ZA200603938B - Pyrazole derivatives as inhibitors of receptor tyroyne kinases - Google Patents

Description

PYRAZOLE DERIVATIVES AS INHIBITORS OF RECEPTOR TYROSINE KINASES

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 TrkA inhibitors in W00220479 and W00220513. Recently,

Japan Tobacco reported pyrazolyl condensed cyclic compounds as Trk inhibitors (JP2003231687A).

In addition to the above, Vertex Pharmaceuticals have described pyrazole compounds as inhibitors of GSK3, Aurora, etc. in W00250065, W00262789 and W003027111; and

AstraZeneca have reported pyrazole compounds as inhibitors against IGF-1 receptor kinase (W00348133).

Summary of the invention

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 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.

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 oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, ewings tumour, neuroblastoma, kaposis 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, renal cancer, lymphoma 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.

Detailed description of the invention

Accordingly, the present invention provides a compound of formula @:

R? x

N_2N = he RS R!

NT

A

@ wherein:

A is a direct bond or Cy.alkylene; wherein said Cialkylene may be optionally substituted by one or more R%,

Ring C is carbocyclyl or heterocyclyl;

R! and R* are independently selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci.alkyl, C,.¢alkenyl,

C,.salkynyl, Cy.salkoxy, Ci.ealkanoyl, C,.¢alkanoyloxy, N~(Ci.¢alkyl)amino, N.N-(Ci.ealkyl);amino, Ci salkanoylamino, N-(Cy.¢alkyl)carbamoyl,

N,N-(C,.¢alkyl),carbamoyl, C1.6alkylS(O), wherein a is 0 to 2, C,¢alkoxycarbonyl,

N-(C1.salkyl)sulphamoyl, N,N-(C1.¢alkyl)sulphamoyl, C.¢alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R! and R? independently of each other may be optionally substituted on carbon by one or more R®; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R’;

R? is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cy.salkyl, C,.alkenyl, Co.alkynyl, C,.¢alkoxy,

C,.alkanoyl, Cy_¢alkanoyloxy, N-(C,_salkyl)amino, N,N-(C;.¢alkyl);amino,

C.¢alkanoylamino, N-(Ci.galkyl)carbamoyl, N,N-(C.salkyl),carbamoyl, C1.6alkylS(O). wherein ais 0 to 2, C;.¢alkoxycarbonyl, N-(C,galkyl)sulphamoyl,

N,N-(C.¢alkyl),sulphamoyl, C,.¢alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein

R? may be optionally substituted on carbon by one or more R!% and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from RY;

R3 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 16alkyl, Cy.¢alkenyl, Ca.alkynyl, Cy.¢alkoxy,

C,.calkanoyl, Cy.¢alkanoyloxy, N-(Ci.salkyl)amino, N,N-(C,.¢alkyl)2amino,

C,.¢alkanoylamino, N-(Cy.salkyl)carbamoyl, N,N-(C1.¢alkyl),carbamoyl, C1.62lkylS(O)a wherein a is 0 to 2, Cj_salkoxycarbonyl, N-(C1.¢alkyl)sulphamoyl, N,N-(Cy.calkyl);sulphamoyl, C,.calkylsulphonylamino, carbocyclyl or heterocyclyl; wherein

R® may be optionally substituted on carbon by one or more R!% and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R';

R® is hydrogen or optionally substituted C1.¢alkyl; wherein said optional substituents are selected from one or more RY

RS and R’ are independently selected from hydrogen, halo, nitro, cyano, hydroxy, triftuoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci.salkyl, Cz-salkenyl,

C,.calkynyl, Cy.¢alkoxy, Cy.¢alkanoyl, C,.¢alkanoyloxy, N-(Ci.salkyl)amino,

N,N-(C,.¢alkyl);amino, C,.salkanoylamino, N-(C.salkyl)carbamoyl,

N,N-(Ci.salkyl);carbamoyl, Ci.¢alkylS(O). wherein a is 0 to 2, Csalkoxycarbonyl,

N-(C1.¢alkyl)sulphamoyl, N,N-(Ci.¢alkyl)zsulphamoyl, C,.¢alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R® and R” independently of each other may be optionally substituted on carbon by one or more R"; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R'; or R® and R’ together with the pyrimidine bond to which they are attached form a 5 or 6 membered carbocyclic ring or a 5S or 6 membered heterocyclic ring wherein said ring is fused to the pyrimidine of formula (I); wherein the double bonds of the resulting bicyclic ring may be further delocalised across the whole of the bicyclic ring; and wherein said carbocyclic ring or heterocyclic ring may be optionally substituted on carbon by one or more R'’; and wherein if said heterocyclic ring contains an _NH- moiety that nitrogen may be optionally substituted by a group selected from RS; n=0, 1, 2 or 3; wherein the values of R® may be the same or different;

R®, R, R?, RR”, RY and R? are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C;.salkyl,

C,.¢alkenyl, Cyealkynyl, Cy.alkoxy, C,.¢alkanoyl, C,.¢alkanoyloxy, N-(Ci.¢alkyl)amino,

N,N-~(C,.¢alkyl),amino, C:.salkanoylamino, N-(Cy.salkyl)carbamoyl, N,N-(Cy.alkyl),carbamoyl, C1.6alkylS(0), wherein ais 0 to 2, C,.salkoxycarbonyl,

N-(C.¢alkyl)sulphamoyl, N,N-(C.salkyl);sulphamoyl, C,.salkylsulphonylamino, carbocyclyl or heterocyclyl; wherein RS, RY RY, R* RY, RY and R? independently of each other may be optionally substituted on carbon by one or more R'%; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from

R*; rR’, RY, RY, RS, R'® and R?® are independently selected from Ci.salkyl, Ci.salkanoyl,

C.¢alkylsulphonyl, C;.calkoxycarbonyl, carbamoyl, N-(C,salkyl)carbamoyl,

N,N-(C.salkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein

R%,R', R®, R*, R' and R* independently of each other may be optionally substituted on carbon by on or more R*;

RY and R® are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cy.¢alkyl, Cz6alkenyl,

C,.¢alkynyl, Cy.¢alkoxy, Cy.¢alkanoyl, C,.¢alkanoyloxy, N-(C;.calkyl)amino,

N,N-(C,¢alkyl);amino, C:salkanoylamino, N-(C.¢alkyl)carbamoyl, N,N-(Ci.salkyl);carbamoyl, C1.¢alkylS(0). wherein a is 0 to 2, C,.salkoxycarbonyl,

N-(Ci.¢alkyl)sulphamoyl, N,N-(Cj.salkyl)zsulphamoyl, C,salkylsulpbonylamino, carbocyclyl or heterocyclyl; wherein R'? and R* independently of each other may be optionally substituted on carbon by one or more R?; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R%;

R? 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

R* is selected from Cyalkyl, Ci.salkanoyl, C,.salkylsulphonyl, C..salkoxycarbonyl, carbamoyl, N-(Ci.¢alkyl)carbamoyl, N,N-(C.¢alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; or a pharmaceutically acceptable salt thereof; with the proviso that said compound is not: 5-bromo-N*-(5-methyl-1H-pyrazol-3-y1)-N’-[1-(2-pyridinyl)propyl]-2,4-pyrimidinediamine; 5-chloro-N*-(5-methyl-1H-pyrazol-3-yl)-N*-[1 -(2-pyridinyl)propyl]-2.4-pyrimidinediamine; 5-bromo-N?-{ 1-(3-methyl-5-isoxazolyl)ethyl]-N*~(5-methyl-1H-pyrazol-3-y1)-2,4- pyrimidinediamine; 5-chloro-N2-[1-(3-methyl-5-isoxazolyl)ethyl]-N*-(5-methyl- 1H-pyrazol-3-yl)-2,4- pyrimidinediamine; 5-bromo-N*-(5 -methyl-1H-pyrazol-3-y1)-N>-[1-(3-pyridinyl)propyl]-2,4-pyrimidinediamine; 5-chloro-N*-(5 -methyl-1H-pyrazol-3-yl)-N>-[1-3 -pyridinyl)propyl]-2,4-pyrimidinediamine; 5-chloro-N*-(5-methyl-1H-pyrazol-3-yl)-N*-[1-(3-pyridinyl)ethy1]-2,4-pyrimidinediamine; 5-bromo-N*-(5-methyl-1H-pyrazol-3-yl)-N’-[1-(3-pyridinyl)ethyl]-2,4-pyrimidinediamine; or 5-bromo-N*-(5-methyl-1H-pyrazol-3 -y1)-N2-[1-(2-pyridinyl)ethyl] -2 A-pyrimidinediamine.

In a further aspect of the invention there is provided a compound of formula (Ia) wherein:

R?

RS N N

NY om

N._.2N — he Rf R! ae

A

(wn n=0,1,20r3 (Ia) wherein:

A is a valence bond or C,.; alkyl;

C is a Cs.saryl, Cs.gheteroaryl, or Cs.cycloalkyl ring;

R! and R? are H, optionally substituted Ci.salkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;

R? is optionally substituted Cysalkyl, optionally substituted cycloalkyl, optionally substituted C;.¢ether, optionally substituted C;.¢amine; optionally substituted, optionally substituted C.sester, or optionally substituted C;.samide or R? and C in combination form a fused 9 or 10 membered aryl optionally substituted with R®;

R?is H, F, Cl, Br, 1, CF3, NH, NO,, OH, OCF3, Ci.ealkyl, OC,.¢alkyl, SCy.alkyl,

Nalkyl, SO,NH;, C(=0)Oalkyl;

R® is H or optionally substituted C, salkyl;

RS and R’ are independently selected from: H, F, Cl, Br, I, CFs, CN, NH, NO, OH,

CH,OH, OCF3, Cy.salkyl, OCy.6 alkyl, SC.6 alkyl, SO.NHz, C(=0)0C;.¢alkyl, Cs.saryl

Cs-Crheterocyclyl or RS and R’ in combination form an optionally substituted fused 5 or 6- membered aryl or heteroaromatic ring, said heteroaromatic ring having at least one nitrogen, oxygen or sulfur atoms, but no more than 2 oxygen atoms or 2 sulfur atoms or 1 oxygen and 1 sulfur atom or two nitrogen atoms wherein such fused ring is optionally substituted with R®

R%is H, F, Cl, Br, I, CFs, CN, NH,, NO,, OH, CH,0H, OCF3, Ci.salkyl, OC. alkyl,

SC,.¢ alkyl, SO,NH,, C(=0)OC;.¢alkyl, Cs.¢aryl, Cs-C; heterocyclyl, optionally substituted

C.¢alkyl, optionally substituted cycloalkyl, optionally substituted C,.¢ether, optionally

Claims (1)

1. Claims:

   1. A compound of formula (I): R7 KA N he od == BNE R’ A @® wherein: Ais a direct bond or Cy.,alkylene; wherein said Calkylene may be optionally substituted by one or more R%; Ring C is carbocyclyl or heterocyclyl; R* and R* are independently selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,.alkyl, C; ¢alkenyl, C,salkynyl, C,.¢alkoxy, Cy.salkanoyl, C;.salkanoyloxy, N-(C;.salkyl)amino, N,N-(C,.¢alkyl),amino, Cyalkanoylamino, N-(C,.salkylcarbamoyl, N,N-(C.salkyl);carbamoyl, Cy¢alkylS(O), wherein a is 0 to 2, Cjalkoxycarbonyl, N-(Cisalkyl)sulphamoyl, N,N-(C,.¢alkyl);sulphamoyl, C,_galkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R' and R* independently of each other may be optionally substituted on carbon by one or more R®, and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R% R? is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,alkyl, C.salkenyl, Cz.salkynyl, C;.salkoxy,

   Ci.¢alkanoyl, C,.salkanoyloxy, N-(Ci.salkyl)amino, N, N-(C;.salkyl),amino, Cisalkanoylamino, N-(C,.salkyl)carbamoyl, N,N-(C,.salkyl)carbamoyl, C,alkylS(O), wherein a is 0 to 2, C, alkoxycarbonyl, N-(C;¢alkyDsulphamoyl, N,N-(C;.¢alkyl),sulphamoyl, Ci.¢alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R® may be optionally substituted on carbon by one or more R'?; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R''; R3 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C.¢alkyl, Ca.salkenyl, Cy.salkynyl, C,_salkoxy,

   C.galkanoyl, Ci.¢alkanoyloxy, N-(C;-¢alkyl)amino, N,N-(C,.¢alkyl);amino,

   Ci.salkanoylamino, N-(Cy.salkyl)carbamoyl, N,N-(Calkyl);carbamoyl, Ci.6alkylS(O)a wherein a is 0 to 2, Cy¢alkoxycarbonyl, N-(C).salkyl)sulphamoyl, N,N-(C;.galkyl);sulphamoyl, C,.¢alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R® may be optionally substituted on carbon by one or more R'% and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R"; R’ is hydrogen or optionally substituted C,.¢alkyl; wherein said optional substituents are selected from one or more R™ R® and R’ are independently selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cy.¢alkyl, C2.salkenyl,

   C,.salkynyl, C,.¢alkoxy, Ci.¢alkanoyl, C,alkanoyloxy, N-(Cy.¢alkyl)amino, N,N=(C,.¢alkyl),amino, Cisalkanoylamino, N-(C1-alkyl)carbamoyl, N,N-(C.alkyl),carbamoyl, C1.¢alkylS(O), wherein a is 0 to 2, C,.salkoxycarbonyl, N-(C,.salkyl)sulphamoyl, N,N-(Ci.¢alkyl);sulphamoyl, C,.¢alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R® and R’ independently of each other may be optionally substituted on carbon by one or more R'%; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R'®; or R® and R together with the pyrimidine bond to which they are attached forma 5 or 6 membered carbocyclic ring or a 5 or 6 membered heterocyclic ring wherein said ring is fused to the pyrimidine of formula (I); wherein the double bonds of the resulting bicyclic ring may be further delocalised across the whole of the bicyclic ring; and wherein said carbocyclic ring or heterocyclic ring may be optionally substituted on carbon by one or more RY; and wherein if said heterocyclic ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R'%; n=0, 1, 2 or 3; wherein the values of R? may be the same or different; RE R' RY RY RY R' and R™ are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C;.salkyl,

   C,.calkenyl, Ca.galkynyl, Cy alkoxy, Ci.calkanoyl, Ci¢alkanoyloxy, N-(C,.¢alkyl)amino,

   ~-132- N,N-(C,_salkyl),amino, C;-salkanoylamino, N-(C\.salkyl)carbamoyl, N,N-(C,.galkyl),carbamoyl, C1-calkylS(O), wherein a is 0 to 2, C;-salkoxycarbonyl, N-(C,.¢alkyl)sulphamoyl, N,N-(Cj.¢alkyl);sulphamoyl, C1.¢alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein RE R'% R'%,R™ RY, R'” and R% independently of each other may be optionally substituted on carbon by one or more R'%; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from

   R%. R’, R'L, R®, R'®, R'® and R*® are independently selected from C,.salkyl, Cj.galkanoyl, Csalkylsulphonyl, Cy alkoxycarbonyl, carbamoyl, N<(Ci.salkyl)carbamoyl, N,N-(C,.ealkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R’ R", RP, RS, R'8 and R% independently of each other may be optionally substituted on carbon by on or more R¥; R* and R* are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,salkyl, Cz.salkenyl, Cpealkynyl, Ciealkoxy, Cisalkanoyl, Ci-alkanoyloxy, N-(C,.¢alkyl)amino, N,N-(C).alkyl),amino, C;.salkanoylamino, N-(C1.¢alkyl)carbamoyl, N,N~(C;¢alkyl);carbamoyl, C.¢alkylS(0)a wherein a is 0 to 2, C,salkoxycarbonyl, N-(C,.salkyl)sulphamoyl, N,N-(C.¢alkyl),sulphamoyl, C1-calkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R' and R? independently of each other may be optionally substituted on carbon by one or more R%, and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R*, R2 is selected from halo, nitro, cyano, hydroxy, triffuoromethoxy, 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 R* is selected from Cy.galkyl, C.salkanoyl, Ci.salkylsulphonyl, Ci.¢alkoxycarbonyl, carbamoyl, N-(Ci.salkyl)carbamoyl, N,N-(C¢alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; or a pharmaceutically acceptable salt thereof;

   with the proviso that said compound is not: 5-bromo-N*-(5-methyl- 1H-pyrazol-3-yl)- N*-[1-(2-pyridinyDpropyl}-2,4-pyrimidinediamine; 5-chloro-N*-(5-methyl-1H-pyrazol-3-y))-N-{1-(2-pyridinyl)propyl]-2,4-pyrimidinediamine; -bromo-N2-[1-(3-methyl-5-isoxazolylethyl]-N*-(5-methyl-1H-pyrazol-3 -yI)-2,4- 5 pyrimidinediamine;

   5.chloro-N2-[1-(3-methyl-5-isoxazolyDethyl}-N*-(5-methyl-1H-pyrazol-3-yl)-2,4- pyrimidinediamine; 5-bromo-N*-(5 -methyl-1H-pyrazol-3-yI)-N*-[1-(3 -pyridinyl)propyl]-2,4-pyrimidinediamine; 5-chloro-N*-(5-methyl-1H-pyrazol-3 -yI)-N2[1-(3 -pyridinyl)propyl}-2,4-pyrimidinediamine; 5-chloro-N*-(5-methyl- 1H-pyrazol-3-yl)-N*-[1-(3-pyridinyl)ethyl]-2,4-pyrimidinediamine; 5-bromo-N*-(5-methyl-1H-pyrazol-3-yl)-N*-[1-(3-pyridinyDethyl]-2,4-pyrimidinediamine; or

   5.bromo-N*-(5-methyl-1H-pyrazol-3-y])-N*-[1-(2-pyridinyDethyl]-2,4-pyrimidinediamine.

   2. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 wherein A is a direct bond.

   3. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according either claim 1 or 2 wherein Ring C is phenyl, thienyl, pyridyl, thiazolyl.

   4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-3 wherein R! is selected from hydrogen, C;.salkyl, Ci.calkoxy, N,N-(C,.salkyl);amino, C;.¢alkylS(O). wherein a is 0 or carbocyclyl; wherein R! may be optionally substituted on carbon by one or more RS; wherein R® is selected from halo or carbocyclyl.

   5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4 wherein R* is hydrogen.

   6. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-5 wherein: R?is selected from Cy.¢alkyl; wherein R? may be optionally substituted on carbon by one or more R':

   RY is selected from halo, hydroxy, carboxy, amino, Ci.salkoxy, N,N-(C,.¢alkyl)yamino, C,salkanoylamino, N-(C.alkyl)carbamoyl, N,N-(Ci.alkyl),carbamoyl or heterocyclyl; wherein R'? may be optionally substituted on carbon by one or more RY: and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R%; RY is selected from hydroxy or Cialkoxy; RY is selected from Ciealkyl.

   7. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to ant one of claims 1-6 wherein R? is selected from halo, nitro, C¢alkyl or Cialkoxy; wherein R® may be optionally substituted on carbon by one or more R'%; and R'is selected from halo.

   8. A compound of formula (f), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7 wherein R® is hydrogen or optionally substituted Cy-salkyl; wherein said optional substituents are selected from one or more R'*; and RM is selected from hydroxy.

   9. A compound of formula m, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-8 wherein: RS and R’ are independently selected from hydrogen, halo, nitro, cyano, amino,

   C,.¢alkyl, N-(C,.salkyl)amino, N,N~(C,.¢alkyl)amino, N~(C¢alkyl)carbamoyl,

   C,.¢alkoxycarbonyl or heterocyclyl; wherein R® and R” independently of each other may be optionally substituted on carbon by one or more R'%; and wherein if said heterocyclyl contains 55 an -NH- moiety that nitrogen may be optionally substituted by a group selected from R'S; or RS and R” together with the pyrimidine bond to which they are attached form a 6 membered carbocyclic ring or a 5 or 6 membered heterocyclic ring wherein said ring is fused to the pyrimidine of formula (I); wherein the double bonds of the resulting bicyclic ring may be further delocalised across the whole of the bicyclic ring; and wherein said carbocyclic ring or heterocyclic ring may be optionally substituted on carbon by one or more R!7; and wherein if said heterocyclic ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from RY;

   RIS is selected from halo, hydroxy, amino, Cy.¢alkoxy, N,N-(C,.¢alkyl),amino, carbocyclyl or heterocyclyl; wherein R'® may be optionally substituted on carbon by one or more R'%; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R%; RY is selected from halo, C;.¢alkyl or Cy.¢alkoxy; wherein R'7 may be optionally substituted on carbon by one or more R'%; R'S is selected from Ci.calkyl; R!8 is selected from C,.¢alkanoyl; RY is selected from halo, hydroxy, Cy-¢alkoxy or heterocyclyl; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R*; R? is selected from C¢alkyl; and R?* is selected from Ci-galkyl.

   10. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-9 whereinn =0 or 1.

   11. A compound of formula (I) (as depicted in claim 1) wherein: A is a direct bond; Ring C is phenyl, thienyl, pyridyl, thiazolyl; R! is selected from hydrogen, methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, cyclopropylmethyl, benzyl, methoxy, ethoxy, propoxy, iSopropoxy, sec-butoxy, dimethylamino, methylthio or cyclopropyl; R2 is selected from methyl, ethyl, trifluoromethyl, hydroxymethyl, carboxymethyl, aminomethyl, methoxymethyl, morpholinomethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1- carboxyethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, acetamidomethyl, 2-[N-methyl-N- (2-methoxyethyl)amino]ethyl, 2-[N-methyl-N-(2-hydroxyethyl)amino]ethyl, 2-(N- methylcarbamoyl)ethyl, 2-[N-(2-hydroxyethyl)carbamoyl]ethyl, 2-(N,N- dimethylcarbamoyl)ethyl, 2-morpholinoethyl, 2-pyrrolidin-1-ylethyl or 2-(1-methylpiperazin- 4-ylethyl, 1-methyl-2-hydroxyethyl; R? is selected from fluoro, nitro, trifluoromethyl or methoxy; R’ is hydrogen; R® is hydrogen, methyl or 2-hydroxyethyl;

   RS and R” are independently selected from hydrogen, fluoro, chloro, bromo, nitro, cyano, amino, methyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, N-methyl-N-propylamino, N-ethylcarbamoyl, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, morpholino, pyrrolidinyl or piperazinyl; wherein R® and R’

   independently of each other may be optionally substituted on carbon by one or more R'; and wherein said piperazinyl may be optionally substituted on nitrogen by a group selected from RS, :

   or R® and R” together with the pyrimidine to which they are attached form a bicyclic ring selected from quinazolinyl, thieno[3 ,2-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, 1H-

   pyrazolo[3,4-d]pyrimidinyl, thieno{3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 5,6,7,8- tetrahydro-pyrido{4,3-d]pyrimidinyl, 5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidinyl or 5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidinyl; and wherein said bicyclic ring may be optionally substituted on carbon by one or more R'7; and wherein said 5,6,7,8-tetrahydro-pyrido[4,3- d]pyrimidinyl, 5,6,7 8-tetrahydro-pyrido[2,3-d]pyrimidinyl or 5,6,7,8-tetrahydro-pyrido[3,4-

   dJpyrimidinyl may be optionally substituted on nitrogen by a group selected from R'%;

   RY is selected from fluoro, hydroxy, amino, ethoxy, dimethylamino, phenyl, pyrrolidinyl, piperazinyl or morpholino; wherein R'® may be optionally substituted on carbon by one or more RY; and wherein said piperazinyl may be optionally substituted on nitrogen by a group selected from RY;

   R'S is selected from methyl;

   Ris selected from fluoro, chloro, methyl, methoxy, ethoxy or propoxy; wherein RY’ may be optionally substituted on carbon by one or more RY;

   R'® is selected from acetyl;

   RY is selected from fluoro, hydroxy, methoxy, piperazinyl, pyrrolidinyl or morpholino; and wherein said piperazinyl may be optionally substituted on nitrogen by a group selected from R*, R? is selected from methyl; R** is selected from methyl; n=0or1; or a pharmaceutically acceptable salt thereof; with the proviso that said compound is not: 5 -bromo-N*-(5-methyl-1H-pyrazol-3-y1)-N’-[1-(2-pyridinyl)propyl]-2,4-pyrimidinediamine; 5-chloro-N*-(5-methyl-1H-pyrazol-3-yl)-N>-[1-(2-pyridinyl)propyl]-2,4-pyrimidinediamine;

   5-bromo-N*-(5-methyl- 1H-pyrazol-3-yl)-N?-[1-(3-pyridinyl)propyl]-2,4-pyrimidinediamine; 5-chloro-N*-(5-methyl-1H-pyrazol-3-yl)-N*-[1-(3 -pyridinyl)propyl]-2,4-pyrimidinediamine; 5-chloro-N*-(5-methyl-1H-pyrazol-3-yl)-N*-[1 -3 -pyridinyl)ethyl]-2,4-pyrimidinediamine; 5-bromo-N*-(5-methyl- 1H-pyrazol-3 -y1)-N2-[1-(3-pyridinyl)ethyl]-2,4-pyrimidinediamine; or 5-bromo-N'-(5-methyl-1H-pyrazol-3-yl)-N>-[1-(2-pyridinyDethyl]-2,4-pyrimidinediamine.

   12. A compound of formula (I) (as depicted in claim 1) selected from: (2R)-2-({4-[(5-cyclopropyl-1H-pyrazol-3 -yl)amino}-5-fluoropyrimidin-2-yl} amino)-2-(4- fluorophenyl)ethanol; 5_bromo-N*-(3-cyclopropyl-1H-pyrazol-5-yI)-N2-[(15)-1-(4-fluorophenylethyl]pyrimidine- 2,4-diamine; (2R)-2-({5-chloro-4- [(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl} amino)-2-(4- fluorophenyl)ethanol; (2R)-2-({5-chloro-4-[(3 -isopropoxy-1H-pyrazol-5 -yDamino]pyrimidin-2-yl} amino)-2-(4- fluorophenyl)ethanol; (35)-3-({5-chloro-4-[(5-cyclopropyl- 1H-pyrazol-3-yl)amino]pyrimidin-2-yl}amino)-3-(4- fluorophenyl)-N-methylpropanamide; 2-({5-chloro-2-{[(1S)-1-(4-fluorophenyl)ethyl] amino }-6-[(5-isopropoxy-1H-pyrazol-3- yl)amino]pyrimidin-4-yl}amino)propane-1,3-diol; ’ 2-[(5-chloro-6-[(3-cyclopropyl- 1H-pyrazol-5 -yDamino}-2- {[(1S)-1-(4-fluorophenyl)ethyl] amino} pyrimidin-4-yl)amino]propane-1,3-diol; 5-chloro-N*-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-{(1 S)-(4-fluoro-phenyl)-ethyl]-6-(4-methyl- piperazin-1-yl)-pyrimidine-2,4-diamine; (2R)-2-({4-[(5-cyclopropyl- 1H-pyrazol-3-yl)amino]-7-fluoroquinazolin-2-yl} amino)-2-(4- fluorophenyl)ethanol; and 2-{(5-chloro-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-{[(1R)-1-(4-fluorophenyl)-2- hydroxyethyl]amino} pyrimidin-4-yl)amino]propane-1,3-diol; or a pharmaceutically acceptable salt thereof.

   13. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-12, which process comprises of: Process a) reaction of a pyrimidine of formula (IT):

   rR? RS L IAN he

   5. N R rR” hd A (on an wherein L is a displaceable group; with an pyrazole amine of formula (III): HN N pe R4 R! (mn or Process b) reacting a pyrimidine of formula (IV): . R7 KA _N

   XN . "NH N_=2N == he Rf Rr! L Iv) wherein L is a displaceable group; with a compound of formula (V): H 2 RN A \)] Process c) reacting a compound of formula (VI):

   EN A (yen (VD) with a compound of formula (VII): R7 6 H R NN, NH SS RS 2 I ®™), R (VID) wherein X is an oxygen atom and q is 1; or X is a nitrogen atom and q is 2; and wherein each R? independently represents a Cy-¢alkyl group; or Process d) reacting a compound of formula (VII): R’ R* R® N R' aa S oO 5 N R? RZ hd A (VIII) with hydrazine; or and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt.

   PCT/GB2004/004784

   14. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-12, for use as a medicament.

   15. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-12, in the manufacture of a medicament for use in the inhibition of Trk activity.

   16. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-12, in the manufacture of a medicament for use in the treatment or prophylaxis of cancer.

   17. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-12, in the manufacture of a medicament for use in the production of an anti-proliferative effect.

   18. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-12, together with at least one pharmaceutically acceptable carrier, diluent or excipient.

   19. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-12, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the inhibition of Trk activity.

   20. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-12, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the treatment or prophylaxis of cancer.

   21. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-12, 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. AMENDED SHEET

   : PCT/GB2004/004784

   22. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-12, for use in the inhibition of Trk activity.

   23. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-12, for use in the treatment of prophylaxis of cancer.

   24. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-12, for use in the production of an anti-proliferative effect.

   25. Use or composition or compound according to claims 16, 20 or 23 wherein said cancer is selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, ewings tumour, neuroblastoma, kaposis sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), small cell lung cancer (SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma, leukaemia, tumours of the central and peripheral nervous system, melanoma, fibrosarcoma and osteosarcoma.

   26. A compound according to any one of claims 1 to 12, 14 or 22 to 24, substantially as herein described with reference to and as illustrated in any of the examples.

   27. A process according to claim 13, substantially as herein described with reference to and as illustrated in any of the examples.

   28. Use according to any one of claims 15 to 17, substantially as herein described with reference to and as illustrated in any of the examples.

   29. A composition according to any one of claims 18 to 21, substantially as herein described with reference to and as illustrated in any of the examples. AMENDED SHEET