4-(3-aminopyrazole) pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer   

FIELD OF THE INVENTION

The present invention relates to novel pyrazole derivatives, their pharmaceutical compositions and methods of use. In addition, the present invention relates to therapeutic methods for the treatment and prevention of cancers and to the use of these pyrazole derivatives in the manufacture of medicaments for use in the treatment and prevention of cancers.

BACKGROUND OF THE INVENTION

Receptor tyrosine kinases (RTK\'s) are a sub-family of protein kinases that play a critical role in cell signalling and are involved in a variety of cancer related processes including cell proliferation, survival, angiogenesis and metastasis. Currently up to 100 different RTK\'s including tropomyosin-related kinases (Trk\'s) have been identified.

Trk\'s are the high affinity receptors activated by a group of soluble growth factors called neurotrophins (NT). The Trk receptor family has three members—TrkA, TrkB and TrkC. Among the NTs there are (i) nerve growth factor (NGF) which activates TrkA, (ii) brain-derived growth factor (BDNF) and NT-4/5 which activate TrkB and (iii) NT3 which activates TrkC. Each Trk receptor contains an extra-cellular domain (ligand binding), a trans-membrane region and an intra-cellular domain (including kinase domain). Upon binding of the ligand, the kinase catalyzes auto-phosphorylation and triggers downstream signal transduction pathways.

Trk\'s are widely expressed in neuronal tissue during its development where Trk\'s are critical for the maintenance and survival of these cells. A post-embryonic role for the Trk/neurotrophin axis (or pathway), however, remains in question. There are reports showing that Trk\'s play important role in both development and function of the nervous system (Patapoutian, A. et al Current Opinion in Neurobiology, 2001, 11, 272-280).

In the past decade, a considerable number of literature documentations linking Trk signalling with cancer have published. For example, while Trk\'s are expressed at low levels outside the nervous system in the adult, Trk expression is increased in late stage prostate cancers. Both normal prostate tissue and androgen-dependent prostate tumours express low levels of Trk A and undetectable levels of Trk B and C. However, all isoforms of Trk receptors as well as their cognate ligands are up-regulated in late stage, androgen-independent prostate cancer. There is additional evidence that these late stage prostate cancer cells become dependent on the Trk/neurotrophin axis for their survival. Therefore, Trk inhibitors may yield a class of apoptosis-inducing agents specific for androgen-independent prostate cancer (Weeraratna, A. T. et al The Prostate, 2000, 45, 140-148).

Furthermore, very recent literature also shows that over-expression, activation, amplification and/or mutation of Trk\'s are associated with secretory breast carcinoma (Cancer Cell, 2002, 2, 367-376), colorectal cancer (Bardelli et al Science, 2003, 300, 949-949) and ovarian cancer (Davidson, B. et al Clinical Cancer Research, 2003, 9, 2248-2259).

There are a few reports of selective Trk tyrosine kinase inhibitors. Cephalon described CEP-751, CEP-701 (George, D. et al Cancer Research, 1999, 59, 2395-2341) and other indolocarbazole analogues (WO0114380) as Trk inhibitors. It was shown that CEP-701 and/or CEP751, when combined with surgically or chemically induced androgen ablation, offered better efficacy compared with mono-therapy alone. GlaxoSmithKline disclosed certain oxindole compounds as Trk A inhibitors in WO0220479 and WO0220513. Recently, Japan Tobacco reported pyrazolyl condensed cyclic compounds as Trk inhibitors (JP2003231687A). Pfizer also recently published certain isothiazole Trk A inhibitors (Bioorg. Med. Chem. Lett. 2006, 16, 3444-3448).

In addition to the above, Vertex Pharmaceuticals have described pyrazole compounds as inhibitors of GSK3, Aurora, etc. in WO0250065, WO0262789, WO03027111 and WO200437814; and AstraZeneca have reported pyrazole compounds as inhibitors against IGF-1 receptor kinase (WO0348133). AstraZeneca have also reported Trk inhibitors in International Applications WO 2005/049033, WO 2005/103010, WO 2006/082392, WO 2006/087530, and WO 2006/087538.

Another such group is the JAK family. The JAK (Janus-associated kinase)/STAT (signal transducers and activators or transcription) signalling pathway is involved in a variety of hyperproliferative and cancer related processes including cell-cycle progression, apoptosis, angiogenesis, invasion, metastasis and evasion of the immune system (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al., Cancer and Metastasis Reviews, 2003, 22, 423-434).

The JAK family consists of four non-receptor tyrosine kinases Tyk2, JAK1, JAK2, and JAK3, which play a critical role in cytokine- and growth factor mediated signal transduction. Cytokine and/or growth factor binding to cell-surface receptor(s), promotes receptor dimerization and facilitates activation of receptor-associated JAK by autophosphorylation. Activated JAK phosphorylates the receptor, creating docking sites for SH2 domain-containing signalling proteins, in particular the STAT family of proteins (STAT1, 2, 3, 4, 5a, 5b and 6). Receptor-bound STATs are themselves phosphorylated by JAKs, promoting their dissociation from the receptor, and subsequent dimerization and translocation to the nucleus. Once in the nucleus, the STATs bind DNA and cooperate with other transcription factors to regulate expression of a number of genes including, but not limited to, genes encoding apoptosis inhibitors (e.g. Bcl-XL, Mcl-1) and cell cycle regulators (e.g. Cyclin D1/D2, c-myc) (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al., Cancer and Metastasis Reviews, 2003, 22, 423-434).

Over the past decade, a considerable amount of scientific literature linking constitutive JAK and/or STAT signalling with hyperproliferative disorders and cancer has been published. Constitutive activation of the STAT family, in particular STAT3 and STATS, has been detected in a wide range of cancers and hyperproliferative disorders (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324). Furthermore, aberrant activation of the JAK/STAT pathway provides an important proliferative and/or anti-apoptotic drive downstream of many kinases (e.g. Flt3, EGFR) whose constitutive activation have been implicated as key drivers in a variety of cancers and hyperproliferative disorders (Tibes et al., Annu Rev Pharmacol Toxicol 2550, 45, 357-384; Choudhary et al., International Journal of Hematology 2005, 82(2), 93-99; Sordella et al., Science 2004, 305, 1163-1167). In addition, impairment of negative regulatory proteins, such as the suppressors of cytokine signalling (SOCS) proteins, can also influence the activation status of the JAK/STAT signalling pathway in disease (J C Tan and Rabkin R, Pediatric Nephrology 2005, 20, 567-575).

Several mutated forms of JAK2 have been identified in a variety of disease settings. For example, translocations resulting in the fusion of the JAK2 kinase domain with an oligomerization domain, TEL-JAK2, Bcr-JAK2 and PCM1-JAK2, have been implicated in the pathogenesis of various heamatologic malignancies (S D Turner and Alesander D R, Leukemia, 2006, 20, 572-582). More recently, a unique acquired mutation encoding a valine-to-phenylalanine (V617F) substitution in JAK2 was detected in a significant number of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis patients and to a lesser extent in several other diseases. The mutant JAK2 protein is able to activate downstream signalling in the absence of cytokine stimulation, resulting in autonomous growth and/or hypersensitivity to cytokines and is believed to play a critical role in driving these diseases (M J Percy and McMullin M F, Hematological Oncology 2005, 23(3-4), 91-93).

JAKs (in particular JAK3) play an important biological roles in the immunosuppressive field and there are reports of using JAK kinase inhibitors as tools to prevent organ transplant rejections (Changelian, P. S. et al, Science, 2003, 302, 875-878). Merck (Thompson, J. E. et al Bioorg. Med. Chem. Lett. 2002, 12, 1219-1223) and Incyte (WO2005/105814) reported imidazole based JAK2/3 inhibitors with enzyme potency at single nM levels. Recent Vertex described azaindoles as JAK inhibitors (WO2005/95400). AstraZeneca have published quinoline-3-carboxamides as JAK3 inhibitors (WO2002/92571).

In addition to the above, Vertex Pharmaceuticals have described pyrazole compounds as inhibitors of GSK3, Aurora, etc. in WO2002/50065, WO2002/62789, WO2003/027111 and WO2004/37814; and AstraZeneca have reported pyrazole compounds as inhibitors against IGF-1 receptor kinase—WO2003/48133—and Trk in WO2005/049033 and WO2005/103010.

SUMMARY

In accordance with the present invention, the applicants have hereby discovered novel pyrazole compounds, or pharmaceutically acceptable salts thereof, which possess Trk kinase inhibitory activity and are accordingly useful for their anti-proliferation and/or proapoptotic (such as anti-cancer) activity and in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said pyrazole compounds, or pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an anti-proliferation and/or proapoptotic effect in warm-blooded animals such as man.

Also in accordance with the present invention the applicants provide methods of using such pyrazole compounds, or pharmaceutically acceptable salts thereof, in the treatment of cancer.

The properties of the compounds claimed in this invention are expected to be of value in the treatment of disease states associated with cell proliferation such as cancers (solid tumors and leukemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi\'s sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.

Furthermore, the compounds, or pharmaceutically acceptable salts thereof, of the invention are expected to be of value in the treatment or prophylaxis of cancers selected from congenital fibrosarcoma, mesoblastic nephroma, mesothelioma, acute myeloblastic leukemia, acute lymphocytic leukemia, multiple myeloma, melanoma, oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi sarcoma, ovarian cancer, breast cancer including secretory breast cancer, colorectal cancer, prostate cancer including hormone refractory prostate cancer, bladder cancer, melanoma, lung cancer—non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma, thyroid cancer including papillary thyroid cancer, mesothelioma and leukaemia; particularly ovarian cancer, breast cancer, colorectal cancer, prostate cancer and lung cancer—NSCLC and SCLC; more particularly prostate cancer; and more particularly hormone refractory prostate cancer.

In accordance with the present invention, the applicants have further hereby discovered novel compounds, and pharmaceutically acceptable salts thereof, which possess JAK kinase inhibitory activity and are accordingly useful for their anti-proliferation and/or pro-apoptotic activity and in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said compound, or pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing it and to its use in the manufacture of medicaments for use in the production of an anti-proliferation and/or pro-apoptotic effect in warm-blooded animals such as man. Also in accordance with the present invention the applicants provide methods of using said compound, or pharmaceutically acceptable salts thereof, in the treatment of myeloproliferative disorders, myelodysplastic syndrome and cancer.

The properties of the compounds claimed in this invention are expected to be of value in the treatment of myeloproliferative disorders, myelodysplastic syndrome, and cancer by inhibiting the tyrosine kinases, particularly the JAK family and more particularly JAK2. Methods of treatment target tyrosine kinase activity, particularly the JAK family activity and more particularly JAK2 activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndrome and cancer related processes. Thus, inhibitors of tyrosine kinase, particularly the JAK family and more particularly JAK2, are expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemias, myelomas and lymphomas, tumours of the central and peripheral nervous system, and other tumour types such as melanoma, fibrosarcoma and osteosarcoma. Tyrosine kinase inhibitors, particularly the JAK family inhibitors and more particularly JAK2 inhibitors are also expected to be useful for the treatment other proliferative diseases including but not limited to autoimmune, inflammatory, neurological, and cardiovascular diseases.

Furthermore, the compound, or pharmaceutically acceptable salts thereof, of the invention is expected to be of value in the treatment or prophylaxis of against myeloproliferative disorders selected from chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi\'s sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer—non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia; particularly myeloma, leukemia, ovarian cancer, breast cancer and prostate cancer.

DETAILED DESCRIPTION

Accordingly, the present invention provides a compound of formula (I):

wherein:

R1 is selected from hydrogen, hydroxy, amino, mercapto, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkylsulphonylamino, 3-5-membered carbocyclyl or 3-5-membered heterocyclyl; wherein R1 may be optionally substituted on carbon by one or more R6; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R7;

R2 and R3 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, (C1-6alkyl)2N—S(O)2—NH—, (C1-6alkyl)NH—S(O)2—NH—, NH2—S(O)2—NH—, (C1-6alkyl)2N—S(O)2—N(C1-6alkyl)-, (C1-6alkyl)NH—S(O)2—N(C1-6alkyl)-, NH2—S(O)2—N(C1-6alkyl)-, N—(C1-6alkyl)-N—(C1-6alkylsulphonyl)amino, C1-6alkylsulphonylamino, carbocyclyl-R19— or heterocyclyl-R21—; wherein R2 and R3 independently of each other may be optionally substituted on carbon by one or more R8; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R9;

R4 is selected from cyano, carboxy, carbamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkanoyl, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkoxycarbonyl, carbocyclyl or heterocyclyl; wherein R4 may be optionally substituted on carbon by one or more R10; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from RH;

R5 is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R5 may be optionally substituted on carbon by one or more R12; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R13;

n=0, 1, 2 or 3; wherein the values of R5 may be the same or different;

R6, R8, R10 and R12 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R6, R8, R10 and R12 independently of each other may be optionally substituted on carbon by one or more R14; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R15;

R7, R9, R11, R13 and R15 are independently selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R7, R9, R11, R13 and R15 independently of each other may be optionally substituted on carbon by on or more R16;

R14 and R16 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R14 and R16 independently of each other may be optionally substituted on carbon by one or more R17; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R18;

R17 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl; and

R19 and R21 are independently selected from a direct bond, —O—, —N(R22)—, —C(O)—, —N(R23)C(O)—, —C(O)N(R24)—, —S(O)s—, —SO2N(R25)— or —N(R26)SO2—; wherein R22, R23, R24, R25 and R26 are independently selected from hydrogen or C1-6alkyl and s is 0-2;

R18 is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to compounds of formula (I), wherein: R1 is selected from hydrogen, hydroxy, amino, mercapto, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkylsulphonylamino, 3-5-membered carbocyclyl or 3-5-membered heterocyclyl; wherein R1 may be optionally substituted on carbon by one or more R6; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R7;

R2 and R3 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, carbocyclyl-R19— or heterocyclyl-R21—; wherein R2 and R3 independently of each other may be optionally substituted on carbon by one or more R8; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R9;

R4 is selected from cyano, carboxy, carbamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkanoyl, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkoxycarbonyl, carbocyclyl or heterocyclyl; wherein R4 may be optionally substituted on carbon by one or more R19; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from RH;

R5 is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R5 may be optionally substituted on carbon by one or more R12; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R13;

n=0, 1, 2 or 3; wherein the values of R5 may be the same or different;

R6, R8, R10 and R12 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R6, R8, R10 and R12 independently of each other may be optionally substituted on carbon by one or more R14; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R15;

R7, R9, R11, R13 and R15 are independently selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R7, R9, R11, R13 and R15 independently of each other may be optionally substituted on carbon by on or more R16;

R14 and R16 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkyl S(O). wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R14 and R16 independently of each other may be optionally substituted on carbon by one or more R17; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R18;

R17 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl; and

R19 and R21 are independently selected from —O—, —N(R22)—, —C(O)—, —N(R23)C(O)—, —C(O)N(R24)—, —S(O)s—, —SO2N(R25)— or —N(R26)SO2—; wherein R22, R23, R24, R25 and R26 are independently selected from hydrogen or C1-6alkyl and s is 0-2;

R18 is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to compounds of formula (I), wherein: R1 is selected from hydrogen, hydroxy, amino, mercapto, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkylsulphonylamino, 3-5-membered carbocyclyl or 3-5-membered heterocyclyl; wherein R1 may be optionally substituted on carbon by one or more R6; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R7;

R2 and R3 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, N—(C1-6alkyl)-N—(C1-6alkylsulphonyl)amino, C1-6alkylsulphonylamino, carbocyclyl-R19— or heterocyclyl-R21—; wherein R2 and R3 independently of each other may be optionally substituted on carbon by one or more R8; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R9;

R4 is selected from cyano, carboxy, carbamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkanoyl, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkoxycarbonyl, carbocyclyl or heterocyclyl; wherein R4 may be optionally substituted on carbon by one or more R10; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R11;

R5 is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R5 may be optionally substituted on carbon by one or more R12; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R13;

n=0, 1, 2 or 3; wherein the values of R5 may be the same or different;

R6, R8, R10 and R12 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R6, R8, R10 and R12 independently of each other may be optionally substituted on carbon by one or more R14; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R15;

R7, R9, R11, R13 and R15 are independently selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R7, R9, R11, R13 and R15 independently of each other may be optionally substituted on carbon by on or more R16;

R14 and R16 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R14 and R16 independently of each other may be optionally substituted on carbon by one or more R17; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R18;

R17 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl; and

R19 and R21 are independently selected from a direct bond, —O—, —N(R22)—, —C(O)—, —N(R23)C(O)—, —C(O)N(R24)—, —S(O)s—, —SO2N(R25)— or —N(R26)SO2—; wherein R22, R23, R24, R25 and R26 are independently selected from hydrogen or C1-6alkyl and s is 0-2;

R18 is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

or a pharmaceutically acceptable salt thereof.

Particular values of the variable groups contained in formula (I) are as follows. Such values may be used, where appropriate, with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.

R1 is selected from C1-6alkyl, C1-6alkoxy, 3-5-membered carbocyclyl, and N,N—(C1-6alkyl)2amino, wherein R1 may be optionally substituted on carbon by one or more R6; and wherein R6 is halo.

R1 is C1-6alkoxy or 3-5-membered carbocyclyl.

R1 is selected from C1-6alkyl, C1-6alkoxy or 3-5-membered carbocyclyl.

R1 is C1-6alkyl or C1-6alkoxy.

R1 is 3-5 membered carbocyclyl.

R1 is N,N(C1-6alkyl)2amino.

R1 is C1-6alkyl.

R1 is C1-4alkyl.

R1 is C1-6alkoxy.

R1 is selected from methyl, methoxy, trifluoroethoxy, isopropoxy, cyclopropyl, and N,N-dimethylamino;

R1 is isopropoxy or cyclopropyl.

R1 is methyl, methoxy, isopropoxy or cyclopropyl.

R1 is selected from methyl, methoxy, isopropoxy, N,N-dimethylamino, and cyclopropyl.

R1 is isopropoxy.

R1 is methyl.

R1 is ethyl.

R1 is selected from methyl, ethyl, propyl, and butyl.

R1 is selected from C1-4alkyl, C1-4alkoxy, and cyclopropyl.

R1 is methoxy.

R1 is cyclopropyl. R1 is N,N-dimethylamino.

R2 is selected from hydrogen, halo, nitro, and C1-6alkyl, wherein R2 may be optionally substituted on carbon by one or more R8; and wherein R8 is halo.

R2 is selected from hydrogen, chloro, fluoro, bromo, nitro, and trifluoromethyl.

R2 is halo.

R2 is C1-6alkyl, wherein R2 may be optionally substituted on carbon by one or more R8; and wherein R8 is halo.

R2 and R3 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, carbocyclyl-R19— or heterocyclyl-R21—; wherein R2 and R3 independently of each other may be optionally substituted on carbon by one or more R8; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R9.

R2 and R3 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, N—(C1-6alkyl)-N—(C1-6alkylsulphonyl)amino, C1-6alkylsulphonylamino, carbocyclyl-R19— or heterocyclyl-R21—; wherein R2 and R3 independently of each other may be optionally substituted on carbon by one or more R8; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R9.

R2 and R3 are independently selected from hydrogen, halo, N—(C1-6alkyl)-N—(C1-6alkylsulphonyl)amino, or heterocyclyl-R21—; wherein R21 is a direct bond.

R2 and R3 are independently selected from hydrogen and halo.

R2 and R3 are independently selected from hydrogen and chloro.

R2 and R3 are independently selected from hydrogen, fluoro, chloro, bromo, N-methyl-N-mesylamino and morpholino.

R2 is halo and R3 is hydrogen.

R2 is chloro and R3 is hydrogen. R2 is chloro or fluoro and R3 is hydrogen. R3 is selected from hydrogen, halo, cyano, N—(C1-6alkyl)-N—(C1-6alkylsulphonyl)amino, C1-6alkyl, (C1-6alkyl)2N—S(O)2—N(C1-6alkyl)-, and heterocyclyl-R21—, wherein R3 may be optionally substituted on carbon by one or more R8; wherein R8 is halo; and wherein R21 is a bond.

R3 is hydrogen.

R3 is halo.

R3 is selected from N—(C1-6alkyl)-N—(C1-6alkylsulphonyl)amino and (C1-6alkyl)2N—S(O)2—N(C1-6alkyl)-.

R3 is selected from heterocyclyl-R21—, wherein R3 may be optionally substituted on carbon by one or more R8; wherein R8 is halo; and wherein R21 is a bond.

R3 is selected from hydrogen, chloro, cyano, trifluoromethyl, (CH3)2N—S(O)2—N(CH3)—, N-methyl-N-mesylamino, and morpholino.

R3 is (CH3)2N—S(O)2—N(CH3)—.

R3 is N-methyl-N-mesylamino,

R3 is morpholino.

R4 is C1-6alkyl.

R4 is methyl.

R5 is halo.

R5 is fluoro.

n=1.

R19 and R21 are independently selected from —O—, —N(R22)—, —C(O)—, —N(R23)C(O)—, —C(O)N(R24)—, —S(O)s—, —SO2N(R25)— or —N(R26)SO2—; wherein R22, R23, R24, R25 and R26 are independently selected from hydrogen or C1-6alkyl and s is 0-2.

Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted herein above) wherein:

R1 is selected from C1-6alkyl, C1-6alkoxy or 3-5-membered carbocyclyl;

R2 and R3 are independently selected from hydrogen, halo, N—(C1-6alkyl)-N—(C1-6alkylsulphonyl)amino, or heterocyclyl-R21—;

R4 is C1-6alkyl;

R5 is halo;

n=1;

R21 is a direct bond;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted herein above) wherein:

R1 is C1-6alkoxy;

R2 and R3 are independently selected from hydrogen and halo;

R4 is C1-6alkyl;

R5 is halo;

n=1;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted herein above) wherein:

R1 is methyl, methoxy, isopropoxy or cyclopropyl;

R2 and R3 are independently selected from hydrogen, fluoro, chloro, bromo, N-methyl-N-mesylamino and morpholino;

R4 is methyl;

R5 is fluoro; and

n=1;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted herein above) wherein:

R1 is selected from C1-6alkyl, C1-6alkoxy, 3-5-membered carbocyclyl, and N,N—(C1-6alkyl)2amino, wherein R1 may be optionally substituted on carbon by one or more R6;

R2 is selected from hydrogen, halo, nitro, and C1-6alkyl, wherein R2 may be optionally substituted on carbon by one or more R8;

R3 is selected from hydrogen, halo, cyano, N—(C1-6alkyl)-N—(C1-6alkylsulphonyl)amino, C1-6alkyl, (C1-6alkyl)2N—S(O)2—N(C1-6alkyl)-, and heterocyclyl-R21—, wherein R3 may be optionally substituted on carbon by one or more R8;

R4 is C1-6alkyl;

R5 is halo;

R6 is halo;

R8 is halo;

R21 is a bond; and

n=1;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted herein above) wherein:

R1 is selected from methyl, methoxy, trifluoroethoxy, isopropoxy, cyclopropyl, and N,N-dimethylamino;

R2 is selected from hydrogen, chloro, fluoro, bromo, nitro, and trifluoromethyl;

R3 is selected from hydrogen, chloro, cyano, trifluoromethyl, (CH3)2N—S(O)2—N(CH3)—, N-methyl-N-mesylamino, and morpholino;

R4 is methyl;

R5 is fluoro; and

n is 1;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted herein above) wherein:

R1 is selected from C1-6alkoxy, wherein R1 may be optionally substituted on carbon by one or more R6;

R2 is selected from hydrogen and halo;

R3 is selected from hydrogen, halo, and heterocyclyl-R21—;

R4 is C1-6alkyl;

R5 is halo;

R6 is halo;

R21 is a bond;

n is 1;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted herein above) wherein:

R1 is selected from C1-4alkyl, C1-4alkoxy, and cyclopropyl;

R2 is selected from hydrogen, halo, nitro, and C1-6alkyl, wherein R2 may be optionally substituted on carbon by one or more R8;

R3 is selected from hydrogen, halo, cyano, N—(C1-6alkyl)-N—(C1-6alkylsulphonyl)amino, C1-6alkyl, (C1-6alkyl)2N—S(O)2—N(C1-6alkyl)-, and heterocyclyl-R21—, wherein R3 may be optionally substituted on carbon by one or more R8;

R4 is C1-6alkyl;

R5 is halo;

R6 is halo;

R8 is halo;

R21 is a bond; and

n=1;

or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, preferred compounds of the invention are any one of the Examples or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, preferred compounds of the invention are any one of: N-{5-fluoro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide; 5-Fluoro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; 5-Chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methoxy-1H-pyrazol-3-yl)-6-(trifluoromethyl)pyrimidine-2,4-diamine; N2-[(1S)-1-(5-Fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine; 5-Chloro-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]pyrimidine-2,4-diamine; 5-Fluoro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; 5-bromo-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; N4-(5-Cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]pyrimidine-2,4-diamine; N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-5-methyl-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; N-{5-chloro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methoxy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide; N-{5-chloro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide; N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methoxy-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine; 5-chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methoxy-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine; 5-fluoro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine; and 5-fluoro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methoxy-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine; or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

In an additional embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the inhibition of Trk activity.

In an additional embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prophylaxis of cancer.

In an additional embodiment the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal such as man.

In an additional embodiment the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prophylaxis of cancers (solid tumors and leukemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi\'s sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation in a warm-blooded animal such as man.

In an additional embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the production of an anti-proliferative effect.

In an additional embodiment, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.

In an additional embodiment, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the production of an pro-apoptotic effect in a warm-blooded animal such as man.

In an additional embodiment, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of myeloproliferative disorders, myelodysplastic syndrome, and cancer in a warm-blooded animal such as man.

In an additional embodiment, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi\'s sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer—non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia.

In an additional embodiment, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer, wherein said cancer is selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi\'s sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer—non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia.

In an additional embodiment the present invention provides a method of inhibiting Trk activity comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a method for the treatment of cancer comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a method for the treatment or prophylaxis of cancer comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a method for the treatment or prophylaxis of cancers (solid tumors and leukemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi\'s sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation in a warm-blooded animal such as man comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a method of producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In an additional embodiment, the present invention provides a method for producing a pro-apoptotic effect in a warm-blooded animal, such as man, in need of such treatment, said method comprising administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically salt thereof.

In an additional embodiment, the present invention provides a method of treating myeloproliferative disorders, myelodysplastic syndrome, and cancer in a warm-blooded animal, such as man, in need of such treatment, said method comprising administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In an additional embodiment, the present invention provides a method of treating chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi\'s sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer—non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma, and leukaemia in a warm-blooded animal, such as man, in need of such treatment, said method comprising administering to said animal an effective amount of a compound of formula (I).

In an additional embodiment, the present invention provides a method of treating myeloma, leukemia, ovarian cancer, breast cancer, and prostate cancer in a warm-blooded animal, such as man, in need of such treatment, said method comprising administering to said animal an effective amount of a compound of formula (I).

In an additional embodiment, the present invention provides a method of treating myeloproliferative disorders, myelodysplastic syndrome and cancers (solid and heamatologic tumors), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi\'s sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation in a warm-blooded animal such as man comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In an additional embodiment, the present invention provides a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment, said method comprising administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein said cancer is selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi\'s sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer—non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia.

In an additional embodiment, the present invention provides a method of producing of a JAK inhibitory effect in a warm-blooded animal, such as man, in need of such treatment, said method comprising administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient.

In an additional embodiment the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the inhibition of Trk activity.

In an additional embodiment the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of cancer.

In an additional embodiment the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the treatment or prophylaxis of cancer.

In an additional embodiment the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the treatment or prophylaxis of cancers (solid tumors and leukemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi\'s sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.

In an additional embodiment the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.

In an additional embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically-acceptable diluent or carrier, for use in the production of an pro-apoptotic effect in a warm-blooded animal such as man. In an additional embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically-acceptable diluent or carrier, for use in the treatment of myeloproliferative disorders, myelodysplastic syndrome, and cancer in a warm-blooded animal such as man.

In an additional embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically-acceptable diluent or carrier, for use in the treatment of chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi\'s sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer—non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma, and leukaemia in a warm blooded animal such as man.

In an additional embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in the treatment of myeloma, leukemia, ovarian cancer, breast cancer, and prostate cancer in a warm-blooded animal, such as man.

In an additional embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically-acceptable diluent or carrier, for use in the treatment of cancer, wherein said cancer is selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi\'s sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer—non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia in a warm blooded animal such as man.

In an additional embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically-acceptable diluent or carrier, for use in the production of a JAK inhibitory effect in a warm blooded animal such as man.

In an additional embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the inhibition of Trk activity.

In an additional embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of cancer.

In an additional embodiment the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a warm-blooded animal such as man.

In an additional embodiment the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of cancers (solid tumours and leukaemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi\'s sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation in a warm-blooded animal such as man.