggatcactac 1200 aagtacctca ccgcttggtt cgagctgctg aaccttccaa agaaaatcat ctttgtgggc 1260 cacgactggg gggcttgtct ggcctttcac tactctacg agcaccaaga caagatcaag 1320 gccatcgtcc atgctgagag tgtcgtggac gtgatcgagt cctgggacga gtggcctgac 1380 atcgaggagg atatcgccct gatcaagagc gaagagggcg agaaaatggt gcttgagaat 1440 aacttcttcg tcgagaccat gctcccaagc aagatcatgc ggaaactgga gcctgaggag 1500 ttcgctgcct acctggagcc attcaaggag aagggcgagg ttagacggcc taccctctcc 1560 tggcctcgcg agatccctct cgttaaggga ggcggtggcg gagggagcgg tggcggaggg 1620 agcaagcttg gtaccgagct cggatccact agatctgtta acgtgtggtg gaattctatg 1680 gcaaagcagt acgactcggt ggagtgccct ttttgtgatg aagtttccaa atacgagaag 1740 ctcgccaaga tcggccaagg caccttcggg gaggtgttca aggccaggca ccgcaagacc 1800 ggccagaagg tggctctgaa gaaggtgctg atggaaaacg agaaggaggg gttccccatt 1860 acagccttgc gggagatcaa gatccttagc ttctaaaaca cgagaatgtg gtcaacttga 1920 ttgagatttg tcgaaccaaa gcttccccct ataaccgctg caagggtagt atatacctgg 1980 tgttcgactt ctgcgagcat gaccttgctg ggctgttgag caatgttttg gtcaagttca 2040 cgctgtctga gatcaagagg gtgatgcaga tgctgcttaa cggcctctac tacatccaca 2100 gaaacaagat cctgcatagg gacatgaagg ctgctaatgt gcttatcact cgtgatgggg 2160 tcctgaagct ggcagacttt gggctggccc gggccttcag cctggccaag aacagccagc 2220 ccaaccgcta caccaaccgt gtggtgacac tctggtaccg gcccccggag ctgttgctcg 2280 gggagcggga ctacggcccc cccattgacc tgtggggtgc tgggtgcatc atggcagaga 2340 tgtggacccg cagccccatc atgcagggca acacggagca gcaccaactc gccctcatca 2400 gtcagctctg cggctccatc acccctgagg tgtggccaaa cgtggacaac tatgagctgt 2460 acgaaaagct ggagctggtc aagggccaga agcggaaggt gaaggacagg ctgaaggcct 2520 atgtgcgtga cccatacgca ctggacctca tcgacaagct gctggtgctg gaccctgccc 2580 agcgcatcga cagcgatgac gccctcaacc acgacttctt ctggtccgac cccatgccct 2640 ccgacctcaa gggcatgctc tccacccacc tgacgtccat gttcgagtac ttggcaccac 2700 cgcgccggaa gggcagccag atcacccagc agtccaccaa ccagagtcgc aatcccgcca 2760 ccaccaacca gacggagttt gagcgcgtct tctggaattc tgcagatatc cagcacagtg 2820 gcggccgctc gagtctagag gctgactaca aagaccatga cggtgattat aaagatcatg 2880 acatcgaacta caaggatgac gatgacaagt gagtttaaac ccgctgatca gcctcgactg 2940 tgccttctag ttgccagcca tctgttgttt gcccctcccc cgtgccttcc ttgaccctgg 3000 aaggtgccac tccactgtc ctttcctaat aaaatgagga aattgcatcg cattgtctga 3060 gtaggtgtca ttctattctg gggggtgggg tggggcagga cagcaagggg gaggattggg 3120 aagaacatag caggcatgct ggggatgcgg tgggctctat ggcttctgag gcgggaagaa 3180 ccagctgggg ctctaggggg tatccccacg cgccctgtag cggcgcatta agcgcggcgg 3240 gtgtggtggt tacgcgcagc gtgaccgcta cacttgccag cgccctagcg cccgctcctt 3300 tcgctttctt cccttcctt ctcgccacgt tcgccggctt tccccgtcaa gctctaaatc 3360 ggggggctccc tttagggttc cgatttagtg ctttacggca cctcgacccc aaaaaacttg 3420 attagggtga tggttcacgt agtgggccat cgccctgata gacggttttt cgccctttga 3480 cgttggagtc cacgttcttt aatagtggac tcttgttcca aactggaaca acactcaacc 3540 ctatctcggt ctattctttt gatttataag ggattttgcc gatttcggcc tattggttaa 3600 aaaatgagct gatttaacaa aaatttaacg cgaattaatt ctgtggaatg tgtgtcagtt 3660 agggtgtgga aagtccccag gctccccagc aggcagaagt atgcaaagca tgcatctcaa 3720 ttagtcagca accaggtgtg gaaagtcccc aggctcccca gcaggcagaa gtatgcaaag 3780 catgcatctc aattagtcag caaccatagt cccgccccta actccgccca tcccgcccct 3840 aactccgccc agttccgccc attctccgcc ccatggctga ctaatttttt ttatttatgc 3900 agaggccgag gccgcctctg cctctgagct attccagaag tagtgaggag gcttttttgg 3960 aggcctaggc ttttgcaaaa agctcccggg agcttgtata tccattttcg gatctgatca 4020 agagacagga tgaggatcgt ttcgcatgat tgaacaagat ggattgcacg caggttctcc 4080 ggccgcttgg gtggagaggc tattcggcta tgactgggca caacagacaa tcggctgctc 4140 tgatgccgcc gtgttccggc tgtcagcgca ggggcgcccg gttctttttg tcaagaccga 4200 cctgtccggt gccctgaatg aactgcagga cgaggcagcg cggctatcgt ggctggccac 4260 gacgggcgtt ccttgcgcag ctgtgctcga cgttgtcact gagcggga gggactggct gctattgggc gaagtgccgg ggcaggatct cctgtcatct caccttgctc ctgccgagaa 4380 agtatccatc atggctgatg caatgcggcg gctgcatacg cttgatccgg ctacctgccc 4440 attcgaccac caagcgaaac atcgcatcga gcgagcacgt actcggatgg aagccggtct tgtcgatcag gatgatctgg acgaagagca tcaggggctc gcgccagccg aactgttcgc 4560 caggctcaag gcgcgcatgc ccgacggcga ggatctcgtc gtgacccatg gcgatgcctg 4620. cttgccgaat atcatggtgg aaaatggccg cttttctgga ttcatcgact gtggccggct gggtgtggcg gaccgctatc aggacatagc gttggctacc cgtgatattg ctgaagagct 4740 tggcggcgaa tgggctgacc gcttcctcgt gctttacggt atcgccgctc ccgattcgca 4800. gcgcatcgcc ttctatcgcc ttcttgacga gttcttctga gcgggactct ggggttcga 4860 atgaccgacc aagcgacgcc caacctgcca tcacgagatt tcgattccac cgccgccttc tatgaaaggt tgggcttcgg aatcgttttc cgggacgccg gctggatgat cctccagcgc 4980 ggggatctca tgctggagtt cttcgcccac cccaacttgt ttattgcagc ttataatggt 5040 tacaaataaa gcaatagcat cacaaatttc acaaataaag catttttttc actgcattct 5100 agttgtggtt tgtccaaact catcaatgta tcttatcatg tctgtatacc gtcgacctct 5160 agctagagct tggcgtaatc atggtcatag ctgtttcctg tgtgaaattg ttatccgctc 5220 acaattccac acaacatacg agccggaagc ataaagtgta aagcctgggg tgcctaatga 5280 gtgagctaac tcacattaat tgcgttgcgc tcactgcccg ctttccagtc gggaaacctg 5340 tcgtgccagc tgcattaatg aatcggccaa cgcgcgggga gaggcggttt gcgtattggg 5400 cgctcttccg cttcctcgct cactgactcg ctgcgctcgg tcgttcggct gcggcgagcg 5460 gtatcagctc actcaaaggc ggtaatacgg ttatccacag aatcagggga taacgcagga 5520 aagaacatgt gagcaaaagg ccagcaaaag gccaggaacc gtaaaaaggc cgcgttgctg 5580 gcgtttttcc ataggctccg cccccctgac gagcatcaca aaaatcgacg ctcaagtcag 5640 aggtggcgaa acccgacagg actataaaga taccaggcgt ttccccctgg aagctccctc 5700 gtgcgctctc ctgttccgac cctgccgctt accggatacc tgtccgcctt tctcccttcg 5760 ggaagcgtgg cgctttctca tagctcacgc tgtaggtatc tcagttcggt gtaggtcgtt 5820 cgctccaagc tgggctgtgt gcacgaaccc cccgttcagc ccgaccgctg cgccttatcc 5880 ggtaactatc gtcttgagtc caacccggta agacacgact tatcgccact ggcagcagcc 5940 actggtaaca ggattagcag agcgaggtat gtaggcggtg ctacagagtt cttgaagtgg 6000 tggcctaact acggctcac tagagaaca gtatttggta tctgcgctct gctgaagcca 6060 gttaccttcg gaaaaagagt tggtagctct tgatccggca aacaaaccac cgctggtagc 6120 ggtttttttg tttgcaagca gcagattacg cgcagaaaaa aaggatctca agaagatcct 6180 ttgatctttt ctacggggtc tgacgctcag tggaacgaaa actcacgtta agggatttg 6240 gtcatgagat tatcaaaaag gatcttcacc tagatccttt taaattaaaa atgaagttt 6300 aaatcaatct aaagtatata tgagtaaact tggtctgaca gttaccaatg cttaatcagt 6360 gaggcaccta tctcagcgat ctgtctattt cgttcatcca tagttgcctg actccccgtc 6420 gtgtagataa ctacgatacg ggagggctta ccatctggcc ccagtgctgc aatgataccg 6480 cgagacccac gctcaccgg tccagattta tcagcaataa accagccagc cggaagggcc 6540 gagcgcagaa gtggtcctgc aactttatcc gcctccatcc agtctattaa ttgttgccgg 6600 gaagctagag tagtagttc gccagttaat agtttgcgca acgttgttgc cattgctaca 6660 ggcatcgtgg tgtcacgctc gtcgtttggt atggcttcat tcagctccgg ttcccaacga 6720 tcaaggcgag ttacatgatc ccccatgttg tgcaaaaaag cggttagctc cttcggtcct 6780 ccgatcgttg tcaagtaa gttggccgca gtgttatcac tcatggttat ggcagcactg 6840 cataattctc ttactgtcat gccatccgta agatgctttt ctgtgactgg tgagtactca 6900 accaagtcat tctgagata gtgtatgcgg cgaccgagtt gctcttgccc ggcgtcaata 6960 cgggataata ccgcgccaca tagcagaact ttaaaagtgc tcatcattgg aaaacgttct 7020 tcggggcgaa aactctcaag gatcttaccg ctgttgagat ccagttcgat gtaacccact 7080 7140. cgtgcaccca actgatcttc agcatctttt actttcacca gcgtttctgg gtgagcaaaa acaggaaggc aaaatgccgc aaaaaaggga ataagggcga cacggaatg ttgaatactc atactcttcc tttttcaata ttattgaagc atttatcagg gttattgtct catgagcgga tacatatttg aatgtattta gaaaaataaa caatagggg ttccgcgcac atttccccga 7338. aaagtgccac ctgacgtc

Claims

1. A kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in, A is selected from the group consisting of cyclohexyl, phenyl, pyridinyl and piperidinyl; X is CH or N; Z is -NH- or -NH-C(=O)-; n is 0 or 1; R 1 is selected from hydrogen, halogen, cyano, (C1-C6)alkyl, and (C1-C6)haloalkyl; R 2 is selected from hydrogen, and (C1-C6) alkyl, or two R 2 Together they form a (C3-C6)cycloalkyl group; m is an integer selected from 1 to 3, and each R 3 each independently selected from hydrogen, -NH-(C1-C3)alkyl-(C1-C3)alkoxy, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)alkylamido, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonylamino, aminosulfonyl, (C1-C6)alkylaminosulfonyl, heterocyclic sulfonyl optionally substituted by (C1-C6)alkyl, carboxyl (C1-C3)alkyl, aminosulfonyl (C1-C3)alkyl, (C1-C6)alkylamido, (C1-C6)alkylsulfonyl, C3)alkylsulfonyl(C1-C3)alkyl, (C1-C3)alkylsulfonyl(C3-C6)cycloalkyl, heterocyclylaminoacyl wherein heteroatoms are optionally substituted by (C1-C6)alkyl, heterocyclyl wherein heteroatoms are optionally substituted by (C1-C6)alkyl, -S(=O)(=NH)(C1-C3)alkyl, and -(C1-C3)alkyl-S(=O)(=NH)(C1-C3)alkyl, wherein the heterocyclyl is a monocyclic ring composed of five, six or seven atoms, wherein one or more atoms constituting the ring are heteroatoms selected from nitrogen, oxygen and sulfur; R 4 is selected from hydrogen and (C1-C6)alkyl.

2. The kinase inhibitor according to claim 1, comprising a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, Where R 3 It is -NH-(C1-C3)alkyl-(C1-C3)alkoxy or carboxy(C1-C3)alkyl.

3. The kinase inhibitor according to claim 1, comprising a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, in, Y is CH or N; m is an integer selected from 1 to 3, and each R 3 Each is independently selected from halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfonylamino, aminosulfonyl, (C1-C6) alkylaminosulfonyl, heterocyclylsulfonyl optionally substituted by (C1-C6) alkyl with a heteroatom, aminosulfonyl(C1-C3) alkyl, (C1-C3) alkylsulfonyl(C1-C3) alkyl, (C1-C3) alkylsulfonyl(C3-C6) cycloalkyl, heterocyclylaminoacyl optionally substituted by (C1-C6) alkyl with a heteroatom, heterocyclyl optionally substituted by (C1-C6) alkyl with a heteroatom, -S(=O)(=NH)(C1-C3) alkyl, and -(C1-C3) alkyl-S(=O)(=NH)(C1-C3) alkyl.

4. The kinase inhibitor according to claim 1, comprising a compound of formula (Ic) or a pharmaceutically acceptable salt thereof, in, R 3 It is a (C1-C6)alkylacylamino group.

5. The kinase inhibitor according to claim 1, comprising a compound of formula (Id) or a pharmaceutically acceptable salt thereof, wherein R 3 is (C1-C6) alkylsulfonyl. The kinase inhibitor according to any one of claims 1 to 5 , wherein X is N.

7. The kinase inhibitor according to claim 1, comprising the following compound or a pharmaceutically acceptable salt thereof:

8. A pharmaceutical composition comprising the kinase inhibitor according to any one of claims 1 to 7, and a pharmaceutically acceptable diluent or carrier, and optionally one or more other active ingredients.

9. Use of a kinase inhibitor according to any one of claims 1 to 7 in the preparation of a medicament for treating a disease carrying a gene selected from CDK9 and / or a CDK9 mutation.

10. Use of the kinase inhibitor according to any one of claims 1 to 7 in the preparation of a medicament for treating leukemia, liver cancer, ovarian cancer, cervical cancer, colorectal cancer, gastrointestinal stromal tumor, or lymphoma.

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