Dihydroisoquinolinone and isoindolinone derivatives and their uses

Abstract

A kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof. Methods and uses of the inhibitor for the treatment of diseases associated with CDK9 and / or its mutagenic activity. [Formula 1] TIFF2023551197000138.tif49170

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical field, in particular to compounds containing dihydroisoquinolinone / isoindolinone structures and pyrimidine / pyridine structures, as well as methods for their preparation, and methods and uses for treating and / or preventing diseases. [Background technology]

[0002] The cyclin-dependent kinase (CDK) protein family consists of members that are key regulators of the cell division cycle (cell cycle CDKs), members involved in regulating gene transcription (transcription CDKs), and members with other functions. CDKs require association with regulatory cyclin subunits for activation. Among the cell cycle CDKs, the cell cycle CDKs CDK1 / cyclin B, CDK2 / cyclin A, CDK2 / cyclin E, CDK4 / cyclin D, and CDK6 / cyclin D are sequentially activated to guide cells through the cell division cycle. The transcription CDKs CDK9 / cyclin T and CDK7 / cyclin H 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 four cyclin partners (cyclin T1, cyclin K, cyclin T2a, or T2b).

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

[0004] Gene transcription by RNA polymerase II is initiated by the assembly of a preinitiation complex at the promoter region and the phosphorylation of Ser5 and Ser7 of the CTD by CDK7 / cyclin H. For the majority of genes, RNA polymerase II terminates mRNA transcription after moving 20 to 40 nucleotides along the DNA template. This promoter-proximal pausing of RNA polymerase II is mediated by negative elongation factors and is recognized as a major regulatory mechanism regulating the expression of genes that are rapidly induced in response to various stimuli (Non-Patent Document 1). P-TEFb is critically involved in overcoming promoter-proximal pausing of RNA polymerase II and transitioning to a productive elongation state through phosphorylation of Ser2 of the CTD and phosphorylation and inactivation of negative elongation factors.

[0005] The activity of P-TEFb itself is regulated by several mechanisms. Approximately half of cellular P-TEFb exists in an inactive complex with 7SK small nuclear RNA (7SK snRNA), La-related protein 7 (LARP7 / PIP7S), and hexamethylene bisacetamide-inducible protein 1 / 2 (HEXIM1 / 2, non-patent literature 2). The other half exists in an active complex containing the bromodomain protein Brd4 (non-patent literature 3). Brd4 recruits P-TEFb to chromatin regions primed for gene transcription through interactions with acetylated histones. Alternating interactions with positive and negative regulatory factors maintain P-TEFb in a functional equilibrium state, and P-TEFb bound to the 7SK snRNA complex serves as a reservoir from which active P-TEFb can be released upon demand for cellular transcription and cell proliferation. Furthermore, the activity of P-TEFb is regulated by post-translational modifications, including phosphorylation / dephosphorylation, ubiquitination, and acetylation.

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

[0007] Cancer is considered 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 a variety of human tumors and contribute to tumor cell long-term survival and treatment resistance. Inhibition of P-TEFb kinase activity has been shown to reduce the transcriptional activity of RNA polymerase II, leading to a decrease in short-lived anti-apoptotic proteins (particularly Mcl-1 and XIAP), thereby restoring the tumor cell's ability to undergo apoptosis. Many other proteins associated with the transformed tumor phenotype (e.g., Myc, NF-kB-responsive gene transcripts, and mitotic kinases) are short-lived proteins or are encoded by short-lived transcripts that are sensitive to the reduction in RNA polymerase II activity mediated by P-TEFb inhibition.

[0008] There has been no research on drug resistance to CDK9 inhibitors. In the present invention, cell lines resistant to CDK9 inhibitors were obtained through long-term administration, and the compounds of the present invention were found to inhibit cell lines with drug resistance due to long-term administration of CDK9 inhibitors. After further protein expression and detection of CDK9 mutant proteins in drug-resistant cell lines, it was found that the compounds of the present invention can overcome drug-resistant mutations in CDK9.

[0009] Furthermore, many viruses rely on the host cell transcription machinery to transcribe their genomes. In the case of HIV-1, RNA polymerase II is recruited to the promoter region within the viral long terminal repeat (LTR). The viral transcription activator (Tat) protein binds to nascent viral transcripts and then overcomes promoter-proximal RNA polymerase II stalling by recruiting P-TEFb, which promotes transcription elongation. Furthermore, Tat protein increases the fraction of active P-TEFb by displacing the P-TEFb inhibitor protein HEXIM1 / 2 within the 7SK snRNA complex. Recent data have shown that inhibition of the kinase activity of P-TEFb is sufficient to block HIV-1 replication at kinase inhibitor concentrations that are not cytotoxic to host cells (reviewed in Non-Patent Document 4). Similarly, recruitment of P-TEFb by viral proteins has been reported for other viruses, such as the B-cell carcinoma-associated Epstein-Barr virus, in which the nuclear antigen EBNA2 protein interacts with P-TEFb (Non-Patent Document 5), and human T-lymphotropic virus type 1 (HTLV-1), in which the transcriptional activator Tax recruits P-TEFb (Non-Patent Document 6).

[0010] Cardiac hypertrophy, an adaptive response of the heart to mechanical overload and pressure (hemodynamic stress, e.g., hypertension, myocardial infarction), can lead to heart failure and death in the long term. Cardiac hypertrophy has been shown to be associated with increased transcriptional activity and RNA polymerase II CTD phosphorylation in cardiomyocytes. P-TEFb was found to be activated by dissociation from the inactive 7SK snRNA / HEXIM1 / 2 complex. These findings suggest pharmacological inhibition of P-TEFb kinase activity as a therapeutic approach to treat cardiac hypertrophy (reviewed in Non-Patent Document 7).

[0011] In summary, multiple lines of evidence suggest that selective inhibition of CDK9 kinase activity in the P-TEFb heterodimer (CDK9 and one of its four cyclin partners (cyclin T1, cyclin K, cyclin T2a, or T2b)) represents an innovative 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, where subgroups of cell cycle CDKs play multiple roles in regulating cell proliferation. Therefore, simultaneous 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 normal proliferating tissues, such as the intestinal mucosa, lymphoid and hematopoietic organs, and reproductive organs. To maximize the therapeutic potential of CDK9 kinase inhibitors, molecules with high selectivity for CDK9 are needed.

[0012] Although various CDK inhibitors are generally known, selective CDK9 inhibitors remain needed for treating diseases such as hyperproliferative, viral and / or cardiac diseases, which may offer one or more advantages over compounds known in the prior art. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Cho et al., Cell Cycle 9, 1697, 2010 [Non-patent document 2] He et al., Mol Cell 29, 588, 2008 [Non-patent document 3] Yang et al., Mol Cell 19, 535, 2005 [Non-patent document 4] Wang & Fischer, Trends Pharmacol Sci 29, 302, 2008 [Non-Patent Document 5] Bark-Jones et al., Oncogene, 25, 1775, 2006 [Non-patent document 6] Zhou et al., J Virol. 80, 4781, 2006 [Non-Patent Document 7] Dey et al., Cell Cycle 6, 1856, 2007 Summary of the Invention

[0014] The present invention provides a kinase inhibitor having the formula (I): [ka] Formula (I) wherein A is selected from the group consisting of cyclohexyl, phenyl, pyridinyl, and piperidyl; X is CH or N; Z is -NH- or -NH-C(=O)-; n is 0 or 1, R 1 is selected from the group consisting of hydrogen, halogen, cyano, (C1-C6) alkyl, and (C1-C6) haloalkyl; R 2 is selected from the group consisting of hydrogen and (C1-C6) alkyl, or two R 2 together form a (C3-C6)cycloalkyl, m is selected from an integer of 1 to 3, and each R 3are independently selected from hydrogen, -NH-(C1-C3)alkyl-(C1-C3)alkoxy, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)alkylacylamino, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonamido, aminosulfonyl, (C1-C6)alkylaminosulfonyl, heterocyclylsulfonyl having heteroatom(s) optionally substituted with (C1-C6)alkyl, carboxyl(C1-C3)alkyl, aminosulfonyl and -(C1-C3)alkyl-S(=O)(=NH)(C1-C3)alkyl, -(C1-C3)alkylsulfonyl(C1-C3)alkyl, -(C1-C3)alkylsulfonyl(C3-C6)cycloalkyl, -(C1-C3)alkylaminoacyl having heteroatom(s) optionally substituted with (C1-C6)alkyl, -(C1-C3)alkyl-S(=O)(=NH)(C1-C3)alkyl, and -(C1-C3)alkyl-S(=O)(=NH)(C1-C3)alkyl; R 4 is selected from the group consisting of hydrogen and (C1-C6) alkyl), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.

[0015] In a preferred embodiment, the present invention provides a compound of formula (Ia): [ka] Formula (Ia) (In the formula, X, n, R 1 , R 2 , R 3 , and R 4 is as defined above), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.

[0016] In this embodiment, X is preferably N, and in another embodiment, R 3is preferably -NH-(C1-C3)alkyl-(C1-C3)alkoxy or carboxyl(C1-C3)alkyl.

[0017] In another preferred embodiment, the present invention provides a compound of formula (Ib): [ka] Formula (Ib) (wherein Y is CH or N, and X, m, n, R 1 , R 2 , R 3 , and R 4 is as defined above), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.

[0018] In a more preferred embodiment, X is N, and in another preferred embodiment, Y is CH.

[0019] In another preferred embodiment, each R 3 are independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonamido, aminosulfonyl, (C1-C6)alkylaminosulfonyl, heterocyclylsulfonyl having heteroatom(s) optionally substituted with (C1-C6)alkyl, aminosulfonyl(C1-C3)alkyl, (C1-C3)alkylsulfonyl(C1-C3 )alkyl, (C1-C3)alkylsulfonyl(C3-C6)cycloalkyl, heterocyclylaminoacyl having heteroatom(s) optionally substituted with (C1-C6)alkyl, heterocyclyl having heteroatom(s) optionally substituted with (C1-C6)alkyl, -S(=O)(=NH)(C1-C3)alkyl, and -(C1-C3)alkyl-S(=O)(=NH)(C1-C3)alkyl.

[0020] In another preferred embodiment, the present invention provides a compound of formula (Ic): [ka] Formula (Ic) (In the formula, X, n, R 1 , R 2 , R 3 , and R 4 is as defined above), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.

[0021] In a more preferred embodiment, R 3 is (C1-C6) alkylacylamino.

[0022] In another preferred embodiment, the present invention provides a compound of formula (Id): [ka] Formula (Id) (In the formula, X, n, R 1 , R 2 , R 3 , and R 4 is as defined above), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.

[0023] In this embodiment, X is preferably N, and in a more preferred embodiment, R 3 is (C1-C6) alkylsulfonyl.

[0024] In another aspect, the present application also relates to a pharmaceutical composition comprising a kinase inhibitor of the present invention and a pharmaceutically acceptable diluent or carrier.

[0025] In another aspect, the application relates to the use of a kinase inhibitor of the present invention in the preparation of a medicament for treating hyperproliferative disorders, virally induced infectious diseases, and cardiovascular diseases.

[0026] In another aspect, the present application also relates to methods of treating hyperproliferative disorders, virally induced infectious diseases, and cardiovascular diseases by using the kinase inhibitors of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0027] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the singular also includes the plural unless the context clearly dictates otherwise. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0028] Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the skill of one in the art are employed in the present invention. Unless specific definitions are provided, the nomenclature used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. The techniques and procedures described above can generally be performed using conventional methods known in the art, as well as methods described in the various general and more specific references cited and discussed throughout this specification.

[0029] The term "alkyl" refers to an aliphatic hydrocarbon group, which may be branched or straight-chain alkyl. Depending on the structure, the alkyl group may be a monoradical or a diradical (i.e., an alkylene group). In the present invention, the alkyl group is preferably an alkyl having 1 to 8 carbon atoms, more preferably a "lower alkyl" having 1 to 6 carbon atoms, and even more preferably an alkyl having 1 to 3 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like. It should be understood that "alkyl" as referred to herein encompasses all possible configurations and conformations of alkyl; for example, "propyl" as referred to herein is intended to encompass n-propyl and isopropyl; "butyl" as referred to herein is intended to encompass n-butyl, isobutyl, and tertiary butyl; "pentyl" as referred to herein is intended to encompass n-pentyl, isopentyl, neopentyl, tert-pentyl, pent-3-yl, and the like.

[0030] The term "alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.

[0031] The term "alkoxyalkyl" refers to an alkyl group, as defined herein, substituted with an alkoxy, as defined herein.

[0032] The term "cycloalkyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen. Cycloalkyl groups include groups having 3 to 12 ring atoms. Depending on the structure, a cycloalkyl group can be a monoradical or a diradical (e.g., a cycloalkylene group). In the present invention, a cycloalkyl group is preferably a cycloalkyl having 3 to 8 carbon atoms, more preferably a "lower cycloalkyl" having 3 to 6 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantyl.

[0033] The terms "alkyl(cycloalkyl)" or "cycloalkylalkyl" refer to an alkyl group, as defined herein, substituted with a cycloalkyl, as defined herein. Non-limiting examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0034] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons (where n is an integer). Aromatic rings can be formed by 5, 6, 7, 8, 9, or 10 or more atoms. Aromatic compounds can be optionally substituted. The term "aromatic" includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (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.

[0035] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. The aryl ring can be formed by 5, 6, 7, 8, 9, or 10 or more carbon atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl. Depending on the structure, the aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0036] The term "aryloxy" refers to -O-aryl, where aryl is as defined herein.

[0037] The term "heteroaryl" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group). Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuryl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, furopyridinyl, and the like.

[0038] As used herein, the term "heteroalkyl" refers to an alkyl, as defined herein, having one or more skeletal chain atom(s) that are heteroatoms such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof. The heteroatom(s) can be located at any position along the heteroalkyl or at the position at which the heteroalkyl is attached to the remainder of the molecule.

[0039] As used herein, the term "heterocycloalkyl" or "heterocyclyl" refers to a non-aromatic ring in which one or more of the atoms forming the ring is a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur. A heterocycloalkyl ring can be a monocyclic or bicyclic ring formed by 3, 4, 5, 6, 7, 8, 9, or 10 or more atoms. A heterocycloalkyl ring can be optionally substituted. Examples of heterocycloalkyls include lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiine, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihyd Examples of heterocycloalkyl groups include, but are not limited to, dolauracil, 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-dithiol, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane. Depending on the structure, heterocycloalkyl groups can be monoradicals or diradicals (i.e., heterocycloalkylene groups).

[0040] The terms "alkyl(heterocycloalkyl)" or "heterocycloalkylalkyl" refer to an alkyl group, as defined herein, substituted with a heterocycloalkyl, as defined herein.

[0041] The term "halo" or "halogen" means fluoro, chloro, bromo, and iodo.

[0042] The terms "haloalkyl," "haloalkoxy," and "haloheteroalkyl" include alkyl, alkoxy, or heteroalkyl structures in which at least one hydrogen has been replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms have been replaced with halogen atoms, the halogen atoms are the same or different from one another.

[0043] The term "hydroxy" refers to the group --OH.

[0044] The term "cyano" refers to the group --CN.

[0045] The term "carboxyl" refers to the group --COOH.

[0046] The term "ester" refers to a chemical moiety having the formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a cyclocarbon), and heterocyclyl (attached through a cyclocarbon).

[0047] The term "amino" refers to the group --NH.sub.2.

[0048] The term "aminoacyl" refers to the group -CO-NH2.

[0049] The term "alkylaminoacyl" refers to the group -CO-NH-R, where R is alkyl, as defined herein.

[0050] The terms "amide" or "amido" refer to -NR-CO-R', where R and R' are independently hydrogen or alkyl.

[0051] The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups, specifically the group -NRR', where R and R' are each independently selected from the group consisting of hydrogen or lower alkyl, with the proviso that -NRR' is not -NH. "Alkylamino" includes a group of compounds in which the nitrogen atom of -NH is attached to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like. "Dialkylamino" includes groups in which the nitrogen atom of -NH is attached to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.

[0052] The term "cycloalkylamino" refers to an amino substituent which is further substituted with one or two cycloalkyl groups, as defined herein.

[0053] The term "heterocycloalkylamino" refers to an amino radical, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0054] The term "alkylaminoalkyl" refers to an alkyl radical, as defined herein, substituted with an alkylamino group, as defined herein.

[0055] The term "aminoalkyl" refers to an alkyl substituent that is further substituted with one or more amino groups.

[0056] The term "aminoalkoxy" refers to an alkoxy substituent which is further substituted with one or more amino groups.

[0057] The terms "hydroxyalkyl" or "hydroxylalkyl" refer to an alkyl substituent that is further substituted with one or more hydroxy groups.

[0058] The term "cyanoalkyl" refers to an alkyl substituent that is further substituted with one or more cyano groups.

[0059] The term "carboxylalkyl" refers to an alkyl substituent which is further substituted with one or more carboxyl groups.

[0060] The term "acyl" refers to the monovalent atomic radical remaining after removal of the hydroxyl group from an organic or inorganic oxyacid and has the general formula RM(O)-, where M is usually C.

[0061] The term "carbonyl" refers to an organic functional group formed by the joining of a carbon atom and an oxygen atom through a double bond (C=O).

[0062] The terms "alkanoyl" or "alkylcarbonyl" refer 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.

[0063] The term "sulfuryl" or "sulfonyl" refers to the functional group left after a sulfonic acid loses its hydroxyl group, specifically the -S(=O)2- group.

[0064] The terms "aminosulfuryl" or "aminosulfonyl" refer to the group -S(=O)2-NH2.

[0065] The terms "alkylsulfuryl" or "alkylsulfonyl" refer to -S(=O)2-R, where R is an alkyl group.

[0066] The terms "alkylsulfurylamide" or "alkylsulfonamide," and "cycloalkylsulfurylamide" or "cycloalkylsulfonamide" refer to an amino radical, as defined herein, substituted with an alkylsulfuryl or cycloalkylsulfuryl group, as defined herein, i.e., -NH-S(=O)-R, where R is alkyl or cycloalkyl, respectively.

[0067] The terms "cycloalkylsulfuryl" and "cycloalkylsulfonyl" refer to -S(=O)2-R, where R is a cycloalkyl group.

[0068] The term "optionally" means that one or more of the events described below may or may not occur, and is intended to include both the event(s) that may occur and the event(s) that may not occur. The term "optionally substituted" or "substituted" means that the referenced group can be substituted with one or more additional groups each independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, cyano, halo, amido, nitro, haloalkyl, amino, methylsulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, an amino-protecting group, and the like, and the amino-protecting group is preferably selected from the group consisting of pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trifluoroacetyl, and the like.

[0069] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesired 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 purified compound in its free acid or free base form with a suitable base or acid, respectively.

[0070] "Solvate" refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to form solvates by trapping a fixed molar ratio of solvent molecules in the crystalline solid state. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of a substance, with the water retaining the molecular state as HO.

[0071] A "metabolite" of a compound disclosed herein is a derivative of that compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to a collection of processes by which a particular substance is transformed by an organism, including, but not limited to, enzyme-catalyzed reactions such as hydrolysis and oxidation. Thus, enzymes can cause specific structural changes in a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, and uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information regarding metabolism can be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of a compound disclosed herein can be identified by either administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are known in the art. In some embodiments, a metabolite of a compound is formed by an oxidation process and corresponds to the corresponding hydroxy-containing compound. In some embodiments, a compound is metabolized to a pharmacologically active metabolite.

[0072] The term "modulate," as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, by way of example only, to enhance the activity of the target, inhibit the activity of the target, limit the activity of the target, or expand the activity of the target.

[0073] The term "prodrug" or "drug precursor" refers to a derivative that may not have pharmacological activity but, in some cases, may be metabolized in the body to form a pharmacologically active compound of the present invention after oral or parenteral administration. Non-limiting examples of prodrugs include esters, carbonates, hemiesters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals, and ketals.

[0074] "Effective amount" refers to an amount of a drug or pharmaceutical agent that elicits the biological or medical response of a tissue, system, animal, or human that is desired, for example, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" refers to any amount that results in improved treatment, cure, prevention, or reversal of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject who does not receive such amount. This term also includes within its scope amounts effective to enhance normal physiological function.

[0075] As used herein, the term "treating" refers to the alleviation of at least one symptom of a disease, disorder, or condition. This term encompasses the administration and / or application of one or more compounds described herein to a subject for the purpose of providing management or amelioration of the condition. For purposes of this disclosure, "treatment" may, but need not, result in a cure. Rather, "treatment" may be a form of management of the condition. When the compounds described herein are used to treat undesirably proliferating cells, including cancer, "treatment" includes the partial or complete destruction of the inappropriately proliferating cells with minimal destructive effects on normal cells. At the cellular level, the desired therapeutic mechanism for undesirably rapidly proliferating cells, including cancer cells, is apoptosis.

[0076] As used herein, the term "preventing" includes either completely preventing or delaying the onset of clinically evident disease progression in at-risk individuals, or preventing or delaying the onset of a pre-clinical stage of disease, including prophylactic measures for individuals at risk of developing disease.

[0077] The term "subject" or "patient" includes organisms, e.g., humans and non-human animals, that may suffer from a cell proliferative disorder or a disorder associated with reduced or insufficient programmed cell death (apoptosis), or that could otherwise benefit from the administration of a compound of the invention. Preferred humans include human patients suffering from or susceptible to a disease or related condition described herein. The term "non-human animal" includes vertebrates, e.g., mammals such as non-human primates, sheep, cows, dogs, cats, and rodents, e.g., mice, as well as non-mammals, such as chickens, amphibians, and reptiles.

[0078] As used herein, GI 50 refers to the concentration of a drug required to inhibit the growth of 50% of cells, i.e., the drug concentration at which the growth of 50% of cells (such as cancer cells) is inhibited or controlled.

[0079] As used herein, IC 50 refers to the amount, concentration, or dosage of a particular test compound that achieves 50% inhibition of a maximal response in an assay that measures such response.

[0080] As used herein, EC 50 refers to the dose, concentration, or amount of a test compound that produces a dose-dependent response of 50% of the maximal expression of a particular response induced, elicited, or potentiated by a particular test compound.

[0081] The terms "diseases associated with CDK9 and / or mutations thereof" or "diseases mediated by CDK9 and / or mutations thereof" include diseases related to or involving the activity of CDK9 and / or mutations thereof (e.g., increased activity of CDK9 and / or mutations thereof), as well as pathological conditions associated with these diseases. Examples of "diseases associated with CDK9 and / or mutations thereof" or "diseases mediated by CDK9 and / or mutations thereof" include diseases caused by increased activity of CDK9 and / or mutations thereof due to mutations in genes that regulate the activity of CDK9 and / or mutations thereof (e.g., LARP7, HEXIM1 / 2, or 7sk snRNA), diseases caused by increased activity of CDK9 and / or mutations thereof due to activation of the CDK9 / cyclin T / RNA polymerase II complex by viral proteins (e.g., HIV TAT or HTLV-TAX), or diseases caused by increased activity of CDK9 and / or mutations thereof due to activation of a mitotic signaling pathway.

[0082] The term "overactivity of CDK9" refers to increased enzymatic activity of CDK9 and / or mutations thereof compared to normal, non-diseased cells, or increased CDK9 activity that leads to undesirable cell proliferation or reduced or insufficient programmed cell death (apoptosis), or mutations that lead to constitutive activation of CDK9.

[0083] The term "hyperproliferative disorder" includes disorders involving unwanted or uncontrolled cell proliferation, including disorders involving reduced or insufficient programmed cell death (apoptosis).

[0084] Kinase inhibitors of the present invention The present invention provides a kinase inhibitor having the formula (I): [ka] Formula (I) wherein A is selected from the group consisting of cyclohexyl, phenyl, pyridinyl, and piperidyl; n is 0 or 1, X is CH or N; Z is -NH- or -NH-C(=O)-; R 1 is selected from the group consisting of hydrogen, halogen, cyano, (C1-C6) alkyl, and (C1-C6) haloalkyl; R 2 is selected from the group consisting of hydrogen and (C1-C6) alkyl, or two R 2 together form a (C3-C6)cycloalkyl, m is selected from an integer of 1 to 3, and each R 3 are independently selected from hydrogen, -NH-(C1-C3)alkyl-(C1-C3)alkoxy, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)alkylacylamino, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonamido, aminosulfonyl, (C1-C6)alkylaminosulfonyl, heterocyclylsulfonyl having heteroatom(s) optionally substituted with (C1-C6)alkyl, carboxyl(C1-C3)alkyl, aminosulfonyl and -(C1-C3)alkyl-S(=O)(=NH)(C1-C3)alkyl, -(C1-C3)alkylsulfonyl(C1-C3)alkyl, -(C1-C3)alkylsulfonyl(C3-C6)cycloalkyl, -(C1-C3)alkylaminoacyl having heteroatom(s) optionally substituted with (C1-C6)alkyl, -(C1-C3)alkyl-S(=O)(=NH)(C1-C3)alkyl, and -(C1-C3)alkyl-S(=O)(=NH)(C1-C3)alkyl; R 4 is selected from the group consisting of hydrogen and (C1-C6) alkyl), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.

[0085] In a preferred embodiment, the present invention provides a compound of formula (Ia): [ka] Formula (Ia) (In the formula, X, n, R 1 , R 2 , R 3 , and R 4 is as defined above), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.

[0086] In this embodiment, X is preferably N, and in another embodiment, R 3 is preferably -NH-(C1-C3)alkyl-(C1-C3)alkoxy or carboxyl(C1-C3)alkyl.

[0087] In another preferred embodiment, the present invention provides a compound of formula (Ib): [ka] Formula (Ib) (wherein Y is CH or N, and X, m, n, R 1 , R 2 , R 3 , and R 4 is as defined above), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.

[0088] In a more preferred embodiment, X is N, and in another preferred embodiment, Y is CH.

[0089] In another preferred embodiment, each R 3are independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonamido, aminosulfonyl, (C1-C6)alkylaminosulfonyl, heterocyclylsulfonyl having heteroatom(s) optionally substituted with (C1-C6)alkyl, aminosulfonyl(C1-C3)alkyl, (C1-C3)alkylsulfonyl(C1-C3 )alkyl, (C1-C3)alkylsulfonyl(C3-C6)cycloalkyl, heterocyclylaminoacyl having heteroatom(s) optionally substituted with (C1-C6)alkyl, heterocyclyl having heteroatom(s) optionally substituted with (C1-C6)alkyl, -S(=O)(=NH)(C1-C3)alkyl, and -(C1-C3)alkyl-S(=O)(=NH)(C1-C3)alkyl.

[0090] In another preferred embodiment, the present invention provides a compound of formula (Ic): [ka] Formula (Ic) (In the formula, X, n, R 1 , R 2 , R 3 , and R 4 is as defined above), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.

[0091] In a more preferred embodiment, R 3 is (C1-C6) alkylacylamino.

[0092] In another preferred embodiment, the present invention provides a compound of formula (Id): [ka] Formula (Id) (In the formula, X, n, R 1 , R 2 , R 3 , and R4 is as defined above), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.

[0093] In this embodiment, X is preferably N, and in a more preferred embodiment, R 3 is (C1-C6) alkylsulfonyl.

[0094] In an exemplary embodiment of the invention, R 1 is preferably selected from the group consisting of hydrogen, chlorine, fluorine, cyano, (C1-C3) alkyl (more preferably methyl), and (C1-C3) haloalkyl (more preferably trifluoromethyl).

[0095] In another exemplary embodiment, R 2 is preferably selected from the group consisting of hydrogen, (C1-C3) alkyl (more preferably methyl), or two R 2 together form cyclopropyl or cyclobutyl.

[0096] In another exemplary embodiment, each R 3 are independently selected from the group consisting of hydrogen, (2-methoxy)ethylamino, chlorine, fluorine, methyl, methoxy, trifluoromethyl, acetylamino, methanesulfonyl, methanesulfonylamino, sulfamoyl, methylsulfamoyl, dimethylsulfamoyl, morpholinosulfonyl, carboxymethyl, sulfamoylmethyl, methanesulfonylmethyl, methanesulfonylcyclopropyl(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.

[0097] In another exemplary embodiment, R 4 is preferably selected from the group consisting of hydrogen and (C1-C3) alkyl (more preferably methyl).

[0098] This specification describes novel kinase inhibitors, including pharmaceutically acceptable salts, solvates, esters, acids, metabolites, and prodrugs of the compounds.

[0099] The compounds of the present invention can exist in free form, for example as a free base, or as a free acid, or as a zwitterion, or in the form of a salt, which can be any salt, either organic or inorganic, in particular any physiologically acceptable organic or inorganic addition salt customarily used in pharmacy.

[0100] Preferred salts for the purposes of the present invention are physiologically acceptable salts of the compounds according to the invention. However, salts which are not themselves suitable for pharmaceutical uses but which can be used, for example, for the isolation or purification of the compounds according to the invention are also included.

[0101] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention; see, for example, SM Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

[0102] Pharmaceutically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, such as salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, bisulfate, phosphoric acid, nitric acid; or salts of, for example, 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, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxybenzoylbenzoic acid, ... These include acid addition salts with organic acids such as diethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic 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, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfonic acid, and thiocyanic acid.

[0103] Pharmaceutically acceptable salts of the compounds according to the present invention also include salts of conventional bases, such as, preferably, alkali metal salts (e.g., sodium salts and potassium salts), alkaline earth metal salts (e.g., calcium salts and magnesium salts), and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, 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-hexadiamine, glucosamine, sarcosine, serinol, tris(hydroxymethyl)aminomethane, aminopropanediol, Sovak base, and 1-amino-2,3,4-butanetriol.

[0104] The present invention includes all possible salts of the compounds of the present invention, either as single salts or as any mixture of said salts in any ratio.

[0105] Solvates are the term used for the purposes of the present invention for those forms of the compounds according to the invention which, in the solid or liquid state, form complexes with solvent molecules by coordination. Hydrates are special forms of solvates in which coordination occurs with water. Hydrates are preferred solvates within the scope of the present invention.

[0106] Furthermore, the present invention also encompasses prodrugs of the compounds according to the present invention. The term "prodrug" encompasses compounds that may themselves be biologically active or inactive, but that are converted into compounds according to the present invention during their residence in the body (e.g., by metabolism or hydrolysis).

[0107] Furthermore, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as a single polymorph or as a mixture of two or more polymorphs in any ratio.

[0108] In this specification, for convenience, the formula of a compound may represent a specific isomer, but the present invention includes all isomers such as geometric isomers, optical isomers based on asymmetric carbon atoms, stereoisomers, tautomers, etc.

[0109] The chiral compounds involved in the present invention may be in any configuration or mixed racemates. When compounds useful according to the present invention have two or more chiral centers, the compounds may exist in diastereoisomeric forms. Diastereoisomeric compounds can be separated by methods known to those skilled in the art (e.g., chromatography or crystallization), and individual enantiomers can be separated as described above. The present invention encompasses the use of various diastereoisomeric forms of compounds useful according to the present invention and mixtures thereof. Compounds useful according to the present invention may exist in different tautomeric forms or as different geometric isomers, and the present invention encompasses the use of each tautomeric and / or geometric isomer of compounds useful according to the present invention, as well as mixtures thereof. Compounds useful according to the present invention may also exist in zwitterionic form. The present invention encompasses the use of each zwitterionic form of compounds useful according to the present invention and mixtures thereof.

[0110] Screening and characterization of pharmaceutically acceptable salts, polymorphs, and / or solvates can be achieved using a variety of techniques, including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, microscopy, and elemental analysis. Spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state). Microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.

[0111] Thus, 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 (e.g., ester) or as a mixture of two or more salts, polymorphs, metabolites, hydrates, solvates, or prodrugs (e.g., esters) in any ratio.

[0112] Treatment Methods and Uses Another subject of the present invention is a method for the treatment and / or prevention of diseases, preferably diseases associated with or mediated by the activity of CDK9 and its mutants, in particular hyperproliferative diseases, virally induced infectious diseases and / or cardiovascular diseases, more preferably hyperproliferative diseases, and the use therefor of the kinase inhibitors of the invention.

[0113] The compounds of the present invention can be used to inhibit the activity or expression of CDK9 and its mutants. Therefore, the compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), or Formula (Id) are valuable therapeutic agents. In one embodiment, the present invention provides a method for treating a disease associated with or mediated by the activity of CDK9 and its mutants in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), or Formula (Id) as defined above. In some embodiments, the disease associated with the activity of CDK9 and its mutants is a hyperproliferative disease, a virus-induced infectious disease, and / or a cardiovascular disease, more preferably a hyperproliferative disease, particularly cancer, more preferably leukemia, liver cancer, ovarian cancer, cervical cancer, colorectal cancer, gastrointestinal stromal tumor, or lymphoma.

[0114] In the context of the present invention, hyperproliferative disorders include, but are not limited to, for example, psoriasis, keloids and other hyperplasias affecting the skin, endometriosis, skeletal disorders, angiogenic or vascular proliferative disorders, pulmonary hypertension, fibrotic disorders, mesangial cell proliferative disorders, colon polyps, polycystic kidney disease, benign prostatic hyperplasia, and solid tumors such as breast cancer, cancer of the respiratory tract, brain, reproductive organs, gastrointestinal tract, urinary tract, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and distant metastases thereof, lymphomas, sarcomas, and leukemias.

[0115] 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 mammary carcinoma.

[0116] Examples of cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma, pleuropulmonary blastoma, and mesothelioma.

[0117] Examples of brain cancers include, but are not limited to, brain stem and hypothalamic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.

[0118] Tumors of the reproductive organs include, but are not limited to, prostate, testicular, endometrial, cervical, ovarian, vaginal, vulvar cancer, and sarcoma of the uterus.

[0119] Tumors of the digestive tract include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, salivary gland cancer, and anal gland adenocarcinomas.

[0120] Tumors of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral, ​​and hereditary and sporadic papillary renal carcinoma.

[0121] Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0122] Examples of liver cancer include hepatocellular carcinoma (liver cell carcinoma with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.

[0123] Skin cancers 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 tumors.

[0124] Head and neck cancers include, but are not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer, oral cavity cancer, squamous cell cancer, and oral melanoma.

[0125] Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.

[0126] Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, malignant histiocytosis, fibrosarcoma, angiosarcoma, hemangiopericytoma, and leiomyosarcoma.

[0127] Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

[0128] A preferred subject of the present invention is the treatment and / or prevention of lung cancer (in particular non-small cell lung cancer), prostate cancer (in particular hormone-independent human prostate cancer), cervical cancer (including multidrug-resistant human cervical cancer), colorectal cancer, melanoma, ovarian cancer, or leukemia (in particular acute myeloid leukemia).

[0129] Fibroproliferative 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, liver cirrhosis, and mesangial cell proliferative disorders, including renal diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, graft rejection, and glomerulopathy.

[0130] Other conditions in humans or other mammals that can be treated by administering 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).

[0131] The compounds of the invention may also be used to prevent and treat diseases of the airways and lungs, diseases of the gastrointestinal tract, and diseases of the bladder and bile duct.

[0132] The above-mentioned disorders are well characterized in humans, but also exist with similar etiology in other animals, including mammals, and can be treated by administering the pharmaceutical compositions of the present invention.

[0133] In a further aspect of the present invention, the compounds according to the present invention are used in a method for preventing and / or treating infectious diseases, particularly virus-induced infectious diseases, including, but not limited to, virus-induced infectious diseases caused by retroviruses, hepadnaviruses, herpesviruses, flaviviridae, and / or adenoviruses, including opportunistic diseases. In a further preferred embodiment of this method, the retrovirus is selected from a lentivirus or an oncoretrovirus, wherein the lentivirus is selected from the group including HIV-1, HIV-2, FIV, BIV, SIV, SHIV, CAEV, VMV, or EIAV, preferably HIV-1 or HIV-2, and the oncoretrovirus is selected from the group including HTLV-I, HTLV-II, or BLV. In a further preferred embodiment of this method, the hepadnavirus is selected from HBV, GSHV or WHV, preferably HBV, the herpesvirus is selected from the group comprising HSV I, HSV II, EBV, VZV, HCMV or HHV8, preferably HCMV, and the Flaviviridae is selected from HCV, West Nile virus or Yellow fever virus.

[0134] The compounds of the present invention are useful in the treatment of cardiovascular diseases such as cardiac hypertrophy, adult congenital heart disease, aneurysms, stable angina, unstable angina, angina pectoris, angioneurotic edema, aortic stenosis, aortic aneurysms, arrhythmias, arrhythmogenic right ventricular dysplasia, arteriosclerosis, arteriovenous malformations, atrial fibrillation, Behcet's syndrome, bradycardia, cardiac tamponade, cardiomegaly, congestive cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and the prevention of cardiovascular disease prevention), carotid stenosis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes, Epstein's anomaly, Eisenmenger syndrome, cholesterol embolism, bacterial endocarditis, fibromuscular dysplasia, congenital heart defects, heart disease, congestive heart failure, valvular heart disease, heart attack, epidural hematoma, subdural hematoma, Hippel-Lindau disease, hyperemia, high blood pressure, pulmonary hypertension, hypertrophic growth, left ventricular hypertrophy, right ventricular hypertrophy, hypoplastic left heart syndrome, hypotension, intermittent claudication, ischemic heart disease, Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome, long QT syndrome, mitral valve prolapse, moyamoya disease, mucocutaneous It is also useful for the prevention and / or treatment of lymph node syndrome, myocardial infarction, myocardial ischemia, myocarditis, pericarditis, peripheral vascular disease, phlebitis, polyarteritis nodosa, pulmonary atresia, Raynaud's disease, restenosis, Sneddon's 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, Wolff-Parkinson-White syndrome.

[0135] The compounds of the present invention are preferably used for the prevention and / or treatment of cardiac hypertrophy, adult congenital heart disease, aneurysms, angina, angina pectoris, arrhythmias, prophylaxis of cardiovascular disease, cardiomyopathy, congestive heart failure, myocardial infarction, pulmonary hypertension, hypertrophic proliferation, restenosis, stenosis, thrombosis and arteriosclerosis.

[0136] Another subject of the present invention is the use of a kinase inhibitor of formula (I), formula (Ia), formula (Ib), formula (Ic) or formula (Id) according to the invention in the preparation of a medicament.

[0137] Another subject of the present invention is the use of a kinase inhibitor of formula (I), formula (Ia), formula (Ib), formula (Ic) or formula (Id) according to the invention in the preparation of a medicinal product for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

[0138] Pharmaceutical Composition Another aspect of the present invention relates to pharmaceutical compositions comprising a kinase inhibitor of the present invention, a pharmaceutically acceptable diluent or carrier, and optionally one or more other active ingredient(s).

[0139] Another aspect of the present invention relates to a pharmaceutical composition comprising a kinase inhibitor of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic) or Formula (Id) of the present invention in combination with an inert, non-toxic, pharmaceutically suitable adjuvant.

[0140] Another aspect of the present invention relates to the use of the pharmaceutical composition of the present invention for the treatment and / or prevention of diseases, in particular the diseases mentioned above.

[0141] Another aspect of the present invention relates to the use of the pharmaceutical composition of the present invention for the treatment and / or prevention of lung cancer (particularly non-small cell lung cancer), prostate cancer (particularly hormone-independent human prostate cancer), cervical cancer (including multidrug-resistant human cervical cancer), colorectal cancer, melanoma, ovarian cancer or leukemia (particularly acute myeloid leukemia).

[0142] The compounds of the present invention can be administered as a single pharmaceutical agent or in combination with one or more additional therapeutic agents, provided that the combination does not cause unacceptable side effects. This pharmaceutical combination includes administering a single pharmaceutical dosage formulation containing a compound of the present invention and one or more additional therapeutic agents, as well as administering a compound of the present invention and each additional therapeutic agent in separate pharmaceutical dosage formulations. For example, a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), or Formula (Id) and a therapeutic agent may be administered to a patient together in a single oral dosage composition, such as a tablet or capsule, or each agent may be administered in a separate dosage formulation.

[0143] When separate dosage formulations are used, the compound of the invention and the one or more additional therapeutic agents may be administered at essentially the same time (e.g., simultaneously) or at different staggered times (e.g., sequentially).

[0144] In particular, the compounds of the present invention may be used in fixed or separate combinations with other antitumor agents, such as alkylating agents, antimetabolites, plant-derived antitumor agents, hormonal therapy agents, topoisomerase inhibitors, camptothecin derivatives, kinase inhibitors, targeted drugs, antibodies, interferons and / or biological response modifiers, antiangiogenic compounds, and other antitumor agents. In this regard, the following is a non-limiting list of examples of secondary agents that may be used in combination with the compounds of the present invention: I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, aruglavin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY80-6946, BAY1000394, benzamidine, benzodiazepine ... Lotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil, chlormadinone, chlormethine, cisplatin, cladribine, clodronate, clofarabine, clarithromycin, Santaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, deslorelin, dibrospidium chloride, docetaxel, doxifluridine, doxorubicin, doxorubicin + estrone, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, endostatin Pirubicin, epithiostanol, epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxim,Goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seed, ibandronate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon alpha, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, Medroxyprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine, methotrexate, methoxsalen, methyl aminolevulinate, methyltestosterone, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, ofatumumab, omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel, paclitaxel Rifermin, palladium-103 seed, pamidronate, panitumumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide, picibanil, pirarubicin, plerixafor, plicamycin, poliglusum, polyestradiol phosphate, polysaccharide-K, porfimer sodium, pralatrexate, prednimustine, procarbazine, Quinagolide, radium-223 chloride, raloxifene, raltitrexed, ranimustine, razoxane, refametinib, regorafenib, risedronate, rituximab, romidepsin, romiplostim, sargramostim, sipuleucel-T, sizofiran, sobuzoxane, glycidazole sodium, sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin, teceleukin, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide,Testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90 glass microparticles, zinostatin, zinostatin stimalamer, zoledronic acid, and zorubicin.

[0145] The compounds of the invention may also be used in the treatment of cancer in combination with radiation therapy and / or surgical intervention.

[0146] The compounds according to the invention can act systemically and / or locally. For this purpose, they can be administered in any suitable manner, such as, for example, orally, parenterally, pulmonary, nasal, sublingually, lingually, buccal, rectally, cutaneously, transdermally, conjunctivally or auricularly, or as an implant or stent.

[0147] For these administration routes, the compounds according to the invention can be administered in suitable dosage forms.

[0148] Suitable for oral administration are dosage forms which function as described in the prior art and deliver the compound according to the invention rapidly and / or in a modified form, such as tablets (coated or uncoated, e.g. tablets with an enteric coating or a coating which is slow to dissolve or is insoluble and controls the release of the compound according to the invention), tablets which disintegrate rapidly in the mouth, or films / wafers, films / lyophilisates, capsules (e.g. hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions containing the compound according to the invention in crystalline and / or amorphous and / or dissolved form.

[0149] Parenteral administration can be carried out either avoiding the absorption step (for example, intravenously, intraarterially, intracardially, intraspinally or intralumbally) or including absorption (for example, intramuscularly, subcutaneously, intradermally, transdermally or intraperitoneally). Suitable dosage forms for parenteral administration are, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

[0150] Examples of suitable for other administration routes are pharmaceutical forms for inhalation (in particular powder inhalers, nebulizers), nasal drops / solutions / sprays; tablets, films / wafers or capsules for lingual, sublingual or buccal administration, suppositories, eye or ear preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (plasters etc.), milks, pastes, foams, powders, implants or stents.

[0151] The compounds according to the present invention can be converted into the dosage forms described.This can be done in a known manner by mixing with inert, non-toxic, pharmaceutically suitable adjuvants.These adjuvants include, inter alia, carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), 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 flavors and / or odor masking agents.

[0152] The present invention further provides medicaments comprising at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable adjuvants, and their use for the above purposes.

[0153] Regardless of the route of administration selected, the kinase inhibitors of the present invention and / or pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0154] Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the present invention may be varied to provide an amount of active ingredient effective to achieve the desired therapeutic response for a particular patient without causing toxicity to that patient.

[0155] Preparation of compounds The compounds of the present invention can be synthesized using standard synthetic methods known to those skilled in the art or by using methods known in the art in combination with the methods described herein. In addition, the solvents, temperatures, and other reaction conditions presented herein may be varied by those skilled in the art. For further guidance, the following synthetic methods may also be used.

[0156] The reactants can be used sequentially to provide compounds described herein, or they can be used to synthesize fragments, which are then combined by methods described herein and / or known in the art.

[0157] The starting materials used in the synthesis of the compounds described herein may be synthesized or obtained from commercial sources. The compounds described herein and other related compounds with different substituents can be synthesized using techniques and materials known to those skilled in the art. The general methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified by using appropriate reagents and conditions recognized by those skilled in the art for the introduction of various moieties into the molecules provided herein.

[0158] The reaction products can be isolated and purified, if desired, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, etc. Such products can be characterized using conventional means, including physical constants and spectral data.

[0159] Non-limiting examples of synthetic schemes for preparing compounds of formula (I) are set forth below. [Example]

[0160] The following specific, non-limiting examples are to be construed as merely illustrative, and not limiting of the invention in any way. Further elaboration is not required, but it is believed that one skilled in the art can, based on the description herein, utilize the present disclosure to its fullest extent.

[0161] Example 1: Synthesis of 6-(2-(((4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka] 1,4-dioxane

[0162] ((1r,4r)-4-((2-Methoxyethyl)amino)cyclohexyl)carbamic acid tert-butyl ester (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 stirred at 80 °C for 16 h. After TLC monitoring showed that a small amount of raw material remained, the reaction was stopped. The reaction solution was cooled to room temperature, filtered, and the filtrate was removed by rotary evaporation. The resulting product was loaded onto silica gel for column chromatography (eluent system: DCM / MeOH = 100:1 → 40:1 → 20:1), affording 6.3 g of a pale yellow solid A2 in 50% yield.

[0163] (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 stirred at room temperature for 2 hours. A large amount of solid precipitate was obtained. The reaction solution was filtered, and the filter cake was dried to obtain 5.1 g of a white solid (dihydrochloride salt) A3 in 94.8% yield.

[0164] 6-(2-Chloropyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (A6): A4 (81 mg, 0.54 mmol, 1.5 equiv.) was dissolved in 1,4-dioxane (10 mL). A5 (100 mg, 0.36 mmol, 1.0 equiv.), potassium carbonate (99 mg, 0.72 mmol, 2 equiv.), and Pd(PPh3)4 (41 mg, 0.036 mmol, 0.1 equiv.) were then added, and the reaction was stirred at 95 °C for 4 h. TLC showed the reaction was complete. The reaction was loaded onto crude silica gel and separated by column chromatography (eluent system: DCM / EA = 3:1) to give compound A6 (60 mg, 64%).

[0165] 6-(2-(((4-((2-Methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-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 raw material had been consumed. Water was added to the mixture, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (eluent system: DCM / MeOH = 30:1) to give the target compound 1 (white solid, 30 mg, 40%). MS: (M+1) 396.2. 1 H NMR(500MHz,DMSO-d6)δ 8.37(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).

[0166] Unless otherwise specified, the following Examples 2 to 25 were synthesized in the same manner as Example 1.

[0167] Example 2: 6-(5-chloro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 2 [ka] MS(ESI) m / z(M+1)+:430.2.

[0168] Example 3: 6-(5-fluoro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 3 [ka] MS(ESI) m / z(M+1)+:414.22.

[0169] Example 4: 6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one 4 [ka] MS(ESI) m / z(M+1)+:410.26.

[0170] Example 5: 5-(2-(((1r,4r))-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)isoindolin-1-one 5 [ka] MS(ESI) m / z(M+1)+:382.22.

[0171] Example 6: 6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)-5-methylpyridin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 6 [ka]

[0172] The synthesis of compound 6 was completed using similar steps as described in Example 1, replacing 2,4-dichloropyrimidine with 4-bromo-2-fluoro-5-methylpyridine. MS (ESI) m / z (M+1)+: 437.29.

[0173] Example 7: 6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)-5-methylpyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 7 [ka] MS(ESI) m / z(M+1)+:410.26.

[0174] Example 8: 6-(5-chloro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyridin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 8 [ka]

[0175] The compound of Example 8 was synthesized using a procedure similar to that described in Example 6. MS (ESI) m / z (M+1)+: 429.21.

[0176] Example 9: 2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidine-5-carbonitrile 9 [ka] MS(ESI) m / z(M+1)+:421.24.

[0177] Example 10: 6-(5-chloro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyridin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 10 [ka]

[0178] The compound of Example 10 was synthesized using a procedure similar to that described in Example 6. MS (ESI) m / z (M+1)+: 457.24.

[0179] Example 11: 6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 11 [ka] MS(ESI) m / z(M+1)+:424.27.

[0180] Example 12: 6'-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-2',3'-dihydron-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one 12 [ka] MS(ESI) m / z(M+1)+:422.26.

[0181] Example 13: 4,4-diethyl-6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 13 [ka] MS(ESI) m / z(M+1)+:452.30.

[0182] Example 14: 4,4-Diisopropyl-6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 14 [ka] MS(ESI) m / z(M+1)+:480.33.

[0183] Example 15: 6-(5-chloro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 15 [ka] MS(ESI) m / z(M+1)+:458.23.

[0184] Example 16: 6-(5-fluoro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 16 [ka] MS(ESI) m / z(M+1)+:442.26.

[0185] Example 17: 6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)-5-methylpyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 17 [ka] MS(ESI) m / z(M+1)+:438.29.

[0186] Example 18: 6-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-2,4,4-trimethyl-3,4-dihydroisoquinolin-1(2H)-one 18 [ka] MS(ESI) m / z(M+1)+:424.27.

[0187] 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(2H)-one 19 [ka] MS(ESI) m / z(M+1)+:472.25.

[0188] Example 20: 5-(5-fluoro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one 20 [ka] MS(ESI) m / z(M+1)+:428.25.

[0189] Example 21: 5-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one 21 [ka] MS(ESI) m / z(M+1)+:410.26.

[0190] Example 22: 5-(5-chloro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one 22 [ka] MS(ESI) m / z(M+1)+:444.22.

[0191] Example 23: 5-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-2,3,3-trimethylisoindolin-1-one 23 [ka] MS(ESI) m / z(M+1)+:424.27.

[0192] Example 24: 5-(5-chloro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-2,3,3-trimethylisoindolin-1-one 24 [ka] MS(ESI) m / z(M+1)+:458.23.

[0193] Example 25: 6'-(2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinolin]-1'-one 25 [ka] MS(ESI) m / z(M+1)+:436.27.

[0194] Example 26: Synthesis of 3-((4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)benzenesulfonamide 26 [ka] Bis(pinacolato)diboron 1,4-dioxane

[0195] 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), bis(pinacolato)diboron (1.2 g, 4.72 mmol, 1.2 equiv), potassium acetate (0.77 g, 7.86 mmol, 2 equiv), and PdCl(dppf) (0.32 g, 0.39 mmol, 0.1 equiv) were added to 1,4-dioxane (20 mL) and stirred at 100 °C for 5 h. The reaction was stopped after TLC monitoring showed no starting material remained. The reaction solution was cooled to room temperature and loaded onto silica gel for column chromatography (eluent system: DCM / EA=3:1) to give a reddish-brown solid A8 (0.9 g, 76%).

[0196] 6-(2-Chloropyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (A9): A8 (300 mg, 0.99 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (10 mL). A4 (178 mg, 1.19 mmol, 1.2 equiv.), potassium carbonate (0.27 g, 1.98 mmol, 2 equiv.), and Pd(PPh3)4 (0.11 g, 0.099 mmol, 0.1 equiv.) were then added and stirred at 95 °C for 4 h. TLC showed the reaction was complete. The system was loaded onto crude silica gel for column chromatography (eluent system: DCM / EA = 3:1) to give the target compound A9 (130 mg, 45%).

[0197] 3-((4-(4,4-Dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)benzenesulfonamide (26): Compound A9 (50 mg, 0.17 mmol, 1.0 equiv.), 4-aminobenzenesulfonamide (30 mg, 0.17 mmol, 1.0 equiv.), p-toluenesulfonic acid (29 mg, 0.17 mmol, 1.0 equiv.), and sec-butanol (2 mL) were added to a bottle and stirred at 120 °C overnight. After filtration, the filter cake was washed with a small amount of methanol and methyl tert-butyl ether to give a pale yellow solid. The solid was transferred to a vial, saturated sodium bicarbonate solution was added, and the mixture was stirred. Finally, the solid was filtered. The solid was washed with methanol and methyl tert-butyl ether to give the target compound 26 (white solid, 30 mg, 41%). MS:(M+1):424.14.1H NMR(500MHz,DMSO-d6)δ 10.08(s,1H), 8.65(d,J=5.2Hz,1H), 8.54(s,1H), 8.20~8.18(m,2H), 8.10(s,1H), 8.01(d,J=8.1Hz,1H), 7. 97~7.94(m,1H), 7.59(d,J=5.2Hz,1H), 7.52~7.44(m,2H), 7.31(s,2H), 3.23(d,J=3.0Hz,2H), 1.37(s,6H).

[0198] Unless otherwise specified, the following Examples 27 to 95 and Examples 99 to 101 were synthesized in the same manner as in Example 26.

[0199] Example 27: (3-((4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)phenyl)methanesulfonamide 27 [ka] MS(ESI) m / z(M+1)+:438.16.

[0200] Example 28: 4,4-dimethyl-6-(2-((3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 28 [ka] MS(ESI) m / z(M+1)+:437.16.

[0201] Example 29: 3-((4-(4,4-dimethyl-1-oxo1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)-N,N-dimethylbenzenesulfonamide 29 [ka] MS(ESI) m / z(M+1)+:452.18.

[0202] Example 30: 4,4-dimethyl-6-(2-((3-(morpholinosulfonyl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 30 [ka] MS(ESI) m / z(M+1)+:494.19.

[0203] Example 31: 3-((4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide 31 [ka] MS(ESI) m / z(M+1)+:438.16.

[0204] Example 32: 4,4-dimethyl-6-(2-((3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 32 [ka] MS(ESI) m / z(M+1)+:423.15.

[0205] 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 33 [ka] MS(ESI) m / z(M+1)+:485.27.

[0206] Example 34: N-(5-((4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)-2-fluorophenyl)methanesulfamide 34 [ka] MS(ESI) m / z(M+1)+:456.15.

[0207] Example 35: 6-(2-((3-(1,4-homopiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 35 [ka] MS(ESI) m / z(M+1)+:443.26.

[0208] Example 36: 6-(2-((4-fluoro-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 36 [ka] MS(ESI) m / z(M+1)+:455.16.

[0209] Example 37: 4,4-dimethyl-6-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 37 [ka] MS(ESI) m / z(M+1)+:433.26.

[0210] Example 38: 4,4-dimethyl-6-(2-((3-(S-methylsulfonimido)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 38 [ka] MS(ESI) m / z(M+1)+:422.17.

[0211] Example 39: 4,4-dimethyl-6-(2-((4-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 39 [ka] MS(ESI) m / z(M+1)+:423.15.

[0212] Example 40: 4,4-dimethyl-6-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 40 [ka] MS(ESI) m / z(M+1)+:443.26.

[0213] 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 41 [ka] MS(ESI) m / z(M+1)+:503.26.

[0214] Example 42: 4,4-dimethyl-6-(2-((4-methyl-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 42 [ka] MS(ESI) m / z(M+1)+:451.18.

[0215] Example 43: 6-(2-((2,4-difluoro-5-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 43 [ka] MS(ESI) m / z(M+1)+:473.15.

[0216] Example 44: 4,4-dimethyl-6-(2-((3-((methylsulfonyl)methyl)-4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 44 [ka] MS(ESI) m / z(M+1)+:505.15.

[0217] Example 45: 6-(2-((4-methoxy-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 45 [ka] MS(ESI) m / z(M+1)+:467.18.

[0218] Example 46: 6-(2-((4-fluoro-3-((methylsulfonyl)methyl)phenyl)amino)pyridin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 46 [ka] MS(ESI) m / z(M+1)+:454.16.

[0219] Example 47: 4,4-dimethyl-6-(2-((2-((methylsulfonyl)methyl)pyridin-4-yl)amino)pyridin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 47 [ka] MS(ESI) m / z(M+1)+:437.16.

[0220] Example 48: 5-(2-((4-fluoro-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one 48 [ka] MS(ESI) m / z(M+1)+:441.14.

[0221] Example 49: 3,3-dimethyl-5-(2-((4-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)isoindolin-1-one 49 [ka] MS(ESI) m / z(M+1)+:423.15.

[0222] Example 50: 5-(5-fluoro-2-((4-fluoro-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one 50 [ka] MS(ESI) m / z(M+1)+:459.13.

[0223] Example 51: 5-(5-chloro-2-((4-fluoro-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one 51 [ka] MS(ESI) m / z(M+1)+:475.10.

[0224] Example 52: 5-(5-chloro-2-((2,4-difluoro-5-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one 52 [ka] MS(ESI) m / z(M+1)+:493.09.

[0225] Example 53: 5-(2-((2,4-difluoro-5-((methylsulfonyl)methyl)phenyl)amino)-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindolin-1-one 53 [ka] MS(ESI) m / z(M+1)+:477.12.

[0226] Example 54: 5-(5-chloro-2-((4-methyl-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one 54 [ka] MS(ESI) m / z(M+1)+:471.13.

[0227] Example 55: 5-(5-fluoro-2-((4-methyl-3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindolin-1-one 55 [ka] MS(ESI) m / z(M+1)+:455.16.

[0228] Example 56: 4,4-dimethyl-6-(2-((2-((methylsulfonyl)methyl)pyridin-4-yl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 56 [ka] MS(ESI) m / z(M+1)+:438.16.

[0229] Example 57: 4,4-dimethyl-6-(2-((4-((methylsulfonyl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 57 [ka] MS(ESI) m / z(M+1)+:438.16.

[0230] Example 58: 4,4-dimethyl-6-(2-((4-((S-methylsulfonimido)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 58 [ka] MS(ESI) m / z(M+1)+:437.18.

[0231] Example 59: 4,4-dimethyl-6-(2-((4-(1-(methylsulfonyl)cyclopropyl)phenyl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 59 [ka] MS(ESI) m / z(M+1)+:463.18.

[0232] Example 60: 6-(5-chloro-2-((4-(1-(methylsulfonyl)cyclopropyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 60 [ka] MS(ESI) m / z(M+1)+:497.14.

[0233] Example 61: 6-(5-fluoro-2-((4-(1-(methylsulfonyl)cyclopropyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 61 [ka] MS(ESI) m / z(M+1)+:481.17.

[0234] 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 62 [ka] MS(ESI) m / z(M+1)+:515.13.

[0235] 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 63 [ka] MS(ESI) m / z(M+1)+:499.16.

[0236] 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 64 [ka] MS(ESI) m / z(M+1)+:507.11.

[0237] 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 65 [ka] MS(ESI) m / z(M+1)+:495.19.

[0238] 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 66 [ka] MS(ESI) m / z(M+1)+:529.15.

[0239] 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 67 [ka] MS(ESI) m / z(M+1)+:513.18.

[0240] 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 68 [ka] MS(ESI) m / z(M+1)+:477.22.

[0241] 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 69 [ka] MS(ESI) m / z(M+1)+:461.25.

[0242] 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 70 [ka] MS(ESI) m / z(M+1)+:457.27.

[0243] 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 71 [ka] MS(ESI) m / z(M+1)+:475.26.

[0244] 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 72 [ka] MS(ESI) m / z(M+1)+:479.24.

[0245] 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 73 [ka] MS(ESI) m / z(M+1)+:479.24.

[0246] 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 74 [ka] MS(ESI) m / z(M+1)+:491.23.

[0247] 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 75 [ka] MS(ESI) m / z(M+1)+:495.21.

[0248] 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 76 [ka] MS(ESI) m / z(M+1)+:509.22.

[0249] 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 77 [ka] MS(ESI) m / z(M+1)+:523.24.

[0250] 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 78 [ka] MS(ESI) m / z(M+1)+:519.26.

[0251] 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 79 [ka] MS(ESI) m / z(M+1)+:493.25.

[0252] 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 80 [ka] MS(ESI) m / z(M+1)+:507.27.

[0253] Example 81: 6-(2-((4-fluoro-3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 81 [ka] MS(ESI) m / z(M+1)+:461.25.

[0254] Example 82: 4,4-methyl-6-(2-((4-methyl-3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-dihydroisoquinolin-1(2H)-one 82 [ka] MS(ESI) m / z(M+1)+:457.27.

[0255] Example 83: 6-(5-fluoro-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 83 [ka] MS(ESI) m / z(M+1)+:461.25.

[0256] Example 84: 6-(2-((3-(4-ethylpiperazin-1-yl)-4-fluorophenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 84 [ka] MS(ESI) m / z(M+1)+:475.26.

[0257] 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 85 [ka] MS(ESI) m / z(M+1)+:489.28.

[0258] Example 86: 6-(2-((3-(4-ethylpiperazin-1-yl)-4-methylphenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 86 [ka] MS(ESI) m / z(M+1)+:471.29.

[0259] Example 87: 6-(2-((3-(4-isopropylpiperazin-1-yl)-4-methylphenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 87 [ka] MS(ESI) m / z(M+1)+:485.30.

[0260] 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 88 [ka] MS(ESI) m / z(M+1)+:477.22.

[0261] 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 89 [ka] MS(ESI) m / z(M+1)+:456.15.

[0262] 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 90 [ka] MS(ESI) m / z(M+1)+:472.12.

[0263] 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 91 [ka] MS(ESI) m / z(M+1)+:452.18.

[0264] 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 92 [ka] MS(ESI) m / z(M+1)+:506.15.

[0265] Example 93: 6-(5-fluoro-2-((4-((S-methylsulfonimido)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 93 [ka] MS(ESI) m / z(M+1)+:455.17.

[0266] Example 94: 6-(5-chloro-2-((4-((S-methylsulfonimido)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 94 [ka] MS(ESI) m / z(M+1)+:471.14.

[0267] Example 95: 4,4-dimethyl-6-(5-methyl-2-((4-((S-methylsulfonimido)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 95 [ka] MS(ESI) m / z(M+1)+:451.19.

[0268] Example 96: (1S,3R)-3-acetylamino-N-(5-chloro-4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-2-yl)cyclohexyl-1-formamide 96 [ka] Pyridine 1,4-dioxane Acetyl chloride

[0269] 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-trimethylpropenylamine (0.82 g, 6.17 mmol, 1.5 equivalents) was added dropwise under an ice bath. The reaction mixture was continuously stirred at 0° C. for 30 minutes. Then, a solution of 2-amino-4-bromo-5-chloropyridine (0.68 g, 3.28 mmol, 0.8 equivalents) and pyridine (0.32 g, 4.11 mmol, 1 equivalent) in tetrahydrofuran was added, and the resulting mixture was stirred at room temperature for 3 hours. The reaction was stopped after TLC monitoring showed that no starting material remained. Saturated sodium carbonate solution was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and then loaded onto silica gel for column chromatography (eluent system: PE / EA=3:1) to give a white solid A11 (1.2 g, 68%).

[0270] 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 equiv) was dissolved in 1,4-dioxane (10 mL), followed by A8 (613 mg, 2.03 mmol, 1.1 equiv), potassium carbonate (0.51 g, 3.7 mmol, 2 equiv), and Pd(PPh) (0.21 g, 0.185 mmol, 0.1 equiv) and stirred at 100 °C for 4 h. TLC showed the reaction was complete. The reaction mixture was loaded onto crude silica gel and separated by column chromatography (eluent system: DCM / EA=3:1) to give the target compound A12 (585 mg, 60%).

[0271] (1S,3R)-3-Acetylamino-N-(5-chloro-4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-2-yl)cyclohexyl-1-formamide (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 30 minutes. After concentration, the resulting mixture was neutralized to pH 10 with saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale 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 then acetyl chloride (16 mg, 0.21 mmol) was added dropwise in an ice bath. After TLC showed the reaction was complete, the reaction was stopped and the obtained material was concentrated for column chromatography (eluent system: DCM / MeOH=30:1) to give 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=3.1Hz,1H), 7.98(d,J=7. 9Hz,1H), 7.78(d,J=7.9Hz,1H), 7.50(d,J=1.7Hz,1H), 7.44(dd,J=7.9,1.7H z,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).

[0272] Unless otherwise specified, the following Examples 97, 98, 102, and 107 were synthesized in a similar manner to Example 96.

[0273] Example 97: (1S,3R)-3-acetylamino-N-(5-chloro-4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)cyclohexyl-1-formamide 97 [ka] MS(ESI) m / z(M+1)+:470.20.

[0274] Example 98: (1S,3R)-3-acetylamino-N-(4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methylpyrimidin-2-yl)cyclohexyl-1-formamide 98 [ka] MS(ESI) m / z(M+1)+:450.25.

[0275] Example 99: 6-(5-chloro-2-((4-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 99 [ka] MS(ESI) m / z(M+1)+:471.12.

[0276] Example 100: 6-(5-fluoro-2-((4-((((((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 100 [ka] MS(ESI) m / z(M+1)+:455.15.

[0277] Example 101: 5-(2-((2,4-difluoro-5-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethylisoindol-1-one 101 [ka] MS(ESI) m / z(M+1)+:459.13.

[0278] Example 102: (1S,3R)-3-acetylamino-N-(5-chloro-4-(3,3-dimethyl-1-oxoindolin-5-yl)pyridin-2-yl)cyclohexane-1-formamide 102 [ka] MS(ESI) m / z(M+1)+:455.18.

[0279] Example 103: (S)-4,4-dimethyl-6-(2-((1-(methanesulfonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 103 [ka] 2-butanol

[0280] (S)-3-((4-(4,4-Dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (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. After LCMS showed the reaction was complete, the reaction was loaded onto crude silica gel, and A14 (70 mg, 44%) was isolated by column chromatography.

[0281] (S)-4,4-Dimethyl-6-(2-(piperidin-3-ylamino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (A15): A14 (70 mg) was dissolved in DCM (3 mL), and TFA (1 mL) was added and stirred at room temperature. After LCMS showed the reaction was complete, the resulting mixture was neutralized to alkaline with saturated sodium bicarbonate and then extracted with ethyl acetate. The organic phase was dried and concentrated, and the residue was separated by column chromatography to give A15 (38 mg, 73%).

[0282] (S)-4,4-Dimethyl-6-(2-((1-(methanesulfonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-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. After LCMS showed the reaction was complete, the mixture was concentrated, and the residue was separated by column chromatography to give 103 (22 mg, 48%). 1H NMR(500MHz,DMSO-d6)δ 8.43(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=10.3Hz,1H), 1.97~1.85(m,2H), 1.62~1.51(m,2H), 1.34(d,J=6.0Hz,6H).

[0283] Unless otherwise specified, the following Examples 104 to 106 were synthesized in the same manner as Example 103.

[0284] Example 104: (R)-4,4-dimethyl-6-(2-(((1-(methylsulfonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 104 [ka] MS(ESI) m / z(M+1)+:430.19.

[0285] Example 105: 4,4-dimethyl-6-(2-((1-(methylsulfonyl)pyrimidin-4-yl)amino)pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 105 [ka] MS(ESI) m / z(M+1)+:430.19.

[0286] Example 106: 2-(1R,4R)-4-((4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidin-2-yl)amino)cyclohexyl)acetic acid 106 [ka] MS(ESI) m / z(M+1)+:409.22.

[0287] Example 107: (R)—N-(5-chloro-4-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-2-yl)piperidine-3-formamide 107 [ka] MS(ESI) m / z(M+1)+:413.17.

[0288] Example 108: Effect of CDK9 inhibitors on cancer cell proliferation By testing the effect of CDK9 inhibitors on cancer cell proliferation, we evaluated the selectivity of the compounds to inhibit cancer cell proliferation.

[0289] In this example, the following were selected: acute myeloid leukemia cell lines OCI-AML-3, MV4-11, MOLM13, MOLM14, histiocytic lymphoma U-937, human chronic myeloid leukemia K562, human colorectal cancer HCT116, DLD1, human ovarian granulosa tumor COV434, human liver cancer HepG2, lymphoma WSU-DLCL2, cervical cancer HeLa, gastrointestinal stromal tumor GIST-T1 (all of the above cells were purchased from Nanjing Cobioer); MOLM13 drug-resistant line MOLM13 BR1 (purchased from MCE, China) obtained by long-term treatment with the CDK9 inhibitor BAY1251152; and HepG2 drug-resistant line HepG2 cells were transfected with guide RNA-PX459 plasmid and then screened for HepG2 CDK9 by prinomycin screening and BAY1251152 screening. After obtaining KI cells, HepG2 KI C20-1 monoclonal cells were obtained through monoclonal screening, and CDK9 resistance mutations were detected by sequencing. Following the construction method, HepG2 KI C20-1 was obtained by knock-in using CRISPR-Cas9 technology.

[0290] In this example, 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 the control compounds dinaciclib, JSH-009, and BAY1251152 (all purchased from MCE, China) were added to the above cells, respectively, and incubated for 72 hours, followed by GI 50 The number of viable cells was detected by quantitative determination of ATP in living cells using Cell Titer-Glo™ (Promega, USA), a chemiluminescent cell viability test kit, which was used as the basis for calculating the ATP content. The results are shown in Tables 1 to 3.

[0291] In the test, the compounds of the present invention were found to have significant inhibitory effects on different cancer cell lines. As shown in Table 1 and the subsequent tables, the inhibitory effects were comparable to those of the control compounds, the pan-CDK inhibitor dinaciclib and the selective CDK9 inhibitor JSH-009, and the antiproliferative activity of most compounds on cells was comparable to or superior to that of the selective CDK9 inhibitor BAY1251152. Furthermore, Table 2 shows significant antiproliferative effects on drug-resistant strains of acute myeloid leukemia cells MOLM13 obtained by treating them with BAY1251152. Therefore, the compounds of the present invention exhibit inhibitory effects that overcome drug resistance. As shown in Table 3, the test results on drug-resistant strains of liver cancer cells HepG2 indicated that the compounds of the present invention can overcome drug resistance, whereas BAY1251152 has obvious drug resistance.

[0292] [Table 1-1]

[0293] [Table 1-2]

[0294] [Table 2]

[0295] [Table 3]

[0296] Example 109: Detection of binding activity of compounds to CDK9 The split luciferase system plasmids were constructed using molecular cloning techniques. The N-terminal domain (NLuc) and C-terminal domain (CLuc) of luciferase were cloned and inserted into the PCDNA3 vector to construct the NLuc-PCDNA3 and CLuc-PCDNA3 vectors, respectively, with polyclonal sites at both ends of the sequence. CDC37 and CDK9 were then cloned into the corresponding vectors to construct the 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.

[0297] HEK-293T cells (purchased from ATCC, USA) were seeded into 10 cm cell culture dishes and allowed to reach a cell density of 70% before use. 2 μg of C37-CL plasmid (SEQ ID NO: 1) and 2 μg of CDK9-NL plasmid (SEQ ID NO: 2) were added to 1 mL of Opti-MEM (product number 2120763, purchased from Gibco, USA), followed by 6 μL of transfection reagent (product number 20200918, purchased from HanBio, China), and then mixed. The mixed transfection complex was added to a 10 cm cell culture dish and cultured at 37°C and 5% CO2 for 24 hours. After 24 hours, HEK-293T cells were digested with trypsin. After counting, the transfected cells were plated into a 96-well white Corning cell culture plate (purchased from Corning, USA) in 100 μL at 5,000 cells / well. After 12 hours, the medium was removed from the 96-well plate, and 100 μL of culture medium containing the corresponding concentrations of test compounds was added, which was then continuously cultured for 12 hours. After 12 hours, 20 μL of Luciferase-Glo (purchased from Promega, USA) test reagent was added to each well. After mixing, the fluorescence value was detected using a microplate reader. Relative activity IC 50 The value was calculated using the following formula: relative activity = (fluorescence value of test drug - background value) / (fluorescence value of DMSO group - background value) × 100%. The test results show that the compounds of the present invention have strong binding activity to CDK9.

[0298] [Table 4]

[0299] Example 110: Enzyme activity assay of CDK9 protein inhibition in vitro DMSO-diluted compounds and control compounds dinaciclib, JSH-009, BAY-1211152, and AZD4573 (all purchased from MCE, China) were mixed with the detected CDK9 / cyclin T1 protein (Invitrogen, USA) and CDK9-L156F mut / cyclin T1 mutant protein (this mutation corresponds to the mutation in HepG2 KI C20-1 constructed as described in Example 108) and incubated at room temperature for 30 minutes. Kinase peptide substrate mix (Invitrogen, USA) and 4x ATP were added and mixed, and the mixture was transferred to a 384-well white opaque plate and incubated at room temperature for 1 hour. 5 μL of development solution (Invitrogen, USA) was added and incubated at room temperature for 1 hour. Finally, stop agent (Invitrogen, USA) was added to stop the reaction. Fluorescence values ​​were read using an MD SpectraMax I3X microplate (Molecular Devices, USA). IC of the compounds of the present invention against the tested CDK9 / cyclin T1 proteins and the CDK9 mutant protein CDK9-L156F mut / cyclin T1 50 The values ​​were calculated by plotting using Prism 5.0 (GraphPad Software, San Diego, CA) based on the fluorescence readings, and are shown in Tables 5 and 6 below. The results show that the compounds of the present invention have significant inhibitory effects on CDK9 and its mutants. That is, in the case of wild-type CDK9 / cyclin T1 protein, the compounds of the present invention show superior or equivalent effects to the control compound, and in the case of CDK9 mutant protein CDK9-L156F mut / cyclin T1, the inhibitory effect of the compounds of the present invention is significantly superior to that of the control compound BAY1251152.

[0300] [Table 5]

[0301] [Table 6] [Industrial Applicability]

[0302] The present invention provides a CDK9 kinase inhibitor that can inhibit the activity of CDK9 and / or its mutant kinases and can be used to treat or prevent diseases associated with or mediated by the activity of CDK9 and / or its mutants. Therefore, the CDK9 kinase inhibitor can be made into a corresponding drug suitable for industrial application.

[0303] Although the present invention is described in detail in this specification, it is not limited thereto. Those skilled in the art can make modifications according to the principle of the present invention. Therefore, all modifications made according to the principle of the present invention should be understood to fall within the protection scope of the present invention.

Claims

1. 1. A kinase inhibitor having the formula (I): 【Chemical 1】 Formula (I) wherein A is selected from the group consisting of cyclohexyl, phenyl, pyridinyl, and piperidyl; X is CH or N; Z is —NH— or —NH—C(═O)—; n is 0 or 1; R １ is selected from the group consisting of hydrogen, halogen, cyano, (C1-C6) alkyl, and (C1-C6) haloalkyl; R ２ is selected from the group consisting of hydrogen and (C1-C6) alkyl, or two R ２ together form a (C3-C6)cycloalkyl, m is selected from an integer from 1 to 3, and each R ３ are independently hydrogen, —NH—(C1-C3)alkyl-(C1-C3)alkoxy, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)alkylacylamino, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonamido, aminosulfonyl, (C1-C6)alkylaminosulfonyl, heterocyclylsulfonyl having heteroatom(s) optionally substituted with (C1-C6)alkyl, carboxyl(C1-C3)alkyl, aminosulfonyl -C1-C3)alkyl, -C1-C3)alkylsulfonyl(C1-C3)alkyl, -C1-C3)alkylsulfonyl(C3-C6)cycloalkyl, -C1-C6)alkylaminoacyl having heteroatom(s) optionally substituted with (C1-C6)alkyl, -C1-C6)alkyl-heterocyclyl having heteroatom(s) optionally substituted with (C1-C6)alkyl, -S(=O)(=NH)(C1-C3)alkyl, and -(C1-C3)alkyl-S(=O)(=NH)(C1-C3)alkyl; R ４ is selected from the group consisting of hydrogen and (C1-C6) alkyl, or a pharmaceutically acceptable salt or solvate thereof.

2. Formula (Ia): 【Chemistry 2】 Formula (Ia) (In the formula, R ３ is —NH—(C1-C3)alkyl-(C1-C3)alkoxy, or carboxyl(C1-C3)alkyl, or a pharmaceutically acceptable salt or solvate thereof.

3. Formula (Ib): 【Chemistry 3】 Formula (Ib) wherein Y is CH or N; m is selected from an integer from 1 to 3, and each R ３ are independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonamido, aminosulfonyl, (C1-C6)alkylaminosulfonyl, heterocyclylsulfonyl having heteroatom(s) optionally substituted with (C1-C6)alkyl, aminosulfonyl(C1-C3)alkyl, (C1-C3)alkylsulfonyl(C1-C3)alkyl, (C1-C3)alkylsulfonyl(C3 2. The kinase inhibitor of claim 1, comprising a compound of the formula: -(C1-C6)cycloalkyl, heterocyclylaminoacyl having a heteroatom(s) optionally substituted with (C1-C6)alkyl, heterocyclyl having a heteroatom(s) optionally substituted with (C1-C6)alkyl, -S(=O)(=NH)(C1-C3)alkyl, and -(C1-C3)alkyl-S(=O)(=NH)(C1-C3)alkyl, or a pharmaceutically acceptable salt or solvate thereof.

4. Formula (Ic): 【Chemistry 4】 Formula (Ic) (In the formula, R ３ is (C1-C6) alkylacylamino), or a pharmaceutically acceptable salt or solvate thereof.

5. Formula (Id): 【Chemistry 5】 Formula (Id) (In the formula, R ３ is (C1-C6) alkylsulfonyl), or a pharmaceutically acceptable salt or solvate thereof.

6. The kinase inhibitor of any one of claims 1 to 5, wherein X is N.

7. 10. The kinase inhibitor of claim 1, comprising the following compound, or a pharmaceutically acceptable salt or solvate thereof: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】

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

9. The kinase inhibitor according to any one of claims 1 to 7, for use in the treatment of hyperproliferative diseases, virally induced infectious diseases and cardiovascular diseases.

10. 10. The kinase inhibitor for use according to claim 9, wherein the hyperproliferative disease is cancer, preferably selected from the group consisting of leukemia, liver cancer, ovarian cancer, cervical cancer, colorectal cancer, gastrointestinal stromal tumors, and lymphoma.

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