Pyrazolyl-pyrimidine derivatives as kinase inhibitors

Abstract

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

Description

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

[0003] Dysfunction of protein kinase (PK) is a hallmark of many diseases. Most oncogenes and proto-oncogenes involved in human cancer encode PK. Enhanced PK activity is also relevant to many non-malignant diseases, such as benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and postoperative stenosis and restenosis.

[0004] PK is also associated with inflammatory conditions and the proliferation of viruses and parasites. PK may also play a major role in the pathogenesis and development of neurodegenerative disorders.

[0005] For general reference to PK dysfunction or disturbances, see, for example, Current Opinion in Chemical Biology, 1999, 3, 459-465; Nature Rev. Drug Discov. 2002; and Carcinogenesis, 2008, 29, 1087-1091.

[0006] Spleen tyrosine kinase (Syk) is a 72 kDa non-receptor cytoplasmic tyrosine kinase. Syk has a primary amino acid sequence similar to zeta-associated protein-70 (ZAP-70) and is involved in receptor-mediated signal transduction. The N-terminal domain of Syk contains two Src homology 2 (SH2) domains, which bind to diphosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) found in the cytoplasmic signaling domains of many immunoreceptor complexes. The C-terminus contains the 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 key role in the signal transduction of the immune receptor mediation in a variety of cell types, including B cells, macrophages, monocytes, mast cells, eosinophils, basophils, neutrophils, dendritic cells, platelets and osteoclasts. Classical immune receptors include B cells and T cell antigen receptors and various immunoglobulin receptors (Fc receptors). Ligand binding causes the activation of immune receptors, which causes Src family kinases to be activated, and the phosphorylation of the activation motif (ITAM) based on the cytoplasm of the receptor-associated transmembrane adaptors (receptor-associated transmembrane adaptors). Syk is combined with the phosphorylated ITAM motif of the adaptor, resulting in the activation of Syk and the phosphorylation and activation of the downstream signaling pathways (Mocsai et al., 2010: 10 (6): 387).

[0007] Syk is essential for B cell activation by B cell receptor (BCR) signal transduction. Syk is activated after binding to phosphorylated BCR, and thus initiates early signal transduction events after BCR activation. A large amount of evidence shows that BCR signal transduction also supports the survival and growth of malignant B cells in patients with B cell leukemia or lymphoma. The mechanism of BCR pathway activation in these diseases includes continuous BCR stimulation of microbial antigens or autoantigens present in the tissue microenvironment, activating mutations in BCR complexes or downstream signal transduction components and ligand-independent tonic BCR signal transduction (ligand-independent tonic BCR signaling). With small molecule targeting key BCR signal transduction mediators (such as Btk or PI3K δ isoforms) have been shown to suppress BCR signal transduction, resulting in valuable methods (Burger and Wiestner, Nat. Rev. Cancer 2018: 18 (3): 148) for the therapeutic benefits in these diseases.

[0008] Therefore, inhibition of Syk activity can be used to treat certain types of cancer in which BCR signaling plays a role in their survival and proliferation, such as non-Hodgkin's lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and T-cell lymphoma. In addition, the role of Syk in ITAM-dependent signaling and its expression in many cell types suggest that compounds that inhibit Syk activity can be used to treat 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).

[0009] Pyrazolylpyrimidine derivatives have previously been described as modulators of protein kinase activity and are therefore useful in the treatment of diseases caused by deregulated protein kinase activity (WO 2012 / 139930).

[0010] Pyrimidine-5-carboxamide compounds used as inhibitors of Syk and / or JAK kinases are described in patent application US20200239458, while solid forms of condensed pyrazines as Syk inhibitors are described in WO 2020172431. Detailed Description of the Invention

[0012] The present inventors have found that compounds of general formula (I) as defined below are kinase inhibitors, and in particular inhibitors of spleen tyrosine kinase (SYK). Therefore, such compounds are useful in treating diseases caused by altered SYK activity.

[0013] Therefore, the first object of the present invention is to provide substituted pyrazolopyrimidine derivatives of formula (I):

[0014]

[0015] in:

[0016] R1 is hydrogen or an optionally substituted group selected from linear or branched (C1-C6)alkyl, (C3-C7)cycloalkyl, aryl, heterocyclyl and heteroaryl;

[0017] 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;

[0018] R3 and R4 are independently hydrogen, linear or branched (C1-C6) alkyl, heteroaryl or heteroaryl (C1-C6) alkyl optionally substituted by halogen, or a group of formula (II):

[0019]

[0020] in:

[0021] R5 is hydrogen, an optionally substituted linear or branched (C1-C6) alkyl, a (C3-C7) cycloalkyl, an aryl, or together with R6, may form an optionally substituted 4- to 7-membered cycloalkyl, or together with R7 or R8, may form an optionally substituted heterocyclyl group;

[0022] R6 is hydrogen or methyl or together with R3 or R4 can form an optionally substituted 4 to 7 membered heterocyclyl group;

[0023] R7 and R8 are independently hydrogen, optionally substituted linear or branched (C1-C6) alkyl, or may form, together with X, an optionally substituted 4- to 7-membered heterocyclyl group, said 4- to 7-membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S, or may form, together with R3 or R4, an optionally substituted 5- to 7-membered heterocyclyl group;

[0024] X is H, N or O;

[0025] Provided that, when X is O, R5 is not phenyl;

[0026] or a pharmaceutically acceptable salt thereof.

[0027] Preferred compounds of formula (I) are those wherein:

[0028] R2 is an optionally substituted linear or branched (C1-C6) alkyl group;

[0029] R3 and R4 are independently hydrogen or a group of formula (II);

[0030]

[0031] in:

[0032] R5 is hydrogen, an optionally substituted linear or branched (C1-C6) alkyl group, a (C3-C7) cycloalkyl group or a phenyl group, or together with R6 can form an optionally substituted 4- to 7-membered cycloalkyl group;

[0033] R6 is hydrogen;

[0034] R7 and R8 are independently hydrogen, optionally substituted linear or branched (C1-C6) alkyl, or may be taken together with X to form an optionally substituted 4- to 7-membered heterocyclyl group, the 4- to 7-membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;

[0035] X is N or O;

[0036] R1 is as defined above;

[0037] Provided that, when X is O, R5 is not phenyl;

[0038] or a pharmaceutically acceptable salt thereof.

[0039] Further preferred compounds of formula (I) are the following compounds, wherein:

[0040] R3 is hydrogen or linear or branched (C1-C6) alkyl, heteroaryl or heteroaryl (C1-C6) alkyl optionally substituted by halogen;

[0041] R4 is hydrogen or a group of formula (II)

[0042]

[0043] in:

[0044] R5 is hydrogen, an optionally substituted linear or branched (C1-C6) alkyl group, a (C3-C7) cycloalkyl group or a phenyl group, or together with R6 can form an optionally substituted 4- to 7-membered cycloalkyl group;

[0045] R6 is hydrogen;

[0046] R7 and R8 are independently hydrogen, optionally substituted linear or branched (C1-C6) alkyl, or may be taken together with X to form an optionally substituted 4- to 7-membered heterocyclyl group, the 4- to 7-membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;

[0047] X is N or O;

[0048] R1 and R2 are as defined above;

[0049] Provided that, when X is O, R5 is not phenyl;

[0050] or a pharmaceutically acceptable salt thereof.

[0051] Even more preferred are compounds of formula (I) wherein:

[0052] R1 is an optionally substituted aryl, heterocyclyl or heteroaryl group;

[0053] R3 is hydrogen;

[0054] R4 is a group of general formula (II):

[0055]

[0056] in:

[0057] R5 is hydrogen, an optionally substituted linear or branched (C1-C6) alkyl group, a (C3-C7) cycloalkyl group or a phenyl group, or together with R6 can form an optionally substituted 4- to 7-membered cycloalkyl group;

[0058] R6 is hydrogen;

[0059] R7 and R8 are independently hydrogen, optionally substituted linear or branched (C1-C6) alkyl, or may form, together with X, an optionally substituted 4- to 7-membered heterocyclic group;

[0060] X is N;

[0061] R2 is as defined above;

[0062] or a pharmaceutically acceptable salt thereof.

[0063] Still even more preferred are compounds of formula (I) wherein:

[0064] R1 is an optionally substituted group selected from phenyl or indolyl;

[0065] R2, R3 and R4 are as defined above;

[0066] or a pharmaceutically acceptable salt thereof.

[0067] Preferred specific compounds of formula (I) (cpd) or salts thereof are the compounds listed below:

[0068] N-[2-(Dimethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 1);

[0069] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2R)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 2);

[0070] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 3);

[0071] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(propan-2-yl)-1H-pyrazole-5-carboxamide (cpd 4);

[0072] N-[2-(Dimethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (cpd 5);

[0073] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(methylamino)ethyl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 6);

[0074] N-(2-aminoethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 7);

[0075] N-(azetidin-3-yl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide trifluoroacetate (cpd 8);

[0076] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(morpholin-4-yl)ethyl]-1H-pyrazole-5-carboxamide (cpd 9);

[0077] N-[2-(Diethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 10);

[0078] N-[(1R,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 11);

[0079] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(propan-2-ylamino)ethyl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 12);

[0080] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd13);

[0081] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (cpd14);

[0082] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N,N,1-trimethyl-1H-pyrazole-5-carboxamide (cpd 15);

[0083] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 16);

[0084] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-(2-fluoroethyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 17);

[0085] 3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-N-[2-(dimethylamino)ethyl]-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 18);

[0086] 3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 19);

[0087] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(1H-pyrazol-3-yl)-1H-pyrazole-5-carboxamide (cpd 20);

[0088] (3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)(4-methylpiperazin-1-yl)methanone (cpd 21);

[0089] N-[2-(Acetylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 22);

[0090] N-(2-amino-2-oxoethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 23);

[0091] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxamide (cpd 24);

[0092] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(1-methyl-1H-imidazol-5-yl)methyl]-1H-pyrazole-5-carboxamide (cpd 25);

[0093] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 26);

[0094] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(pyridin-2-ylmethyl)-1H-pyrazole-5-carboxamide (cpd 27);

[0095] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-(1H-imidazol-2-ylmethyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 28);

[0096] N-[(2R)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 29);

[0097] N-[(2S)-1-(Dimethylamino)propan-2-yl]-1-methyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl]-1H-pyrazole-5-carboxamide (cpd 30);

[0098] N-(1-azabicyclo[2.2.2]oct-3-yl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 31);

[0099] 5-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide (cpd 32);

[0100] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxybutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 33);

[0101] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 34);

[0102] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,4-dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 35);

[0103] (3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)(piperazin-1-yl)methanone hydrochloride (cpd 36);

[0104] N-[(1S,2R)-2-aminocyclohexyl]-3-(2-{[3-methoxy-5-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 37);

[0105] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3-chloro-1-methyl-1H-indol-5-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 38);

[0106] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 39);

[0107] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-difluorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 40);

[0108] N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 41);

[0109] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (cpd 42);

[0110] N-[3-(Dimethylamino)propyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 43);

[0111] (3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)[(2S)-2-(propan-2-yl)aziridin-1-yl]methanone (cpd 44);

[0112] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-(2,2-dimethylpropyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 45);

[0113] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(2-methylpropyl)-1H-pyrazole-5-carboxamide (cpd 46);

[0114] N-(Cyclopropylmethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 47);

[0115] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-fluoro-5-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 48);

[0116] 3-{2-[(4,6-dimethylpyridin-2-yl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 49);

[0117] 3-{2-[(3,5-difluorophenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (cpd 50);

[0118] 1-Methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (cpd 51);

[0119] 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 52);

[0120] N-[(1S,2S)-2-aminocyclohexyl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 53);

[0121] 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-1-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (cpd 54);

[0122] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1H-pyrazole-5-carboxamide (cpd 55);

[0123] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1H-pyrazole-5-carboxamide (cpd 56);

[0124] N-[(2S)-1-(3,3-difluoroazetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 57);

[0125] 1-Methyl-N-[(2S)-1-(pyrrolidin-1-yl)propan-2-yl]-3-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 58);

[0126] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-chloro-1-methyl-1H-indol-5-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 59);

[0127] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 60);

[0128] N-[(2S)-1-(azetidin-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 61);

[0129] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-1-methyl-3-(2-{[3-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-1H-pyrazole-5-carboxamide (cpd 62);

[0130] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 63);

[0131] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 64);

[0132] N-[(2S)-1-(Dimethylamino)propan-2-yl]-3-{2-[(3-fluoro-5-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 65);

[0133] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-[2-(1,3-benzodioxol-5-ylamino)pyrimidin-4-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 66);

[0134] 3-{2-[(3,5-Dimethoxyphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 67);

[0135] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-1-methyl-3-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 68);

[0136] 3-{2-[(3,5-Dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidin-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (cpd 69);

[0137] 3-{2-[(3-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidin-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (cpd 70);

[0138] 3-{2-[(3,5-Dimethoxyphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-(dimethylamino)-1-oxopropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 71);

[0139] 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-N-[2-(dimethylamino)ethyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 72);

[0140] N-[(2S)-1-(Dimethylamino)propan-2-yl]-3-{2-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 73);

[0141] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 74);

[0142] N-[(2S)-1-(Dimethylamino)propan-2-yl]-1-methyl-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 75);

[0143] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-1-methyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl]-1H-pyrazole-5-carboxamide (cpd 76);

[0144] N,N,1-Trimethyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl]-1H-pyrazole-5-carboxamide (cpd 77);

[0145] 3-{2-[(3-cyano-5-methoxyphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 78);

[0146] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-cyano-5-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 79);

[0147] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(5-methoxypyridin-3-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 80);

[0148] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(3S)-piperidin-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 81);

[0149] N-(2-aminocyclohexyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 82);

[0150] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrazole-5-carboxamide (cpd 83);

[0151] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(piperidin-1-yl)ethyl]-1H-pyrazole-5-carboxamide (cpd 84);

[0152] (3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)[(3R)-3-hydroxypyrrolidin-1-yl]methanone (cpd 85);

[0153] [(3S)-3-(Dimethylamino)pyrrolidin-1-yl](3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)methanone (cpd 86);

[0154] [(3R)-3-(Dimethylamino)pyrrolidin-1-yl](3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)methanone (cpd 87);

[0155] (3-Aminopyrrolidin-1-yl)(3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)methanone (cpd 88);

[0156] (3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methanone (cpd 89);

[0157] (3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)[(3S)-3-hydroxypyrrolidin-1-yl]methanone (cpd 90);

[0158] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-[(1R,2S)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 91);

[0159] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 92);

[0160] N-[(2S)-1-Hydroxypropan-2-yl]-1-methyl-3-{2-[(1,2,3-trimethyl-1H-indol-5-yl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 93);

[0161] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidin-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (cpd 94);

[0162] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 95);

[0163] (1R,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl(3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)methanone hydrochloride (cpd 96);

[0164] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(3R)-piperidin-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 97);

[0165] N-[(1R,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 98);

[0166] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 99);

[0167] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 100);

[0168] N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 101);

[0169] N-[(2S)-1-(azetidin-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 102);

[0170] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-3-methyl-1-(pyrrolidin-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (cpd 103);

[0171] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide hydrochloride (cpd 104);

[0172] N-[(2S)-1-(azetidin-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 105);

[0173] N-[(1S)-1-cyclohexyl-2-hydroxyethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 106);

[0174] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(1S)-1-phenyl-2-(pyrrolidin-1-yl)ethyl]-1H-pyrazole-5-carboxamide (cpd 107);

[0175] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 108);

[0176] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 109);

[0177] 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 110);

[0178] 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 111);

[0179] 1-Methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-3-methyl-1-(pyrrolidin-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (cpd 112);

[0180] N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-difluorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 113);

[0181] 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-N-[(1S,2R)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 114);

[0182] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-[(1S,2R)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 115);

[0183] N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 116);

[0184] 3-{2-[(3,5-Dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-3-methyl-1-(pyrrolidin-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (cpd 117);

[0185] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 118);

[0186] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-cyanophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 119);

[0187] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-ethyl-N-[(1S,2R)-2-hydroxycyclohexyl]-1H-pyrazole-5-carboxamide (cpd 120);

[0188] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-ethyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 121);

[0189] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-ethyl-N-[(3R)-piperidin-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 122) and

[0190] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (cpd 123).

[0191] With regard to any specific compound of formula (I) of the present invention (optionally in the form of a pharmaceutically acceptable salt), see the experimental section and claims.

[0192] If there is a stereoisomer source center (stereogenic center) or another form of isomer center in the compound of the present invention, this paper is intended to contain all forms of this isomer or these isomers, including enantiomers and diastereomers. The compound containing the stereoisomer source center can be used as a mixture of racemic mixture, enantiomer enrichment, or racemic mixture can be separated using well-known technology, and single enantiomer can be used alone. In the case where compound has unsaturated carbon-carbon double bond, cis (Z) and trans (E) isomers are both within the scope of the present invention.

[0193] In cases where a compound can exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is considered to be included in the present invention, whether it exists in equilibrium or predominantly in one form. Thus, unless otherwise specified, when R2 is hydrogen in a compound of formula (I), and only one of the following tautomeric forms of formula (la) or (lb) is indicated, the remaining one should still be intended to be included within the scope of the present invention:

[0194]

[0195] Pharmaceutically acceptable salts of the compounds of 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.

[0196] Pharmaceutically acceptable salts of the compounds of formula (I) also include salts with inorganic or organic bases, such as hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals, in particular sodium, potassium, calcium, ammonium or magnesium, acyclic or cyclic amines.

[0197] A further object of the present invention are the compounds of formula (I) as defined above, as well as their isomers, tautomers, hydrates, solvates, complexes, metabolites, prodrugs, carriers and N-oxides.

[0198] A metabolite of a compound of formula (I) is any compound into which the same compound of formula (I) is converted in vivo (e.g., after administration to a mammal in need thereof). However, generally, this does not represent a limiting example, and after administration of a compound of formula (I), the same derivative may be converted into a variety of easily excreted compounds, including, for example, more soluble derivatives, such as hydroxylated derivatives. Therefore, any of these hydroxylated derivatives may be considered a metabolite of a compound of formula (I), depending on the metabolic pathways that occur therefrom.

[0199] A prodrug is any covalently bonded compound which releases the active parent drug according to formula (I) in vivo. N-oxides are compounds of formula (I) wherein the nitrogen and oxygen are tethered by a coordinate bond.

[0200] By the term "branched or branched (C1-C6)alkyl", thus including (C1-C4)alkyl, we intend any group such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, etc.

[0201] By the term "branched or branched (C2-C6)alkenyl" we intend any group such as, for example, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1-hexenyl, and the like.

[0202] With the term "branched or branched (C2-C6)alkynyl" we intend any group such as, for example, ethynyl, 2-propynyl, 4-pentynyl and the like.

[0203] By the term "(C3-C7)cycloalkyl", unless otherwise specified, we intend to mean a 3- to 7-membered all-carbon monocyclic ring which may contain one or more double bonds but does not have a completely conjugated π-electron system. Examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, and cycloheptadiene.

[0204] The term "aryl" refers to a monocyclic, bicyclic or polycyclic hydrocarbon having 1 to 4 ring systems, optionally further fused or linked to each other by single bonds, wherein at least one of the carbon rings is "aromatic", wherein the term "aromatic" refers to a completely conjugated π-electron bond system. Non-limiting examples of such aryl groups are phenyl groups, α- or β-naphthyl groups, α- or β-tetrahydronaphthalenyl groups, biphenyl groups and indanyl groups.

[0205] The term "heteroaryl" refers to an aromatic heterocyclic ring, typically a 5- to 7-membered heterocyclic ring having 1 to 3 heteroatoms selected from N, O or S; the heteroaryl ring may optionally be further fused to or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings. Non-limiting examples of such heteroaryl groups are, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, thiadiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, indazolyl, cinnolinyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, benzo[1,5]dioxinyl, benzo[1,6]dioxinyl, benzo[1,7]dioxinyl, benzo[1,8]dioxinyl, benzo[1,9]dioxinyl, benzo[1,10]dioxinyl, benzo[1,11]dioxinyl, benzo[1,12]dioxinyl, benzo[1,13]dioxinyl, benzo[1,14]dioxinyl, benzo[1,15]dioxinyl, benzo[1,16]dioxinyl, benzo[1,17]dioxinyl, benzo[1,18]dioxinyl, benzo[1,19]dioxinyl, benzo[1,2 ... enzo[1,4]dioxinyl), benzothiazolyl, benzothienyl, benzofuranyl, isoindolyl, benzimidazolyl, benzoxazolyl, quinolyl, isoquinolyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, 2,3-dihydroindole, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, benzopyranyl, 2,3-dihydrobenzoxazinyl, 2,3-dihydroquinoxalinyl, and the like.

[0206] For term " heterocyclic radical ", it is intended to refer to a saturated or partially unsaturated carbocyclic ring of 3 to 7 yuan in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulphur. The limiting examples of heterocyclic radical groups are for example pyranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, thiazolinyl, thiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyridyl, 1,3-dioxolanyl (1,3-dioxolanyl), piperidyl, piperazinyl, morpholinyl etc. Heterocycle can optionally also be fused or connected with aromatic and non-aromatic carbocyclic ring or heterocycle.

[0207] According to the present invention and unless otherwise specified, any of the above R1, R2, R3 and R4 groups may be optionally substituted at any of their free positions by one or more groups, for example 1 to 6 groups, independently selected from: halogen, nitro, oxo (=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, alkyleneaminooxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, Heterocyclyloxycarbonyl, amino, urea, alkylamino, dialkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, hydroxyaminocarbonyl, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio, phosphonate and alkylphosphonate.

[0208] Accordingly, each of the above-mentioned substituents may be further substituted with one or more of the above-mentioned groups, where appropriate.

[0209] In this respect, by the term "halogen" we intend a fluorine, chlorine, bromine or iodine atom.

[0210] By the term "cyano" we intend a -CN residue.

[0211] With the term "nitro" we intend a -NO2 group.

[0212] By the term "alkenyl" or "alkynyl" we intend any of the aforementioned straight or branched (C2-C6) alkyl groups further bearing a double or triple bond. Non-limiting examples of alkenyl or alkynyl groups of the present invention are, for example, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1-hexenyl, ethynyl, 2-propynyl, 4-pentynyl, and the like.

[0213] By the term "polyfluorinated alkyl or alkoxy" we intend any of the above straight or branched (C1-C6) alkyl or alkoxy groups substituted with more than one fluorine atom, such as, for example, trifluoromethyl, trifluoroethyl, 1,1,1,3,3,3-hexafluoropropyl, trifluoromethoxy, and the like.

[0214] With the terms "alkoxy, aryloxy, heterocyclyloxy" and derivatives thereof we intend any of the above-mentioned (C1-C6)alkyl, aryl or heterocyclyl groups attached to the rest of the molecule via an oxygen atom (-O-).

[0215] From the above it will be clear to the skilled person that any group whose name is a composite name, such as for example arylamino, needs to be intended to follow the conventional interpretation of the part from which it is derived, such as an amino group further substituted by aryl, wherein aryl is as defined above.

[0216] Likewise, any terms such as, for example, alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkyloxycarbonyl, and the like include groups in which the alkyl, alkoxy, aryl, (C3-C7)cycloalkyl, and heterocyclyl portions are as defined above.

[0217] The present invention also provides a method for preparing a compound of formula (I) as defined above by using the following reaction routes and synthetic schemes, using techniques available in the art and readily available starting materials. The preparation of certain embodiments of the present invention is described in the following examples, but one of ordinary skill in the art will recognize that the described preparations can be readily adapted to prepare other embodiments of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be carried out by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by conventional modifications to the reaction conditions. Alternatively, other reactions mentioned herein or known in the art will be considered to have adaptability for preparing other compounds of the present invention.

[0218] The compound of the present invention can be prepared from readily available starting materials using the following general method and procedure. Unless otherwise indicated, starting material is a known compound or can be prepared from a known compound according to well-known procedures. It should be understood that, unless otherwise indicated, different process conditions may be used when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure) are described. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions may be determined by conventional optimization procedures by those skilled in the art.

[0219] Intermediate compounds of formula (V) can be prepared as reported in Scheme 1 below.

[0220] Solution 1

[0221]

[0222] Therefore, the method of the present invention comprises the following steps:

[0223] Step 1) making a compound of formula (III):

[0224]

[0225] wherein R2 is hydrogen or selected from linear or branched (C1-C6) alkyl, (C2-C6) alkenyl,

[0226] an optionally substituted group of (C2-C6)alkynyl and (C3-C7)cycloalkyl, and R9 is a group selected from a linear or branched (C1-C6)alkyl group,

[0227] Reaction with dimethylformamide-dialkyl acetal;

[0228] Step 2) the obtained compound of formula (IV):

[0229]

[0230] wherein R2 and R9 are as defined above,

[0231] With a compound of formula (V):

[0232]

[0233] wherein R1 is hydrogen or selected from linear or branched (C1-C6) alkyl, (C3-C7) cycloalkyl,

[0234] an optionally substituted group of an aryl group, a heterocyclic group, and a heteroaryl group,

[0235] Reaction to obtain a compound of formula (VI):

[0236]

[0237] wherein R1, R2 and R9 are as defined above.

[0238] Compounds of formula (VI) as reported in step 2 can alternatively be prepared according to the following steps: Step 3) making formula (IV):

[0239]

[0240] wherein R2 and R9 are as defined in step 1) above, reacted with guanidine carbonate;

[0241] Step 4) In the presence of palladium, the obtained compound of formula (VII):

[0242]

[0243] Wherein R2 and R9 are as defined above

[0244] With a compound of formula (VIII):

[0245]

[0246] wherein R1 is as defined in step 2) above and Y is iodine or bromine, to obtain a compound of formula (VI):

[0247]

[0248] wherein R1, R2 and R9 are as defined above;

[0249] or

[0250] Step 5) The compound of formula (VII) obtained as reported in step 3) is reacted in the presence of iodine and CuI:

[0251]

[0252] Reaction with isoamyl nitrite and diiodomethane or cesium iodide to obtain a compound of formula (IX) wherein R2 and R9 are as defined above;

[0253] Step 6) Then, in the presence of palladium, the obtained compound of formula (IX):

[0254]

[0255] wherein R2 and R9 are as defined above,

[0256] With a compound of formula (X):

[0257]

[0258] wherein R1 is as defined above,

[0259] Reaction to obtain a compound of formula (VI):

[0260]

[0261] wherein R1, R2 and R9 are as defined above.

[0262] The target compound of formula (I) of the present invention can be prepared as reported in the following Scheme 2:

[0263] Option 2

[0264]

[0265] 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 defined above.

[0266] Therefore, the method of the present invention comprises the following steps:

[0267] Step 7) the compound of formula (VI) obtained as described in step 2, 4 or 6:

[0268]

[0269] wherein R1 is hydrogen or an optionally substituted group selected from a linear or branched (C1-C6)alkyl group, a (C3-C7)cycloalkyl group, an aryl group, a heterocyclyl group, and a heteroaryl group; R2 is hydrogen or an optionally substituted group selected from a linear or branched (C1-C6)alkyl group, a (C2-C6)alkenyl group, a (C2-C6)alkynyl group, and a (C3-C7)cycloalkyl group, and R9 is a group selected from a linear or branched (C1-C6)alkyl group,

[0270] reacting under acidic or alkaline hydrolysis conditions to obtain a compound of formula (XI) or a corresponding salt;

[0271]

[0272] wherein R1 and R2 are as defined above;

[0273] Step 8) reacting the compound of formula (XI) or the corresponding salt described in step 7 with the compound of formula (XII):

[0274]

[0275] wherein R3 and R4 are independently hydrogen, a linear or branched chain optionally substituted by halogen

[0276] (C1-C6)alkyl, heteroaryl and heteroaryl(C1-C6)alkyl or a group of formula (II),

[0277]

[0278] in:

[0279] R5 is hydrogen, an optionally substituted linear or branched (C1-C6) alkyl, a (C3-C7) cycloalkyl, an aryl, or together with R6, may form an optionally substituted 4- to 7-membered cycloalkyl, or together with R7 or R8, may form an optionally substituted heterocyclyl group;

[0280] R6 is hydrogen or methyl or together with R3 or R4 can form an optionally substituted 4 to 7 membered heterocyclyl group;

[0281] R7 and R8 are independently hydrogen, optionally substituted linear or branched (C1-C6) alkyl, or may form, together with X, an optionally substituted 4- to 7-membered heterocyclyl group, said 4- to 7-membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S, or may form, together with R3 or R4, an optionally substituted 5- to 7-membered heterocyclyl group;

[0282] X is H, N or O,

[0283] Reaction to obtain a compound of formula (I)

[0284]

[0285] wherein R1, R2, R3 and R4 are as defined above.

[0286] According to step 1 of the method The synthesis of enaminone derivatives of formula (IV) is accomplished using N,N-dimethylformamide-dialkyl acetals, such as, for example, dimethylformamide-di-tert-butyl acetal, dimethylformamide-diethyl acetal, etc., with or without a suitable solvent such as DMF, DMA, toluene, etc., at a temperature ranging from rt to 150° C. (by both conventional heating or microwave heating) and for a time ranging from 30 min to about 24 h.

[0287] According to step 2 of the method , a compound of formula (IV) is reacted with a derivative of formula (V) in the presence of a base optionally selected from AcOK, EtONa, TEA, K CO or Na CO in a suitable solvent such as, for example, DMF, EtOH or toluene at a temperature in the range of rt to 150° C. (both by conventional heating or microwave heating) and for a time in the range of about 1 h to about 48 h. Preferably, the reaction is carried out in EtOH at 150° C. for 2 hours in a microwave apparatus.

[0288] According to step 3 of the method , reacting a compound of formula (IV) with guanidine or a salt thereof or a protected synthetic equivalent such as Boc-guanidine, finally in the presence of a base selected from AcOK, EtONa, TEA, K2CO3 or Na2CO3, in a suitable solvent such as, for example, DMF, EtOH, PrOH, n-BuOH or toluene, at a temperature in the range of rt to 150°C (by both conventional heating or microwave heating) and for a time in the range of about 1 h to about 48 h.

[0289] According to step 4 of the method, according to conventional methods known in the literature, a compound of formula (VII) as defined above is reacted with a compound of formula (VIII) as defined above. As an example, the reaction can be carried out in a suitable solvent such as DMF, DME, dioxane or CH3CN and in the presence of Pd2(dba)3, BINAP or 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl (X-phos) and a base such as K2CO3, potassium phosphate or Cs2CO3, at a temperature in the range of rt to 110°C, and for a period of 2h to about 24h, to obtain a compound of formula (VI).

[0290] According to step 5 of the method , using isoamyl nitrite and diiodomethane or cesium iodide, in the presence of iodine and CuI, in a suitable solvent such as dioxane, THF, Et2O or DME, at a temperature ranging from rt to about 100°C, and for a time of about 1 hour to about 16 hours.

[0291] According to step 6 of the method , the reaction of a compound of formula (IX) with a compound of formula (X) is carried out in a suitable solvent such as dioxane, DMF, DME or CH3CN and in the presence of a catalytic amount of Pd(OAc)2, BINAP or Xantphos and a base such as K2CO3, potassium phosphate or Cs2CO3, at a temperature ranging from rt to 110°C and for a time ranging from about 2h to about 24h.

[0292] According to step 7 of the method , the compound of formula (VI) can be converted into the corresponding derivative or its salt of formula (XI) by alkaline or acidic hydrolysis conditions well known in the art. Preferably, the reaction is carried out in the presence of a suitable solvent (such as lower alcohol, THF, DMF or its mixture) with an alkaline aqueous solution such as lithium hydroxide, sodium hydroxide or potassium hydroxide aqueous solution (preferably, the reaction is carried out in the range of about rt to about 80 ° C, and the duration range is about 2h to about 24h. Depending on the operating conditions adopted, the compound of formula (XI) can be obtained in its acidic form or alternatively as a salt.

[0293] According to step 8 of the method, a carboxylic acid of formula (XI) is amidated to give the corresponding compound of formula (I), in the presence of ammonium chloride or a suitable primary or secondary amine of formula R3R4NH (XII), under basic conditions, preferably with DIPEA or TEA, in a suitable solvent such as DCM, DMF, THF, 1,4-dioxane or DMA, in the presence of a suitable condensing agent such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (DHBT), o-benzotriazolyltetramethylisouronium tetrafluoroborate (TBTU), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU). The reaction is optionally carried out in the presence of a suitable catalyst such as 4-dimethylaminopyridine, or in the presence of an additional coupling reagent such as N-hydroxybenzotriazole (HOBt), at rt for a time ranging from about 2 h to about 24 h.

[0294] In summary, it is clear to those skilled in the art that, according to procedures well known in the art, the conversion of the compound of formula (I) into its pharmaceutically acceptable salt, or alternatively the conversion of the corresponding salt into the free compound (I) is still within the scope of the present invention. When preparing the compound of formula (I) according to any variation of this method (all variations are intended to be within the scope of the present invention), the optional functional groups in the starting materials, reagents or their intermediates, as well as functional groups that may cause undesirable side reactions, need to be appropriately protected according to conventional techniques.

[0295] Protection of such reactive centers, and subsequent deprotection at the end of synthetic transformations, can be accomplished following standard procedures as described, for example, in Green, Theodora W. and Wuts, Peter GM - Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons Inc., New York (NY), 1999.

[0296] According to any variation of the process for preparing the compounds of formula (I), the starting materials and any additional reactants are known or readily prepared according to known methods.

[0297] Compounds of formula (III) can be prepared as described in WO 2012 / 139930.

[0298] The compound of formula (V) is commercially available or can be prepared by a known method (J. Med. Chem., 2004, vol47, p.4716-4730).

[0299] Compounds of formula (VIII), (X) and (XII) are commercially available or can be prepared by known methods.

[0300] The final compounds can be isolated and purified using conventional procedures, such as chromatography and / or crystallization and salt formation.

[0301] The compounds of general formula (I) as defined above can be converted into pharmaceutically acceptable salts.

[0302] According to the synthetic method described above, the synthesis of the compound of general formula (I) can be carried out in a stepwise manner, thus if necessary, before carrying out subsequent reactions, by standard purification techniques, such as for example column chromatography, every kind of intermediate is separated and purified. Alternatively, two or more steps of the synthetic sequence can be carried out in a program known in the art called "one-pot", whereby only the compound obtained by two or more steps is separated and purified.

[0303] In the case where the compound of formula (I) contains one or more asymmetric centers, the compound can be separated into single stereoisomers by procedures known to those skilled in the art. Such procedures include standard chromatographic techniques, including chromatography or crystallization using chiral stationary phases. General methods for separating compounds containing one or more asymmetric centers are reported, for example, in Jacques, Jean; Collet, André; Wilen, Samuel H., Enantiomers, Racemates, and Resolutions, John Wiley & Sons Inc., New York (NY), 1981.

[0304] The present invention also provides methods for treating diseases caused by and / or associated with 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, MN K2, MPS1, MST4, NEK6, NIM1, P38alpha, PAK4, PDGFR, PDK1, PERK, PIM1, PIM2, PIM3, PKAalpha, PKCbeta, PLK1, RET, R0S1, SULU1, Syk, TLK2, TRKA, TYK, VEGFR2, VEGFR3, ZAP70; more particularly PIM1, PIM2, PIM3, MPS1, JAK2, JAK3, more particularly Syk family kinases, the method comprising administering an effective amount of a compound of formula (I) as defined above to a mammal (more particularly a human) in need thereof.

[0305] In addition, the present invention provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in a method for treating a disease caused by and / or associated with disordered protein kinase activity reported above (particularly Syk kinase activity), the method comprising administering an effective amount of a compound of formula (I) as defined above to a mammal (preferably a human) in need thereof.

[0306] A preferred method of the present invention is to treat a disease caused by and / or associated with deregulated protein kinase activity, the disease being selected from the group consisting of cancer, cell proliferative disorders, viral infections, immune disorders, neurodegenerative disorders, and cardiovascular diseases. More preferably, the disease is cancer.

[0307] According to the most preferred embodiment of the present invention, the cancer is selected from the group consisting of:

[0308] Epithelial 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 lymphoid lineage, 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 tumors of the myeloid lineage, including acute and chronic Myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous systems, including gliomas, glioblastomas, glioblastoma multiforme, astrocytomas, oligodendrogliomas, paragangliomas, neuroblastomas, and schwannomas; and other tumors, including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid cancers such as papillary and medullary thyroid cancer, Kaposi's sarcoma, chondrosarcoma, and cholangiocarcinoma.

[0309] Another preferred method of the invention is the treatment of specific cell proliferation disorders such as, for example, benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, and post-operative stenosis and restenosis.

[0310] Another preferred method of the present invention is the treatment of viral infections, particularly preventing the development of AIDS in HIV infected individuals.

[0311] Another preferred method of the present invention is the treatment of immune disorders, such as inflammatory diseases 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, diverticular disease, myasthenia gravis, vasculitis, psoriasis, scleroderma, asthma, allergies, systemic sclerosis, vitiligo, arthritis such as osteoarthritis, juvenile rheumatoid arthritis, ankylosing spondylitis.

[0312] Another preferred method of the invention is the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.

[0313] Another preferred method of the present invention is the treatment of specific cardiovascular diseases, such as coronary heart disease, cardiomyopathy, ischemic heart disease, heart failure, hypertensive heart disease, inflammatory heart disease, and valvular heart disease.

[0314] Additionally, the methods of the present invention provide for inhibition of tumor angiogenesis and metastasis, as well as treatment of organ transplant rejection and host-versus-graft disease.

[0315] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, carrier and / or diluent.

[0316] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) and one or more chemotherapeutic agents (e.g., cytostatics or cytotoxic agents). Cytostatics or cytotoxic agents include, but are not limited to, antibiotic agents, alkylating agents, antimetabolites, hormone agents, immune agents, interferon-type agents, 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), farnesyl transferase inhibitors, ras-raf signaling pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, 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 antigen-binding fragments thereof specifically bound to PD-1 or PD-L1.

[0317] If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range.

[0318] The present invention also provides an in vitro method for inhibiting Syk protein kinase activity, which comprises contacting Syk kinase with an effective amount of a compound of formula (I) as defined above.

[0319] Additionally, the present invention provides a product comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

[0320] The compounds of formula (I) of the present invention suitable for administration to mammals (eg, to humans) can be administered by usual routes, and the dosage level depends on the age, weight and condition of the patient and the administration route.

[0321] For example, a suitable dosage for oral administration of a compound of formula (I) may be in the range of about 10 mg to about 1000 mg per dose, 1 to 5 times a day. The compounds of the present invention may be administered in a variety of dosage forms, such as oral administration in the form of tablets, capsules, sugar or film-coated tablets, liquid solutions or suspensions; rectal administration in the form of suppositories; parenteral administration, such as intramuscular administration, or by intravenous and / or intrathecal and / or intraspinal injection or infusion.

[0322] The pharmaceutical compositions containing the compounds of the present invention are usually prepared according to conventional methods and administered in suitable pharmaceutical forms.

[0323] For example, solid oral forms can contain, together with the active compound, a diluent such as lactose, dextrose, sugar (saccharose), sucrose (sucrose), cellulose, corn starch or potato starch; a lubricant such as silicon dioxide, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycol; a binder such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; a disintegrant such as starch, alginic acid, alginates or sodium starch glycolate; an effervescent mixture (effervescing mixtures); a dye; a sweetener; a wetting agent such as lecithin, polysorbate, lauryl sulfate (laurylsulphates); and non-toxic and pharmacologically inactive substances commonly used in pharmaceutical preparations. These pharmaceutical preparations can be prepared in a known manner, for example, by mixing, granulating, tableting, sugar coating or film coating processes.

[0324] Liquid dispersions for oral administration may be, for example, syrups, emulsions and suspensions.

[0325] As an example, a syrup may contain sucrose or sucrose together with glycerol and / or mannitol and sorbitol as a carrier.

[0326] Suspensions and emulsions may contain natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol as examples of carriers.

[0327] The suspension or solution for intramuscular injection may contain, together with the active compound, a pharmaceutically acceptable carrier, such as sterile water, olive oil, ethyl oleate, glycols, such as propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride.

[0328] Solutions for intravenous injection or infusion may contain sterile water as a carrier, or preferably they may be in the form of sterile, aqueous, isotonic, saline solutions, or they may contain propylene glycol as a carrier.

[0329] The suppository may contain a pharmaceutically acceptable carrier together with the active compound, for example cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. In another aspect, the present invention provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use as a medicament.

[0330] Finally, the present invention provides the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof in the preparation of a medicament having anticancer activity.

[0331] Experimental part

[0332] The abbreviations and abbreviations used herein and throughout the specification have the following meanings:

[0333] Preparation of compounds of formula (I)

[0334] With respect to any specific compound of formula (I) of the present invention (optionally in the form of a pharmaceutically acceptable salt), see the experimental section and claims. With reference 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.

[0335] For the purpose of better illustrating the present invention without imposing any limitation thereto, the following examples are given.

[0336] As used herein, the symbols and conventions used in the methods, schemes, and examples are consistent with those used in the contemporary scientific literature (e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry).

[0337] Compound names are IUPAC names, generated using ACD Name (by Advanced Chemistry Development, Inc.).

[0338] Unless otherwise stated, all materials (including anhydrous solvents such as DMF, THF, DCM) were obtained from commercial suppliers of the best quality and used without further purification. All reactions involving air- or moisture-sensitive compounds were carried out under nitrogen or argon atmosphere.

[0339] General purification and analytical methods

[0340] The synthetic preparation of some compounds of formula (I) of the present invention is described in the following examples.

[0341] The compounds of the present invention prepared according to the following examples are further characterized by1 H NMR and / or HPLC / MS analytical data; HPLC / MS data were collected according to either the LCQ or LCT method. Flash chromatography was performed on silica gel (Merck grade 9395, 60A).

[0342] HPLCLCQ method

[0343] HPLC-MS / UV analysis is carried out on LCQ DecaXP (Thermo, San Jose, US) ion trap instrument equipped with electrospray (ESI) ion source.Mass spectrometer is connected to Surveyor HPLC system (Thermo, San Jose, US) with UV photodiode array detector (UV detects 215-400nm).Use Waters XSelect CSH C18 post 50x4.6 mm, 3.5 μm particle size.Mobile phase A is ammonium acetate 5mM buffer (pH 4.5, uses acetic acid): acetonitrile 95:5, and mobile phase B is ammonium acetate 5mM buffer (pH 4.5, uses acetic acid): acetonitrile 5:95.Gradient is from 0 to 100% B in 7 minutes, keeps 100% B 2 minutes.Flow 1mL / min.Injection volume 10 μ L.Retention time (HPLC rt) is provided with minute.Full scan, mass range is from 50 to 1200amu. The heating capillary temperature was 200° C. and the spray voltage value was set to 4 kV. The masses are given as m / z ratios.

[0344] Instrument control, data acquisition, and processing were performed by using Xcalibur 1.4SR1 software (Thermo).

[0345] HPLC LCT method

[0346] HPLC-MS / UV analysis and high resolution mass spectrometry (HRMS) were performed on a Waters Alliance LC 2795 equipped with a Waters PDAUV detector 2996 and a TOF Waters LCT Premier XE mass detector (ESI interface) supported by a Waters reagent manager liquid pump. The assay was based on a universal gradient reversed phase chromatography that allowed identity-purity determination to be supplemented by determining and confirming the expected accurate mass of the compound in the same run. Compound identity was achieved by online serial ESI(+) full scan MS detection, and sample purity was obtained as the relative "area percentage" of the integrated LC / UV trace from 216 to 400 nm. The liquid chromatograph was equipped with a Waters XBridge CSH C18 column (3.0×30 mm, 3.5 μm particle size) thermostated at 50° C. Alternatively, a Supelco column Ascentis Express C18 (2.7×30 mm×3 μm) was used.

[0347] Mobile phase A was 0.05% w / v formic acid in high-purity 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. The gradient was from 0 to 100% B over 17.5 minutes, held at 100% B for 5 minutes. The flow rate was 0.8 mL / min, and the injection volume was 4 μL. The ESI source was operated at 100°C, 2.5 kV capillary voltage, 60 V cone, 600 L / hr nitrogen desolvation flow at 350°C, and 10 L / hr nitrogen cone flow. The "normal" Z focus was set to 140. The analyzer was typically optimized for a 7200 V flight tube.

[0348] In order to obtain high-resolution mass spectra, the eluent from the HPLC column is separated and, before it enters the MS source, a stream of 30 / 10 / 60 (v / v / v) mixture of MeOH / iPrOH / H containing 0.01% w / v formic acid and 80nM trimethoprim (Trimethoprim) is mixed at 25 μL / min with 100 μL / min from a Waters reagent management pump. Trimethoprim is selected as a stable, soluble and suitable reference compound for real-time single-point mass calibration. Under "W" mode, ES (+) full scan 80-1200amu center of mass data acquisition is carried out at a 2Hz sampling rate. The LCT embedded PC provides real-time data center of mass and real-time mass calibration based on trimethoprim. The H+ reference mass is 291.1452Da. The MS spectrum of appropriate intensity (40 to 2000 analyte counts) is averaged to obtain the final result.

[0349] 1H-NMR spectra were recorded at a constant temperature of 28°C on a Varian INOVA 400 spectrometer and a Varian INOVA 500 spectrometer. The Varian INOVA 400 spectrometer was operated at 400.5 MHz and equipped with a 5 mm 1 H{ 15 N- 31 The P}z-axis PFG indirect detection probe, a Varian INOVA500 spectrometer operating at 499.7 MHz and equipped with a 5 mm 1 H{ 13 C- 15 The chemical shift is based on the non-deuterated residual solvent signal (DMSO-d5: 1 H 2.50 ppm) was used as the reference. 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 number of protons. Example

[0350] Step 1 5-((E)-3-Dimethylamino-acryloyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(IV), R2 = methyl, R9 = ethyl]

[0351]

[0352] To ethyl 5-acetyl-2-methyl-2H-pyrazole-3-carboxylate (2 g, 10.19 mmol, 1 eq.) in a CEM reactor was added N,N-dimethylformamide diethyl acetal (10.48 ml, 61.2 mmol, 6 eq.). The mixture was heated in a CEM explorer microwave. TM The mixture was stirred at 140° C. for 3 hours. The volatiles were removed under vacuum and the solids were rinsed with hexanes and filtered to give the title compound as 2.45 g of a dark yellow powder in 95% yield.

[0353] LC / MS (254 nm) HPLC LCT-formic acid Rt 6.73 min.

[0354] 1H NMR (500 MHz, DMSO-d6) δ ppm 7.72 (d, J = 12.5 Hz, 1H), 7.12 (s, 1H), 5.83 (d, J = 12.7 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.13 (s, 3H), 3.14 (s, 3H), 2.87 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). HRMS (ESI) for C12H18N3O3 [M+H] + The calculated value is 252.1343 and the measured value is 252.1342.

[0355] Following this same procedure, but employing appropriately substituted derivatives, the following compounds were prepared:

[0356] 5-((Z)-3-Dimethylamino-acryloyl)-2H-pyrazole-3-carboxylic acid ethyl ester [(IV), R2=H, R9=ethyl]

[0357] 5-((Z)-3-Dimethylamino-acryloyl)-2-ethyl-2H-pyrazole-3-carboxylic acid ethyl ester [(IV), R2 = ethyl, R9 = ethyl]

[0358] Steps 2 and 3 5-(2-Amino-pyrimidin-4-yl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VII), R2 = methyl, R9 = ethyl]

[0359]

[0360] 5-((E)-3-dimethylamino-acryloyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (7.75g, 30.84mmol, 1 equivalent) and guanidine carbonate (8.34g, 46.26mmol, 1.5 equivalents) were loaded into a CEM microwave reactor (divided into six batches) and suspended in ethanol (100ml, 0.3M). The mixture was stirred at 150°C for 2 hours in a CEM explorer microwave. Six batches were collected and dried. The residue was suspended in water (50ml) and treated with HCl 1N at 0°C until pH = 2. The suspension was stirred at 0°C for 1 hour, then filtered, and the solid was washed with water and dried. 7.6g of crude material (title compound and its corresponding acid) was dissolved in ethanol (115ml) and 96% sulfuric acid (21ml, 378mmol, 12 equivalents) was added. The mixture was heated at reflux for 7 h, half of the volatiles were removed under vacuum, and the mixture was diluted with water (200 ml) and ethyl acetate (100 ml). Under the stirring of concentrated NaOH, the pH was adjusted to 9, the layers were separated, and the aqueous phase was extracted with AcOEt (3 × 50 mL). The organic layers combined were washed with salt water, dried over sodium sulfate, and after removing the solvent, a solid was obtained, which was ground with diisopropyl ether to give the title compound (6.38 g, 58%) as a pale yellow solid.

[0361] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 4.43 min.

[0362] 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.28 (d, J = 5.2 Hz, 1H), 7.32 (s, 1H), 7.06 (d, J = 5.2 Hz, 1H), 6.67 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 4.19-4.12 (m, 3H), 1.33 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C11H14N5O2 [M+H]+ 248.1142, found 248.1139.

[0363] According to the same method, but using the appropriate derivative and the appropriate guanidine derivative, the following compounds were prepared:

[0364] 5-(2-Amino-pyrimidin-4-yl)-2H-pyrazole-3-carboxylic acid ethyl ester [(VII), R2=H, R9=ethyl]

[0365] 5-(2-Amino-pyrimidin-4-yl)-2-ethyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VII), R2 = ethyl, R9 = ethyl]

[0366] 5-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3,5-dimethyl-phenyl, R2 = methyl, R9 = ethyl]

[0367]

[0368] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 7.56 min.

[0369] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.52 (s, 1H), 8.52 (d, J = 5.1 Hz, 1H), 7.49 (s, 2H), 7.44 (s, 1H), 7.28 (d, J = 5.1 Hz, 1H), 6.62 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.19 (s, 3H), 2.27 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C19H22N5O2 [M+H]+ 352.1768, found 352.1765.

[0370] 5-[2-(1,5-Dimethyl-1H-pyrazol-3-ylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 1,5-dimethyl-1H-pyrazol-3-yl, R2 = methyl, R9 = ethyl]

[0371]

[0372] LC / MS (254 nm) HPLC method (IP) LCT-Formic acid Rt 9.60 min.

[0373] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.17 (s, 1H), 8.45 (d, J = 5.0 Hz, 1H), 7.39 (s, 1H), 7.24 (d, J = 5.0 Hz, 1H), 6.47 (s, 1H), 4.34 (q, J = 7.0 Hz, 2H), 4.18 (s, 3H), 3.67 (s, 3H), 2.23 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H); HRMS (ESI) calcd for C16H20N7O2 [M+H]+ 342.1673, found 342.1674.

[0374] 2-Methyl-5-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 1-methyl-1H-pyrazol-4-yl, R2 = methyl, R9 = ethyl]

[0375]

[0376] LC / MS (254 nm) HPLC method (IP) LCT-Formic acid Rt 9.18 min.

[0377] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.52 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 7.90 (s, 1H), 7.55 (br.s., 1H), 7.42 (s, 1H), 7.20 (d, J = 5.0 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.19 (s, 3H), 3.82 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C15H18N7O2 [M+H]+ 328.1517, found 328.1517.

[0378] 2-Methyl-5-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = tetrahydro-pyran-4-yl, R2 = methyl, R9 = ethyl]

[0379]

[0380] LC / MS (254 nm) HPLC method (IP) LCT-formic acid Rt 8.79 min.

[0381] 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.32 (d, J = 5.0 Hz, 1H), 7.34 (s, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 5.0 Hz, 1H), 4.36-4.33 (m, 2H), 4.16 (s, 3H), 3.98 (br. s., 2H), 3.92-3.83 (m, 2H), 3.46-3.37 (m, 2H), 1.84 (d, J = 11.6 Hz, 2H), 1.59-1.43 (m, 2H), 1.34 (s, 1H); HRMS (ESI) calcd for C16H22N5O3 [M+H]+ 332.1717, found 332.1713.

[0382] 5-[2-(3,5-Dimethoxy-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3,5-dimethoxy-phenyl, R2 = methyl, R9 = ethyl]

[0383]

[0384] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 6.84 min.

[0385] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.67 (s, 1H), 8.54 (d, J = 5.0 Hz, 1H), 7.49-7.45 (m, 1H), 7.32 (d, J = 5.2 Hz, 1H), 7.20 (d, J = 2.3 Hz, 2H), 6.14 (t, J = 2.2 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.19 (s, 3H), 3.76 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C19H22N5O4 [M+H]+ 384.1667, found 384.1666.

[0386] 5-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3,5-dimethyl-phenyl, R2 = H, R9 = ethyl]

[0387]

[0388] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 6.6 min.

[0389] 1 H NMR (500 MHz, DMSO-d6) δ ppm 14.45 (br.s., 1H), 9.52 (s, 1H), 8.54 (br.s., 1H), 7.47 (br.s., 2H), 7.39 (s, 1H), 7.33 (d, J = 5.0 Hz, 1H), 6.62 (s, 1H), 4.33 (q, J = 6.7 Hz, 2H), 2.26 (s, 6H), 1.33 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C18H20N5O2 [M+H]+ 338.1612, found 338.1607.

[0390] Alternatively, the reaction can be carried out with substituted guanidines to directly obtain the corresponding carboxylic acids or their salts.

[0391] 5-[2-(3,5-Dimethoxy-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3,5-dimethoxy-phenyl, R2 = methyl]

[0392]

[0393] A suspension of ethyl 5-((E)-3-dimethylamino-acryloyl)-2-methyl-2H-pyrazole-3-carboxylate (3.64 g, 14.4 mmol), N-(3,5-dimethoxy-phenyl)-guanidine hydrochloride (4.0 g, 17.3 mmol, 1.2 equiv) and potassium carbonate (3.6 g, 25.9 mmol, 1.8 equiv) in n-butanol (70 mL) was stirred at 113° C. (internal temperature) for 24 h, after which HPLC / MS inspection showed complete conversion. The reaction mixture was cooled to room temperature, diluted with 70 mL of water and 25 mL of AcOEt, and stirred until the suspended solids were 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 brought to an acidic pH (approximately 3-4) with 2N HCl (16 mL) under stirring. The resulting suspension was stirred for 10 minutes and then filtered through a sintered glass Buchner funnel with a porosity of 4 (the filtration was quite slow). The filter cake was washed twice with 5 mL of water and then twice with 10 mL of MTBE. The solid was collected and dried in an oven at 45-50° C. under vacuum (20-30 mm Hg) until the weight was constant, yielding 3.23 g of the desired product as a beige solid. Yield: 63%.

[0394] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 4.13 min.

[0395] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.67 (s, 1H), 8.56 (d, J = 5.0 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J = 5.0 Hz, 1H), 7.22 (d, J = 2.3 Hz, 2H), 6.17 (t, J = 2.3 Hz, 1H), 4.21 (s, 3H), 3.81-3.76 (m, 6H); HRMS (ESI) calcd for C17H18N5O4 [M+H]+ 356.1354, found 356.1366.

[0396] Step 45-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3,5-dimethyl-phenyl, R2 = methyl, R9 = ethyl]

[0397]

[0398] Ethyl 5-(2-amino-pyrimidin-4-yl)-2-methyl-2H-pyrazole-3-carboxylate (200 mg, 0.81 mmol, 1 eq), 3,5-dimethyl-iodobenzene (175 μl, 1.21 mmol, 1.5 eq) and cesium carbonate (527 mg, 1.62 mmol, 2 eq) were suspended in previously degassed dioxane (8 ml) and subjected to three vacuum / argon cycles. 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 argon and subjected to three vacuum / argon cycles. The mixture was heated at 100° C. for 6 h, then cooled to room temperature and diluted with water, extracted three times with AcOEt, the organics collected and washed with brine, and the volatiles removed under reduced pressure. The crude solid was purified by flash chromatography on silica gel (eluent: DCM:EtOH 99 / 1) to give 160 mg (56% yield) of the title compound.

[0399] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 7.56 min.

[0400] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.52 (s, 1H), 8.52 (d, J = 5.1 Hz, 1H), 7.49 (s, 2H), 7.44 (s, 1H), 7.28 (d, J = 5.1 Hz, 1H), 6.62 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.19 (s, 3H), 2.27 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C19H22N5O2 [M+H]+ 352.1768, found 352.1765.

[0401] Following this same procedure, but employing appropriately substituted derivatives, the following compounds were prepared:

[0402] 5-[2-(3,5-Dichloro-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3,5-dichloro-phenyl, R2 = methyl, R9 = ethyl] 28% yield

[0403]

[0404] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 8.21 min.

[0405] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.16 (s, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 1.8 Hz, 2H), 7.47 (s, 1H), 7.42 (d, J = 5.2 Hz, 1H), 7.14 (t, J = 1.9 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.20 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C17H16Cl2N5O2 [M+H]+ 392.0676, found 392.0675.

[0406] 5-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-2-ethyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3,5-dimethyl-phenyl, R2 = ethyl, R9 = ethyl]

[0407]

[0408] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 7.18 min.

[0409] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.51 (s, 1H), 8.55 (d, J = 5.2 Hz, 1H), 7.48 (s, 1H), 7.30 (d, J = 5.2 Hz, 1H), 7.28 (s, 2H), 6.67 (s, 1H), 4.80 (q, J = 7.1 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.25 (s, 6H), 1.31 (t, J = 7.0 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H); HRMS (ESI) calcd for C20H24N5O2 [M+H]+ 366.1925, found 366.1921.

[0410] 2-Methyl-5-(2-m-tolylamino-pyrimidin-4-yl)-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 2-m-tolyl, R2 = methyl, R9 = ethyl]

[0411]

[0412] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 7.18 min.

[0413] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.62 (s, 1H), 8.52 (d, J = 5.0 Hz, 1H), 7.74 (s, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.44 (s, 1H), 7.30 (d, J = 5.0 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 4.34 (q, J = 7.0 Hz, 2H), 4.19 (s, 3H), 2.31 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C18H20N5O2 [M+H]+ 338.1612, found 338.1615.

[0414] 5-[2-(3,5-Difluoro-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3,5-difluoro-phenyl, R2 = methyl, R9 = ethyl]

[0415]

[0416] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 7.37 min.

[0417] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.17 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 7.67-7.58 (m, 2H), 7.45 (s, 1H), 7.42 (d, J = 5.2 Hz, 1H), 6.76 (tt, J = 2.3, 9.2 Hz, 1H), 4.34 (q, J = 7.0 Hz, 2H), 4.20 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C17H16F2N5O2 [M+H]+ 360.1267, found 360.1274.

[0418] 5-{2-[3-Chloro-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3-chloro-4-(4-methyl-piperazin-1-yl)-phenyl, R2 = methyl, R9 = ethyl]

[0419]

[0420] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 5.80 min.

[0421] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.76 (s, 1H), 8.53 (d, J = 5.0 Hz, 1H), 8.16 (br.s., 1H), 7.59 (dd, J = 2.5, 8.8 Hz, 1H), 7.45 (s, 1H), 7.31 (d, J = 5.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 4.19 (s, 3H), 2.93 (br.s., 4H), 2.47 (br.s., 4H), 2.23 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); HRMS (ESI) calculated for C22H27ClN7O2 [M+H] + is 456.1910, found to be 456.1901.

[0422] 5-[2-(3-Cyano-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3-cyano-phenyl, R2 = methyl, R9 = ethyl]

[0423]

[0424] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 6.73 min.

[0425] 1H NMR (500 MHz, DMSO-d6) δ ppm 10.12 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.49 (t, J = 1.7 Hz, 1H), 7.98 (ddd, J = 0.8, 2.3, 8.4 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.46 (s, 1H), 7.41 (d, J = 5.0 Hz, 1H), 7.41 (ddd, J = 0.9, 1.4, 7.5 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.20 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H); HRMS (ESI) calculated for C18H17N6O2 [M+H] + is 349.1408, found to be 349.1416.

[0426] 5-[2-(3,5-Dimethoxy-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3,5-dimethoxy-phenyl, R2 = methyl, R9 = ethyl]

[0427]

[0428] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 6.84 min.

[0429] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.67 (s, 1H), 8.54 (d, J = 5.0 Hz, 1H), 7.49-7.45 (m, 1H), 7.32 (d, J = 5.2 Hz, 1H), 7.20 (d, J = 2.3 Hz, 2H), 6.14 (t, J = 2.2 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.19 (s, 3H), 3.76 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C19H22N5O4 [M+H]+ 384.1667, found 384.1666.

[0430] 5-[2-(3-Methoxy-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3-methoxy-phenyl, R2 = methyl, R9 = ethyl]

[0431]

[0432] LC / MS (254 nm) HPLC method (IP) LCT-Formic acid Rt 11.81 min.

[0433] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.70 (s, 1H), 8.54 (d, J = 5.0 Hz, 1H), 7.75 (br. s., 1H), 7.46 (s, 1H), 7.32 (d, J = 5.0 Hz, 1H), 7.27 (dd, J = 0.8, 8.2 Hz, 1H), 7.21-7.15 (m, 1H), 6.57-6.52 (m, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.19 (s, 3H), 3.79 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C18H20N5O3 [M+H]+ 354.1561, found 354.1564.

[0434] 2-Methyl-5-[2-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-yl]-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3,4,5-trimethoxy-phenyl, R2 = methyl, R9 = ethyl]

[0435]

[0436] LC / MS (254 nm) HPLC method (IP) LCT-Formic acid Rt 11.04 min.

[0437] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.59 (s, 1H), 8.53 (d, J = 5.0 Hz, 1H), 7.49-7.48 (m, 1H), 7.34 (s, 2H), 7.30 (d, J = 5.0 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.18 (s, 3H), 3.82 (s, 6H), 3.63 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C20H24N5O5 [M+H]+ 414.1772, found 414.1772.

[0438] 5-[2-(3-Fluoro-5-methoxy-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3-fluoro-5-methoxy-phenyl, R2 = methyl, R9 = ethyl]

[0439]

[0440] LC / MS (254 nm) HPLC method (IP) LCT-Formic acid Rt 12.60 min.

[0441] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.91 (s, 1H), 8.58 (d, J = 5.2 Hz, 1H), 7.47-7.42 (m, 2H), 7.37 (d, J = 5.0 Hz, 1H), 7.36-7.31 (m, 1H), 6.41 (td, J = 2.2, 10.8 Hz, 1H), 4.34 (q, J = 7.0 Hz, 2H), 4.20 (s, 3H), 3.79 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C18H19FN5O3 [M+H]+ 372.1467, found 372.1465.

[0442] 5-[2-(3-Cyano-5-methoxy-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3-cyano-5-methoxy-phenyl, R2 = methyl, R9 = ethyl] 87% yield

[0443]

[0444] LC / MS (254 nm) HPLC method (IP) LCT-formic acid Rt 12.08 min.

[0445] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.09 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 7.93-7.90 (m, 1H), 7.88 (t, J = 1.9 Hz, 1H), 7.46 (s, 1H), 7.41 (d, J = 5.2 Hz, 1H), 7.02 (dd, J = 1.4, 2.3 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.20 (s, 3H), 3.84 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C19H19N6O3 [M+H]+ 379.1513, found 379.1514.

[0446] 5-[2-(5-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 5-methoxy-pyridin-3-yl, R2 = methyl, R9 = ethyl] 37% yield

[0447]

[0448] LC / MS (254 nm) HPLC method (IP) LCT-formic acid Rt 8.62 min.

[0449] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.97 (s, 1H), 8.59 (d, J = 5.0 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.19 (br.s., 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.46 (s, 1H), 7.39 (d, J = 5.0 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.19 (s, 3H), 3.88 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); HRMS (ESI) calcd for C17H19N6O3 [M+H]+ 355.1513, found 355.1518.

[0450] 5-[2-(3,5-bis-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3,5-bis-trifluoromethyl-phenyl, R2 = methyl, R9 = ethyl]

[0451]

[0452] 5-[2-(3-Methoxy-5-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3-methoxy-5-trifluoromethyl-phenyl, R2 = methyl, R9 = ethyl]

[0453]

[0454] 5-[2-(4,6-Dimethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 4,6-dimethyl-pyridin-2-yl, R2 = methyl, R9 = ethyl]

[0455]

[0456] 2-Methyl-5-[2-(3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3-trifluoromethyl-phenyl, R2 = methyl, R9 = ethyl]

[0457]

[0458] 5-[2-(Benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl, R2 = methyl, R9 = ethyl]

[0459]

[0460] 5-[2-(3,4-Dimethoxy-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [(VI), R1 = 3,4-dimethoxy-phenylamino)-pyrimidin-4-yl, R2 = methyl, R9 = ethyl]

[0461]

[0462] Step 5 3-(2-iodopyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester [(IX), R2 = methyl, R9 = ethyl]

[0463]

[0464] To a solution of ethyl 5-(2-amino-pyrimidin-4-yl)-2-methyl-2H-pyrazole-3-carboxylate (450 mg, 1.82 mmol, 1 eq) in degassed anhydrous dioxane (11 ml) was added 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). The reaction mixture was heated at T = 90°C for 2 hours, then cooled to room temperature and diluted with water, and extracted three times with AcOEt. The organics were collected and washed with 10% ammonia solution, 5% aqueous Na2S2O5 solution, and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (eluent: hexane / AcOEt 8 / 2) to give 230 mg (35% yield) of the title compound.

[0465] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 6.43 min.

[0466] 1H NMR (500 MHz, DMSO-d6) δ ppm 1.34 (t, J = 7.1 Hz, 3H) 4.19 (s, 3H) 4.34 (q, J = 7.1 Hz, 2H) 7.44 (s, 1H) 7.98 (d, J = 5.2 Hz, 1H) 8.57 (d, J = 5.2 Hz, 1H); HRMS (ESI) calcd for C11H11IN4O2 [M+H]+ 359, found 359.0013.

[0467] Step 6 1-Methyl-3-{2-[(1,2,3-trimethyl-1H-indol-5-yl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxylic acid ethyl ester [(VI), R1 = 1,2,3-trimethyl-1H-indol-5-yl, R2 = methyl, R9 = ethyl]

[0468]

[0469] Ethyl 3-(2-iodopyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (86 mg, 0.24 mmol, 1 eq), 1,2,3-trimethyl-1H-indol-5-amine (42 mg, 0.24 mmol, 1 eq), and KCO (99.5 mg, 0.72 mmol, 3 eq) were suspended in previously degassed dioxane (4 ml) and subjected to three vacuum / argon cycles. Xantphos (27.8 mg, 0.048 mmol, 0.2 eq) and Pd(OAc) (5.4 mg, 0.024 mmol, 0.1 eq) were added under argon and subjected to three vacuum / argon cycles. The mixture was heated at 100°C for 3 hours, then cooled to room temperature and diluted with water. The mixture was extracted three times with AcOEt, the organics collected and washed with brine, and the volatiles removed under reduced pressure. The crude solid was purified by flash chromatography on silica gel (eluent: DCM / AcOEt 9 / 1) to give 10 mg (10% yield) of the title compound.

[0470] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 7.38 min.

[0471] 1H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (t, J = 7.1 Hz, 3H) 2.23 (s, 3H) 2.33 (s, 3H) 3.62 (s, 3H) 4.20 (s, 3H) 4.35 (q, J = 7.1 Hz, 2H) 7.21 (dd, J = 8.5, 1.5 Hz, 1H) 7.22 (d, J = 5.0 Hz, 1H) 7.25 (d, J = 8.7 Hz, 1H) 7.48 (s, 1H) 8.25 (br. s., 1H) 8.47 (d, J = 5.0 Hz, 1H) 9.44 (s, 1H); HRMS (ESI) calcd for C22H24N6O2 [M+H]+ 405.2034, found 405.2033.

[0472] 3-{2-[(3-chloro-1-methyl-1H-indol-5-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester [(VI), R1 = 3-chloro-1-methyl-1H-indol-5-yl, R2 = methyl, R9 = ethyl]

[0473]

[0474] Ethyl 3-(2-iodopyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (140 mg, 0.39 mmol, 1 eq), 3-chloro-1-methyl-1H-indol-5-amine (84.5 mg, 0.47 mmol, 1.2 eq) and cesium carbonate (381 mg, 1.17 mmol, 3 eq) were suspended in previously degassed dioxane (8 ml) and subjected to three vacuum / argon cycles. 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 argon and subjected to three vacuum / argon cycles. The mixture was heated at 100° C. for 7 h, then cooled to room temperature and diluted with water, extracted three times with AcOEt, the organics collected and washed with brine, and the volatiles removed under reduced pressure. The crude solid was purified by flash chromatography on silica gel (eluent: DCM / AcOEt 95 / 5) to give 24 mg (15% yield) of the title compound.

[0475] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 7.22 min.

[0476] 1H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (t, J = 7.1 Hz, 3H) 3.76 (s, 3H) 4.21 (s, 3H) 4.34 (q, J = 7.2 Hz, 2H) 7.29 (d, J = 5.0 Hz, 1H) 7.37 (dd, J = 8.9, 1.5 Hz, 1H) 7.43 (d, J = 8.8 Hz, 1H) 7.48 (s, 1H) 7.58 (s, 1H) 8.53 (d, J = 4.9 Hz, 1H) 8.59 (br. s., 1H) 9.70 (s, 1H); HRMS (ESI) calcd for C20H19ClN6O2 [M+H]+ 411.1331, found 411.1340.

[0477] Step 7 2-Methyl-5-(2-m-tolylamino-pyrimidin-4-yl)-2H-pyrazole-3-carboxylic acid [(XI), R1 = 2-m-tolyl, R2 = methyl] 100% yield

[0478]

[0479] Sodium hydroxide 2N (10.5 ml) was added to a solution of ethyl 2-methyl-5-(2-m-tolylamino-pyrimidin-4-yl)-2H-pyrazole-3-carboxylate (260 mg, 0.77 mmol, 1 eq) in ethanol (21 ml), and the mixture was stirred at room temperature for 4 hours. HCl 2N was added to reach pH <5, and the precipitate was filtered, washed with water and Et2O, and dried in vacuo to give the title compound in quantitative yield.

[0480] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 4.26 min.

[0481] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.60 (s, 1H), 8.51 (d, J = 5.0 Hz, 1H), 7.69 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.38 (s, 1H), 7.29 (d, J = 5.2 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 4.18 (s, 3H), 2.30 (s, 3H); HRMS (ESI) calcd for C16H16N5O2 [M+H]+ 310.1299, found 310.1302.

[0482] Following this same procedure, but employing appropriately substituted derivatives, the following compounds were prepared:

[0483] 5-[2-(3,5-difluoro-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3,5-difluoro-phenyl, R2 = methyl] quantitative yield

[0484]

[0485] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 4.51 min.

[0486] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.16 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 7.68-7.58 (m, 2H), 7.42 (d, J = 5.2 Hz, 1H), 7.38 (s, 1H), 6.76 (tt, J = 2.2, 9.3 Hz, 1H), 4.19 (s, 3H); HRMS (ESI) calculated for C15H12F2N5O2 [M+H]+ is 332.0954, found 332.0956.

[0487] 5-{2-[3-chloro-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3-chloro-4-(4-methyl-piperazin-1-yl)-phenyl, R2 = methyl] quantitative yield

[0488]

[0489] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 3.57 min.

[0490] 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.99 (s, 1H), 9.69 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.72 (dd, J = 2.1, 8.7 Hz, 1H), 7.29 (d, J = 5.2 Hz, 1H), 7.19 (s, 1H), 7.15 (d, J = 8.8 Hz, 1H), 4.17 (s, 3H), 2.98 (br.s., 4H), 2.35 (br.s., 3H); HRMS (ESI) calcd for C20H23ClN7O2 [M+H]+ 428.1597, found 428.1607.

[0491] 5-[2-(3-Chloro-1-methyl-1H-indol-5-ylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3-chloro-1-methyl-1H-indol-5-yl, R2 = methyl] 93% yield

[0492]

[0493] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 4.53 min.

[0494] 1 H NMR (500 MHz, DMSO-d6) δ ppm 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) calculated for C18H16ClN6O2 [M+H]+ is 383.1018, found 383.1006.

[0495] 1-Methyl-3-{2-[(1,2,3-trimethyl-1H-indol-5-yl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxylic acid [(XI), R1 = 1,2,3-trimethyl-1H-indol-5-yl, R2 = methyl]

[0496]

[0497] Alternatively, the acid or its salt can be prepared as reported below:

[0498] 5-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3,5-dimethyl-phenyl, R2 = methyl]

[0499]

[0500] Lithium hydroxide monohydrate (47.8 mg, 1.138 mmol, 2.5 equivalents) and ethanol (1 ml) dissolved in water (2 ml) were added sequentially to a solution of ethyl 5-[2-(3,5-dimethyl-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylate (160 mg, 0.455 mmol, 1 equivalent) in THF (2 ml). The mixture was stirred at room temperature for 16 h and then treated with HCl 1N until pH = 3 was reached. The organic matter was removed under reduced pressure, and the precipitate was filtered and rinsed with water and Et2O to give 132 mg (90% yield) of the title compound, which was used without further purification.

[0501] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 4.55 min.

[0502] 1 H NMR (500 MHz, DMSO-d6) δ ppm 13.66 (br.s, 1H), 9.55 (s, 1H), 8.51 (d, J = 5.0 Hz, 1H), 7.48 (br.s, 2H), 7.38 (s, 1H), 7.28 (d, J = 5.0 Hz, 1H), 6.62 (br.s, 1H), 4.18 (s, 3H), 2.26 (s, 6H); HRMS (ESI) calculated for C17H18N5O2 [M+H]+ is 324.1455, found 324.1454.

[0503] Following this same procedure, but employing appropriately substituted derivatives, the following compounds were prepared:

[0504] 5-[2-(3-Methoxy-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3-methoxy-phenyl, R2 = methyl] 94% yield

[0505]

[0506] LC / MS (254 nm) HPLC method (IP) LCT-formic acid Rt 9.53 min.

[0507] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.68 (s, 1H), 8.53 (d, J = 5.2 Hz, 1H), 7.68 (s, 1H), 7.40 (s, 1H), 7.31 (d, J = 5.2 Hz, 2H), 7.21-7.17 (m, 1H), 6.54 (dd, J = 2.2, 7.9 Hz, 1H), 4.18 (s, 3H), 3.77 (s, 3H); HRMS (ESI) calculated for C16H16N5O3 [M+H]+ is 326.1248, found 326.1248.

[0508] 5-[2-(3,5-Dimethoxy-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3,5-dimethoxy-phenyl, R2 = methyl] 92% yield

[0509]

[0510] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 4.13 min.

[0511] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.67 (s, 1H), 8.56 (d, J = 5.0 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J = 5.0 Hz, 1H), 7.22 (d, J = 2.3 Hz, 2H), 6.17 (t, J = 2.3 Hz, 1H), 4.21 (s, 3H), 3.81-3.76 (m, 6H); HRMS (ESI) calcd for C17H18N5O4 [M+H]+ 356.1354, found 356.1366.

[0512] 2-Methyl-5-[2-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-yl]-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3,4,5-trimethoxy-phenyl, R2 = methyl] 80% yield

[0513]

[0514] LC / MS (254 nm) HPLC method (IP) LCT-formic acid Rt 9.02 min.

[0515] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.56 (s, 1H), 8.52 (d, J = 5.0 Hz, 1H), 7.44 (s, 1H), 7.33 (s, 2H), 7.29 (d, J = 5.2 Hz, 1H), 4.17 (s, 3H), 3.80 (s, 6H), 3.62 (s, 3H); HRMS (ESI) calculated for C18H20N5O5 [M+H]+ is 386.1459, found 386.1471.

[0516] 5-[2-(3-Fluoro-5-methoxy-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3-fluoro-5-methoxy-phenyl, R2 = methyl] 99% yield

[0517]

[0518] LC / MS (254 nm) HPLC method (IP) LCT-formic acid Rt 10.53 min.

[0519] 1 H NMR (500 MHz, DMSO-d6) δ ppm 13.71 (br.s., 1H), 9.88 (s, 1H), 8.56 (d, J = 5.0 Hz, 1H), 7.45-7.30 (m, 4H), 6.41 (td, J = 2.2, 10.8 Hz, 1H), 4.18 (s, 3H), 3.78 (s, 3H); HRMS (ESI) calculated for C16H15FN5O3 [M+H]+ is 344.1154, found 344.1140.

[0520] 2-Methyl-5-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2H-pyrazole-3-carboxylic acid [(XI), R1 = 1-methyl-1H-pyrazol-4-yl, R2 = methyl] 72% yield

[0521]

[0522] LC / MS (254 nm) HPLC method (IP) LCT-formic acid Rt 5.87 min.

[0523] 1H NMR (500 MHz, DMSO-d6) δ ppm 13.60 (br.s., 1H), 9.51 (s, 1H), 8.45 (d, J = 5.0 Hz, 1H), 7.90 (s, 1H), 7.66-7.53 (m, 1H), 7.37 (br.s., 1H), 7.20 (d, J = 5.2 Hz, 1H), 4.18 (s, 3H), 3.82 (s, 3H); HRMS (ESI) calculated for C13H14N7O2 [M+H]+ is 300.1204, found 300.1203.

[0524] 2-Methyl-5-[2-(3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3-trifluoromethyl-phenyl, R2 = methyl]

[0525]

[0526] LC / MS (254 nm) HPLC method (IP) LCT-formic acid Rt 11.49 min.

[0527] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.96 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.44 (s, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 5.2 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 4.16 (s, 3H); HRMS (ESI) calcd for C16H13F3N5O2 [M+H]+ 364.1016, found 364.1007.

[0528] 5-[2-(3-Cyano-5-methoxy-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3-cyano-5-methoxy-phenyl, R2 = methyl] 96% yield

[0529]

[0530] LC / MS (254 nm) HPLC method (IP) LCT-formic acid Rt 10.05 min.

[0531] 1H NMR (500 MHz, DMSO-d6) δ ppm 10.06 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 7.89 (d, J = 1.2 Hz, 2H), 7.41 (t, J = 2.5 Hz, 2H), 7.06-6.98 (m, 1H), 4.19 (s, 3H), 3.83 (s, 3H); HRMS (ESI) calculated for C17H15N6O3 [M+H]+ is 351.1200, found 351.1201.

[0532] 5-[2-(5-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 5-methoxy-pyridin-3-yl, R2 = methyl] 87% yield

[0533]

[0534] LC / MS (254 nm) HPLC method (IP) LCT-Formic acid Rt 5.40 min.

[0535] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.13 (s, 1H), 8.67 (s, 1H), 8.60 (d, J = 5.0 Hz, 1H), 8.22 (s, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.46-7.38 (m, 2H), 4.19 (s, 3H), 3.90 (s, 3H); HRMS (ESI) calculated for C15H15N6O3 [M+H]+ is 327.1200, found 327.1199.

[0536] 5-[2-(3,5-Bis-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3,5-bis-trifluoromethyl-phenyl, R2 = methyl]

[0537]

[0538] 5-[2-(3-Methoxy-5-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3-methoxy-5-trifluoromethyl-phenyl, R2 = methyl]

[0539]

[0540] 5-[2-(4,6-Dimethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 4,6-dimethyl-pyridin-2-yl, R2 = methyl]

[0541]

[0542] 5-[2-(3,5-Dichloro-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3,5-dichloro-phenyl, R2 = methyl]

[0543]

[0544] 5-[2-(Benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 2-(benzo[1,3]dioxol-5-yl, R2 = methyl]

[0545]

[0546] 5-[2-(1,5-Dimethyl-1H-pyrazol-3-ylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 1,5-dimethyl-1H-pyrazol-3-yl, R2 = methyl]

[0547]

[0548] 2-Methyl-5-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-2H-pyrazole-3-carboxylic acid [(XI), R1 = tetrahydro-pyran-4-yl, R2 = methyl]

[0549]

[0550] 5-[2-(3-Cyano-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3-cyano-phenyl, R2 = methyl]

[0551]

[0552] 5-[2-(3,4-Dimethoxy-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3,4-dimethoxy-phenyl, R2 = methyl]

[0553]

[0554] 5-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-2-ethyl-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3,5-dimethyl-phenyl, R2 = ethyl]

[0555]

[0556] 5-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-2H-pyrazole-3-carboxylic acid [(XI), R1 = 3,5-dimethyl-phenyl, R2 = H]

[0557]

[0558] Step 8

[0559] N-[2-(dimethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 1) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-(dimethylamino)ethyl, R4 = H]

[0560]

[0561] 5-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid (25 mg, 0.077 mmol, 1 eq) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU) (37 mg, 0.12 mmol, 1.5 eq) were suspended in anhydrous 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 h and then diluted with H₂O (5 ml) and extracted three times with AcOEt (3×4 ml). The organic layer was collected and washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by flash chromatography on silica gel (eluent DCM / MeOH 9:1) to afford the title compound in 52% yield.

[0562] LC / MS (254 nm) HPLC Method (IP) LCQ Deca XP-Acetate buffer Rt 5.23 min.

[0563] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.71 (t, J = 5.1 Hz, 1H), 8.49 (d, J = 5.2 Hz, 1H), 7.47 (s, 2H), 7.42 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 6.61 (s, 1H), 4.14 (s, 3H), 3.36 (q, J = 6.0 Hz, 2H), 2.47 (br. s, 2H), 2.27 (s, 6H), 2.24 (br. s., 6H); HRMS (ESI) calcd for C21H27N7O [M+H]+ 394.235, found 394.2357.

[0564] Following this same procedure, but employing the appropriate amine derivatives which were ultimately salified or protected, the following compounds were prepared:

[0565] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2R)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd2) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2R)-1-hydroxypropan-2-yl, R4 = H]

[0566]

[0567] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.46(s,1H),8.49(d,J=5.0Hz,1H),8.45(d,J=8.2Hz,1H),7.47(s,3H),7.25(d,J=5.0Hz,1H),6.61(s,1H),4.75(t,J=5.8Hz,1H),4.13(s,3H),3.98(qd,J=6.5,7.7Hz,1H),3.47-3.41(m,1H),3.34-3.30(m,1H),2.27(s,6H),1.12(d,J=6.7Hz,3H); HRMS(ESI) calculated for C20H24N6O2[M+H]+ is 381.2034, found to be 381.2031.

[0568] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 3) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2S)-1-hydroxypropan-2-yl, R4 = H]

[0569]

[0570] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.46 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.45 (d, J = 8.1 Hz, 1H), 7.47 (s, 2H), 7.25 (d, J = 5.2 Hz, 1H), 6.61 (s, 1H), 4.74 (t, J = 5.8 Hz, 1H), 4.13 (s, 3H), 4.03-3.91 (m, 1H), 3.44 (td, J = 5.6, 10.9 Hz, 1H), 2.27 (s, 6H), 1.12 (d, J = 6.7 Hz, 3H); HRMS (ESI) calcd for C20H24N6O2 [M+H]+ 381.2034, found 381.2036.

[0571] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(propan-2-yl)-1H-pyrazole-5-carboxamide (cpd 4) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = propan-2-yl, R4 = H]

[0572]

[0573] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.46 (s, 1H), 8.59 (d, J = 7.9 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.48 (s, 2H), 7.46 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 6.61 (s, 1H), 4.13 (s, 3H), 4.11-4.01 (m, 1H), 2.27 (s, 6H), 1.16 (d, J = 6.6 Hz, 6H); HRMS (ESI) calcd for C20H24N6O [M+H]+ 365.2085, found 365.2087.

[0574] N-[2-(dimethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (cpd 5) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = [2-(dimethylamino)ethyl, R4 = methyl]

[0575]

[0576] 1H 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) calcd for C22H29N7O [M+H]+ 408.2507, found 408.2518.

[0577] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(methylamino)ethyl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 6) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-(methylamino)ethyl, R4 = H]

[0578]

[0579] 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) calcd for C20H26N7OCl [M+H]+ 380.2194, found 380.2186.

[0580] N-(2-aminoethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 7) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-aminoethyl, R4 = H]

[0581]

[0582] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.49 (s, 1H), 8.94 (t, J = 5.7 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.92 (br. s., 3H), 7.48 (s, 1H), 7.46 (s, 2H), 7.26 (d, J = 5.2 Hz, 1H), 6.62 (s, 1H), 4.16 (s, 3H), 3.50 (quin, J = 5.8 Hz, 2H), 2.98 (sxt, J = 5.9 Hz, 2H), 2.27 (s, 6H); HRMS (ESI) calcd for C19H24N7OCl [M+H]+ 366.2037, found 366.2033.

[0583] N-(Azetidin-3-yl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide trifluoroacetate (cpd 8) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = azetidin-3-yl, R4 = H]

[0584]

[0585] 1 H NMR (DMSO-d6, 500 MHz): δ ppm 9.47 (s, 1H), 9.41 (d, J = 7.0 Hz, 1H), 8.68 (br. s., 2H), 8.51 (d, J = 5.0 Hz, 1H), 7.50 (s, 1H), 7.46 (s, 2H), 7.27 (d, J = 5.0 Hz, 1H), 6.63 (s, 1H), 4.82 (sxt, J = 7.8 Hz, 1H), 4.16-4.24 (m, 2H), 4.15 (s, 3H), 4.01-4.12 (m, 2H), 2.28 ppm (s, 6H); HRMS (ESI) calcd for C22H24N7O3F3 [M+H]+ 378.2037, found 378.2034.

[0586] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(morpholin-4-yl)ethyl]-1H-pyrazole-5-carboxamide (cpd 9) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-morpholin-4-ylethyl, R4 = H]

[0587]

[0588] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.46 (s, 1H), 8.72 (t, J = 5.6 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.46 (s, 2H), 7.41 (s, 1H), 7.26 (d, J = 5.0 Hz, 1H), 6.62 (s, 1H), 4.14 (s, 3H), 3.57 (t, J = 4.6 Hz, 4H), 3.37 (q, J = 6.3 Hz, 2H), 2.46 (t, J = 6.7 Hz, 2H), 2.41 (br. s., 4H), 2.27 (s, 6H); HRMS (ESI) calcd for C23H29N7O2 [M+H]+ 436.2456, found 436.2447.

[0589] N-[2-(Diethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 10) [(I), R1 = 3,5-dimethylphenyl), R2 = methyl, R3 = 2-(diethylamino)ethyl, R4 = H]

[0590]

[0591] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.46 (s, 1H), 8.90 (br.t, J = 4.5 Hz, 1H), 8.50 (d, J = 5.0 Hz, 1H), 7.46 (s, 2H), 7.43 (s, 1H), 7.26 (d, J = 5.0 Hz, 1H), 6.62 (s, 1H), 4.15 (s, 3H), 3.51 (br.q, J = 5.3 Hz, 2H), 3.03 (br.s., 6H), 2.27 (s, 6H), 1.20-1.03 (m, 6H); HRMS (ESI) calcd for C23H31N7O [M+H]+ 422.2663, found 422.2666.

[0592] N-[(1R,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 11) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (1R,2R)-2-aminocyclohexyl, R4 = H]

[0593]

[0594] 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 = 13.4 Hz, 1H), 1.86 (d, J = 13.6 Hz, 1H), 1.73 (d, J = 8.1 Hz, 2H), 1.52-1.35 (m, 2H), 1.33-1.18 (m, J = 11.2, 11.2 Hz, 2H); HRMS (ESI) calculated for C23H30N7OCl[M+H]+ is 420.2507, found to be 420.2503.

[0595] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(propan-2-ylamino)ethyl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 12) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-(propan-2-ylamino)ethyl, R4 = H]

[0596]

[0597] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.46 (s, 1H), 8.98 (t, J = 5.6 Hz, 1H), 8.50 (d, J = 5.0 Hz, 1H), 8.51 (br. s., 2H), 7.48 (s, 1H), 7.46 (s, 2H), 7.26 (d, J = 5.0 Hz, 1H), 6.62 (s, 1H), 4.16 (s, 3H), 3.56 (q, J = 5.9 Hz, 2H), 3.08 (t, J = 5.6 Hz, 2H), 2.27 (s, 6H), 1.23 (d, J = 6.4 Hz, 6H); HRMS (ESI) calcd for C22H30N7OCl[M+H]+ 408.2507, found 408.2502.

[0598] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd13) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = H, R4 = H]

[0599]

[0600] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.46 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.21 (br.s., 1H), 7.62 (br.s., 1H), 7.47 (s, 2H), 7.44 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 6.61 (s, 1H), 4.14 (s, 3H), 2.27 (s, 6H); HRMS (ESI) calcd for C17H18N6O [M+H]+ 323.1615, found 323.1611.

[0601] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (cpd14) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = methyl, R4 = H]

[0602]

[0603] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.45 (s, 1H), 8.73 (d, J = 4.7 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.46 (s, 2H), 7.39 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 6.61 (s, 1H), 4.14 (s, 3H), 2.77 (d, J = 4.6 Hz, 3H), 2.27 (s, 6H); HRMS (ESI) calcd for C18H20N6O [M+H]+ 337.1772, found 337.1775.

[0604] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N,N,1-trimethyl-1H-pyrazole-5-carboxamide (cpd 15) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = dimethylamino, R4 = methyl]

[0605]

[0606] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.51 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.47 (s, 2H), 7.27 (d, J = 5.0 Hz, 1H), 7.04 (s, 1H), 6.60 (s, 1H), 3.96 (s, 3H), 3.11 (s, 3H), 3.04 (s, 3H), 2.25 (s, 6H); HRMS (ESI) calcd for C19H22N6O [M+H]+ 351.1928, found 351.1925.

[0607] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 16) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-methoxyethyl, R4 = H]

[0608]

[0609] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.82 (t, J = 5.5 Hz, 1H), 8.49 (d, J = 5.2 Hz, 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) calcd for C20H24N6O2 [M+H]+ 381.2034, found 381.2034.

[0610] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-(2-fluoroethyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 17) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-fluoroethyl, R4 = H]

[0611]

[0612] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.46 (s, 1H), 9.01 (t, J = 5.5 Hz, 1H), 8.50 (d, J = 5.0 Hz, 1H), 7.49 (s, 1H), 7.46 (s, 2H), 7.25 (d, J = 5.2 Hz, 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) calcd for C19H21N6OF [M+H]+ 369.1834, found 369.1831.

[0613] 3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-N-[2-(dimethylamino)ethyl]-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 18) [(I), R1 = 3,5-bis(trifluoromethyl)phenyl, R2 = methyl, R3 = 2-(dimethylamino)ethyl, R4 = H]

[0614]

[0615] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.41 (s, 1H), 9.72 (br. s., 1H), 8.98 (t, J = 5.5 Hz, 1H), 8.66 (d, J = 5.2 Hz, 1H), 8.60 (s, 2H), 7.62 (s, 1H), 7.45 (s, 1H), 7.42 (d, J = 5.0 Hz, 1H), 4.17 (s, 3H), 3.61 (q, J = 5.8 Hz, 2H), 3.26 (t, J = 5.0 Hz, 1H), 2.84 (s, 6H); HRMS (ESI) calcd for C21H22N7OF6Cl [M+H]+ 502.1785, found 502.1777.

[0616] 3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 19) [(I), R1 = 3,5-bis(trifluoromethyl)phenyl, R2 = methyl, R3 = (2S)-1-hydroxypropan-2-yl, R4 = H]

[0617]

[0618] 1H NMR (500 MHz, DMSO-d6) δ ppm 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) calculated for C20H18N6O2F6[M+H]+ as 489.1468, found as 489.146.

[0619] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(1H-pyrazol-3-yl)-1H-pyrazole-5-carboxamide (cpd 20) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 1H-pyrazol-3-yl, R4 = H]

[0620]

[0621] 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.50 (br.s., 1H), 11.16 (s, 1H), 9.49 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 7.72 (s, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.48 (s, 2H), 7.26 (d, J = 5.0 Hz, 1H), 6.61 (br.s, 2H), 4.19 (s, 3H), 2.27 (s, 6H); HRMS (ESI) calcd for C20H20N8O [M+H] + 389.1833, found 389.1833.

[0622] (3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)(4-methylpiperazin-1-yl)methanone (cpd 21) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, NR3R4 = 4-methylpiperazin-1-yl]

[0623]

[0624] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.52 (s, 1H), 8.50 (d, J = 5.0 Hz, 1H), 7.47 (s, 2H), 7.27 (d, J = 5.0 Hz, 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) calcd for C22H27N7O [M+H]+ 406.235, found 406.2351.

[0625] N-[2-(Acetylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 22) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-acetylaminoethyl, R4 = H]

[0626]

[0627] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.46 (s, 1H), 8.79 (t, J = 5.6 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.98 (t, J = 5.7 Hz, 1H), 7.46 (s, 2H), 7.42 (s, 1H), 7.25 (d, J = 5.0 Hz, 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) calcd for C21H25N7O2 [M+H]+ 408.2143, found 408.2156.

[0628] N-(2-amino-2-oxoethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 23) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-amino-2-oxoethyl, R4 = H]

[0629]

[0630] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.94 (t, J = 6.0 Hz, 1H), 8.50 (d, J = 5.0 Hz, 1H), 7.48 (s, 1H), 7.46 (s, 2H), 7.44 (br.s, 1H), 7.26 (d, J = 5.2 Hz, 1H), 7.09 (br.s, 1H), 6.61 (s, 1H), 4.14 (s, 3H), 3.80 (d, J = 6.1 Hz, 2H), 2.27 (s, 6H); HRMS (ESI) calcd for C19H21N7O2 [M+H]+ 380.183, found 380.1829.

[0631] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxamide (cpd 24) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2,2,2-trifluoroethylamino, R4 = H]

[0632]

[0633] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.49 (s, 1H), 9.43 (t, J = 6.3 Hz, 1H), 8.51 (d, J = 5.0 Hz, 1H), 7.56 (s, 1H), 7.47 (s, 2H), 7.26 (d, J = 5.0 Hz, 1H), 6.62 (s, 1H), 4.15 (s, 3H), 4.09 (dq, J = 6.1, 9.6 Hz, 2H), 2.27 (s, 6H); HRMS (ESI) calcd for C19H19N6OF3 [M+H]+ 405.1645, found 405.1648.

[0634] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(1-methyl-1H-imidazol-5-yl)methyl]-1H-pyrazole-5-carboxamide (cpd 25) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (3-methylimidazol-4-yl)methyl, R4 = H]

[0635]

[0636] 1H NMR (500 MHz, DMSO-d6) δ pppm 9.45 (s, 1H), 9.16 (t, J = 5.3 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.56 (s, 1H), 7.48 (s, 1H), 7.46 (s, 2H), 7.25 (d, J = 5.2 Hz, 1H), 6.84 (s, 1H), 6.61 (s, 1H), 4.44 (d, J = 5.3 Hz, 2H), 4.15 (s, 3H), 3.63 (s, 3H), 2.25 (s, 6H); HRMS (ESI) calcd for C22H24N8O [M+H]+ 417.2146, found 417.2155.

[0637] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 26) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2S)-1-hydroxy-3-methylbutan-2-yl, R4 = H]

[0638]

[0639] 1 H 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 Hz, 1H), 0.91 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H); HRMS (ESI) calculated for C22H28N6O2 [M+H] + 409.2347, found 409.2352.

[0640] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(pyridin-2-ylmethyl)-1H-pyrazole-5-carboxamide (cpd 27) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = pyridin-2-ylmethyl, R4 = H]

[0641]

[0642] 1 H 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,2H),7.36(d,J=7.8Hz,1H),7.2 9(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) calculated for C23H23N7O[M+H]+ as 414.2037, found as 414.2043.

[0643] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-(1H-imidazol-2-ylmethyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 28) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 1H-imidazol-2-ylmethyl, R4 = H]

[0644]

[0645] 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.85 (br. s., 1H), 9.46 (s, 1H), 9.24 (t, J = 5.7 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.50 (s, 1H), 7.45 (s, 2H), 7.25 (d, J = 5.2 Hz, 1H), 7.03 (s, 1H), 6.82 (s, 1H), 6.60 (s, 1H), 4.47 (d, J = 5.6 Hz, 2H), 4.17 (s, 3H), 2.26 (s, 6H); HRMS (ESI) calcd for C21H22N8O [M+H]+ 403.199, found 403.1994.

[0646] N-[(2R)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 29) [(I), R1 = 3,5-dimethoxyphenyl, R2 = methyl, R3 = (2R)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0647]

[0648] 1 H NMR(500MHz,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) calculated for C23H29N7O3[M+H]+ as 452.2405, found as 452.2407.

[0649] N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl]-1H-pyrazole-5-carboxamide (cpd 30) [(I), R1 = oxan-4-yl, R2 = methyl, R3 = (2S)-1-(dimethylamino)propan-2-yl, R4 = H]

[0650]

[0651] 1H NMR(500MHz,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 = 6.7 Hz, 1H), 2.16 (s, 6H), 1.84 (d, J = 12.4 Hz, 2H), 1.60-1.48 (m, 2H), 1.12 (d, J = 6.6 Hz, 3H); HRMS (ESI) calculated for C19H29N7O2[M+H]+ is 388.2456, found to be 388.2455.

[0652] N-(1-Azabicyclo[2.2.2]octan-3-yl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 31) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 1-azabicyclo[2.2.2]octan-3-yl, R4 = H]

[0653]

[0654] 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) calculated for C24H29N7O[M+H]+ is 432.2507, found to be 432.2505.

[0655] 5-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide (cpd 32) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (1R,2R)-2-hydroxycyclohexyl, R4 = H]

[0656]

[0657] 1 H 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) calculated for C23H28N6O2[M+H]+ as 421.2347, found as 421.2349.

[0658] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxybutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 33) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2S)-1-hydroxybutan-2-yl, R4 = H]

[0659]

[0660] 1H NMR (500 MHz, DMSO-d6) δ ppm 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),4.71(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) calculated for C21H26N6O2[M+H]+ is 395.219, found to be 395.2185.

[0661] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 34) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-hydroxyethyl, R4 = H]

[0662]

[0663] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.45 (s, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.46 (s, 2H), 7.44 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 6.61 (s, 1H), 4.76 (t, J = 5.7 Hz, 1H), 4.13 (s, 3H), 3.51 (q, J = 6.0 Hz, 2H), 3.31 (q, J = 6.0 Hz, 2H), 2.27 (s, 6H); HRMS (ESI) calcd for C19H22N6O2 [M+H]+ 367.1877, found 367.1872.

[0664] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,4-dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 35) [(I), R1 = 3,4-dimethoxyphenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0665]

[0666] 1H NMR(500MHz,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,1 H), 3.79 (s, 3H), 3.72 (s, 3H), 3.22-3.01 (m, 4H), 2.55-2.35 (m. partially overlapped with water, 2H), 1.95 (quin, J = 6.8 Hz, 2H), 1.10 (d, J = 6.7 Hz, 3H); HRMS (ESI) calculated for C23H29N7O3 [M+H] + as 452.2405, found as 452.2413.

[0667] (3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)(piperazin-1-yl)methanone hydrochloride (cpd 36) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, NR3R4 = piperazin-1-ylamino]

[0668]

[0669] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.53 (s, 1H), 9.13 (br.s., 2H), 8.50 (d, J = 5.0 Hz, 1H), 7.47 (s, 2H), 7.28 (d, J = 5.0 Hz, 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) calcd for C21H26N7OCl[M+H]+ 392.2194, found 392.2207.

[0670] N-[(1S,2R)-2-aminocyclohexyl]-3-(2-{[3-methoxy-5-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 37) [(I), R1 = 3-methoxy-5-(trifluoromethyl)phenyl, R2 = methyl, R3 = (1S,2R)-2-aminocyclohexyl, R4 = H]

[0671]

[0672] 1 H NMR (500 MHz, DMSO-d6) δ ppm 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.s.,1H),4.14(s,3H),3.85(s,3H),1.87-1.56(m,6H),1.52-1.32(m,2H); HRMS(ESI) calculated for C23H27N7O2F3Cl[M+H]+ as 490.2173, found as 490.2173.

[0673] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3-chloro-1-methyl-1H-indol-5-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 38) [(I), R1 = 3-chloro-1-methylindol-5-yl, R2 = methyl, R3 = (1S,2R)-2-aminocyclohexyl, R4 = H]

[0674]

[0675] 1 H 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.s., 1H), 4.14 (s, 3H), 3.76 (s, 3H), 3.42 (s, 1H), 1.88-1.56 (m, 6H), 1.53-1.32 (m, 2H); HRMS (ESI) calculated for C24H28N8OCl2[M+H]+ is 479.2069, found to be 479.2074.

[0676] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 39) [(I), R1 = 3-methoxyphenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0677]

[0678] 1 H NMR(500MHz,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 overlaps with water,2H)2.07-1.88(m,2H),1.11(d,J=6.7Hz,3H); HRMS(ESI) calculated for C22H27N7O2[M+H]+ is 422.2299, found to be 422.2306.

[0679] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-difluorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 40) [(I), R1 = 3,5-difluorophenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0680]

[0681] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.10 (s, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.45 (d, J = 8.2 Hz, 1H), 7.67-7.57 (m, 2H), 7.45 (s, 1H), 7.38 (d, J = 5.2 Hz, 1H), 6.76 (tt, J = 2.3, 9.3 Hz, 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 = 6.9 Hz, 2H), 1.16-1.04 (m, 3H); HRMS (ESI) calculated for C21H23N7OF2[M+H]+ is 428.2005, found 428.2006.

[0682] N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 41) [(I), R1 = 3-methylphenyl, R2 = methyl, R3 = (2S)-1-hydroxy-3-methylbutan-2-yl, R4 = H]

[0683]

[0684] 1 H 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) calculated for C21H26N6O2[M+H]+ as 395.219, found as 395.2196.

[0685] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (cpd 42) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2S)-1,1,1-trifluoropropan-2-yl, R4 = H]

[0686]

[0687] 1H NMR (500 MHz, DMSO-d6) δδppm 9.49 (s, 1H), 9.23 (d, J = 8.7 Hz, 1H), 8.51 (d, J = 5.0 Hz, 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, 15.3 Hz, 1H), 4.14 (s, 3H), 2.27 (s, 6H), 1.36 (d, J = 7.2 Hz, 3H); HRMS (ESI) calcd for C20H21N6OF3[M+H]+ 419.1802, found 419.1813.

[0688] N-[3-(Dimethylamino)propyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 43) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 3-(dimethylamino)propyl, R4 = H]

[0689]

[0690] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.46 (s, 1H), 8.78 (t, J = 5.6 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.47 (s, 2H), 7.25 (d, J = 5.0 Hz, 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 = 7.0 Hz, 2H); HRMS (ESI) calcd for C22H29N7O [M+H]+ 408.2507, found 408.2499.

[0691] (3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)[(2S)-2-(propan-2-yl)aziridin-1-yl]methanone (cpd 44) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, NR3R4 = (1R,2S)-2-propan-2-ylaziridin-1-ylamino]

[0692]

[0693] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.51 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.47 (s, 2H), 7.28 (d, J = 5.0 Hz, 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, 13.2 Hz, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H); HRMS (ESI) calcd for C22H26N6O [M+H]+ 391.2241, found 391.2246.

[0694] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-(2,2-dimethylpropyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 45) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2,2-dimethylpropyl, R4 = H]

[0695]

[0696] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.49 (s, 1H), 8.72 (t, J = 6.3 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.49 (s, 2H), 7.27 (d, J = 5.0 Hz, 1H), 6.61 (s, 1H), 4.12 (s, 3H), 3.08 (d, J = 6.4 Hz, 2H), 2.26 (s, 6H), 0.91 (s, 9H); HRMS (ESI) calcd for C22H28N6O [M+H]+ 393.2398, found 393.2399.

[0697] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(2-methylpropyl)-1H-pyrazole-5-carboxamide (cpd 46) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-methylpropyl, R4 = H]

[0698]

[0699] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.48 (s, 1H), 8.78 (t, J = 5.9 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.48 (s, 2H), 7.44 (s, 1H), 7.26 (d, J = 5.0 Hz, 1H), 6.61 (s, 1H), 4.13 (s, 3H), 3.07 (t, J = 6.4 Hz, 2H), 2.27 (s, 6H), 1.84 (quin, J = 6.7, 13.5 Hz, 1H), 0.90 (d, J = 6.7 Hz, 6H); HRMS (ESI) calcd for C21H26N6O [M+H]+ 379.2241, found 379.2254.

[0700] N-(Cyclopropylmethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 47) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = cyclopropylmethyl, R4 = H]

[0701]

[0702] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.87 (t, J = 5.7 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.48 (s, 2H), 7.46 (s, 1H), 7.26 (d, J = 5.0 Hz, 1H), 6.62 (s, 1H), 4.14 (s, 3H), 3.13 (t, J = 6.3 Hz, 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) calcd for C21H24N6O [M+H]+ 377.2085, found 377.209.

[0703] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-fluoro-5-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 48) [(I), R1 = 3-fluoro-5-methoxyphenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0704]

[0705] 1H NMR(500MHz,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 overlapped with water, 2H) 2.12-1.89 (m, 2H), 1.11 (d, J = 6.9 Hz, 3H); HRMS (ESI) calculated for C22H26N7O2F [M+H] + as 440.2205, found as 440.2202.

[0706] 3-{2-[(4,6-dimethylpyridin-2-yl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 49) [(I), R1 = 4,6-dimethylpyridin-2-yl, R2 = methyl, R3 = (2S)-1-hydroxy-3-methylbutan-2-yl, R4 = H]

[0707]

[0708] 1 H 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,1 H), 3.59-3.43 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 1.92 (qd, J = 6.7, 13.5 Hz, 1H), 0.91 (dd, J = 6.8, 9.5 Hz, 6H); HRMS (ESI) calculated for C21H27N7O2[M+H]+ is 410.2299, found to be 410.2301.

[0709] 3-{2-[(3,5-difluorophenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (cpd 50) [(I), R1 = 3,5-difluorophenyl, R2 = methyl, R3 = (2S)-1,1,1-trifluoropropan-2-yl, R4 = H]

[0710]

[0711] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.12 (s, 1H), 9.20 (d, J = 8.7 Hz, 1H), 8.61 (d, J = 5.2 Hz, 1H), 7.68-7.57 (m, 3H), 7.39 (d, J = 5.0 Hz, 1H), 6.81-6.70 (m, 1H), 4.90-4.73 (m, 1H), 4.15 (s, 3H), 1.37 (d, J = 7.2 Hz, 3H); HRMS (ESI) calcd for C18H15N6OF5 [M+H]+ 427.13, found 427.1308.

[0712] 1-Methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (cpd 51) [(I), R1 = 3-methylphenyl, R2 = methyl, R3 = (2S)-1,1,1-trifluoropropan-2-yl, R4 = H]

[0713]

[0714] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.57 (s, 1H), 9.22 (d, J = 8.7 Hz, 1H), 8.51 (d, J = 5.2 Hz, 1H), 7.72 (s, 1H), 7.64-7.57 (m, 2H), 7.28 (d, J = 5.2 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 6.79 (d, J = 7.5 Hz, 1H), 4.89-4.73 (m, 1H), 4.15 (s, 3H), 2.31 (s, 3H), 1.37 (d, J = 7.0 Hz, 3H); HRMS (ESI) calcd for C19H19N6OF3 [M+H]+ 405.1645, found 405.1649.

[0715] 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 52) [(I), R1 = 3-chloro-4-(4-methylpiperazin-1-yl)phenyl, R2 = methyl, R3 = (2S)-1-hydroxy-3-phenylpropan-2-yl, R4 = H]

[0716]

[0717] 1 H 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=8.8Hz,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.s,4H),2.75(dd,J=9.7,13.7Hz,1H),2.48(br.s.,4H),2.23(s,3H); HRMS(ESI) calculated for C29H33N8O2Cl[M+H]+ as 561.2488, found as 561.2498.

[0718] N-[(1S,2S)-2-aminocyclohexyl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 53) [(I), R1 = 3-methylphenyl, R2 = methyl, R3 = (1S,2S)-2-aminocyclohexyl, R4 = H]

[0719]

[0720] 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,1H),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) calculated for C22H27N7O[M+H]+ as 406.235, found as 406.2348.

[0721] 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-1-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (cpd 54) [(I), R1 = 3-chloro-4-(4-methylpiperazin-1-yl)phenyl, R2 = methyl, R3 = (2S)-1,1,1-trifluoropropan-2-yl, R4 = H]

[0722]

[0723] 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, 15.4 Hz, 1H), 4.14 (s, 3H), 2.93 (br.s., 4H), 2.47 (br.s., 4H), 2.23 (s, 3H), 1.37 (d, J = 7.2 Hz, 3H); HRMS (ESI) calculated for C23H26N8OF3Cl [M+H] + is 523.1943, found to be 523.1951.

[0724] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1H-pyrazole-5-carboxamide (cpd 55) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2S)-1,1,1-trifluorobutan-2-yl, R4 = H]

[0725]

[0726] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.51 (s, 1H), 9.14 (d, J = 9.0 Hz, 1H), 8.51 (d, J = 5.0 Hz, 1H), 7.63 (s, 1H), 7.49 (s, 2H), 7.27 (d, J = 5.2 Hz, 1H), 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 = 7.3 Hz, 3H); HRMS (ESI) calcd for C21H23N6OF3 [M+H]+ 433.1958, found 433.1959.

[0727] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1H-pyrazole-5-carboxamide (cpd 56) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2R)-1,1,1-trifluorobutan-2-yl, R4 = H]

[0728]

[0729] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.51 (s, 1H), 9.14 (d, J = 9.0 Hz, 1H), 8.51 (d, J = 5.0 Hz, 1H), 7.63 (s, 1H), 7.49 (s, 2H), 7.27 (d, J = 5.2 Hz, 1H), 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 = 7.4 Hz, 3H); HRMS (ESI) calcd for C21H23N6OF3 [M+H]+ 433.1958, found 433.1957.

[0730] N-[(2S)-1-(3,3-difluoroazetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 57) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2S)-1-(3,3-difluoroazetidin-1-yl)propan-2-yl, R4 = H]

[0731]

[0732] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.49 (d, J = 5.2 Hz, 1H), 7.48 (s, 2H), 7.45 (s, 1H), 7.26 (d, J = 5.0 Hz, 1H), 6.62 (s, 1H), 4.13 (s, 3H), 3.98 (quin, J = 6.9, 13.9 Hz, 1H), 3.73-3.53 (m, 4H), 2.70-2.56 (m, 2H), 2.27 (s, 6H), 1.13 (d, J = 6.7 Hz, 3H); HRMS (ESI) calcd for C23H27N7OF2 [M+H]+ 456.2318, found 456.232.

[0733] 1-Methyl-N-[(2S)-1-(pyrrolidin-1-yl)propan-2-yl]-3-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 58) [(I), R1 = 3,4,5-trimethoxyphenyl, R2 = methyl, R3 = (2S)-1-pyrrolidin-1-ylpropan-2-yl, R4 = H]

[0734]

[0735] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.53 (s, 1H), 8.51 (d, J = 5.03 Hz, 2H), 7.50 (s, 1H), 7.31 (s, 2H), 7.26 (d, J = 5.19 Hz, 1H), 4.07-4.20 (m, 4H), 3.80 (s, 6H), 3.63 (s, 3H), 2.60-2.38 (m. partially overlapped with water, 6H), 1.69 (br. s., 4H), 1.08-1.20 (m, 3H); HRMS (ESI) calcd for C25H33N7O4 [M+H]+ 496.2667, found 496.2666.

[0736] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-chloro-1-methyl-1-indol-5-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 59) [(I), R1 = 3-chloro-1-methylindol-5-yl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0737]

[0738] 1 H 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=6.9,11.6Hz,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) calculated for C24H27N8OCl[M+H]+ as 479.2069, found as 479.2068.

[0739] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 60) [(I), R1 = 3,5-dichlorophenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0740]

[0741] 1H NMR (500 MHz, DMSO-d6) δ ppm 10.08 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 8.45 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 2.0 Hz, 2H), 7.43 (s, 1H), 7.38 (d, J = 5.0 Hz, 1H), 7.14 (t, J = 1.8 Hz, 1H), 4.14 (s, 3H), 3.93 (br.s., 1H), 3.17 (br.s, 4H), 2.42 (br.s., 2H), 1.96 (br.s, 2H), 1.10 (d, J = 6.7 Hz, 3H); HRMS (ESI) calculated for C21H23N7OCl2[M+H]+ is 460.1414, found to be 460.1415.

[0742] N-[(2S)-1-(azetidin-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 61) [(I), R1 = 3,5-dichlorophenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)-3-methylbutan-2-yl, R4 = H]

[0743]

[0744] 1 H 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),4.12(s,3H),3.83-3.68(m,1H),3. 22-2.95 (m, 4H), 2.47 (d, J = 6.1 Hz, 2H), 1.92 (quin, J = 6.9 Hz, 2H), 1.80 (dspt, J = 6.4 Hz, 1H), 0.87 (t, J = 7.3 Hz, 6H); HRMS (ESI) calculated for C23H27N7OCl2[M+H]+ is 488.1727, found 488.174.

[0745] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-1-methyl-3-(2-{[3-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-1H-pyrazole-5-carboxamide (cpd 62) [(I), R1 = 3-(trifluoromethyl)phenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0746]

[0747] 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=5.2Hz,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 = 6.7 Hz, 3H); HRMS (ESI) calculated for C22H24N7OF3[M+H]+ is 460.2067, found to be 460.2072.

[0748] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 63) [(I), R1 = 3,5-bis(trifluoromethyl)phenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0749]

[0750] 1H NMR (500 MHz, DMSO-d6) δ ppm 10.40 (s, 1H), 8.64 (d, J = 5.0 Hz, 1H), 8.60 (s, 2H), 8.39 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.42 (d, J = 5.2 Hz, 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 = 6.7 Hz, 3H); HRMS (ESI) calculated for C23H23N7OF6[M+H]+ is 528.1941, found to be 528.1951.

[0751] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 64) [(I), R1 = 3,5-dimethoxyphenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0752]

[0753] 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 = 6.9 Hz, 2H), 1.10 (d, J = 6.7 Hz, 3H); HRMS (ESI) calculated for C23H29N7O3 [M+H] + as 452.2405, found as 452.2408.

[0754] N-[(2S)-1-(dimethylamino)propan-2-yl]-3-{2-[(3-fluoro-5-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 65) [(I), R1 = 3-fluoro-5-methoxyphenyl, R2 = methyl, R3 = (2S)-1-(dimethylamino)propan-2-yl, R4 = H]

[0755]

[0756] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.84 (s, 1H), 8.56 (d, J = 5.19 Hz, 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, 2.27 Hz, 1H), 4.14 (m, 4H), 3.78 (s, 3H), 2.54-2.05 (m.br., 8H) 1.14 (d, J = 6.41 Hz, 3H); HRMS (ESI) calcd for C21H26N7O2F [M+H]+ 428.2205, found 428.2202.

[0757] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-[2-(1,3-benzodioxol-5-ylamino)pyrimidin-4-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 66) [(I), R1 = 1,3-benzodioxol-5-yl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0758]

[0759] 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),7.41(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, 11.6 Hz, 1H), 2.38 (dd, J = 6.1, 11.6 Hz, 1H), 1.95 (quin, J = 6.9 Hz, 2H), 1.10 (d, J = 6.7 Hz, 3H); HRMS (ESI) calculated for C22H25N7O3 [M+H] + as 436.2092, found as 436.21.

[0760] 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 67) [(I), R1 = 3,5-dimethoxyphenyl, R2 = methyl, R3 = (2S)-1-(dimethylamino)propan-2-yl, R4 = H]

[0761]

[0762] 1 H NMR (500 MHz, DMSO-d6) δ ppm 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) calculated for C22H29N7O3[M+H]+ as 440.2405, found as 440.2404.

[0763] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-1-methyl-3-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 68) [(I), R1 = 3,4,5-trimethoxyphenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0764]

[0765] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.52 (s, 1H), 8.50 (d, J = 5.0 Hz, 1H), 8.40 (d, J = 8.2 Hz, 1H), 7.49 (s, 1H), 7.31 (s, 2H), 7.26 (d, J = 5.2 Hz, 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, 16.2 Hz, 4H), 2.45-2.31 (m, 2H), 2.04-1.87 (m, 2H), 1.10 (d, J = 6.7 Hz, 3H); HRMS (ESI) calculated for C24H31N7O4 [M+H] + as 482.2511, found as 482.2514.

[0766] 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidin-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (cpd 69) [(I), R1 = 3,5-dimethoxyphenyl, R2 = methyl, R3 = (2S)-1-pyrrolidin-1-ylpropan-2-yl, R4 = H]

[0767]

[0768] 1 H NMR (500 MHz, DMSO-d6) δ ppm 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) calculated for C24H31N7O3[M+H]+ as 466.2561, found as 466.256.

[0769] 3-{2-[(3-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidin-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (cpd 70) [(I), R1 = 3-methoxyphenyl, R2 = methyl, R3 = (2S)-1-pyrrolidin-1-ylpropan-2-yl, R4 = H]

[0770]

[0771] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.63 (s, 1H), 8.55-8.46 (m, 2H), 7.65-7.61 (m, 2H), 7.37 (dd, J = 1.2, 8.1 Hz, 1H), 7.29 (d, J = 5.2 Hz, 1H), 7.19 (t, J = 8.2 Hz, 1H), 6.54 (dd, J = 1.8, 8.1 Hz, 1H), 4.13 (s, 4H), 3.77 (s, 3H), 2.62-2.51 (m, 6H), 1.69 (br. s., 4H), 1.16 (d, J = 6.7 Hz, 3H); HRMS (ESI) calcd for C23H29N7O2 [M+H]+ 436.2456, found 436.2455.

[0772] 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-(dimethylamino)-1-oxopropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 71) [(I), R1 = 3,5-dimethoxyphenyl, R2 = methyl, R3 = (2S)-1-(dimethylamino)-1-oxopropan-2-yl, R4 = H]

[0773]

[0774] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.62 (s, 1H), 8.87 (d, J = 7.5 Hz, 1H), 8.52 (d, J = 5.0 Hz, 1H), 7.59 (s, 1H), 7.28 (d, J = 5.0 Hz, 1H), 7.18 (d, J = 2.1 Hz, 2H), 6.12 (t, J = 2.2 Hz, 1H), 4.88 (t, J = 7.2 Hz, 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) calcd for C22H27N7O4 [M+H]+ 454.2198, found 454.2198.

[0775] 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-N-[2-(dimethylamino)ethyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 72) [(I), R1 = 3,5-dimethoxyphenyl, R2 = methyl, R3 = 2-(dimethylamino)ethyl, R4 = H]

[0776]

[0777] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.60 (s, 1H), 8.64 (t, J = 5.7 Hz, 1H), 8.52 (d, J = 5.0 Hz, 1H), 7.42 (s, 1H), 7.28 (d, J = 5.0 Hz, 1H), 7.17 (d, J = 2.3 Hz, 2H), 6.13 (t, J = 2.2 Hz, 1H), 4.13 (s, 3H), 3.75 (s, 6H), 2.40 (t, J = 6.7 Hz, 2H), 2.19 (s, 6H); HRMS (ESI) calcd for C21H27N7O3 [M+H]+ 426.2248, found 426.224.

[0778] N-[(2S)-1-(Dimethylamino)propan-2-yl]-3-{2-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 73) [(I), R1 = 1,5-dimethylpyrazol-3-yl, R2 = methyl, R3 = (2S)-1-(dimethylamino)propan-2-yl, R4 = H]

[0779]

[0780] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.52 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H), 8.42 (d, J = 5.2 Hz, 1H), 7.44 (s, 1H), 7.21 (d, J = 5.0 Hz, 1H), 6.56 (s, 1H), 4.17-4.04 (m, 4H), 3.63 (s, 3H), 2.40 (dd, J = 7.9, 12.0 Hz, 1H), 2.26 (s, 3H), 2.22-2.19 (m, 1H), 2.17 (s, 6H), 1.16-1.11 (m, 3H); HRMS (ESI) calcd for C19H27N9O [M+H]+ 398.2412, found 398.2413.

[0781] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 74) [(I), R1 = 1,5-dimethylpyrazol-3-yl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0782]

[0783] 1 H 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 = 7.0 Hz, 0H), 2.42-2.35 (m, 1H), 2.27 (s, 3H), 1.94 (quin, J = 6.9 Hz, 2H), 1.11 (d, J = 6.7 Hz, 3H); HRMS (ESI) calculated for C20H27N9O [M+H] + as 410.2412, found as 410.2407.

[0784] N-[(2S)-1-(Dimethylamino)propan-2-yl]-1-methyl-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 75) [(I), R1 = 1-methylpyrazol-4-yl, R2 = methyl, R3 = (2S)-1-(dimethylamino)propan-2-yl, R4 = H]

[0785]

[0786] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.49 (br.s., 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.43 (d, J = 5.0 Hz, 1H), 7.97 (br.s., 1H), 7.61-7.40 (m, 2H), 7.17 (d, J = 5.0 Hz, 1H), 4.14 (s, 3H), 4.11 (s, 0H), 3.84 (s, 3H), 2.40 (dd, J = 7.9, 12.2 Hz, 1H), 2.24-2.19 (m, 1H), 2.17 (s, 6H), 1.14 (d, J = 6.7 Hz, 3H); HRMS (ESI) calculated for C20H27N9O [M+H] + is 410.2412, found 410.2407.

[0787] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-1-methyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl]-1H-pyrazole-5-carboxamide (cpd 76) [(I), R1 = oxan-4-yl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0788]

[0789] 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=6.5,19.5H z, 4H), 2.48-2.44 (m, 1H), 2.39-2.33 (m, 1H), 1.94 (quin, J = 6.9 Hz, 2H), 1.84 (d, J = 12.4 Hz, 2H), 1.59-1.47 (m, 2H), 1.10 (d, J = 6.7 Hz, 3H); HRMS (ESI) calculated for C20H29N7O2[M+H]+ as 400.2456, found as 400.2455.

[0790] N,N,1-Trimethyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl]-1H-pyrazole-5-carboxamide (cpd 77) [(I), R1 = oxan-4-yl, R2 = methyl, R3 = methyl, R4 = methyl]

[0791]

[0792] 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.30 (d, J = 4.9 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 5.2 Hz, 1H), 6.96 (br.s., 1H), 3.98 (br.s., 1H), 3.91 (s, 3H), 3.89-3.84 (m, 2H), 3.43-3.36 (m, 1H), 3.04 (d, J = 19.7 Hz, 6H), 1.83 (d, J = 12.0 Hz, 2H), 1.56-1.44 (m, 2H); HRMS (ESI) calcd for C16H22N6O2 [M+H]+ 331.1877, found 331.187.

[0793] 3-{2-[(3-Cyano-5-methoxyphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 78) [(I), R1 = 3-cyano-5-methoxyphenyl, R2 = methyl, R3 = (2S)-1-(dimethylamino)propan-2-yl, R4 = H]

[0794]

[0795] 1 H 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),7.8 3(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) calculated for C22H26N8O2[M+H]+ as 435.2252, found as 435.2252.

[0796] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-cyano-5-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 79) [(I), R1 = 3-cyano-5-methoxyphenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0797]

[0798] 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=1.5H z,1H),7.46(s,1H),7.36(d,J=5.0Hz,1H),7.01(dd,J=1.4,2.3Hz,1H),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) calculated for C23H26N8O2[M+H]+ as 447.2252, found as 447.2251.

[0799] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(5-methoxypyridin-3-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 80) [(I), R1 = 5-methoxypyridin-3-yl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0800]

[0801] 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=2.3 Hz,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) calculated for C21H26N8O2[M+H]+ as 423.2252, found as 423.2252.

[0802] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(3S)-piperidin-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 81) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (3S)-piperidin-3-yl, R4 = H]

[0803]

[0804] 1 H NMR(500MHz,DMSO-d6)δppm 9.49(s,1H),8.99-8.90(br.s.1H,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 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) calculated for C22H28N7OCl[M+H]+ is 406.235, and the found value is 406.2349.

[0805] N-(2-aminocyclohexyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 82) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-aminocyclohexyl, R4 = H]

[0806]

[0807] 1 H NMR (500 MHz, DMSO-d6) δ ppm (s, 1H), 8.79 (d, J = 8.7 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.85 (br. s., 3H), 7.51 (s, 1H), 7.48 (s, 2H), 7.26 (d, J = 5.0 Hz, 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) calcd for C23H30N7OCl[M+H]+ 420.2507, found 420.2503.

[0808] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrazole-5-carboxamide (cpd 83) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-pyrrolidin-1-ylethyl, R4 = H]

[0809]

[0810] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.86 (br.s., 1H), 8.50 (d, J = 5.0 Hz, 1H), 7.48-7.42 (m, 3H), 7.26 (d, J = 5.2 Hz, 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) calculated for C23H29N7O [M+H] + 420.2507, found 420.2491.

[0811] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(piperidin-1-yl)ethyl]-1H-pyrazole-5-carboxamide (cpd 84) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = 2-piperidin-1-ylethyl, R4 = H]

[0812]

[0813] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.46 (s, 1H), 8.72 (br.s., 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.46 (s, 2H), 7.41 (s, 1H), 7.26 (d, J = 5.0 Hz, 1H), 6.62 (s, 1H), 4.14 (s, 3H), 3.34 (br.s. partially overlaps with water signal, 2H), 2.41 (br.s., 6H), 2.27 (s, 6H), 1.67-1.30 (m, 6H); HRMS (ESI) calculated for C24H31N7O [M+H]+ is 434.2663, found 434.2661.

[0814] (3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)[(3R)-3-hydroxypyrrolidin-1-yl]methanone (cpd 85) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, NR3R4 = (3R)-3-hydroxypyrrolidin-1-ylamino]

[0815]

[0816] 1 H NMR (500 MHz, DMSO-d6) (mixture of conformers) δ ppm 9.53 and 9.52 (2xs, 1H), 8.50 (d, J = 5.0 Hz, 1H), 7.48 (d, J = 2.7 Hz, 2H), 7.27 (d, J = 5.0 Hz, 1H), 7.22 and 7.16 (2xs, 1H), 6.60 (s, 1H), 5.07 (t, J = 3.9 Hz, 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) calculated for C21H24N6O2[M+H]+ is 393.2034, found to be 393.203.

[0817] [(3S)-3-(Dimethylamino)pyrrolidin-1-yl](3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)methanone (cpd 86) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, NR3R4 = (3S)-3-(dimethylamino)pyrrolidin-1-ylamino]

[0818]

[0819] 1 H NMR (500 MHz, DMSO-d6) (mixture of conformers) δ ppm 9.52 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.48 (s, 2H), 7.28 and 7.26 (2xd J = 5.2 Hz, 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) calculated for C23H29N7O [M+H] + as 420.2507, found as 420.2506.

[0820] [(3R)-3-(Dimethylamino)pyrrolidin-1-yl](3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)methanone (cpd 87) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, NR3R4 = (3R)-3-(dimethylamino)pyrrolidin-1-ylamino]

[0821]

[0822] 1H NMR (500 MHz, DMSO-d6) (mixture of conformers) δ ppm 9.52 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.48 (s, 2H), 7.28 and 7.26 (2xd J = 5.2 Hz, 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) calculated for C23H29N7O [M+H] + as 420.2507, found as 420.2503.

[0823] (3-Aminopyrrolidin-1-yl)(3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)methanone (cpd 88) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, NR3R4 = 3-aminopyrrolidin-1-ylamino]

[0824]

[0825] 1 H NMR (500 MHz, DMSO-d6) (mixture of conformers) δ ppm 9.54 and 9.52 (2xs, 1H), 8.50 (d, J = 5.0 Hz, 1H), 7.48 (s, 2H), 7.27 and 7.26 (2xd, J = 5.0 Hz, 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) calcd for C21H25N7O [M+H]+ 392.2194, found 392.2194.

[0826] (3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methanone (cpd 89) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, NR3R4 = (2S)-2-(hydroxymethyl)pyrrolidin-1-ylamino]

[0827]

[0828] 1H NMR (500 MHz, DMSO-d6) (mixture of conformers) δ ppm 9.51 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.48 (s, 2H), 7.26 (d, J = 5.0 Hz, 1H), 7.18 and 7.10 (2xs, 1H), 6.60 (s, 1H), 4.91 and 4.82 (2xt, J = 5.8 Hz, 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) calculated for C22H26N6O2 [M+H] + is 407.219, found to be 407.2193.

[0829] (3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)[(3S)-3-hydroxypyrrolidin-1-yl]methanone (cpd 90) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, NR3R4 = (3S)-3-hydroxypyrrolidin-1-ylamino]

[0830]

[0831] 1 H NMR (500 MHz, DMSO-d6) (mixture of conformers) δ ppm 9.53 and 9.52 (2xs, 1H), 8.50 (d, J = 5.0 Hz, 1H), 7.48 (s, 2H), 7.27 (d, J = 5.0 Hz, 1H), 7.22 and 7.16 (2xs, 1H), 6.60 (s, 1H), 5.09 and 5.08 (2xd, J = 4.6 Hz, 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) calculated for C21H24N6O2 [M+H] + is 393.2034, found to be 393.2027.

[0832] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-[(1R,2S)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 91) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (1R,2S)-2-hydroxycyclohexyl, R4 = H]

[0833]

[0834] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.48 (s, 2H), 7.25 (d, J = 5.0 Hz, 1H), 6.61 (s, 1H), 4.65 (d, J = 3.8 Hz, 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) calcd for C23H28N6O2 [M+H]+ 421.2347, found 421.2345.

[0835] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 92) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (1S,2R)-2-aminocyclohexyl, R4 = H]

[0836]

[0837] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.51 (s, 1H), 8.50 (d, J = 5.0 Hz, 1H), 8.47 (d, J = 7.9 Hz, 1H), 7.87 (br. s., 3H), 7.60 (s, 1H), 7.51 (s, 2H), 7.27 (d, J = 5.0 Hz, 1H), 6.62 (s, 1H), 4.33 (m, 1H), 4.14 (s, 3H), 3.37 (m overlaps with water signal, 1H), 2.28 (s, 6H), 1.80-1.34 (m, 8H); HRMS (ESI) calcd for C23H30N7OCl[M+H]+ 420.2507, found 420.2509.

[0838] N-[(2S)-1-Hydroxypropan-2-yl]-1-methyl-3-{2-[(1,2,3-trimethyl-1H-indol-5-yl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 93) [(I), R1 = 1,2,3-trimethylindol-5-yl, R2 = methyl, R3 = (2S)-1-hydroxypropan-2-yl, R4 = H]

[0839]

[0840] 1 H NMR(500MHz,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) calculated for C23H27N7O2[M+H]+ as 434.2299, found as 434.2291.

[0841] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidin-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (cpd 94) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2S)-1-pyrrolidin-1-ylpropan-2-yl, R4 = H]

[0842]

[0843] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.54 (d, J = 8.1 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.48 (s, 2H), 7.45 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 6.62 (s, 1H), 4.13 (s, 3H), 4.17-4.07 (m, 1H), 2.60-2.35 (m partially overlaps with DMSO signal, 6H), 2.27 (s, 6H), 1.72-1.62 (m, 4H), 1.14 (d, J = 6.6 Hz, 3H); HRMS (ESI) calcd for C24H31N7O [M+H]+ 434.2663, found 434.2684.

[0844] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 95) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0845]

[0846] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.50 (s, 1H), 8.55 (br. s., 1H), 8.52 (d, J = 5.0 Hz, 1H), 7.51 (s, 2H), 7.48 (s, 1H), 7.29 (d, J = 5.0 Hz, 1H), 6.65 (s, 1H), 4.17 (s, 3H), 4.05-3.94 (m, 1H), 3.50-3.10 (m partially overlaps with water signal, 6H), 2.30 (s, 6H), 2.10-1.93 (m, 2H), 1.14 (d, J = 6.7 Hz, 3H); HRMS (ESI) calcd for C23H29N7O [M+H]+ 420.2507, found 420.252.

[0847] (1S,4R)-2,5-Diazabicyclo[2.2.1]hept-2-yl(3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)methanone hydrochloride (cpd 96) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, NR3R4 = (1S,4R)-2,5-diazabicyclo[2.2.1]hept-2-ylamino]

[0848]

[0849] 1H NMR (500 MHz, DMSO-d6) (mixture of conformers) δ ppm 9.55 and 9.54 (2x s, 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 = 5.2 Hz, 1H), 7.48 and 7.45 (2xs, 2H), 7.30 and 7.27 (2xd, J = 5.2 Hz, 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) calculated for C22H26N7OCl[M+H]+ as 404.2194, found as 404.2199.

[0850] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(3R)-piperidin-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 97) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (3R)-piperidin-3-yl, R4 = H]

[0851]

[0852] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.49 (s, 1H), 8.85 (m, 4H), 8.50 (d, J = 5.19 Hz, 1H), 7.52 (s, 1H), 7.47 (s, 2H), 7.26 (d, J = 5.03 Hz, 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) calcd for C22H28N7OCl[M+H]+ 406.235, found 406.235.

[0853] N-[(1R,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 98) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (1R,2S)-2-aminocyclohexyl, R4 = H]

[0854]

[0855] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.51 (s, 1H), 8.50 (d, J = 5.03 Hz, 1H), 8.47 (d, J = 8.08 Hz, 1H), 7.87 (d, J = 3.66 Hz, 3H), 7.60 (s, 1H), 7.51 (s, 2H), 7.27 (d, J = 5.03 Hz, 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) calcd for C23H30N7OCl[M+H]+ 420.2507, found 420.2514.

[0856] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 99) [(I), R1 = (3,5-dichlorophenyl), R2 = methyl, R3 = (1S,2R)-2-aminocyclohexyl, R4 = H]

[0857]

[0858] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.12 (s, 1H), 8.62 (d, J = 5.19 Hz, 1H), 8.43 (d, J = 7.78 Hz, 1H), 8.02 (d, J = 1.83 Hz, 2H), 7.90 (d, J = 3.51 Hz, 3H), 7.59 (s, 1H), 7.40 (d, J = 5.03 Hz, 1H), 7.15 (t, J = 1.83 Hz, 1H), 4.32 (br.s., 1H), 4.14 (s, 3H), 3.48-3.40 (m overlaps with water signal, 1H), 1.86-1.32 (m, 8H); HRMS (ESI) calculated for C21H24N7OCl3[M+H]+ is 460.1414, found to be 460.1419.

[0859] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 100) [(I), R1 = 3,5-dimethoxyphenyl, R2 = methyl, R3 = (1S,2R)-2-aminocyclohexyl, R4 = H]

[0860]

[0861] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.62 (s, 1H), 8.53 (d, J = 5.03 Hz, 1H), 8.43 (d, J = 7.78 Hz, 1H), 7.89 (d, J = 3.36 Hz, 3H), 7.60 (s, 1H), 7.31 (d, J = 5.19 Hz, 1H), 7.20 (d, J = 2.14 Hz, 2H), 6.13 (t, J = 2.21 Hz, 1H), 4.31 (br.s., 1H), 4.13 (s, 3H), 3.76 (s, 6H), 3.48-3.40 (m overlaps with water signal, 1H), 1.88-1.33 (m, 8H); HRMS (ESI) calculated for C23H30N7O3Cl [M+H] + as 452.2405, found as 452.2396.

[0862] N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 101) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (1S,2S)-2-aminocyclohexyl, R4 = H]

[0863]

[0864] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.52 (d, J = 8.39 Hz, 1H), 8.49 (d, J = 5.03 Hz, 1H), 7.49 (s, 1H), 7.48 (s, 2H), 7.25 (d, J = 5.03 Hz, 1H), 6.61 (s, 1H), 4.13 (s, 3H), 3.40-3.50 (m, 1H), 2.54 (td, J = 10.90, 4.10 Hz, 1H), 2.27 (s, 6H), 1.90-1.17 (m, 8H); HRMS (ESI) calcd for C23H29N7O [M+H]+ 420.2507, found 420.2515.

[0865] N-[(2S)-1-(azetidin-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 102) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)-3-methylbutan-2-yl, R4 = H]

[0866]

[0867] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.49 (s, 1H), 8.85 (d, J = 7.78 Hz, 1H), 8.50 (d, J = 5.19 Hz, 1H), 7.52 (s, 1H), 7.47 (s, 2H), 7.26 (d, J = 5.03 Hz, 1H), 6.62 (s, 1H), 4.14 (s, 3H), 4.13-4.09 (m.br., 1H), 3.90-3.20 (m overlaps with water signal, 6H) (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) calculated for C25H33N7O [M+H] + is 448.282, found to be 448.2822.

[0868] 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-3-methyl-1-(pyrrolidin-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (cpd 103) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2S)-3-methyl-1-pyrrolidin-1-ylbutan-2-yl, R4 = H]

[0869]

[0870] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.49 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.41 (d, J = 9.0 Hz, 1H), 7.50 (s, 2H), 7.48 (s, 1H), 7.27 (d, J = 5.0 Hz, 1H), 6.61 (s, 1H), 4.11 (s, 3H), 4.03-3.92 (m, 1H), 2.59 (dd, J = 9.1, 12.1 Hz, 1H), 2.53-2.47 (m. overlapping, 2H) 2.47 (dd, J = 4.7, 12.2 Hz, 1H), 2.40 (s, 2H), 2.27 (s, 6H), 1.94-1.77 (m, 1H), 1.65 (br.s., 4H), 0.90 (d, J = 8.2 Hz, 3H), 0.89 (d, J = 8.4 Hz, 3H); HRMS (ESI) calculated for C26H35N7O [M+H] + 462.2976, found 462.2983.

[0871] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide hydrochloride (cpd 104) [(I), R1 = 3,5-dimethylphenyl, R2 = H, R3 = (1S,2R)-2-aminocyclohexyl, R4 = H]

[0872]

[0873] 1 H NMR (500 MHz, DMSO-d6) δ ppm 14.5-13.5 (br.s., 1H), 9.49 (s, 1H), 8.53 (d, J = 5.19 Hz, 1H), 8.21 (br.s., 1H), 7.90 (d, J = 2.90 Hz, 3H), 7.54 (br.s., 1H), 7.48 (s, 2H), 7.34 (d, J = 5.03 Hz, 1H), 6.63 (s, 1H), 4.33 (br.s., 1H), 3.50-3.40 (m overlaps with water signal, 1H), 2.27 (s, 6H), 1.90-1.17 (m, 8H); HRMS (ESI) calculated for C22H28N7OCl[M+H]+ is 406.235, found to be 406.236.

[0874] N-[(2S)-1-(azetidin-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 105) [(I), R1 = 3,5-dimethylphenyl, R2 = H, R3 = (2S)-1-(azetidin-1-yl)-3-methylbutan-2-yl, R4 = H]

[0875]

[0876] 1H NMR(500MHz,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.4H),3.17(d,J=4 .88Hz,2H),2.27(s,6H),1.92(quin,J=6.63Hz,2H),1.80(dq,J=13.17,6.54Hz,1H),0.87(dd,J=9.76,6.86Hz,6H); HRMS(ESI)calculated for C24H31N7O[M+H]+434.2663, found 434.2668.

[0877] N-[(1S)-1-cyclohexyl-2-hydroxyethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 106) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (1S)-1-cyclohexyl-2-hydroxyethyl, R4 = H]

[0878]

[0879] 1 H NMR (500 MHz, DMSO-d6) δ ppm 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) calculated for C25H32N6O2[M+H]+ as 449.266, found as 449.2665.

[0880] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(1S)-1-phenyl-2-(pyrrolidin-1-yl)ethyl]-1H-pyrazole-5-carboxamide (cpd 107) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (1S)-1-phenyl-2-pyrrolidin-1-ylethyl, R4 = H]

[0881]

[0882] 1 H NMR(500MHz,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,2 H),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 = 10.9 Hz, 2H), 2.60-2.48 (m, 4H), 2.30 (s, 6H), 1.67 (br.s., 4H); HRMS (ESI) calculated for C29H33N7O [M+H] + as 496.282, found as 496.2823.

[0883] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 108) [(I), R1 = 3-methylphenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0884]

[0885] 1 H NMR(500MHz,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,1H),7.18(t,J=7.78Hz,1H),6.79(d,J=7.63Hz,1H),4.14(s,3H),3.92(dqu in, J = 13.93, 6.77, 6.77, 6.77, 6.77 Hz, 1H), 3.38-3.29 (m. overlapped with water signal, 2H), 3.04-3.24 (m, 4H), 2.32 (s, 3H), 2.00-1.90 (m. 2H), 1.10 (d, J = 6.71 Hz, 3H); HRMS (ESI) calculated for C22H27N7O [M+H] + as 406.235, found as 406.2349.

[0886] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 109) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (2S)-1-hydroxy-3-phenylpropan-2-yl, R4 = H]

[0887]

[0888] 1 H NMR(500MHz,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, 13.7 Hz, 1H), 2.73 (dd, J = 9.5, 13.9 Hz, 1H), 2.29 (s, 6H); HRMS (ESI) calculated for C26H28N6O2 [M+H] + is 457.2347, found to be 457.2354.

[0889] 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 110) [(I), R1 = 3-chloro-4-(4-methylpiperazin-1-yl)phenyl, R2 = methyl, R3 = (2S)-1-hydroxypropan-2-yl, R4 = H]

[0890]

[0891] 1H NMR(500MHz,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)calculated for C23H29N8O2Cl[M+H]+485.2175, found to be 485.2172.

[0892] 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 111) [(I), R1 = 3-chloro-4-(4-methylpiperazin-1-yl)phenyl, R2 = methyl, R3 = (2S)-1-hydroxy-3-methylbutan-2-yl, R4 = H]

[0893]

[0894] 1 H NMR(500MHz,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.s., 4H), 2.52-2.40 (br.s., partial overlap with water, 4H) 2.23 (s, 3H), 1.98-1.87 (m, 1H), 0.91 (dd, J = 6.8, 9.7 Hz, 6H); HRMS (ESI) calculated for C25H33N8O2Cl [M+H] + 513.2488, found 513.2498.

[0895] 1-Methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-3-methyl-1-(pyrrolidin-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (cpd 112) [(I), R1 = 3-methylphenyl, R2 = methyl, R3 = (2S)-3-methyl-1-pyrrolidin-1-ylbutan-2-yl, R4 = H]

[0896]

[0897] 1 H NMR(500MHz,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=5.0Hz,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) calculated for C25H33N7O[M+H]+ as 448.282, found as 448.2827.

[0898] N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-difluorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 113) [(I), R1 = 3,5-difluorophenyl, R2 = methyl, R3 = (1S,2S)-2-aminocyclohexyl, R4 = H]

[0899]

[0900] 1H NMR (500 MHz, DMSO-d6) δ ppm 10.11 (s, 1H), 8.59 (d, J = 5.03 Hz, 1H), 8.49 (d, J = 8.39 Hz, 1H), 7.62 (dd, J = 10.45, 2.21 Hz, 2H), 7.50 (s, 1H), 7.38 (d, J = 5.03 Hz, 1H), 6.76 (tt, J = 9.21, 2.31 Hz, 1H), 4.14 (s, 3H), 3.41-3.50 (m, 1H), 2.55 (td, J = 10.50, 3.50 Hz, 1H), 1.93-1.18 (m, 8H); HRMS (ESI) calculated for C21H23N7OF2[M+H]+ is 428.2005, found 428.2004.

[0901] 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-N-[(1S,2R)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 114) [(I), R1 = 3-chloro-4-(4-methylpiperazin-1-yl)phenyl, R2 = methyl, R3 = (1S,2R)-2-hydroxycyclohexyl, R4 = H]

[0902]

[0903] 1 H NMR(500MHz,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.,partial overlap with water,4H),2.23(s,3H),1.78-1.15(m,8H); HRMS(ESI) calculated for C26H33N8O2Cl[M+H]+ as 525.2488, found as 525.2492.

[0904] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-[(1S,2R)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 115) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (1S,2R)-2-hydroxycyclohexyl, R4 = H]

[0905]

[0906] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.48 (s, 1H), 8.49 (d, J = 5.03 Hz, 1H), 8.16 (d, J = 7.78 Hz, 1H), 7.49 (s, 1H), 7.48 (s, 2H), 7.25 (d, J = 5.19 Hz, 1H), 6.61 (s, 1H), 4.64 (d, J = 3.81 Hz, 1H), 4.12 (s, 3H), 3.78-3.90 (m, 2H), 2.27 (s, 6H), 1.84-1.17 (m, 8H); HRMS (ESI) calcd for C23H28N6O2 [M+H]+ 421.2347, found 421.2345.

[0907] N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 116) [(I), R1 = 3,5-dichlorophenyl, R2 = methyl, R3 = (1S,2S)-2-aminocyclohexyl, R4 = H]

[0908]

[0909] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.10 (s, 1H), 8.62-8.59 (m, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.00-7.97 (m, 2H), 7.47 (s, 1H), 7.38 (d, J = 5.0 Hz, 1H), 7.13 (t, J = 1.8 Hz, 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) calcd for C21H23N7OCl2 [M+H]+ 460.1414, found 460.1427.

[0910] 3-{2-[(3,5-Dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-3-methyl-1-(pyrrolidin-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (cpd 117) [(I), R1 = 3,5-dichlorophenyl, R2 = methyl, R3 = (2S)-3-methyl-1-pyrrolidin-1-ylbutan-2-yl, R4 = H]

[0911]

[0912] 1 H NMR(500MHz,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) calculated for C24H29N7OCl2[M+H]+ is 502.1884, found to be 502.1893.

[0913] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 118) [(I), R1 = 3,5-dimethylphenyl, R2 = methyl, R3 = (1S,2S)-2-hydroxycyclohexyl, R4 = H]

[0914]

[0915] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.46 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.46 (d, J = 8.2 Hz, 1H), 7.47 (s, 3H), 7.25 (d, J = 5.2 Hz, 1H), 6.61 (s, 1H), 4.61 (d, J = 5.2 Hz, 1H), 4.13 (s, 3H), 3.66-3.53 (m, 1H), 3.42-3.28 (m, overlap 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) calculated for C23H28N6O2 [M+H] + as 421.2347, found as 421.235.

[0916] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-cyanophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide formate (cpd 119) [(I), R1 = 3-cyanophenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = H]

[0917]

[0918] 1 H NMR(500MHz,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(d d,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, partial overlap with water 1H) 2.43-2.38 (m, 1H), 1.95 (quin, J = 7.0 Hz, 2H), 1.11 (d, J = 6.7 Hz, 3H); HRMS (ESI) calculated for C23H26N8O3 [M+H] + 417.2146, found 417.2161.

[0919] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-ethyl-N-[(1S,2R)-2-hydroxycyclohexyl]-1H-pyrazole-5-carboxamide (cpd 120) [(I), R1 = 3,5-dimethylphenyl, R2 = ethyl, R3 = (1S,2R)-2-hydroxycyclohexyl, R4 = H]

[0920]

[0921] 1 H NMR (500 MHz, DMSO-d6) δ ppm 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) calculated for C24H30N6O2[M+H]+ as 435.2503, found as 435.2502.

[0922] N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-ethyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 121) [(I), R1 = 3,5-dimethylphenyl, R2 = ethyl, R3 = (1S,2R)-2-aminocyclohexyl, R4 = H]

[0923]

[0924] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.51 (s, 1H), 8.51 (d, J = 5.03 Hz, 1H), 8.46 (d, J = 7.93 Hz, 1H), 7.88 (d, J = 4.27 Hz, 3H), 7.61 (s, 1H), 7.52 (s, 2H), 7.28 (d, J = 5.03 Hz, 1H), 6.62 (s, 1H), 4.66-4.45 (m, 2H), 4.34 (br.s., 1H), 3.74-3.50 (m, 1H), 2.28 (s, 6H), 1.88-1.31 (m, 8H), 1.42 (t, J = 7.17 Hz, 3H); HRMS (ESI) calculated for C24H32N7OCl[M+H]+ as 434.2663, found as 434.2658.

[0925] 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-ethyl-N-[(3R)-piperidin-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 122) [(I), R1 = 3,5-dimethylphenyl, R2 = ethyl, R3 = (3R)-piperidin-3-yl, R4 = H]

[0926]

[0927] 1 H NMR(500MHz,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),8.5 0(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 = 7.17 Hz, 3H); HRMS (ESI) calculated for C23H30N7OCl [M+H] + as 420.2507, found as 420.2513.

[0928] N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (cpd 123) [(I), R1 = 3,5-dimethoxyphenyl, R2 = methyl, R3 = (2S)-1-(azetidin-1-yl)propan-2-yl, R4 = methyl]

[0929]

[0930] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.62 (s, 1H), 8.49-8.55 (m, 1H), 7.31 (d, J = 5.03 Hz, 1H), 7.18 (m.3H), 6.13 (br.s., 1H), 4.00 (m.6H), 3.76-3.60 (m.br.1H) 3.74 (s.6H), 3.16-3.10 (m.2H), 3.06-2.69 (m.br.4H), 2.04-1.60 (m.br.2H), 1.25 (m.3H); HRMS (ESI) calculated for C24H31N7O3 [M+H]+ is 466.2561, found 466.2564.

[0931] Biochemical kinase inhibition assays for SYK in the KinaseGlo and ADPGlo assay formats

[0932] The recombinant protein SYK FL was produced at NMS as a His GST-fusion protein by baculovirus infection in insect cells. In-house protein preparations were >80% homogeneous as judged by SDS-PAGE and characterized by N-terminal sequence analysis and electrospray ionization mass spectrometry.

[0933] SYK was preactivated at a concentration of 1 μM with 400 μM ATP in kinase buffer (50 mM Hepes pH 7.5, 10 mM MgCl 2 , 1 mM DTT, 3 μM Na 3 VO 4 and 0.2 mg / mL BSA) at 28° C. for 60 minutes before the kinase reaction.

[0934] KinaseGlo assay format

[0935] Compounds were serially diluted 3-fold from 10 μM to 0.0005 μM and then incubated at room temperature for 60 minutes in the presence of 2.5 μM ATP, 125 μM peptide substrate BioDBn*327, and 2.5 nM preactivated enzyme in a final volume of 20 μL of kinase buffer (50 mM Hepes pH 7.5, 10 mM MgCl , 1 mM DTT, 3 μM Na VO , and 0.2 mg / mL BSA). The final concentration of DMSO was 1%. The assay was run in an automated format on a 384-well plate (Perkin Elmer cat. # 6005301).

[0936] ADPGlo assay format

[0937] The test compound that 5 microlitres are dissolved in 3% DMSO and is carried out 4 times serial dilution from 10 μM to 0.0006 μM is pipetted into 384-well Optiplate (n*6005310-Perkin Elmer).The recombinant pre-activated SYK solution of 1.8nM that 5 microlitres are diluted in its specific kinase buffer is added in the plate containing compound, and incubated at room temperature 30 minutes.Add the mixture of ATP (adenosine 5 '-triphosphate disodium salt (Promega)) and peptide substrate BioDBn*327 (TwinHelix) that 5 microlitres are diluted in kinase buffer to start reaction.

[0938] The final concentrations of preactivated SYK, ATP, and BioDBn*327 were 0.6 nM, 60 μM, and 125 μM, respectively.

[0939] The reaction mixture was incubated at room temperature for 60 minutes, and then 15 μL of The reaction was stopped by using reagent 1 of the kit (V9102-Promega).

[0940] After 60 minutes, add Reagent 2, and the luminescent signal of the plate was then measured by a Pherastar plate reader (BMG).

[0941] Data Analysis

[0942] Each 384-well plate contained at least one standard cpd curve and reference wells for Z' and signal background assessment (total enzyme activity compared to fully inhibited enzyme) (J. Biomol. Screening, 1999, 4, 67-73).

[0943] All information regarding plate dilution, distribution, and inhibition raw data is tracked via barcode reading and stored in an Oracle database. Data for each molecule is analyzed using an in-house customized version of the SW software package “Assay Explorer,” which provides a sigmoidal fit of the eight dilution curves used for IC50 determination using the following 4-parameter logistic equation:

[0944] y = bottom + (top - bottom) / (1 + 10^((logIC50 - x) * slope))

[0945] Where x is the logarithm of the inhibitor concentration and y is the response;

[0946] IC50 was defined as the concentration of compound required to inhibit 50% of maximal phosphorylation.

[0947] Representative compounds of the invention of formula (I) were tested against Syk in the specific in vitro kinase assay described above.

[0948] Table A below reports the in vitro activity data of the compounds of formula (I) against Syk kinase as reported above. As will be appreciated by those skilled in the art, most compounds showed an IC of 50 The values are <0.5 μM and are therefore particularly advantageous in the treatment of diseases caused by and / or associated with deregulated Syk kinase activity, such as cancer.

[0949] Table A

[0950]

[0951]

[0952] To support the unexpected activity of the compounds of the present application relative to the closest compounds described in prior art application WO 2012 / 139930, we report in Table B below the structural and biochemical data of the Syk assay obtained for three reference compounds, namely compounds 7, 14 and 39.

[0953] Table B

[0954]

[0955] From the above data, it is clear to a person skilled in the art that the compounds of formula (I) of the present invention are highly potent against Syk kinase, while the compounds of the prior art can be considered to be inactive. Sequence Listing <110> Nerviano Medical Sciences <120> Pyrazolyl-pyrimidine derivatives as kinase inhibitors <130> NMS 115 <150> 20197710.5 <151> 2020-09-23 <160> 1 <170> PatentIn version 3.5 <210> 1 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> Artificial <220> <221> MOD_RES <222> (20)..(20) <223> amidation <400> 1 Lys Lys Lys Lys Lys Glu Gln Glu Asp Glu Pro Glu Gly Asp Tyr Phe 1 5 10 15 Glu Trp Leu Glu 20

Claims

1. A compound of formula (I): in: R1 is a group selected from the following: phenyl optionally substituted by a group selected from halogen, cyano, C1-C6 alkyl, polyfluoro C1-C6 alkyl, C1-C6 alkoxy and piperazinyl substituted by C1-C6 alkyl; tetrahydropyranyl; benzo[1,3]dioxolyl; or indolyl, pyrazolyl or pyridinyl optionally substituted by a group selected from halogen, C1-C6 alkyl and C1-C6 alkoxy; R2 is hydrogen or a linear or branched C1-C6 alkyl group; R4 is hydrogen or a linear or branched C1-C6 alkyl group, R3 is a linear or branched C1-C6 alkyl group optionally substituted by halogen; a pyrazolyl group; an imidazolyl C1-C6 alkyl group; or a pyridyl C1-C6 alkyl group; or a group of formula (II): in: R5 is hydrogen; a straight or branched C1-C6 alkyl group; a C3-C7 cycloalkyl group; a phenyl group; or R6 together can form a cyclohexyl group; or together with R7 or R8 can form a piperidinyl group; R6 is hydrogen or can form a pyrrolidinyl group together with R4; R7 and R8 are independently hydrogen; linear or branched C1-C6 alkyl; or can form, together with X being O or N, a 4- to 7-membered heterocyclyl group, the 4- to 7-membered heterocyclyl group optionally containing one additional heteroatom selected from N and O, optionally substituted by halogen; or can form, together with R4, a piperazinyl group optionally substituted with a C1-C6 alkyl group; X is H, N or O, wherein when X is H, R7 and R8 are absent, and when X is O, one of R7 and R8 is absent; Provided that, when X is O, R5 is not phenyl; or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R2 is a linear or branched C1-C6 alkyl group; R4 is hydrogen; R3 is a group of formula (II): in: R5 is hydrogen, a linear or branched C1-C6 alkyl group, a C3-C7 cycloalkyl group, or can form a cyclohexyl group together with R6; R6 is hydrogen; R7 and R8 are independently hydrogen, linear or branched C1-C6 alkyl, or can form together with X a 4- to 7-membered heterocyclyl group, the 4- to 7-membered heterocyclyl group optionally containing one additional heteroatom selected from N and O; X is N or O.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 2, wherein: R3 is a group of formula (II): Where X is N.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R1 is phenyl optionally substituted by a group selected from halogen, cyano, C1-C6 alkyl, polyfluorinated C1-C6 alkyl and C1-C6 alkoxy; R4 is hydrogen; R3 is a group of formula (II): in: R5 and R6 are as defined in claim 3; R7 and R8 can form together with X a heterocyclic group selected from pyrrolidinyl and pyrimidinyl; X is N; R2 is defined according to any one of claims 1 to 3.

5. A compound selected from the group consisting of: N-[2-(Dimethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 1); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2R)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 2); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 3); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(propan-2-yl)-1H-pyrazole-5-carboxamide (cpd 4); N-[2-(Dimethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (cpd 5); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(methylamino)ethyl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 6); N-(2-aminoethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 7); N-(azetidin-3-yl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide trifluoroacetate (cpd 8); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(morpholin-4-yl)ethyl]-1H-pyrazole-5-carboxamide (cpd 9); N-[2-(Diethylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 10); N-[(1R,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 11); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(propan-2-ylamino)ethyl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 12); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd13); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (cpd14); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N,N,1-trimethyl-1H-pyrazole-5-carboxamide (cpd15); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-(2-methoxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 16); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-(2-fluoroethyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 17); 3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-N-[2-(dimethylamino)ethyl]-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 18); 3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 19); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(1H-pyrazol-3-yl)-1H-pyrazole-5-carboxamide (cpd 20); (3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)(4-methylpiperazin-1-yl)methanone (cpd 21); N-[2-(Acetylamino)ethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 22); N-(2-amino-2-oxoethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 23); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxamide (cpd 24); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(1-methyl-1H-imidazol-5-yl)methyl]-1H-pyrazole-5-carboxamide (cpd 25); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 26); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(pyridin-2-ylmethyl)-1H-pyrazole-5-carboxamide (cpd 27); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-(1H-imidazol-2-ylmethyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 28); N-[(2R)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 29); N-[(2S)-1-(Dimethylamino)propan-2-yl]-1-methyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl]-1H-pyrazole-5-carboxamide (cpd 30); N-(1-azabicyclo[2.2.2]oct-3-yl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 31); 5-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide (cpd 32); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxybutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 33); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 34); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,4-dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 35); (3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)(piperazin-1-yl)methanone hydrochloride (cpd 36); N-[(1S,2R)-2-aminocyclohexyl]-3-(2-{[3-methoxy-5-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 37); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3-chloro-1-methyl-1H-indol-5-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 38); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 39); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-difluorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 40); N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 41); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (cpd 42); N-[3-(Dimethylamino)propyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 43); (3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)[(2S)-2-(propan-2-yl)aziridin-1-yl]methanone (cpd 44); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-N-(2,2-dimethylpropyl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 45); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-(2-methylpropyl)-1H-pyrazole-5-carboxamide (cpd 46); N-(Cyclopropylmethyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 47); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-fluoro-5-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 48); 3-{2-[(4,6-dimethylpyridin-2-yl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 49); 3-{2-[(3,5-difluorophenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (cpd 50); 1-Methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (cpd 51); 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 52); N-[(1S,2S)-2-aminocyclohexyl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 53); 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-1-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-5-carboxamide (cpd 54); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1H-pyrazole-5-carboxamide (cpd 55); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1H-pyrazole-5-carboxamide (cpd 56); N-[(2S)-1-(3,3-difluoroazetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 57); 1-Methyl-N-[(2S)-1-(pyrrolidin-1-yl)propan-2-yl]-3-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 58); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-chloro-1-methyl-1H-indol-5-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 59); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 60); N-[(2S)-1-(azetidin-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 61); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-1-methyl-3-(2-{[3-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-1H-pyrazole-5-carboxamide (cpd 62); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-(2-{[3,5-bis(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide (cpd 63); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 64); N-[(2S)-1-(Dimethylamino)propan-2-yl]-3-{2-[(3-fluoro-5-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 65); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-[2-(1,3-benzodioxol-5-ylamino)pyrimidin-4-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 66); 3-{2-[(3,5-Dimethoxyphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 67); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-1-methyl-3-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 68); 3-{2-[(3,5-Dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidin-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (cpd 69); 3-{2-[(3-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidin-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (cpd 70); 3-{2-[(3,5-Dimethoxyphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-(dimethylamino)-1-oxopropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 71); 3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-N-[2-(dimethylamino)ethyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 72); N-[(2S)-1-(Dimethylamino)propan-2-yl]-3-{2-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 73); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 74); N-[(2S)-1-(Dimethylamino)propan-2-yl]-1-methyl-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 75); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-1-methyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl]-1H-pyrazole-5-carboxamide (cpd 76); N,N,1-trimethyl-3-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl]-1H-pyrazole-5-carboxamide (cpd77); 3-{2-[(3-cyano-5-methoxyphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-(dimethylamino)propan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 78); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-cyano-5-methoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 79); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(5-methoxypyridin-3-yl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 80); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(3S)-piperidin-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 81); N-(2-aminocyclohexyl)-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 82); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrazole-5-carboxamide (cpd 83); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[2-(piperidin-1-yl)ethyl]-1H-pyrazole-5-carboxamide (cpd 84); (3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)[(3R)-3-hydroxypyrrolidin-1-yl]methanone (cpd 85); [(3S)-3-(Dimethylamino)pyrrolidin-1-yl](3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)methanone (cpd 86); [(3R)-3-(Dimethylamino)pyrrolidin-1-yl](3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)methanone (cpd 87); (3-Aminopyrrolidin-1-yl)(3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)methanone (cpd 88); (3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methanone (cpd 89); (3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)[(3S)-3-hydroxypyrrolidin-1-yl]methanone (cpd 90); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-[(1R,2S)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 91); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 92); N-[(2S)-1-Hydroxypropan-2-yl]-1-methyl-3-{2-[(1,2,3-trimethyl-1H-indol-5-yl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 93); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-1-(pyrrolidin-1-yl)propan-2-yl]-1H-pyrazole-5-carboxamide (cpd 94); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 95); (1R,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl(3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazol-5-yl)methanone hydrochloride (cpd 96); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(3R)-piperidin-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 97); N-[(1R,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 98); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 99); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 100); N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 101); N-[(2S)-1-(azetidin-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 102); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-3-methyl-1-(pyrrolidin-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (cpd 103); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide hydrochloride (cpd 104); N-[(2S)-1-(azetidin-1-yl)-3-methylbutan-2-yl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 105); N-[(1S)-1-cyclohexyl-2-hydroxyethyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 106); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(1S)-1-phenyl-2-(pyrrolidin-1-yl)ethyl]-1H-pyrazole-5-carboxamide (cpd 107); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-1-methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-1H-pyrazole-5-carboxamide (cpd 108); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 109); 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-N-[(2S)-1-hydroxypropan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 110); 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 111); 1-Methyl-3-{2-[(3-methylphenyl)amino]pyrimidin-4-yl}-N-[(2S)-3-methyl-1-(pyrrolidin-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (cpd 112); N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-difluorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 113); 3-(2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-N-[(1S,2R)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 114); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-[(1S,2R)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 115); N-[(1S,2S)-2-aminocyclohexyl]-3-{2-[(3,5-dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 116); 3-{2-[(3,5-Dichlorophenyl)amino]pyrimidin-4-yl}-1-methyl-N-[(2S)-3-methyl-1-(pyrrolidin-1-yl)butan-2-yl]-1H-pyrazole-5-carboxamide (cpd 117); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methyl-1H-pyrazole-5-carboxamide (cpd 118); N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3-cyanophenyl)amino]pyrimidin-4-yl}-1-methyl-1H-pyrazole-5-carboxamide (cpd 119); 3-{2-[(3,5-Dimethylphenyl)amino]pyrimidin-4-yl}-1-ethyl-N-[(1S,2R)-2-hydroxycyclohexyl]-1H-pyrazole-5-carboxamide (cpd 120); N-[(1S,2R)-2-aminocyclohexyl]-3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-ethyl-1H-pyrazole-5-carboxamide hydrochloride (cpd 121); 3-{2-[(3,5-dimethylphenyl)amino]pyrimidin-4-yl}-1-ethyl-N-[(3R)-piperidin-3-yl]-1H-pyrazole-5-carboxamide hydrochloride (cpd 122) and N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-{2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-yl}-N,1-dimethyl-1H-pyrazole-5-carboxamide (cpd 123).

6. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1, comprising the steps of: Step 1) Compound of formula (III) Mixed with dimethylformamide-dialkyl acetal to obtain a compound of formula (IV) wherein R2 is as defined in claim 1 and R9 is a group selected from a linear or branched C1-C6 alkyl group; Step 2) The compound of formula (IV) obtained in step 1 is reacted with the compound of formula (V) wherein R1 is as defined in claim 1, Reaction to obtain a compound of formula (VI) wherein R1, R2 and R9 are as defined above; Alternatively, the compound of formula (VI) reported in step 2 can be prepared according to the following steps: Step 3) making the compound of formula (IV) wherein R2 and R9 are defined as in step 1); Reaction with guanidine carbonate to obtain a compound of formula (VII) Step 4) In the presence of palladium, the compound of formula (VII) obtained in step 3 and the compound of formula (VIII) are reacted wherein R1 is as defined in claim 1, and Y is iodine or bromine, Reaction to obtain a compound of formula (VI) wherein R1, R2 and R9 are as defined above; or Step 5) In the presence of iodine and CuI, the compound of formula (VII) obtained as reported in step 3) is reacted with Reaction with isoamyl nitrite and diiodomethane or cesium iodide to obtain a compound of formula (IX) wherein R2 and R9 are as defined above; Step 6) Then, in the presence of palladium, the obtained compound of formula (IX) is and a compound of formula (X) wherein R1 is as defined in claim 1, Reaction to obtain a compound of formula (VI) wherein R1, R2 and R9 are as defined above; The compounds of formula (I) can be prepared according to a process comprising the following steps: Step 7) the compound of formula (VI) obtained in step 2, 4 or 6 wherein R1 and R2 are as defined in claim 1, and R9 is a group selected from linear or branched C1-C6 alkyl groups, Reaction under acid or alkaline hydrolysis conditions to obtain a compound of formula (XI) or a corresponding salt wherein R1 and R2 are as defined above; Step 8) The compound of formula (XI) or the corresponding salt described in step 7 is reacted with the compound of formula (XII) wherein R3 and R4 are as defined in claim 1, Reaction to obtain a compound of formula (I) wherein R1, R2, R3 and R4 are as defined in claim 1.

7. Use of a compound as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease caused by and / or associated with deregulated Syk kinase activity.

8. The use according to claim 7, wherein the disease is selected from the group consisting of cancer, cell proliferative disorders and immune-related disorders.

9. The use according to claim 8, wherein the disease is cancer.

10. The use according to claim 9, wherein the cancer is selected from the group consisting of: epithelial cancers; hematopoietic tumors of the lymphoid lineage; hematopoietic tumors of the myeloid lineage; tumors of mesenchymal origin; tumors of the central and peripheral nervous systems; and other tumors.

11. The method of claim 9, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, kidney cancer, liver cancer, colon cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, prostate cancer, skin cancer, leukemia, fibrosarcoma, rhabdomyosarcoma, glioma, melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, and thyroid cancer.

12. The method of claim 9, wherein the cancer is selected from the group consisting of small cell lung cancer, squamous cell carcinoma, acute lymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, angioimmunoblastic T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, Burkitt lymphoma, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, promyelocytic leukemia, glioblastoma, glioblastoma multiforme, astrocytoma, oligodendroglioma, paraganglioma, neuroblastoma, schwannoma, papillary thyroid carcinoma, medullary thyroid carcinoma, Kaposi's sarcoma, chondrosarcoma, and cholangiocarcinoma.

13. Use according to claim 8, wherein the treatment is combined with radiotherapy or with a chemotherapy regimen.

14. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, carrier or diluent.

15. The pharmaceutical composition of claim 14, further comprising one or more chemotherapeutic agents.

16. A product or kit comprising a compound as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

17. Use of a compound as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament having anticancer activity.

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