Pyrazolyl-pyrimidine derivatives as kinase inhibitors

Abstract

The present invention relates to pyrazolyl-pyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing them, and their use as therapeutic agents. The compounds are kinase inhibitors, particularly inhibitors of spleen tyrosine kinase (SYK), and can be used in the treatment of cancer, cell proliferation disorders, viral infections, immune disorders, neurodegenerative disorders, and cardiovascular diseases.

Description

[Technical Field]

[0001] The present invention relates to pyrazolyl-pyrimidine derivatives, methods for preparing them, pharmaceutical compositions containing them, and their use as therapeutic agents, in particular, their use as therapeutic agents in the treatment of diseases caused by dysregulated protein kinase activity (e.g., cancer, cell proliferation disorders, viral infections, immune disorders, neurodegenerative disorders, and cardiovascular diseases). [Background technology]

[0002] Protein kinase (PK) dysfunction is characteristic of many diseases. The majority of oncogenes and proto-oncogenes involved in human cancer encode PKs. Enhanced PK activity is also involved in numerous non-malignant diseases, including benign prostatic hyperplasia, familial adenomatous polyposis, polyposis, neurofibromatosis, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, and stenosis and restenosis after surgery.

[0003] PK is involved in inflammatory states and also in the proliferation of viruses and parasites. Furthermore, PK may play a major role in the pathogenesis and development of neurodegenerative disorders.

[0004] For general references regarding PK dysfunction or deregulation, see, for example, "Current Opinion in Chemical Biology, 1999, 3, 459-465," "Nature Rev. Drug Discov. 2002," and "Carcinogenesis, 2008, 29, 1087-1091."

[0005] Spleen tyrosine kinase (Syk) is a 72 kDa non-receptor cytoplasmic tyrosine kinase. Syk has a primary amino acid sequence similar to that of zeta-associated protein-70 (ZAP-70) and is involved in receptor-mediated signaling. The N-terminal domain of Syk contains two Src-homology2 (SH2) domains, which bind to diphosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) found in the cytoplasmic signaling domains of many immune receptor complexes. The C-terminus contains a catalytic domain. Syk is expressed in many cell types involved in adaptive and innate immunity, including lymphocytes (B cells, T cells, and NK cells), granulocytes (basophils, neutrophils, and eosinophils), monocytes, macrophages, dendritic cells, and mast cells. Syk plays a crucial role in immune receptor-mediated signaling in various cell types, including B cells, macrophages, monocytes, mast cells, eosinophils, basophils, neutrophils, dendritic cells, platelets, and osteoclasts. Classical immune receptors include B cell and T cell antigen receptors, as well as various immunoglobulin receptors (Fc receptors). Ligand binding leads to immune receptor activation, which in turn activates Src family kinases and phosphorylates the immune receptor tyrosine-based activation motif (ITAM) on the cytoplasmic surface of the receptor-associated transmembrane adapter. Syk binds to the phosphorylated ITAM motif on the adapter, thereby leading to Syk activation, subsequent phosphorylation, and activation of downstream signaling pathways (Mocsai et al., 2010: 10(6):387).

[0006] Syk is essential for B cell activation via B cell receptor (BCR) signaling. Syk is activated upon binding to phosphorylated BCR, thereby initiating the initial signaling events that follow BCR activation. There is also ample evidence that BCR signaling supports the survival and proliferation of malignant B cells in patients with B-cell leukemia or lymphoma. Mechanisms of BCR pathway activation in these diseases include continuous BCR stimulation by microbial or autoantigens present in the tissue microenvironment, activation of mutations in the BCR complex or downstream signaling components, and ligand-independent persistent BCR signaling. Targeting key BCR signaling mediators with small molecules (e.g., Btk, or delta isoforms of PI3K) has demonstrated to be a beneficial approach to inhibit BCR signaling and achieve therapeutic effects in these diseases (Burger and Wiestner, Nat. Rev. Cancer 2018: 18(3):148).

[0007] Therefore, inhibition of Syk activity may be useful in the treatment of certain types of cancer in which BCR signaling plays a role in their survival and proliferation, such as non-Hodgkin lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, and T-cell lymphoma. Furthermore, the role of Syk in ITAM-dependent signaling and its expression in many cell types suggest that compounds inhibiting Syk activity may be useful in the treatment of disorders involving the immune system and inflammation. Such disorders include: type I hypersensitivity reactions (allergic rhinitis, allergic asthma, and atopic dermatitis); autoimmune diseases (rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, and immune thrombocytopenic purpura); (Pamuk and Tsokos, Arthritis Res Ther. 2010;12(6):222).

[0008] Pyrazolylpyrimidine derivatives have been previously described as modulators of protein kinase activity and are therefore useful in the treatment of diseases caused by dysregulated protein kinase activity (WO2012 / 139930).

[0009] Pyrimidine-5-carboxamide compounds acting as inhibitors of Syk and / or JAK kinase are described in patent application US20200239458, while the solid form of condensed pyrazine as a Syk inhibitor is described in WO2020172431. [Prior art documents] [Patent Documents]

[0010] [Patent Document 1] International Publication No. 2012 / 139930 [Patent Document 2] U.S. Patent Application Publication No. 2020 / 0239458 [Patent Document 3] International Publication No. 2020 / 172431 [Non-patent literature]

[0011] [Non-Patent Document 1] Current Opinion in Chemical Biology, 1999, 3, 459-465 [Non-Patent Document 2] Nature Rev. Drug Discov. 2002 [Non-Patent Document 3] Carcinogenesis, 2008, 29,1087-1091 [Non-Patent Document 4] Mocsai et al., 2010: 10(6):387 [Non-Patent Document 5] Burger and Wiestner, Nat. Rev. Cancer 2018: 18(3):148 [Non-Patent Document 6] Pamuk and Tsokos, Arthritis Res Ther. 2010;12(6):222 [Overview of the project] [Means for solving the problem]

[0012] The inventors have discovered that compounds represented by the general formula (I) defined below are kinase inhibitors, and in particular, inhibitors of spleen tyrosine kinase (SYK). Therefore, such compounds are useful for treating diseases caused by modified SYK activity.

[0013] Therefore, the object of the first aspect of the present invention is formula (I):

[0014] [ka] [During the ceremony, R1 is either hydrogen or an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C3-C7) cycloalkyl, aryl, heterocyclyl, and heteroaryl groups; R2 is hydrogen, or an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, and (C3-C7) cycloalkyl groups; R3 and R4 are independently hydrogen, or a linear or branched (C1-C6) alkyl which may be substituted with a halogen, heteroaryl or heteroaryl(C1-C6)alkyl, or formula (II):

[0015] [ka] It is a base represented by, Here, R5 may be hydrogen, or a substituted linear or branched (C1-C6) alkyl, (C3-C7) cycloalkyl, or aryl group, or together with R6 may form a substituted 4- to 7-membered cycloalkyl group, or together with R7 or R8 may form a substituted heterocyclyl group; R6 may be hydrogen or methyl, or together with R3 or R4, form a 4- to 7-membered heterocyclic group; R7 and R8 can independently form hydrogen, a substituted linear or branched (C1-C6) alkyl group, or a substituted 4- to 7-membered heterocyclyl group (wherein the heterocyclyl group may contain one additional heteroatom selected from N, O, and S) together with X, or a substituted 5- to 7-membered heterocyclyl group together with R3 or R4; X is H, N, or O; However, if X is O, then R5 is not phenyl. The objective is to provide a substituted pyrazolopyrimidine derivative represented by or a pharmaceutically acceptable salt thereof. [Modes for carrying out the invention]

[0016] A preferred compound represented by formula (I) is formula (I) [wherein, R2 is a linear or branched (C1-C6) alkyl group, which may be substituted; R3 and R4 are independently hydrogen or formula (II)

[0017] [ka] It is a base represented by; Here, R5 may be hydrogen, or a substituted linear or branched (C1-C6) alkyl, (C3-C7) cycloalkyl, or phenyl, or together with R6 to form a substituted 4- to 7-membered cycloalkyl; R6 is hydrogen; R7 and R8 can independently form hydrogen, a substituted linear or branched (C1-C6) alkyl group, or a substituted 4- to 7-membered heterocyclyl group (wherein the heterocyclyl group may contain one additional heteroatom selected from N, O, and S); X is either N or O; R1 is as defined above; However, if X is O, then R5 is not phenyl. It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0018] A more preferred compound represented by formula (I) is formula (I) [wherein, R3 is hydrogen, or a linear or branched (C1-C6) alkyl which may be substituted with a halogen, heteroaryl, or heteroaryl(C1-C6)alkyl; R4 is either hydrogen or formula (II)

[0019] [ka] It is a base represented by; Here, R5 may be hydrogen, or a substituted linear or branched (C1-C6) alkyl, (C3-C7) cycloalkyl, or phenyl, or together with R6 to form a substituted 4- to 7-membered cycloalkyl; R6 is hydrogen; R7 and R8 can independently form hydrogen, a substituted linear or branched (C1-C6) alkyl group, or a substituted 4- to 7-membered heterocyclyl group (wherein the heterocyclyl group may contain one additional heteroatom selected from N, O, and S); X is either N or O; R1 and R2 are as defined above; However, if X is O, then R5 is not phenyl. It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0020] Even more preferable is formula (I) [wherein, R1 is an optionally substituted aryl, heterocyclyl, or heteroaryl group; R3 is hydrogen; R4 is given by general formula (II):

[0021] [ka] It is a base represented by; Here, R5 may be hydrogen, or a substituted linear or branched (C1-C6) alkyl, (C3-C7) cycloalkyl, or phenyl, or together with R6 to form a substituted 4- to 7-membered cycloalkyl; R6 is hydrogen; R7 and R8 can independently be hydrogen, or a substituted linear or branched (C1-C6) alkyl group, or together with X, form a substituted 4- to 7-membered heterocycline; X is N; R2 is as defined above. It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0022] Even more preferable is formula (I) [wherein, R1 is an optionally substituted group selected from phenyl or indolyl; R2, R3, and R4 are as defined above. It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0023] Preferred specific compounds (cpd) or salts thereof represented by formula (I) are the following compounds: N-[2-(dimethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 1); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(2R)-1-hydroxypropane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 2); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-hydroxypropane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 3); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(propan-2-yl)-1H-pyrazole-5-carboxamide (compound 4); N-[2-(dimethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (compound 5); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[2-(methylamino)ethyl]-1H-pyrazole-5-carboxamide hydrochloride (compound 6); N-(2-aminoethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 7); N-(azetidine-3-yl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide trifluoroacetate (compound 8); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-5-carboxamide (compound 9); N-[2-(diethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 10); N-[(1R,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 11); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[2-(propan-2-ylamino)ethyl]-1H-pyrazole-5-carboxamide hydrochloride (compound 12); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 13); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (compound 14); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N,N,1-trimethyl-1H-pyrazole-5-carboxamide (compound 15); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 16); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(2-fluoroethyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 17); 3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-N-[2-(dimethylamino)ethyl]-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 18); 3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 19); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(1H-pyrazole-3-yl)-1H-pyrazole-5-carboxamide (compound 20); (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)(4-methylpiperazine-1-yl)methanone (Compound 21); N-[2-(acetylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (Compound 22); N-(2-amino-2-oxoethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (Compound 23); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxamide (compound 24); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(1-methyl-1H-imidazole-5-yl)methyl]-1H-pyrazole-5-carboxamide (compound 25); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 26); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(pyridine-2-ylmethyl)-1H-pyrazole-5-carboxamide (compound 27); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(1H-imidazole-2-ylmethyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 28); N-[(2R)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 29); N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-yl]-1H-pyrazole-5-carboxamide (compound 30); N-(1-azabicyclo[2.2.2]octa-3-yl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 31); 5-[2-(3,5-dimethylphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ((1R,2R)-2-hydroxycyclohexyl)-amide (compound 32); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-hydroxybutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 33); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 34); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,4-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 35); (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)(piperazine-1-yl)methanone hydrochloride (compound 36); N-[(1S,2R)-2-aminocyclohexyl]-3-(2-{[3-methoxy-5-(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 37); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3-chloro-1-methyl-1H-indole-5-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 38); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 39); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-difluorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 40); N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 41); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (compound 42); N-[3-(dimethylamino)propyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 43); (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)[(2S)-2-(propan-2-yl)aziridine-1-yl]methanone (compound 44); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(2,2-dimethylpropyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 45); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(2-methylpropyl)-1H-pyrazole-5-carboxamide (compound 46); N-(cyclopropylmethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 47); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-fluoro-5-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 48); 3-{2-[(4,6-dimethylpyridine-2-yl)amino]pyrimidine-4-yl}-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 49); 3-{2-[(3,5-difluorophenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (compound 50); 1-Methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (compound 51); 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]aminopyrimidine-4-yl)-N-[(2S)-1-hydroxy-3-phenylpropane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 52); N-[(1S,2S)-2-aminocyclohexyl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 53); 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]aminopyrimidine-4-yl)-1-methyl-N-[(2S)-1,1,1-trifluoropropane-2-yl]-1H-pyrazole-5-carboxamide (compound 54); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1H-pyrazole-5-carboxamide (compound 55); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1H-pyrazole-5-carboxamide (compound 56); N-[(2S)-1-(3,3-difluoroazetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 57); 1-Methyl-N-[(2S)-1-(pyrroridine-1-yl)propan-2-yl]-3-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 58); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-chloro-1-methyl-1H-indole-5-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 59); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 60); N-[(2S)-1-(azetidine-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 61); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-1-methyl-3-(2-{[3-(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-1H-pyrazole-5-carboxamide (compound 62); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-1-methyl-1H-pyrazole-5-carboxamide (compound 63); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 64); N-[(2S)-1-(dimethylamino)propan-2-yl]-3-{2-[(3-fluoro-5-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 65); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-[2-(1,3-benzodioxol-5-ylamino)pyrimidine-4-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 66); 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 67); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-1-methyl-3-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 68); 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidine-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (compound 69); 3-{2-[(3-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidine-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (compound 70); 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-(dimethylamino)-1-oxopropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 71); 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-N-[2-(dimethylamino)ethyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 72); N-[(2S)-1-(dimethylamino)propan-2-yl]-3-{2-[(1,5-dimethyl-1H-pyrazole-3-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 73); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(1,5-dimethyl-1H-pyrazole-3-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 74); N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-3-{2-[(1-methyl-1H-pyrazole-4-yl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 75); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-1-methyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-yl]-1H-pyrazole-5-carboxamide (compound 76); N,N,1-trimethyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-yl]-1H-pyrazole-5-carboxamide (compound 77); 3-{2-[(3-cyano-5-methoxyphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-(dimethylamino)propane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 78); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-cyano-5-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 79); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(5-methoxypyridine-3-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 80); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(3S)-piperidine-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (compound 81); N-(2-aminocyclohexyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 82); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[2-(pyrroridine-1-yl)ethyl]-1H-pyrazole-5-carboxamide (Compound 83); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[2-(piperidine-1-yl)ethyl]-1H-pyrazole-5-carboxamide (compound 84); (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)[(3R)-3-hydroxypyrrolidine-1-yl]methanone (compound 85); [(3S)-3-(dimethylamino)pyrroridine-1-yl](3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)methanone (compound 86); [(3R)-3-(dimethylamino)pyrroridine-1-yl](3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)methanone (compound 87); (3-aminopyrrolidine-1-yl)(3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)methanone (compound 88); (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]methanone (compound 89); (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)[(3S)-3-hydroxypyrrolidine-1-yl]methanone (compound 90); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(1R,2S)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 91); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 92); N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-3-{2-[(1,2,3-trimethyl-1H-indole-5-yl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 93); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidine-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (compound 94); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 95); (1R,4S)-2,5-diazabicyclo[2.2.1]hepta-2-yl(3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)methanone hydrochloride (compound 96); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(3R)-piperidine-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (compound 97); N-[(1R,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 98); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 99); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 100); N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 101); N-[(2S)-1-(azetidine-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 102); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-3-methyl-1-(pyrrolidine-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (compound 103); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide hydrochloride (compound 104); N-[(2S)-1-(azetidine-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 105); N-[(1S)-1-cyclohexyl-2-hydroxyethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 106); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(1S)-1-phenyl-2-(pyrrolidine-1-yl)ethyl]-1H-pyrazole-5-carboxamide (compound 107); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 108); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-hydroxy-3-phenylpropane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 109); 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]amino}pyrimidine-4-yl)-N-[(2S)-1-hydroxypropane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 110); 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]aminopyrimidine-4-yl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 111); 1-Methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-3-methyl-1-(pyrrolidine-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (compound 112); N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-difluorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 113); 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]aminopyrimidine-4-yl)-N-[(1S,2R)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 114); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(1S,2R)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 115); N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 116); 3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-3-methyl-1-(pyrrolidine-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (compound 117); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 118); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-cyanophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 119); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-ethyl-N-[(1S,2R)-2-hydroxycyclohexyl]-1H-pyrazole-5-carboxamide (compound 120); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-ethyl-1H-pyrazole-5-carboxamide hydrochloride (compound 121); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-ethyl-N-[(3R)-piperidine-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (compound 122); and, N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (compound 123).

[0024] For reference to any specific compound represented by formula (I) of the present invention, which may be in the form of a pharmaceutically acceptable salt, see the Experimental Section and the Claims.

[0025] If a stereocenter or another form of isomeric center is present in the compounds of the present invention, all forms of such isomers, including enantiomers and diastereomers, are intended to be encompassed by the present invention. Compounds containing a stereocenter can be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture can be separated using known techniques, and the individual enantiomers can be used individually. If the compound has an unsaturated carbon-carbon double bond, both cis (Z) and trans (E) isomers fall within the scope of the present invention.

[0026] Where a compound can exist in tautomer forms such as keto-enol tautomers, each tautomer form is intended to be included within the scope of the present invention, whether it exists in equilibrium or one form is dominant. Therefore, unless otherwise indicated, if R2 is hydrogen in a compound represented by formula (I) and only one of the following tautomer forms of formula (la) or formula (lb) is shown, the remaining one must also be intended to be included within the scope of the present invention:

[0027] [ka]

[0028] pharmaceutically acceptable salts of the compound represented by formula (I) include salts with inorganic or organic acids, such as nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, oxalic acid, fumaric acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, isethionic acid, salicylic acid, succinic acid, and p-toluenesulfonic acid.

[0029] pharmaceutically acceptable salts of the compound represented by formula (I) also include salts with inorganic or organic bases, such as alkali metals or alkaline earth metals, particularly hydroxides, carbonates or bicarbonates of sodium, potassium, calcium, ammonium or magnesium, and acyclic or cyclic amines.

[0030] Further objects of the present invention are compounds represented by formula (I) as defined above, as well as their isomers, tautomers, hydrates, solvates, complexes, metabolites, prodrugs, carriers, and N-oxides.

[0031] A metabolite of the compound represented by formula (I) is any compound to which this same compound represented by formula (I) is converted in vivo, for example, when administered to a mammal that needs it. Typically, but not limited to, when the compound represented by formula (I) is administered, this same derivative can be converted to a variety of compounds, including more soluble derivatives such as readily excreted hydroxylated derivatives. Therefore, depending on the metabolic pathway thus produced, any of these hydroxylated derivatives can be considered a metabolite of the compound represented by formula (I).

[0032] A prodrug is any covalently bonded compound that releases an active parent drug in vivo according to formula (I). An N-oxide is a compound represented by formula (I) in which nitrogen and oxygen are linked by a coordinate bond.

[0033] The term “linear or branched (C1-C6) alkyl” (which includes (C1-C4) alkyl) is intended to refer to any of the following groups, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, etc.

[0034] The term "linear or branched (C2-C6) alkenyl" is intended to refer to any of the following groups, for example: vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1-hexenyl, etc.

[0035] The term "linear or branched (C2-C6) alkynyl" is intended to refer to any of the following groups, such as ethynyl, 2-propynyl, or 4-pentynyl.

[0036] The term "(C3-C7) cycloalkyl" refers to all 3- to 7-membered carbon monocyclic rings that do not have a fully conjugated π-electron system, although they may contain one or more double bonds, unless otherwise specified. Examples of cycloalkyl groups, though not limited to them, include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, and cycloheptadiene.

[0037] The term "aryl" means a monocyclic, dicyclic, or polycyclic hydrocarbon having 1 to 4 ring systems, which may optionally be further condensed or bonded to each other by single bonds, wherein at least one of the carbocyclic rings is "aromatic," where "aromatic" means a fully conjugated π-electron bonding system. Non-limiting examples of such aryl groups are phenyl, α- or β-naphthyl, α- or β-tetrahydronaphthalenyl, biphenyl, and indanyl groups.

[0038] The term "heteroaryl" refers to an aromatic heterocyclic ring, typically a 5-7 membered heterocyclic ring having 1-3 heteroatoms selected from N, O, or S; the heteroaryl ring may optionally be further condensed or bonded to aromatic and non-aromatic carbocyclic and heterocyclic rings. Non-restrictive examples of such heteroaryl groups include, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, furanil, oxazolyl, isoxazolyl, pyrazolyl, thiophenyl, thiadiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, indazolyl, sinnolinyl, benzo[1,3]dioxolyl, benzo[1,4]dioxynyl, benzothiazolyl, benzothiophenyl, benzofuranil, isoindolinyl, benzimidazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranil, 2,3-dihydrobenzothiophenyl, benzopyranil, 2,3-dihydrobenzoxazinyl, and 2,3-dihydroquinoxalinyl.

[0039] The term "heterocyclyl" refers to a 3- to 7-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur. Non-limiting examples of heterocyclyl groups include, for example, pyranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyridinyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, and morpholinyl. The heterocyclyl ring may optionally be further condensed or bonded to aromatic and non-aromatic carbocyclic rings and heterocyclic rings.

[0040] According to the present invention, unless otherwise specified, any of the above R1, R2, R3, and R4 groups may optionally have a halogen, nitro, oxo group (=O), cyano, (C1-C6) alkyl, polyfluorinated alkyl, polyfluorinated alkoxy, alkenyl, alkynyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, (C3-C7) cycloalkyl, hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, aryl Kylideneaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, amino, ureido, alkylamino, dialkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, hydroxyaminocarbonyl It may be substituted with one or more groups independently selected from alkoxyimino, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio, phosphonate and alkylphosphonate, for example, 1 to 6 groups.

[0041] Next, where appropriate, each of the substituents may be further substituted with one or more of the groups described above.

[0042] In this context, the term "halogen" refers to fluorine, chlorine, bromine, or iodine atoms.

[0043] The term "cyano" refers to the -CN residue.

[0044] The term "nitro" refers to the -NO2 group.

[0045] The terms "alkenyl" or "alkynyl" refer to the linear or branched (C2-C6) alkyl groups having further double or triple bonds. Non-limiting examples of alkenyl or alkynyl groups in the present invention include vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1-hexenyl, ethynyl, 2-propynyl, and 4-pentinyl.

[0046] The terms "polyfluorinated alkyl" or "polyfluorinated alkoxy" refer to the linear or branched (C1-C6) alkyl or (C1-C6) alkoxy groups substituted with two or more fluorine atoms, such as trifluoromethyl, trifluoroethyl, 1,1,1,3,3,3-hexafluoropropyl, and trifluoromethoxy.

[0047] The terms "alkoxy, aryloxy, heterocyclyloxy" and their derivatives refer to the (C1-C6) alkyl, aryl, or heterocyclyl groups bonded to the remainder of the molecule via an oxygen atom (-0-).

[0048] As will be apparent to those skilled in the art from the above, any group whose name is a compound name such as "arylamino" is intended to be conventionally interpreted by the part from which it is derived, for example, by an amino group further substituted with aryl (where aryl is as defined above).

[0049] Similarly, terms such as alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, and cycloalkyloxycarbonyl all encompass groups in which the alkyl, alkoxy, aryl, (C3-C7)cycloalkyl, and heterocyclyl portions are as defined above.

[0050] The present invention also provides a method for preparing the compound represented by formula (I) as defined above by using the reaction pathway and synthesis scheme described below, using techniques available in the art and readily available starting materials. Although the preparation of specific embodiments of the present invention is described in the following examples, as will be recognized to those skilled in the art, the preparations described can be readily adapted to the preparation of other embodiments of the present invention. For example, the preparation of compounds of the present invention not illustrated can be carried out by modifications that are obvious to those skilled in the art, such as appropriately protecting interfering groups, appropriately replacing reagents with others known in the art, or by commonplace changes to reaction conditions. Alternatively, other reactions mentioned herein or known in the art will be deemed capable of being adapted to prepare other compounds of the present invention.

[0051] The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. Unless otherwise indicated, the starting materials are known compounds or can be prepared from known compounds according to well-known procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure) are described, it is understood that different process conditions may also be used unless otherwise indicated. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by those skilled in the art using routine optimization methods.

[0052] The intermediate compound represented by formula (V) can be prepared as reported in Scheme 1 below.

[0053] Scheme 1

[0054] [ka]

[0055] Therefore, the preparation method of the present invention includes the following steps: Stage (1) Equation (III):

[0056] [ka] [In the formula, R2 is hydrogen or an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl and (C3-C7) cycloalkyl groups, and R9 is a group selected from linear or branched (C1-C6) alkyl groups.] A step of mixing the compound represented by dimethylformamide-dialkylacetal; Stage (2) Equation (IV):

[0057] [ka] [In the formula, R2 and R9 are as defined above.] The resulting compound is represented by formula (V):

[0058] [ka] [In the formula, R1 is hydrogen or an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C3-C7) cycloalkyl, aryl, heterocyclyl, and heteroaryl groups.] When reacted with a compound represented by formula (VI):

[0059] [ka] [In the formula, R1, R2, and R9 are as defined above.] The step of obtaining the compound represented by [the symbol].

[0060] The compound represented by formula (VI) reported in step 2 can alternatively be prepared according to the following steps: Stage (3) Equation (IV):

[0061] [ka] [In the formula, R2 and R9 are as defined in step (1) above.] The step of reacting it with guanidine carbonate; Stage (4) Formula (VII):

[0062] [ka] [In the formula, R2 and R9 are as defined above.] The resulting compound represented by formula (VIII):

[0063] [ka] [In the formula, R1 is as defined in step (2) above, and Y is iodine or bromine.] The compound represented by equation (VI) is reacted with palladium in the presence of palladium to produce equation (VI):

[0064] [ka] [In the formula, R1, R2, and R9 are as defined above.] The step of obtaining the compound represented by; Or, Equation (VII) obtained in step (5) as reported in step (3):

[0065] [ka] The step of reacting a compound represented by isoamyl nitrite and diiodomethane or cesium iodide with iodine or CuI to obtain a compound represented by formula (IX) [wherein R2 and R9 are as defined above]; Step (6) Next, equation (IX):

[0066] [ka] [In the formula, R2 and R9 are as defined above.] The resulting compound is represented by formula (X):

[0067] [ka] [In the formula, R1 is as defined above.] The compound represented by equation (VI) is reacted with palladium in the presence of palladium to produce equation (VI):

[0068] [ka] [In the formula, R1, R2, and R9 are as defined above.] The step of obtaining the compound represented by [the symbol].

[0069] The compound represented by formula (I), which is the subject of this invention, can be prepared as reported in Scheme 2 below:

[0070] Scheme 2

[0071] [ka]

[0072] In the above scheme, R1, R2, R3, and R4 are as defined in formula (I); R9 is a group selected from the linear or branched (C1-C6) alkyl groups as defined above.

[0073] Therefore, the preparation method of the present invention includes the following steps: Step (7) Formula (VI) obtained as described in Steps 2, 4, or 6

[0074] [ka] [In the formula, R1 is hydrogen or an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C3-C7) cycloalkyl, aryl, heterocyclyl, and heteroaryl groups; R2 is hydrogen or an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, and (C3-C7) cycloalkyl groups; and R9 is a group selected from linear or branched (C1-C6) alkyl groups.] The compound represented by formula (XI) is reacted under acidic or basic hydrolysis conditions to obtain formula (XI).

[0075] [ka] [In the formula, R1 and R2 are as defined above.] A step of obtaining a compound represented by or the corresponding salt; Step (8) The compound represented by formula (XI) or the corresponding salt described in Step 7 is given by formula (XII)

[0076] [ka] [In the formula, R3 and R4 are independently hydrogen, or a linear or branched (C1-C6) alkyl which may be substituted with a halogen, heteroaryl and heteroaryl(C1-C6)alkyl, or formula (II)

[0077]

Chem.

[0078]

Chem.

[0079] According to step 1 of the preparation method, the synthesis of the enaminone derivative represented by formula (IV) is carried out using N,N-dimethylformamide-dialkylacetal (for example, dimethylformamide-di-tert-butylacetal, dimethylformamide-diethylacetal, etc.) in the presence or absence of a suitable solvent (for example, DMF, DMA, toluene, etc.) at a temperature in the range of room temperature to 150 °C (in any case, by conventional heating or microwave heating) for a time in the range of 30 minutes to about 24 hours.

[0080] According to step 2 of the preparation method, the compound represented by formula (IV) is reacted with the derivative represented by formula (V) in a suitable solvent (for example, DMF, EtOH or toluene) at a temperature in the range of room temperature to 150 °C (in any case, by conventional heating or microwave heating) for a time in the range of about 1 to about 48 hours, optionally in the presence of a base (for example, a base selected from AcOK, EtONa, TEA, K2CO3 or Na2CO3). Preferably, the reaction is carried out in a microwave apparatus at 150 °C for 2 hours in EtOH.

[0081] According to step 3 of the preparation method, the compound represented by formula (IV) is finally reacted with guanidine or its salt or a protected synthetic equivalent (for example, Boc-guanidine) in a suitable solvent (for example, DMF, EtOH, PrOH, n-BuOH or toluene) at a temperature in the range of room temperature to 150 °C (in any case, by conventional heating or microwave heating) for a time in the range of about 1 to about 48 hours, in the presence of a base selected from AcOK, EtONa, TEA, K2CO3 or Na2CO3.

[0082] According to step 4 of the preparation method, the compound represented by formula (VII) as defined above is reacted with the compound represented by formula (VIII) as defined above, in accordance with a conventional method well known in the literature. For example, the reaction can be carried out in a suitable solvent (e.g., DMF, DME, dioxane, or CH3CN) in the presence of Pd2(dba)3, BINAP, or 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl (X-phos) and a base (e.g., K2CO3, potassium phosphate, or Cs2CO3) at a temperature ranging from room temperature to 110°C for a period of 2 to about 24 hours to obtain the compound represented by formula (VI).

[0083] According to step 5 of the preparation method, the reaction is carried out in the presence of iodine or CuI in a suitable solvent (e.g., dioxane, THF, Et2O, or DME) at a temperature ranging from room temperature to about 100°C for about 1 to 16 hours using isoamyl nitrite and diiodomethane or cesium iodide.

[0084] According to step 6 of the preparation method, the reaction between the compound represented by formula (IX) and the compound represented by formula (X) is carried out in a suitable solvent (e.g., dioxane, DMF, DME, or CH3CN) in the presence of a catalytic amount of Pd(OAc)2, BINAP, or Xantphos and a base (e.g., K2CO3, potassium phosphate, or Cs2CO3) at a temperature ranging from room temperature to 110°C for a period of about 2 to about 24 hours.

[0085] According to step 7 of the preparation method, the compound represented by formula (VI) can be converted to the derivative represented by the corresponding formula (XI) or its salt via basic or acidic hydrolysis conditions widely known in the art. Preferably, the reaction is carried out using an alkaline aqueous solution such as aqueous lithium hydroxide, aqueous sodium hydroxide, or aqueous potassium hydroxide in the presence of a suitable solvent (e.g., a lower alcohol, THF, DMF, or a mixture thereof). Preferably, the reaction is carried out using lithium hydroxide in a THF / MeOH / water mixture at a temperature in the range of about room temperature to about 80°C for a time in the range of about 2 to about 24 hours. Depending on the operating conditions used, the compound represented by formula (XI) can be obtained in its acidic form or as a salt.

[0086] According to step 8 of the preparation method, the amidation of the carboxylic acid represented by formula (XI) to produce the corresponding compound represented by formula (I) is carried out under basic conditions (preferably using DIPEA or TEA) in the presence of ammonium chloride or a suitable primary or secondary amine represented by formula R3R4NH(XII), in a suitable solvent (e.g., DCM, DMF, THF, 1,4-dioxane or DMA), with a suitable coupling agent (e.g., dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3'-dimethylaminopropyl The reaction is carried out in the presence of (Pyrocarbodiimide) (EDC), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (DHBT), O-benzotriazolyltetramethylisouronium tetrafluoroborate (TBTU), benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), or 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU). The reaction is optionally carried out in the presence of a suitable catalyst (e.g., 4-dimethylaminopyridine) or an additional coupling reagent (e.g., N-hydroxybenzotriazole (HOBt)) at room temperature for a period of about 2 to about 24 hours.

[0087] From all of the above, it will be apparent to those skilled in the art that the conversion of the compound represented by formula (I) to its pharmaceutically acceptable salt or the conversion of the corresponding salt to the free compound (I) according to procedures well known to those skilled in the art is within the scope of the present invention. When preparing the compound represented by formula (I) according to any variation of the preparation method (all of which are intended to be within the scope of the present invention), any functional groups in the starting materials, reagents or intermediates that may cause undesirable side reactions must be adequately protected according to conventional art.

[0088] Such protection of reaction centers and subsequent deprotection at the end of synthetic transformations can be achieved by following standard procedures, for example, as described in "Green, Theodora W. and Wuts, Peter GM - Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons Inc., New York (NY), 1999".

[0089] According to any modified version of the method for preparing the compound represented by formula (I), the starting material and any other reactants are known or readily prepared according to known methods.

[0090] The compound represented by formula (III) can be prepared as described in WO2012 / 139930.

[0091] The compound represented by formula (V) is commercially available or can be prepared by known methods (J. Med. Chem., 2004, vol 47, p.4716-4730).

[0092] The compounds represented by formulas (VIII), (X), and (XII) are commercially available or can be prepared by known methods.

[0093] The final compound can be isolated and purified using conventional procedures, such as chromatography and / or crystallization and salt formation.

[0094] The compound represented by the general formula (I) defined above can be converted into a pharmaceutically acceptable salt.

[0095] The synthesis of the compound represented by general formula (I) using the synthetic method described above can be carried out stepwise, thereby isolating and purifying each intermediate as needed before subsequent reactions using standard purification techniques such as column chromatography. Alternatively, two or more steps of the synthetic sequence can be carried out as a so-called "one-pot" method known in the art, thereby isolating and purifying only the compound obtained from two or more steps.

[0096] If a compound represented by general formula (I) contains one or more chiral centers, the compound can be separated into a single stereoisomer by means known to those skilled in the art. Such procedures include standard chromatographic techniques (e.g., chromatography using a chiral stationary phase) or crystallization. General methods for separating compounds containing one or more chiral centers are reported, for example, in "Jacques, Jean; Collet, Andre; Wilen, Samuel H., Enantiomers, Racemates, and Resolutions, John Wiley & Sons Inc., New York (NY), 1981".

[0097] The present invention further relates to dysregulated protein kinase activity (particularly ABL, ACK1, AKT1, ALK, AUR1, AUR2, BRK, BUB1, CDC7 / DBF4, CDK2 / CYCA, CHK1, CK2, EEF2K, EGFR1, EphA2, EphB4, ERK2, FAK, FGFR1, FLT3, GSK3beta, Haspin, IGFR1, IKK2, IR, JAK1, JAK2, JAK3, KIT, LCK, LYN, MAPKAPK2, MELK, MET, MNK2, MPS1, MST4, NEK6, NIM1, P38alpha, PAK4, PDGFR, The present invention also provides a method for treating diseases caused by and / or related to PDK1, PERK, PIM1, PIM2, PIM3, PKAalpha, PKCbeta, PLK1, RET, R0S1, SULU1, Syk, TLK2, TRKA, TYK, VEGFR2, VEGFR3, ZAP70; and in particular PIM1, PIM2, PIM3, MPS1, JAK2, JAK3, and more particularly Syk family kinases), wherein the method comprises administering an effective amount of a compound represented by formula (I) as defined above to a mammal (more specifically, a human) in need of such treatment.

[0098] Furthermore, the present invention provides a compound represented by formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in a method for treating diseases resulting from and / or related to dysregulated protein kinase activity (particularly Syk kinase activity) as reported above, wherein the method comprises administering an effective amount of the compound represented by formula (I) as defined above to a mammal (preferably human) in need of such treatment.

[0099] A preferred method of the present invention is to treat diseases caused by and / or associated with dysregulated protein kinase activity, selected from the group consisting of cancer, cell proliferation disorders, viral infections, immunodeficiencies, neurodegenerative disorders, and cardiovascular diseases. More preferably, the disease is cancer.

[0100] According to the most preferred embodiment of the present invention, the cancer is selected from the group consisting of: carcinomas, such as bladder cancer, breast cancer, kidney cancer, liver cancer, colon cancer, lung cancer (including small cell lung cancer), esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, prostate cancer, and skin cancer (including squamous cell carcinoma); hematopoietic tumors of the lymphatic system (including leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B cell lymphoma, angioimmunoblastic T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma); hematopoietic tumors of the myeloid cell line (including acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin, such as fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous systems (including glioma, glioblastoma, glioblastoma multiforme, astrocytoma, oligodendroglioma, paraganglioma, neuroblastoma, and schwannoma); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid cancer (e.g., papillary thyroid cancer and medullary thyroid cancer), Kaposi sarcoma, chondrosarcoma, and cholangiocarcinoma).

[0101] Another preferred method of the present invention is to treat certain cell proliferation disorders, such as benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, and stricture and restenosis after surgery, etc.

[0102] Another preferred method of the present invention is to treat viral infections, particularly the prevention of the onset of AIDS in HIV-infected individuals.

[0103] Another preferred method of the present invention is to treat immune disorders, such as inflammation and autoimmune diseases, for example, multiple sclerosis, rheumatoid arthritis (RA), systemic lupus erythematosus, inflammatory bowel disease (IBD), Crohn's disease, irritable bowel syndrome, pancreatitis, ulcerative colitis, diverticulosis, myasthenia gravis, vasculitis, psoriasis, scleroderma, asthma, allergies, systemic sclerosis, vitiligo, arthritis (e.g., osteoarthritis), juvenile rheumatoid arthritis, and ankylosing spondylitis.

[0104] Another preferred method of the present invention is to treat neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease.

[0105] Another preferred method of the present invention is to treat certain cardiovascular diseases, such as coronary heart disease, cardiomyopathy, ischemic heart disease, heart failure, hypertensive heart disease, inflammatory heart disease, and valvular heart disease.

[0106] Furthermore, the method of the present invention also provides inhibition of tumor angiogenesis and metastasis, as well as treatment of organ graft rejection and host-versus-graft disease.

[0107] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, carrier and / or diluent.

[0108] The present invention further provides pharmaceutical compositions comprising a compound represented by formula (I) in combination with one or more chemotherapeutic agents (for example, cell proliferation inhibitors or cytotoxic agents). Examples of cell proliferation inhibitors or cytotoxic agents include, but are not limited to, the following: antibiotic-type drugs, alkylating agents, antimetabolites, hormones, immunological agents, interferon-type drugs, cyclooxygenase inhibitors (e.g., COX-2 inhibitors), matrix metalloproteinase inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenic agents (e.g., angiogenesis inhibitors), farnesyltransferase inhibitors, ras-raf signaling pathway inhibitors, cell cycle inhibitors, other CDKS inhibitors, tubulin conjugates, topoisomerase I inhibitors, topoisomerase II inhibitors, aromatase inhibitors, kinesin inhibitors, therapeutic monoclonal antibodies, mTOR inhibitors, histone deacetylase inhibitors, hypoxia response inhibitors, PD-1 antagonists or their antigen-binding fragments that specifically bind to PD-1 or PD-L1, etc.

[0109] When formulated as a fixed dose, such combination products use the compounds of the present invention within the dosage range described below and other pharmaceutically active agents within the approved dosage range.

[0110] The present invention also provides an in vitro method for inhibiting Syk protein kinase activity, the method comprising contacting the Syk kinase with an effective amount of a compound represented by formula (I) as defined above.

[0111] Furthermore, the present invention also provides products comprising a compound represented by formula (I) as defined above or a pharmaceutically acceptable salt thereof and one or more chemotherapeutic agents, as combination preparations for simultaneous, individual, or sequential use in anticancer therapy.

[0112] The compound represented by formula (I) of the present invention, suitable for administration to mammals (e.g., humans), can be administered via a normal route, and the dose level depends on the patient's age, weight and condition, as well as the route of administration.

[0113] For example, an appropriate dose for oral administration of the compound represented by formula (I) may be approximately 10 to 1000 mg per dose, 1 to 5 times per day. The compounds of the present invention can be administered in various forms, for example, orally in the form of tablets, capsules, sugar-coated or film-coated tablets, liquids or suspensions; rectally in the form of suppositories; and parenterally, for example, by intramuscular or intravenous and / or intrathecal injection or infusion.

[0114] Pharmaceutical compositions containing the compounds of the present invention are typically prepared according to conventional methods and administered in an appropriate pharmaceutical form.

[0115] For example, the oral solid form may contain, along with the active compound, the following: diluents, e.g., lactose, dextrose, saccharose, sucrose, cellulose, corn starch, or potato starch; lubricants, e.g., silica, talc, stearic acid, magnesium stearate, or calcium stearate, and / or polyethylene glycol; binders, e.g., starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; disintegrants, e.g., starch, alginic acid, alginate, or sodium starch glycolate; foaming mixtures; dyes; sweeteners; humectants, e.g., lecithin, polysorbate, lauryl sulfate; and generally non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. These pharmaceutical preparations can be prepared by known methods, for example, using a mixing process, granulation process, tableting process, sugar coating process, or film coating process.

[0116] Liquid dispersions for oral administration may include, for example, syrups, emulsions, and suspensions.

[0117] As an example, the syrup may contain saccharose as a carrier, or may contain saccharose together with glycerin and / or mannitol and sorbitol.

[0118] The suspensions and emulsions may contain, as examples of carriers, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

[0119] The suspension or solution for intramuscular injection may contain, along with the active compound, a pharmaceutically acceptable carrier, such as sterile water, olive oil, ethyl oleate, glycol (e.g., propylene glycol), and, if desired, an appropriate amount of lidocaine hydrochloride.

[0120] Solutions for intravenous injection or infusion may contain sterile water as a carrier, or they may preferably be in the form of sterile, aqueous, isotonic saline, or they may contain propylene glycol as a carrier.

[0121] The suppository may contain, along with the active compound, a pharmaceutically acceptable carrier, such as cocoa butter, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester surfactant, or lecithin. In another embodiment, the present invention provides a compound represented by formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0122] Finally, the present invention provides the use of a compound represented by formula (I) as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product having anticancer activity.

[0123] Experiment Section The abbreviations and shortened terms used in this specification and throughout the detailed description have the following meanings:

[0124] [Table 1]

[0125] Preparation of the compound represented by formula (I) For reference to any specific compound represented by formula (I) of the present invention, which may be in the form of a pharmaceutically acceptable salt, see the Experimental Section and the Claims. Referring to the following examples, the compounds of the present invention were synthesized using the methods described herein or other methods well known in the art.

[0126] For the purpose of better illustrating the present invention, the following examples are described without any limitations.

[0127] Where used herein, the symbols and conventions used in the preparation methods, schemes, and examples are the same as those used in modern scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0128] The compound name is an IUPAC name created using the ACD Name (by Advanced Chemistry Development, Inc.).

[0129] Unless otherwise indicated, all materials (including anhydrous solvents such as DMF, THF, and DCM) were obtained from commercial suppliers of the highest quality and used without further purification. All reactions involving air or moisture-sensitive compounds were carried out under a nitrogen or argon atmosphere.

[0130] General purification and analytical methods The synthetic preparation of some of the compounds represented by formula (I) of the present invention is described in the following examples.

[0131] The compounds of the present invention prepared according to the following examples are: 1 The samples were characterized by 1H NMR and / or HPLC / MS analysis data; HPLC / MS data were collected according to either LCQ or LCT methods. Flash chromatography was performed on silica gel (Merck grade 9395, 60A).

[0132] HPLC LCQ method HPLC-MS / UV analysis was performed using an LCQ DecaXP (Thermo, San Jose, US) ion trap instrument equipped with an electrospray (ESI) ion source. The mass spectrometer was connected to a Surveyor HPLC system (Thermo, San Jose, US) equipped with a UV photodiode array detector (UV detection 215-400 nm). A Waters XSelect CSH C18 column, 50 × 4.6 mm, with a particle size of 3.5 μm was used. Mobile phase A was 5 mM ammonium acetate buffer (pH 4.5 with acetic acid):acetonitrile (95:5), and mobile phase B was 5 mM ammonium acetate buffer (pH 4.5 with acetic acid):acetonitrile (5:95). A gradient from 0%B to 100%B was maintained over 7 minutes, with 100%B held for 2 minutes. Flow rate was 1 mL / min. Injection volume was 10 μL. Retention time (HPLC rt) is shown in minutes. Full scan, mass range 50-1200 amu. The heated capillary temperature was 200°C, and the spray voltage was set to 4kV. Mass is given in m / z ratio. Instrument control, data acquisition, and processing were performed using Xcalibur 1.4SR1 software (Thermo).

[0133] HPLC LCT method HPLC-MS / UV analysis and high-resolution mass spectroscopy (HRMS) were performed on a Waters Alliance LC2795 equipped with a Waters PDA UV detector 2996 and a TOF Waters LCT Premier XE mass detector (ESI interface) (supported by a Waters Reagent Manager liquid pump). This assay is based on general gradient reversed-phase chromatography, which can complement a characterization-purity assay by determining and confirming the expected and accurate mass of the compound in the same run. Compound characterization was performed by online serial ESI(+) Full Scan MS detection, and sample purity was obtained as the relative "area percentage" of the integrated LC / UV trace at 216–400 nm. The liquid chromatograph was equipped with a Waters XBridge CSH C18 column (3.0 x 30 mm, particle size 3.5 μm) temperature-controlled to 50°C. Alternatively, a Supelco column Ascentis Express C18 (2.7 × 30 mm × 3 μm) was used.

[0134] Mobile phase A was 0.05% w / v formic acid in highly purified water, and mobile phase B was a 70 / 25 / 5 (v / v / v) mixture of MeOH / iPrOH / H2O (containing 0.035% w / v formic acid). A gradient from 0%B to 100%B was applied over 17.5 minutes, with 100%B held for 5 minutes. Flow rate was 0.8 mL / min, injection volume 4 μL. The ESI source was operated at 100°C, 2.5 kV capillary voltage, 60 V cone, 600 L / hour nitrogen desolvation flow at 350°C, and 10 L / hour nitrogen cone flow. The "Normal" Z focus was set to 140. The analytical instrument was optimized with a standard 7200 V flight tube.

[0135] To obtain a high-resolution mass spectrum, the eluate from the HPLC column was split, and 25 μL / min was mixed with a flow of 100 μL / min of a 30 / 10 / 60 (v / v / v) mixture of MeOH / iPrOH / H2O (containing 0.01% w / v formic acid and 80 nM trimethoprim supplied from a Waters Reagent Manager pump before entering the MS source). Trimethoprim was selected as a stable and soluble appropriate reference compound for real-time single-point mass correction. ES(+) full scan 80 - 1200 amu centroid data acquisition was performed at a sampling rate of 2 Hz in "W" mode. The LCT integrated PC provided both real-time data centering based on trimethoprim and real-time mass correction. A H+ reference mass of 291.1452 Da. MS spectra of appropriate intensity (40 - 2000 analyte counts) were averaged to obtain the final result.

[0136] 1 The 1H-NMR spectra were recorded at a constant temperature of 28 °C on a Varian INOVA 400 spectrometer (operating at 400.5 MHz and equipped with a 5 mm 1 1H{ 15 15N- 31 31P} z-axis PFG Indirect Detection probe) and a Varian INOVA 500 spectrometer (operating at 499.7 MHz and equipped with a 5 mm 1 1H{ 13 13C- 15 15N} triple resonance Indirect Detection probe). Chemical shifts were referenced to the non-deuterated residual solvent signal (DMSO-d6: 1 2.50 ppm for 1H). The data are reported as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qt = quintet, br.s = broad singlet, dd = doublet of doublets, ddd = doublet of doublets of doublets, m = multiplet), coupling constant (J, Hz), and proton number.

Example

[0137] Example Step 1 5-((E)-3-dimethylaminoacryloyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(IV), R2=methyl, R9=ethyl]

[0138] [ka]

[0139] 5-acetyl-2-methyl-2H-pyrazole-3-carboxylate ethyl ester (2 g, 10.19 mmol, 1 eq.) was added to N,N-dimethylformamide diethyl acetal (10.48 mL, 61.2 mmol, 6 eq.) in a CEM reactor. The mixture was stirred in a CEM explorer microwave (registered trademark) at 140°C for 3 hours. Volatile substances were removed under reduced pressure, the solid was rinsed with hexane, and filtered to obtain 2.45 g of the title compound as a dark yellow powder in 95% yield. LC / MS (254nm) HPLC LCT-formic acid Rt 6.73 min 1 H NMR (500MHz, DMSO-d6) δppm 7.72(d, J=12.5Hz, 1H), 7.12(s, 1H), 5.83(d, J=12.7Hz, 1H), 4.30(q, J=7 .1Hz, 2H), 4.13(s, 3H), 3.14(s, 3H), 2.87(s, 3H), 1.31(t, J=7.1Hz, 3H). HRMS(ESI) C12H18N3O3[M+H] + The calculated value for this is 252.1343, and the measured value is 252.1342.

[0140] The following compounds were prepared using the same method, except that appropriate substituted derivatives were used: 5-((Z)-3-dimethylaminoacryloyl)-2H-pyrazole-3-carboxylate ethyl ester [(IV), R2=H, R9=ethyl].

[0141] 5-((Z)-3-dimethylaminoacryloyl)-2-ethyl-2H-pyrazole-3-carboxylate ethyl ester [(IV), R2=ethyl, R9=ethyl].

[0142] Stages 2 and 3 5-(2-aminopyrimidine-4-yl)-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VII), R2=methyl, R9=ethyl]

[0143] [ka]

[0144] 5-((E)-3-dimethylamino-acryloyl)-2-methyl-2H-pyrazole-3-carboxylate ethyl ester (7.75 g, 30.84 mmol, 1 eq.) and guanidine carbonate (8.34 g, 46.26 mmol, 1.5 eq.) were loaded into a CEM microwave reactor (in six batches) and suspended in ethanol (100 mL, 0.3 M). The mixture was stirred in a CEM explorer microwave at 150 °C for 2 hours. The six batches were collected and dried. The residue was suspended in water (50 mL) and treated with HCl 1N at 0 °C until pH=2. The suspension was stirred at 0 °C for 1 hour, then filtered, the solid was washed with water, and dried. 7.6 g of the crude material (title compound and its corresponding acid) was dissolved in ethanol (115 mL), and 96% sulfuric acid (21 mL, 378 mmol, 12 eq.) was added. The mixture was heated under reflux temperature for 7 hours, and half of the volatile substances were removed under reduced pressure. The mixture was then diluted with water (200 mL) and ethyl acetate (100 mL). While stirring, the pH was adjusted to 9 with concentrated NaOH, the layers were separated, and the aqueous phase was extracted with AcOEt (3 × 50 mL). The organic layers were combined and washed with brine, then dehydrated with sodium sulfate, and after removing the solvent, a solid was obtained. The solid was ground with diisopropyl ether to obtain the title compound as a pale yellow solid (6.38 g, 58%). LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 4.43 min 1 H NMR (500MHz, DMSO-d6) δppm 8.28(d, J=5.2Hz, 1H), 7.32(s, 1H), 7.06(d, J=5.2Hz, 1H), 6.67(s, 2H), 4.32(q, J=7.1Hz, 2H), 4.19-4.12(m, 3H), 1.33(t, J=7.1Hz, 3H); HRMS(ESI) C11H14N5O2[M+H] + The calculated value for this is 248.1142, and the measured value is 248.1139.

[0145] The following compounds were prepared according to the same method, except that appropriate derivatives and appropriate guanidine derivatives were used: 5-(2-aminopyrimidine-4-yl)-2H-pyrazole-3-carboxylate ethyl ester [(VII), R2=H, R9=ethyl].

[0146] 5-(2-aminopyrimidine-4-yl)-2-ethyl-2H-pyrazole-3-carboxylate ethyl ester [(VII), R2=ethyl, R9=ethyl].

[0147] 5-[2-(3,5-dimethylphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3,5-dimethylphenyl, R2=methyl, R9=ethyl]

[0148] [ka] LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 7.56 min 1H NMR (500MHz, DMSO-d6) δppm 9.52(s, 1H), 8.52(d, J=5.1Hz, 1H), 7.49(s, 2H), 7.44(s, 1H), 7.28(d, J=5.1Hz, 1H), 6.62(s, 1H), 4.34(q, J=7.1Hz, 2H), 4.19(s, 3H), 2.27(s, 6H), 1.34(t, J=7.1Hz, 3H); HRMS(ESI) C19H22N5O2[M+H] + The calculated value for this is 352.1768, and the measured value is 352.1765.

[0149] 5-[2-(1,5-dimethyl-1H-pyrazole-3-ylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=1,5-dimethyl-1H-pyrazole-3-yl, R2=methyl, R9=ethyl]

[0150] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 9.60 min 1 H NMR (500MHz, DMSO-d6) δppm 10.17(s, 1H), 8.45(d, J=5.0Hz, 1H), 7.39(s, 1H), 7.24(d, J=5.0Hz, 1H), 6.47(s, 1H) , 4.34(q, J=7.0Hz, 2H), 4.18(s, 3H), 3.67(s, 3H), 2.23(s, 3H), 1.34(t, J=7.2Hz, 3H); HRMS(ESI) C16H20N7O2[M+H] + The calculated value for this is 342.1673, and the measured value is 342.1674.

[0151] 2-methyl-5-[2-(1-methyl-1H-pyrazole-4-ylamino)-pyrimidine-4-yl]-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=1-methyl-1H-pyrazole-4-yl, R2=methyl, R9=ethyl]

[0152] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 9.18 min 1 H NMR (500MHz, DMSO-d6) δppm 9.52(s, 1H), 8.46(d, J=5.0Hz, 1H), 7.90(s, 1H), 7.55(br. HRMS(ESI) C15H18N7O2[M+H] + The calculated value for this is 328.1517, and the measured value is 328.1517.

[0153] 2-methyl-5-[2-(tetrahydropyran-4-ylamino)pyrimidine-4-yl]-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=tetrahydropyran-4-yl, R2=methyl, R9=ethyl]

[0154] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 8.79 min 1 H NMR (500MHz, DMSO-d6) δppm 8.32(d, J=5.0Hz, 1H), 7.34(s, 1H), 7.21(d, J=7.8Hz, 1H), 7.05(d, J=5.0Hz, 1H), 4.36-4.33(m, 2H), 4.16(s, 3H), 3.98(br. HRMS(ESI) C16H22N5O3[M+H] + The calculated value for this is 332.1717, and the measured value is 332.1713.

[0155] 5-[2-(3,5-dimethoxyphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3,5-dimethoxyphenyl, R2=methyl, R9=ethyl]

[0156] [ka] LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 6.84 min 1 H NMR (500MHz, DMSO-d6) δppm 9.67(s, 1H), 8.54(d, J=5.0Hz, 1H), 7.49-7.45(m, 1H), 7.32(d, J=5.2Hz, 1H), 7.20(d, J=2.3Hz, 2 H), 6.14(t, J=2.2Hz, 1H), 4.33(q, J=7.2Hz, 2H), 4.19(s, 3H), 3.76(s, 6H), 1.34(t, J=7.1Hz, 3H); HRMS(ESI) C19H22N5O4[M+H] + The calculated value for this is 384.1667, and the measured value is 384.1666.

[0157] 5-[2-(3,5-dimethylphenylamino)-pyrimidine-4-yl]-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3,5-dimethylphenyl, R2=H, R9=ethyl]

[0158] [ka] LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 6.6 min 1H NMR (500MHz, DMSO-d6) δppm 14.45(br. s., 1H), 9.52(s, 1H), 8.54(br. s., 1H), 7.47(br. HRMS(ESI) C18H20N5O2[M+H] + The calculated value for this is 338.1612, and the measured value is 338.1607.

[0159] Alternatively, the reaction with the substituted guanidine could be carried out to directly obtain the corresponding carboxylic acid or its salt.

[0160] 5-[2-(3,5-dimethoxyphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=3,5-dimethoxyphenyl, R2=methyl]

[0161] [ka]

[0162] A suspension of 5-((E)-3-dimethylaminoacryloyl)-2-methyl-2H-pyrazole-3-carboxylate ethyl ester (3.64 g, 14.4 mmol), N-(3,5-dimethoxyphenyl)-guanidine hydrochloride (4.0 g, 17.3 mmol, 1.2 eq), and potassium carbonate (3.6 g, 25.9 mmol, 1.8 eq) in n-butanol (70 mL) was stirred at 113 °C (internal temperature) for 24 hours, after which HPLC / MS check indicated that the conversion was complete. The reaction mixture was cooled to room temperature and diluted with 70 mL of water and 25 mL of AcOEt, and stirred until the suspended solid was completely dissolved. The phases were separated, and the organic layer was extracted three times with 30 mL of water. The aqueous phases were combined and the pH was adjusted to an acidic pH (approximately 3-4) with 2N HCl (16 mL) while stirring. The resulting suspension is stirred for 10 minutes, then filtered through a sintered glass Buchner funnel (porosity 4 (very slow filtration)). The cake is washed twice with 5 mL of water on the filter media, then twice with 10 mL of MTBE. The solid is collected and dried in an oven under reduced pressure (20-30 mm Hg) at 45-50°C until constant weight is obtained, yielding 3.23 g of the desired product as a beige solid. Yield: 63%. LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 4.13 min 1 H NMR (500MHz, DMSO-d6) δppm 9.67(s, 1H), 8.56(d, J=5.0Hz, 1H), 7.43(s, 1H), 7.35(d, J=5.0Hz, 1H), 7. 22(d, J=2.3Hz, 2H), 6.17(t, J=2.3Hz, 1H), 4.21(s, 3H), 3.81-3.76(m, 6H); HRMS(ESI) C17H18N5O4[M+H] + The calculated value for this is 356.1354, and the measured value is 356.1366.

[0163] Stage 4 5-[2-(3,5-dimethylphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3,5-dimethylphenyl, R2=methyl, R9=ethyl]

[0164] [ka]

[0165] 5-(2-aminopyrimidine-4-yl)-2-methyl-2H-pyrazole-3-carboxylate ethyl ester (200 mg, 0.81 mmol, 1 eq.), 3,5-dimethyliodobenzene (175 μL, 1.21 mmol, 1.5 eq.), and cesium carbonate (527 mg, 1.62 mmol, 2 eq.) were suspended in pre-degassed dioxane (8 mL), and three cycles (vacuum / argon) were performed. XPhos (85 mg, 0.18 mmol, 0.22 eq.) and Tris(dibenzylideneacetone)dipalladium(0) (74 mg, 0.08 mmol, 0.1 eq.) were added under an argon atmosphere, and three cycles (vacuum / argon) were performed. The mixture was heated at 100°C for 6 hours, then cooled to room temperature, diluted with water, extracted three times with AcOEt, the organic phase was collected, washed with brine, and volatile substances were removed under reduced pressure. The crude solid was purified by silica gel flash chromatography (eluent: DCM:EtOH 99 / 1) to obtain 160 mg (56% yield) of the title compound. LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 7.56 min 1 H NMR (500MHz, DMSO-d6) δppm 9.52(s, 1H), 8.52(d, J=5.1Hz, 1H), 7.49(s, 2H), 7.44(s, 1H), 7.28(d, J=5.1Hz, 1H), 6.62(s, 1H), 4.34(q, J=7.1Hz, 2H), 4.19(s, 3H), 2.27(s, 6H), 1.34(t, J=7.1Hz, 3H); HRMS(ESI) C19H22N5O2[M+H] +The calculated value for this is 352.1768, and the measured value is 352.1765.

[0166] The following compounds were prepared using the same method, except that appropriate substituted derivatives were used: 5-[2-(3,5-dichlorophenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3,5-dichlorophenyl, R2=methyl, R9=ethyl] 28% yield

[0167] [ka] LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 8.21 min 1 H NMR (500MHz, DMSO-d6) δppm 10.16(s, 1H), 8.62(d, J=5.2Hz, 1H), 8.01(d, J=1.8Hz, 2H), 7.47(s, 1H), 7.42(d, J=5.2H) z, 1H), 7.14(t, J=1.9Hz, 1H), 4.33(q, J=7.2Hz, 2H), 4.20(s, 3H), 1.33(t, J=7.1Hz, 3H); HRMS(ESI) C17H16Cl2N5O2[M+H] + The calculated value for this is 392.0676, and the measured value is 392.0675.

[0168] 5-[2-(3,5-dimethylphenylamino)-pyrimidine-4-yl]-2-ethyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3,5-dimethylphenyl, R2=ethyl, R9=ethyl]

[0169] [ka] LC / MS (254nm) HPLC (IP) method: LCQ Deca XP-acetate buffer, Rt 7.18 min 1H NMR (500MHz, DMSO-d6) δppm 9.51(s, 1H), 8.55(d, J=5.2Hz, 1H), 7.48(s, 1H), 7.30(d, J=5.2Hz, 1H), 7.28(s, 2H), 6.67(s, 1H), 4. 80(q, J=7.1Hz, 2H), 4.30(q, J=7.1Hz, 2H), 2.25(s, 6H), 1.31(t, J=7.0Hz, 3H), 1.28(t, J=7.2Hz, 3H); HRMS(ESI) C20H24N5O2[M+H] + The calculated value for this is 366.1925, and the measured value is 366.1921.

[0170] 2-methyl-5-(2-m-tolylaminopyrimidine-4-yl)-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=2-m-tolyl, R2=methyl, R9=ethyl]

[0171] [ka] LC / MS (254nm) HPLC (IP) method: LCQ Deca XP-acetate buffer, Rt 7.18 min 1 H NMR (500MHz, DMSO-d6) δppm 9.62(s, 1H), 8.52(d, J=5.0Hz, 1H), 7.74(s, 1H), 7.56(d, J=8.2Hz, 1H), 7.44(s, 1H), 7.30(d, J=5.0Hz, 1H), 7.18 (t, J=7.9Hz, 1H), 6.79(d, J=7.3Hz, 1H), 4.34(q, J=7.0Hz, 2H), 4.19(s, 3H), 2.31(s, 3H), 1.34(t, J=7.1Hz, 3H); HRMS(ESI) C18H20N5O2[M+H] + The calculated value for this is 338.1612, and the measured value is 338.1615.

[0172] 5-[2-(3,5-difluorophenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3,5-difluorophenyl, R2=methyl, R9=ethyl]

[0173] [ka] LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 7.37 min 1 H NMR (500MHz, DMSO-d6) δppm 10.17(s, 1H), 8.61(d, J=5.2Hz, 1H), 7.67-7.58(m, 2H), 7.45(s, 1H), 7.42(d, J=5.2Hz, 1H) ), 6.76(tt, J=2.3, 9.2Hz, 1H), 4.34(q, J=7.0Hz, 2H), 4.20(s, 3H), 1.34(t, J=7.1Hz, 3H); HRMS(ESI) C17H16F2N5O2[M+H] + The calculated value for this is 360.1267, and the measured value is 360.1274.

[0174] 5-{2-[3-chloro-4-(4-methylpiperazine-1-yl)-phenylamino]pyrimidine-4-yl}2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3-chloro-4-(4-methylpiperazine-1-yl)-phenyl, R2=methyl, R9=ethyl]

[0175] [ka] LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 5.80 min 1H NMR (500MHz, DMSO-d6) δppm 9.76 (s, 1H), 8.53 (d, J=5.0Hz, 1H), 8.16 (br. s., 1H), 7.59(dd, J=2.5, 8.8Hz, 1H), 7.45(s, 1H), 7.31(d, J=5.0Hz, 1H), 7.13(d, J=8.8Hz, 1H), 4.34(q, J=7.2Hz, 2H), 4.19(s, 3H), 2.93(br. HRMS(ESI) C22H27ClN7O2[M+H] + The calculated value for this is 456.1910, and the measured value is 456.1901.

[0176] 5-[2-(3-cyanophenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3-cyanophenyl, R2=methyl, R9=ethyl]

[0177] [ka] LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 6.73 min 1 H NMR (500MHz, DMSO-d6) δppm 10.12(s, 1H), 8.61(d, J=5.2Hz, 1H), 8.49(t, J=1.7Hz, 1H), 7.98(ddd, J=0.8, 2.3, 8.4Hz, 1H), 7.52(t, J=7.9Hz, 1H), 7.46( s, 1H), 7.41(d, J=5.0Hz, 1H), 7.41(ddd, J=0.9, 1.4, 7.5Hz, 1H), 4.34(q, J=7.1Hz, 2H), 4.20(s, 3H), 1.34(t, J=7.2Hz, 3H); HRMS(ESI) C18H17N6O2[M+H] + The calculated value for this is 349.1408, and the measured value is 349.1416.

[0178] 5-[2-(3,5-dimethoxyphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3,5-dimethoxyphenyl, R2=methyl, R9=ethyl]

[0179] [ka] LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 6.84 min 1 H NMR (500MHz, DMSO-d6) δppm 9.67(s, 1H), 8.54(d, J=5.0Hz, 1H), 7.49-7.45(m, 1H), 7.32(d, J=5.2Hz, 1H), 7.20(d, J=2.3Hz, 2 H), 6.14(t, J=2.2Hz, 1H), 4.33(q, J=7.2Hz, 2H), 4.19(s, 3H), 3.76(s, 6H), 1.34(t, J=7.1Hz, 3H); HRMS(ESI) C19H22N5O4[M+H] + The calculated value for this is 384.1667, and the measured value is 384.1666.

[0180] 5-[2-(3-methoxyphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3-methoxyphenyl, R2=methyl, R9=ethyl]

[0181] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 11.81 min 1H NMR (500MHz, DMSO-d6) δppm 9.70(s, 1H), 8.54(d, J=5.0Hz, 1H), 7.75(br. s., 1H), 7.46(s, 1H), 7.32(d, J=5.0Hz, 1H), 7.27(dd, J=0.8, 8.2Hz, 1H), 7.21-7.15(m, 1H) , 6.57-6.52(m, 1H), 4.34(q, J=7.1Hz, 2H), 4.19(s, 3H), 3.79(s, 3H), 1.34(t, J=7.1Hz, 3H); HRMS(ESI) C18H20N5O3[M+H] + The calculated value for this is 354.1561, and the measured value is 354.1564.

[0182] 2-methyl-5-[2-(3,4,5-trimethoxyphenylamino)-pyrimidine-4-yl]-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3,4,5-trimethoxyphenyl, R2=methyl, R9=ethyl]

[0183] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 11.04 min 1 H NMR (500MHz, DMSO-d6) δppm 9.59(s, 1H), 8.53(d, J=5.0Hz, 1H), 7.49-7.48(m, 1H), 7.34(s, 2H), 7.30(d, J=5.0Hz, 1 H), 4.33(q, J=7.1Hz, 2H), 4.18(s, 3H), 3.82(s, 6H), 3.63(s, 3H), 1.34(t, J=7.1Hz, 3H); HRMS(ESI) C20H24N5O5[M+H] + The calculated value for this is 414.1772, and the measured value is 414.1772.

[0184] 5-[2-(3-fluoro-5-methoxyphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3-fluoro-5-methoxyphenyl, R2=methyl, R9=ethyl]

[0185] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 12.60 min 1 H NMR (500MHz, DMSO-d6) δppm 9.91(s, 1H), 8.58(d, J=5.2Hz, 1H), 7.47-7.42(m, 2H), 7.37(d, J=5.0Hz, 1H), 7.36-7.31(m, 1H), 6. 41(td, J=2.2, 10.8Hz, 1H), 4.34(q, J=7.0Hz, 2H), 4.20(s, 3H), 3.79(s, 3H), 1.34(t, J=7.1Hz, 3H); HRMS(ESI) C18H19FN5O3[M+H] + The calculated value for this is 372.1467, and the measured value is 372.1465.

[0186] 5-[2-(3-cyano-5-methoxyphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3-cyano-5-methoxyphenyl, R2=methyl, R9=ethyl] 87% yield

[0187] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 12.08 min 1 H NMR (500MHz, DMSO-d6) δppm 10.09(s, 1H), 8.61(d, J=5.2Hz, 1H), 7.93-7.90(m, 1H), 7.88(t, J=1.9Hz, 1H), 7.46(s, 1H), 7.41(d, J=5.2H) z, 1H), 7.02(dd, J=1.4, 2.3Hz, 1H), 4.33(q, J=7.2Hz, 2H), 4.20(s, 3H), 3.84(s, 3H), 1.34(t, J=7.1Hz, 3H); HRMS(ESI) C19H19N6O3[M+H] + The calculated value for this is 379.1513, and the measured value is 379.1514.

[0188] 5-[2-(5-methoxypyridine-3-ylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=5-methoxypyridine-3-yl, R2=methyl, R9=ethyl] 37% yield

[0189] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 8.62 min 1 H NMR (500MHz, DMSO-d6) δppm 9.97(s, 1H), 8.59(d, J=5.0Hz, 1H), 8.50(d, J=2.0Hz, 1H), 8.19(br. s., 1H), 7.91(d, J=2.6Hz, 1H), 7.46(s, 1H), 7.39(d, J=5.0Hz, 1H), 4.34(q, J=7.1Hz, 2H), 4.19(s, 3H), 3.88(s, 3H), 1.34(t, J=7.1Hz, 3H); HRMS(ESI) C17H19N6O3[M+H] + The calculated value for this is 355.1513, and the measured value is 355.1518.

[0190] 5-[2-(3,5-bis-trifluoromethyl-phenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3,5-bis-trifluoromethyl-phenyl, R2=methyl, R9=ethyl]

[0191] [ka]

[0192] 5-[2-(3-methoxy-5-trifluoromethylphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3-methoxy-5-trifluoromethylphenyl, R2=methyl, R9=ethyl]

[0193] [ka]

[0194] 5-[2-(4,6-dimethylpyridine-2-ylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=4,6-dimethylpyridine-2-yl, R2=methyl, R9=ethyl]

[0195] [ka]

[0196] 2-methyl-5-[2-(3-trifluoromethylphenylamino)-pyrimidine-4-yl]-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3-trifluoromethylphenyl, R2=methyl, R9=ethyl]

[0197] [ka]

[0198] 5-[2-(benzo[1,3]dioxol-5-ylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=benzo[1,3]dioxol-5-ylamino)-pyrimidine-4-yl, R2=methyl, R9=ethyl]

[0199] [ka]

[0200] 5-[2-(3,4-dimethoxyphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester [(VI), R1=3,4-dimethoxyphenylamino)-pyrimidine-4-yl, R2=methyl, R9=ethyl]

[0201] [ka]

[0202] Stage 5 Ethyl 3-(2-iodopyrimidine-4-yl)-1-methyl-1H-pyrazole-5-carboxylate [(IX), R2=methyl, R9=ethyl]

[0203] [ka]

[0204] 5-(2-aminopyrimidine-4-yl)-2-methyl-2H-pyrazole-3-carboxylate ethyl ester (450 mg, 1.82 mmol, 1 eq.) was dissolved in degassed dried dioxane (11 mL). CuI (156 mg, 0.82 mmol, 0.45 eq.), CsI (708 mg, 2.73 mmol, 1.5 eq.), iodine (323 mg, 1.28 mmol, 0.7 eq.), and isoamyl nitrite (535 μL, 4.01 mmol, 2.2 eq.) were added to the solution. The reaction mixture was heated at T=90°C for 2 hours, then cooled to room temperature, diluted with water, and extracted three times with AcOEt. The organic phase was collected and washed with 10% ammonia solution, 5% aqueous Na2S2O5 solution, and brine. The organic layer was dehydrated with anhydrous Na2SO4 and evaporated dry. The crude product was purified by silica gel flash chromatography (eluent: hexane / AcOEt 8 / 2) to obtain 230 mg (35% yield) of the title compound. LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 6.43 min 1 H NMR (500 MHz, DMSO-d6) δppm 1.34(t, J=7.1Hz, 3H)4.19(s, 3H)4.34(q, J=7.1Hz, 2H)7.44(s, 1H)7.98(d, J=5.2Hz, 1H)8.57(d, J=5.2Hz, 1H); HRMS(ESI) C11H11IN4O2[M+H]+ The calculated value for this is 359, and the measured value is 359.0013.

[0205] Stage 6 Ethyl 1-methyl-3-{2-[(1,2,3-trimethyl-1H-indole-5-yl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxylate[(VI), R1=1,2,3-trimethyl-1H-indole-5-yl, R2=methyl, R9=ethyl]

[0206] [ka]

[0207] Ethyl 3-(2-iodopyrimidine-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (86 mg, 0.24 mmol, 1 eq.), 1,2,3-trimethyl-1H-indole-5-amine (42 mg, 0.24 mmol, 1 eq.), and K2CO3 (99.5 mg, 0.72 mmol, 3 eq.) were suspended in pre-degassed dioxane (4 mL), and three cycles (vacuum / argon) were performed. Xantphos (27.8 mg, 0.048 mmol, 0.2 eq.) and Pd(OAc)2 (5.4 mg, 0.024 mmol, 0.1 eq.) were added under an argon atmosphere, and three cycles (vacuum / argon) were performed. The mixture was heated at 100°C for 3 hours, then cooled to room temperature, diluted with water, extracted three times with AcOEt, the organic phase was collected, washed with brine, and volatile substances were removed under reduced pressure. The crude solid was purified by silica gel flash chromatography (eluent: DCM / AcOEt 9 / 1) to obtain 10 mg (10% yield) of the title compound. LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 7.38 min 1H NMR (500 MHz, DMSO-d6) δppm 1.35(t, J=7.1Hz, 3H)2.23(s, 3H)2.33(s, 3H)3.62(s, 3H)4.20(s, 3H)4.35(q, J=7.1Hz, 2H) 7.21(dd, J=8.5, 1.5Hz, 1H)7.22(d, J=5.0Hz, 1H)7.25(d, J=8.7Hz, 1H)7.48(s, 1H)8.25(br. s., 1H)8.47(d, J=5.0Hz, 1H)9.44(s, 1H); HRMS(ESI) C22H24N6O2[M+H] + The calculated value for this is 405.2034, and the measured value is 405.2033.

[0208] Ethyl 3-{2-[(3-chloro-1-methyl-1H-indole-5-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxylate[(VI), R1=3-chloro-1-methyl-1H-indole-5-yl, R2=methyl, R9=ethyl]

[0209] [ka]

[0210] Ethyl 3-(2-iodopyrimidine-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (140 mg, 0.39 mmol, 1 eq.), 3-chloro-1-methyl-1H-indole-5-amine (84.5 mg, 0.47 mmol, 1.2 eq.), and cesium carbonate (381 mg, 1.17 mmol, 3 eq.) were suspended in pre-degassed dioxane (8 mL), and three cycles (vacuum / argon) were performed. XPhos (74.5 mg, 0.156 mmol, 0.4 eq.) and Tris(dibenzylideneacetone)dipalladium(0) (71.6 mg, 0.078 mmol, 0.2 eq.) were added under an argon atmosphere, and three cycles (vacuum / argon) were performed. The mixture was heated at 100°C for 7 hours, then cooled to room temperature, diluted with water, extracted three times with AcOEt, the organic phase was collected, washed with brine, and volatile substances were removed under reduced pressure. The crude solid was purified by silica gel flash chromatography (eluent: DCM / AcOEt 95 / 5) to obtain 24 mg (15% yield) of the title compound. LC / MS (254nm) HPLC (IP) method: LCQ Deca XP-acetate buffer, Rt 7.22 min 1 H NMR (500 MHz, DMSO-d6) δppm 1.35(t, J=7.1Hz, 3H)3.76(s, 3H)4.21(s, 3H)4.34(q, J=7.2Hz, 2H)7.29(d, J=5.0Hz, 1H)7.37(d d, J=8.9, 1.5Hz, 1H)7.43(d, J=8.8Hz, 1H)7.48(s, 1H)7.58(s, 1H)8.53(d, J=4.9Hz, 1H)8.59(br. s., 1H)9.70(s, 1H); HRMS(ESI) C20H19ClN6O2[M+H] + The calculated value for this is 411.1331, and the measured value is 411.1340.

[0211] Stage 7 2-methyl-5-(2-m-tolylaminopyrimidine-4-yl)-2H-pyrazole-3-carboxylic acid [(XI), R1=2-m-tolyl, R2=methyl] 100% yield

[0212] [ka]

[0213] 10.5 mL of 2N sodium hydroxide was added to a solution of 2-methyl-5-(2-m-tolylaminopyrimidine-4-yl)-2H-pyrazole-3-carboxylate ethyl ester (260 mg, 0.77 mmol, 1 eq.) dissolved in ethanol (21 mL), and the mixture was stirred at room temperature for 4 hours. 2N HCl was added to adjust the pH to < 5, the precipitate was filtered, washed with water and Et2O, and dried under reduced pressure to obtain the title compound in quantitative yield. LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 4.26 min 1 H NMR (500MHz, DMSO-d6) δppm 9.60(s, 1H), 8.51(d, J=5.0Hz, 1H), 7.69(s, 1H), 7.61(d, J=7.9Hz, 1H), 7.38(s, 1H), 7.29 (d, J=5.2Hz, 1H), 7.18(t, J=7.8Hz, 1H), 6.78(d, J=7.5Hz, 1H), 4.18(s, 3H), 2.30(s, 3H); HRMS(ESI) C16H16N5O2[M+H] + The calculated value for this is 310.1299, and the measured value is 310.1302.

[0214] The following compounds were prepared using the same method, except that appropriate substituted derivatives were used: 5-[2-(3,5-difluorophenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1=3,5-difluorophenyl, R2=methyl] Quantitative yield

[0215] [ka] LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 4.51 min 1 H NMR (500MHz, DMSO-d6) δppm 10.16(s, 1H), 8.60(d, J=5.2Hz, 1H), 7.68-7.58(m, 2H), 7.42(d, J=5.2Hz, 1H), 7.38(s, 1H), 6.76(tt, J=2.2, 9.3Hz, 1H), 4.19(s, 3H); HRMS(ESI) C15H12F2N5O2[M+H] + The calculated value for this is 332.0954, and the measured value is 332.0956.

[0216] 5-{2-[3-chloro-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidine-4-yl}-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=3-chloro-4-(4-methyl-piperazin-1-yl)-phenyl, R2=methyl] Quantitative yield

[0217] [ka] LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 3.57 min 1 H NMR (500MHz, DMSO-d6) δppm 11.99(s, 1H), 9.69(s, 1H), 8.48(d, J=5.2Hz, 1H), 8.03(d, J=2.4Hz, 1H), 7.72(dd, J=2.1, 8 .7Hz, 1H), 7.29(d, J=5.2Hz, 1H), 7.19(s, 1H), 7.15(d, J=8.8Hz, 1H), 4.17(s, 3H), 2.98(br. s., 4H), 2.35(br. s., 3H); HRMS(ESI) C20H23ClN7O2[M+H] + The calculated value for this is 428.1597, and the measured value is 428.1607.

[0218] 5-[2-(3-chloro-1-methyl-1H-indole-5-ylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1=3-chloro-1-methyl-1H-indole-5-yl, R2=methyl] 93% yield

[0219] [ka] LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 4.53 min 1 H NMR (500MHz, DMSO-d6) δppm 13.60(br. s., 1H), 9.64(br. s., 1H), 8.50(br. s., 1H), 8.41(br. s., 1H), 7.56-7.33(m, 4H), 7.26(br. s., 1H), 4.19(s, 3H), 3.76(s, 3H); HRMS(ESI) C18H16ClN6O2[M+H] + The calculated value for this is 383.1018, and the measured value is 383.1006.

[0220] 1-Methyl-3-{2-[(1,2,3-trimethyl-1H-indole-5-yl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxylic acid[(XI), R1=1,2,3-trimethyl-1H-indole-5-yl, R2=methyl]

[0221] [ka]

[0222] Alternatively, the acid or its salt could be prepared as reported below.

[0223] 5-[2-(3,5-dimethylphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=3,5-dimethylphenyl, R2=methyl]

[0224] [ka]

[0225] 5-[2-(3,5-dimethylphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylate ethyl ester (160 mg, 0.455 mmol, 1 eq.) was dissolved in THF (2 mL). To this solution, lithium hydroxide monohydrate (47.8 mg, 1.138 mmol, 2.5 eq.) dissolved in water (2 mL) and ethanol (1 mL) were added sequentially. The mixture was stirred at room temperature for 16 hours, and then treated with HCl 1N until the pH became 3. Organic matter was removed under reduced pressure, the precipitate was filtered, and rinsed with water and Et2O to obtain 132 mg (90% yield) of the title compound. This was used without further purification. LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 4.55 min 1 H NMR (500MHz, DMSO-d6) δppm 13.66(br. s, 1H), 9.55(s, 1H), 8.51(d, J=5.0Hz, 1H), 7.48(br. s, 2H), 7.38(s, 1H), 7.28(d, J=5.0Hz, 1H), 6.62(br. s, 1H), 4.18(s, 3H), 2.26(s, 6H); HRMS(ESI) C17H18N5O2[M+H] + The calculated value for this is 324.1455, and the measured value is 324.1454.

[0226] The following compounds were prepared using the same method, except that appropriate substituted derivatives were used: 5-[2-(3-methoxyphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=3-methoxyphenyl, R2=methyl] 94% yield

[0227] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 9.53 min 1 H NMR (500MHz, DMSO-d6) δppm 9.68(s, 1H), 8.53(d, J=5.2Hz, 1H), 7.68(s, 1H), 7.40(s, 1H), 7.31(d, J=5.2Hz , 2H), 7.21-7.17(m, 1H), 6.54(dd, J=2.2, 7.9Hz, 1H), 4.18(s, 3H), 3.77(s, 3H); HRMS(ESI) C16H16N5O3[M+H] + The calculated value for this is 326.1248, and the measured value is 326.1248.

[0228] 5-[2-(3,5-dimethoxyphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=3,5-dimethoxyphenyl, R2=methyl] 92% yield

[0229] [ka] LC / MS (254nm) HPLC method (IP): LCQ Deca XP-acetate buffer, Rt 4.13 min 1 H NMR (500MHz, DMSO-d6) δppm 9.67(s, 1H), 8.56(d, J=5.0Hz, 1H), 7.43(s, 1H), 7.35(d, J=5.0Hz, 1H), 7. 22(d, J=2.3Hz, 2H), 6.17(t, J=2.3Hz, 1H), 4.21(s, 3H), 3.81-3.76(m, 6H); HRMS(ESI) C17H18N5O4[M+H] + The calculated value for this is 356.1354, and the measured value is 356.1366.

[0230] 2-Methyl-5-[2-(3,4,5-trimethoxyphenylamino)-pyrimidine-4-yl]-2H-pyrazole-3-carboxylic acid [(XI), R1=3,4,5-trimethoxyphenyl, R2=methyl] 80% yield

[0231] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 9.02 min 1 H NMR (500MHz, DMSO-d6) δppm HRMS(ESI) C18H20N5O5[M+H] + The calculated value for this is 386.1459, and the measured value is 386.1471.

[0232] 5-[2-(3-fluoro-5-methoxyphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=3-fluoro-5-methoxyphenyl, R2=methyl] 99% yield

[0233] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 10.53 min 1 H NMR (500MHz, DMSO-d6) δppm 13.71(br. HRMS(ESI) C16H15FN5O3[M+H] + The calculated value for this is 344.1154, and the measured value is 344.1140.

[0234] 2-methyl-5-[2-(1-methyl-1H-pyrazole-4-ylamino)-pyrimidine-4-yl]-2H-pyrazole-3-carboxylic acid[(XI), R1=1-methyl-1H-pyrazole-4-yl, R2=methyl] 72% yield

[0235] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 5.87 min 1 H NMR (500MHz, DMSO-d6) δppm 13.60(br. s., 1H), 9.51(s, 1H), 8.45(d, J=5.0Hz, 1H), 7.90(s, 1H), 7.66-7.53(m, 1H), 7.37(br. HRMS(ESI) C13H14N7O2[M+H] + The calculated value for this is 300.1204, and the measured value is 300.1203.

[0236] 2-methyl-5-[2-(3-trifluoromethylphenylamino)-pyrimidine-4-yl]-2H-pyrazole-3-carboxylic acid[(XI), R1=3-trifluoromethylphenyl, R2=methyl]

[0237] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 11.49 min 1 H NMR (500MHz, DMSO-d6) δppm 9.96(s, 1H), 8.49(d, J=5.2Hz, 1H), 8.44(s, 1H), 8.04(d, J=9.0Hz, 1H), 7.53(t, J= 7.9Hz, 1H), 7.32(d, J=5.2Hz, 1H), 7.26(d, J=7.6Hz, 1H), 7.00(s, 1H), 4.16(s, 3H); HRMS(ESI) C16H13F3N5O2[M+H] + The calculated value for this is 364.1016, and the measured value is 364.1007.

[0238] 5-[2-(3-cyano-5-methoxyphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=3-cyano-5-methoxyphenyl, R2=methyl] 96% yield

[0239] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 10.05 min 1 H NMR (500MHz, DMSO-d6) δppm HRMS(ESI) C17H15N6O3[M+H] + The calculated value for this is 351.1200, and the measured value is 351.1201.

[0240] 5-[2-(5-methoxypyridine-3-ylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=5-methoxypyridine-3-yl, R2=methyl] 87% yield

[0241] [ka] LC / MS (254nm) HPLC (IP) LCT - Formic Acid Rt 5.40 min 1 H NMR (500MHz, DMSO-d6) δppm HRMS (ESI) C15H15N6O3[M+H] + The calculated value for this is 327.1200, and the measured value is 327.1199.

[0242] 5-[2-(3,5-bis-trifluoromethyl-phenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=3,5-bis-trifluoromethyl-phenyl, R2=methyl]

[0243] [ka]

[0244] 5-[2-(3-methoxy-5-trifluoromethylphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=3-methoxy-5-trifluoromethylphenyl, R2=methyl]

[0245] [ka]

[0246] 5-[2-(4,6-dimethylpyridine-2-ylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=4,6-dimethylpyridine-2-yl, R2=methyl]

[0247] [ka]

[0248] 5-[2-(3,5-dichlorophenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=3,5-dichlorophenyl, R2=methyl]

[0249] [ka]

[0250] 5-[2-(benzo[1,3]dioxol-5-ylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=2-(benzo[1,3]dioxol-5-yl, R2=methyl]

[0251] [ka]

[0252] 5-[2-(1,5-dimethyl-1H-pyrazole-3-ylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=1,5-dimethyl-1H-pyrazole-3-yl, R2=methyl]

[0253] [ka]

[0254] 2-methyl-5-[2-(tetrahydropyran-4-ylamino)-pyrimidine-4-yl]-2H-pyrazole-3-carboxylic acid[(XI), R1=tetrahydropyran-4-yl, R2=methyl]

[0255] [ka]

[0256] 5-[2-(3-cyanophenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=3-cyanophenyl, R2=methyl]

[0257] [ka]

[0258] 5-[2-(3,4-dimethoxyphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid[(XI), R1=3,4-dimethoxyphenyl, R2=methyl]

[0259] [ka]

[0260] 5-[2-(3,5-dimethylphenylamino)-pyrimidine-4-yl]-2-ethyl-2H-pyrazole-3-carboxylic acid[(XI), R1=3,5-dimethylphenyl, R2=ethyl]

[0261] [ka]

[0262] 5-[2-(3,5-dimethylphenylamino)-pyrimidine-4-yl]-2H-pyrazole-3-carboxylic acid[(XI), R1=3,5-dimethylphenyl, R2=H]

[0263] [ka]

[0264] Stage 8 N-[2-(dimethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 1)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=2-(dimethylamino)ethyl, R4=H]

[0265] [ka]

[0266] 5-[2-(3,5-dimethylphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid (25 mg, 0.077 mmol, 1 eq.) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) (37 mg, 0.12 mmol, 1.5 eq.) were suspended in dry DMA (1 mL). After stirring for 5 minutes, N,N-diisopropylethylamine (DIPEA) (27 μL, 0.15 mmol, 2 eq.) and 2-dimethylamine-ethylamine (12.7 μL, 0.12 mmol, 1.5 eq.) were added, and the final mixture was stirred at room temperature for 16 hours. Then, it was diluted with H2O (5 mL) and extracted three times with AcOEt (3 x 4 mL). The organic layer was collected, washed with brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel flash chromatography (eluent DCM / MeOH 9:1) to obtain the title compound in 52% yield. LC / MS (254nm) HPLC (IP) method: LCQ Deca XP-acetate buffer, Rt 5.23 min 1 H NMR (500MHz, DMSO-d6) δppm 9.47(s, 1H), 8.71(t, J=5.1Hz, 1H), 8.49(d, J=5.2Hz, 1H), 7.47(s, 2H), 7.42(s, 1H) ), 7.25(d, J=5.0Hz, 1H), 6.61(s, 1H), 4.14(s, 3H), 3.36(q, J=6.0Hz, 2H), 2.47(br. s, 2H), 2.27(s, 6H), 2.24(br. s., 6H); HRMS(ESI) C21H27N7O[M+H] + The calculated value for this is 394.235, and the measured value is 394.2357.

[0267] The following compounds were prepared by this same method, except that a suitable amine derivative was used, and finally by chlorination or protection.

[0268] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2R)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (Compound 2) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2R)-1-hydroxypropan-2-yl, R4 = H]

[0269]

Chem.

[0270] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (Compound 3) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2S)-1-hydroxypropan-2-yl, R4 = H]

[0271]

Chem.

[0272] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(propan-2-yl)-1H-pyrazole-5-carboxamide (compound 4)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=propan-2-yl, R4=H]

[0273] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.46(s, 1H), 8.59(d, J=7.9Hz, 1H), 8.49(d, J=5.0Hz, 1H), 7.48(s, 2H), 7.46(s, 1H), 7.25(d, J =5.0Hz, 1H), 6.61(s, 1H), 4.13(s, 3H), 4.11-4.01(m, 1H), 2.27(s, 6H), 1.16(d, J=6.6Hz, 6H); HRMS(ESI) C20H24N6O[M+H] + The calculated value for this is 365.2085, and the measured value is 365.2087.

[0274] N-[2-(dimethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (compound 5)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=[2-(dimethylamino)ethyl, R4=methyl]

[0275] [Chem.] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.51 (d, J = 5.6 Hz, 1H), 8.49 (br.s., 1H), 7.47 (s, 2H), 7.26 (br.s., 1H), 7.09 - 6.91 (m, 1H), 6.60 (s, 1H), 4.05 - 3.83 (m, 3H), 3.75 - 3.43 (m, 2H), 3.18 - 2.95 (m, 3H), 2.34 (br.s., 3H), 2.25 (s, 6H), 1.95 (br.s., 3H); HRMS (ESI) C22H29N7O [M + H] + Calculated value for [compound] is 408.2507, measured value is 408.2518.

[0276] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(methylamino)ethyl]-1H-pyrazole-5-carboxamide hydrochloride (Compound 6) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-(methylamino)ethyl, R4 = H]

[0277] [Chem.] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.49 (s, 1H), 9.00 (t, J = 5.6 Hz, 1H), 8.67 (br.s., 2H), 8.50 (d, J = 5.0 Hz, 1H), 7.46 (s, 2H), 7.26 (d, J = 5.2 Hz, 1H), 6.62 (s, 1H), 4.16 (s, 3H), 3.58 - 3.53 (m, 2H), 3.09 (quin, J = 5.9 Hz, 2H), 2.59 (t, J = 5.4 Hz, 3H), 2.31 - 2.22 (m, 6H); HRMS (ESI) C20H26N7OCl [M + H] + Calculated value for [compound] is 380.2194, measured value is 380.2186.

[0278] N-(2-aminoethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 7)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=2-aminoethyl, R4=H]

[0279] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.49(s, 1H), 8.94(t, J=5.7Hz, 1H), 8.50(d, J=5.2Hz, 1H), 7.92(br. s., 3H), 7.48(s, 1H), 7.46(s, 2H), 7.26(d, J=5.2Hz, 1H), 6.62(s, 1H), 4.1 6(s, 3H), 3.50(quin, J=5.8Hz, 2H), 2.98(sxt, J=5.9Hz, 2H), 2.27(s, 6H); HRMS(ESI) C19H24N7OCl[M+H] + The calculated value for this is 366.2037, and the measured value is 366.2033.

[0280] N-(azetidine-3-yl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide trifluoroacetate (compound 8)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=azetidine-3-yl, R4=H]

[0281] [ka] 1H NMR (DMSO-d6, 500MHz): δ ppm 9.47 (s, 1H), 9.41 (d, J=7.0Hz, 1H), 8.68 (br. s., 2H), 8.51(d, J=5.0Hz, 1H), 7.50(s, 1H), 7.46(s, 2H), 7.27(d, J=5.0Hz, 1H), 6.63(s , 1H), 4.82(sxt, J=7.8Hz, 1H), 4.16-4.24(m, 2H), 4.15(s, 3H), 4.01-4.12(m, 2H), 2.28 ppm(s, 6H); HRMS(ESI) C22H24N7O3F3[M+H] + The calculated value for this is 378.2037, and the measured value is 378.2034.

[0282] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-5-carboxamide (compound 9)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=2-morpholine-4-ylethyl), R4=H]

[0283] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.46(s, 1H), 8.72(t, J=5.6Hz, 1H), 8.49(d, J=5.0Hz, 1H), 7.46(s, 2H), 7.41(s, 1H), 7.26(d, J=5.0Hz, 1H ), 6.62(s, 1H), 4.14(s, 3H), 3.57(t, J=4.6Hz, 4H), 3.37(q, J=6.3Hz, 2H), 2.46(t, J=6.7Hz, 2H), 2.41(br. s., 4H), 2.27(s, 6H); HRMS(ESI) value C23H29N7O2[M+H] + The calculated value for this is 436.2456, while the measured value is 436.2447.

[0284] N-[2-(diethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 10)[(I), R1=3,5-dimethylphenyl), R2=methyl, R3=2-(diethylamino)ethyl, R4=H]

[0285] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.46(s, 1H), 8.90(br. t, J=4.5Hz, 1H), 8.50(d, J=5.0Hz, 1H), 7.46(s, 2H), 7.43(s, 1H), 7.26(d, J=5.0Hz, 1H), 6.62(s, 1H), 4.15(s, 3H), 3.51(br. q, J=5.3Hz, 2H), 3.03(br. s., 6H), 2.27(s, 6H), 1.20-1.03(m, 6H); HRMS(ESI) C23H31N7O[M+H] + The calculated value for this is 422.2663, and the measured value is 422.2666.

[0286] N-[(1R,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 11)[(I), R1=3,5-dimethylphenyl), R2=methyl, R3=(1R,2R)-2-aminocyclohexyl, R4=H]

[0287] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.46(s, 1H), 8.80(d, J=8.8Hz, 1H), 8.50(d, J=5.0Hz, 1H), 8.06(br. s., 3H), 7.51(s, 1H), 7.47(s, 2H), 7.26(d, J=5.0Hz, 1H), 6.62(s, 1H), 4.15(s, 3H), 3.92-3.79(m, 1H), 3.03-2.94(m, 1H), 2.27(s, 6H), 2.07(d, J=13.4Hz, 1H), 1.86(d, J=13.6Hz, 1H), 1.73(d, J=8.1Hz, 2H), 1.52-1.35(m, 2H), 1.33-1.18(m, J=11.2, 11.2Hz, 2H); HRMS(ESI) C23H30N7OCl[M+H] + The calculated value for this is 420.2507, and the measured value is 420.2503.

[0288] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[2-(propan-2-ylamino)ethyl]-1H-pyrazole-5-carboxamide hydrochloride (compound 12)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=2-(propan-2-ylamino)ethyl, R4=H]

[0289] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.46(s, 1H), 8.98(t, J=5.6Hz, 1H), 8.50(d, J=5.0Hz, 1H), 8.51(br. s., 2H), 7.48(s, 1H), 7.46(s, 2H), 7.26(d, J=5.0Hz, 1H), 6.62(s, 1H), 4.16(s, 3H) , 3.56(q, J=5.9Hz, 2H), 3.08(t, J=5.6Hz, 2H), 2.27(s, 6H), 1.23(d, J=6.4Hz, 6H); HRMS(ESI) C22H30N7OCl[M+H] + The calculated value for this is 408.2507, and the measured value is 408.2502.

[0290] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 13)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=H, R4=H]

[0291] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.46(s, 1H), 8.49(d, J=5.0Hz, 1H), 8.21(br. s., 1H), 7.62(br. HRMS(ESI) C17H18N6O[M+H] + The calculated value for this is 323.1615, and the measured value is 323.1611.

[0292] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (compound 14)[(I), R1=(3,5-dimethylphenyl), R2=methyl, R3=methyl, R4=H]

[0293] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.45(s, 1H), 8.73(d, J=4.7Hz, 1H), 8.49(d, J=5.0Hz, 1H), 7.46(s, 2H), 7.39(s, 1H), 7.25(d, J=5.0Hz, 1H), 6.61(s, 1H), 4.14(s, 3H), 2.77(d, J=4.6Hz, 3H), 2.27(s, 6H); HRMS(ESI) C18H20N6O[M+H] + The calculated value for this is 337.1772, and the measured value is 337.1775.

[0294] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N,N,1-trimethyl-1H-pyrazole-5-carboxamide (compound 15)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=dimethylamino, R4=methyl]

[0295] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.51(s, 1H), 8.50(d, J=5.2Hz, 1H), 7.47(s, 2H), 7.27(d, J=5.0Hz, 1H), 7.0 4(s, 1H), 6.60(s, 1H), 3.96(s, 3H), 3.11(s, 3H), 3.04(s, 3H), 2.25(s, 6H); HRMS(ESI) C19H22N6O[M+H] + The calculated value for this is 351.1928, and the measured value is 351.1925.

[0296] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 16)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=2-methoxyethyl, R4=H]

[0297] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.47(s, 1H), 8.82(t, J=5.5Hz, 1H), 8.49(d, J=5.2Hz, 1H), 7.47(s, 2H), 7.45(s, 1H), 7.25(d, J=5.0 Hz, 1H), 6.61(s, 1H), 4.14(s, 3H), 3.49-3.44(m, 2H), 3.43-3.38(m, 2H), 3.27(s, 3H), 2.27(s, 6H); HRMS(ESI) C20H24N6O2[M+H] + The calculated value for this is 381.2034, and the measured value is 381.2034.

[0298] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(2-fluoroethyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 17)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=2-fluoroethyl, R4=H]

[0299] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.46(s, 1H), 9.01(t, J=5.5Hz, 1H), 8.50(d, J=5.0Hz, 1H), 7.49(s, 1H), 7.46(s, 2H), 7.25(d , J=5.2Hz, 1H), 6.61(s, 1H), 4.62-4.47(m, 2H), 4.15(s, 3H), 3.62-3.50(m, 2H), 2.27(s, 6H); HRMS(ESI) C19H21N6OF[M+H] + The calculated value for this is 369.1834, and the measured value is 369.1831.

[0300] 3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-N-[2-(dimethylamino)ethyl]-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 18)[(I), R1=3,5-bis(trifluoromethyl)phenyl, R2=methyl, R3=2-(dimethylamino)ethyl, R4=H]

[0301] [ka] 1H NMR (500MHz, DMSO-d6) δppm 10.41(s, 1H), 9.72(br. s., 1H), 8.98(t, J=5.5Hz, 1H), 8.66(d, J=5.2Hz, 1H), 8.60(s, 2H), 7.62(s, 1H), 7.45(s, 1H), 7.42(d, J=5.0Hz, 1H), 4.17(s, 3H), 3.61(q, J=5.8Hz, 2H), 3.26(t, J=5.0Hz, 1H), 2.84(s, 6H); HRMS(ESI) C21H22N7OF6Cl[M+H] + The calculated value for this is 502.1785, and the measured value is 502.1777.

[0302] 3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 19)[(I), R1=3,5-bis(trifluoromethyl)phenyl, R2=methyl, R3=(2S)-1-hydroxypropan-2-yl, R4=H]

[0303] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 10.41(s, 1H), 8.64(d, J=5.2Hz, 1H), 8.61(s, 2H), 8.37(d, J=8.1Hz, 1H), 7.61(s, 1H), 7.44(s, 1H), 7.41(d, J=5.2Hz, 1H), 4. 75(t, J=5.8Hz, 1H), 4.13(s, 3H), 4.03-3.92(m, 1H), 3.45(td, J=5.6, 10.9Hz, 1H), 3.34-3.30(m, 1H), 1.13(d, J=6.7Hz, 3H); HRMS(ESI) C20H18N6O2F6[M+H] + The calculated value for this is 489.1468, and the measured value is 489.146.

[0304] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(1H-pyrazole-3-yl)-1H-pyrazole-5-carboxamide (compound 20)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=1H-pyrazole-3-yl, R4=H]

[0305] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 12.50(br. s., 1H), 11.16(s, 1H), 9.49(s, 1H), 8.51(d, J=5.2Hz, 1H), 7.72(s, 1H), 7.68(d, J=2.1Hz, 1H), 7.48(s, 2H), 7.26(d, J=5.0Hz, 1H), 6.61(br. s, 2H), 4.19(s, 3H), 2.27(s, 6H); HRMS(ESI) C20H20N8O[M+H] + The calculated value for this is 389.1833, and the measured value is 389.1833.

[0306] (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)(4-methylpiperazine-1-yl)methanone (compound 21) [(I), R1=(3,5-dimethylphenyl), R2=methyl, NR3R4=4-methylpiperazine-1-yl]

[0307] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.52(s, 1H), 8.50(d, J=5.0Hz, 1H), 7.47(s, 2H), 7.27(d, J=5.0Hz, 1H), 6.97(s, 1H), 6.61(s, 1H), 3.95(s, 3H), 3.79-3.45(m, 4H), 2.37(br. s., 4H), 2.26(s, 6H), 2.21(s, 3H); HRMS(ESI) C22H27N7O[M+H] +The calculated value for this is 406.235, and the measured value is 406.2351.

[0308] N-[2-(acetylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 22)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=2-acetamidoethyl, R4=H]

[0309] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.46(s, 1H), 8.79(t, J=5.6Hz, 1H), 8.49(d, J=5.0Hz, 1H), 7.98(t, J=5.7Hz, 1H), 7.46(s, 2H), 7.42(s, 1H), 7. 25(d, J=5.0Hz, 1H), 6.61(s, 1H), 4.14(s, 3H), 3.31-3.25(m, 2H), 3.24-3.16(m, 2H), 2.27(s, 6H), 1.81(s, 3H); HRMS(ESI) C21H25N7O2[M+H] + The calculated value for this is 408.2143, and the measured value is 408.2156.

[0310] N-(2-amino-2-oxoethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 23)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(2-amino-2-oxoethyl), R4=H]

[0311] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.47(s, 1H), 8.94(t, J=6.0Hz, 1H), 8.50(d, J=5.0Hz, 1H), 7.48(s, 1H), 7.46(s, 2H), 7.44(br. HRMS(ESI) C19H21N7O2[M+H] + The calculated value for this is 380.183, and the measured value is 380.1829.

[0312] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxamide (compound 24)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=2,2,2-trifluoroethylamino, R4=H]

[0313] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.49(s, 1H), 9.43(t, J=6.3Hz, 1H), 8.51(d, J=5.0Hz, 1H), 7.56(s, 1H), 7.47(s, 2H), 7. 26(d, J=5.0Hz, 1H), 6.62(s, 1H), 4.15(s, 3H), 4.09(dq, J=6.1, 9.6Hz, 2H), 2.27(s, 6H); HRMS(ESI) C19H19N6OF3[M+H] + The calculated value for this is 405.1645, and the measured value is 405.1648.

[0314] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(1-methyl-1H-imidazole-5-yl)methyl]-1H-pyrazole-5-carboxamide (compound 25)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(3-methylimidazole-4-yl)methyl, R4=H]

[0315] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.45(s, 1H), 9.16(t, J=5.3Hz, 1H), 8.49(d, J=5.0Hz, 1H), 7.56(s, 1H), 7.48(s, 1H), 7.46(s, 2H), 7.25( d, J=5.2Hz, 1H), 6.84(s, 1H), 6.61(s, 1H), 4.44(d, J=5.3Hz, 2H), 4.15(s, 3H), 3.63(s, 3H), 2.25(s, 6H); HRMS(ESI) C22H24N8O[M+H] + The calculated value for this is 417.2146, and the measured value is 417.2155.

[0316] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 26)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(2S)-1-hydroxy-3-methylbutan-2-yl, R4=H]

[0317] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.48(s, 1H), 8.49(d, J=5.0Hz, 1H), 8.36(d, J=9.0Hz, 1H), 7.51(s, 1H), 7.49(s, 2H) ), 7.26(d, J=5.0Hz, 1H), 6.61(s, 1H), 4.59(t, J=5.6Hz, 1H), 4.12(s, 3H), 3.86-3. 74(m, 1H), 3.57-3.50(m, 1H), 3.50-3.44(m, 1H), 2.26(s, 6H), 1.97-1.85(m, J=6.7 , 6.7, 6.7, 6.7, 6.7, 6.7, 6.7Hz, 1H), 0.91(d, J=6.9Hz, 3H), 0.89(d, J=6.9Hz, 3H); HRMS(ESI) C22H28N6O2[M+H] + The calculated value for this is 409.2347, and the measured value is 409.2352.

[0318] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(pyridine-2-ylmethyl)-1H-pyrazole-5-carboxamide (compound 27)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=pyridine-2-ylmethyl, R4=H]

[0319] [ka] 1 1H NMR (500MHz, DMSO-d6) δppm 9.48(s, 1H), 9.39(t, J=6.0Hz, 1H), 8.52(ddd, J=0.9, 1.6, 4.7Hz, 1H), 8 .50(d, J=5.0Hz, 1H), 7.78(dt, J=1.8, 7.7Hz, 1H), 7.55(s, 1H), 7.47(s, 2 H), 7.36(d, J=7.8Hz, 1H), 7.29(ddd, J=0.9, 4.8, 7.4Hz, 1H), 7.27(d, J=5 .0Hz, 1H), 6.61(s, 1H), 4.56(d, J=5.9Hz, 2H), 4.16(s, 3H), 2.26(s, 6H); HRMS(ESI) C23H23N7O[M+H] + The calculated value for this is 414.2037, and the measured value is 414.2043.

[0320] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(1H-imidazole-2-ylmethyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 28)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=1H-imidazole-2-ylmethyl, R4=H]

[0321] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 11.85(br. s., 1H), 9.46(s, 1H), 9.24(t, J=5.7Hz, 1H), 8.49(d, J=5.0Hz, 1H), 7.50(s, 1H), 7.45(s, 2H), 7.25(d, J=5.2Hz, 1H), 7.03(s, 1H), 6.82(s, 1H), 6.60(s, 1H), 4.47(d, J=5.6Hz, 2H), 4.17(s, 3H), 2.26(s, 6H); HRMS(ESI) C21H22N8O[M+H] + The calculated value for this is 403.199, and the measured value is 403.1994.

[0322] N-[(2R)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 29)[(I), R1=3,5-dimethoxyphenyl, R2=methyl, R3=(2R)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0323] [ka] 1H NMR (500 MHz, DMSO-d6) δppm 9.59(s, 1H), 8.52(d, J=5.03Hz, 1H), 8.42(d, J=8.39Hz, 1H), 7.45(s, 1H), 7.28(d, J=5.03Hz, 1H), 7.17(d, J=2.29Hz, 2H), 6.13(t, J=2.21Hz, 1H), 4.12(s, 3H), 3.90(d, J=7.93Hz, 1H), 3.75(s, 6H), 3.05-3.19(m, 4H), 2.31-2.48(m, 2H), 1.94(t, J=6.94Hz, 2H), 1.09(d, J=6.71Hz, 3H); HRMS(ESI) C23H29N7O3[M+H] + The calculated value for this is 452.2405, and the measured value is 452.2407.

[0324] N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-yl]-1H-pyrazole-5-carboxamide (compound 30)[(I), R1=oxan-4-yl, R2=methyl, R3=(2S)-1-(dimethylamino)propan-2-yl, R4=H]

[0325] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 8.39(d, J=8.2Hz, 1H), 8.30(d, J=5.0Hz, 1H), 7.37(s, 1H), 7.14-7.07(m, 1H), 7.05-7.02(m, 1H), 4.16-4.07(m, 4H), 4.01(br. s., 1H), 3.88(d, J=11.6Hz, 2H), 3.40(t, J=11.2Hz, 2H), 2.40-2.35(m, 1H), 2.20(d, J=6. 7Hz, 1H), 2.16(s, 6H), 1.84(d, J=12.4Hz, 2H), 1.60-1.48(m, 2H), 1.12(d, J=6.6Hz, 3H); HRMS(ESI) C19H29N7O2[M+H] + The calculated value for this is 388.2456, and the measured value is 388.2455.

[0326] N-(1-azabicyclo[2.2.2]octa-3-yl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 31)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=1-azabicyclo[2.2.2]octan-3-yl, R4=H]

[0327] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.49(s, 1H), 8.69(d, J=6.9Hz, 1H), 8.49(d, J=5.0Hz, 1H), 7.53(s, 1H), 7.51(s, 2H), 7.27(d, J=5.0Hz, 1H), 6.62(s, 1H), 4.12(s, 3H), 3.93(br. q, J=7.5Hz, 1H), 3.08(ddd, J=2.2, 10.2, 13.3Hz, 1H), 2.86(dddd, J=2.1, 4.8, 10.8, 13.1Hz, 1H), 2.75-2.60(m, 4H), 2.27(s, 6H), 1.85(sxt, J=2.8Hz, 1H), 1.83-1.71(m, 1H), 1.65-1.50(m, 2H), 1.32(dd, J=11.3, 13.6Hz, 1H); HRMS(ESI) C24H29N7O[M+H] + The calculated value for this is 432.2507, and the measured value is 432.2505.

[0328] 5-[2-(3,5-dimethylphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ((1R,2R)-2-hydroxycyclohexyl)-amide (compound 32)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(1R,2R)-2-hydroxycyclohexyl, R4=H]

[0329] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.46(s, 1H), 8.49(d, J=5.0Hz, 1H), 8.46(d, J=8.4Hz, 1H), 7.47(s, 3H), 7.25(d, J=5.2Hz, 1H), 6.61(s, 1H), 4.61(d, J=5.2Hz, 1H), 4 .13(s, 3H), 3.66-3.54(m, 1H), 2.27(s, 6H), 1.90(d, J=9.8Hz, 1H), 1.83(d, J=8.8Hz, 1H), 1.65(d, J=8.5Hz, 2H), 1.33-1.10(m, 4H); HRMS(ESI) C23H28N6O2[M+H] + The calculated value for this is 421.2347, and the measured value is 421.2349.

[0330] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-hydroxybutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 33)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(2S)-1-hydroxybutan-2-yl, R4=H]

[0331] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.47(s, 1H), 8.49(d, J=5.0Hz, 1H), 8.38(d, J=8.7Hz, 1H), 7.49(s, 1H), 7.48(s, 2H), 7.25(d, J=5.0Hz, 1H), 6.61(s, 1H), 4.7 1(t, J=5.6Hz, 1H), 4.13(s, 3H), 3.90-3.75(m, 1H), 2.26(s, 6H), 1.74-1.58(m, 1H), 1.51-1.38(m, 1H), 0.88(t, J=7.5Hz, 3H); HRMS(ESI) C21H26N6O2[M+H] + The calculated value for this is 395.219, and the measured value is 395.2185.

[0332] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 34)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=2-hydroxyethyl, R4=H]

[0333] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.45(s, 1H), 8.71(t, J=5.6Hz, 1H), 8.49(d, J=5.0Hz, 1H), 7.46(s, 2H), 7.44(s, 1H), 7.25(d, J=5.0Hz, 1H), 6.61(s, 1H), 4.76(t, J=5.7Hz, 1H), 4.13(s, 3H), 3.51(q, J=6.0Hz, 2H), 3.31(q, J=6.0Hz, 2H), 2.27(s, 6H); HRMS(ESI) C19H22N6O2[M+H] + The calculated value for this is 367.1877, and the measured value is 367.1872.

[0334] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,4-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 35)[(I), R1=3,4-dimethoxyphenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0335] [ka] 1H NMR (500 MHz, DMSO-d6) δppm 9.44(s, 1H), 8.47(d, J=5.0Hz, 1H), 8.42(d, J=8.2Hz, 1H), 7.68(d, J=1.8Hz, 1H), 7.46(s, 1H), 7.23(dd, J=2.4, 8.5Hz, 2H), 6 .89(d, J=8.8Hz, 1H), 4.13(s, 3H), 3.91(td, J=7.0, 14.4Hz, 1H), 3.79(s, 3H), 3.72(s, 3H), 3.22-3.01(m, 4H), 2.55-2.35(m. Partially overlapping with water, 2H), 1.95(quin, J=6.8Hz, 2H), 1.10(d, J=6.7Hz, 3H); HRMS(ESI) C23H29N7O3[M+H] + The calculated value for this is 452.2405, and the measured value is 452.2413.

[0336] (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)(piperazine-1-yl)methanone hydrochloride (compound 36) [(I), R1=3,5-dimethylphenyl, R2=methyl, NR3R4=piperazine-1-ylamino]

[0337] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.53(s, 1H), 9.13(br. s., 2H), 8.50(d, J=5.0Hz, 1H), 7.47(s, 2H), 7.28(d, J=5.0Hz, 1H), 7.08(s, 1H), 6.61(s, 1H), 3.98(s, 3H), 3.84(br. s., 4H), 3.21(br. s., 4H), 2.26(s, 6H); HRMS(ESI) C21H26N7OCl[M+H] + The calculated value for this is 392.2194, and the measured value is 392.2207.

[0338] N-[(1S,2R)-2-aminocyclohexyl]-3-(2-{[3-methoxy-5-(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 37)[(I), R1=3-methoxy-5-(trifluoromethyl)phenyl, R2=methyl, R3=(1S,2R)-2-aminocyclohexyl, R4=H]

[0339] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 10.03(s, 1H), 8.59(d, J=5.2Hz, 1H), 8.39(d, J=7.9Hz, 1H), 7.97(s, 1H), 7.88(br. s., 3H), 7.82(t, J=1.8Hz, 1H), 7.57(s, 1H), 7.37(d, J=5.0Hz, 1H), 6.83(s, 1H), 4.33(br. HRMS(ESI) C23H27N7O2F3Cl[M+H] + The calculated value for this is 490.2173, and the measured value is 490.2173.

[0340] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3-chloro-1-methyl-1H-indole-5-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 38)[(I), R1=3-chloro-1-methylindole-5-yl, R2=methyl, R3=(1S,2R)-2-aminocyclohexyl, R4=H]

[0341] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.58(s, 1H), 8.50(d, J=5.0Hz, 1H), 8.45(d, J=7.8Hz, 1H), 8.34(br. s., 1H), 7.88(br. s., 3H), 7.59(s, 1H), 7.51-7.45(m, 2H), 7.45-7.40(m, 1H), 7.27(d, J=5.0Hz, 1H), 4.32(br. HRMS(ESI) C24H28N8OCl2[M+H] + The calculated value for this is 479.2069, and the measured value is 479.2074.

[0342] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 39)[(I), R1=3-methoxyphenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0343] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.63(s, 1H), 8.51(d, J=5.0Hz, 1H), 8.44(d, J=8.4Hz, 1H), 7.65-7.59(m, 1H), 7.46(s, 1H), 7.38(dd, J=1.1, 8.2Hz, 1H), 7.28(d, J=5.0Hz, 1H), 7.19(t, J=8.1Hz, 1H), 6.54(dd, J=2.1, 7.8Hz, 1H), 4.13(s, 3H), 3.99-3.87(m, 1H), 3.77(s, 3H), 3.16(d, J=3.4Hz, 4H), 2.55-2.35(m. Partially overlapping with water, 2H)2.07-1.88(m, 2H), 1.11(d, J=6.7Hz, 3H); HRMS(ESI) C22H27N7O2[M+H] +The calculated value for this is 422.2299, and the measured value is 422.2306.

[0344] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-difluorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 40)[(I), R1=3,5-difluorophenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0345] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 10.10(s, 1H), 8.59(d, J=5.2Hz, 1H), 8.45(d, J=8.2Hz, 1H), 7.67-7.57(m, 2H), 7.45(s, 1H), 7.38(d, J=5.2Hz, 1H), 6.76(tt, J=2. 3, 9.3Hz, 1H), 4.14(s, 3H), 3.96-3.86(m, 1H), 3.24-3.03(m, 4H), 2.49-2.36(m, 2H), 1.94(quin, J=6.9Hz, 2H), 1.16-1.04(m, 3H); HRMS(ESI) C21H23N7OF2[M+H] + The calculated value for this is 428.2005, and the measured value is 428.2006.

[0346] N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 41)[(I), R1=3-methylphenyl, R2=methyl, R3=(2S)-1-hydroxy-3-methylbutan-2-yl, R4=H]

[0347] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.56(s, 1H), 8.50(d, J=5.0Hz, 1H), 8.35(d, J=9.0Hz, 1H), 7.75(s, 1H), 7.59(d , J=8.5Hz, 1H), 7.52(s, 1H), 7.28(d, J=5.0Hz, 1H), 7.17(t, J=7.8Hz, 1H), 6.78 (d, J=7.5Hz, 1H), 4.60(t, J=5.6Hz, 1H), 4.13(s, 3H), 3.84-3.74(m, 1H), 3.59- 3.44(m, 2H), 2.31(s, 3H), 1.91(d, J=6.9Hz, 1H), 0.91(dd, J=6.9, 10.2Hz, 6H); HRMS(ESI) C21H26N6O2[M+H] + The calculated value for this is 395.219, and the measured value is 395.2196.

[0348] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (compound 42)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(2S)-1,1,1-trifluoropropan-2-yl, R4=H]

[0349] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.49(s, 1H), 9.23(d, J=8.7Hz, 1H), 8.51(d, J=5.0Hz, 1H), 7.60(s, 1H), 7.48(s, 2H), 7.26(d, J=5.0 Hz, 1H), 6.62(s, 1H), 4.81(qd, J=7.6, 15.3Hz, 1H), 4.14(s, 3H), 2.27(s, 6H), 1.36(d, J=7.2Hz, 3H); HRMS(ESI) C20H21N6OF3[M+H] + The calculated value for this is 419.1802, and the measured value is 419.1813.

[0350] N-[3-(dimethylamino)propyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 43)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=3-(dimethylamino)propyl, R4=H]

[0351] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.46(s, 1H), 8.78(t, J=5.6Hz, 1H), 8.49(d, J=5.0Hz, 1H), 7.47(s, 2H), 7.25(d, J=5.0Hz, 1H), 6.61(s, 1H) ), 4.13(s, 3H), 3.29-3.23(m, 2H), 2.27(s, 6H), 2.26-2.22(m, 2H), 2.13(s, 6H), 1.64(quin, J=7.0Hz, 2H); HRMS(ESI) C22H29N7O[M+H] + The calculated value for this is 408.2507, and the measured value is 408.2499.

[0352] (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)[(2S)-2-(propan-2-yl)aziridin-1-yl]methanone (compound 44)[(I), R1=3,5-dimethylphenyl, R2=methyl, NR3R4=(1R,2S)-2-propan-2-ylaziridin-1-ylamino]

[0353] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.51(s, 1H), 8.50(d, J=5.2Hz, 1H), 7.47(s, 2H), 7.28(d, J=5.0Hz, 1H), 7.26(s, 1H), 6.61(s, 1H), 4.49-4.39(m, 1H), 4 .23(s, 3H), 4.18-4.10(m, 2H), 2.25(s, 6H), 1.78(qd, J=6.6, 13.2Hz, 1H), 0.97(d, J=6.7Hz, 3H), 0.91(d, J=6.7Hz, 3H); HRMS(ESI) C22H26N6O[M+H] + The calculated value for this is 391.2241, and the measured value is 391.2246.

[0354] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(2,2-dimethylpropyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 45)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=2,2-dimethylpropyl, R4=H]

[0355] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.49(s, 1H), 8.72(t, J=6.3Hz, 1H), 8.49(d, J=5.0Hz, 1H), 7.49(s, 2H), 7.27(d, J=5. 0Hz, 1H), 6.61(s, 1H), 4.12(s, 3H), 3.08(d, J=6.4Hz, 2H), 2.26(s, 6H), 0.91(s, 9H); HRMS(ESI) C22H28N6O[M+H] + The calculated value for this is 393.2398, and the measured value is 393.2399.

[0356] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(2-methylpropyl)-1H-pyrazole-5-carboxamide (compound 46)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=2-methylpropyl, R4=H]

[0357] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.48(s, 1H), 8.78(t, J=5.9Hz, 1H), 8.49(d, J=5.0Hz, 1H), 7.48(s, 2H), 7.44(s, 1H), 7.26(d, J=5.0Hz, 1H), 6.61 (s, 1H), 4.13(s, 3H), 3.07(t, J=6.4Hz, 2H), 2.27(s, 6H), 1.84(quind, J=6.7, 13.5Hz, 1H), 0.90(d, J=6.7Hz, 6H); HRMS(ESI) C21H26N6O[M+H] + The calculated value for this is 379.2241, and the measured value is 379.2254.

[0358] N-(cyclopropylmethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 47)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=cyclopropylmethyl, R4=H]

[0359] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.47(s, 1H), 8.87(t, J=5.7Hz, 1H), 8.49(d, J=5.0Hz, 1H), 7.48(s, 2H), 7.46(s, 1H), 7.26(d, J=5.0Hz, 1H), 6.62( s, 1H), 4.14(s, 3H), 3.13(t, J=6.3Hz, 2H), 2.27(s, 6H), 1.09-0.95(m, 1H), 0.52-0.37(m, 2H), 0.29-0.18(m, 2H); HRMS(ESI) C21H24N6O[M+H] + The calculated value for this is 377.2085, and the measured value is 377.209.

[0360] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-fluoro-5-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 48)[(I), R1=3-fluoro-5-methoxyphenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0361] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.84(s, 1H), 8.56(d, J=5.2Hz, 1H), 8.47(d, J=6.6Hz, 1H), 7.45(s, 1H), 7.39(s, 1H), 7.38-7.34(m, 1H), 7.33(d, J=5. 0Hz, 1H), 6.41(td, J=2.3, 10.8Hz, 1H), 4.14(s, 3H), 4.03-3.88(m, 1H), 3.78(s, 3H), 3.30-3.00(m, 4H), 2.54-2.38(m. Partially overlapping with water, 2H)2.12-1.89(m, 2H), 1.11(d, J=6.9Hz, 3H); HRMS(ESI) C22H26N7O2F[M+H] + The calculated value for this is 440.2205, and the measured value is 440.2202.

[0362] 3-{2-[(4,6-dimethylpyridine-2-yl)amino]pyrimidine-4-yl}-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 49)[(I), R1=4,6-dimethylpyridine-2-yl, R2=methyl, R3=(2S)-1-hydroxy-3-methylbutan-2-yl, R4=H]

[0363] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.44(s, 1H), 8.56(d, J=5.0Hz, 1H), 8.38(d, J=9.0Hz, 1H), 8.12(s, 1H), 7.55(s, 1H), 7.37(d, J=5.0Hz, 1H), 6.73(s, 1H), 4.60(br. s., 1H), 4.13(s, 3H), 3.87-3.72(m, 1H), 3.59-3.43(m, 2H), 2.36(s, 3H) , 2.33(s, 3H), 1.92(qd, J=6.7, 13.5Hz, 1H), 0.91(dd, J=6.8, 9.5Hz, 6H); HRMS(ESI) C21H27N7O2[M+H] + The calculated value for this is 410.2299, and the measured value is 410.2301.

[0364] 3-{2-[(3,5-difluorophenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (compound 50)[(I), R1=3,5-difluorophenyl, R2=methyl, R3=(2S)-1,1,1-trifluoropropan-2-yl, R4=H]

[0365] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 10.12(s, 1H), 9.20(d, J=8.7Hz, 1H), 8.61(d, J=5.2Hz, 1H), 7.68-7.57(m, 3H), 7.39(d, J=5.0Hz, 1H), 6.81-6.70(m, 1H), 4.90-4.73(m, 1H), 4.15(s, 3H), 1.37(d, J=7.2Hz, 3H); HRMS(ESI) C18H15N6OF5[M+H] + The calculated value for this is 427.13, and the measured value is 427.1308.

[0366] 1-Methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (compound 51)[(I), R1=3-methylphenyl, R2=methyl, R3=(2S)-1,1,1-trifluoropropan-2-yl, R4=H]

[0367] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.57(s, 1H), 9.22(d, J=8.7Hz, 1H), 8.51(d, J=5.2Hz, 1H), 7.72(s, 1H), 7.64-7.57(m, 2H), 7.28(d, J=5.2Hz, 1H), 7.18(t, J=7.9Hz, 1H), 6.79(d, J=7.5Hz, 1H), 4.89-4.73(m, 1H), 4.15(s, 3H), 2.31(s, 3H), 1.37(d, J=7.0Hz, 3H); HRMS(ESI) C19H19N6OF3[M+H] + The calculated value for this is 405.1645, and the measured value is 405.1649.

[0368] 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]aminopyrimidine-4-yl)-N-[(2S)-1-hydroxy-3-phenylpropane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 52)[(I), R1=3-chloro-4-(4-methylpiperazine-1-yl)phenyl, R2=methyl, R3=(2S)-1-hydroxy-3-phenylpropane-2-yl, R4=H]

[0369] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.68(s, 1H), 8.50(d, J=5.2Hz, 1H), 8.50(d, J=8.2Hz, 1H), 7.92(d, J=2.4Hz, 1H ), 7.82(dd, J=2.0, 8.8Hz, 1H), 7.42(s, 1H), 7.32-7.22(m, 5H), 7.16(d, J=8.8H z, 1H), 7.21-7.11(m, 1H), 4.89(t, J=5.7Hz, 1H), 4.17-4.07(m, 1H), 4.03(s, 3H) ), 3.56-3.48(m, 1H), 3.48-3.40(m, 1H), 2.96(dd, J=4.7, 13.9Hz, 1H), 2.94(br. HRMS(ESI) C29H33N8O2Cl[M+H] + The calculated value for this is 561.2488, and the measured value is 561.2498.

[0370] N-[(1S,2S)-2-aminocyclohexyl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 53)[(I), R1=3-methylphenyl, R2=methyl, R3=(1S,2S)-2-aminocyclohexyl, R4=H]

[0371] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.55(s, 1H), 8.54-8.44(m, 2H), 7.69(s, 1H), 7.63(d, J=8.2Hz, 1H), 7.51-7.48(m, 1H), 7.27(d, J=5.0Hz, 1H), 7.19(t, J=7.8Hz, 1 H), 6.79(d, J=7.5Hz, 1H), 4.16-4.10(m, 3H), 3.45(d, J=5.2Hz, 1H), 2.60-2.53(m, 1H), 2.31(s, 3H), 1.91-1.80(m, 2H), 1.66(br. s., 3H), 1.38-1.02(m, 5H); HRMS(ESI) C22H27N7O[M+H] + The calculated value for this is 406.235, and the measured value is 406.2348.

[0372] 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]aminopyrimidine-4-yl)-1-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (compound 54)[(I), R1=3-chloro-4-(4-methylpiperazine-1-yl)phenyl, R2=methyl, R3=(2S)-1,1,1-trifluoropropan-2-yl, R4=H]

[0373] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.69(s, 1H), 9.19(d, J=8.8Hz, 1H), 8.52(d, J=5.0Hz, 1H), 7.99(d, J=2.4Hz, 1H), 7.71(dd, J=2.5, 8.8Hz, 1H), 7.58(s, 1H), 7.29(d, J=5.2Hz, 1H), 7.13(d, J=8.8Hz, 1H), 4.82(qd, J=7.6, 15.4Hz, 1H), 4.14(s, 3H), 2.93(br. s., 4H), 2.47(br. s., 4H), 2.23(s, 3H), 1.37(d, J=7.2Hz, 3H); HRMS(ESI) C23H26N8OF3Cl[M+H] +The calculated value for this is 523.1943, and the measured value is 523.1951.

[0374] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1H-pyrazole-5-carboxamide (compound 55)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(2S)-1,1,1-trifluorobutan-2-yl, R4=H]

[0375] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.51(s, 1H), 9.14(d, J=9.0Hz, 1H), 8.51(d, J=5.0Hz, 1H), 7.63(s, 1H), 7.49(s, 2H), 7.27(d, J=5.2Hz, 1 H), 6.62(s, 1H), 4.68-4.50(m, 1H), 4.15(s, 3H), 2.27(s, 6H), 1.89-1.66(m, 2H), 0.96(t, J=7.3Hz, 3H); HRMS(ESI) C21H23N6OF3[M+H] + The calculated value for this is 433.1958, and the measured value is 433.1959.

[0376] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1H-pyrazole-5-carboxamide (compound 56)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(2R)-1,1,1-trifluorobutan-2-yl, R4=H]

[0377] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.51(s, 1H), 9.14(d, J=9.0Hz, 1H), 8.51(d, J=5.0Hz, 1H), 7.63(s, 1H), 7.49(s, 2H), 7.27(d, J=5.2Hz, 1 H), 6.62(s, 1H), 4.68-4.49(m, 1H), 4.15(s, 3H), 2.27(s, 6H), 1.88-1.64(m, 2H), 0.96(t, J=7.4Hz, 3H); HRMS(ESI) C21H23N6OF3[M+H] + The calculated value for this is 433.1958, and the measured value is 433.1957.

[0378] N-[(2S)-1-(3,3-difluoroazetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 57)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(2S)-1-(3,3-difluoroazetidine-1-yl)propan-2-yl, R4=H]

[0379] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.47(s, 1H), 8.54(d, J=8.4Hz, 1H), 8.49(d, J=5.2Hz, 1H), 7.48(s, 2H), 7.45(s, 1H), 7.26(d, J=5.0Hz, 1H), 6.62(s, 1H), 4.13(s, 3H), 3.98(quind, J=6.9, 13.9Hz, 1H), 3.73-3.53(m, 4H), 2.70-2.56(m, 2H), 2.27(s, 6H), 1.13(d, J=6.7Hz, 3H); HRMS(ESI) C23H27N7OF2[M+H] + The calculated value for this is 456.2318, and the measured value is 456.232.

[0380] 1-Methyl-N-[(2S)-1-(pyrrolidine-1-yl)propan-2-yl]-3-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 58)[(I), R1=3,4,5-trimethoxyphenyl, R2=methyl, R3=(2S)-1-pyrrolidine-1-ylpropan-2-yl, R4=H]

[0381] [ka] 1 ¹H NMR (500 MHz, DMSO-d6) δppm 9.53 (s, 1H), 8.51 (d, J=5.03Hz, 2H), 7.50 (s, 1H), 7.31 (s, 2H), 7.26 (d, J=5.19Hz, 1H), 4.07-4.20 (m, 4H), 3.80 (s, 6H), 3.63 (s, 3H), 2.60-2.38 (m, partially overlapping with water, 6H), 1.69 (br, s, 4H), 1.08-1.20 (m, 3H); HRMS (ESI) C25H33N7O4[M+H] + The calculated value for this is 496.2667, and the measured value is 496.2666.

[0382] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-chloro-1-methyl-1H-indole-5-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 59)[(I), R1=3-chloro-1-methylindole-5-yl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0383] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.56(s, 1H), 8.49(d, J=5.0Hz, 1H), 8.41(d, J=8.4Hz, 1H), 8.28(s, 1H), 7.51(dd, J=2. 0, 9.0Hz, 1H), 7.47(s, 1H), 7.44(s, 1H), 7.42(d, J=8.8Hz, 1H), 7.24(d, J=5.0Hz, 1H), 4.12(s, 3H), 3.97-3.84(m, 1H), 3.76(s, 3H), 3.23-3.05(m, 4H), 2.46(dd, J=6.9, 11.6 Hz, 1H), 2.37(dd, J=6.7, 11.6Hz, 1H), 1.95(quin, J=6.9Hz, 2H), 1.11(d, J=6.7Hz, 3H); HRMS(ESI) C24H27N8OCl[M+H] + The calculated value for this is 479.2069, and the measured value is 479.2068.

[0384] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 60)[(I), R1=3,5-dichlorophenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0385] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 10.08(s, 1H), 8.60(d, J=5.2Hz, 1H), 8.45(d, J=8.4Hz, 1H), 7.98(d, J=2.0Hz, 2H) , 7.43(s, 1H), 7.38(d, J=5.0Hz, 1H), 7.14(t, J=1.8Hz, 1H), 4.14(s, 3H), 3.93(br. HRMS(ESI) C21H23N7OCl2[M+H] +The calculated value for this is 460.1414, and the measured value is 460.1415.

[0386] N-[(2S)-1-(azetidine-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 61)[(I), R1=3,5-dichlorophenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)-3-methylbutan-2-yl, R4=H]

[0387] [ka] 1 1H NMR (500MHz, DMSO-d6) δppm 10.10(s, 1H), 8.60(d, J=5.2Hz, 1H), 8.32(d, J=9.2Hz, 1H), 7.99(d, J=2 .0Hz, 2H), 7.45(s, 1H), 7.40(d, J=5.2Hz, 1H), 7.13(t, J=1.9Hz, 1H), 4.1 2(s, 3H), 3.83-3.68(m, 1H), 3.22-2.95(m, 4H), 2.47(d, J=6.1Hz, 2H), 1.92(quin, J=6.9Hz, 2H), 1.80(dspt, J=6.4Hz, 1H), 0.87(t, J=7.3Hz, 6H); HRMS(ESI) C23H27N7OCl2[M+H] + The calculated value for this is 488.1727, and the measured value is 488.174.

[0388] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-1-methyl-3-(2-{[3-(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-1H-pyrazole-5-carboxamide (compound 62)[(I), R1=3-(trifluoromethyl)phenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0389] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 10.03(s, 1H), 8.57(d, J=5.2Hz, 1H), 8.41(d, J=8.4Hz, 1H), 8.36(t, J=1.9Hz, 1H ), 8.08(dd, J=1.3, 8.2Hz, 1H), 7.54(t, J=8.0Hz, 1H), 7.43(s, 1H), 7.35(d, J=5.2 Hz, 1H), 7.30(d, J=7.6Hz, 1H), 4.13(s, 3H), 3.97-3.85(m, 1H), 3.20-3.07(m, 4H) , 2.48-2.44(m, 1H), 2.41-2.37(m, 1H), 2.02-1.88(m, 2H), 1.11(d, J=6.7Hz, 3H); HRMS(ESI) C22H24N7OF3[M+H] + The calculated value for this is 460.2067, and the measured value is 460.2072.

[0390] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-1-methyl-1H-pyrazole-5-carboxamide (compound 63)[(I), R1=3,5-bis(trifluoromethyl)phenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0391] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 10.40(s, 1H), 8.64(d, J=5.0Hz, 1H), 8.60(s, 2H), 8.39(d, J=8.4Hz, 1H), 7.61(s, 1H), 7.42(d, J=5.2Hz, 1H), 7.40(s, 1H), 4.13 (s, 3H), 3.97-3.85(m, 1H), 3.22-3.05(m, 4H), 2.47-2.42(m, 1H), 2.42-2.37(m, 1H), 2.01-1.87(m, 2H), 1.10(d, J=6.7Hz, 3H); HRMS(ESI) C23H23N7OF6[M+H] +The calculated value for this is 528.1941, and the measured value is 528.1951.

[0392] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 64)[(I), R1=3,5-dimethoxyphenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0393] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.59(s, 1H), 8.52(d, J=5.0Hz, 1H), 8.42(d, J=8.4Hz, 1H), 7.46(s, 1H), 7.28(d, J=5.0Hz, 1H), 7.17(d, J=2.1Hz, 2H), 6.13(t, J=2.2Hz) , 1H), 4.13(s, 3H), 3.96-3.85(m, 1H), 3.75(s, 6H), 3.20-3.05(m, 4H), 2.48-2.32(m, 2H), 1.95(t, J=6.9Hz, 2H), 1.10(d, J=6.7Hz, 3H); HRMS(ESI) C23H29N7O3[M+H] + The calculated value for this is 452.2405, and the measured value is 452.2408.

[0394] N-[(2S)-1-(dimethylamino)propan-2-yl]-3-{2-[(3-fluoro-5-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 65)[(I), R1=3-fluoro-5-methoxyphenyl, R2=methyl, R3=(2S)-1-(dimethylamino)propan-2-yl, R4=H]

[0395] [ka] 1H NMR (500 MHz, DMSO-d6) δppm 9.84 (s, 1H), 8.56 (d, J=5.19Hz, 1H), 8.49 (br. s., 1H), 7.46(s, 1H), 7.40(s, 1H), 7.32-7.37(m, 2H), 6.41(dt, J=10.87, 2.27Hz, 1H), 4.14(m, 4H), 3.78(s, 3H), 2.54-2.05(m. br., 8H)1.14(d, J=6.41Hz, 3H); HRMS(ESI) C21H26N7O2F[M+H] + The calculated value for this is 428.2205, and the measured value is 428.2202.

[0396] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-[2-(1,3-benzodioxol-5-ylamino)pyrimidine-4-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 66)[(I), R1=1,3-benzodioxol-5-yl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0397] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.49(s, 1H), 8.46(d, J=5.0Hz, 1H), 8.43(d, J=8.2Hz, 1H), 7.48(d, J=2.0Hz, 1H), 7.4 1(s, 1H), 7.25(dd, J=2.1, 8.5Hz, 1H), 7.24(d, J=5.0Hz, 0H), 6.85(d, J=8.5Hz, 1H), 5. 97(s, 2H), 4.13(s, 3H), 3.97-3.84(m, 1H), 3.21-3.04(m, 4H), 2.47(dd, J=7.0, 11.6H z, 1H), 2.38(dd, J=6.1, 11.6Hz, 1H), 1.95(quin, J=6.9Hz, 2H), 1.10(d, J=6.7Hz, 3H); HRMS(ESI) C22H25N7O3[M+H] + The calculated value for this is 436.2092, and the measured value is 436.21.

[0398] 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 67)[(I), R1=3,5-dimethoxyphenyl, R2=methyl, R3=(2S)-1-(dimethylamino)propan-2-yl, R4=H]

[0399] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.60(s, 1H), 8.52(d, J=5.2Hz, 1H), 8.46(d, J=8.4Hz, 1H), 7.46(s, 1H), 7.28(d, J=5.0Hz, 1H), 7.17(d, J=2 .3Hz, 2H), 6.13(t, J=2.2Hz, 1H), 4.13(s, 3H), 4.17-4.07(m, 1H), 3.75(s, 6H), 2.43-2.31(m, 1H), 2.18(br. s., 7H), 1.12(d, J=6.7Hz, 3H); HRMS(ESI) C22H29N7O3[M+H] + The calculated value for this is 440.2405, and the measured value is 440.2404.

[0400] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-1-methyl-3-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 68)[(I), R1=3,4,5-trimethoxyphenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0401] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.52(s, 1H), 8.50(d, J=5.0Hz, 1H), 8.40(d, J=8.2Hz, 1H), 7.49(s, 1H), 7.31(s, 2H), 7.26(d, J=5.2Hz, 1H), 4.13(s, 3H), 3.94-3 .86(m, 1H), 3.80(s, 6H), 3.63(s, 3H), 3.13(dd, J=6.8, 16.2Hz, 4H), 2.45-2.31(m, 2H), 2.04-1.87(m, 2H), 1.10(d, J=6.7Hz, 3H); HRMS(ESI) C24H31N7O4[M+H] + The calculated value for this is 482.2511, and the measured value is 482.2514.

[0402] 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidine-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (compound 69)[(I), R1=3,5-dimethoxyphenyl, R2=methyl, R3=(2S)-1-pyrrolidine-1-ylpropan-2-yl, R4=H]

[0403] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.60(s, 1H), 8.52(d, J=5.0Hz, 1H), 8.48(d, J=8.4Hz, 1H), 7.46(s, 1H), 7.28(d, J=5.0Hz, 1H), 7.18(d, J=2.3Hz, 2H), 6.13(t , J=2.3Hz, 1H), 4.12(s, 3H), 4.12-4.06(m, 1H), 3.75(s, 6H), 2.49-2.39(m, 5H), 1.67(t, J=2.9Hz, 4H), 1.14(d, J=6.6Hz, 3H); HRMS(ESI) C24H31N7O3[M+H] + The calculated value for this is 466.2561, and the measured value is 466.256.

[0404] 3-{2-[(3-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidine-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (compound 70)[(I), R1=3-methoxyphenyl, R2=methyl, R3=(2S)-1-pyrrolidine-1-ylpropan-2-yl, R4=H]

[0405] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.63(s, 1H), 8.55-8.46(m, 2H), 7.65-7.61(m, 2H), 7.37(dd, J=1.2, 8.1Hz, 1H), 7.29(d, J=5.2Hz, 1H), 7 .19(t, J=8.2Hz, 1H), 6.54(dd, J=1.8, 8.1Hz, 1H), 4.13(s, 4H), 3.77(s, 3H), 2.62-2.51(m, 6H), 1.69(br. s., 4H), 1.16(d, J=6.7Hz, 3H); HRMS(ESI) C23H29N7O2[M+H] + The calculated value for this is 436.2456, and the measured value is 436.2455.

[0406] 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-(dimethylamino)-1-oxopropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 71)[(I), R1=3,5-dimethoxyphenyl, R2=methyl, R3=(2S)-1-(dimethylamino)-1-oxopropan-2-yl, R4=H]

[0407] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.62(s, 1H), 8.87(d, J=7.5Hz, 1H), 8.52(d, J=5.0Hz, 1H), 7.59(s, 1H), 7.28(d, J=5.0Hz, 1H), 7.18(d, J=2.1Hz, 2H), 6.12(t, J=2.2Hz, 1H), 4.88(t, J=7.2Hz, 1H), 4.12(s, 3H), 3.75(s, 6H), 3.06(s, 3H), 2.86(s, 3H), 1.32-1.26(m, 3H); HRMS(ESI) C22H27N7O4[M+H] + The calculated value for this is 454.2198, and the measured value is 454.2198.

[0408] 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-N-[2-(dimethylamino)ethyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 72)[(I), R1=3,5-dimethoxyphenyl, R2=methyl, R3=2-(dimethylamino)ethyl, R4=H]

[0409] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.60(s, 1H), 8.64(t, J=5.7Hz, 1H), 8.52(d, J=5.0Hz, 1H), 7.42(s, 1H), 7.28(d, J=5.0Hz, 1H), 7.17( d, J=2.3Hz, 2H), 6.13(t, J=2.2Hz, 1H), 4.13(s, 3H), 3.75(s, 6H), 2.40(t, J=6.7Hz, 2H), 2.19(s, 6H); HRMS(ESI) C21H27N7O3[M+H] + The calculated value for this is 426.2248, and the measured value is 426.224.

[0410] N-[(2S)-1-(dimethylamino)propan-2-yl]-3-{2-[(1,5-dimethyl-1H-pyrazole-3-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 73)[(I), R1=1,5-dimethylpyrazole-3-yl, R2=methyl, R3=(2S)-1-(dimethylamino)propan-2-yl, R4=H]

[0411] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.52(s, 1H), 8.49(d, J=8.2Hz, 1H), 8.42(d, J=5.2Hz, 1H), 7.44(s, 1H), 7.21(d, J=5.0Hz, 1H), 6.56(s, 1H), 4.17-4.0 4(m, 4H), 3.63(s, 3H), 2.40(dd, J=7.9, 12.0Hz, 1H), 2.26(s, 3H), 2.22-2.19(m, 1H), 2.17(s, 6H), 1.16-1.11(m, 3H); HRMS(ESI) C19H27N9O[M+H] + The calculated value for this is 398.2412, and the measured value is 398.2413.

[0412] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(1,5-dimethyl-1H-pyrazole-3-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 74)[(I), R1=1,5-dimethylpyrazole-3-yl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0413] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.53(s, 1H), 8.47(d, J=8.2Hz, 1H), 8.42(d, J=5.0Hz, 1H), 7.44(s, 1H), 7.21(d, J=5.0Hz, 1H), 6.57(s, 1H), 4.13(s, 3H), 3.97-3.87(m, 1H) ), 3.63(s, 3H), 3.29-3.02(m, 4H), 2.47(d, J=7.0Hz, 0H), 2.42-2.35(m, 1H), 2.27(s, 3H), 1.94(quin, J=6.9Hz, 2H), 1.11(d, J=6.7Hz, 3H); HRMS(ESI) C20H27N9O[M+H] + The calculated value for this is 410.2412, and the measured value is 410.2407.

[0414] N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-3-{2-[(1-methyl-1H-pyrazole-4-yl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 75)[(I), R1=1-methylpyrazole-4-yl, R2=methyl, R3=(2S)-1-(dimethylamino)propan-2-yl, R4=H]

[0415] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 9.49(br. s., 1H), 8.46(d, J=8.4Hz, 1H), 8.43(d, J=5.0Hz, 1H), 7.97(br. s., 1H), 7.61-7.40(m, 2H), 7.17(d, J=5.0Hz, 1H), 4.14(s, 3H), 4.11(s, 0H), 3.84(s, 3H) ), 2.40(dd, J=7.9, 12.2Hz, 1H), 2.24-2.19(m, 1H), 2.17(s, 6H), 1.14(d, J=6.7Hz, 3H); HRMS(ESI) C20H27N9O[M+H] + The calculated value for this is 410.2412, and the measured value is 410.2407.

[0416] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-1-methyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-yl]-1H-pyrazole-5-carboxamide (compound 76)[(I), R1=oxan-4-yl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0417] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 8.36(d, J=8.2Hz, 1H), 8.30(d, J=4.9Hz, 1H), 7.37(s, 1H), 7.09(br. s., 1H), 7.03(d, J=5.0Hz, 1H), 4.11(s, 3H), 4.06-3.95(m, 1H), 3.94-3.83(m, 3H), 3.40(t, J=11.4Hz, 2H), 3.12(qd, J=6.5, 19.5Hz, 4 H), 2.48-2.44(m, 1H), 2.39-2.33(m, 1H), 1.94(quin, J=6.9Hz, 2H), 1.84(d, J=12.4Hz, 2H), 1.59-1.47(m, 2H), 1.10(d, J=6.7Hz, 3H); HRMS(ESI) C20H29N7O2[M+H] + The calculated value for this is 400.2456, and the measured value is 400.2455.

[0418] N,N,1-trimethyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-yl]-1H-pyrazole-5-carboxamide (compound 77)[(I), R1=oxan-4-yl, R2=methyl, R3=methyl, R4=methyl]

[0419] [ka] 1H NMR (500MHz, DMSO-d6) δppm 8.30 (d, J=4.9Hz, 1H), 7.15 (d, J=7.6Hz, 1H), 7.03 (d, J=5.2Hz, 1H), 6.96 (br. s., 1H), 3.98 (br. HRMS(ESI) C16H22N6O2[M+H] + The calculated value for this is 331.1877, and the measured value is 331.187.

[0420] 3-{2-[(3-cyano-5-methoxyphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 78)[(I), R1=3-cyano-5-methoxyphenyl, R2=methyl, R3=(2S)-1-(dimethylamino)propan-2-yl, R4=H]

[0421] [ka] 1 1H NMR (500MHz, DMSO-d6) δppm 10.01(s, 1H), 8.59(d, J=5.2Hz, 1H), 8.44(d, J=8.4Hz, 1H), 7.91(t, J=2.1Hz, 1H), 7.83(t, J=1.5Hz, 1H), 7.46(s, 1H), 7.36(d, J=5.2Hz, 1H), 7.01(dd, J=1.3, 2.4Hz, 1H), 4.13(s, 3H), 4.10(s, 0H), 3.83(s, 3H), 2. 41-2.34(m, 1H), 2.22-2.18(m, 1H), 2.17(s, 5H), 1.13(d, J=6.6Hz, 3H); HRMS(ESI) C22H26N8O2[M+H] + The calculated value for this is 435.2252, and the measured value is 435.2252.

[0422] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-cyano-5-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 79)[(I), R1=3-cyano-5-methoxyphenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0423] [ka] 1 H NMR (500MHz, DMSO-d6) δppm 10.01(s, 1H), 8.59(d, J=5.2Hz, 1H), 8.41(d, J=8.4Hz, 1H), 7.91(t, J=2.1Hz, 1H), 7.83(t, J=1.5Hz, 1H), 7.46(s, 1H), 7.36(d, J=5.0Hz, 1H), 7.01(dd, J=1.4, 2.3Hz, 1 H), 4.13(s, 3H), 3.96-3.87(m, 1H), 3.83(s, 3H), 3.19-3.06(m, 4H), 2.46(dd, J=7. 0, 11.6Hz, 1H), 2.40-2.33(m, 1H), 1.94(quin, J=7.0Hz, 2H), 1.10(d, J=6.7Hz, 3H); HRMS(ESI) C23H26N8O2[M+H] + The calculated value for this is 447.2252, and the measured value is 447.2251.

[0424] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(5-methoxypyridine-3-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 80)[(I), R1=5-methoxypyridine-3-yl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0425] [ka] 1H NMR (500MHz, DMSO-d6) δppm 9.89(s, 1H), 8.56(d, J=5.2Hz, 1H), 8.52(d, J=2.0Hz, 1H), 8.44(d, J=8.4Hz, 1H), 8.12(t, J=2.3Hz, 1H), 7.91(d, J=2.6Hz, 1H), 7.47(s, 1H), 7.34(d, J=5.0Hz, 1H), 4.14(s, 3H), 3.95-3.88(m, 1H), 3.86(s, 3H), 3.19-3.06(m, 4H), 2.46(dd, J=7.0, 11.7Hz, 1H), 2.40-2.32(m, 1H), 1.94(quin, J=6.9Hz, 2H), 1.10(d, J=6.7Hz, 3H); HRMS(ESI) C21H26N8O2[M+H] + The calculated value for this is 423.2252, and the measured value is 423.2252.

[0426] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(3S)-piperidine-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (compound 81)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(3S)-piperidine-3-yl, R4=H]

[0427] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.49(s, 1H), 8.99-8.90(br. s. 1 H, 8.85(d, J=7.8Hz, 1H), 8.87-8.80(br. s., 1H), 8.50(d, J=5.03Hz, 1H), 7.52(s, 1H), 7.47(s, 2H), 7.26(d, J=5.2Hz, 1H), 6.62(s, 1H), 4.14(s, 3H), 3.33(m Partially overlaps with the water signal, 2H, 3.22-3.14 (m, 1H), 2.92-2.77 (m, 2H), 2.27 (s, 6H), 1.95-1.50 (m, 4H).; HRMS(ESI) C22H28N7OCl[M+H] + The calculated value for this is 406.235, and the measured value is 406.2349.

[0428] N-(2-aminocyclohexyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 82)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=2-aminocyclohexyl, R4=H]

[0429] [ka] 1 H NMR (500 MHz, DMSO-d6) δ ppm (s, 1H), 8.79 (d, J=8.7Hz, 1H), 8.50 (d, J=5.2Hz, 1H), 7.85 (br. s., 3H), 7.51(s, 1H), 7.48(s, 2H), 7.26(d, J=5.0Hz, 1H), 6.62(s, 1H), 4.15(s , 3H), 3.88-3.80(m, 1H), 3.00-2.90(m, 1H), 2.27(s, 6H), 2.10-1.20(m, 8H).; HRMS(ESI) C23H30N7OCl[M+H] + The calculated value for this is 420.2507, and the measured value is 420.2503.

[0430] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[2-(pyrrolidine-1-yl)ethyl]-1H-pyrazole-5-carboxamide (compound 83)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=2-pyrrolidine-1-ylethyl, R4=H]

[0431] [ka] 1H NMR (500 MHz, DMSO-d6) δppm 9.47 (s, 1H), 8.86 (br. s., 1H), 8.50(d, J=5.0Hz, 1H), 7.48-7.42(m, 3H), 7.26(d, J=5.2Hz, 1H), 6.62(s, 1H), 4.15(s, 3H), 3.44(br. s., 2H), 2.70(br. s. 2H), 1.79(br. s. 4H),; HRMS(ESI) C23H29N7O[M+H] + The calculated value for this is 420.2507, and the measured value is 420.2491.

[0432] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[2-(piperidine-1-yl)ethyl]-1H-pyrazole-5-carboxamide (compound 84)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=2-piperidine-1-ylethyl, R4=H]

[0433] [ka] 1 ¹H NMR (500 MHz, DMSO-d6) δppm 9.46 (s, 1H), 8.72 (br. s., 1H), 8.49 (d, J=5.0Hz, 1H), 7.46 (s, 2H), 7.41 (s, 1H), 7.26 (d, J=5.0Hz, 1H), 6.62 (s, 1H), 4.14 (s, 3H), 3.34 (br. s. 2H), 2.41 (br. s., 6H), 2.27 (s, 6H), 1.67-1.30 (m, 6H).; HRMS (ESI) C24H31N7O[M+H] + The calculated value for this is 434.2663, and the measured value is 434.2661.

[0434] (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)[(3R)-3-hydroxypyrrolidine-1-yl]methanone (compound 85)[(I), R1=3,5-dimethylphenyl, R2=methyl, NR3R4=(3R)-3-hydroxypyrrolidine-1-ylamino]

[0435] [ka] 1 H NMR (500 MHz, DMSO-d6) (mixture of conformers) δppm 9.53 and 9.52 (2xs, 1H), 8.50 (d, J=5.0Hz, 1H), 7.48 (d, J=2.7Hz, 2H), 7.27 (d, J=5.0Hz, 1H), 7.22 and 7.16(2xs, 1H), 6.60(s, 1H), 5.07(t, J=3.9Hz, 1H), 4.35 and 4.31(2xm, 1H), 4.05(s, 3H), 3.81-3.40(m, 4H), 2.25(s, 6H), 2.03-1.80(m, 2H).; HRMS(ESI) C21H24N6O2[M+H] + The calculated value for this is 393.2034, and the measured value is 393.203.

[0436] [(3S)-3-(dimethylamino)pyrrolidine-1-yl](3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)methanone (compound 86)[(I), R1=3,5-dimethylphenyl, R2=methyl, NR3R4=(3S)-3-(dimethylamino)pyrrolidine-1-ylamino]

[0437] [ka] 1H NMR (500 MHz, DMSO-d6) (mixture of conformers) δppm 9.52(s, 1H), 8.50(d, J=5.2Hz, 1H), 7.48(s, 2H), 7.28 and 7.26(2xd J=5.2Hz, 1H), 7.18 and 7.17(2xs, 1H), 6.60(s, 1H), 4.04 and 4.03(2xs, 3H), 3.86-3.21(m, 4H), 2.80-2.70(m, 1H), 2.25(s, 6H), 2.19(s, 3H), 2.14(s, 3H), 2.12-2.00(m, 1H), 1.84-1.70(m, 1H).; HRMS(ESI) C23H29N7O[M+H] + The calculated value for this is 420.2507, and the measured value is 420.2506.

[0438] [(3R)-3-(dimethylamino)pyrrolidine-1-yl](3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)methanone (compound 87)[(I), R1=3,5-dimethylphenyl, R2=methyl, NR3R4=(3R)-3-(dimethylamino)pyrrolidine-1-ylamino]

[0439] [ka] 1 H NMR (500 MHz, DMSO-d6) (mixture of conformers) δppm 9.52(s, 1H), 8.50(d, J=5.2Hz, 1H), 7.48(s, 2H), 7.28 and 7.26(2xd J=5.2Hz, 1H), 7.18 and 7.17(2xs, 1H), 6.60(s, 1H), 4.04 and 4.03(2xs, 3H), 3.86-3.21(m, 4H), 2.80-2.70(m, 1H), 2.25(s, 6H), 2.19(s, 3H), 2.14(s, 3H), 2.12-2.00(m, 1H), 1.84-1.70(m, 1H).; HRMS(ESI) C23H29N7O[M+H] + The calculated value for this is 420.2507, and the measured value is 420.2503.

[0440] (3-aminopyrrolidine-1-yl)(3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)methanone (compound 88) [(I), R1=3,5-dimethylphenyl, R2=methyl, NR3R4=3-aminopyrrolidine-1-ylamino]

[0441] [ka] 1 H NMR (500 MHz, DMSO-d6) (mixture of conformers) δppm 9.54 and 9.52 (2xs, 1H), 8.50 (d, J=5.0Hz, 1H), 7.48 (s, 2H), 7.27 and 7.26 (2xd, J=5.0Hz, 1H), 7.22 and 7.15(2xs, 1H), 6.60(s, 1H), 4.05(s, 3H), 3.84-3.22(m, 5H), 2.25(s, 6H), 2.04-1.95(m, 1H), 1.73-1.64(m, 1H).; HRMS(ESI) C21H25N7O[M+H] + The calculated value for this is 392.2194, and the measured value is 392.2194.

[0442] (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]methanone (compound 89)[(I), R1=3,5-dimethylphenyl, R2=methyl, NR3R4=(2S)-2-(hydroxymethyl)pyrrolidine-1-ylamino]

[0443] [ka] 1H NMR (500 MHz, DMSO-d6) (mixture of conformers) δppm 9.51 (s, 1H), 8.49 (d, J=5.0Hz, 1H), 7.48 (s, 2H), 7.26 (d, J=5.0Hz, 1H), 7.18 and 7.10(2xs, 1H), 6.60(s, 1H), 4.91 and 4.82(2xt, J=5.8Hz, 1H), 4.18 and 4.12(2xm, 1H), 4.03 and 3.93(2xs, 3H), 3.70-3.15(m, 4H), 2.25(s, 6H), 2.00-1.74(m, 4H).; HRMS(ESI) C22H26N6O2[M+H] + The calculated value for this is 407.219, and the measured value is 407.2193.

[0444] (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)[(3S)-3-hydroxypyrrolidine-1-yl]methanone (compound 90)[(I), R1=3,5-dimethylphenyl, R2=methyl, NR3R4=(3S)-3-hydroxypyrrolidine-1-ylamino]

[0445] [ka] 1 ¹H NMR (500 MHz, DMSO-d6) (mixture of conformational isomers) δppm 9.53 and 9.52 (2xs, 1H), 8.50 (d, J=5.0Hz, 1H), 7.48 (s, 2H), 7.27 (d, J=5.0Hz, 1H), 7.22 and 7.16 (2xs, 1H), 6.60 (s, 1H), 5.09 and 5.08 (2xd, J=4.6Hz, 1H), 4.35 and 4.32 (2xm, 1H), 4.05 and 4.04 (2xs, 3H), 3.78-3.54 (m, 4H), 2.25 (s, 6H), 2.03-1.80 (m, 2H).; HRMS (ESI) C21H24N6O2[M+H] + The calculated value for this is 393.2034, and the measured value is 393.2027.

[0446] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(1R,2S)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 91)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(1R,2S)-2-hydroxycyclohexyl, R4=H]

[0447] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.47(s, 1H), 8.49(d, J=5.0Hz, 1H), 8.15(d, J=7.8Hz, 1H), 7.49(s, 1H), 7.48(s, 2H), 7.25(d, J=5.0Hz, 1H), 6.61(s, 1H), 4.65(d, J=3.8Hz, 1H), 4.12(s, 3H), 3.85(m, 1H), 3.83(m, 1H), 2.26(s, 6H), 1.77-1.25(m, 8H).; HRMS(ESI) C23H28N6O2[M+H] + The calculated value for this is 421.2347, and the measured value is 421.2345.

[0448] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 92)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(1S,2R)-2-aminocyclohexyl, R4=H]

[0449] [ka] 1¹H NMR (500 MHz, DMSO-d6) δppm 9.51 (s, 1H), 8.50 (d, J=5.0Hz, 1H), 8.47 (d, J=7.9Hz, 1H), 7.87 (br. s., 3H), 7.60 (s, 1H), 7.51 (s, 2H), 7.27 (d, J=5.0Hz, 1H), 6.62 (s, 1H), 4.33 (m, 1H), 4.14 (s, 3H), 3.37 (m, 1H, overlapping with water signal), 2.28 (s, 6H), 1.80-1.34 (m, 8H).; HRMS (ESI) C23H30N7OCl[M+H] + The calculated value for this is 420.2507, and the measured value is 420.2509.

[0450] N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-3-{2-[(1,2,3-trimethyl-1H-indole-5-yl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 93)[(I), R1=1,2,3-trimethylindole-5-yl, R2=methyl, R3=(2S)-1-hydroxypropan-2-yl, R4=H]

[0451] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.32 (s, 1H), 8.44 (d, J=5.0Hz, 1H), 8.43 (d, J=7.3Hz, 1H), 8.10 (br. s., 1H), 7.46(s, 1H), 7.29(dd, J=8.7, 2.0Hz, 1H), 7.25(d, J=8.7Hz, 1H), 7.18(d, J=5 .0Hz, 1H), 4.75(t, J=5.8Hz, 1H), 4.13(s, 3H), 3.99(m, 1H), 3.62(s, 3H), 3.47-3.30(m Partially overlaps with the water signal, 2H), 2.32(s, 3H), 2.20(s, 3H), 1.13(d, J=6.7Hz, 3H).; HRMS(ESI) C23H27N7O2[M+H] + The calculated value for this is 434.2299, and the measured value is 434.2291.

[0452] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidine-1-yl)propane-2-yl]-1H-pyrazole-5-carboxamide (compound 94)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(2S)-1-pyrrolidine-1-ylpropane-2-yl, R4=H]

[0453] [ka] 1 ¹H NMR (500 MHz, DMSO-d6) δppm 9.47 (s, 1H), 8.54 (d, J=8.1Hz, 1H), 8.49 (d, J=5.0Hz, 1H), 7.48 (s, 2H), 7.45 (s, 1H), 7.25 (d, J=5.0Hz, 1H), 6.62 (s, 1H), 4.13 (s, 3H), 4.17-4.07 (m, 1H), 2.60-2.35 (m, 6H, partially overlapping with the DMSO signal), 2.27 (s, 6H), 1.72-1.62 (m, 4H), 1.14 (d, J=6.6Hz, 3H).; HRMS (ESI) C24H31N7O[M+H] + The calculated value for this is 434.2663, and the measured value is 434.2684.

[0454] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 95)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0455] [ka] 1¹H NMR (500 MHz, DMSO-d6) δppm 9.50 (s, 1H), 8.55 (br. s., 1H), 8.52 (d, J=5.0Hz, 1H), 7.51 (s, 2H), 7.48 (s, 1H), 7.29 (d, J=5.0Hz, 1H), 6.65 (s, 1H), 4.17 (s, 3H), 4.05-3.94 (m, 1H), 3.50-3.10 (m, 6H, partially overlapping with the water signal), 2.30 (s, 6H), 2.10-1.93 (m, 2H), 1.14 (d, J=6.7Hz, 3H).; HRMS (ESI) C23H29N7O[M+H] + The calculated value for this is 420.2507, and the measured value is 420.252.

[0456] (1S,4R)-2,5-diazabicyclo[2.2.1]hepta-2-yl(3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)methanone hydrochloride (compound 96) [(I), R1=3,5-dimethylphenyl, R2=methyl, NR3R4=(1S,4R)-2,5-diazabicyclo[2.2.1]heptan-2-ylamino]

[0457] [ka] 1 ¹H NMR (500 MHz, DMSO-d6) (mixture of conformational isomers) δppm 9.55 and 9.54 (2xs, 1H), 9.45 and 9.38 (2x br.s., 1H), 9.07 and 8.97 (2x br.s., 1H), 8.51 and 8.50 (2xd, J=5.2Hz, 1H), 7.48 and 7.45 (2xs, 2H), 7.30 and 7.27 (2xd, J=5.2Hz, 1H), 7.18 and 7.12 (2xS, 1H), 6.61 (s, 1H), 4.87 and 4.82 (2xs, 1H), 4.50 and 4.44 (2xs, 1H), 4.09 and 4.02(2xs, 3H), 3.95-3.24(m, 4H), 2.26(s, 6H), 2.22-1.80(m, 2H).; HRMS(ESI) C22H26N7OCl[M+H] +The calculated value for this is 404.2194, and the measured value is 404.2199.

[0458] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(3R)-piperidine-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (compound 97)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(3R)-piperidine-3-yl, R4=H]

[0459] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.49(s, 1H), 8.85(m, 4H), 8.50(d, J=5.19Hz, 1H), 7.52(s, 1H), 7.47(s, 2H), 7.26(d, J=5.03Hz, 1H), 6.62(s, 1H), 4.14(s, 3H), 3.42-2.74(m. br., 5H)2.27(s, 6H), 1.98-1.53(m. br., 4H); HRMS(ESI) C22H28N7OCl[M+H] + The calculated value for this is 406.235, and the measured value is 406.235.

[0460] N-[(1R,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 98)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(1R,2S)-2-aminocyclohexyl, R4=H]

[0461] [ka] 1¹H NMR (500 MHz, DMSO-d6) δppm 9.51 (s, 1H), 8.50 (d, J=5.03Hz, 1H), 8.47 (d, J=8.08Hz, 1H), 7.87 (d, J=3.66Hz, 3H), 7.60 (s, 1H), 7.51 (s, 2H), 7.27 (d, J=5.03Hz, 1H), 6.62 (s, 1H), 4.33 (br. s., 1H), 4.14 (s, 3H), 3.35 (m. overlaps with water signal, 1H), 2.28 (s, 6H), 185-1.30 (m. 8H); HRMS (ESI) C23H30N7OCl[M+H] + The calculated value for this is 420.2507, and the measured value is 420.2514.

[0462] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 99)[(I), R1=(3,5-dichlorophenyl), R2=methyl, R3=(1S,2R)-2-aminocyclohexyl, R4=H]

[0463] [ka] 1 ¹H NMR (500 MHz, DMSO-d6) δppm 10.12 (s, 1H), 8.62 (d, J=5.19Hz, 1H), 8.43 (d, J=7.78Hz, 1H), 8.02 (d, J=1.83Hz, 2H), 7.90 (d, J=3.51Hz, 3H), 7.59 (s, 1H), 7.40 (d, J=5.03Hz, 1H), 7.15 (t, J=1.83Hz, 1H), 4.32 (br. s., 1H), 4.14 (s, 3H), 3.48-3.40 (m overlapping with water signal, 1H), 1.86-1.32 (m, 8H); HRMS (ESI) C21H24N7OCl3[M+H] + The calculated value for this is 460.1414, and the measured value is 460.1419.

[0464] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 100)[(I), R1=3,5-dimethoxyphenyl, R2=methyl, R3=(1S,2R)-2-aminocyclohexyl, R4=H]

[0465] [ka] 1 ¹H NMR (500 MHz, DMSO-d6) δppm 9.62 (s, 1H), 8.53 (d, J=5.03Hz, 1H), 8.43 (d, J=7.78Hz, 1H), 7.89 (d, J=3.36Hz, 3H), 7.60 (s, 1H), 7.31 (d, J=5.19Hz, 1H), 7.20 (d, J=2.14Hz, 2H), 6.13 (t, J=2.21Hz, 1H), 4.31 (br. s., 1H), 4.13 (s, 3H), 3.76 (s, 6H), 3.48-3.40 (m, overlapping with water signal, 1H), 1.88-1.33 (m, 8H); HRMS (ESI) C23H30N7O3Cl[M+H] + The calculated value for this is 452.2405, and the measured value is 452.2396.

[0466] N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 101)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(1S,2S)-2-aminocyclohexyl, R4=H]

[0467] [ka] 1H NMR (500 MHz, DMSO-d6) δppm 9.47(s, 1H), 8.52(d, J=8.39Hz, 1H), 8.49(d, J=5.03Hz, 1H), 7.49(s, 1H), 7.48(s, 2H), 7.25(d, J=5.03Hz, 1H) , 6.61(s, 1H), 4.13(s, 3H), 3.40-3.50(m, 1H), 2.54(td, J=10.90, 4.10Hz, 1H), 2.27(s, 6H), 1.90-1.17(m, 8H); HRMS(ESI) C23H29N7O[M+H] + The calculated value for this is 420.2507, and the measured value is 420.2515.

[0468] N-[(2S)-1-(azetidine-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 102)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)-3-methylbutan-2-yl, R4=H]

[0469] [ka] 1 ¹H NMR (500 MHz, DMSO-d6) δppm 9.49 (s, 1H), 8.85 (d, J=7.78Hz, 1H), 8.50 (d, J=5.19Hz, 1H), 7.52 (s, 1H), 7.47 (s, 2H), 7.26 (d, J=5.03Hz, 1H), 6.62 (s, 1H), 4.14 (s, 3H), 4.13-4.09 (m. br., 1H), 3.90-3.20 (m. 6H) (overlaps with water signal) (2.27 (s, 6H), 2.17-2.07 (m. br., 2H), 1.85-1.74 (m, 1H), 0.93-0.85 (m, 6H); HRMS (ESI) C25H33N7O[M+H] + The calculated value for this is 448.282, and the measured value is 448.2822.

[0470] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-3-methyl-1-(pyrrolidine-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (compound 103)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(2S)-3-methyl-1-pyrrolidine-1-ylbutan-2-yl, R4=H]

[0471] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.49(s, 1H), 8.49(d, J=5.0Hz, 1H), 8.41(d, J=9.0Hz, 1H), 7.50(s, 2H), 7.48(s, 1H), 7.27(d, J=5. 0Hz, 1H), 6.61(s, 1H), 4.11(s, 3H), 4.03-3.92(m, 1H), 2.59(dd, J=9.1, 12.1Hz, 1H), 2.53-2.47(m. The DMSO signal overlaps with the following frequencies: 2H)2.47(dd, J=4.7, 12.2Hz, 1H), 2.40(s, 2H), 2.27(s, 6H), 1.94-1.77(m, 1H), 1.65(br. s., 4H), 0.90(d, J=8.2Hz, 3H), 0.89(d, J=8.4Hz, 3H); HRMS(ESI) C26H35N7O[M+H] + The calculated value for this is 462.2976, and the measured value is 462.2983.

[0472] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide hydrochloride (compound 104)[(I), R1=3,5-dimethylphenyl, R2=H, R3=(1S,2R)-2-aminocyclohexyl, R4=H]

[0473] [ka] 1¹H NMR (500 MHz, DMSO-d6) δppm 14.5-13.5 (br. s., 1H), 9.49 (s, 1H), 8.53 (d, J=5.19Hz, 1H), 8.21 (br. s., 1H), 7.90 (d, J=2.90Hz, 3H), 7.54 (br. s., 1H), 7.48 (s, 2H), 7.34 (d, J=5.03Hz, 1H), 6.63 (s, 1H), 4.33 (br. s., 1H), 3.50-3.40 (m, overlapping with water signal, 1H), 2.27 (s, 6H), 1.90-1.17 (m, 8H); HRMS (ESI) C22H28N7OCl[M+H] + The calculated value for this is 406.235, and the measured value is 406.236.

[0474] N-[(2S)-1-(azetidine-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 105)[(I), R1=3,5-dimethylphenyl, R2=H, R3=(2S)-1-(azetidine-1-yl)-3-methylbutan-2-yl, R4=H]

[0475] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 13.98 (br. s., 1H), 9.45 (s, 1H), 8.51 (d, J=3.66Hz, 1H), 8.22 (br. s., 1H), 7.48(s, 3H), 7.31(d, J=5.03Hz, 1H), 6.62(s, 1H), 3.70-3.82(m, 1H), 3.20-3.05(m. HRMS(ESI) C24H31N7O[M+H] + The calculated value for this is 434.2663, and the measured value is 434.2668.

[0476] N-[(1S)-1-cyclohexyl-2-hydroxyethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 106)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(1S)-1-cyclohexyl-2-hydroxyethyl, R4=H]

[0477] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.49(s, 1H), 8.49(d, J=5.19Hz, 1H), 8.37(d, J=9.00Hz, 1H), 7.51(s, 1H), 7.50(s, 2H), 7.26(d, J=5.19Hz, 1H), 6.61(s, 1H) , 4.57(t, J=5.72Hz, 1H), 4.12(s, 3H), 3.74-3.86(m, 1H), 3.50-3.58(m, 1H), 3.44-3.50(m, 1H), 2.27(s, 6H), 1.80-0.95(m. 11H); HRMS(ESI) C25H32N6O2[M+H] + The calculated value for this is 449.266, and the measured value is 449.2665.

[0478] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(1S)-1-phenyl-2-(pyrrolidine-1-yl)ethyl]-1H-pyrazole-5-carboxamide (compound 107)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(1S)-1-phenyl-2-pyrrolidine-1-ylethyl, R4=H]

[0479] [ka] 1H NMR (500 MHz, DMSO-d6) δppm 9.50(s, 1H), 9.15(d, J=8.4Hz, 1H), 8.50(d, J=5.0Hz, 1H), 7.60(s, 1H), 7.51(s, 2H), 7.43(d, J=7.3Hz, 2H), 7.33(t, J=7.5Hz, 2H), 7.28-7.25(m, 2H), 6.63(s, 1H), 5.19-5.10(m, 1H), 4.10(s, 3H), 2.97(t, J=10.9Hz, 2H), 2.60-2.48(m, 4H), 2.30(s, 6H), 1.67(br. s., 4H); HRMS(ESI) C29H33N7O[M+H] + The calculated value for this is 496.282, and the measured value is 496.2823.

[0480] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 108)[(I), R1=3-methylphenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0481] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.55(s, 1H), 8.50(d, J=5.19Hz, 1H), 8.46(d, J=8.39Hz, 1H), 7.69(s, 1H), 7.63(d, J=8.24Hz, 1H), 7.46(s, 1H), 7.27(d, J=5.03Hz, 1 H), 7.18(t, J=7.78Hz, 1H), 6.79(d, J=7.63Hz, 1H), 4.14(s, 3H), 3.92(dquin, J=13.93, 6.77, 6.77, 6.77, 6.77Hz, 1H), 3.38-3.29(m. Overlapping with the water signal, 2H), 3.04-3.24(m, 4H), 2.32(s, 3H), 2.00-1.90(m, 2H), 1.10(d, J=6.71Hz, 3H); HRMS(ESI) C22H27N7O[M+H] +The calculated value for this is 406.235, and the measured value is 406.2349.

[0482] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 109)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(2S)-1-hydroxy-3-phenylpropan-2-yl, R4=H]

[0483] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.47(s, 1H), 8.55(d, J=8.5Hz, 1H), 8.49(d, J=5.2Hz, 1H), 7.48(s, 2H), 7.44(s, 1H), 7.31-7.12(m, 6H), 6.62(s, 1H), 4.87(t, J=5.6Hz, 1H), 4 .18-4.08(m, 1H), 4.04(s, 3H), 3.54-3.46(m, 1H), 3.46-3.40(m, 1H), 2.95(dd, J=4.7, 13.7Hz, 1H), 2.73(dd, J=9.5, 13.9Hz, 1H), 2.29(s, 6H); HRMS(ESI) C26H28N6O2[M+H] + The calculated value for this is 457.2347, and the measured value is 457.2354.

[0484] 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]aminopyrimidine-4-yl)-N-[(2S)-1-hydroxypropane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 110)[(I), R1=3-chloro-4-(4-methylpiperazine-1-yl)phenyl, R2=methyl, R3=(2S)-1-hydroxypropane-2-yl, R4=H]

[0485] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.67(s, 1H), 8.51(d, J=5.03Hz, 1H), 8.41(d, J=8.08Hz, 1H), 7.95(d, J=2.44Hz, 1H), 7.76(dd, J=8.77, 2.36Hz, 1H), 7.47(s, 1H), 7 .27(d, J=5.19Hz, 1H), 7.14(d, J=8.85Hz, 1H), 4.76(t, J=5.80Hz, 1H), 4.13(s, 3H), 3.94-4.03(m, 1H), 3.45-3.36(m, 2H), 2.93(br. s, 4H), 2.54-2.43(m, br, partially overlapping with water, 4H), 2.23(s, 3H)1.14(d, J=6.71Hz, 3H); HRMS(ESI) C23H29N8O2Cl[M+H] + The calculated value for this is 485.2175, and the measured value is 485.2172.

[0486] 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]amino}pyrimidine-4-yl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 111)[(I), R1=3-chloro-4-(4-methylpiperazine-1-yl)phenyl, R2=methyl, R3=(2S)-1-hydroxy-3-methylbutan-2-yl, R4=H]

[0487] [ka] 1H NMR (500 MHz, DMSO-d6) δppm 9.69(s, 1H), 8.51(d, J=5.2Hz, 1H), 8.31(d, J=9.0Hz, 1H), 8.02(d, J=2.6Hz, 1H), 7.70(dd, J=2.5, 8.8Hz, 1H), 7.51-7.46(m, 1H), 7.28(d, J=5.2Hz, 1H), 7.12(d, J=8.8Hz, 1H), 4.61(t, J=5.6Hz, 1H), 4.12(s, 3H), 3.84-3.74(m, 1H), 3.60-3.44(m, 2H), 2.92(br. HRMS(ESI) C25H33N8O2Cl[M+H] + The calculated value for this is 513.2488, and the measured value is 513.2498.

[0488] 1-Methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-3-methyl-1-(pyrrolidine-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (compound 112)[(I), R1=3-methylphenyl, R2=methyl, R3=(2S)-3-methyl-1-pyrrolidine-1-ylbutan-2-yl, R4=H]

[0489] [ka] 1H NMR (500 MHz, DMSO-d6) δppm 9.56(s, 1H), 8.50(d, J=5.2Hz, 1H), 8.39(d, J=9.0Hz, 1H), 7.79(s, 1H), 7.56(d, J=8.4Hz, 1H), 7.50-7.47(m, 1H), 7.28(d, J=5.0H) z, 1H), 7.16(t, J=7.8Hz, 1H), 6.79(d, J=7.5Hz, 1H), 4.12(s, 3H), 3.98(td, J=4.4, 9.3Hz, 1H), 2.63-2.57(m, 1H), 2.52-2.47(br. m., partially overlapping with water, 3H), 2.44-2.38(m, 2H), 2.32(s, 3H), 1.86(dd, J=6.6, 12.4Hz, 1H), 1.65(br. s., 4H), 0.90(t, J=7.3Hz, 6H); HRMS(ESI) C25H33N7O[M+H] + The calculated value for this is 448.282, and the measured value is 448.2827.

[0490] N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-difluorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 113)[(I), R1=3,5-difluorophenyl, R2=methyl, R3=(1S,2S)-2-aminocyclohexyl, R4=H]

[0491] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 10.11(s, 1H), 8.59(d, J=5.03Hz, 1H), 8.49(d, J=8.39Hz, 1H), 7.62(dd, J=10.45, 2.21Hz, 2H), 7.50(s, 1H), 7.38(d, J=5.03 Hz, 1H), 6.76(tt, J=9.21, 2.31Hz, 1H), 4.14(s, 3H), 3.41-3.50(m, 1H), 2.55(td, J=10.50, 3.50Hz, 1H), 1.93-1.18(m, 8H); HRMS(ESI) C21H23N7OF2[M+H] +The calculated value for this is 428.2005, and the measured value is 428.2004.

[0492] 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]aminopyrimidine-4-yl)-N-[(1S,2R)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 114)[(I), R1=3-chloro-4-(4-methylpiperazine-1-yl)phenyl, R2=methyl, R3=(1S,2R)-2-hydroxycyclohexyl, R4=H]

[0493] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.69(s, 1H), 8.51(d, J=5.18Hz, 1H), 8.13(d, J=7.78Hz, 1H), 7.97(d, J=2.59Hz, 1H), 7.76(dd, J=8.69, 2.44Hz, 1H), 7.49 (s, 1H), 7.28(d, J=5.19Hz, 1H), 7.13(d, J=8.85Hz, 1H), 4.68(d, J=3.81Hz, 1H), 4.13(s, 3H), 3.78-3.92(m, 2H), 2.92(br. s., 4H), 2.54-2.42(m. br., partially overlapping with water, 4H), 2.23(s, 3H), 1.78-1.15(m, 8H); HRMS(ESI) C26H33N8O2Cl[M+H] + The calculated value for this is 525.2488, and the measured value is 525.2492.

[0494] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(1S,2R)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 115)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(1S,2R)-2-hydroxycyclohexyl, R4=H]

[0495] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.48(s, 1H), 8.49(d, J=5.03Hz, 1H), 8.16(d, J=7.78Hz, 1H), 7.49(s, 1H), 7.48(s, 2H), 7.25(d, J=5.19Hz, 1H), 6.61(s, 1H), 4.64(d, J=3.81Hz, 1H), 4.12(s, 3H), 3.78-3.90(m, 2H), 2.27(s, 6H), 1.84-1.17(m, 8H); HRMS(ESI) C23H28N6O2[M+H] + The calculated value for this is 421.2347, and the measured value is 421.2345.

[0496] N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 116)[(I), R1=3,5-dichlorophenyl, R2=methyl, R3=(1S,2S)-2-aminocyclohexyl, R4=H]

[0497] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 10.10(s, 1H), 8.62-8.59(m, 1H), 8.49(d, J=8.4Hz, 1H), 8.00-7.97(m, 2H), 7.47(s, 1H), 7.38(d, J=5.0 Hz, 1H), 7.13(t, J=1.8Hz, 1H), 4.15-4.11(m, 3H), 3.49-3.41(m, 1H), 2.59-2.52(m, 1H), 1.88-1.09(m. 8H); HRMS(ESI) C21H23N7OCl2[M+H] + The calculated value for this is 460.1414, and the measured value is 460.1427.

[0498] 3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-3-methyl-1-(pyrrolidine-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (compound 117)[(I), R1=3,5-dichlorophenyl, R2=methyl, R3=(2S)-3-methyl-1-pyrrolidine-1-ylbutan-2-yl, R4=H]

[0499] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 10.10(s, 1H), 8.60(d, J=5.0Hz, 1H), 8.37(d, J=9.2Hz, 1H), 8.00(d, J=1.8Hz, 2H), 7.45(s, 1H), 7.40(d, J=5.0Hz, 1H), 7.13(t, J =1.8Hz, 1H), 4.17-4.08(m, 3H), 4.03-3.93(m, 1H), 2.63-2.54(m, 2H), 2.44-2.36(m, 4H), 1.86(dd, J=6.8, 12.4Hz, 1H), 1.65(br. s., 4H), 0.90(dd, J=7.1, 7.9Hz, 6H); HRMS(ESI) C24H29N7OCl2[M+H] + The calculated value for this is 502.1884, and the measured value is 502.1893.

[0500] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 118)[(I), R1=3,5-dimethylphenyl, R2=methyl, R3=(1S,2S)-2-hydroxycyclohexyl, R4=H]

[0501] [ka] 1¹H NMR (500 MHz, DMSO-d6) δppm 9.46 (s, 1H), 8.49 (d, J=5.0Hz, 1H), 8.46 (d, J=8.2Hz, 1H), 7.47 (s, 3H), 7.25 (d, J=5.2Hz, 1H), 6.61 (s, 1H), 4.61 (d, J=5.2Hz, 1H), 4.13 (s, 3H), 3.66-3.53 (m, 1H), 3.42-3.28 (m, overlapping with water, 1H), 2.27 (s, 6H), 1.97-1.76 (m, 2H), 1.64 (br. s, 2H), 1.35-1.13 (m, 4H); HRMS (ESI) C23H28N6O2[M+H] + The calculated value for this is 421.2347, and the measured value is 421.235.

[0502] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-cyanophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamidoformate (compound 119)[(I), R1=3-cyanophenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=H]

[0503] [ka] 1 ¹H NMR (500 MHz, DMSO-d6) δppm 10.04 (s, 1H), 8.59 (d, J=5.0Hz, 1H), 8.44 (d, J=8.4Hz, 1H), 8.31 (t, J=1.7Hz, 1H), 8.28 (s, 1H), 8.14 (dd, J=1.2, 8.4Hz, 1H), 7.52 (t, J=8.0Hz, 1H), 7.47 (s, 1H), 7.41 (d, J=7.8Hz, 1H), 7.36 (d, J=5.0Hz, 1H), 4.14 (s, 3H), 3.99-3.84 (m, 1H), 3.24-3.09 (m, 4H), 2.55-2.48 (m, partially overlapping with water) 1H)2.43-2.38(m, 1H), 1.95(quin, J=7.0Hz, 2H), 1.11(d, J=6.7Hz, 3H); HRMS(ESI) C23H26N8O3[M+H] +The calculated value for this is 417.2146, and the measured value is 417.2161.

[0504] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-ethyl-N-[(1S,2R)-2-hydroxycyclohexyl]-1H-pyrazole-5-carboxamide (compound 120)[(I), R1=3,5-dimethylphenyl, R2=ethyl, R3=(1S,2R)-2-hydroxycyclohexyl, R4=H]

[0505] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.49(s, 1H), 8.49(d, J=5.19Hz, 1H), 8.16(d, J=7.63Hz, 1H), 7.49(s, 2H), 7.48(s, 1H), 7.26(d, J=5.19Hz, 1H), 6.61(s, 1H) , 4.64(d, J=3.97Hz, 1H), 4.54(q, J=7.17Hz, 2H), 3.79-3.90(m, 2H), 2.26(s, 6H), 1.80-1.28(m, 8H), 1.38(t, J=7.17Hz, 3H); HRMS(ESI) C24H30N6O2[M+H] + The calculated value for this is 435.2503, and the measured value is 435.2502.

[0506] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-ethyl-1H-pyrazole-5-carboxamide hydrochloride (compound 121)[(I), R1=3,5-dimethylphenyl, R2=ethyl, R3=(1S,2R)-2-aminocyclohexyl, R4=H]

[0507] [ka] 1H NMR (500 MHz, DMSO-d6) δppm 9.51(s, 1H), 8.51(d, J=5.03Hz, 1H), 8.46(d, J=7.93Hz, 1H), 7.88(d, J=4.27Hz, 3H), 7.6 1(s, 1H), 7.52(s, 2H), 7.28(d, J=5.03Hz, 1H), 6.62(s, 1H), 4.66-4.45(m, 2H), 4.34(br. HRMS (ESI) C24H32N7OCl[M+H] + The calculated value for this is 434.2663, and the measured value is 434.2658.

[0508] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-ethyl-N-[(3R)-piperidine-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (compound 122)[(I), R1=3,5-dimethylphenyl, R2=ethyl, R3=(3R)-piperidine-3-yl, R4=H]

[0509] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.50(s, 1H), 8.95(d, J=9.46Hz, 1H), 8.86(d, J=7.47Hz, 1H), 8.78-8.89(m, 1H), 8.50(d, J=5.03Hz, 1H), 7.52(s, 1H), 7.48 (s, 2H), 7.27(d, J=5.19Hz, 1H), 6.62(s, 1H), 4.56(m, 2H), 4.09-4.22(m, 1H), 3.40-2.73(m, 4H)2.27(s, 6H), 1.95-1.55(m. 4H), 1.39(t, J=7.17Hz, 3H); HRMS(ESI) C23H30N7OCl[M+H] + The calculated value for this is 420.2507, and the measured value is 420.2513.

[0510] N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (compound 123)[(I), R1=3,5-dimethoxyphenyl, R2=methyl, R3=(2S)-1-(azetidine-1-yl)propan-2-yl, R4=methyl]

[0511] [ka] 1 H NMR (500 MHz, DMSO-d6) δppm 9.62(s, 1H), 8.49-8.55(m, 1H), 7.31(d, J=5.03Hz, 1H), 7.18(m. 3H), 6.13(br. s., 1H), 4.00(m. HRMS(ESI) C24H31N7O3[M+H] + The calculated value for this is 466.2561, and the measured value is 466.2564.

[0512] Biochemical kinase inhibition assay for SYK in KinaseGlo e ADPGlo assay format The recombinant protein SYK FL was produced as a His GST fusion protein via NMS in insect cells through baculovirus infection. In-house protein preparations were >80% homogeneous as determined by SDS-PAGE and were characterized by N-terminal sequencing analysis and electrospray mass spectrometry.

[0513] Immediately before the kinase reaction, SYK was pre-activated at a concentration of 1 μM using 400 μM ATP in a kinase buffer (50 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM DTT, 3 μM Na3VO4, and 0.2 mg / mL BSA) at 28°C for 60 minutes.

[0514] KinaseGlo assay format The compound was serially diluted threefold from 10 μM to 0.0005 μM and then incubated at room temperature for 60 minutes in 20 μL of kinase buffer (50 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM DTT, 3 μM Na3VO4, and 0.2 mg / mL BSA) in the presence of 2.5 μM ATP, 125 μM peptide substrate BioDBn*327, and 2.5 nM pre-activated enzyme. The final concentration of DMSO was 1%. The assay was performed in an automated format on a 384-well plate (Perkin Elmer cat.#6005301).

[0515] ADPGlo assay format 5 μL of the test compound, dissolved in 3% DMSO and serially diluted fourfold from 10 μM to 0.0006 μM, was pipetteed into a 384-well Optiplate (n*6005310-Perkin Elmer). 5 μL of 1.8 nM recombinant pre-activated SYK solution, diluted in specific kinase buffer, was added to the compound-containing plate and incubated at room temperature for 30 minutes. 5 μL of a mixture of ATP (adenosine 5'-triphosphate, disodium salt (Promega)) and the peptide substrate BioDBn*327 (TwinHelix), diluted in kinase buffer, was added to initiate the reaction. The final concentrations of pre-activated SYK, ATP, and BioDBn*327 were 0.6 nM, 60 μM, and 125 μM, respectively.

[0516] The reaction mixture was incubated at room temperature for 60 minutes, then stopped by adding Reagent 1 (15 μL) from the ADPGlo® kit (V9102-Promega).

[0517] After 60 minutes, ADPGlo® reagent 2 was added, and then the luminescence signal of the plate was measured using a Pherastar plate reader (BMG).

[0518] Data Analysis Each 384-well plate contained at least one curve for standard cpd, as well as reference wells for Z' and signal vs. background evaluation (total enzyme activity vs. completely inhibited enzyme) (J. Biomol. Screening, 1999, 4, 67-73). All information regarding raw data on plate dilution, distribution, and inhibition was tracked by barcode scanning and stored in an Oracle DB. Data for each molecule was analyzed using an internally customized version of the SW package "Assay Explorer," which uses a four-parameter logistic equation. y=bottom+(top-bottom) / (1+10^((logIC50-x)*slope)) [Here, x is the logarithm of the inhibitor concentration, and y is the response.] This provides a sigmoid fitting of eight dilution curves for determining IC50 using [the specified method].

[0519] IC50 is defined as the concentration of a compound required to inhibit 50% of maximum phosphorylation.

[0520] A representative compound of the present invention, represented by formula (I), was tested against Syk in the specific in vitro kinase assay described above.

[0521] Table A below reports the in vitro activity data of compounds represented by formula (I) against Syk kinase, as reported above. As will be understood by those skilled in the art, most of these compounds exhibit an IC50 value of <0.5 μM against Syk, and are therefore particularly advantageous in the treatment of diseases (e.g., cancer) caused by and / or related to dysregulated Syk kinase activity.

[0522] [Table 2]

[0523] To support the unexpected activity of the compounds in this application relative to the closest compounds described in prior art application WO2012 / 139930, the structures and biochemical data obtained for the Syk assay for three reference compounds (i.e., compound 7, compound 14, and compound 39) are reported in Table B below.

[0524] [Table 3]

[0525] From the above data, it will be apparent to those skilled in the art that the compound represented by formula (I) of the present invention is highly potent against Syk kinase, while the prior art compound is inactive.

Claims

1. Equation (I): 【Chemistry 1】 [During the ceremony, R1 is hydrogen, or an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C3-C7) cycloalkyl, aryl, heterocyclyl, and heteroaryl groups; R2 is hydrogen, or an optionally substituted group selected from linear or branched (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, and (C3-C7) cycloalkyl groups; R3 and R4 are independently hydrogen, or a linear or branched (C1-C6) alkyl which may be substituted with a halogen, heteroaryl or heteroaryl(C1-C6)alkyl, or formula (II): 【Chemistry 2】 It is a base represented by, Here, R5 may be hydrogen, or a substituted linear or branched (C1-C6) alkyl, (C3-C7) cycloalkyl, or aryl group, or together with R6 may form a substituted 4- to 7-membered cycloalkyl group, or together with R7 or R8 may form a substituted heterocyclyl group; R6 may be hydrogen or methyl, or together with R3 or R4, it may form a 4- to 7-membered heterocyclic group; R7 and R8 can independently form hydrogen, a substituted linear or branched (C1-C6) alkyl group, or, if X is N, a substituted 4- to 7-membered heterocyclyl group (wherein the heterocyclyl group may contain one additional heteroatom selected from N, O, and S), or a substituted 5- to 7-membered heterocyclyl group together with R3 or R4; X is H, N, or O; However, if X is H, R7 and R8 do not exist, and if X is O, R8 does not exist and R5 is not phenyl. A compound represented by or a pharmaceutically acceptable salt thereof.

2. R2 is a linear or branched (C1-C6) alkyl group which may be substituted; R3 and R4 are independently hydrogen or formula (II) 【Transformation 3】 It is a base represented by; Here, R5 may be hydrogen, or a substituted linear or branched (C1-C6) alkyl, (C3-C7) cycloalkyl, or phenyl, or together with R6 to form a substituted 4- to 7-membered cycloalkyl; R6 is hydrogen; R7 and R8 can independently form hydrogen, a substituted linear or branched (C1-C6) alkyl group, or, if X is N, a substituted 4- to 7-membered heterocyclyl group (wherein the heterocyclyl group may contain one additional heteroatom selected from N, O, and S); X is either N or O; R1 is as defined in claim 1; However, if X is O, then R8 does not exist and R5 is not phenyl; A compound represented by formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

3. R3 is hydrogen, or a linear or branched (C1-C6) alkyl which may be substituted with a halogen, heteroaryl, or heteroaryl(C1-C6)alkyl; R4 is either hydrogen or formula (II) 【Chemistry 4】 It is a base represented by; R1, R2, R5, R6, R7, R8 and X are as defined in claim 2; A compound represented by formula (I) as described in claim 2, or a pharmaceutically acceptable salt thereof.

4. R1 is an optionally substituted aryl, heterocyclyl, or heteroaryl group; R3 is hydrogen; R4 is general formula (II): 【Transformation 5】 It is a base represented by; Here, R5 and R6 are as defined in claim 3; R7 and R8 can independently be hydrogen, or a substituted linear or branched (C1-C6) alkyl group, or together with X, form a substituted 4- to 7-membered heterocycline; X is N; R2 is as defined in claims 1 to 3; A compound represented by formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. R1 is an optionally substituted group selected from phenyl or indolyl; R2, R3, and R4 are as defined in claim 4; A compound represented by formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. below: N-[2-(dimethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 1); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(2R)-1-hydroxypropane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 2); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-hydroxypropane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 3); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(propan-2-yl)-1H-pyrazole-5-carboxamide (compound 4); N-[2-(dimethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (compound 5); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[2-(methylamino)ethyl]-1H-pyrazole-5-carboxamide hydrochloride (compound 6); N-(2-aminoethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 7); N-(azetidine-3-yl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide trifluoroacetate (compound 8); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-5-carboxamide (compound 9); N-[2-(diethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 10); N-[(1R,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 11); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[2-(propan-2-ylamino)ethyl]-1H-pyrazole-5-carboxamide hydrochloride (compound 12); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 13); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (compound 14); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N,N,1-trimethyl-1H-pyrazole-5-carboxamide (compound 15); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 16); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(2-fluoroethyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 17); 3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-N-[2-(dimethylamino)ethyl]-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 18); 3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-N-[(2S)-1-hydroxypropane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 19); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(1H-pyrazole-3-yl)-1H-pyrazole-5-carboxamide (compound 20); (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)(4-methylpiperazine-1-yl)methanone (Compound 21); N-[2-(acetylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (Compound 22); N-(2-amino-2-oxoethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (Compound 23); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxamide (compound 24); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(1-methyl-1H-imidazole-5-yl)methyl]-1H-pyrazole-5-carboxamide (compound 25); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 26); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(pyridine-2-ylmethyl)-1H-pyrazole-5-carboxamide (compound 27); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(1H-imidazole-2-ylmethyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 28); N-[(2R)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 29); N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-yl]-1H-pyrazole-5-carboxamide (compound 30); N-(1-azabicyclo[2.2.2]octa-3-yl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 31); 5-[2-(3,5-dimethylphenylamino)-pyrimidine-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ((1R,2R)-2-hydroxycyclohexyl)-amide (compound 32); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-hydroxybutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 33); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 34); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,4-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 35); (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)(piperazine-1-yl)methanone hydrochloride (compound 36); N-[(1S,2R)-2-aminocyclohexyl]-3-(2-{[3-methoxy-5-(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 37); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3-chloro-1-methyl-1H-indole-5-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 38); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 39); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-difluorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 40); N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 41); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluoropropane-2-yl]-1H-pyrazole-5-carboxamide (compound 42); N-[3-(dimethylamino)propyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 43); (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)[(2S)-2-(propan-2-yl)aziridine-1-yl]methanone (compound 44); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-(2,2-dimethylpropyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 45); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-(2-methylpropyl)-1H-pyrazole-5-carboxamide (compound 46); N-(cyclopropylmethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 47); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-fluoro-5-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 48); 3-{2-[(4,6-dimethylpyridine-2-yl)amino]pyrimidine-4-yl}-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 49); 3-{2-[(3,5-difluorophenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluoropropane-2-yl]-1H-pyrazole-5-carboxamide (compound 50); 1-Methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1,1,1-trifluoropropane-2-yl]-1H-pyrazole-5-carboxamide (compound 51); 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]amino}pyrimidine-4-yl)-N-[(2S)-1-hydroxy-3-phenylpropane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 52); N-[(1S,2S)-2-aminocyclohexyl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 53); 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]amino}pyrimidine-4-yl)-1-methyl-N-[(2S)-1,1,1-trifluoropropane-2-yl]-1H-pyrazole-5-carboxamide (compound 54); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1H-pyrazole-5-carboxamide (compound 55); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1H-pyrazole-5-carboxamide (compound 56); N-[(2S)-1-(3,3-difluoroazetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 57); 1-Methyl-N-[(2S)-1-(pyrroridine-1-yl)propan-2-yl]-3-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 58); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-chloro-1-methyl-1H-indole-5-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 59); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 60); N-[(2S)-1-(azetidine-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 61); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-1-methyl-3-(2-{[3-(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-1H-pyrazole-5-carboxamide (compound 62); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidine-4-yl)-1-methyl-1H-pyrazole-5-carboxamide (compound 63); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 64); N-[(2S)-1-(dimethylamino)propan-2-yl]-3-{2-[(3-fluoro-5-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 65); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-[2-(1,3-benzodioxol-5-ylamino)pyrimidine-4-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 66); 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 67); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-1-methyl-3-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 68); 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidine-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (compound 69); 3-{2-[(3-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidine-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (compound 70); 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-(dimethylamino)-1-oxopropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 71); 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-N-[2-(dimethylamino)ethyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 72); N-[(2S)-1-(dimethylamino)propan-2-yl]-3-{2-[(1,5-dimethyl-1H-pyrazole-3-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 73); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(1,5-dimethyl-1H-pyrazole-3-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 74); N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-3-{2-[(1-methyl-1H-pyrazole-4-yl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 75); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-1-methyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-yl]-1H-pyrazole-5-carboxamide (compound 76); N,N,1-trimethyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-yl]-1H-pyrazole-5-carboxamide (compound 77); 3-{2-[(3-cyano-5-methoxyphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-(dimethylamino)propane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 78); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-cyano-5-methoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 79); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(5-methoxypyridine-3-yl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 80); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(3S)-piperidine-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (compound 81); N-(2-aminocyclohexyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 82); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[2-(pyrrolidine-1-yl)ethyl]-1H-pyrazole-5-carboxamide (Compound 83); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[2-(piperidine-1-yl)ethyl]-1H-pyrazole-5-carboxamide (Compound 84); (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)[(3R)-3-hydroxypyrrolidine-1-yl]methanone (compound 85); [(3S)-3-(dimethylamino)pyrroridine-1-yl](3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)methanone (compound 86); [(3R)-3-(dimethylamino)pyrroridine-1-yl](3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)methanone (compound 87); (3-aminopyrrolidine-1-yl)(3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)methanone (Compound 88); (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]methanone (compound 89); (3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)[(3S)-3-hydroxypyrrolidine-1-yl]methanone (compound 90); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(1R,2S)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 91); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 92); N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-3-{2-[(1,2,3-trimethyl-1H-indole-5-yl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 93); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidine-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (compound 94); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 95); (1R,4S)-2,5-diazabicyclo[2.2.1]hepta-2-yl(3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-yl)methanone hydrochloride (compound 96); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(3R)-piperidine-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (compound 97); N-[(1R,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 98); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 99); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (compound 100); N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 101); N-[(2S)-1-(azetidine-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 102); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-3-methyl-1-(pyrrolidine-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (compound 103); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide hydrochloride (compound 104); N-[(2S)-1-(azetidine-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 105); N-[(1S)-1-cyclohexyl-2-hydroxyethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 106); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(1S)-1-phenyl-2-(pyrrolidine-1-yl)ethyl]-1H-pyrazole-5-carboxamide (compound 107); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-1H-pyrazole-5-carboxamide (compound 108); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-1-hydroxy-3-phenylpropane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 109); 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]amino}pyrimidine-4-yl)-N-[(2S)-1-hydroxypropane-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 110); 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]amino}pyrimidine-4-yl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (compound 111); 1-Methyl-3-{2-[(3-methylphenyl)amino]pyrimidine-4-yl}-N-[(2S)-3-methyl-1-(pyrrolidine-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (compound 112); N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-difluorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 113); 3-(2-{[3-chloro-4-(4-methylpiperazine-1-yl)phenyl]amino}pyrimidine-4-yl)-N-[(1S,2R)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 114); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(1S,2R)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 115); N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 116); 3-{2-[(3,5-dichlorophenyl)amino]pyrimidine-4-yl}-1-methyl-N-[(2S)-3-methyl-1-(pyrrolidine-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (compound 117); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (compound 118); N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3-cyanophenyl)amino]pyrimidine-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (compound 119); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-ethyl-N-[(1S,2R)-2-hydroxycyclohexyl]-1H-pyrazole-5-carboxamide (compound 120); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-ethyl-1H-pyrazole-5-carboxamide hydrochloride (compound 121); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidine-4-yl}-1-ethyl-N-[(3R)-piperidine-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (compound 122); And, N-[(2S)-1-(azetidine-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (compound 123) A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

7. A method for preparing a compound represented by formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, comprising the following steps: Stage (1) Equation (III): 【Transformation 6】 [In the formula, R2 is as defined in claim 1, and R9 is a group selected from linear or branched (C1-C6) alkyl groups.] A step of mixing the compound represented by dimethylformamide-dialkylacetal; Stage (2) Formula (IV): 【Transformation 7】 [In the formula, R2 and R9 are as defined above.] The resulting compound represented by formula (V) is: 【Transformation 8】 [In the formula, R1 is as defined in claim 1] When reacted with a compound represented by formula (VI): 【Chemistry 9】 [In the formula, R1, R2, and R9 are as defined above.] The step of obtaining a compound represented by; Alternatively, prepare the compound represented by formula (VI) reported in step 2 according to the following steps: Stage (3) Formula (IV): 【Chemistry 10】 [In the formula, R2 and R9 are as defined in step (1) above.] The step of reacting it with guanidine carbonate; Stage (4) Formula (VII): 【Chemistry 11】 [In the formula, R2 and R9 are as defined above.] The resulting compound represented by formula (VIII): 【Chemistry 12】 [In the formula, R1 is as defined in claim 1, and Y is iodine or bromine.] The compound represented by is reacted with palladium in the presence of palladium, and formula (VI): 【Chemistry 13】 [In the formula, R1, R2, and R9 are as defined above.] The step of obtaining a compound represented by; Or, Step (5) Equation (VII) obtained as reported in Step (3): 【Chemistry 14】 The step of reacting a compound represented by with isoamyl nitrite and diiodomethane or cesium iodide in the presence of iodine and CuI to obtain a compound represented by formula (IX) [wherein R2 and R9 are as defined above]; Stage (6) Next, formula (IX): 【Chemistry 15】 [In the formula, R2 and R9 are as defined above.] The resulting compound is represented by formula (X): 【Chemistry 16】 [In the formula, R1 is as defined in claim 1] The compound represented by is reacted with palladium in the presence of palladium, and formula (VI): 【Chemistry 17】 [In the formula, R1, R2, and R9 are as defined above.] The step of obtaining a compound represented by; Prepare the compound represented by formula (I) by a method comprising the following steps: Step (7) Formula (VI) obtained as described in Step 2, 4, or 6 [Chemistry 18] [In the formula, R1 and R2 are as defined in claim 1, and R9 is a group selected from linear or branched (C1-C6) alkyl groups.] The compound represented by formula (XI) is reacted under acidic or basic hydrolysis conditions to obtain the compound represented by formula (XI). 【Chemistry 19】 [In the formula, R1 and R2 are as defined above.] A step of obtaining a compound represented by or the corresponding salt; Step (8) The compound represented by formula (XI) or the corresponding salt described in Step 7 is given formula (XII) 【Chemistry 20】 [In the formula, R3 and R4 are as defined in claim 1.] When reacted with a compound represented by formula (I), 【Chemistry 21】 [In the formula, R1, R2, R3, and R4 are as defined in claim 1.] The step of obtaining the compound represented by [the symbol].

8. A pharmaceutical composition for treating mammals suffering from diseases caused by and / or related to dysregulated Syk kinase activity, comprising a compound selected from the compound represented by formula (I) as defined in claim 1 and the compound described in claim 6, or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8, wherein the disease is selected from the group consisting of cancer, cell proliferation disorders, and immune-related disorders.

10. The pharmaceutical composition according to claim 9, wherein the disease is cancer.

11. The pharmaceutical composition according to claim 10, wherein the cancer is selected from the group consisting of the following: Cancers including bladder cancer, breast cancer, kidney cancer, liver cancer, colon cancer, lung cancer (including small cell lung cancer), esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, prostate cancer, and skin cancer (including squamous cell carcinoma); Lymphoid hematopoietic malignancies, including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, angioimmunoblastic T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma; Hematopoietic malignancies of the myeloid system, including acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; Tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; Tumors of the central and peripheral nervous system, including gliomas, glioblastomas, glioblastomas multiforme, astrocytomas, oligodendrogliomas, paragliomas, neuroblastomas, and schwannomas; and Other tumors, including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, xanthoma cornea, thyroid cancer (including papillary and medullary thyroid carcinoma), Kaposi's sarcoma, chondrosarcoma, and cholangiocarcinoma.

12. A compound selected from the compound represented by formula (I) as defined in claim 1 and the compound described in claim 6, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

13. A pharmaceutical composition comprising a compound selected from the compound represented by formula (I) as defined in claim 1 and the compound described in claim 6, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient, carrier, or diluent.

14. Furthermore, the pharmaceutical composition according to claim 13, comprising one or more chemotherapeutic agents.

15. A product or kit comprising, as a combination preparation for simultaneous, individual or sequential use in anticancer therapy, a compound selected from the compound represented by formula (I) as defined in claim 1 and the compound described in claim 6, or a pharmaceutically acceptable salt thereof, and one or more chemotherapeutic agents.

16. The use of a compound selected from the compound represented by formula (I) as defined in claim 1 and the compound described in claim 6, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product having anticancer activity.

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