MX2008009676A

MX2008009676A - Pyrimidine derivatives

Info

Publication number: MX2008009676A
Application number: MXMX/A/2008/009676A
Authority: MX
Inventors: Grant Kettle Jason; Christophe Barlaam Bernard; Read Jon; Leach Andrew; Ducray Richard; Marie Paul Lambertvan Der Brempt Christine
Original assignee: Astrazeneca Ab; Astrazeneca Uk Limited; Christophe Barlaam Bernard; Ducray Richard; Grant Kettle Jason; Marie Paul Lambertvan Der Brempt Christine; Leach Andrew; Read Jon
Priority date: 2006-01-26
Filing date: 2008-07-25
Publication date: 2008-10-03

Abstract

The invention concerns benzamide compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, ring A, n, R3, and R4are as defined in the description. The present invention also relates to processes for the preparation of such compounds, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours or other proliferative conditions which are sensitive to the inhibition of EphB4, and/or EphA2 and/or Src kinases.

Description

DERIVATIVES OF PYRIMIDINE Description of the Invention The present invention relates to novel pyrimidine derivatives, to pharmaceutical compositions containing these derivatives and to their use in therapy, particularly in the prevention and treatment of solid tumor disease in a warm-blooded animal such as a human . Many of the current treatment regimens of cell proliferation diseases such as psoriasis and cancer use compounds that inhibit DNA synthesis. Such compounds are generally toxic to cells but their toxic effect on rapidly dividing cells such as tumor cells may be beneficial. Alternative methods of attacking tumors using agents that act on mechanisms other than inhibition of DNA synthesis have the potential to exhibit improved selectivity of action. In recent years it has been discovered that a cell can become cancerous by virtue of the transformation of a portion of its DNA into an oncogene, that is, a gene that, during activation, leads to the formation of malignant tumor cells (Bradshaw, Mutaqenesis 1986, 1_, 91). Several such oncogenes result in the production of peptides that are receptors of growth factors. Activation of the growth factor receptor complex subsequently leads to an increase in cell proliferation. It is known, for example, that several oncogenes encode tyrosine kinase enzymes and that certain growth factor receptors are also tyrosine kinase enzymes (Yarden et al., Ann.Rev. Biochem., 1988, 57, 443; Larsen et al. col., Ann. Reports in Med. Chem., 1989, Chpt. 13). The first group of tyrosine kinases to be identified, was presented from such viral oncogenes, for example tyrosine kinase pp60v Src (otherwise known as v-Src), and the corresponding tyrosine kinases in normal cells, for example tyrosine kinase pp60c Src (otherwise known as c-Src). The receptor tyrosine kinases are important in the transmission of biochemical signals that initiate a variety of cellular responses including proliferation, survival and migration. Large enzymes are those that traverse the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor (EGF) and an intracellular portion that functions as a kinase for amino acids of tyrosine phosphorylate in proteins and therefore to promote cell proliferation. Several classes of receptor tyrosine kinases are known (Wilks, Advances in Cancer Research, 1993, 60 43-73) and are classified based on the family of the growth factor to which they bind. This classification includes receptor tyrosine kinases of class I comprising the EGF family of receptor tyrosine kinases such as EGF, TGFα, Neu and erbB receptors, receptor tyrosine kinases of class II comprise the insulin family of receptor tyrosine kinases such as the insulin receptors and IGF1 and the insulin-related receptor (IRR) and the receptor tyrosine kinases of the class III comprise the family of the platelet-derived growth factor (PDGF, for its acronym in English ) of receptor tyrosine kinases such as PDGFa, PDGF and colony stimulation factor 1 receptors (CSF1). The Eph family is the best-known family of receptor tyrosine kinases, with 14 receptors and 8 coagulated ephrin ligands identified in mammals (reviewed in Kullander and Klein, Nature Reviews Molecular Cell Biolov, 2002, 3, 475-486). The host family is further subdivided into two sub-families, which are defined largely by the homology of the extracellular domains and by their affinity to a particular type of ligand. In general, all Ephs contain an intracellular tyrosine kinase domain and an Ig-like extracellular domain with a cysteine-rich region with 19 conserved cysteines and two fibronectin domains of type III. Class A of Ephs consists of 8 receivers, called EphA1-8, which bind generally to its cognate class ephrinA of ligands, called ephrinA1-5. Class B consists of 6 receptors, called EphB1-6, that bind to their cognate ligands ephrinB, called ephrinB1-3. The Eph receptor ligands are unusual and different for most other receptor tyrosine kinase ligands, because they bind to cells, via a glycosylphosphatidylinositol linkage in ephrinA ligands or an integral transmembrane region in ephrinB ligands. The binding of the ephrin ligand to the partner Eph induces a change of adaptation within the intracellular domain Eph that allows the phosphorylation of tyrosine residues within an inhibitory juxtamembrane region, which attenuates this inhibition of catalytic site and allows additional phosphorylation to stabilize the active adaptation and generate more binding sites for downstream signaling effectors. In addition, evidence indicates that Eph / Ephrin signaling can regulate other cellular responses such as proliferation and survival. There is evidence of growth whose Eph receptor signaling can contribute to tumorigenesis in a wide variety of human cancers, in tumor cells directly or indirectly via vascularization modulation. For example, many Eph receptors are overexpressed in several types of tumors (reviewed in Surawska et al., Cvtokine & amp;; Growth Factor Reviews, 2004, 15, 419-433, Nakamoto and Bergemann, Microscopy Res and Technique. 2002, 59, 58-67); the levels of EphA2 and another EphA receptor are elevated in different tumors such as leukemias, breast, liver, lung, ovarian and prostate. Similarly, expression of EphB receptors including EphB4 is up-regulated in tumors such as neuroblastomas, leukemias, breast, liver, lung and colon. On the other hand, several in vitro and in vivo studies, particularly concerning EphA2 and EphB4, have indicated that over-expression of Eph receptors in cancer cells can confer tumorigenic phenotypes such as proliferation and invasion, according to the putative function in oncogenesis. For example, the inhibition of EphB4 expression using Interference RNA or anti-sense oligodeoxynucleotides, inhibited the proliferation, survival and invasion of PC3 cells of prostate cancer in vitro and in vivo in a xenograft model (Xia et al., Cancer Res. 2005, 65., 4623 -4632). Overexpression of EphA2 in MCF-10A mammary epithelial cells is sufficient to cause tumorigenesis (Zelinski et al., Cancer Res .. 2001, 6JL 2301-2306). Inhibition of EphA2 function with therapeutic antibodies (Coffman et al., Cancer Res. 2003, 63, 7907-7912) or with interfering RNA (Landen et al., Cancer Res. 2005, 1_5, 6910-6918 ) has been shown to inhibit tumor growth in in vivo models of xenograft. The expression of dead kinase EphA2 mutant receptors in breast cancer cell lines inhibits the growth and metastasis of xenograft tumors in vivo, in accordance with the essential function of the kinase domain (Fang et al.

Oncoaene.2005, 24, 7859-7868). In addition to the convincing role of Eph receptors in tumor cells, there is good evidence that EphA2 and EphB4 can contribute to tumor vascularization (reviewed in Brantley-Sieders et al., Current Pharmaceutical Desiqn, 2004, 10, 3431-3442, Cheng et al., Cvtokine and Growth Factor Reviews, 2002, 1_3, 75-85). Members of the Eph family including EphA2 and EphB4 are expressed on endothelial cells. Transgenic studies have shown that the disruption of EphB4 (Gerety et al., Molecular Cell, 1999, 4, 403-414) or its ligand ephrinB2 (Wang et al., Cell 1998, 93, 741-753) causes the embryonic mortality associated with vascular modeling defects according to a critical function in the development of the vessel. The activation of EphB4 stimulates the proliferation and in vitro migration of endothelial cells (Steinle et al., J. Biol. Chem., 2002, 277, 43830-43835). On the other hand, the inhibition of EphB4 signaling using the extracellular soluble domains of EphB4, has been shown to inhibit tumor growth and angiogenesis in in vivo xenograft studies (Martiny-Baron et al., Neoplasia, 2004, 6, 248-257 , Kertesz et al., Blood, 2005, previously published online). Similarly, soluble EphA2 inhibited tumor vascularization in a variety of in vivo models (Brantley et al., Oncoqen, 2002, 2J_, 7011-7026, Cheng et al., Neoplasia, 2003, 5, 445-456).

Accordingly, it has been recognized that an inhibitor of Eph receptors, particularly EphB4 or EphA2, should have value as a selective inhibitor of the proliferation and survival of tumor cells by targeting tumor cells directly or via effects on tumor vascularization. Thus, such inhibitors will be valuable as therapeutic agents for the containment and / or treatment of the tumor disease. It is also known that certain tyrosine kinases belong to the class of non-receptor tyrosine kinases that are localized intracellularly and are involved in the transmission of biochemical signals such as those that promote the mobility, diffusion and invasion of tumor cells and subsequently tumor metastatic growth. (Ullrich et al., Cell 1990, 6, 203-212, Bolen et al., FASEB J .. 1992, 6, 3403-3409, Brickell et al., Critical Reviews in Oncogenesis, 1992, 3, 401-406, Bohlen et al., Oncoaene, 1993, 8, 2025-2031, Courtneidge et al., Semin. Cancer Biol. 1994, 5, 239-246, Lauffenburger et al., Cell, 1996, 84. 359-369, Hanks. et al., BioEssavs, 1996, 19, 137-145, Parsons et al., Current Opinion in Cell Bioloqy, 1997, 9, 187-192, Brown et al., Biochimica et Biophvsica Acta. 1996, 1287, 121- 149 and Schlaepfer et al., Progress In Biophysics and Molecular Biology, 1999, 7, 435-478). Various classes of non-receptor tyrosine kinases are known including the Src family such as Src, Lyn and Yes tyrosine kinases, the Abl family such as Abl and Arg and the Jak family such as Jak1 and Tyk2.

It is known that the Src family of non-receptor tyrosine kinases is highly regulated in normal cells and in the absence of extracellular stimuli is maintained in an inactive adaptation. Nevertheless, some members of the Src family, for example c-Src tyrosine kinase, are frequently significantly activated (compared to normal cell levels) in common human cancers such as gastrointestinal cancer, for example colon, rectal and stomach cancer ( Cartwright et al., Proc. Nati, Acad. Sci. USA, 1990. 87. 558-562 and Mao et al., Oncoqene, 1997, 1_5, 3083-3090) and breast cancer (Muthuswamy et al., Oncoqene. 1995, JM_, 1801-1810). The Src family of non-receptor tyrosine kinases has also been localized in other common human cancers such as non-small cell lung cancers (NSCLCs) including adenocarcinomas and squamous cell lung cancer (Mazurenko et al., European Journal of Cancer 1992, 28, 372-7), bladder cancer (Fanning et al., Cancer Research, 1992, 52., 1457-62), cancer of the esophagus (Jankowski et al., Gut. 1992, 33 , 1033-8), prostate cancer, ovarian cancer (Wiener et al., Clin Cancer Research 1999, 5, 2164-70) and pancreatic cancer (Lutz et al., Biochem. And Biophvs. Res. Comm. , 1998, 243.503-8). Although other human tumor tissues are tested to determine the Src family of tyrosine kinases or receptors, it is expected that their widespread prevalence will be established.

It is further known that the predominant function of the non-receptor tyrosine kinase c-Src is to regulate the assembly of focal adhesion complexes through interaction with a number of cytoplasmic proteins including, for example, focal adhesion kinase and paxilin. In addition, c-Src binds to the signaling pathways that regulate the actin cytoskeleton that facilitate cell mobility. Likewise, the important functions are performed by the non-receptor tyrosine kinases c-Src, c-Yes and c-Fyn in integrin-mediated signaling and in the intercellular junctions dependent on the alteration of cadherin (Owens et al., Molecular Bioloqy of the Cell, 2000, ü, 51-64 and Klinghoffer et al., EMBO Journal, 1999, 18. 2459-2471). Cellular mobility is necessarily required for a localized tumor to progress through the diffusion stages in the bloodstream, invasion of other tissues and initiation of metastatic tumor growth. For example, the progress of the colon tumor from the location of invasive metastatic disease to diffusion has been coated with the activity of the non-receptor tyrosine kinase c-Src (Brunton et al., Oncoqene., 1997, 1-4, 283- 293, Fincham et al., EMBO J, 1998, 1_7, 81-92 and Verbeek et al., EXP, Cell Research, 1999, 248, 531-537). It has therefore been recognized that an inhibitor of such non-receptor tyrosine kinases will be valuable as a selective inhibitor of the mobility of tumor cells and as a selective inhibitor of the diffusion and invasion of mammalian cancer cells that lead to inhibition of growth. metastatic tumor. Particularly an inhibitor of such non-receptor tyrosine kinases will be valuable as an anti-invasion agent for use in the containment and / or treatment of solid tumor disease. The Applicants have found that certain pyrimidines are useful in the inhibition of the EphB4 kinase and, in some cases also EphA2 and Src. Such pyrimidines are therefore useful in therapy, where such enzymes are involved. According to a first aspect of the invention, a compound of formula (I) is provided (I) wherein R1 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more substituent groups selected from cyano, nitro, -OR2, -NR2aR2b, -C (0) NR2aR2b, -N (R2a) C (0) R2, halo or haloalkyl of 1 to 6 carbon atoms (such as trifluoromethyl), where R2 , R2a and R2 are selected from hydrogen or alkyl of 1 to 6 carbon atoms such as methyl, or R2a and R2b together with the nitrogen atom to which they are attached can form a 5- or 6-membered heterocyclic ring, optionally containing a additional heteroatom selected from N, O or S; ring A is a 5 or 6 membered carbocyclic or heterocyclic fused ring, which is saturated or unsaturated, and is optionally substituted at any available carbon atom with one or more substituent groups selected from halo, cyano, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -S (0) Z-alkyl of 1 to 6 carbon atoms (where z is 0, 1 or 2), or -NRaRb (where Ra and Rb each is independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, or alkylcarbonyl of 1 to 4 carbon atoms), and wherein any nitrogen atom in the ring is optionally substituted by an alkyl of 1 to 6 carbon atoms or a alkylcarbonyl of 1 to 6 carbon atoms; n is 0, 1, 2 or 3 and each R3 group is independently selected from halo, trifluoromethyl, cyano, nitro or a sub-formula group (i): -Xl-Ru (i) where X1 is selected from a direct bond or O, S, SO, S02, OS02, NR3, CO, CH (OR13), CONR13, N (R13) CO, S02N (R13), N (R13) S02, C ( R13) 20, C (R13) 2S, C (R13) 2N (R13) and N (R13) C (R13) 2, wherein R13 is hydrogen or alkyl of 1 to 6 carbon atoms and R11 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl 0 Heterocyclyl, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, arylalkyl 1 to 6 carbon atoms or heterocyclyl-alkyl of 1 to 6 carbon atoms, any of which may be optionally substituted with one or more groups selected from halo, trifluoromethyl, cyano, nitro, hydroxy , amino, carboxy, carbam alkoxy of 1 to 6 carbon atoms, alkennioxyl of 2 to 6 carbon atoms, alkynyloxy of 2 to 6 atoms, alkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, di- (alkyl of 1 to 6 carbon atoms) amino, alkoxycarbonyl of 1 to 6 carbon atoms, N-alkylcarbamof 1 to 6 carbon atoms carbon, N, N-di- (alkyl of 1 to 6 carbon atoms) carbam alkanof 2 to 6 carbon atoms, alkanxy of 2 to 6 carbon atoms, alkanmino of 2 to 6 carbon atoms, N-alkyl from 1 to 6 carbon atoms-alkanmino of 2 to 6 carbon atoms, alkanmino of 3 to 6 carbon atoms rbonone, N-alkyl of 1 to 6 carbon atoms-alkenmino of 3 to 6 carbon atoms, alkynylamino of 3 to 6 carbon atoms, N-alkyl of 1 to 6 carbon atoms-alkynylamino of 3 to 6 carbon atoms , N-alkylsulfamof 1 to 6 carbon atoms, N, N-di- (alkyl of 1 to 6 carbon atoms) sulfam alcansulfonylamino of 1 to 6 carbon atoms and N-alkyl of 1 to 6 carbon atoms- alkanesulphonylamino of 1 to 6 carbon atoms, and any heterocyclyl group within R optionally has 1 or 2 oxo or thioxo substituents; and R4 is a group of sub-formula (iii) (iii) wherein R5, R6, R7, R8, and R9 are each independently selected from: (a) the groups hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, 3 to 12 carbon atoms, carbocyclyl, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-1-alkyl 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) and wherein any aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl -alkyl of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) are optionally substituted on any available carbon atom by halo, hydroxy, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxy -alkyl of 1 to 6 carbon atoms, alkoxy 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, or ?,? - dialkylamino of 1 to 6 carbon atoms, and any nitrogen atom present in a heterocyclyl group can, depending on the valence considerations, be replaced by a selected group of hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl from 1 to 6 carbon atoms, and wherein any sulfur atom can optionally be oxidized to sulfur oxide; (b) a group of sub-formula (iv): -X2-R14 (iv) where X2 is selected from O, NR 6, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR16), CON (R16), N (R16) CO, -N (R 6) C (0) N (R16) -, -N (R16) C (0) 0-, SON (R16), N (R16) SO, S02N (R16), N (R16) S02, C (R16) 20, C (R16) 2S and N (R16) C (R16) 2, wherein each R16 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, R14 is hydrogen, alkyl of 1 to 6 atoms of carbon, trifluoromethyl, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 6 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, or mono- or bicyclic heterocyclyl ring of 4 to 8 members (including heteroaryl rings of 5 or 6 members) or heterocyclyl alkyl groups of 1 to 6 bicyclic carbon atoms of 4 to 8 carbon atoms (including alkyl groups of 1 to 6 carbon atoms of 5 or 6 members) and wherein any aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-alkyl groups of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) carbon) are optionally substituted at any available carbon atom by oxo, halo, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or N, N-dialkylamino of 1 to 6 carbon atoms and any nitrogen atom present in the heterocyclyl portions may, depending on the valence considerations, be replaced by a group selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and wherein any sulfur atom may optionally be oxidized to a sulfur oxide; (c) to the group of the sub-formula (v): -X3-R15-Z (v) where X3 is a direct bond or is selected from O, NR17, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR17), CON (R17), N (R7) CO, -N (R17) C (0) N (R17) -, -N (R7) C (0) 0 -, S02N (R17), N (R17) S02, C (R7) 20, C (R17) 2S and N (R17) C (R17) 2, wherein each R17 is independently selected from hydrogen or alkyl from 1 to 6 carbon atoms; R15 is an alkylene of 1 to 6 carbon atoms, 2 to 6 carbon atoms alkenylene or alkynylene of 2 to 6 carbon atoms, arylene, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl (including heteroaryl), any of which which may be optionally substituted by one or more groups selected from halo, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, amino, alkylamino of 1 to 6 carbon atoms or of di- (C 1-6 alkyl) amino, Z is halo, trifluoromethyl, cyano, nitro, aryl, carbocyclyl of 3 to 12 carbon atoms or heterocyclyl (including heteroaryl), optionally having 1 or 2 substituents, which may be same or different, selected from halo, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and alkoxy of 1 to 6 carbon atoms and wherein any heterocyclyl group within of 2 optionally has 1 or 2 substituents oxo, or Z is a group of sub-formula (vi) -X4-R18 (vi) where X4 is selected from O, NR19, S, SO, S02, OS02, CO, C (0) 0, OC (O) , CH (OR19), CON (R9), N (R19) CO, S02N (R19), -N (R19) C (0) N (R19) -, -N (R19) C (0) 0-N (R19) S02, C (R19) 20, C (R19) 2S and N (R19) C (R19) 2, wherein each R19 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; and R18 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl) or heterocyclyl-alkyl of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) optionally having 1 or 2 substituents, which may be the same or different, selected from halo, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and alkoxy of 1 to 6 carbon atoms, and wherein any heterocyclyl group within R18 optionally carries 1 or 2 oxo substituents; or (d) R5 and R6, R6 and R7, R7 and R8 or R8 and R9 are joined together to form a 5, 6 or 7 membered fused ring, wherein the ring is unsaturated or partially or completely saturated and is optionally substituted at any available carbon atom by halo, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, amino, N-alkylamino of 1 to 6 carbon atoms, or?,? - dialkylamino of 1 to 6 carbon atoms, and the ring may contain one or more heteroatoms selected from oxygen, sulfur or nitrogen, where the sulfur atoms may optionally be oxidized to a sulfur oxide, where any CH2 group may be replaced by a C (O) group , and wherein the nitrogen atoms, depending on the valence considerations, can be substituted where R21 is selected from hydrogen or alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that if ring A, together with the phenyl ring to which it is attached, forms an indazol-4-yl group, then R1 is not hydrogen. According to a second aspect of the present invention, a compound of formula (I) is provided wherein R 1 is selected from hydrogen or optionally substituted alkyl of 1 to 6 carbon atoms, optionally substituted C 2 -C 6 alkenyl or optionally substituted C 2 -C 6 alkynyl; ring A is a 5- or 6-membered carbocyclic or heterocyclic ring that is optionally substituted on a carbon atom by one or more halo groups or alkyl groups of 1 to 6 carbon atoms, and where any nitrogen atom on the ring is optionally substituted by alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms; n is 0, 1, 2 or 3 and each R3 group is independently selected from halo, trifluoromethyl, cyano, nitro or a sub-formula group (I): -X'-R11 (i) where X1 is selected from a bond direct or O, S, SO, S02, OS02, NR13, CO, CH (OR13), CONR13, N (R13) CO, S02N (R13), N (R13) S02, C (R13) 20, C (R13) 2S, C (R13) 2N ( R13) and N (R13) C (R13) 2, wherein R13 is hydrogen or alkyl of 1 to 6 carbon atoms and R11 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms carbon, alkynyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl or heterocyclyl, alkyl of 1 to 6 carbon atoms-cycloalkyl of 3 to 8 carbon atoms, alkylaryl of 1 to 6 carbon atoms or alkylheterocyclyl of 1 to 6 carbon atoms, any of which may be optionally substituted with one or more groups selected from halo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, alkoxy of 1 to 6 carbon atoms, alkennioxyl of 2 to 6 carbon atoms, alkynyloxy of 2 to 6 atoms, alkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, di- (alkyl of 1 to 6 carbon atoms) amino, alkoxycarbonyl of 1 to 6 carbon atoms, N-alkylcarbamoyl of 1 to 6 carbon atoms, N, N-di- (alkyl of 1 to 6 carbon atoms) carbamoyl, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, alkanoylamino of 2 to 6 carbon atoms, alkanoylamino of 2 to 6 carbon atoms, N-alkyl of 1 to 6 atoms carbon-alkanoyl of 2 to 6 carbon atoms, alkenoylamino of 3 to 6 carbon atoms, N-alkyl of 1 to 6 carbon atoms-alkenoylamino of 3 to 6 carbon atoms, alkynylamino of 3 to 6 carbon atoms, N-alkyl of 1 to 6 carbon atoms-alkynylamino of 3 to 6 carbon atoms, N-alkylsulfamoyl of 1 to 6 carbon atoms, N, N-di- (alkyl of 1 to 6 carbon atoms) sulfamoyl, alcansulfonylamino from 1 to 6 carbon atoms and N-alkyl of 1 to 6 carbon atoms-alcansulfonylamino of 1 to 6 carbon atoms, and any heterocyclyl group within R 1 ti optionally 1 or 2 oxo or thioxo substituents; and R 4 is an optionally substituted phenyl ring, wherein one or more adjacent substituents can be joined together to form a fused bicyclic or tricyclic ring; or a pharmaceutically acceptable salt thereof. It should be untood that, assuming that any of the compounds of formula (I) defined above can exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any optically active or racemic form that Own the previous activity. The synthesis of optically active forms can be performed by standard techniques of organic chemistry well known in the art, for example by synthesis of the optically active starting materials or by the resolution of a racemic form. Similarly, the aforementioned activity can be evaluated using the standard laboratory techniques referred to below. It should be untood that certain compounds of formula (I) defined above may exhibit the phenomenon of tautomerism. Particularly, tautomerism can affect any heterocyclic group having 1 or 2 oxo substituents. It should also be untood that the present invention includes in its definition any tautomeric form, or a mixture thereof, which possesses the aforementioned activity and should not be simply limited to any one tautomeric form used within the drawings of the formulas or named in the examples. It should be understood that certain compounds of formula I above may exist in unsolvated as well as solvated forms, such as, for example, hydrated forms. It should also be understood that the present invention encompasses all solvates that possess anticancer or antitumor activity. It should also be understood that certain compounds of formula I may exhibit polymorphism, and that the present invention comprises all forms possessing anticancer or antitumor activity. Where the optional substituents are selected from "one or more" substituent groups, it should be understood that this definition includes all substituents that are chosen from one of the specified groups, or substituents that are chosen from two or more specified groups. In this specification the generic term "alkyl" includes the straight chain and branched chain alkyl groups such as propyl, isopropyl and tere-butyl. Although references to individual alkyl groups such as "propyl" are specific only to the linear chain version, references to alkyl groups with individual branched chains such as "isopropyl" are specific only to the branched chain version. An analogous convention applies to other generic terms, for example alkoxy (1 to 6 carbon atoms) include methoxy, ethoxy and isopropoxy, alkylamino (1 to 6 carbon atoms) includes methylamino, ethylamino and isopropylamino and di [ (alkyl of 1 to 6 carbon atoms)] amino includes dimethylamino, diethylamino and N-methyl-N-isopropylamino. Similarly the alkenyl or alkynyl groups may be straight or branched chain. The term "aryl" refers to phenyl or naphthyl, particularly phenyl. The terms "halo" or "halogen" refer to fluoro, chloro, bromo, or iodo. The term "heterocyclyl" or "heterocyclic ring", unless otherwise defined herein, the partially saturated ring saturated or unsaturated, mono, bicyclic or tricyclic containing 3-15 atoms of which at refers less an atom is chosen from nitrogen, sulfur or oxygen. These groups may, unless otherwise specified, be carbon or bound nitrogen. In addition, a sulfur atom of the ring can optionally be oxidized to form S-oxides. More particularly, a "heterocyclyl" or "heterocyclic ring" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3-12 atoms, and especially 4 to 10 atoms, of which at least one atom is chosen from nitrogen, sulfur or oxygen. The monocyclic "heterocyclyls" or "heterocyclic rings" conveniently contain 3-7 ring atoms, in particular 5 or 6 ring atoms. Examples and suitable values of the term "heterocyclyl" are thienyl, piperidinyl, morpholinyl, furyl, thiazolyl, pyridyl, imidazolyl, 1, 2,4-triazolyl, thiomorpholinyl, coumarinyl, pyrimidinyl, phthalidyl, pyrazolyl, pyrazinyl, pyridazinyl, benzothienyl, benzimidazolyl , tetrahydrofuryl, [1, 2,4] triazolo [4,3-a] pyrimidinyl, piperidinyl, indolyl, indazolyl, benzothiazolyl, benzoxazolyl, 1, 3-benzodioxolyl, pyrrolidinyl, pyrrolyl, quinolinyl, isoquinolinyl, isoxazolyl, benzofuranyl, 1, 2,3-thiadiazolyl, 1, 2,5-thiadiazolyl, pyrimidinyl, 2, 1-benzisoxazolyl, 4,5,6,7-tetrahydro-2H-indazolyl, imidazo [2, 1 -b] [1,3] thiazolyl , tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, 2,3-dihydro-1 -benzofurilo, 2,3-dihydro-1, 4-benzodioxinyl, 1,3-benzothiazolyl, 3, 4-dihydro-2H-benzodioxepinilo, 2, 3 dihydro-1, 4-benzodioxinyl, chromanyl, 2,3-dihydrobenzofuranyl, imidazo [2,1-b] [1, 3] thiazolyl, isoindolinyl, oxazolyl, pyridazinyl, quinoxalinyl, tetrahydrofuryl, 4,5,6,7-tetrahydro-1-benzofuryl, 4,5,6,7-tetrahydro-2H-indazolyl, 4,5,6,7-tetrahydro-1 H-indolyl, tetrahydropyranyl or 1, 2, 3, 4-tetrahydroquinolinyl. The heterocyclyl groups may be non-aromatic or aromatic in nature. Heterocyclyl aromatic groups are specifically referred to as heteroaryl. Heteroaryl groups are fully unsaturated, mono or bicyclic rings containing 3-12 atoms of which at least one atom is selected from nitrogen, sulfur or oxygen, which may, unless otherwise specified, be carbon or bound nitrogen. "Heteroaryl" conveniently refers to a fully unsaturated, monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 8-10 atoms of which at least one atom is selected from nitrogen, sulfur or oxygen, which may, unless otherwise specified, be carbon or nitrogen bound. Examples and convenient values of the term "heteroaryl" are thienyl, furyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, triazolyl, pyranyl, indolyl, pyrimidyl, pyrazinyl, pyridazinyl, benzothienyl, pyridyl and quinolyl. As stated above, when R 1 is an optionally substituted alkyl of 1 to 6 carbon atoms, optionally substituted C 2-6 alkenyl or optionally substituted C 2 -C 6 alkynyl, the optional substituents are conveniently selected from cyano , -OR2, -NR2aR2b, -C (0) NR2aR2b, or -N (R2a) C (0) R2, halo or haloalkyl of 1 to 6 carbon atoms such as trifluoromethyl, where R2, R2a and R2b are selected from hydrogen or alkyl of 1 to 6 carbon atoms such as methyl, or R2a and R2b together with the nitrogen atom to which they are attached can form a heterocyclic ring optionally containing an additional heteroatom. In one embodiment of the invention, R1 is hydrogen. In a further embodiment, n is 0, 1, or 2. For example, n is 0 or 1. In yet another embodiment, n is 1. Where n is 1 or more, a substituent R3 is conveniently placed on the ortho atom -carbon of the ring, forming a compound of formula (IA) (IA) where A, R1, R3 and R4 are defined as herein in relation to formula (I), R3a is a group R3 as defined herein, and particularly is halo, and m is 0, 1 or 2. The examples particular of groups A are defined below, and include for example groups A 'as defined below. Particularly A is -OCH20-, 0-CF2-0-, -OCH = N-, - N = CH-0-, -S-CH = N-, -N = CH-S-, -NH-N = CH -, or-CH = N-NH-.

When n other than zero, particular examples of the groups R 3 or R 3a are groups selected from halo, trifluoromethyl, cyano, hydroxy, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and alkoxy of 1 to 6 carbon atoms. For example, R3 or R3a can be selected from chloro, fluoro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, ethynyl, methoxy and ethoxy. In one embodiment, R3 or R3a is halo, such as bromine, chlorine or fluoro, and in particular chlorine. In a particular embodiment, n is 1 and R3 or R3a is halo such as chloro. Conveniently in the formula (IA), m is 0. Examples of the ring A include a compound of the group of formulas -CR22 = CR22-CR22 = CR22-, -N = CR22-CR22 = CR22-, CR22 = N-CR22 = CR22-, -CR = CR22-N = CR22-, -CR22 = CR2 -CR22 = N-, -N = CR22-N = CR22-, -CR22 = N-CR 2 = N-, -N = CR22-CR22 = N-, -N = N-CR22 = CR22-, -CR 2 = CR22-N = N-, -CR22 = CR22-0-, -0-CR22 = CR22 -, - CR22 = CR22-S-, - S-CR22 = CR22-, -CR22H-CR22H-0-, -0-CR22H-CR 2 H-, -CR22H-CR22H-S-, -S-CR22H-CR22H-, -0-CR22H-0-, -0 -CF2-0-, -0-CR22H-CR 2H-0-, -S-CR22H-S-, -S-CR22H-CR22H-S-, -CR 2 = CR22-N R22-, -NR20-CR22 = CR22-, D-CR22H-CR22H-NR20-, -NR20-CR22H-CR22H-, -N = CR22-NR20-, -NR20-CR2 = N-, D-NR20-CR 2H-NR20-, -OCR22 = N -, -N = CR22-0-. -S-CR22 = N-. -N = CR22-S-. -0-CR22H-NR20-, -NR20- CR22H-0-, -S-CR22H-NR20-, -NR20-CR22H-S-, -0-N = CR22-, CR22 = NO, -SN = CR22-, -CR22 = NS-, -O-NR20-CR22H-, -CR2 H- R20-O-,? -S-NR20-CR22H-, -CR22H-NR20-S-, -NR 0 -N = CR22-, -CR22 = N-NR20-, -NR20-NR20-CR22H-, -CR22H-NR20-NR20-, - N = N-NR20- or -NR20-N = N-, wherein each R20 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and wherein each R22 is independently selected from hydrogen, halo or alkyl of 1 to 6 carbon atoms. In a particular embodiment, where a group A includes more than one group R20 or R22, at least such a group is hydrogen. Particular examples of the R20 groups include hydrogen, methyl, ethyl or methylcarbonyl, in particular hydrogen. Particular examples of the R22 groups include hydrogen, chloro, fluoro, methyl or ethyl, in particular hydrogen. In a particular embodiment, ring A is fused is a 5-membered fused ring. Therefore the particular examples of A are ring A composed of a group of formula -CH = CH-0-, -0-CH = CH-, -CH = CH-S-, -S-CH = CH-, -CH2-CH2-0-, -0-CH2-CH2-, -CH2-CH2-S-, -S-CH2-CH2-, -0-CH2-0-, -0-CH2-CH2-0-, -S-CH2-S-, -S-CH2-CH2-S-, -CH = CH-N R20-, -NR20-CH = CH-, -CH2-CH2-NR20-, -N R20-CH2-CH2 -, -N = CH-NR20-, -NR20-CH = N-, -NR20-CH2-NR20-, -OCH = N-, -N = CH-0-, -S-CH = N-, -N = CH-S-, -0-CH2-NR20-, -NR20-CH2-O-, -S-CH2-N R20-, -N R20-CH2-S-, -0-N = CH-, -CH = N-0-, -SN = CH-, -CH = NS-, -ON R20-CH2-, -CH2- NR20-O-, -S-NR20-CH2-5 -CH2-NR 0-S-, -NR20-N = CH-, -CH = N-NR-, -NR20-NR20-CH2-, -CH2-NR20-NR20-, -N = N- R20- or -NR20-N = N-. Particular examples of R20 include hydrogen, methyl, and acetyl. For example, R20 is hydrogen. In one embodiment, ring A includes a nitrogen atom. For example, it is a group of formula -CH = CH-NR20- or -NR20-CH = CH-. Ring A can also include two nitrogen atoms. For example, it can be a group of formula-NR 0-N = CH-, -CH = N-NR 20-, -NR 20 -NR 20 -CH 2 -, or -CH 2 -N R 20 -N R 20 and particularly is a group-NR 0-N = CH- or -CH = N-NR20-. In another embodiment, ring A includes a nitrogen and an oxygen atom. Therefore it is conveniently selected from -0-N = CH-, -CH = N-0-, -O-NR20-CH2- or -CH2-NR20-O-. In yet a further embodiment, ring A is a group of formula -0-CH2-0- or -0-CF2-0-, in particular -0-CH2-0-. Particularly, examples of compounds of formula (I) are compounds of formula (IB) (IB) where R1, R2, R3 and n are as defined. Particular examples of the p-substituted phenyl groups R4 are groups of secondary formula where R5, R6, R7, R8 and R9 are independently selected: (a) hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 at 8 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-alkyl of 1 to 6 carbon atoms (including heteroaryl-alkyl), 1 to 6 carbon atoms); (b) a group of sub-formula (iv): -X2-Ru (iv) where X2 is selected from O, NR16S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR16), CON (R16), N (R16) CO, -N (R16) C (0) N (R16) -, -N (R16) C (0) 0-S02N (R16), N (R16) S02, C (R16) 20, C (R16) 2S and N (R16) C (R16) 2, wherein each R16 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, R14 is hydrogen, alkyl of 1 to 6 atoms carbon, trifluoromethyl, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl) or heterocyclyl-alkyl of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms); (c) to the group of the sub-formula (v): -X3-R15-Z (v) where X3 is a direct bond or is selected from O, NR17, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR17), CON (R17), N (R17) CO, -N (R17) C (0) N (R17) -, -N (R17) C (0) 0-, S02N (R17), N (R17) S02, C (R17) 20, C (R17) 2S and N (R17) C (R17) 2, wherein each R17 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; R15 is an alkylene of 1 to 6 carbon atoms, 2 to 6 carbon atoms, alkenylene or alkynylene of 2 to 6 carbon atoms, arylene, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl (including heteroaryl), any of which which may be optionally substituted by one or more groups selected from halo, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, amino, alkylamino of 1 to 6 carbon atoms or of di- (C 1-6 -alkyl) amino, Z is halo, trifluoromethyl, cyano, nitro, aryl, carbocyclyl of 3 to 12 carbon atoms or heterocyclyl (including heteroaryl), optionally having 1 or 2 substituents, which may be same or different, selected from halo, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and alkoxy of 1 to 6 carbon atoms and wherein any heterocyclyl group within of Z optionally has 1 or 2 substituents oxo, or Z is a group of sub-formula (vi) -X4-R18 (vi) where X4 is selected from O, NR19, S, SO, S02, OS02, CO, C (0) 0, OC (O) , CH (OR19), CON (R19), N (R19) CO, S02N (R19), -N (R19) C (0) N (R19) -, -N (R19) C (0) 0-N ( R19) S02, C (R19) 20, C (R9) 2S and N (R19) C (R19) 2, wherein each R19 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; and R18 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl) or heterocyclyl-alkyl of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) optionally having 1 or 2 substituents, which may be the same or different, selected from halo, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and alkoxy of 1 to 6 carbon atoms, and wherein any heterocyclyl group within R 8 optionally carries 1 or 2 oxo substituents; or (d) R5 and R6, R6 and R7, R7 and R8 or R8 and R9 are joined together to form a fused ring, which is optionally substituted, and which may contain one or more heteroatoms selected from oxygen, sulfur or nitrogen, where the sulfur atoms can optionally be oxidized to a sulfur oxide, where any CH2 group can be replaced by a C (O) group, and where the nitrogen atoms, depending on the valence considerations, can be replace with a group R21, where R21 is selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms. In particular at least one, for example at least two of R5, R6, R7, R8 and R9 are hydrogen. In one embodiment, at least three of R5, R6, R7, R8 and R9 are hydrogen. In one embodiment, at least one of R5, R6, R7, R8 and R9 is different from hydrogen. In a particular embodiment, at least one of R6, R7 or R8 is other than hydrogen. Particular examples of R5, R6, R7, R8 and R9, where they are other than hydrogen, include halo, trifluoromethoxy, cyano, alkenyl of 2 to 8 carbon atoms, heterocyclyl, a group of sub-formula (iv) -X2- R'4 (iv) where X2 is selected from O, NR16, S02, CON (R16), N (R16) CO, S02N (R16), N (R16) S02, where each R16 is independently selected from hydrogen or alkyl from 1 to 6 carbon atoms, and R14 is hydrogen, alkyl of 1 to 6 carbon atoms or trifluoromethyl, or a group of sub-formula (v): -X3-R, 5-Z (v) where X3 is a bond direct or is selected from O, CON (R17), N (R7) CO, S02N (R17), N (R17) S02, wherein each R17 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, and particularly is hydrogen, R15 is alkylene of 1 to 6 carbon atoms, and Z is cyano, or heterocyclyl having optionally 1 or 2 substituents, which may be the same or different, selected from halo or alkyl of 1 to 6 carbon atoms, or Z is a group of s ub-formula (vi) -X-R'8 (vi) where X4 is selected from O, NR19 CON (R19), N (R19) CO, S02N (R19) or N (R19) S02, wherein each R19 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; and R18 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, or heterocyclyl. The particular examples of the heterocyclic groups for R5, R6, R7, R8 and R9 and Z include saturated five or six member rings containing at least one nitrogen atom and optionally also one or more other heteroatoms selected from oxygen, nitrogen and sulfur.

These can be linked to the phenyl ring in the case of R5, R6, R7, R8 and R9, or to the group R15 in the case of Z via a carbon or a nitrogen atom. In a particular embodiment, at least one of R5, R6, R7, R8 and R9 or Z is a heterocyclic group attached to N. Particular examples of such groups include pyrrolidine and N-morpholino. Specific examples of R5, R6, R7, R8 or R9 groups which are other than hydrogen include chloro, fluoro, methyl, methoxy, ethoxyethoxy, trifluoromethoxy, ethynyl, cyano, hydroxymethyl, hydroxyethyl, cyanomethyl, amido, N-methylamido, N - (2-methoxyethyl) amido, 4- (pyridin-2-ylmethoxy), N-methylmethanesulfonamido, pyrrolidin-1-ethoxy, morpholino, 2-morpholin-4-ylethoxy, 2-hydroxyethyl-N-methylsulfonamido, dietilaminoetilamido, 4-methylpiperazin-1 -yl-ethoxy, fluorobenzyloxy, sulfonamido, metansulfonamido, metoxietilsulfonamido, acetamido, N-methylacetamido, metilacetamidometilo, methylsulfonyl and dimethylamino. Where R5 and R6, R6 and R7, R7 and R8 or R8 and R9 are joined to form a fused ring, the ring conveniently includes at least one heteroatom. Particularly, a fused ring formed by R5 and R6, R6 and R7, R7 and R8 or R8 and R9 contains one or two nitrogen atoms or a nitrogen atom and a sulfur atom. The ring conveniently includes 5 ring atoms including carbon atoms to which R5 and R6, R6 and R7, R7 and R8 or R8 and R9 are attached. The fused rings formed by R5 and R6, R6 and R7, R7 and R or R and R may have optional substituents that may be selected from those listed above for R3. Particular examples include fused ring formed by R5 and R6, R6 and R7, R7 and R8 or R8 and R9 and the phenyl ring to which are attached include indolyl, indazolyl, benzothiazolyl and indolone. In another embodiment, the invention provides a compound of formula (IC) (IC) where R1, R3, R4 and n are as defined herein, the ratio of formula (I) and A 'is selected from a group -OCH20-, -OCF2O-, -CH = CH-NR20- or -NR20-CH = CH-, -0-N = CH-, -CH = N-0-, -O-NR20-CH2-, -CH2-NR20-O-, -NR20-N = CH-, -CH = NN R20-, -NR20-NR20-CH2- or -CH2-NR20-NR20. Particularly, A "is selected from -OCH20-, -OCF20-, -CH = CH-NR20-, -NR20-CH = CH-, -0-N = CH-, -CH = N-0-, -O- NR20-CH2-, -CH2-NR20-O-, -NR20-N = CH- or -CH = N-NR20- Particular examples of compounds of formula (IC) are the compounds of formula (IB) as established previously specified, and these form a particular aspect of the invention The particular options for R1, R3, R4, n and R20 in formula (IC) are as set forth herein with reference to formula (I). compounds of formula (IB) form a particular aspect of the invention The novel novel particular compounds of the invention include, for example, compounds of formula (I), or the pharmaceutically acceptable salts thereof, wherein, unless state otherwise, each of R1, R2, R3, ring A, not R4 have any of the meanings defined above or in the following paragraphs (1) to (34) 1. Ring A was selected na: -CR22 = CR22-CR 2 = CR22-, -N = CR2-CR22 = CR22-, CR22 = CR22 = N-CR22-, -CR22 = CR22-N = CR22-, -CR22 = CR22-CR22 = N-, -N = CR22-N = CR22-, -CR = N-CR = N-, -N = CR22-CR22 = N-, -N = N-CR22 = CR22-, -CR22 = CR22-N = N-, -CR22 = CR22-0-, -0-CR22 = CR22 -, - CR22 = CR22-S-, -S-CR22 = CR22-, -CR22H-CR 2H-0-, -0-CR22H-CR22H-, -CR22H-CR22H-S-, -S-CR22H-CR 2 H-, -0-CR22H-0-, -0-CF2-0- , -0-CR22H-CR22H-0-, -S-CR22H-S-, -S-CR22H-CR22H-S-, -CR22 = CR22-NR22-, -NR20-CR2 = CR22-, D-CR22H-CR22H -NR20-, -NR20-CR22H-CR22H-, -N = CR22-NR20-, -NR20-CR22 = N-, D-NR20-CR22H-NR20-, -OCR22 = N-, -N = CR22-0- , -S-CR22 = N-, -N = CR22-S-, -0-CR22H-N R20-, -NR20-CR22H-0-, -S-CR22H-NR20-, -N R20-CR22H-S- , -0-N = CR22-, CR22 = NO, -SN = CR22-, -CR22 = NS-, -O-NR20-CR22H-, -CR22H-N R20-O-,? - S-NR20-CR22H-, -CR22H-NR20-S-, -NR20-N = CR22-, -CR22 = NN R20-, -NR20-NR20-CR22H-, -CR22H-NR20-NR20-, -N = N-NR20- or -NR20-N = N-, wherein each R20 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and wherein each R22 is independently selected from hydrogen, halo, cyano, hydroxy, carbon-alkyl of 1 to 6 atoms, alkoxy of 1 to 6 carbon atoms, -S (0) z-alkyl of 1 to 6 carbon atoms (where z is 0, 1 or 2), or - NRaRb (wherein each Ra and Rb is independently selected from hydrogen, alkyl of 1 to 2 carbon atoms, or alkanoyl of 1 to 2 carbon atoms). 2. Ring A is selected from -N = CR22-CR22 = CR22-, -CR22 = N-CR22 = CR22-, -CR22 = CR 2 -N = CR22-, -CR22 = CR22-CR22 = N-, - CR22 = CR 2-0-, -0-CR = CR22-, -0-CR22H-0-, -0-CF2-0-, -0-CR22H-CR22H-0-, -CR 2 = CR22-NR20- , -NR20-CR22 = CR22-t-CR22H-CR22H-NR20-, -NR20-CR22H-CR22H-, -OCR2 = N-, -N = CR22-O-, -S-CR22 = N-, -N = CR22-S-, -NR20-N = CR22-, or -CR 2 = NN R20-, wherein each R20 is independently selected from hydrogen, from 1 to 2 carbon atoms, alkyl or alkylcarbonyl of 1 to 2 carbon atoms, and wherein each R22 is independently selected from hydrogen, halo, cyano, hydroxy, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, -S (0) z-alkyl of 1 to 2 carbon atoms ( where z is 0, 1 or 2), or -NRaR (where Ra and Rb each is independently selected from hydrogen, alkyl of 1 to 2 carbon atoms, or alkanoyl of 1 to 2 carbon atoms). 3. Ring A is selected from -0-CR22H-0-, -0-CF2-0-, -OCR22 = N-, -N = CR22-0-, -S-CR22 = N-, -N = CR 2-S-, -NR20-N = CR22-, or -CR 2 = N-NR20-, wherein each R20 is independently selected from hydrogen, alkyl of 1 to 2 carbon atoms or alkylcarbonyl of 1 to 2 carbon atoms, and wherein each R22 is independently selected from hydrogen, halo, cyano, hydroxy, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, -S (0) z-alkyl of 1 to 2 carbon atoms ( where z is 0, 1 or 2), or -NRaRb (where Ra and Rb each is independently selected from hydrogen, alkyl of 1 to 2 carbon atoms, or 1 to 2 carbon atoms of alkanoyl). 4. Ring A is selected from -0-CR22H-0-, -0-CF2-0-, -OCR22 = N-, -N = CR22-0-, -S-CR22 = N-, -N = CR22 -S-, -N R20-N = CR22-, or -CR22 = N-NR20-, wherein each R20 is independently selected from hydrogen, or alkyl of 1 to 2 carbon atoms, and wherein each R22 is independently selected from hydrogen , halo, or methyl. 5. Ring A is selected from: -CR22 = CR22-CR22 = CR22-, -N = CR22-CR22 = CR22-, -CR22 = N-CR2 = CR22-, -CR2 = CR22-N = CR22-, -CR22 = CR22-CR22 = N-, -N = CR2 -N = CR22-, -CR22 = N-CR22 = N-, -N = CR22-CR22 = N-, -N = N-CR22 = CR22-, -CR22 = CR22-N = N-, -CR22 = CR22-0-, -0-CR2 = CR22-, -CR22 = CR22-S-, -S-CR22 = CR22-, -CR22H-CR22H-0-, -0-CR H-CR22H-, - CR22H-CR22H-S-, -S-CR H-CR2 H-, -0-CR 2H-0-, -O-CF2-O-, -0-CR22H-CR22H-0-, -S-CR22H- S -, -S-CR22H-CR22H-S-, -CR 2 = CR22-NR20-, -NR20-CR22 = CR22-, -CR 2H-CR22H-NR20-, -NR20-CR 2H-CR22H-, -N = CR22-NR20-, -NR20-CR22 = N-, -NR20-CR22H-NR20-, -OCR22 = N-, -N = CR22-0-, -S-CR22 = N-, -N = CR 2-S -, -0-CR22H-NR20-, -NR 0 -CR22H-O-, -S-CR22H-N R20-, -NR20-CR22H-S-, -0-N = CR22-, -CR22 = N-0 -, -SN = CR22-, -CR22 = NS-, -O-NR 0 -CR22H-, -CR22H-NR 0 -O-, -SN R20-CR22H-, -CR22H-NR20-S-, -NR20- NR20-CR22H-, -CR22H-NR20-NR20-, -N = N-NR20-, or -NR20-N = N-, wherein each R20 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and wherein each R22 is independently selected from hydrogen, halo, cyano, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -S (0) 2-alkyl of 1 to 6 carbon atoms ( where z is 0, 1 or 2), or -NRaRb (where Ra and Rb are each independently selected from hydrogen, alkyl of 1 to 2 carbon atoms, or alkanoyl of 1 to 2 carbon atoms). 6. Ring A is selected from -N = CR22-CR22 = CR22-, -CR22 = N-CR22 = CR22-, -CR2 = CR22-N = CR22-, -CR22 = CR22-CR22 = N-, -CR22 = CR22-0-, -0-CR22 = CR22-, -0-CR22H-0-, -0-CF2-0-, -0-CR22H-CR22H-0-, -CR 2 = CR22-NR20-, - N R20-CR22 = CR22-, -CR 2H-CR22H-NR20-, -N R20-CR H-CR22H-, -OCR22 = N-, -N = CR22-O-, -S-CR22 = N-, or -N = CR 2-S-, wherein each R 20 is independently selected from hydrogen, alkyl of 1 to 2 carbon atoms or alkylcarbonyl of 1 to 2 carbon atoms, and wherein each R 22 is independently selected from hydrogen, halo, cyano, hydroxy, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, -S (0) z-alkyl of 1 to 2 carbon atoms (where z is 0, 1 or 2), or -NRaRb ( where Ra and Rb each is independently selected from hydrogen, alkyl of 1 to 2 carbon atoms, or alkanoyl of 1 to 2 carbon atoms). 7. Ring A is selected from -0-CR22H-0-, -0-CF2-0-, -OCR22 = N-, -N = CR -0-, -S-CR22 = N-, or -N = CR22-S-, wherein each R20 is independently selected from hydrogen, alkyl of 1 to 2 carbon atoms or alkylcarbonyl of 1 to 2 carbon atoms, and wherein each R22 is independently selected from hydrogen, halo, cyano, hydroxy, alkyl 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, S (0) z-alkyl of 1 to 2 carbon atoms (where z is 0, 1 or 2), or -NRaRb (where Ra and Rb each one is independently selected from hydrogen, alkyl of 1 to 2 carbon atoms, or alkanoyl of 1 to 2 carbon atoms). 8. Ring A is selected from -0-CR22H-0-, -0-CF2-0-, -OCR22 = N-, -N = CR22-0-, -S-CR22 = N-, or -N = CR22-S-, wherein each R20 is independently selected from hydrogen, or alkyl of 1 to 2 carbon atoms, and wherein each R22 is independently selected from hydrogen, halo, or methyl. 9. R1 is hydrogen or an alkyl group of 1 to 4 carbon atoms which is optionally substituted with one or more substituents selected from cyano, -OR2, -NR2aR2, -C (0) NR2aR b, or -N (R2a) C (0) R2, halo or haloalkyl of 1 to 6 carbon atoms (such as trifluoromethyl), wherein R2, R and R are selected from hydrogen or alkyl of 1 to 4 carbon atoms; 10. R is hydrogen or an alkyl group of 1 to 2 carbon atoms, which is optionally substituted with one or more substituents selected from cyano, -OR2, -NR2aR2b, -C (0) NR2aR2b, or -N (R2a) C (0) R 2, halo or haloalkyl of 1 to 6 carbon atoms (such as trifluoromethyl), wherein R 2, R 2a and R b are selected from hydrogen or alkyl of 1 to 6 carbon atoms; 11. R1 is hydrogen or an alkyl group of 1 to 2 carbon atoms, which is optionally substituted with one or more substituents selected from cyano, -OR2, -NR2aR2b, wherein R2, R and R2b are selected from hydrogen or alkyl of 1 to 2 carbon atoms; 12. R is hydrogen or an alkyl group of 1 to 2 carbon atoms; 13. R is hydrogen; 14. R1 is alkyl of 1 to 2 carbon atoms a group, which is optionally substituted with one or more substituents selected from cyano, -OR2, -NR2aR2b, wherein R2, R2a and R2b are selected from hydrogen or alkyl of 1 to 2 carbon atoms; 15. R1 is an alkyl group of 1 to 2 carbon atoms; 16. R1 is methyl; 17. n is 0, 1, or 2; 18. n is O or 1; 19. n is 0; 20. n is 1; 21. each R3 group present is independently selected from halo, trifluoromethyl, cyano, nitro or a group of sub-formula (I): -X ^ R11 (i) where X1 is selected from a direct bond or O, S, SO, S02, OS02, NR13, CO, CH (OR13), CONR13, N (R13) CO, S02N (R13), N (R13) S02, C (R13) 20, C (R13) 2S, C (R13) 2N ( R13) and N (R13) C (R13) 2, wherein R13 is hydrogen or alkyl of 1 to 6 carbon atoms and R11 is selected from hydrogen, or alkyl of 1 to 6 carbon atoms, which may be optionally substituted with one or more groups selected from halo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, and alkoxy of 1 to 6 carbon atoms; 22. each R3 group present is independently selected from halo, trifluoromethyl, cyano, nitro or a group of sub-formula (I): -X'-R11 (i) wherein X1 is selected from a direct bond or O, NR13, CO , CONR13, N (R13) CO, wherein R13 is hydrogen or alkyl of 1 to 6 carbon atoms and R1 is selected from hydrogen or alkyl of 1 to 6 carbon atoms, which may be optionally substituted with one or more groups selected from halo, cyano, or alkoxy of 1 to 6 carbon atoms; 23. each R3 group present is independently selected from halo, trifluoromethyl, cyano, nitro or a group of sub-formula (i): -Xl-R "(i) wherein X1 is selected from a direct bond or O ,, CONR 3, wherein R13 is hydrogen or alkyl of 1 to 6 carbon atoms and R11 is selected from hydrogen or alkyl of 1 to 6 atoms of carbon, which may be optionally substituted with one or more alkoxy groups of 1 to 2 carbon atoms, 24. each R3 group present is independently selected from halo or a group of sub-formula (i): -X'-R11 (i) wherein X1 is selected from a direct bond or O ,, CONR13, wherein R13 is hydrogen or alkyl of 1 to 6 carbon atoms and R 1 is selected from hydrogen, alkyl of 1 to 2 carbon atoms, any of which may optionally be substituted with one or more alkoxy groups of 1 to 2 carbon atoms; . each R3 group present is independently selected from fluoro, chloro, cyano, -CONH2, or alkyl of 1 to 2 carbon atoms optionally substituted by alkoxy of 1 to 2 carbon atoms; 26. R4 is a group of sub-formula (iii) (¡O where R5, R6, R7, R8 and R9 are independently selected from: (a) hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-alkyl of 1 to 6 carbon atoms (including heteroaryl-alkyl) from 1 to 6 carbon atoms) and wherein any aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-alkyl groups of 1 to 6 carbon atoms carbon (including heteroaryl-alkyl of 1 to 6 carbon atoms) is optionally substituted on any carbon atoms by halo, hydroxy, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms , alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 ato carbon atoms, N-alkylamino of 1 to 6 carbon atoms, or?,? - dialkylamino of 1 to 6 carbon atoms and any nitrogen atom present in the heterocyclyl portions can, depending on the valence considerations, be replaced by a group selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and wherein any sulfur atom may optionally be oxidized to a sulfur oxide; (b) a group of sub-formula (iv); -X2-R14 (iv) where X2 is selected from O, NR16, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR16), CON (R16), N (R16) )CO, -N (R16) C (0) N (R16) -, -N (R6) C (0) 0-, SON (R16), N (R16) SO, S02N (R16), N (R6) S02 , C (R16) 20, C (R16) 2S and N (R16) C (R16) 2, wherein each R16 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, R14 is hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, or a mono- or bicyclic heterocyclyl ring of 4 to 8 members (including the heteroaryl rings of 5 or 6 carbon atoms) or heterocyclyl-alkyl groups of 1 to 6 mono or bicyclic carbon atoms of 4 to 8 members (including heteroaryl-alkyl groups of 1 to 6 carbon atoms of 5 or 6 members) and wherein any aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-alkyl groups of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) is optionally substituted on any carbon atom by oxo, halo, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms or, alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, or α, β-dialkylamino of 1 to 6 carbon atoms and any nitrogen atom present in the heterocyclyl portions may, depending on valence considerations, be replaced by a group selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and where any sulfur atom may optionally be oxidized to a sulfur oxide; (c) a group of sub-formula (v): -X3- 15-Z (v) where X3 is a direct bond or is selected from O, NR17, S, SO, S02, OS02l CO, C (0) 0 , OC (O), CH (OR17), CON (R17), N (R7) CO, -N (R7) C (0) N (R17) -, -N (R7) C (0) 0 -, S02N (R17), N (R17) S02, C (R17) 20, C (R17) 2S and N (R17) C (R17) 2, wherein each R17 is independently selected from hydrogen or alkyl of 1 to 6 atoms carbon or; R15 is an alkylene of 1 to 6 carbon atoms, alkenylene of 2 to 6 carbon atoms or alkynylene of 2 to 6 carbon atoms, arylene, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl (including heteroaryl), any of which which may be optionally substituted by one or more groups selected from halo, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, amino, alkylamino of 1 to 6 carbon atoms or di- ( alkyl of 1 to 6 carbon atoms) amino; Z is halo, trifluoromethyl, cyano, nitro, aryl, carbocyclyl of 3 to 12 carbon atoms or heterocyclyl (including heteroaryl) optionally having 1 or 2 substituents, which may be equal or different, selected from halo, alkyl from 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and alkoxy of 1 to 6 carbon atoms and wherein any heterocyclyl group within Z optionally has 1 or 3 oxo substituents, or Z is a group of sub-formula (vi) -X4-R18 (vi) where X4 is selected from O, NR19, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR19 ), CON (R19), N (R9) CO, S02N (R19), -N (R19) C (0) N (R19) -, -N (R19) C (0) 0-N (R19) S02 , C (R19) 20, C (R19) 2S and N (R9) C (R19) 2, wherein each R19 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; and R18 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, carbocyclyl of 3 to 13 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl) or heterocyclyl-alkyl of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) optionally has 1 or 2 substituents, which may be the same or different, selected halo, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 and alkoxy of 1 to 6 carbon atoms, and wherein any heterocyclyl group within R18 optionally has 1 or 2 oxo substituents; or (d) R5 and R6, R6 and R7, R7 and R8 or R8 and R9 are joined together to form a 5-6-7 membered saturated or unsaturated ring, which is optionally substituted at any carbon atom by halo, alkyl from 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, amino, N-alkylamino of 1 to 6 carbon atoms, or N, N-dialkylamino of 1 to 6 carbon atoms, and which may contain one or more heteroatoms selected from oxygen, sulfur or nitrogen, where the sulfur atoms can optionally be oxidized to a sulfur oxide, where any CH2 group can be replaced by a C (O) group, and where the nitrogen atoms, depending on the valence considerations, can be substituted by a group R21, where R2 is selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms; 27. R4 is a group of sub-formula (iia) (iiia) wherein R6, R7, and R8 are independently selected from: hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, of 2 to 8 atoms carbon alkynyl, aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-alkyl of 1 to 6 carbon atoms (including heteroaryl-1-alkyl) 6 carbon atoms) and wherein any aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-alkyl groups of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) are optionally substituted at any carbon atom by halo, hydroxy, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, carbon alkoxy of 1 to 6 atoms, alkylcarbonyl of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, or ?,? - dialkylamino of 1 to 6 carbon atoms and any nitrogen atom present in the heterocyclyl portions can, depending on the valence considerations, be replaced by a selected group of hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl from 1 to 6 carbon atoms, (b) a group of sub-formula (iv): -X2-R14 (iv) where X2 is selected from O, NR16, S, SO, S02, OSOz, CO, C (0) ) 0, OC (O), CH (OR16), CON (R16), N (R16) CO, -N (R16) C (0) N (R16) -, -N (R16) C (0) 0- , SON (R16), N (R16) SO, S02N (R16), N (R6) S02, C (R16) 20, C (R6) 2S and N (R16) C (R16) 2, where each R16 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl , carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, or a mono- or bicyclic heterocyclyl ring of 4 to 8 members (including 5- or 6-membered heteroaryl rings) or heterocyclyl-alkyl groups of 1 to 6 mono- or bicyclic carbon atoms of 4 to 8 members (including heteroaryl-alkyl groups of 1 to 6 carbon atoms of 4 to 8 members) and in wherein any aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-alkyl groups of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6) carbon atoms) is optionally substituted on any carbon atom by oxo, halo, cyano, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, or can?,? - dialkylamino of 1 to 6 carbon atoms and any nitrogen atom present in the heterocyclyl portions, depending on the valence considerations, is You can replace with a group you select of hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and wherein any sulfur atom may optionally be oxidized to a sulfur oxide; (c) a group of sub-formula (v): -X3-R15-Z (v) where X3 is a direct bond or is selected from O, NR17, S, SO, S02, OS02) CO, C (0) 0, OC (O), CH (OR17), CON (R17), N (R17) CO, -N (R17) C (0) N (R17) -, -N (R17) C (0) 0-, S02N (R17), N (R17) S02, C (R17) 20, C (R17) 2S and N (R17) C (R17) 2, wherein each R17 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; R 5 is an alkylene of 1 to 6 carbon atoms, alkenylene of 2 to 6 carbon atoms or alkynylene of 2 to 6 carbon atoms, arylene, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl (including heteroaryl), which may be optionally substituted by one or more groups selected from halo, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, amino, alkylamino of 1 to 6 carbon atoms or (some 1 to 6 carbon atoms) amino; Z is halo, trifluoromethyl, cyano, nitro, aryl, carbocyclyl of 3 to 12 carbon atoms or heterocyclyl (including heteroaryl) optionally having 1 to 2 substituents, which may be the same or different, selected from halo, alkyl from 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and alkoxy of 1 to 6 carbon atoms and wherein any heterocyclyl group within Z optionally has 1 or 2 oxo substituents, or Z is a group of sub-formula (vi) -X4-R18 (vi) where X4 is selected from O, NR19, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR19) , CON (R19), N (R19) CO, S02N (R19), -N (R19) C (0) N (R19) -, -N (R19) C (0) 0-N (R19) S02, C (R19) 20, C (R9) 2S and N (R19) C (R9) 2, wherein each R19 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; and R18 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl) or heterocyclyl-alkyl of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) optionally having 1 or 2 substituents, which may be the same or different, selected from halo, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and alkoxy of 1 to 6 carbon atoms, and wherein any heterocyclyl group within R18 has optionally 1 or 2 oxo substituents; or (d) R6 and R7, or R7 and R8 are joined together to form a saturated, or unsaturated, 5-, 6- or 7-membered fused ring, which is optionally substituted on any carbon atom by halo, alkyl of 1 to 6 carbon atoms. carbon, hydroxyalkyl of 1 to 6 carbon atoms, amino, N-alkylamino of 1 to 6 carbon atoms, or α, β-dialkylamino of 1 to 6 carbon atoms, and which may contain one or more heteroatoms selected from oxygen, sulfur or nitrogen, where the sulfur atoms can optionally be oxidized to a sulfur oxide, where any CH2 group can be replaced by a C (O) group, and where the nitrogen atoms, depending on the valence considerations, can be replace with a group R21, where R2 is selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms. 28. R4 is a group of sub-formula (iiia): (iiia) wherein R6, R7, and R8 are independently selected from: hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, heterocyclyl (including heteroaryl), and wherein any aryl or heterocyclyl group (including heteroaryl) is optionally substituted on any carbon atom by halo, hydroxy, cyano, amino, alkyl of 1 to 6 carbon atoms , hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and any nitrogen atom present in the heterocyclyl portions, depending on the valence considerations, can be substituted by a group selected from hydrogen, alkyl of 1 to 6 carbon atoms. to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms; (b) a group of sub-formula (iv): -X2-R14 (iv) where X2 is selected from O, NR16, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR16), CON (R16), N (R16) CO, SON (R16), N (R16) SO, S02N (R16), and N (R6) SOz, where each R16 is independently selected from hydrogen or alkyl from 1 to 6 carbon atoms, R14 is hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms carbon, or a 4- to 8-membered mono- or bicyclic heterocyclyl ring (including 5- or 6-membered heteroaryl rings) and wherein any aryl, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl groups (including heteroaryl) are optionally substituted in any carbon atom by oxo, halo, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, N-alquilamin or from 1 to 6 carbon atoms, or?,? -di-alkylamino of 1 to 6 carbon atoms and any nitrogen atom present in the heterocyclyl portions, depending on the valence considerations, can be replaced by a selected group of hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and wherein any sulfur atom may be optionally oxidized to sulfur oxide; (c) a group of sub-formula (v): -X3-R, 5-Z (v) where X3 is a direct bond or is selected from O, NR17, S, SO, S02l OS02, CO, C (0) ) 0, OC (O), CON (R17), N (R17) CO, S02N (R17), and N (R17) S02, wherein each R7 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; R15 is an alkylene of 1 to 6 carbon atoms, alkenylene of 2 to 6 carbon atoms or alkynylene of 2 to 6 carbon atoms, arylene, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl (including heteroaryl), any of which can be optionally substituted by one or more groups selected from halo, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, amino, alkylamino of 1 to 6 carbon atoms or di- (alkyl 1 to 6 carbon atoms) amino; Z is halo, trifluoromethyl, cyano, nitro, aryl, or heterocyclyl (including heteroaryl) optionally having 1 or 2 substituents, which may be the same or different, selected from halo, and alkoxy having from 1 to 6 carbon atoms and wherein any heterocyclyl group within Z optionally has 1 or 2 oxo substituents, or Z is a sub-formula group (vi) -X4-18 (vi) wherein X4 is selected from O, NR19, S, SO, S02, OS02, CO, C (0) 0, OC (O), CON (R19), N (R19) CO, S02N (R19), and N (R19) S02, wherein each R19 is independently selected from hydrogen or alkyl of 1 to 4 carbon atoms; and R18 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, aryl, or heterocyclyl (including heteroaryl) optionally having 1 or 2 substituents, which may be the same or different, selected from halo, alkyl of 1 to 6 carbon atoms, and alkoxy of 1 to 6 carbon atoms, and wherein any heterocyclyl group within R18 optionally has 1 or 2 oxo substituents; 29. R4 is a group of sub-formula (iiib): (Ib) wherein at least one of R6 and R8 is a 5-, 6- or 7-membered heterocyclic ring that binds to nitrogen and the other is independently selected from: hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro , alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, aryl, heterocyclyl (including heteroaryl), and wherein any aryl or heterocyclyl group (including heteroaryl) is optionally substituted in any carbon atom by halo, hydroxy, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and any nitrogen atom present in the heterocyclyl portions, depending on the the valence considerations can be substituted by a selected group of hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms; (b) a group of sub-formula (iv) -X2-R14 (iv) where X2 is selected from O, NR 6, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR16), CON (R16), N (R16) CO, SON (R16), N (R16) SO, S02N (R16), and N (R16) S02, where each R6 is independently selected from hydrogen or alkyl 1 to 6 carbon atoms, R14 is hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, or 4- to 8-membered mono- or bicyclic heterocyclyl ring (including 5- or 6-membered heteroaryl rings) and wherein any aryl, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl groups (including heteroaryl) are optionally substituted at any carbon atom by oxo , halo, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, o N, N-dialkylamino of 1 to 6 carbon atoms and any nitrogen atom present in the heterocyclyl portions, depending on the valence considerations, can be substituted by a group selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and wherein any sulfur atom can optionally be oxidized to a sulfur oxide; (c) a group of sub-formula (v): -X3-R15-Z (v) where X3 is a direct bond or is selected from O, NR17, S, SO, S02, OS02, CO, C (0) 0, OC (O), CON (R17), N (R17) CO, S02N (R17), and N (R17) S02, wherein each R7 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; R15 is a C1-C6alkylene, alkenylene of 2 to 6 carbon atoms or alkynylene of 2 to 6 carbon atoms, arylene, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl (including heteroaryl), any of which it may be optionally substituted by one or more groups selected from halo, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, amino, alkylamino of 1 to 6 carbon atoms or di- (alkyl) from 1 to 6 carbon atoms) amino; Z is halo, trifluoromethyl, cyano, nitro, aryl, or heterocyclyl (including heteroaryl) optionally having 1 or 2 substituents, which may be the same or different, selected from halo, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms and wherein any heterocyclyl group within Z optionally has 1 or 2 oxo substituents, or, Z is a group of sub-formula (vi) -X4-R18 (vi) wherein X4 is selected from O, NR19, S , SO, S02, OS02, CO, C (0) 0, OC (O), CON (R19), N (R19) CO, S02N (R19), and N (R19) S02, where each R19 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; and R18 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, aryl, or heterocyclyl (including heteroaryl) optionally having 1 or 2 substituents, which may be the same or different, selected from halo, alkyl of 1 to 6 carbon atoms. carbon, and alkoxy of 1 to 6 carbon atoms, and wherein any heterocyclyl group within R18 optionally has 1 or 2 oxo substituents; 30. R4 is a group of sub-formula (iiib): (iiib) wherein at least one of R and R is a 5- or 6-membered heterocyclic ring that binds to nitrogen and the other is independently selected from: hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl 1 to 6 carbon atoms, alkenyl 2 to 8 carbon atoms, alkynyl 2 to 8 carbon atoms, aryl, heterocyclyl (including heteroaryl), and wherein any aryl or heterocyclyl group (including heteroaryl) is optionally substituted at any carbon atom by halo , hydroxy, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and any nitrogen atom present in the heterocyclic portions, depending on the valence considerations , it can be substituted by a selected group of hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms; (b) a group of sub-formula (iv) -X2-R14 (iv) where X2 is selected from O, NR16, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR16), CON (R16), N (R6) CO, SON (R16), N (R6) SO, S02N (R16), and N (R16) S02, where each R16 is independently selected from hydrogen or alkyl 1 to 6 carbon atoms, R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, or a 4- to 8-membered mono- or bicyclic heterocyclyl ring (including 5- or 6-membered heteroaryl rings) and wherein any aryl, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl groups (including heteroaryl) are optionally substituted at any carbon atom by oxo, halo, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms , or N, N-dialkylamino of 1 to 6 carbon atoms and any nitrogen atom present in the heterocyclyl portions, depending on the valence considerations, can be substituted by a group selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and wherein any sulfur atom can optionally be oxidized to a sulfur oxide; (c) a group of sub-formula (v): -X3-R1S-Z (v) where X3 is a direct bond or is selected from O, NR17, S, SO, S02, OS02, CO, C (0) 0, OC (O), CON (R17), N (R7) CO, S02N (R17), and N (R17) S02, wherein each R17 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; R15 is a C1-C6alkylene, alkenylene of 2 to 6 carbon atoms or alkynylene of 2 to 6 carbon atoms, arylene, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl (including heteroaryl), any of which it may be optionally substituted by one or more groups selected from halo, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, amino, alkylamino of 1 to 6 carbon atoms or di- (alkyl) from 1 to 6 carbon atoms) amino; Z is halo, trifiuoromethyl, cyano, nitro, aryl, or heterocyclyl (including heteroaryl) optionally having 1 or 2 substituents, which may be the same or different, selected from halo, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms and wherein any heterocyclyl group within Z optionally has 1 or 2 oxo substituents, or, Z is a group of sub-formula (vi) -X4-R18 (vi) wherein X4 is selected from O, NR19, S , SO, S02, OS02, CO, C (0) 0, OC (O), CON (R19), N (R19) CO, S02N (R19), and N (R19) S02, where each R 9 is independently selected of hydrogen or alkyl of 1 to 6 carbon atoms; and R18 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, aryl, or heterocyclyl (including heteroaryl) optionally having 1 or 2 substituents, which may be the same or different, selected from halo, alkyl of 1 to 6 carbon atoms. carbon, and alkoxy of 1 to 6 carbon atoms, and wherein any heterocyclyl group within R18 optionally has 1 or 2 oxo substituents; 31. R4 is a group of sub-formula (iiib): (iiib) wherein at least one of R6 and R8 is morpholin-4-yl and the other is independently selected from: hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkenyl 2 to 8 carbon atoms, aryl, heterocyclyl (including heteroaryl), and wherein any aryl or heterocyclyl group (including heteroaryl) is optionally substituted at any carbon atom by halo, hydroxy, cyano, amino, alkyl 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and any nitrogen atom present in the heterocyclyl portions, depending on the valence considerations, can be replaced by a group selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms; (b) a group of sub-formula (iv) -X2-R14 (iv) where X2 is selected from O, NR16, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR16), CON (R16), N (R16) CO, SON (R16), N (R16) SO, S02N (R16), and N (R16) S02, wherein each R16 is independently selected from hydrogen or alkyl 1 to 6 carbon atoms, R14 is hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, or a heterocyclyl ring mono- or bicyclic 4 to 8 members (including 5 or 6 membered heteroaryl rings) and wherein any aryl, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl groups (including heteroaryl) are optionally substituted at any carbon atom by oxo, halo , cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, or ?,? - dialkylamino of 1 to 6 carbon atoms and any nitrogen atom present in the heterocyclyl portions, depending on the valence considerations, can be substituted by a group selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and wherein any sulfur atom can optionally be oxidized to a sulfur oxide; (c) a group of sub-formula (v): -X3-R15-Z (v) where X3 is a direct bond or is selected from O, NR17, S, SO, S02, OS02, CO, C (0) 0, OC (O), CON (R17), N (R17) CO, S02N (R17), and N (R17) S02, wherein each R17 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; R15 is a C1-C6alkylene, alkenylene of 2 to 6 carbon atoms or alkynylene of 2 to 6 carbon atoms, arylene, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl (including heteroaryl), any of which it may be optionally substituted by one or more groups selected from halo, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, amino, alkylamino of 1 to 6 carbon atoms odi - (a I or 1 to 6 carbon atoms) amino; Z is halo, trifiuoromethyl, cyano, nitro, aryl, or heterocyclyl (including heteroaryl) optionally having 1 or 2 substituents, which may be the same or different, selected from halo, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms and wherein any heterocyclyl group within Z optionally has 1 or 2 oxo substituents, or, Z is a group of sub-formula (vi) -X4-R18 (vi) wherein X4 is selected from O, NR19, S , SO, S02, OS02, CO, C (0) 0, OC (O), CON (R19), N (R19) CO, S02N (R19), and N (R19) SOz, where each R 9 is independently selected of hydrogen or alkyl of 1 to 6 carbon atoms; and R18 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, aryl, or heterocyclyl (including heteroaryl) optionally having 1 or 2 substituents, which may be the same or different, selected from halo, alkyl of 1 to 6 carbon atoms. carbon, and alkoxy of 1 to 6 carbon atoms, and wherein any heterocyclyl group within R 8 optionally has 1 or 2 oxo substituents; 32. R4 is a group of sub-formula (iiib): wherein at least one of R6 and R8 is morpholin-4-yl and another is independe selected from: hydrogen, halo, trifluoromethyl, cyano, alkyl of 1 to 4 carbon atoms, phenyl, 5- or 6-membered heterocyclyl (including heteroaryl) comprising one or more heteroatoms selected from N, from O or S, and wherein any alkyl group of 1 to 4 carbon atoms, aryl or heterocyclyl (including heteroaryl) is optionally substituted on any available atom of carbon by halo, hydroxy, cyano, amino, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, and any nitrogen atom present in the heterocyclyl portions, depending on the considerations of valence, can be substituted by a group selected from hydrogen, alkyl of 1 to 6 carbon atoms or 1 to 4 carbon atoms alkylcarbonyl; or (b) a sub-formula group (iv): -X2-R14 (iv) where X2 is selected from O, NR16, S, SO, S02, OS02, CO, CON (R16), N (R16) CO , SON (R16), N (R6) SO, S02N (R16), and N (R16) S02, wherein each R16 is independe selected from hydrogen or alkyl of 1 to 4 carbon atoms, R14 is hydrogen, or alkyl of 1 to 6 carbon atoms; 33. R4 is a group of sub-formula (iiib): (iüb) wherein R6 and R8 are 5 or 6 membered heterocyclic rings attached to nitrogen; 34. R4 is a group of sub-formula (iiib): (iiib) wherein R6 and R8 are morpholin-4-?? In a particular group of the compounds of the invention, R1 is hydrogen or an alkyl group as defined in paragraphs (9) to (12) above (particularly methyl) and ring A, R3, n, and R4 have the definitions established in this.

In a particular additional group of the compounds of the invention, R1 is an alkyl group as defined in the above paragraphs (14) to (16), particularly a methyl group, and the ring A, R3, n, and R4 have the definitions set forth herein. In a further group of the compounds of the invention, R 4 is a subgroup of formula (iiib) as defined in the preceding paragraphs (29) to (34), and particularly a subgroup of formula (iüb) as defined in the paragraphs previous (33) to (34), and ring A, R1, R3, and n have the definitions set forth herein. In a further group of the compounds of the invention: R1 is an alkyl group as defined in the above paragraphs (14) to (16), particularly a methyl group, R4 is a subgroup of formula (iiib) as defined in previous paragraphs (29) to (34), and particularly a subgroup of formula (iiib) as defined in the preceding paragraphs (33) to (34), and ring A, R1, R3, and n have the definitions set forth in I presented. The compounds of formula I describe the first aspect of the above invention all with the proviso that if ring A, together with the phenyl ring to which it is attached, forms an indazol-4-yl group, then R1 is not hydrogen. Convenie, the compounds of formula (I) defined in the second aspect of the invention are also subjected to such a condition. This condition excludes the compounds of the structural formula shown below: wherein R1 is hydrogen. A particular group of compounds of formula I is under the condition that if ring A, together with the phenyl ring to which it is attached, forms an indazol-4-yl group, then R1 is an alkyl group of 1 to 6 carbon atoms , particularly an alkyl group of 1 to 2 carbon atoms, and more particularly methyl. A further group of compounds of formula I is under the condition that if ring A together with the phenyl ring to which it is attached forms an indazolyl group, then R1 is an alkyl group of 1 to 6 carbon atoms, particularly an alkyl group 1 to 2 carbon atoms and more particularly methyl. A particular group of compounds of formula I is under the condition that, if ring A, together with the phenyl ring to which it is attached, forms an indazol-4-yl group, then R 1 is an alkyl group of 1 to 6 carbon atoms. carbon, particularly an alkyl group of 1 to 2 carbon atoms, and more particularly methyl, and R 4 is a subgroup of formula (iiib) as defined in the preceding paragraphs (29) to (34), and particularly a subgroup of formula (iiib) as defined in the preceding paragraphs (33) to (34). A particular group of compounds of the invention has the general structural formula (ID) shown below (ID) wherein R is an alkyl group of 1 to 6 carbon atoms, which is optionally substituted with one or more substituents selected from cyano, -OR2, -NR2aR2b, wherein R2, R2a and R2b are selected from hydrogen or alkyl of 1 to 2 carbon atoms; and R3, n, R22, and R4 have the definitions set forth herein. In a particular group of compounds of formula (ID), • R1 is as defined in the preceding paragraphs (14) to (16), • R22 is as defined in the preceding paragraphs (1) to (8), • R3, if present, is as defined in paragraphs previous (21) to (25), • n is as defined in the preceding paragraphs (17) to (20), and · R4 is as defined in the preceding paragraphs (26) to (34). In compounds of formula (ID), R1 is conveniently an alkyl group as defined in preceding paragraphs (14) to (16) above. In particular compounds of formula (ID), R1 is methyl. In compounds of formula (ID), n is conveniently 0 or 1, particularly 0. In compounds of formula (ID), R22 is conveniently hydrogen, halo, or alkyl of 1 to 2 carbon atoms, and is especially hydrogen, methyl or chloro . In compounds of formula (ID), R4 is conveniently a phenyl group as defined in the preceding paragraphs (26) to (34), and particularly a phenyl group as defined in the preceding paragraphs (29) to (34), and more particularly a phenyl group as defined in the preceding paragraphs (33) or (34). In a particular subgroup of compounds of formula (ID): R1 is an alkyl group as defined in preceding paragraphs (14) to (16) above; • n is 0; · R22 is hydrogen, halo, or alkyl of 1 to 2 carbon atoms; and • R4 is a phenyl group as defined in the preceding paragraphs (29) to (34). In a more particular subgroup of compounds of formula (ID): • R1 is methyl; • n is 0; • R22 is hydrogen, methyl or chlorine; and • R4 is a phenyl group as defined in the preceding paragraphs (33) or (34). A particular additional group of the compounds of the invention has the general structural formula (IE) shown below (IE) wherein R1, R22, R3, n, and R4 have any of the definitions set forth herein. In a particular group of compounds of formula (IE), • R1 is as defined in the preceding paragraphs (9) a (16), • R22 is as defined in the preceding paragraphs (1) to (8), • R3, if present, is as defined in the preceding paragraphs (21) to (25), • n is as defined in the preceding paragraphs (17) to (20), and • R4 is as defined in the preceding paragraphs (26) to (34). In the compounds of formula (IE), R 1 is conveniently hydrogen or alkyl of 1 to 2 carbon atoms, particularly methyl. In a particular group of compounds of formula (IE), R1 is methyl. In compounds of formula (IE), n is conveniently 0 or 1, particularly 0. In compounds of formula (IE), R22 is conveniently hydrogen, halo, or alkyl of 1 to 2 carbon atoms, and is especially hydrogen, methyl or chloro . In compounds of formula (IE), R4 is conveniently a phenyl group as defined in the preceding paragraphs (26) to (34), and particularly a phenyl group as defined in the preceding paragraphs (29) to (34), and more particularly a phenyl group as defined in the preceding paragraphs (33) or (34). In a particular subgroup of compounds of formula (IE): R is hydrogen or an alkyl group as defined in the preceding paragraphs (14) to (16); • n is 0; • R is hydrogen, halo, or alkyl of 1 to 2 carbon atoms; and • R4 is a phenyl group as defined in the preceding paragraphs (29) to (34). In a more particular subgroup of compounds of formula (IE): • R is methyl; • n is 0; • R22 is hydrogen, methyl or chlorine; and • R4 is a phenyl group as defined in the preceding paragraphs (33) or (34). A further particular group of compounds of the invention has the general structural formula (IF) shown below wherein R1, R22, R3, n, and R4 have any of the definitions set forth herein. In a particular group of the compound formula (IF), • R1 is as defined in the preceding paragraphs (9) a (16), • R is as defined in the preceding paragraphs (1) to (8), • R3, if present, is as defined in the preceding paragraphs (21) to (25), • n is as defined in the preceding paragraphs (17) to (20) above, and • R4 is as defined in the preceding paragraphs (26) to (34). In compounds of formula (IF), R 1 is conveniently hydrogen or alkyl of 1 to 2 carbon atoms, particularly methyl. In a particular group of compounds of formula (IE), R1 is methyl. In compounds of formula (IF), n is conveniently 0 or 1, particularly 0. In compounds of formula (IF), R 22 is conveniently hydrogen, halo, or alkyl of 1 to 2 carbon atoms, and is especially hydrogen, methyl or chloro . In compounds of formula (IF), R4 is conveniently a phenyl group as defined in the preceding paragraphs (26) to (34), and particularly a phenyl group as defined in the preceding paragraphs (29) to (34), and more particularly a phenyl group as defined in the preceding paragraphs (33) or (34). In a particular subgroup of compounds of formula (IF): R1 is hydrogen or an alkyl group as defined in the preceding paragraphs (14) to (16); • n is 0; • R is hydrogen, halo, or alkyl of 1 to 2 carbon atoms; and • R4 is a phenyl group as defined in the preceding paragraphs (29) to (34). In a more particular subgroup of compounds of formula (IF): • R1 is methyl; • n is 0; • R22 is hydrogen, methyl or chlorine; and • R4 is a phenyl group as defined in the preceding paragraphs (33) or (34). A further particular group of the compounds of the invention has the general structural formula (IG) shown below (IG) wherein R1, R22, R3, n, and R4 have any of the definitions set forth herein. In a particular group of compounds of formula (IG), • R1 is as defined in the preceding paragraphs (9) a (16), • R is as defined in the preceding paragraphs (1) to (8), • R3, if present, is as defined in the preceding paragraphs (21) to (25), · n is as defined in the previous paragraphs (17) a (20), and • R4 is as defined in the preceding paragraphs (26) to (34). In the compounds of formula (IG), R 1 is conveniently hydrogen or alkyl of 1 to 2 carbon atoms, particularly methyl. In a particular group of compounds of formula (IE), R1 is methyl. In the compounds of formula (IG), n is conveniently 0 or 1, particularly 0. In the compounds of formula (IG), R22 is conveniently hydrogen, halo, or alkyl of 1 to 2 carbon atoms, and is especially hydrogen, methyl or chlorine. In compounds of formula (IG), R4 is conveniently a phenyl group as defined in the preceding paragraphs (26) to (34), and particularly a phenyl group as defined in the preceding paragraphs (29) to (34), and more particularly a phenyl group as defined in the preceding paragraphs (33) or (34) above. In a particular subgroup of compounds of formula (IG): R1 is hydrogen or an alkyl group as defined in the preceding paragraphs (14) to (16); • n is 0; • R22 is hydrogen, halo, or alkyl of 1 to 2 carbon atoms; and • R4 is a phenyl group as defined in the preceding paragraphs (29) to (34) above. • In a more particular subgroup of compounds of formula (IG): • R1 is methyl; • n is 0; • R22 is hydrogen, methyl or chlorine; and • R4 is a phenyl group as defined in the preceding paragraphs (33) or (34). Particular compounds of the invention include any of the following: N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (3,4,5-trimethoxyphenyl) pyrimidine-2,4 -diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (2-chlorophenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2-1 H -indazol-6-ylpyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2-phenylpyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (2-fluorophenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (3-fluorophenyl) pyrimidine-2,4-d-amine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (4-f I o rof e n i I) p i r i m i d i n a -2, 4-d i a m i n a; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (3-ethynylphenyl) pyrimidine-2,4-diamine; 3- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl} amino) benzonitrile; 4- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl.} Amino) benzonitrile; [3- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) arnino] pyrirnidin-2-yl} amino) phenyl] methanol; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (4-methoxyphenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (3-chlorophenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (4-chlorophenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (2,4-difluorophenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (3,5-difluorophenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2-1 H-indol-5-i I p i r i m i d i n a - 2, 4 - d i a m i n a; [4- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl] amino) phenol] acetonitrile; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2-1 H -indol-4-yl-pyrimidine-2,4-d-amine; 3- ( { 4 - [(5-Chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl} amino) benzamide; 4- ( { 4 - [(5-chloro-1,3-benzodioxol-4-M) amino] pyrimidin-2-yl} amino) benzamide; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2-1 H-indol-6-ylpyridin-2,4-d-amine; 3- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl} amino) -N- (2-methoxyethyl) benzamide; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- [4- (pyridin-2-ylmethoxy) phenyl] pyrimidine-2,4-diamine; 1 - [4- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl} amino) phenyl] -N-methylmethanesulfonamide; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- [3- (2-pyrrolidin-1-ylethoxy) phenyl] pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (3-chloro-4-morpholin-4-ylphenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- [4- (2-morpholin-4-ylethoxy) phenyl] pyrimidine-2,4-diamine; 4- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl} amino) -N- (2-hydroxyethyl) -N-methylbenzenesulfonamide; 4- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl}. Amino) -N- [2- (diethylamino) ethyl] benzamide; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2-. { 4- [2- (4-methyl-piperazin-1-yl) -ethoxy] -phenyl} pyrimidine-2,4-d-amine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2-. { 4 - [(3-Fluorobenzyl) oxy] -3-methoxyphenyl} pyrimidine-2,4-d-amine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2-. { 4 - [(2-Fluorobenzyl) oxy] -3-methoxyphenyl} pyrimidine-2,4-d-amine; 4- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl} amino) -N- (2-methoxyethyl) benzenesulfonamide; N- [4- ( { 4 - [(5-chloro-1,3-benzodioxol-4-M) amino] pyrimidin-2-yl} amino) phenyl] -N-methylacetamide; N- [5- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl} amino) -2-methylphenyl] acetamide; N- [4- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl} amino) benzyl] acetamide; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- [3- (methylsulfonyl) phenyl] pyrimidine-2,4-diamine; 4- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl} amino) benzenesulfonamide; 3- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl} amino) benzenesulfonamide; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- [4- (trifluoromethoxy) phenyl] pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (4-morpholin-4-ylphenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (2-morpholin-4-ylphenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (3-morpholin-4-ylphenyl) pyrimidine-2,4-d-amine; N-4- (5-chloro-1,3-benzodioxol-4-M) -N-2- [4- (2-ethoxyethoxy) phenyl] pyrimidina-2,4-d-amine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (2,3,4-trimethoxyphenyl) pyrimidine-2,4-diamine; N- [3- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidine-2-yl} amino) phenyl] methanesulfonamide; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- [3- (dimethylamino) phenyl] pyrimidine-2,4-diamine; 2- [4- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl} amino) phenyl] ethanol; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (3-chloro-4-fluorophenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (4-chloro-2-fluorophenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (3-chloro-2-fluorophenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (5-chloro-2-fluorophenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (4-chloro-3-fluorophenyl) pyrimidine-2,4-diamine; 5- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl}. Amino) -1,3-dihydro-2H-indol-2-one; N- [4- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl}. Aniino) phenyl] acetamide; 3- ( { 4 - [(5-Chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl}. Amino) -N-methylbenzamide; 4- ( { 4 - [(5-chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl}. Amino) -N-methylbenzamide; N-2-1, 3-benzothiazol-6-yl-N-4- (5-chloro-1,3-benzodioxol-4-yl) pyrimidine-2,4-d-amine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (2,5-dimethoxyphenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (2,4-dimethoxyphenyl) pyrimidin-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (3,5-dimethoxyphenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (3,4-dimethoxyphenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (5-chloro-2-methoxyphenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (2-chloro-5-methoxyphenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- (3-chloro-2-methoxyphenyl) pyrimidine-2,4-diamine; N-4- (5-chloro-1,3-benzodioxol-4-yl) -N-2- [3- (1, 3-oxazol-5-yl) phenyl] pyrimidine-2,4-diamine; N-4- (1 H -indazol-7-yl) -N-2- (3,4,5-trimethoxyphenyl) pyrimidine-2,4-diamine; N '- (1 -methylindol-4-yl) -N- (3,4,5-trimethoxyphenyl) -pyrimidine-2,4-d i a m a n a; N '- (5-bromobenzo [1,3] dioxol-4-yl) -N- (3,4,5-trimethoxyphenyl) -pyrimidine-2,4-diamine; N '-benzo [1,3] dioxol-4-yl-N- (3,4,5-trimethoxyphenyl) -pyrimidine-2,4-diamine; N '- (5-fluorobenzo [1,3] dioxol-4-yl) -N- (3,4,5-trimethoxyphenyl) -pyrimidine-2,4-di amine; N '- (2,2-difluorobenzo [1,3] dioxol-4-yl) -N- (3,4,5-trimethoxyphenyl) -pyrimidine-2,4-diamine; 1 - [7- [2- (3,4,5-Trimetoxy-phenyl) aminopyrimidin-4-yl] amino-2,3-dihydroindol-1-yl] ethanone; N '- (1 H -indol-4-yl) -N- (3,4,5-trimethoxyphenyl) -pyrimidine-2,4-diamine; N '- (6-chlorobenzofuran-7-yl) -N- (3-methylsulfonylphenyl) pyrimidine-2,4-diamine; N '- (2,3-dihydrobenzofuran-7-yl) -N- (3-methylsulfonylphenyl) pyrimidine-2,4-diamine; N '- (benzofuran-7-yl) -N- (3-methylsulfonylphenyl) pyrimidine-2,4-d i a m a n a; N '- (1 H-benzotriazol-4-yl) -N- (3-methylsulfonylphenyl) pyrimidine-2,4-diamine; N '- (3-chloro-1 H -indol-7-yl) -N- (3-methylsulfonylphenyl) pyrimidine-2,4-diamine; N '- (6-methoxybenzo [1,3] dioxol-4-M) -N- (3-methylsulfonylphenyl) pyrimidine-2,4-diamine; 4 - [[2 - [(3-methylsulfonylphenyl) amino] pyrimidin-4-yl] amino] benzo [1,3] dioxol-5-carboxamide; N, -isoquinolin-5-yl-N- (3-methylsulfonylphenyl) pyrimidine-2,4-diamine; N'-benzooxazol-7-yl-N- (3-methylsulfonMphenyl) pyrimidine-2,4-diamine; N'-benzooxazol-4-yl-N- (3-methylsulfonylphenyl) pyrimidine-2,4-diamine; 3- [4- (1 H -indazol-4-yl-methyl-amino) pyrimidin-2-yl] -N, N-dimethyl-benzamide; N-methyl-N- [2- (3-methylsulfonylphenyl) pyrimidin-4-yl] -1 H -indazol-4-amine; 3- [4- (1 H -indazol-4-yl-methyl-amino) pyrimidin-2-yl] benzenesulfonamide; [3- [4- (1 H -indazol-4-yl-methyl-amino) pyrimidin-2-yl] phenyl] methanol; N- [3- [4- (1 H -indazol-4-yl-methyl-amino) pyrimidin-2-yl] phenyl] methanesulfonamide; N - ^. S-dimorpholinopheni-N'-O H -indazol-4-yl) -N'-methyl-pyrimidine-2,4-diamine; [4 - [[2 - [(3,5-dimorpholin-4-ylphenyl) amino] pyrimidin-4-yl] amino] -1 H -indazol-6-yl] methanol; N- (3,5-dimorpholinophenyl) -N '- (3-methyl-1 H -indazol-4-yl) pyrimidine-2,4-diamine; N, -benzooxazol-7-yl-N- (3,5-d¡mo-pholin-4-ylphenyl) pyrimidine-2,4-diamine; N'-benzooxazol-7-yl-N- (3,5-dimorpholinophenyl) -N'-methyl-pyrimidine-2,4-d-amine; N- (3,5-dimorpholin-4-ylphenyl) -N, -methyl-N '- (3-methyl-1 H -indazol-4-yl) pyrimidine-2,4-diamine; N'-methyl-N'-IS-methyl-1 H -indazol-4-yl) -N- (3-methylsulfonylphenyl) pyrimidine-2,4-diamine; N- (3,5-dimorpholin-4-ylphenyl) -N'-quinolin-5-yl-pyrimidine-2,4-diamine; N '- (2,2-difluorobenzo [1,3] dioxol-4-yl) -N- (3,5-dimorpholin-4-ylphenyl) pyrimidine-2,4-diamine; N- (3,5-dimorfoMn-4-ylphenyl) -N '- (1 H -indol-4-yl) pyrimidine-2,4-diamine; N- (3,5-dimorpholin-4-ylphenyl) -N '- (2,5-dioxabicyclo [4.4.0] deca-6,8,10-trien-10-yl) pyrimidine-2,4-diamine; N '- (1 H-benzotriazol-4-yl) -N- (3,5-dimorpholin-4-i I f e n i I) p i ri m i d i n a-2, 4-d i a m a n; N '- (3-chloro-1 H -indol-7-yl) -N- (3,5-dimorpholin-4-ylphenyl) pyrimidine-2,4-diamine; N- (3,5-dimorpholin-4-ylphenyl) -N '- (1 H -indazol-7-yl) pyrimidine-2,4-diamine; or a pharmaceutically acceptable salt thereof. A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid addition salt of a compound of the invention which is sufficiently basic, for example, an acid addition salt, for example, an inorganic acid or organic, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic acid. Furthermore, a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which produces a physiologically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine. The compounds of the invention can be administered in the form of a prodrug which is a compound that is analyzed in the human or animal body to release a compound of the invention. A prodrug can be used to alter the physical characteristics and / or the pharmacokinetic characteristics of a compound of the invention. A prodrug can be formed when the compound of the invention contains a group or a convenient substituent to which a property modification group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed into a carboxy group or a hydroxy group in a formula compound (I) and the amide derivatives in vivo cleavable which can be formed into a carboxy group or an amino group in a compound formula (I). Therefore, the present invention includes the compounds of formula (I) as defined above when available by organic synthesis and when available within the human or animal body by division of a prodrug thereof. Therefore, the present invention includes the compounds of formula (I) that are produced by synthetic organic means and also such compounds that are produced in the human or animal body by metabolizing a precursor compound, i.e. a compound of formula ( I) can be a compound produced synthetically or a compound produced by metabolization. A suitable pharmaceutically acceptable prodrug of a compound formula (I) is one that is based on reasonable medical judgment that is suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzvmoloqy. Vol. 42, p. 309-396, published by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, published by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, published by Krogsgaard-Larsen and H. Bundgaard, Chapter 5"Design and Application of Pro-drugs", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Druq Delivery Reviews. 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences. 77, 285 (1988); f) N. Kakeva. v col .. Chem. Pharm. Bull .. 32. 692 M984): g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and h) E. Roche (ed.), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987. A suitable pharmaceutically acceptable prodrug of a formula (I) compound having a carboxy group is, for example, an in vivo cleavable ester of the same. An in vivo cleavable ester of a formula (I) compound containing a carboxy group is, for example, a pharmaceutically acceptable ester, which is divided in the human or animal body to produce the original acid. The pharmaceutically acceptable esters suitable for carboxy include alkyl esters (of 1 to 6 carbon atoms) such as methyl, ethyl and tere-butyl alkoxymethyl esters (of 1 to 6 carbon atoms) such as of methoxymethyl esters, pivaloyloxymethyl esters (of 1 to 6 carbon atoms, alkyloyloxymethyl esters 3-phtalidyl esters, cycloalkylcarbonyloxy (of 3 to 8 carbon atoms) -alkyl (of 1 to 6 carbon atoms) such as cyclopentylcarbonyloxymethyl esters and 1-cyclohexylcarbonyloxyethyl, 2-oxo-1 , 3-dioxolenylesters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and alkoxycarbonyloxy (of 1 to 6 carbon atoms) -alkyl (of 1 to 6 carbon atoms) such as rrietoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters A suitable pharmaceutically acceptable prodrug of a formula (I) compound possessing a hydroxy group is, for example, an ester or ether cleavable in vivo thereof An ester or ether in vivo cleavable from a compound of formula I) containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether, which is divided in the human or animal body to produce the original hydroxy compound. Groups for a hydroxy group include inorganic esters such as phosphate esters (including cyclic phosphoramide esters). Additional convenient pharmaceutically acceptable ester forming groups for a hydroxy group includes alkanoyl groups (of 1 to 10 carbon atoms) such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, alkoxycarbonyl groups (of 1 to 10 carbon atoms) ) such as ethoxycarbonyl, N, N- [di (C 1 to C 4) alkyl carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N, N-dialkylaminomethyl, morpholinomethyl, piperazin-1-methylmethyl and 4-alkyl (1 to 4 carbon atoms) piperazin-1-methylmethyl The convenient pharmaceutically acceptable ether forming groups for a hydroxy group includes groups a- acyloxyalkyl such as acetoxymethyl and pivaloyloxymethyl groups A suitable pharmaceutically acceptable prodrug of a formula (I) compound having an amino group is, for example, an amide derivative ividible in vivo of the same. Suitable pharmaceutically acceptable amides of an amino group include, for example, an amide formed with alkanoyl groups (of 1 to 10 carbon atoms) such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, α, β-dialkylaminomethyl, morpholinomethyl, piperazin-1-methylmethyl and 4-alkyl (1 to 4 carbon atoms) piperazin-1-methylmethyl . The in vivo effects of a compound formula (I) can be partially exerted by one or more metabolites that are formed within the human or animal body after administration of a compound formula (I). As indicated above, the in vivo effects of a compound formula (I) can also be exerted by the metabolization of a precursor compound (a prodrug). Preparation of compounds of formula I The synthesis of optically active forms can be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis of the optically active starting materials or by the resolution of a racemic form. The compounds of formula (I) can be prepared by several conventional methods as is evident to a chemist. Particularly, the compounds of formula (I) can be prepared by reacting a compound of formula (II): OI) wherein R4 is as defined in relation to formula (I) with the proviso that any functional group is optionally protected, and L is a leaving group, with a compound formula (III) (III) where A, R1, R3 and n are as defined in relation to formula (I) with the proviso that any functional group is optionally protected. Then, any protecting group can be removed using conventional methods, and if required, the compound of formula (I) can be converted to a different compound of formula (I) or a salt, again using conventional chemical methods. Suitable leaving groups L are halo such as chloro. The reaction is conveniently carried out in an organic solvent such as an alkanol of 1 to 6 carbon atoms, for example, N-butanol, dimethylamine (DMA), or N-methylpyrrolidine (NMP) or mixtures thereof. An acid, particularly, and an inorganic acid such as hydrochloric acid is conveniently added to the reaction mixture. The reaction is conveniently conducted at elevated temperatures for example 80-150 ° C, conveniently at the reflux temperature of the solvent.

The compounds of formula (II) can be prepared by various methods including, for example, where L is a halogen, by the reaction of a compound formula (IV) (IV) where R4 is as defined with reference to formula (I), with a halogenating agent such as phosphorus oxychloride. The reaction is conducted under appropriate reaction conditions for the halogenation agent used. For example, it can be conducted at elevated temperatures, for example 50-100 ° C, in an organic solvent such as acetonitrile or dichloromethane (DCM).

The compounds of formula (IV) are conveniently prepared by reacting a compound of formula (V) (V) with a compound of formula (VI) N I H (VI) where R4 is as defined with reference to formula (I). The reaction is conveniently carried out in an organic solvent such as diglyme, again at elevated temperatures, for example 120-180 ° C, and conveniently at the reflux temperature of the solvent.

Alternatively, the compounds of formula (I) can be prepared by the reaction of a formula compound (VII) (VII) where A, R3 R1 and n are as defined with reference to formula (I) with the proviso that any functional group can optionally be protected, and L is a leaving group as defined with reference to formula (II), with a compound of formula (VI) as defined above. Again any protecting group can be removed using conventional methods, and if required, the compound of formula (I) can be converted to a different compound of formula (I) or a salt, again using conventional chemical methods. The conditions for carrying out such a reaction are broadly similar to those required for the reaction between the compounds (II) and (III). The compounds of formula (VII) are conveniently prepared by reacting a compound of formula (III) as defined above with a compound of formula (VIII) (VIII) where L and L1 are leaving groups such as halogen, and particularly chloro. The reaction is conveniently carried out in the presence of a strong base such as sodium hydride, in an organic solvent such as DMA. The decreased temperatures are conveniently used, for example -20 ° C to 20 ° C, conveniently at about 0 ° C. The compounds of formula (I I I) are known compounds or can be prepared from known compounds using analogous methods, which would be apparent to the skilled chemist. For example, examples of compounds of formula (I I I) and their preparation are described in WO2001094341. It will also be appreciated that in some of the reactions mentioned herein may be necessary / desired to protect any sensitive group in the compounds. For example where protection is necessary or desirable and convenient methods for protection are known to those skilled in the art. Conventional protection groups can be used according to standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Therefore, if the reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein. A suitable protection group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl group, ethoxycarbonyl or t-butoxycarbonyl, an arylmethoxycarbonyl group, example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The conditions of deprotection for the above protection groups necessarily vary with the choice of the protection group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be removed for example, by hydrolysis with a convenient base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group can be removed, for example, by treatment with a convenient acid such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group, can be removed, for example , by hydrogenation on a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris (trifluoroacetate). A suitable alternative protection group for a primary amino group is, for example, a phthaloyl group which can be removed by treatment with alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The conditions of deprotection for the above protection groups will necessarily vary with the choice of the protection group. Thus, for example, an acyl group such as an alkanoyl or aroyl group can be removed, for example, by hydrolysis with a convenient base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an arylmethyl group such as a benzyl group can be removed, for example, by hydrogenation over a catalyst such as palladium-in-carbon. A suitable protection group for a carboxy group is, for example, an esterification group, for example a methyl or ethyl group can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-group. butyl can be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which can be removed, for example, by hydrogenation on a catalyst such as palladium-on -carbon. Protecting groups can be eliminated at any convenient stage of synthesis using conventional techniques well known in the chemical art. The compounds of formula I can be converted to other compounds of formula I using standard procedures conventional in the art. Examples of the types of conversion reactions that can be used to convert a compound of formula (I) to a different compound of formula (I), include the introduction of a substituent by means of an aromatic substitution reaction or a reaction of nucleophilic substitution, reduction of substituents, alkylation of substituents and oxidation of substituents. The reactants and the reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of an alkyl group using an alkyl halide and a Lewis acid (such as aluminum trichloride) under Friedel Crafts conditions.; and the introduction of a halo group. Particular examples of the nucleophilic substitution reactions include the introduction of an alkoxy group or a monoalkylamino group, a dialkylamino group or a heterocycle containing N using the standard conditions. Particular examples of the reduction reactions include the reduction of a carbonyl group to a hydroxy group with sodium borohydride or a nitro group to an amino group by catalytic hydrogenation with a nickel catalyst or by treatment with iron in the presence of hydrochloric acid with heating. The preparation of the particular compounds of formula (I), such as the compounds of formula (IA), (IB), (IC), (ID), (IE), (IF), and (IG), with the methods described above, forms a further aspect of the invention. According to a further aspect of the invention, there is provided a pharmaceutical composition, comprising a compound of formula (I) and particularly a compound of formula (IA), (IB), (IC), (ID), (IE) , (IF), and (IG), or a pharmaceutically acceptable salt thereof, as defined above in association with a pharmaceutically acceptable diluent or carrier. The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), such as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. In general, the aforementioned compositions can be prepared in a conventional manner using conventional excipients. The compound of formula (I) will normally be administered to a warm-blooded animal in a unit dose within the range of body area of 5-5000 mg / m 2 of the animal, i.e. about 0.1 -100 mg / kg, and this normally provides a therapeutically effective dose. A unit dosage form such as a tablet or a capsule will generally contain, for example 1-250 mg of active ingredient. Preferably a daily dose in the range of 1-50 mg / kg is used. However, the daily dose will necessarily vary depending on the patient treated, particular route of administration, and severity of the disease being treated. Therefore the treating physician of any particular patient can determine the optimal dosage.

Biological Assays A) EphB4 Enzyme Assay in vitro This assay detects phosphorylation inhibitors by EphB4 of a polypeptide substrate using the Alphascreen ™ luminescence detection technology. Briefly, recombinant EpliB4 was incubated with a biotinylated polypeptide substrate (biotin-poly-GAT) in the presence of magnesium ATP. The reaction was stopped by the addition of EDTA, together with the streptavidin-coated donor granules which bind to the biotin substrate containing any phosphorylated tyrosine residue. The anti-phosphotyrosine antibodies present in the acceptor granules bind to the phosphorylated substrate, thus bringing the donor and acceptor granules in close proximity. The subsequent excitation of the donor granules in singlet oxygen species generated at 680 nm that interact with a chemiluminizer in acceptor granules, leading to an emission of light at 520-620 nm. The intensity of the signal is directly proportional to the level of substrate phosphorylation and inhibition is thus measured by a decrease in the signal. The test compounds were prepared as stock solutions of 10 mM in DMSO (Sigma-Aldrich Company Ltd, Gillingham Dorset SP84XT Catalog No. 154938) and serially diluted with 5% DMSO to give a range of test concentrations in 6x the final concentration required. An aliquot of 2 μl of each compound dilution was transferred to appropriate wells of 384-well low volume white well plates (Greiner, Stroudwater, Business Park Stonehouse, Gloucestershire, GL10 3SX, Cat No. 784075) in duplicate . Each plate also contained control wells: the maximum signal was created using wells containing 22 μ? of 5% DMSO, and the minimum signal corresponding to the 100% inhibition was created using wells containing 22 μ? of 0.5 M EDTA (Sigma-Aldrich Company Ltd, Catalog No. E7889). For the test, in addition to 22 μ? of the compound or control, each well of the test plate contained; 10 μ? of the assay mixture containing the final buffer (10 mM Tris, 100 μg EGTA, 10 mM magnesium acetate, 4 μ? ATP, 500 μ ?? DTT, 1 mg / ml BSA), 0.25 ng of active EphB4 recombinant (amino acids 563-987; Swiss-Prot Acc. No. P54760) (ProQinase GmbH, Breisacher Str. 117, D-79106 Freiburg, Germany, Catalog No. 0178-0000-3) and 5 nM of poly-GAT substrate ( CisBio International, BP 84175, 30204 Bagnols / Céze Cedex, France, Catalog No. 6 1GATBLB). The assay plates were then incubated at room temperature for 1 hour. The reaction was then stopped by the addition of the stop buffer of 52 μ? / ???? (10 mM Tris, 495 mM EDTA, 1 mg / ml BSA) containing 0.25 ng of each of the anti-phospho-tyrosine-100 AlphaScreen acceptor granules and streptavidin-coated acceptor granules (Perkin Elmer, Catalog No. 6760620M). The plates were sealed under natural lighting conditions, wrapped in aluminum foil and incubated in the dark for more than 20 hours. The signal of the resulting test was determined on the Perkin Elmer EnVision plate reader. The minimum value was subtracted from all the values, and the signal plotted against the concentration of the compound to generate the IC50 data. B) EphB4 cell assay in vitro This assay identifies the inhibitors of the EphB4 cell by measuring a decrease in the phosphorylation of EphB4 following the treatment of cells with compound. The endpoint of the assay used an ELISA sandwich to detect the phosphorylation status of EphB4. Briefly, Myc-labeled EphB4 from the treated treated cell was captured in the ELISA plate via an anti-c-Myc antibody. The phosphorylation state of captured EphB4 was then measured using a generic phosphotyrosine antibody conjugated with HRP via a colorimetric output catalyzed by HRP, with the phosphorylation level EphB4 directly proportional to the color intensity. The absorbance was measured spectrophotometrically at 450 nm. The integral human EphB4 (Swiss-Prot Acc. No. P54760) was cloned using standard cDNA techniques prepared from HUVEC using RT-PCR. The cDNA fragment was then sub-cloned into a cDNA3.1 expression vector containing a Myc-His epitope tag to generate the integral EphB4 containing a Myc-His tag at the C-terminus (Invitrogen Ltd. Paisley, United Kingdom). CHO-K1 cells (LGC Promochem, Teddington, Middlesex, UK, Catalog No. CCL-61) were maintained in the HAM's F12 medium (Sigma-Aldrich Compant Ltd, Gillingham, Dorset SP8 4XT, Catalog No. N4888) containing 10 % heat inactivated calf fetal serum (PAA lab GmbH, Pasching Austria Catalog No. PAA-A15-043) and 1% glutamax-1 (Invitrogen Ltd., Catalog No. 35050-038) at 37 ° C with 5 % C02. CHO-K1 cells were engineered to express stability of the EphB4-Myc-His construct using stable standard transfection techniques, to generate cells called hereafter EphB4-CHO. For each assay, 10,000 EphB4-CHO cells were seeded in each well of Costar 96-well tissue culture plate (Fisher Scientific UK, Loughborough, Leicestershire, UK, Catalog No. 3598) and cultured overnight in complete media . On day 2, the cells were incubated overnight at 90 μ? / ???? of media containing 0.1% Hyclone clean serum (Fisher Scientific, United Kingdom, Catalog No. SH30068.02). The test compounds were prepared as common solutions of 10 mM in DMSO (Sigma-Aldrich Compay Ltd, Gillingham, Dorset SP8 4XT Catalog No. 154938) and serially diluted with serum-free media to give a range of test concentrations in 10x. of the final concentration required. An aliquot of 10 μ? of each dilution of compound was transferred to cell plates in duplicate wells, and cells incubated for 1 hour at 37 ° C. Each plate also contained control wells: a maximum signal was created using untreated cells, and the corresponding minimum signal at 100% inhibition was created using wells containing a known reference compound to abolish EphB4 activity. Recombinant Efrin-B2-Fc (R & amp; amp;; D Systems, Abingdon Science Park, Abingdon, Oxon OX14 3NB UK, Catalago No. 496-EB), an Fc-labeled form of the cognate ligand of EphB4, was pre-pooled at a concentration of 3 pg / ml with 0.3 pg / ml Anti-human IgG, specific to the Fe fragment (Jackson ImmunoResearch Labs, Northfield Business Park, Soham, Cambridgeshire, UK CB7 5UE, Catalog No. 109-005-008) in serum-free media for 30 minutes at 4 ° C with occasional mixing . After treatment of the compound, the cells were stimulated with ephrin-B2 pooled in a final concentration of 1 pg / ml for 20 minutes at 37 ° C to induce EphB4 phosphorylation. After stimulation, the medium was removed and the cells used in 100 μ? / ???? of lysis buffer (25 mM Tris HCI, 3 mM EDTA, 3 mM EGTA, 50 mM NaF, 2 mM orthovanadate, 0.27 M, sucrose, 10 mM ß-glycerophosphate, 5 mM sodium pyrophosphate, 2% Triton X-100, pH 7.4). Each well of a 96-well ELISA Marp plate (Nunc; Fisher Scientific, UK, Loughborough, Leicestershire, UK, Catalog No. 456537) was coated overnight at 4 ° C with 100 μ? of anti-c-Myc antibody in buffered Phosphate Saline (10 pg / ml, produced in AstraZeneca). The plates were washed twice with PBS containing 0.05% Tween-20 and blocked with 250 μ? / ???? 3% TopBlock (Fluka) (Sigma-Aldrich Company Ltd, Gillingham, Dorset SP8 4XT, Catalog No. 37766) for a minimum of 2 hours at room temperature. The plates were washed twice with PBS / 0.05% Tween-20 and incubated with 100 μ? / ???? of the cell lysate overnight at 4 ° C. The ELISA plates were washed overnight four times with PBS / 0.05% Tween-20 and incubated for 1 hour at room temperature with 100 μ? /? of anti-phosphotyrosine 4G10 antibody conjugated with HRP (Upstate, Dundee Technology Park, Dundee, United Kingdom, DD2 1 SW, Catalog No. 16-105) diluted 1: 6000 in 3% Superior Block. The ELISA plates were washed four times with PBS / 0.05% Tween-20 and developed with 100 μ? /? of TMB substrate (Sigma Aldrich Company Ltd, Catalog No. T0440). The reaction was stopped after 15 minutes with the addition of 25 μ? / ???? of sulfuric acid. The absorbances were determined at 450 nm using the Tecan SpectraFluor Pulus. The minimum value was subtracted from all the values, and the signal plotted against the composite concentration to generate the IC50 data. C) Src Assay In Vitro Enzyme Assay The ability of test compounds to inhibit phosphorylation of a tyrosine containing the polypeptide substrate by c-Src enzyme kinase was determined using a conventional ELISA assay with an endpoint colorimetric. Each well of 384-well Matrix plates (Matrix, Brooke Park, Wilmslow, Cheshire, SK9 3LP, UK, Catalog No. 4311) were coated overnight at 4 ° C with 40 μ? of 10 ug / ml pEAY synthetic polyamino acid substrate stock (Sigma-Aldrich Company Ltd, Gillingham, Dorset, SP8 4XT, UK, Catalog No. P3899) in phosphate buffered saline (PBS). Immediately before the assay, the plates were washed with 100 μ? / ???? of PdBS containing Tween-20 and then with 50 mM HEPES pH7.4. The test compounds were prepared as stock solutions of 10 mM in DMSO (Sigma-Aldrich Company Ltd, Gillingham, Dorset, SP8 4XT, United Kingdom, Catalog No. 154938) and serially diluted with 10% DMSO to give a range of the test concentrations in 4x of the final concentration required. An aliquot of 10 μ? of each compound dilution was transferred to the appropriate ELISA wells in duplicate. Each plate also contained control wells: the maximum signal was created using wells containing 10 μ? of 10% DMSO, and the minimum signal corresponding to the 100% inhibition was created using the wells containing 10 μ? of 0.5 M EDTA (Sigma-Aldrich Company Ltd, Catalog No. E7889). 10 μ? of a solution that contains 8.8 μ? ATP and 80 mM MnC12 were added to each well to give a final concentration of 2.2 μm and 20 mM respectively. The reaction was initiated by the addition of 20 μ? / ???? of the assay buffer (final concentration of 50 mM HEPES, 0.1 mM sodium orthovanadate, 0.01% BSA, 0.1 mM DTT, 0.05% Triton X-100, pH 7.4) containing active human recombinant c-Scr kinase (Upstate, Dundee, United Kingdom, DD2 1SW, Catalog No. 14-117). The plates were then incubated at room temperature for 20 minutes before the kinase reaction that was stopped by the addition of 20 μ? / ???? of 0.5 M EDTA. The plates were washed three times with 100 μ? / ???? of PBS-Tween20 and then 40 μ? of a PBS-Tween20 and 0.5% of the BSA solution containing against the phosphotyrosine antibody 4G10-HRP (Upstate, Catalog No. 16-105) added to each well. The plates were incubated for 1 hour at room temperature before being washed three times with 100 μ? / ???? of PBS-Tween 20. The plates were developed with 40 μ? / ???? of the TMB substrate solution in DMSO (Sigma-Aldrich Company Ltd, Catalog No. T2885) for up to one hour at room temperature. The reaction was then stopped with the addition of 20 μ? / ???? of sulfuric acid and the absorbances determined at 450 nm using a plate reading spectrophotometer. The minimum value was subtracted from all the values, and the signal plotted against the concentration of the compound to generate the IC50 data. The compounds of the invention were active in the above assays, for example, generally showing the IC50 values of less than 100 μ? in assay A and assay B. Preferred compounds of the invention generally show IC50 values of less than 30 μ? in assay A and assay B. For example, Compound 59 of the examples showed an IC5o of 0.46 μ? in the A test, an IC50 of 1.25 μ? in trial B, an IC50 of 0.33 μ? in test C. In addition, the illustrative IC50 values obtained using test B for a selection of the compounds exemplified in the present application are shown in table A below. Table A- Means of the IC- values? obtained using Test B Medium Compound IC50 No. I M1 219 0.14 227 0.19 241 0.13 258.08 293 0.23 309 2.53 318 0.05 The compounds of the invention were also found active in a KinaseProfile ™ assay for the EphA2 kinase activity operated by Upstate of Charlotteville, VA 22903, US. For example, the compound of Example 1 above showed an IC50 of 15 nM in this assay. As a result of their activity in the analyzes described above, the compounds of the present invention are useful in the treatment of diseases or medical conditions mediated alone or in part by the enzymatic activity of EphB4, ie, the compounds can be used to produce an effect inhibitory EphB4 in a warm-blooded animal in need of such treatment. Thus, the compounds of the present invention provide a method for treating the proliferation of malignant cells characterized by the inhibition of the EphB4 enzyme, ie, the compounds can be used to produce an anti-proliferative effect mediated alone or in part by the inhibition of EphB4. In addition, certain compounds of the invention can also be active against the enzyme kinases Ser or EphA2, ie the compounds can also be used to produce an inhibitory effect of a Src kinase and EphA2 in a warm-blooded animal in need of such treatment. Thus, the compounds of the present invention provide a method for treating the proliferation of malignant cells characterized by the inhibition of EphB4, EphA2 or Src enzymes, ie, the compounds can be used to produce a mediated anti-proliferative effect alone or in part by inhibition kinase EphB4, EphA2 or Src. According to a further aspect of the invention, there is provided the use of a compound of the formula (IH) (IH) where R1 is selected from hydrogen, alkyl is from 1 to 6 carbon atoms, alkenyl is from 2 to 6 carbon atoms, or alkynyl is from carbon atoms, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by one or more substituent groups of cyano, nitro, -OR2, -NR2aR2b, -C (0) NR2aR2b, or -N (R2a) C (0) R2, halo or halo of 1 to 4 carbon atoms-alkyl, where R2, R2a and R2b are selected from hydrogen or alkyl of 1 to 6 carbon atoms, such as methyl, or R2a and R2b together with the nitrogen atom to which they are attached can form a 5- or 6-membered heterocyclic ring, optionally containing a heteroatom additional selected N, O or S; ring A is fused to a 5- or 6-membered heterocyclic or carbocyclic ring, which is saturated or unsaturated, and is optionally substituted on any available carbon atom by one or more substituent groups selected from the group halo, cyano, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, -S (0) z-alkyl of 1 to 6 carbon atoms (where z is 0, 1 or 2), or -NRaRb (where Ra and Rb are each independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, or alkylcarbonyl of 1 to carbon atoms), and wherein any of the nitrogen atoms in the ring are optionally substituted by an alkyl of 1 to 6 carbon atoms or an alkylcarbonyl of 1 to 6 carbon atoms; n is 0, 1, 2 or 3 and each R3 group is independently selected from halo, trifluoromethyl, cyano, nitro or a group of sub-formula (i): -X1R11 (i) where X1 is selected from a direct bond u, O, S, SO, S02, OS02, NR13, CO, CH (OR13), CONR13, N (R13) CO, S02N (R13), N (R3) S02, C (R13) 20, C (R13) 2S, C (R13) 2N (R13) and N (R3) C (R13) 2, wherein R13 is hydrogen or alkyl of 1 to 6 carbon atoms; and R11 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl or heterocyclyl, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, aryl of 1 to 6 carbon atoms or heterocyclyl of 1 to 5 carbon atoms-alkyl, any of which may be optionally substituted with one or more groups selected from halo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, alkoxy of 1 to 6 carbon atoms, alkennioxyl of 2 to 6 carbon atoms, alkynyloxy of 2 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms carbon, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, di (alkyl of 1 to 6 carbon atoms) amino, alkoxycarbonyl of 1 to 6 carbon atoms, N-alkylcarbamoyl of 1 to 6 carbon atoms, N, N-di (alkyl of 1 to 6 carbon atoms) carbamoyl, alkanil of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 atoms of carbon, alkylamino of 2 to 6 carbon atoms, N-alkyl of 1 to 6 carbon atoms-alkylamino of 2 to 6 carbon atoms, alkenylamino of 3 to 6 carbon atoms, N-alkyl of 1 to 6 carbon atoms carbon-alkenylamino of 3 to 6 carbon atoms, alkynylamino of 3 to 6 carbon atoms, N-alkyl of 1 to 6 carbon atoms-alkynylamino of 3 to 6 carbon atoms, N-alkylsufamoyl of 1 to 6 carbon atoms , N, N-di- (alkyl of 1 to 6 carbon atoms) sulfamoyl, alkanesulfonylamino of 1 to 6 carbon atoms and N-alkyl of 1 to 6 carbon atoms-alkanesulfonylamino of 1 to 6 carbon atoms, and any heterocyclic group within R11 that optionally supports 1 or 2 oxo or thioxo substituents; Y R4 is a group of the sub-formula (Mi) (iii) where R5, R6, R7, R8 and R9 are each independently selected from: (i) hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms. , alkynyl of 2 to 8 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, aryl of 1 to 6 carbon atoms-alkyl, heterocyclyl (including heteroaryl), heterocyclyl of 1 to 6 carbon atoms-alkyl (including heteroaryl of 1 to 6 carbon atoms-alkyl) and wherein any aryl, carbocyclyl of at 12 carbon atoms, aryl of 1 to 6 carbon atoms-alkyl, heterocyclyl (including heteroaryl), heterocyclyl of 1 to 6 carbon atoms-alkyl (including heteroaryl of 1 to 6 carbon atoms-alkyl) are optionally substituted on any of the available carbon atoms by halo, hydroxy, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxy of 1 to 6 carbon atoms-alkyl, alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, or α, β-di-alkylamino of 1 to 6 carbon atoms, and any of the nitrogen atoms present in a heterocyclyl group may, depending on the considerations of the Valencia, to be replaced by a selection group hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and where any of the sulfur atoms can optionally be oxidized in a sulfur oxide; (ii) a group of sub-formula (iv) -X2-R14 (vi) where X2 is selected from O, NR16, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR16), CON (R16), N (R16) CO, -N (R 6) C (0) N (R16) -, -N (R16) C (0) 0-, SON (R16), N (R6) SO, S02N (R16), N (R16) S02 , C (R16) 20, C (R16) 2S and N (R6) C (R16) 2, wherein each R16 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, R14 is hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, aryl of 1 to 6 carbon atoms-alkyl, or a ring heterocyclyl, bicyclic or 4- to 8-membered mono (including 5- or 6-membered heteroaryl rings) or heterocyclyl groups of 1 to 6 carbon atoms-bicyclic alkyl or 4- to 8-membered mono (including heteroaryl groups of 1 to 6 atoms) carbon-alkyl of 5 or 6 members) and wherein any aryl group, carbocyclyl of 3 to 12 carbon atoms, aryl of 1 to 6 carbon atoms-alkyl, heterocyclyl (including heteroaryl), heterocyclyl of 1 to 6 carbon atoms, carbon-alkyl (including heteroaryl of 1 at 6 carbon atoms-alkyl) are optionally substituted on any of the available carbon atoms by oxo, halo, cyano amino, alkyl of 1 to carbon atoms, hydroxy of 1 to 6 carbon atoms-alkyl, alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, or α, β-di-alkylamino of 1 to 6 carbon atoms and any of the nitrogen atoms present in the heterocyclyl fractions may, depending on the considerations of the valence, to be substituted by a group selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and wherein any sulfur atom can optionally be oxidized in a sulfur oxide; iii) a group of the sub-formula (v): -X3-R15-Z (v) Where X3 is a direct link or is selected from O, NR17, S, S02, OS02, CO, C (0) 0, OC (O), CH (OR17), CON (R17), N (R17) CO, -N (R17) C (0) N (R17) -, -N (R17) C (0) 0-, S02N ( R17), N (R17) S02, C (R17) 20, C (R17) 2S and N (R17) C (R17) 2, wherein each R7 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; R 5 is an alkylene of 1 to 6 carbon atoms, alkenylene of 2 to 6 carbon atoms or an alkynylene of 2 to 6 carbon atoms, arylene, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl (including heteroaryl), of which it may be optionally substituted by one or more groups selected from halo, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, amino, alkylamino of 1 to 6 carbon atoms or (alkyl of 1 to 6 carbon atoms) amino; Z is halo, trifluoromethyl, cyano, nitro, aryl, carbocyclyl of 3 to 12 carbon atoms or heterocyclyl (including heteroaryl) optionally bearing 1 or 2 substituents, which may be the same or different, selected from halo, alkyl from 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and alkoxy of 1 to 6 carbon atoms and wherein any heterocyclyl group within Z optionally supports 1 or 2 oxo substituents, or Z is a group of the sub-formula (vi) -X4-R18 (vi) where X4 is selected from O, NR19, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH ( OR19), CON (R19), N (R19) CO, S02N (R19), -N (R19) C (0) N (R19) -, -N (R19) C (0) 0-N (R19) S02 , C (R19) 20, C (R19) 2S and N (R19) C (R19) 2, wherein each R19 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; and R18 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, aryl of 1 to 6 carbon atoms-alkyl, heterocyclyl (including heteroaryl) or heterocyclyl of 1 to 6 carbon atoms-alkyl (including heteroaryl of 1 to 6 carbon atoms-alkyl) optionally bearing 1 or 2 substituents, which may be the same or different , selected from halo, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and alkoxy of 1 to 6 carbon atoms, and wherein any heterocyclyl group within R18 optionally supports 1 or 2 oxo substituents; or (iv) R5 and R6, R6 and R7, R7 and R8 or R8 and R9 are joined together to form a 5, 6 or 7 membered ring, wherein the ring is not saturated or partially or completely saturated and is optionally substituted at any available carbon atom by halo, alkyl of 1 to 6 carbon atoms, hydroxy of 1 to 6 carbon atoms-alkyl, amino, N-alkylamino of 1 to 6 carbon atoms, or N, N-di-alkylamino from 1 to 6 carbon atoms, and the may contain one or more heteroatoms selected from oxygen, sulfur or nitrogen, where the sulfur atoms may optionally be oxidized in a sulfur oxide, where any CH2 group may be replaced by a C group (O ), and where the nitrogen atoms, depending on the valence considerations, can be replaced by a group R21, where R21 is selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer.

According to another as of the present invention there is provided a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH), or a pharmaceutically acceptable salt thereof, as defined herein above for use in a method of treating the human or animal body by therapy. Thus according to a further as of the invention there is provided a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or ( IH), or a pharmaceutically acceptable salt thereof, as defined herein above for use as a medicament. According to a further as of the invention there is provided a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH) ), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the production of an EphB4 inhibitory effect in a warm-blooded animal such as a man. According to another as of the invention there is provided the use of a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH) ), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of an EphB4 inhibitory effect in a warm-blooded animal such as a man. According to a further as of the invention there is provided the use of a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or ( IH), or a pharmaceutically acceptable salt thereof, as defined herein above in the manufacture of a medicament for use in the production of an inhibitory effect kinase Src, EphA2 and EphB4 in a warm-blooded animal such as a man. According to another feature of this as of the invention is provided a method for producing an EphB4 inhibitory effect in a warm-blooded animal, such as a man, in need of such treatment comprising administering to the animal the effective amount of a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH), or a pharmaceutically acceptable salt thereof, as defined above .

According to another feature of this as of the invention, a method is provided for producing an inhibitory effect of Src, EphB4 and EphA2 kinase in a warm-blooded animal, such as a man, in need of such a treatment comprising administering to the animal the effective amount of a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH), or a pharmaceutically acceptable salt thereof, as defined above. According to a further as of the invention, a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH) is provided ), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the production of an anti-angiogenic effect in a warm-blooded animal such as a man. According to a further as of the invention, the use of a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) is provided or (IH), or a pharmaceutically acceptable salt thereof, as defined above in the manufacture of a medicament for use in the production of an anti-angiogenic effect in a warm-blooded animal such as a man.

According to another feature of this as of the invention there is provided a method for producing an anti-angiogenic effect in a warm-blooded animal, such as man, in need of such a treatment comprising administering to the animal an effective amount of a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH) or a pharmaceutically acceptable salt thereof, as defined above. According to another characteristic of the invention there is provided a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH) , or a pharmaceutically acceptable salt thereof, as defined herein above in the manufacture of a medicament for use in the treatment of cancer. According to a further feature of this as of the invention there is provided a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH), or a pharmaceutically acceptable salt thereof, as defined above, for use in the treatment of cancer.

According to a further feature of this aspect of the invention there is provided a method of treating cancer in a warm-blooded animal, such as a man, in need of such treatment comprising administering to the animal an effective amount of a compound of the invention. Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH), or a pharmaceutically acceptable salt thereof, as defined above. In a further aspect of the present invention there is provided the use of a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH), or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for use in the treatment of solid tumor disease, in particular in neuroblastomas, breast, liver, lung and colon cancer or leukemia In a further aspect of the present invention there is provided a method of treating neuroblastomas, breast, liver, lung and colon cancer or leukemias in a warm-blooded animal, such as a man, in need of such treatment comprising administering to the animal a effective amount of a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH), or a pharmaceutically acceptable salt thereof, as defined above. The anti-cancer treatment defined hereinbefore may be applied as a single therapy or may involve, in addition to the compound of the invention, surgery, radiotherapy or conventional chemotherapy. Such a treatment as a whole can be achieved by the mode of simultaneous, sequential or separate administration of the individual components of the treatment. In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology the other components of such treatment as a whole in addition to the anti-angiogenic treatment defined hereinbefore can be: surgery, radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumor agents: (i) other antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (eg, cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluorouirimidines type fluorouracil-5 and tegafur, raltitrexed, methotrexate, arabinoside cytosine, and hydroxyurea); antitumor antibiotics (for example anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids type vincristine, vinblastine, vindesine and vinorelbine and taxoid type inhibitors of taxol and taxotero and polokinase); and topoisomerase inhibitors (e.g., etoposide and teniposide epipodophyllotoxins, amsacrine, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxifene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin) and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., as anastrozole, letrozole, vorazole and exemestane) and 5a-reductase inhibitors such as finasteride; (iii) anti-invasion agents (e.g. c-Src family inhibitors type e 4- (6-chloro-2,3-methylenedioxyanilino) -7- [2- (4-methylpiperazin-1-yl) ethoxy] -5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N- (2-chloro-6-methylphenyl) -2-. {6- [4- (2-hydroxyethyl) piperazine- 1-yl] -2-methylpyrimidin-4-ylamino.] Thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem. 2004, 47, 6658-6661), and marimastat-type metalloproteinase inhibitors, inhibitors of urokinase-type plasminogen-activating receptor function or Heparanase antibodies); (iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (eg, anti-erbB2 trastuzumab antibody [Herceptin ™], anti-EGFR pantimumab antibody, of the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies described by Stern et al., Critical reviews in oncology / hematology, 2005, vol.54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal epidermal growth factor family (eg, tyrosine kinase inhibitors of the EGFR family such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6). - (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, ZD1839), N- (3-ethylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) -quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatiniba, inhibitors of the growth factor family of hepatocytes, family inhibitors of the platelet-derived growth factor family such as imatiniba, serine / threonine kinase inhibitors (eg inhibitors of Ras / Raf signaling such as farnesyl transferase inhibitors, eg sorafenib (BAY 43-9006 )), inhibitors of cell signaling through MEK and / or AKT kinases, inhibitory s of the hepatocyte growth factor family, c-kit inhibitors, alb kinase inhibitors, IGF kinase receptor inhibitors (insulin-like growth factor); aurora kinase inhibitors (eg AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors (v) anti-angiogenic agents such as which inhibit the effects of vascular endothelial growth factor, [e.g. the bevacizumab antibody (Avastin ™) of anti-vascular endothelial cell growth factor and inhibitors of VEGF receptor tyrosine kinase such as 4- (4-bromo- 2-fluoroanilino) -6-methoxy-7- (l-methylpiperidin-4-ylmethoxy) quinazoline (ZD6474; Example 2 within WO 01/32651), 4- (4-fluoro-2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814) , compounds such as those described in International Patent Applications W097 / 22596, WO97 / 30035, WO 97/32856 and W098 / 13354 and the compounds that work r other mechanisms (for example, linomide, inhibitors of the ß3 integrin function and angiostatin)]; (vi) damaging vascular agents such as Combretastatin A4 and compounds described in International Patent Applications WO99 / 02166, WO00 / 40529, WO 00/41669, WO01 / 92224, WO02 / 04434 and WO02 / 08213; (vii) antisense therapeutics, for example those directed to the listings marked above, such as ISIS 2503, an anti-ras antisense; (viii) methods of gene therapy, including for example methods for substituting aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (prodrug therapy of the enzyme directed to the gene) methods such as for example those using deaminase cytosine, thymidine kinase or a bacterial nitoreductase enzyme and methods for increasing the patient's tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (ix) immunotherapy methods, which include for example ex-vivo methods and in vivo methods to increase the immunogenicity of the patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or colony stimulation factor. of the granulocyte-macrophage, methods for decreasing T-cell anergy, methods using transfected immune cells such as transfected cytokine dendritic cells, methods for using transfected cytokine tumor cell lines and methods using anti-idiotypic antibodies. According to this aspect of the invention there is provided a pharmaceutical composition comprising a compound of the formula (I) as defined herein and an additional anti-tumor substance as defined above for the overall treatment of cancer. As stated above, the size of the dose required for the therapeutic or prophylactic treatment of a particular disease of cell proliferation will necessarily be varied depending on the host treated, the route of administration and severity of the disease being treated. It is considered a dose unit in the range, for example, 1-100 mg / kg, preferably 1-50 mg / kg. In addition to their use in therapeutic medicine, the compounds of formula (I), (IA), (IB) or (IC) and their pharmaceutically acceptable salts thereof, are also useful as pharmacological tools in the development and standardization of the in vitro and in vivo test systems for the evaluation of the effects of inhibitors of anti-angiogenic activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents . The invention will now be illustrated in the following examples in which, generally:? For examples 1 to 9 (i) the operations were performed at room temperature, that is, in the range of 17 to 25 ° C and under an atmosphere of an inert gas such as nitrogen or argon unless otherwise indicated; (ii) in general, the course of the reactions was followed by thin layer chromatography (TLC) and / or analytical high pressure liquid chromatography (HPLC); the reaction times given are not necessarily the minimum achievable; (iii) when necessary, the organic solutions were dried in anhydrous magnesium sulfate, the working procedures were performed using the traditional layer that separates the techniques or an automated liquid handler ALLEXIS (MTM), the evaporations were performed either by rotary evaporation in vacuum or in a Genevac HT-4 / EZ-2. (iv) the yields, where they were presented, were not necessarily the maximum obtainable, and when necessary, the reactions were repeated if a larger quantity of the reaction product was required; (v) in general, the structures of the final products of formula I were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrum techniques; Electrospray Mass Spectrum data were obtained using a Waters ZMD or Waters ZQ LC / mass spectrometer that acquired positive and negative ion data, generally, only ions with reference to the parent structure are described; the chemical values of the proton change of the NMR were measured on the delta scale using a spectrometer, either Bruker Spectrospin DPX300 operating on a 300 MHz force, a Bruker Dpx400 operating at 400MHz or a Bruker Advance operating at 500MHz. The following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiple; Br, broad; (vi) unless otherwise indicated the compounds containing an asymmetric carbon and / or sulfur atom were not resolved; (vii) the intermediates were not necessarily completely purified but their structures and purity were determined by TLC, CLAR analytical assay, infrared (IR) and / or NMR analysis; (viii) Unless otherwise stated, the chromatography column (by the instantaneous procedure) and the medium pressure liquid chromatography (MPLC) were made in Merck Kieselgel silica (Art. 9385); (ix) Preparatory HPLC was performed on C18 reversed-phase silica, for example on a Waters 'Xterra' preparative reverse phase column (5 microns silica, diameter 19 mm, length 100 mm in length) using decreasing polar mixtures as eluent, for example decreasing polar mixtures of water (containing 1% acetic acid or 1% aqueous ammonium hydroxide (d = 0.88)) and acetonitrile; (x) the following CLAR analytical methods were used; In general, the reverse phase of silica was used with a flow rate of approximately 1 ml per minute and the detection was by Electrospray Mass Spectrometry and by UV absorbance at a wavelength of 254 nm; for each method Solvent A was water and Solvent B was acetonitrile; the following columns and solvent mixtures were used: - The preparatory HPLC was performed on C18 reverse phase silica, on a Phenomenex "Gemini" preparative reverse phase column (5 microns silica, 110A, 21.1 mm diameter, 100 mm length ) using decreasing polar mixtures as eluent, eg decreasing polar mixtures of water (containing 0.1% formic acid or 0.1% ammonium) as solvent A and acetonitrile as solvent B; any of the following preparative HPLC methods were used: Method A: a solvent gradient in 9.5 minutes, at 25 minutes per minute, of 85:15 of a mixture of solvents A and B respectively in a mixture of 5:95 of the solvents A and B. Method B: a solvent gradient in 9.5 minutes, at 25 minutes per minute, of a mixture of 60:40 of the solvents A and B respectively in 5:95 of a mixture of solvents A and B. (xi) where certain compounds were obtained as an acid addition salt, for example a mono-hydrochloride salt or a di-hydrochloride salt, the stoichiometry of the salt was based on the number and nature of the basic groups in the compound, the exact stoichiometry of the salt was not generally determined, for example by means of elementary data analysis; For examples 10 to 28 (i) the temperatures are given in degrees Celsius (° C); the operations were carried out at room temperature, that is, at a temperature in the range of 18 to 25 ° C; (ii) the organic solutions were dried in anhydrous magnesium sulfate or anhydrous sodium sulfate; the evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600 to 4000 Paséales, 4.5 to 30 mmHg) with a bath temperature of up to 60 ° C; (iii) chromatography means flash chromatography on silica gel; Thin layer chromatography (TLC) was performed on silica gel plates; (iv) in general, the course of the reactions was followed by TLC and / or analytical LC-MS, and reaction times are given for illustration only. Retention times (tR) were measured in a Waters 2790 / ZMD Micromass LC / MS system equipped with a Waters Symmetry column (C18, 3.5 μ ?, 4.6 x 50 mm); UV detection 254 nM and MS; elution: flow rate 2.5 ml / min, linear gradient of 95% water - 5% methanol containing 5% formic acid to 40% water - 55% acetonitrile - 5% methanol containing 5% formic acid during 3 minutes; then the linear gradient in 95% acetonitrile - 5% methanol containing 5% formic acid for 1 minute; (v) the final products had a satisfactory spectrum of (NMR) proton nuclear magnetic resonance and / or data from Mass Spectrum; (vi) the returns are given for illustration only and are not necessarily those that can be obtained by the development of the diligent process; the preparations were repeated if more material was required; (vu) when given, the NMR data in the form of delta values for important diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 500 MHz using the dimethyl sulfoxide perdeuterio (DMSO-d6) as solvent unless otherwise indicated; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiple; Br, broad; (viii) chemical symbols have their usual meanings; SI units and symbols are used; (ix) the solvent indexes are given in terms of volume: volume (v / v); and (x) the Mass Spectrum were operated with an electron energy of 70 electron volts in the chemical ionization mode (Cl) using a direct exposure test; where the indicated ionization was effected by the impact of the electron (El), the rapid bombardment of the atom (FAB) or electroaspersion (ESP); the values for m / z are given; generally, only the ions that indicate the sourdough are registered; and unless stated otherwise, the quoted mass ion is (MH) + which refers to the protonated mass; the reference to M + is towards the mass of ion generated by the loss of an electron; and the reference to M-H + is towards the mass of ion generated by the loss of a proton; (xi) unless otherwise indicated compounds containing an asymmetrically substituted carbon and / or a sulfur atom that has not been resolved; (XII) where a synthesis is described as being analogous to that described in a previous example, the amounts used are the equivalents to the millimolar index of those used in the previous example; (xiii) all microwave reactions were performed on a microwave personal synthesizer EMRYS ™ Optimizer EXP; (xiv) prepare high performance liquid chromatography (CLAR) was performed on a Waters instrument using the following conditions: Column: 30 mm x 15 cm Xterra Waters, C18, 5 mm solvent A: Water with 1% acetic acid 1% or 2 g / 1 ammonium carbonate Solvent B: Acetonitrile Flow rate: 40 mi / minute Function Time: 15 minutes with about 10 minutes of gradient 5-95% B Wavelength: 254 nm Injection volume: 2.0-4.0 mi; In addition, the following abbreviations have been used, when necessary: - DMSO Dimethylsulfoxide NMP 1 -methyl-2-pyrryliddinone DMA N, N -dimethylacetamide DCM Dichloromethane THF Tetrahydrofuran; DMF N, N-dimethylformamide; DTAD di-tert-butyl azodicarboxylate; DI PEA di-isopropylethylamine; IPA alcohol sopropyl; Diethyl ether; and TFA trifluoroacetic acid. Example 1 Step I 2-Chloro-N- (5-chloro-1,3-benzodioxol-4-yl) pyrimidin-4-amine Sodium hydride (13.4 g, 60% dispersion in mineral oil) was added in portions to (5-chloro-1,3-benzodioxol-4-yl) amine (11.5 g, prepared as described in WO2001094341) in DMA (100 mi) at 0 ° C. 2,4-Dichloropyrimidine (10 g) were added and the reaction heated to room temperature and stirred overnight. The reaction was quenched cautiously with water, the solution filtered and concentrated and the residue dissolved in DCM, washed with water and brine, dried and concentrated to give the title compound as a dark brown oil which was used without further purification (16 g). , 85%); NMR spectrum (300 MHz, DMSO) 6.10 (s, 2H), 6.58 (d, IH), 6.94 (d, IH), 7.05 (d, 1H), 8.15 (d, 1H), 9.76 (s, 1H); Mass Spectrum M * 284.4.

Step 2 N-4- (5-Chloro-1,3-benzodioxol-4-in-N-2- (3,4,5-trimethoxyphenyl) pyrimidine-2,4-diamine (Compound No. 1) Compound 1 3, 4, 5-trimethoxyaniline (103 mg) and 2-chloro-N- (5-chloro-1,3-benzodioxol-4-yl) pyrimidin-4-amine (200 mg) were dissolved in n-butanol (1 mi) and DMA (1 mL) and a solution of HCl in diethyl ether (0.7 mL, 1M) added. The reaction was heated at 120 ° C for 3 hours then cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase chromatography to give the title compound as a solid (69 mg, 23%); NMR spectrum (300 MHz, DMSO) 3.58 (s, 9H), 5.98 (s, 2H), 8.85 (s, 1H), 6.10 (d, 1H), 6.87 (d, 1H), 7.02 (d, 1H) , 7.05 (s, 2H), 7.99 (d, 1H); Mass Spectrum MH * 431.38. Example 2 The procedure described above in example 1 was repeated using the appropriate aniline (whose sources were commercial or prepared as described in the method section below). Thus the compounds described below in the table were obtained Example 3 2r (3,4,5-trimethoxyphenyl) amino-1-pyrimidine-4 (3H) -one 3,4,5-trimethoxyaniline (6.82 g) and 2- (methylthio) pyrimidin-4 (3H) -one (5.26 g) were suspended in diglyme (50 ml) and heated at 165 ° C for 18 hours under nitrogen to give a red solution. The reaction was cooled to room temperature then poured into 500 ml of diethyl ether with stirring to give an oily precipitate which was filtered and redissolved in (250 ml) of water. A solid precipitate formed which was stirred for 30 minutes then filtered to give the title compound as a cream solid (3.80 g, 37%); NMR spectrum (300 MHz, DMSO) 3.63 (s, 3H), 3.76 (s, 6H), 5.80 (d, 1H), 6.95 (s, 2H), 7.76 (d, 1H); Mass Spectrum MH + 278.5.

Step 2 4-Chloro-N- (3,4,5-trimethoxyphenyl) pyrimidin-2-amine 2 - [(3,4,5-Tr ~ methoxy-phenyl) amino] pyrimidin-4 (3H) -one (4.7 g) were suspended in acetonitrile (100 ml). (10 ml) of phosphorus oxychloride were added dropwise to give a dark solution. The reaction was heated to 85 ° C for 2-5 hours after it was further added (2 ml) of phosphorus oxychloride and the reaction heated overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (150 ml) and aggregates (100 ml) of ice water. The mixture was stirred while the saturated sodium bicarbonate solution was added to give pH = 8. The organic layer was separated, washed with brine (25 ml), dried and concentrated to give a yellow solid. This was triturated with iso-hexane and filtered to give the title compound as a yellow solid (4.07 g, 81%); NMR spectrum (300 MHz, DMSO) 3.63 (s, 3H), 3.76 (s, 6H), 6.94 (d, 1H), 7.13 (s, 2H), 8.43 (d, 1H), 9.87 (s, 1H); Mass Spectrum MH + 296.5.

Step 3 N-4- (1 H-ldazol-7-ihN-2- (3,4,5-trimethoxy-phenyl-pyrimidine-2,4-diamine (Compound No. 68) Compound 68 7-Aminoindazole (33 mg) and 4-chloro-N- (3,4,5-trimethoxy-phenyl) pyrimidin-2-amine (70 mg) were dissolved in NMP (1 ml) and a solution of HCl in dioxane (0.07 ml, 4M) added. The reaction was heated at 130 ° C for 5 hours then cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase chromatography to give the title compound as a solid (44 mg, 47%); NMR spectrum (300 MHz, DMSO) 3.58 (s, 6H), 3.61 (s, 3H), 6.18 (d, 1H), 7.09 (m, 3H), 7.54 (d, 1H), 7.71 (d, 1H) , 8.05 (d, 1H), 8.10 (s, 1H), 8.95 (s, IH), 9.11 (s, IH), 12.82 (s, IH): Mass Spectrum M + 392.4.

Example 4 The procedure described in Example 3 above was repeated using the appropriate aniline. Thus the compounds described below were obtained in table 2.

Table 2 Example 5 Acid 3 ({4- {5-Chloro-1,3-benzodoloxol-4-yl) aminoTpyrimidin-2-yl) amino) benzoic acid Compound 155 3-Aminobenzoic (6.1 g) and 2-chloro-N- (5-chloro-1,3-benzodioxol-4-yl) pyrimidn-4-amino (9 g) were dissolved in DMA (120 ml) and a solution of HCl in dioxane (11.1 ml, 4 M) was added. The reaction was heated at 96 ° C for 4 hours then cooled to room temperature and added DIPEA (5 ml). The solution was concentrated in vacuo. The water was added and the resulting solid filtered and triturated with methanol and dried under vacuum to give the title compound as a white solid (9.8 g, 80%); NMR spectrum (300 MHz, DMSO) 6.00 (s, 2H), 6.17 (d, 1H), 6.90 (d, 1H), 7.03 (d, 1H), 7.18 (t, 1H), 7.41 (d, 1H), 8.04 (m, 3H), 9.00 (s, 1H), 9.28 (s, 1H), 12.72 (Br s, 1H); Mass Spectrum MH + 385.36.

Example 6 Step 1 3 - ((4-f (5-Chloro-1,3-benzodioxol-4-yl) aminolpyrimidin-2-yl) amine) benzoyl chloride 3- ( { 4 - [(5-Chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl} amino) benzoic acid (3.61 g, example 5) were added to the thionyl (35 ml) at 0 ° C. A drop of DMF was added and the solution stirred at 0 ° C for 2 hours, then concentrated in vacuo and azeotroped with toluene to give the title compound as a yellow solid (3.7 g, 98%) which was used without further purification. . Step 2 3 - ((4-r (5-Chloro-1,3-benzodioxol-4-yl) am i nolpirim id i gigilla mino) -N.N-dimet ilbenza mida Compound 156 3- ( { 4 - [(5-Chloro-1,3-benzodioxol-4-yl) amino] pyrimidin-2-yl} amino) -benzoic chloride (100 mg) were dissolved in THF dry (5 mL) and a dimethylamine (5 mL, 2M in THF) were added and the reaction stirred at room temperature for 2 hours. The solution was concentrated in vacuo and the residue purified by reverse phase chromatography to give the title compound as a solid (61 mg, 52%); NMR spectrum (300 MHz, DMSO) 2.84 (s, 3H), 2.97 (s, 3H), 6.00 (s, 2H), 6.16 (d, 1H), 6.79 (d, 1H), 6.90 (d, 1H), 7.02 (d, 1H), 7.13 (t, 1H), 7.58 (s, 1H), 7.69 (d, 1H), 8.00 (d, 1H), 8.98 (s, 1H), 9.20 (s, 1H) ); Mass Spectrum MH + 412.42. Example 7 The procedure described in Example 6 above was repeated using the appropriate aniline. In this manner, the compounds described below were obtained in Table 3. Table 3 Example 8 7-f (2- (3 - (methylsulfonyl) phenylamino) pyrimidine-4-yl) amino1-1.3-benzodioxole-5-carbonitrile Compound 207 HCl (1 drop, 4N in dioxane) was added to a solution of 7 - [(2-chloropyrimidin-4-yl) amino] benzo [1,3] dioxol-5-carbonitrile (83 mg-method 23 ) and 3-methylsulfinylaniline hydrochloride (69 mg) in iso-propanol (0.5 ml) and NMP (0.5 ml) and heated at 110 ° C for 20 minutes (microwave), the solution was cooled and DIPEA was added before concentration in empty. The residue was purified by flash-phase chromatography to obtain the base compound as a beige solid (21 mg, 17%); NMR spectrum (300 MHz, DMSO) 3.16 (s, 3H), 6.20 (s, 2H), 6.43-6.46 (m, 1H), 7.23 (s, 1H), 7.42-7.49 (m, 2H), 7.99 ( d, 1H), 8.12 (d, 1H), 8.17 (s, 1H), 8.20 (s, 1H), 9.37 (s, 1H), 9.63 (s, 1H); Mass Spectrum MH + 410.33. Example 9 The procedure described in Example 8 above was repeated using the appropriate chloropyrimidine and aniline. In this way, the compounds described in Table 4 were obtained as follows: Table 4 R3 EXAMPLE 10 Raw material (1) 2-chloro-N- (5-c > orobenzoF1.31dioxol-4-ih-N-methyl-pyrimidine-4-amine 2-Chloro-N- (5-chloro-1,3-benzodioxol-4-yl) pyrimidine-4-amine (1.5 g, 5.30 mmol, see Example 1, Step 1) was dissolved in DMF (30 ml) . Potassium carbonate (1, g, 8.0 mmol) was added, followed by iodomethane (0.36 mL, 5.8 mmol) and the mixture was stirred overnight. After evaporation under reduced pressure, the residue was dissolved in atilla acetate, washed with water and brine, dried and evaporated to obtain a brown oil (1.54 g, 98%) which solidified in the following; NMR spectrum (500 MHz, DMSOd6 at 353 ° K) 3.33 (s, 3H), 6.29 (s, 2H), 7.12 (broad, 1H), 7.00 (d, 1H), 7.10 (d, 1H), 8.12 ( broad, 1H); Mass Spectrum MH + 298. (2) (5-chlorobenzoH .3T-dioxol-4-yl) - (2-chloropyrimidine-4-haloalkyltonitrile) Following the same procedure as for (1) above, 2-chloro-N- (5-chloro-1,3-benzodioxol-4-yl) pyrimidine-4-amine (1.5 g, 5.30 mol) was reacted with iodoacetonitrile (0.42). mi, 5.8 mmol) to obtain a yellow solid (1.53 g, 89%) after trituration in ether / pentane: NMR spectrum 4.95 (s, 2H), 6.18 (d, 2H), 6.42 (s, 1H), 7.11 (d, 1H), 7.16 (d, 1H), 8.26 (s, 1H); Mass Spectrum MH + 323. 13J 2-chloro-N- (5-chlorobenzori.31dioxol-4-n-N- (2-methoxyethyl) pyrimidine-4-amine Following the same procedure as for (1) above, 2-chloro-N- (5-chloro-1,3-benzodioxol-4-yl) pyrimidine-4-amine (1.5 g, 5.30 mmol) was reacted with 2-bromoethyl methyl ether (0.55 ml, 5.8 mmol) to obtain a brown oil (1.2 g, 67%); NMR spectrum 3.21 (s, 3H), 3.53 (t, 2H), 3.83-3.92 (m, 1H), 4.09-4.19 (m, 1H), 6.13-6.21 (m, 3H), 7.08 (d, 1H) , 7.15 (d, 1H), 8.10 (d, 1H); Mass Spectrum MH + 342. (4) 2-r (chlorobenzoH, 31-dioxol-4-yl) - (2-chloropyrimidine-4-di-aminoethanol) Following the same procedure as for (1) above, 2-chloro-N- (5-chloro-1,3-benzodioxol-4-yl) pyrimidine-4-amine (2.0 g, 7.07 mmol) was reacted with 2-bromoethyl t-butyl ether (1.92 ml, 10.6 mmol) to obtain 2-chloro-N- (5-chlorobenxo [1,3] dioxol-4-yl) -N- [2 - [(t-butyloxy] ethyl] pyrimidine- 4-amine as a white solid (2.2 g, 81%) after chromatography on silica gel (EtOAc and petroleum ether, 1: 9); NMR spectrum 1.04 (s, 9H), 3.52 (t, 2H), 3.79-3.87 (m, 1H), 3.98-4.04 (m, 1H), 6.13 (s.2H), 6.16 (d, 1H), 7.05 (d, 1H), 7.12 (d, 1H), 8.09 (d, 1H); Mass Spectrum ?? - 384. 2-chloro-N- (5-chlorobenzo [1,3] dioxol-4-yl) - N- [2 - [(t-butyloxy] ethyl] pyrimidine-4-amine (2.1 g) was dissolved in 1: 1 mixture of methylene chloride and TFA (40 ml) and stirred at room temperature for 2 hours. was then removed and the residue dissolved in ether, washed with aqueous sodium bicarbonate and saline, dried, concentrated and purified by silica gel chromatography (EtOAc and petroleum ether, 3: 7) to obtain the base compound as a solid. white (1.06%, 44%); NMR spectrum (500 MHz, DMSOd6 + TFAd at 297 ° K) 3.59 (t, 2H), 3.70-3.78 (m, 1H), 3.99-4.08 (1H, m), 6.12 -6.18 (m, 3H), 7.06 (d, 1H), 7.14 (d, 1H), 8.08 (d, 1H): Mass Spectrum MH + 328. Final compounds N'-tS-ctorobenzori.SIdioxol- -in-N '-methyl-N-pheni'-pyrimidine-2,4-diamine Compound 211 A mixture of 2-chloro-N- (5-chloro-benzo [1,3] dioxol-4-yl) -N-methyl-pyrimidine-4-amine (50 mg, 0.17 mmol), aniline (0.19 mmol), 4N HCl in dioxane (10 ul) and 1-pentanol (1 ml) was heated at 120 ° C for 1 hour. The reaction mixture was cooled to room temperature, evaporated under reduced pressure and purified in a preparative CLAR-MS system (Column: C18, 5 microns, 19 mm diameter, 100 mm length; elution with a gradient of water and acetonitrile containing 2 g / l of ammonium carbonate); evaporation of the collected fractions and the base compound was obtained (65 mh, 61%); NMR spectrum (500 MHz, DMSOd6 + TFAd) Major rotamer: 3.43 (s, 3H), 5.97 (d, 1H), 6.18 (s, 2H), 7.06-7.22 (m, 2H), 7.24 (t, 1H) , 7.46 (t, 2H), 7.62 (d, 2H), 7.92 (d, 1H); Mass Spectrum MH '355. The procedure described above was repeated using the appropriate aniline and intermediate 2-chloropyrimidine. In this manner, the compounds described in Table 5 below were obtained. Table 5 EXAMPLE 11 Raw material 2-Chloro-N- (5-f-luorobenzo-3-thioxol-4-yl) -pyrimidine-4-amine The base compound was prepared from 5-fluorobenzo [1,3] dioxol-4-amine following the procedure described in Example 1, Step 1, except THF was used as a solvent (30% yield): NMR spectrum 6.09 (s) , 2H), 6.62 (broad s, 1H), 6.79 (dd, 1H), 6.87 (dd, 1H), 8.16 (d, 1H), 9.77 (broad s, 1H); Mass Spectrum MH + 268. Final compounds The procedure described in Example 10 (Final compounds) was repeated using the appropriate aniline and 2-chloro-N- (5-fluorobenzo [1,3] dioxol-4-yl) pyrimidine-4 -amine. In this manner, the compounds described in Table 6 below were obtained. Table 6 Example 12 Starting material N-benzof 1, 31-dioxol-4-yl-2-chloro-pyrimidin-4-amine A mixture of 2,4-dichloropyrimidine (4.0 g, 27 mmol), of 4-aminobenzodioxole (3.7 g, 27 mmol) and diethylisopropylamine (5.1 ml, 29.7 mmol) in DMF (25 ml) was stirred at 50 ° C for 18 hours, then at 80 ° C for 9 hours. After concentration under vacuum, the residue was partitioned between water and ethyl acetate and the precipitate was filtered, washed with water then ether and dried under vacuum. The organic layer of the filtrate was dried, evaporated and the residue was purified on silica gel (10 to 50% EtOAc in petroleum ether) to give a solid, which was combined with the precipitate to provide 3.35 g of the title compound Spectrum MRI 6.05 (s, 2H), 6.68 (broad s, 1H), 6.81 (d, 1H), 6.87 (t, 1H), 7.05 (broad s, 1H), 8.15 (d, 111), 9.83 (s broad) , 1 HOUR); Mass Spectrum MH + 250. Final Compounds The procedure described in Example 10 (Final compounds) was repeated using N-benzo [1,3] dioxol-4-yl-2-chloro-pyrimidin-4-amine and the appropriate aniline. Thus, the compounds described in Table 7 below were obtained. Table 7 EXAMPLE 13 Starting material N-benzoyl 1,3-dioxol-4-yl-2-chloro-N-methyl-pyrimidin-4-amine title compound was prepared following procedure as per Example 10 (starting material (1)) except that cesium carbonate was used as a base (68% yield); NMR spectrum 3.36 (s, 3H), 6.06 (s, 2H), 6.41 (broad s, 1H), 6.88-6.91 (m, 1H), 6.94-6.98 (m, 2H), 8.07 (d, 1H); Mass Spectrum MH + 264. Final Compounds The procedure described in Example 10 (Final Compounds) was repeated using N-benzo [1,3] dioxol-4-yl-2-chloro-N-methyl-pyrimidin-4-amine and the appropriate aniline Thus the compounds described in Table 8 below were obtained. Table 8 EXAMPLE 14 Starting material N- (2-methylsulfonylpyrimidin-4-yl) -1H-indazol-4-amine A mixture of 4-chloro-2-methylthiopyrimidine (2.75 ml, 23.7 mmol) and 4-aminoindazole (3.0 g, 22.5 mmol) and hydrogen chloride (1 drop, 4N in dioxane) in n-butanol (45 ml) was heated at 80 ° C for 4 hours. Diethyl ether was added and the resulting precipitate was filtered and rinsed with ether. This solid was recovered in water, the pH was adjusted to 7 by the addition of aqueous sodium bicarbonate and the solid was filtered and rinsed with water, ether and dried under vacuum to yield 5.7 g (93%) of a yellow solid. pale. NMR spectrum: (500 MHz, DMSO) 2.46 (s, 3H), 6.69 (d, 1H), 7.23 (d, 1H), 7.31 (t, 1H), 7.71 (d, 1H), 8.16 (d, 1H) ), 8.23 (s, 1H), 9.71 (s, 1H), 13.1 (broad s, 1H); Mass Spectrum: MH + 258.

M-chloroperbenzoic acid (6.81 g, 27.7 mmol) was added to an ice-cooled solution of N- (2-methylsulfanylpyrimidin-4-yl) -1 H -indazol-4-amine (3 g, 11.6 mmol) in DMF (80 mi) The mixture was then stirred at room temperature for 3 hours. The mixture was concentrated, diluted in DCM, washed with sodium bicarbonate and brine, and dried over MgSO4. After evaporation of the solvents, the residue was triturated in EtOAc / ether and dried to give N- (2-methylsulfonylpyrimidin-4-yl) -1 H -indazol-4-amine (2.4 g, 71%) as a solid. NMR spectrum: (500 MHz, DMSO) 3.31 (s, 3H), 7.13 (d, 1H), 7.32-7.38 (m, 2H), 7.66 (broad s, 1H), 8.23 (s, 1H), 8.47 ( d, 1H), 10.3 (broad s, 1H), 13.1 (broad s, 1H); Mass Spectrum: MH + 290. Final compounds N- (3,5-dimethoxyphenyl) -N '- (1 H -indazol-4-yl) pyrimidine-2,4-diamine Compound 292 A solution of 4N HCl in dioxane (0.1 ml) was added to a mixture of N- (2-methylsulfonylpyrimidin-4-yl) -1H-indazol-4-amine (87 mg, 0 3 mmol) and 3.5- dimethoxyaniline (1 eq.) in 2-pentanol (0.9 ml). The mixture was irradiated on a Personal Chemistry EMRYSTM Optimizer EXP microwave synthesizer at 170 ° C for 10 minutes. The reaction mixture was cooled to room temperature and purified in a preparative HPLC-20 EM system (Column C18, 5 microns, 19 mm in diameter, 100 mm in length, elution with a gradient of water and acetonitrile containing 2 g / 1 ammonium carbonate); evaporation of the collected fractions gave the title compound (65 mg, 61%); NMR spectrum: 3.66 (s, 6H), 6.09 (t, 1H), 6.47 (d, 1H), 7.04 (d, 2H), 7.20 (d, 1H), 7.28 (dd, 1H), 7.97 (d, 1H), 8.10 (s, 1H), 8.30 (s, 1H), 9.13 (s, 1H), 9.39 (s, 1H), 13.06 (s, 1H); Mass Spectrum MH + 363. The procedure described above was repeated using the appropriate aniline. Thus, the compounds described in Table 9 below were obtained.

EXAMPLE 15 N '- (5-ChlorobenzoM. 31d -oxo-4-yl) -N' - (2-dimethylaminoethene-N- (3-methylsulfonylphenyl) pyrimidine-2,4-d-amine Compound 305 2-Chloro-N- (5-chloro-1,3-benzodioxol-4-yl) pyrimidin-4-amine (2.0 g, 7.07 mmol) was dissolved in DMF (20 mL). Sodium hydride (60%, 680 mg, 17 mmol) was added, followed by 2-dimethylaminoethyl chloride (hydrochloride, 1.22 g, 8.5 mmol) and the mixture was heated at 50 ° C overnight. After evaporation under reduced pressure, the residue was purified on chromatography on silica gel (0-5% MeOH in methylene chloride) to yield N- (5-chlorobenzo [1,3] dioxol-4-yl) -N - (2-chloropyrimidin-4-yl) -N ', N-dimethyl-ethane-1,2-diamine as a colorless oil (8.45 mg, 33%); NMR spectrum (500 Hz, DMSOd6 + TFAd) 2.91 (d, 6H), 3.34 (t, 2H), 3.88-3.93 (m, 1H), 4.44-4.47 (m, 1H), 6.18-6.25 (m, 3H) ), 7.12 (d, 1H), 7.19 (d, 1H), 8.17 (broad, 1H); Mass Spectrum MH + 355. The procedure described in Example 10 (Final compounds) was repeated using N- (5-chlorobenzo [1,3] dioxol-4-yl) -N- (2-chloropyrimidin-4-yl) -N ', N-dimethyl-ethane-1,2-diamine (20 mg, 0.06 mmol) and 3-methylsulfonylniline hydrochloride (13 mg, 0.06 mmol) except that the mixture was heated for 3 hours. Yield: 10 mg, 36%; NMR spectrum (500 MHz, DMSOd6 + TFAd) 2.69 (s, 6H), 3.27-3.29 (m, 2H), 3.29 (s, 3H), 3.91-3.95 (m, 1H), 4.45-4.50 (m, 1H) ), 6.02 (d, 1H), 6.23 (d, 2H), 7.16 (d, 1H), 7.23 (d, 1H), 7.73-7.82 (m, 2H), 7.91 (d, 1H), 8.10 (d, 1H), 8.21 (s, 1H); Mass Spectrum MH + 490. Example 16 N '- (6-chlorobenzofuran-7-yl) -N- (3-methylsulfonylphenyl) pyrimidine-2,4-diamine Sodium hydride (13.4 g, 60% dispersion in mineral oil) was added in portions to an ice-cooled solution of 3-methylthioformanilide (6.7 g, 40 mmol) [prepared by heating 3-methylthioaniline (13.9 g) in formic acid (50 mL) for 2 h at reflux, the evaporation of the solvent was partitioned between ethyl acetate / aqueous sodium bicarbonate and chromatography on silica gel (10% EtOAc in DCM)] in THF (200 mL). The mixture was stirred at room temperature for 10 minutes, then cooled to 0 ° C. 4-Chloro-2-methylsulfonylpyrimidine was added (8.49, 44.1 mmol, L. Xu et al., J. Org. Chem. 2003, 68, 5388) in portions of the mixture. The reaction was warmed to room temperature, stirred for one hour and rapidly quenched carefully with water. The mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was triturated in 20 ml of diethyl ether to give N- (4-chloropyrimidin-2-yl) -N- (3-methylsulfanylphenyl) formamide as a solid (9 g). Aqueous 2N sodium hydroxide (20 mL, 40 mmol) was added to a solution of this solid (9 g) in THF-methanol (50 mL: 50 mL). After 15 minutes with stirring at room temperature, the mixture was evaporated under vacuum. The residue was diluted with EtOAc, washed with water and brine, dried and concentrated to give 4-chloro-N- (3-methylsulfanylphenyl) pyrimidin-2-amine (7.1 g, 71%). NMR spectrum (500 MHz, DMSO) 2.51 (s, 3H), 6.76 (d, 1H), 6.98 (m, 1H), 7.29 (m, 2H), 7.64 (s, 1H), 8.29 (d, 1H); Mass Spectrum MH + 252 M-chloroperbenzoic acid (13.6 g, 70% strength, 55 mmol) was added in portions to an ice-cooled solution of 4-chloro-N- (3-methylsulfanylphenyl) pyrimidin-2-amine (6.6) g, 26.3 mmol) in DCM (250 ml). The mixture was stirred at room temperature for 1 hour. The mixture was washed with aqueous sodium dithionate, aqueous sodium bicarbonate, then brine. After evaporation of the solvent, the residue was purified by chromatography on silica gel (15% EtOAc in DCM) to give 4-chloro-N- (3-methylsulfonylphenyl) pyrimidin-2-amine (6 g, 80%) as a solid of white color. NMR spectrum (500 MHz, DMSO) 3.20 (s, 3H), 7.07 (d, 1H), 7.58 (m, 2H), 7.99 (m, 1H), 8.39 (s, 1H), 8.52 (d, 1H) 10.44 (s, 1H); Mass Spectrum MH + 284.

Compound 306 4-Chloro-N- (3-methylsulfonylphenyl) pyrimidin-2-amine (200 mg, 0.69 mmol) and 6-chlorobenzofuran-7-amine (127 mg, 0.76 mmol, P16 P. et al., J. Med. Chem. 2004, 47, 871) in isopropanol (3 ml). 1 M HCl in diethyl ether (1 drop) was added. The reaction was heated at 90 ° C for 1 hour then cooled to room temperature and concentrated in vacuo. The residue was injected directly into a column of CLAR (C18, microns, 19 mm in diameter, 100 mm in length) of a preparative HPLC-EM system eluting with a mixture of water and acetonitrile containing 2 g / 1 of sodium carbonate. ammonium (gradient). After evaporation of the solvents, the mixture was further purified by chromatography on silica gel (eluting with 20% to 30% EtOAc in DCM) to give the title compound as a white solid (85 mg, %); NMR spectrum (500 MHz, DMSO) 3.09 (s, 3H), 6.24 (m, 1H), 7.05 (s, 1H), 7.11 (m, 1H), 7.29 (d, 1H), 7.45 (d, 1H) , 7.63 (d, 1H), 7.71 (m, 1H), 7.98 (m, 1H), 8.02 (s, 1H), 8.07 (d, 1H), 9.36 (s, 1H), 9.45 (s, 1H); Mass Spectrum MH + 415. Example 17 The procedure described above was repeated using the appropriate aniline. Thus the compounds described in Table 10 below were obtained. Table 10 Note 1: 2,3-dihydrobenzofuran-7-amine (Birch A. and colloborators J. Med. Chem., 1999, 42, 3342) Note 2: Benzofuran-7-amine (Foot P and coloaboradores, J Med. Chem, 2004, 47, 871) Note 3: 3-chloro-1 H-indol-7-amine (Foot P and coloaborators, J Med. Chem, 2004, 47, 871) Note 4: 6-methoxybenzo [1,3] d -oxo-4-amine (Astrazeneca, PCT Appl.W02002016352) Note 5: 4-aminobenzo [1,3] dioxol-5-carboxamide (Dallacker F., Annalen, 1960, 633, 14) Note 6: 5- aminoisoquinoline and 4-chloro-N- (3-methylsulfonylphenyl) pyrimidine-2 -amine were reacted using the Buchwald type conditions (procedure described in Example 24, Step 2, except that the mixture was irradiated in a microwave at 130 ° C for 15 minutes) N'-benzooxazol-7-yl-N- (3 -methylsulfonylphenyl) pyrimidine-2,4-diamine The procedure described in Example 16 was repeated using tere-butyl N- (3-amino-2-hydroxy-phenyl) carbamate [365 mg, 16 mmol; obtained from 2,6-dinitrophenol by hydrogenation with 10% palladium on carbon in ethanol to obtain 2,6-diaminophenol (quantitative) and di-tert-butyldicarbonate treatment (3.2 g, 1 equivalent) in THE (50 ml) and chromatography on silica gel (eluent: 4% EtOAc in DCM)] as aniline. After cooling, the crude mixture was concentrated and treated with 50% TFA in DCM (10 mL) for 1 hour at room temperature. After evaporation of the solvents, the residue was injected directly into a column of CLAR (C18, microns, 19 mm in diameter, 100 mm in length) of a preparative HPLC-system eluting with a mixture of water and acetonitrile which contains 2 g / 1 of ammonium carbonate (gradient) to give 2-amino-6 - [[2 - [(3-methylsulfonylphenyl) amino] pyrimidin-4-yl] amino] phenol (290 mg, 53%). NMR spectrum: (500 MHz, DMSO) 3.13 (s, 3H), 4.7 (m, 2H), 6.25 (d, 1H), 6.49 (m, 1H), 6.61 (t, 1H), 6.71 (d, 1H) ), 7.42 (m, 2H), 7.97 (m, 1H), 8.16 (d, 1H), 8.26 (s, 1H), 8.71 (s, 1H), 9.53 (s, 111); Mass Spectrum: MH + 372.

Compound 315 A mixture of 2-amino-6 [[2 - [(3-methylsulfonylphenyl) amino] pyrimidin-4-yl] amino] phenol (260 mg, 0.70 mmol), trimethylortoformate (0.614 mL, 5.6 mmol) and toluenesulfonic (5 mg) was heated at 95 ° C for 30 minutes. After evaporation of the solvent, the residue was purified by chromatography on silica gel (eluent: 60% EtOAc in DCM) to give the title compound (60 mg, 22%) as a white solid. NMR spectrum: (500 MHz, DMSO) 3.14 (s, 3H), 6.45 (d, 1H), 7.41-7.33 (m, 3H), 7.55 (d, 1H), 7.91 (d, 1H), 8.00 (d , 1H), 8.13 (d, 1H), 8.19 (s, 1H), 8.75 (s, 1H), 9.57 (s, 1H), 9.69 (s, 1H); Mass Spectrum: MH + 382. EXAMPLE 19 N'-Benzooxazol-4-yl-N- (3-methylsulfonylpheninopyrim id in-2,4-d amine Compound 316 The procedure described in Example 18 was repeated using tere-butyl N- (2-amino-6-hydroxy-phenyl) carbamate (365 mg, 1.63 mmol, Astrazeneca, PCT Int. App. WO 2003053960 p 59 Ex. 3 starting material) such as aniline: 2-amino-34 [2 - [(3-methylsulfonylphenyl) amino] pyrimidin-4-yl] amino] phenol (260 mg, 47%), brown solid; NMR spectrum: (500 MHz, DMSO) 3.14 (s, 3H), 4.30 (m, 2H), 6.05 (d, 1H), 6.48 (m, 1H), 6.62 (m, 1H), 6.73 (d, 1H) ), 7.39 (m, 2H), 7.96 (d, 1H), 8.20 (m, 2H), 8.51 (s, 1H), 9.30 (m, 1H), 9.43 (s, 1H); Mass Spectrum: MH + 372. N'-benzooxazol-4-yl-N- (3-methylsulfonylphenyl) pyrimidine-2,4-diamine (90 mg, 36%), white solid; NMR spectrum: (500 MHz, DMSO) 3.16 (s, 3H), 6.68 (d, 1H), 7.50-7.39 (m, 4H), 8.14 (d, 2H), 8.32 (m, 2H), 8.76 (s) , 1H), 9.63 (s, 1H), 9.67 (s, 1H); Mass Spectrum: MH + 382. EXAMPLE 20 3-í4- (1 H -indazol-4-yl-methyl-amino) pyrimidin-2-yn-N-dimethyl-benzamide A mixture of 4-chloro-2-methylthiopyrimidine (2.4 ml, 20.7 mmol) and 1-benzylindazole-4-amine (4.15 g, 18.6 mmol, Kampe W. et al., Ger. Offen DE2737630) and hydrogen chloride (1 drop, 4N in dioxane) in n-butanol (55 ml) was heated to reflux for 3 hours. After cooling and evaporation of the solvent, the residue was stirred with water. The pH was adjusted to 7 by the addition of aqueous sodium bicarbonate and the mixture was extracted with DCM. The organic layer was washed with water and brine, and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluent: 10% s 70% EtOAc in petroleum ether) to give 1-benzyl-N- (2-methylsulfanylpyrimidin-4-yl) indazol-4-amine (5.6 g, 78%) as an orange solid. NMR spectrum: (500 IvlHz, DMSO) 2.36 (s, 3H), 5.65 (s, 2H), 6.69 (d, 1H), 7.40-7.20 (m, 7H), 7.76 (d, 1H), 8.17 (d) , 1H), 8.28 (s, 1H), 9.73 (s, 1H); Mass Spectrum: MH + 348.

Methyl iodide (1 ml, 16.1 mmol) was added to a mixture of 1-benzyl-N- (2-methylsulfanylpyrimidin-4-yl) indazol-4-amine (5.6 g, 16.1 mmol) and cesium carbonate (10.5 g). , 32.3 mmol) in acetonitrile (60 ml). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with acetonitrile and the solids filtered. After evaporation of the solvents, the residue was dissolved in DCM, filtered and purified by chromatography on silica gel (eluent: 10 to 40% EtOAc in petroleum ether) to give benzyl-N-methyl-N- (2 -methylsulfanylpyrimidin-4-yl) indazol-4-amine (5 g, 86%) as a solid. NMR spectrum: (500 MHz, DMSO) 2.41 (s, 3H), 3.52 (s, 3H), 5.70 (s, 2H), 5.95 (d, 1H), 7.13 (d, 1H), 7.34-7.25 (m , 5H), 7.47 (t, 1H), 7.75 (d, 1H), 7.91 (d, 1H), 7.96 (s, 1H).

Potassium tert-butoxide (97 ml, 97 mmol, 1M solution in THF) was added to a mixture of 1-benzyl-N-methyl-N- (2-methylsulfanylpyrimidin-4-yl) pindazol-4-amine (5 g). , 13.85 mmol) in DMSO (9.9 ml) -THF (20 ml) at room temperature. Oxygen was bubbled through the solution for 20 minutes while maintaining the temperature below 30 ° C with a cooling bath. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluent: 10% to 70% EtOAc in petroleum ether) to give N-methyl-N- (2-methylsulfanylpyrimidin-4-yl) -1 H-indazol-4-amine (3.1 g, 83%) as a white solid. NMR spectrum: (500 MHz, DMSO) 2.44 (s, 3H), 3.52 (s, 3H), 5.91 (d, 1H), 7.09 (d, 1H), 7.44 (t, 1H), 7.56 (d, 1H) ), 7.91 (m, 2H), 13.34 (broad s, 1H).

M-chloroperbenzoic acid (6.81 g, 27.7 mmol) was added to an ice-cooled solution of N-methyl-N- (2-methylsulfanylpyrimidin-4-yl) -1H-indazol-4-amine (3 g, 11 l). mmol) in DMF (80 ml). The mixture was then stirred at room temperature for 4 hours. The mixture was concentrated, diluted in DCM, washed with sodium bicarbonate and brine, and dried over MgSO4. After evaporation of the solvents, the residue was triturated in ether and dried to give N-methyl-N- (2-methylsulfonylpyrimidin-4-yl) -1 H -indazol-4-amine (2.4 g, 72%) as a white solid. NMR spectrum: (500 MHz, DMSO) 3.30 (s, 3H), 3.59 (s, 3H), 6.39 (m, 1H), 7.18 (d, 1H), 7.48 (t, 1H), 7.63 (d, 1H) ), 7.99 (s, 1H), 8.23 (d, 1H).

Compound 317 A mixture of N-methyl-N- (2-methylsulfonylpyrimidin-4-yl) -1 H -indazol-4-amine (200 mg, 0.66 mmol), 3-amino-N, N-dimethyl-benzamide (130 mg, 0.79 mmol) and hydrogen chloride (4N in dioxane, 0.165 mL, 0.66 mmol) in 2-pentanol (3 mL) was irradiated on a Personal Chemistry EMRYSTM Optimizer EXP microwave synthesizer at 150 ° C for 10 minutes. After cooling and evaporation of the solvents, the residue was dissolved in DMF (1.5 ml) and concentrated aqueous ammonia (50 pl) was added. The mixture was injected into a column of CLAR (C18, 5 microns, 19 mm in diameter, 100 mm long) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g / 1 of ammonium carbonate (gradient). Evaporation of the fractions gave the title compound (69 mg, 27%). NMR spectrum: (500 MHz, DMSO) 2.90-2.97 (broad s, 31-1), 2.97 (broad s, 311), 3.55 (s, 3H), 5.74 (d, 1H), 6.86 (d, 1H) , 7.10 (d, 1H), 7.22 (dd, 1H), 7.45 (dd, 1H), 7.55 (d, 1H), 7.75 (d, 1H), 7.80 (d, 1H), 7.88 (d, 1H), 7.92 (s, 1H), 9.34 (s, 1H), 13.31 (s broad, 1H); Mass Spectrum: MH + 388. EXAMPLE 21 The procedure described in Example 20 above was repeated using the appropriate aniline in the last step. Thus the compounds described in Table 11 below were obtained.

Table 11 Example 22 N- (3,5-dimorpholin-4-yl-n-N '- (1 H -indazol-4-yl) pyrimidine-2,4-diamine A mixture of 3,5-d-morpholin-4-ylalanyl (500 mg, 1.90 mmol) in formic acid (8 mL) was refluxed for 2 hours. After cooling, the mixture was concentrated and the residue was dissolved in EtOAc, washed with saturated aqueous sodium bicarbonate and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluent: 1% to 4% methanol in DCM) to give 3,5-dimorpholin-4-ylformanilide (400 mg, 58%) as a solid. Mass Spectrum: MH + 292. 3,5-dimorpholin-4-ylformanilide (400 mg, 1.37 mmol) and 4-chloro-2-methylsulfonylpyrimidine (291 mg, 1.51 mmol) were reacted according to the procedure in Example 16, step 1, to give 4- chloro-N- (3,5-dimorpholin-4-ylphenyl) pyrimidin-2-amine (314 mg, 61%) as a solid. NMR spectrum: (500 MHz, DMSO) 3.06 (m, 8H), 3.72 (m, 8H), 6.19 (s, 1H), 6.91 (m, 3H), 8.41 (d, 1H), 9.74 (s, 1H) ); Mass Spectrum: MH + 376.

Compound 323 4-chloro-N- (3,5-dimorpholin-4-ylphenyl) pyrimidin-2-amine (100 mg, 0.27 mmol) and 4-aminoindazole (39 mg, 0.29 mmol) were reacted according to the procedure in Example 16, step 3, to give the title compound (70 mg, 56%) as a solid. NMR spectrum: (500 MHz, DMSO) 2.96 (m, 8H), 3.66 (m, 8H), 6.09 (s, 1H), 6.42 (d, 1H), 6.88 (s, 2H), 7.18 (d, 1H) ), 7.25 (t, 1H), 7.91 (m, 1H), 8.07 (d, 1H), 8.27 (s, 1H), 8.87 (s, 1H), 9.33 (s, 1H), 13.03 (m, 1H); Mass Spectrum: Mhf 473. EXAMPLE 23 The procedure described above in Example 22, step 3 was prepared using the appropriate aniline. Thus the compounds described in Table 12 below were obtained.

Note 1: 3-chloro-1 H-indazol-4-amine was made as follows: 3-chloro-4-nitro-1 H-indazole (500 mg, 2.54 mmol, M. Benchidmi et al., J. Het. ., 1979, 16, 1599) in ethanol (20 ml) was hydrogenated at atmospheric pressure in the presence of platinum (IV) oxide (50 mg) at room temperature for 1 hour. After filtration of the catalyst, the mixture was concentrated and purified by chromatography on silica gel (eluent: 0% to 6% EtOAc in DCM) to give 3-chloro-1 H-indazol-4-amine (242 mg, 57% ) as an orange solid. NMR spectrum: (500 MHz, DMSO) 5.57 (s, 2H), 6.21 (d, 1H), 6.61 (d, 1H), 7.05 (t, 1H), 12.84 (m, 1H); Mass Spectrum: MH + 168. Note 2: 3-methyl-1 H-indazol-4-amine was made as follows: A solution of dimethylzinc (2.07 mL, 4.14 mmol, 2M in toluene was added dropwise to a mixture of 3-bromo-4-nitro-1H-indazole (500 mg, 2.07 mmol, M. Benchidmi et al, J. Het Chem., 1979, 16, 1599) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium ( 11) (43 mg, 0.062 mmol) in 1,4-dioxane (8 mL) under argon.The mixture was heated under reflux for 2 hours.After cooling, methanol (0.5 mL) was added, followed by 2N hydrochloric acid ( 3 mL) and DCM (10 mL) This mixture was stirred for 30 minutes, the organic layer was collected, washed with saturated aqueous sodium bicarbonate, water and brine, and dried over MgSO4, this solution was concentrated under vacuum to give 3-methyl-4-nitro-1 H-indazole (235 mg, 64%) as a solid used without purification in the next step: NMR spectrum: (500 MHz, DMSO) 2.61 (s, 3H), 7.52 (m , 1H), 7.93 (m, 2H), 13.54 (m, 1H); Mass Spectrum: MH + 178. 3-methyl-4-nitr-1 H-indazole (100 mg, 0.56 mmol) in ethanol (10 mL) was hydrogenated at atmospheric pressure in the presence of platinum (IV) oxide (10 mg) at room temperature for 1 hour. After filtration of the catalyst, the mixture was concentrated to give 3-methyl-1 H-indazol-4-amine (90 mg, 75%) as a yellow solid. NMR spectrum: (500 MHz, DMSO) 2.58 (s, 3H), 5.26 (s, 2H), 6.12 (d, 1H), 6.55 (d, 1H), 6.92 (t, 1H), 12.14 (m, 1H) ); Mass Spectrum: MH + 148. EXAMPLE 24 N'-Benzooxazol-7-yl-N- (3,5-dimorpholin-4-ylphenyl) pyrimidine-2,4-diamine A mixture of benzooxazol-7-amine (135 mg, 1.01 mmol, Astrazeneca, PCT Appl. WO2003053960), 2,4-dichloropyrimidine (150 mg, 1.01 mmol), DBU (0.197 mL, 1.32 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (58 mg, 0.1 mmol, also called xantho) and tris (dibenzylidenacetone) dipalladium (0) (58 mg, 0.1 mmol, also called Pd2dba3) in dioxane (3 mL) under argon were irradiated in a Personal Chemistry EMRYS ™ Optimizer EXP microwave synthesizer at 110 ° C for 10 minutes. After cooling and evaporation of the solvents, the residue was dissolved in DCM and purified by chromatography on silica gel (eluent: 30% to 60% EtOAc in in petroleum ether) to give N- (2-chloropyrimidin-4-yl) ) benzooxazol-7-amine (88 mg, 35%) as a beige solid. Mass Spectrum: MH + 247.

Compound 327 A mixture of N- (2-chloropyrimidin-4-yl) benzooxazol-7-amine (75 mg, 0.3 mmol), 3,5-dimorpholin-4-ylaniline (79 mg, 0.3 mmol), DBU (60 μm) 1, 0.4 mmol), xantphos (17 mg, 0.03 mmol) and Pd2dba3 (17 mg, 0.03 mmol) in dioxane (2 ml) under argon was irradiated on a microwave synthesizer Personal Chemistry EMRYS ™ Optimizer EXP at 150 ° C for 20 minutes. minutes After cooling, concentrated aqueous ammonium (2 drops) was added and the mixture was injected into a column of CLAR (C18, 5 microns, 19 mm in diameter, 100 mm in length) a preparative HPLC-EM system eluting with a mixture of water and acetonitrile containing 2 g / l of ammonium carbonate (gradient). Evaporation of the fractions afforded the title compound (20 mg, 14%). NMR spectrum: (500 MHz, DMSO) 2.92 (m, 8H), 3.65 (m, 8H), 6.06 (s, 1H), 6.352 (d, 1H), 6.82 (s, 2H), 7.33 (t, 1H) ), 7.50 (d, 1H), 7.98 (broad, 1H), 8.06 (d, 1H), 8.74 (s, 1H), 8.85 (s, 1H), 9.55 (s, 1H); Mass Spectrum: MH + 474. Example 25 N'-benzooxazol-7-yl-N- (3,5-dimorpholinophenyl) -N'-methyl-pyrimidine-2,4-diamine (compound 328) N- (2-chloropyrimidin-4) -yl) benzooxazol-7-amine (600 mg, 2.44 mmol) was reacted with methyl iodide according to the procedure of Example 10 (starting material (I)) to give N- (2-chloropyrimidin-4-yl) -N-methyl-benzooxazol-7-amine (363 mg, 57%) as a gum. NMR spectrum: (500 MHz, DMSO) 3.50 (s, 3H), 6.43 (m, 1H), 7.53 (m, 2H), 7.84 (m, 1H), 8.10 (m, 1H), 8.79 (s, 1H) ). N- (2-chloropyrimidin-4-yl) -N-methyl-benzooxazol-7-amine (180 mg, 0.69 mmol) was reacted with 3,5-dimorpholin-4-ylaniline according to the procedure in Example 24, Step 2 to give the title compound (15 mg, 4%) as a white solid; NMR spectrum (500 MHz, DMSO) 2.99-3.05 (m, 8H), 3.53 (s, 3H), 3.67-3.73 (m, 8H), 5.75 (d, 1H), 6.10 (t, 1H), 6.93 ( d, 2H), 7.45 (d, 1H), 7.48 (d, 1H), 7.50 (s, 1H), 7.78 (dd, 1H), 7.92 (d, 1H), 8.90 (broad, 1H); Mass Spectrum: MH + 488. EXAMPLE 26 N- (3,5-Dimorpholin-4-ylphenn-N'-methyl-N '- (3-methyl-1 H -indazol-4-iPpyrimidine-2,4- diamine (compound 329) Yodide (9.31 g, 36.8 mmol) and potassium hydroxide (3.81 g, 68. 1 mmol) were added to a solution of 4-nitro-1 H-indazole (3 g, 18.4 mmol) in DMF (40 mL) at room temperature. The mixture was stirred at room temperature for 2.5 hours, and poured into 10% aqueous sodium hydrogensulfite (200 ml). The precipitate was filtered, washed with water and dried over phosphorus pentoxide to give 3-iodo-4-nitro-1 H-indazole (5 g, 94%) as a light yellow solid. NMR spectrum: (500 MHz, DMSO) 7.60 (t, 1H), 7.86 (d, 1H), 8.00 (d, 1H), 14.3 (m, 1H); Mass Spectrum: M-H_ 288. Potassium tert-butoxide (23.5 mL, IM in THF, 23.5 mmol) was added dropwise to an ice-cooled solution of 3-iodo-4-nitro-1 H-indazole ( 4.85 g, 16.8 mmol) in THF (30 mL) under argon. The mixture was stirred at 0 ° C for 1 hour. 4-Methoxybenzyl chloride (2.5 ml, 18.5 mmol) and tetrabutylammonium iodide (63 mg, 0.17 mmol) were added and the mixture was stirred at 70 ° C for 2.5 hours. The mixture was cooled and concentrated under vacuum. The residue was dissolved in ethyl acetate, washed with water and brine and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluent: 10% to 40% EtOAc in petroleum ether) to give 3-iodo-1 - [(4-methoxyphenyl) methyl] -4 -nitro-indazole (4.4 g, 64%) as a solid. NMR spectrum: (500 MHz, DMSO) 3.71 (s, 3H), 5.71 (s, 2H), 6.89 (d, 2H), 7.25 (d, 2H), 7.64 (t, 1H), 7.87 (d, 1H) ), 8.27 (d, 1H). A solution of dimethylzinc (9.05 ml, 18.1 mmol, 2M in toluene) was added dropwise to a mixture of 3-iodo-1 - [(4-methoxyphenyl) methyl] -4-nitro-indazole (3.7 g, 9.05 mmol ) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (189 mg, 0.27 mmol) in 1,4-dioxane (30 ml) under argon. The mixture was heated at 100 ° C for 1.5 hour. After cooling, methanol (3 ml) was added, followed by 2N hydrochloric acid until the pH became acidic. This mixture was stirred for 10 minutes, extracted with EtOAc, washed with saturated aqueous sodium bicarbonate, water and brine, and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluent: 10% to 25% EtOAc in petroleum ether) to give 1 - [(4-methoxyphenyl) methyl] -3-methyl-4 -nitro-indazole (1.07 g, 40%) as a yellowish solid. NMR spectrum: (500 MHz, DMSO) 2.59 (s, 3H), 3.70 (s, 3H), 5.61 (s, 2H), 6.87 (d, 2H), 7.22 (d, 2H), 7.56 (t, 1H) ), 7.92 (d, 1H), 8.19 (d, 1H). 1 - [(4-methoxyphenyl) methyl] -3-methyl-4-nitro-indazole (1 g, 3.37 mmol) in ethanol (30 ml) was hydrogenated at atmospheric pressure in the presence of platinum (IV) oxide (80 mg) ) at room temperature for 1 hour. After filtration of the catalyst, the mixture was concentrated to give 1 - [(4-methoxyphenyl) methyl] -3-methylindazol-4-amine (900 mg, 100%) as a yellow gum. NMR spectrum: (500 MHz, DMSO) 2.58 (s, 3H), 3.68 (s, 3H), 5.30 (s, 2H), 5.33 (s, 2H), 6.15 (d, 1H), 6.66 (d, 1H) ), 6.84 (d, 2H), 6.95 (t, 1H), 7.13 (d, 2H); Mass Spectrum: MH + 268. A mixture of 4-chloro-2-methylthiopyrimidine (0.4 ml, 3.45 mmol), 1 - [(4-methoxyphenyl) methyl] -3-methylindazol-4-amine (0.83 g, 3.11 mmol) and hydrogen chloride (1 drop, 7N in dioxane) in n-butanol (10 mL) was heated at 80 ° C for 2 hours. After cooling and evaporation of the solvents, water was added. The pH was adjusted to 8 by the addition of aqueous ammonia and the mixture was extracted with EtOAc. The precipitate that formed at the interface was filtered, washed with water and ether and dried to give a solid. The organic layer was washed with water and brine, and dried over MgSO4. After evaporation of the solvents, the residue was triturated with ether. The two batches were combined to give 1 - [(4-methoxyphenyl) methyl] -3-methyl-N- (2-methylsulfanylpyrimidin-4-yl) indazol-4-amine (1 g, 74%) as a solid of color White. NMR spectrum: (500 MHz, DMSO) 2.31 (s, 3H), 2.41 (s, 3H), 3.70 (s, 3H), 5.47 (s, 2H), 6.28 (d, 1H), 6.86 (d, 2H) ), 7.02 (d, 1H), 7.19 (d, 2H), 7.33 (t, 1H), 7.50 (d, 1H), 8.05 (d, 1H), 9.41 (s, 1H); Mass Spectrum: MH + 392. Methyl iodide (0.17 mL, 2.69 mmol) was added to a mixture of 1 - [(4-methoxyphenyl) methyl] -3-methyl-N- (2-methylsulfanylpyrimidin-4-yl) indazole -4-amine (1 g, 2.56 mmol) and cesium carbonate (1.25 g, 3.84 mmol) in acetonitrile (6 mL). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with acetonitrile and the solids filtered. After evaporation of the solvents, the residue was dissolved in DCM, filtered and purified by chromatography on silica gel (eluent: 10 to 40% EtOAc in petroleum ether) to give 1 - [(4-methoxyphenyl) methyl] - N, 3-dimethyl-N- (2-methylsulfanylpyrimidin-4-yl) indazol-4-amine (0.7 g, 67%) as a solid. Mass Spectrum: MH + 406. M-chloroperbenzoic acid (909 mg, 3.7 mmol) was added to an ice-cooled solution of 1 - [(4-methoxyphenyl) methyl] -N, 3-dimethyl-N- (2-methylsulfanylpyrimidine) -4-yl) indazol-4-amine (600 mg, 1.48 mmol) in DMF (17 ml). The mixture was then stirred at room temperature for 1.5 hour. 10% aqueous sodium metabisulfite was added. The mixture was concentrated, diluted in DCM, washed with sodium bicarbonate and brine, and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluent: 10 to 50% EtOAc in petroleum ether) to give 1 - [(4-methoxyphenyl) methyl] -N, 3-dimethyl. -N- (2-methylsulfonylpyrimidin-4-yl) indazol-4-amine (0.6 g, 92%) as a solid. NMR spectrum: (500 MHz, DMSO) 2.17 (s, 3H), 3.39 (s, 3H), 3.51 (s, 3H), 3.71 (s, 3H), 5.53 (m, 2H), 6.04 (d, 1H) ), 6.89 (d, 2H), 7.12 (d, 1H), 7.28 (d, 2H), 7.50 (t, 1H), 7.82 (d, 1H), 8.15 (d, 1H). A mixture of 1 - [(4-methoxyphenyl) methyl] -N, 3-dimethyl-N- (2-methylsulfonylpyrimidin-4-yl) indazol-4-amine (200 mg, 0.46 mmol), 3,5-dimorpholine- 4-ilaniline (127 mg, 0.46 mmol) and hydrogen chloride (4N in dioxane, 7 drops) in 2-pentanol (4 ml) was irradiated in a microwave synthesizer Personal Chemistry EMRYS ™ Optimizer EXP at 150 ° C for 30 minutes . After the cooling and evaporation of the solvents, water was added. The pH was adjusted to pH 7 by the addition of aqueous ammonium. The mixture was extracted with EtOAc. The organic layer was washed with sodium bicarbonate and brine, and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluent: 0 to 5% methanol in EtOAc-DCM (1: 4)) to give N- (3,5-dimorpholine). 4-ylphenyl) -N '- [1 - [(4-methoxyphenyl) methyl] -3-methyl-indazol-4-yl] -N'-methyl-pyrimidine-2,4-diamine (71 mg, 25%); Mass Spectrum: MH + 621. A mixture of N- (3,5-dimorpholin-4-ylphenyl) -N '- [1 - [(4-methoxyphenyl) methyl] -3-methyl-indazol-4-yl] - N'-methyl-pyrimidine-2,4-diamine (100 mg, 0.16 mmol) and anisole (1 drop) in TFA (1 mL) was irradiated on a Personal Chemistry EMRYS ™ Optimizer EXP microwave synthesizer at 130 ° C for 40 minutes. minutes After cooling and evaporation of the solvents, the residue was dissolved in DCM. A few drops of 6N ammonia in methanol followed by water (0.5 ml) were added. The organic layer was collected and purified by chromatography on silica gel (eluent: 0 to 5% methanol in DCM). Trituration of the resulting solid in ether gave the title compound (54 mg, 67%) as a white solid. NMR spectrum: (500 MHz, DMSO) 2.20 (s, 3H), 3.07 (m, 8H), 3.56 (s, 3H), 3.72 (m, 8H), 5.23 (s broad, 1H), 6.12 (s broad) , 1H), 7.02 (m, 3H), 7.41 (m, 1H), 7.51 (m, 1H), 7.75 (s broad, 1H), 8.89 (broad s, 1H), 12.9 (m, 1H); Mass Spectrum: MH + 501. Example 27 N'-methyl-N '- (3-methyl-1H-indazol-4-in-N- (3-methylsulfonylphenyl) pyrimidine-2,4-diamine (compound 330) The last 2 steps of the procedure in Example 26 were repeated using 1 - [(4-methoxyphenyl) methyl] -N, 3-dimethyl-N- (2-methylsulfonylpyrimidin-4-yl) indazol-4-amine (286 mg, 0.65 mmol) and 3-methylsulfonylaniline hydrochloride (142 mg, 0.65 mmol) to give the title compound (61 mg, 23% over 2 steps). NMR spectrum: (500 MHz, DMSO) 2.20 (s, 3H), 3.17 (s, 3H), 3.53 (s, 3H), 5.34 (broad s, 1H), 7.03 (broad, 1H), 7.43 (m, 2H), 7.54 (m, 2H), 7.91-7.82 (m, 2H), 8.82 (s broad, 1H), 9.70 (broad s, 1H), 12.9 (m, 1H); Mass Spectrum: MH + 409. Example 28 4-chloro-N- (3,5-dimorpholin-4-ylphenyl) pyrimidine- 2-amine (70 mg, 0.19 mmol) and the corresponding aniline (0.22 mmol) were dissolved in pentanol (1 mL) 4M HCl in dioxane (0.1 mL) was added.The reaction was heated at 100 ° C for 15 hours after cooled to room temperature and concent Ró in vacuo. The residue was dissolved in DMF (1 ml) and injected directly into a CLAR column (C18, 5 microns, 19 mm in diameter, 100 mm in length) of a preparative HPLC-system eluting with a mixture of water and acetonitrile containing 2 g / l of ammonium carbonate (gradient). Evaporation of the solvents gave the title compound as a solid. The Examples in Table 13 below were made according to the above procedure. Table 13 Note l: 3-chloro-1 H-indol-7-amine (AstraZeneca, PCT Application W0200234744) Method Section Method 1 1 -fluoro-3-methyl Isulfon i-5-nitro-benzene A mixture of 1-fluoro -3-iodo-5-nitrobenzene (1.95 g), copper iodide (I) (2.23 g) and sodium methansulfinate (0.75 g, 85%) in DMF (25 ml) was heated to 110 ° C. overnight, then poured into a mixture of ethyl acetate and water and filtered. The organic layer was separated, dried and concentrated in vacuo and the residue was triturated with methanol to give the title compound as a brown solid (0.6 g, 37%); NMR spectrum (300 MHz, DMSO) 3.40 (s, 3H), 8.31 (m, 1H), 8.52 (m, 2H); Mass Spectrum M + 219.0. The procedure described above was prepared using the appropriate iodobenzene. Thus, the Example described below was obtained: Method 2 4- (3-methylsulfonyl-5-n-tro-phenyl) morpholine Morpholine (0.77 ml) and 1-fluoro-3-methylsulfonyl-5-nitro-benzene (0.35 g - Method 1) in DMSO (15 g. mi) were heated at 100 ° C for 6 hrs. The solution was cooled, poured into water and the resulting precipitate was filtered and dried to give the title compound as an orange solid (0.39 g, 85%); NMR spectrum (300 MHz, DMSO) 3.25-3.42 (m + s, 7H), 3.76 (m, 4H), 7.75 (m, 1H), 57.94 (m, 2H). The procedure described above was prepared using the appropriate fluorobenzene. Thus, the Examples described below were obtained: Method 3 4- (3-fluoro-5-nitro-pheninmorpholine and 4- (3-morpholin-4-yl-5-nitro-pheno-phopholine) Morpholine (12 ml) and 1,3-difluoro-5-nitrobenzene (4 g) in DMSO (50 ml) were heated at 100 ° C for 4 days. The solution was cooled, poured into water and the resulting precipitate was filtered and dried. This was purified by chromatography using 25% to 60% ethyl acetate in iso-hexane as eluent to give first 4- (3-fluoro-5-nitro-phenyl) morpholine as a yellow solid (2.86 g, 50%). %); NMR spectrum (300 MHz, DMSO) 3.30 (m, 4H), 3.72 (m, 4H), 7.24 (m, 1H), 7.38 (m, 1H), 7.52 (m, 1H); followed by 4- (3-morpholin-4-yl-5-nitro-phenyl) morpholine as an orange solid (2.11 g, 29%); Mass Spectrum MH + 294.50. Method 4 3,5-dinitrobenzenesulfonamide Thionyl chloride (20 ml) was added dropwise to water (70 ml) at 0 ° C with vigorous stirring. The solution was stirred for 1 hour at 5 ° C and at 18 ° C for 50 minutes. Copper (I) chloride (0.16 g) was added to give a pale vede solution which was stirred at room temperature for 5 minutes then cooled to -1 ° C. Separately, 3,5-dinitroaniline (5 g) was added to HCI c. (25 ml) and stirred for 1 hour at room temperature. The solution was cooled to -10 ° C and treated dropwise with a solution of sodium nitrite (2.26 g) in water (20 ml). The resulting dark orange solution was stirred at -10 ° C for 10 minutes then added at -5 ° C to the copper (I) chloride solution of the first stage for 5 minutes. The reaction was stirred at -5 ° C for 1 hour then filtered to give a pale pink solid dried in vacuo. This solid was added in portions to a solution of ammonium in methanol (7N, 200 ml) at 0 ° C and the reaction was stirred for 2 hrs then concentrated in vacuo. The resulting solid was triturated with methanol, then water and filtered and dried to give the title compound as a beige solid (2.88 g, 43%); NMR spectrum (300 MHz, DMSO) 7.86 (broad s, 2H) 5 8.80 (m, 2H), 8.90 (m, 1H): Mass Spectrum M + 246.39. Method 5 3-m or rf ol i n-4-yl-5-n i tro-benzoic acid Sodium hydroxide (1.8 ml, 2N) was added to a solution of ethyl 3-morpholin-4-yl-5-nitro-benzoate (337 mg - Method 2b) in methanol (10 ml) and THF (10 ml) and it was stirred for 3 hours at room temperature. Water (3 ml) was added, followed by HCI ac. (1.6 ml, 2N) and the resulting precipitate was filtered and dried to give the title compound as a yellow solid (0.23 g, 76%); Mass Spectrum MH * 253.44. Method 6 3-Methylsulfonyl-5-nitro-benzoic acid 3-Methylsulfonylbenzoic acid (0.75 g) was added to sulfuric acid c. (1.2 ml) and heated to 80 ° C. Steamy nitric acid (0.6 ml) was added dropwise maintaining the temperature at 80-85 ° C, and the reaction was stirred at this temperature for 2 hours. The reaction was cooled to room temperature and poured into 20 mL of ice-water to give a white solid which was filtered, washed with water and dried in vacuo to give the title compound as a white solid (0.69. g, 75%); NMR spectrum (300 MHz, DMSO) 3.44 (s, 3H), 8.75 (t, 1H), 8.84-8.87 (m, 2H). Method 7 3-morpholin-4-yl-5-nitro-benzamide HATU (0.45 g) was added to a solution of 3-morpholin-4-yl-5-nitro-benzoic acid (0.23 g - Method 5), ammonium chloride (146 mg) and DIPEA (0.21 ml) in DMF (1 g). mi) and the reaction was stirred overnight. The solution was concentrated in vacuo and partitioned between ethyl acetate and the saturated aqueous sodium bicarbonate solution. The organic layer was dried and concentrated to give the title compound as a yellow solid (0.2 g, 87%); Mass Spectrum ?? - 252.47. The procedure described above was prepared using the appropriate acid. Thus, the compounds described below were obtained: Method 8 3-fluoro-5-methylsulfonyl-aniline A mixture of 1-fluoro-3-methylsulfonyl-5-nitro-benzene (0.2 g - Method 1) and 10% Pd / C (50 mg) in ethanol (20 ml) was stirred under a hydrogen atmosphere overnight . The solution was filtered and concentrated to give the title compound as a pale brown oil (0.18 g, 100%); Mass Spectrum M + 189.03. The procedure described above was prepared using the appropriate nitrobenzene. Thus, the Examples described below were obtained: Method 9 N- (3-amino-5-methylsulfonyl-phenyl) methanesulfonamide Methanesulfonyl chloride (62 μ?) Was added to a solution of 5-methylsulfonylbenzene-1,3-diamine (0.15 g - Method 8c) and pyridine (0.33 ml) in DCM (15 ml) and the reaction was stirred for two hours at room temperature. The solution was washed with water, dried and concentrated and the residue was purified by chromatography to give the title compound as a brown oil (45 mg, 21%); Mass Spectrum MH * 265.36. The procedure described above was prepared using the appropriate aniline. Thus, the compounds described below were obtained: Method 10 (3-amino-5-morpholin-4-yl-phenyl) methanol (3-amino-5-morpholin-4-yl-phenyl) methanol Lithium aluminum hydride (0.48 mL, 1M in THF) was added dropwise to ethyl 3-amino-5-morpholin-4-yl-benzoate (0.1 g-8 g method) in THF (3 mL) and the mixture it was stirred overnight at room temperature. Water (0.1 ml) was added, followed by aqueous sodium hydroxide (0.1 ml, 1M), then magnesium sulfate (1 g) and diethyl ether (10 ml) were added. The mixture was stirred at room temperature for 20 minutes then filtered and washed with ether. The filtrate was concentrated in vacuo and the residue was purified by chromatography using 0 to 10% methanol in DCM as eluent to give the title compound as an orange solid (80 mg, 96%); NMR spectrum (300 MHz, DMSO) 2.99 (m, 4H), 3.70 (m, 4H), 4.30 (m, 2H), 4.85 (broad s, 2H), 6.02 (m, 1H), 6.07 (s, 1H) ), 6.11 (s, 1H); Mass Spectrum MH + 209.52. The procedure described above was prepared using the appropriate ester. Thus, the compound described below was obtained: Method 11 ethyl 3-methanesulfonamido-5-morpholin-4-yl-benzoate Methanesulfonyl chloride (127 μg) was added to a solution of ethyl 3-amino-5-morpholin-4-yl-benzoate (0.344 g - Method 8g) and pyridine (0.54 ml) in THF (3 ml) and the The reaction was stirred overnight at room temperature. The solution was concentrated in vacuo and the residue was partitioned between 1M HCl and diethyl ether. The organic layer was concentrated and triturated with diethyl ether and iso-hexane to give the title compound as a yellow solid (404 mg, 89%); NMR spectrum (300 MHz, DMSO) 1.22 (t, 3H), 3.03 (m, 4H), 3.65 (m, 4H), 4.21 (q, 2H), 6.91 (m, 1H), 7.14 (m, 1H) 7.20 (m, 1H), 9.68 (s, 1H); Mass Spectrum MH + 329.49. The procedure described above was prepared using the appropriate aniline. Thus, the Example described below was obtained: Method 12 Acid 3-methan its lfonamido-5-morfol i? -4-i I -benzoic Lithium hydroxide (71 mg) and ethyl 3-methanesulfonamido-5-morpholin-4-yl-benzoate (404 mg - Method 11) in THF (3 mL) and water (0.1 mL) were stirred for 48 hours then concentrated in vacuo The residue was dissolved in water (5 ml) and the pH adjusted to 5. The resulting precipitate was filtered and dried to give the title compound as a yellow solid (0.26 g, 71%); Mass Spectrum ?? - 301.47. Method 13 N- (3-methansulfonamido-5-morpholin-4-yl-phenincarbamate tere-butyl) Diphenylphosphoryl azide (0.224 ml) was added to a solution of 3-methanesulfonamido-5-morpholin-4-yl-benzoic acid (0.26 g -Method 12) and DI PEA (0.18 ml) in tert-butanol (10 ml) and the reaction was heated at 80 ° C for 5 hours. The reaction was concentrated in vacuo and the residue was purified by chromatography using 0 to 100% ethyl acetate in iso-hexane then 5% methanol in DCM as eluent to give the title compound as a white foam (150 mg , 35%); Mass Spectrum MH + 372.49.

Method 14 N- (3-amino-5-morfoMn-4-yl-phenyl) methanesulfonamide N- (3-methanesulfonamido-5-morpholin-4-yl-phenyl) carbamate tere-butyl (0.15 g - Method 13) and HCl c. (3 mL) in methanol (5 mL) were heated at 70 ° C for 5 hours then cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, and the combined organic layers were dried and concentrated and the residue was purified by chromatography using ethyl acetate as eluent followed by trituration with ethyl acetate-diethylether-sodium acetate. hexane to give the title compound as a white solid (24 mg, 22%); NMR spectrum (300 MHz, DMSO) 2.92 (s, 3H) 5 2.96 (m, 4H), 3.70 (m, 4H) 3 5.90 (m, 1H), 6.00 (m, 2H), 9.20 (s broad, 1H ); Mass Spectrum MH + 272.46. Method 15 2-chloro-5- (hydroxymethyl) -3-nitro-benzenesulfonamide Borane in THF (12 mL, 1IM) was added dropwise to 4-chloro-3-nitro-5-sulfamoyl-benzoic acid (1.6 g) in THF (30 mL) and the reaction was stirred overnight at room temperature . Methanol was added dropwise and the reaction mixture was stirred for 20 minutes at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and ethyl acetate, dried and concentrated. The residue was purified by chromatography using 0 to 100% ethyl acetate in iso-hexane then 5% methanol in DCM as eluent to give the title compound as a yellow solid (2.5g,> 100%); NMR spectrum (300 MHz, DMSO) 4.52 (m, 2H), 5.60 (t, 1H), 7.82 (s broad, 2H), 8.04 (s, 1H), 8.14 (s, 1H); Mass Spectrum MH + 265.33. The procedure described above was prepared using, in this case, the appropriate methyl benzoate ester (rather than benzoic acid). Thus, the compound described below was obtained: Method 16 3- (hydroxymethyl) -5-methyl-benzenesulfonamide A mixture of 2-chloro-5- (hydroxymethyl) -3-nitro-benzenesulfonamide (2.5 g - Method 15) and 10% Pd / C (200 mg) in ethanol (200 ml) was stirred under an atmosphere of hydrogen at 50 ° C overnight. The solution was cooled, filtered and concentrated, and the residue was purified by chromatography using 0 to 25% methanol in DCM as eluent to give the title compound as a white solid (509 mg, 51%); NMR spectrum (300 MHz, DMSO) 4.40 (m, 2H), 5.19 (t, 1H), 5.44 (broad s, 2H), 6.68 (s, 1H), 6.90 (m, 1H), 6.94 (s, 1H) ), 7.09 (broad s, 2H); Mass Spectrum MH + 203. Method 17 7-aminobenzoM .31dioxol-5-carbonitrile Zinc powder (125 mg), zinc cyanide (560 mg), tris (dibenzylidene ketone) dipalladium (0) (290 mg) and 1,1'-bis (diphenylphosphino) ferrocene (350 mg) were added to a solution of 6 mg. -bromobenzo [1,3] dioxol-4-amine (1 g, prepared as described in WO2004005284) and DIPEA (0.69 ml) in DMF (30 ml) and the reaction was heated at 110 ° C overnight. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and filtered. The combined organic extracts were dried and concentrated to give a brown oil which was purified by chromatography using ethyl acetate: iso-hexane (80% to 50%) as eluent to give the title compound as a yellow solid ( 548 mg, 73%); NMR spectrum (300 MHz, DIVISO) 5.42 (broad s, 2H), 6.06 (s, 2H), 6.66 (s, 2H): Mass Spectrum MH * 161. Method 18 N- (6-formylbenzon .31dioxol-4 -yl) tere-butyl carbamate N-butyllithium (9.96 ml, 2.5M in hexanes) was added dropwise to a solution of tere-butyl N- (6-bromobenzo [1, 3] dioxol-4-yl) carbamate (3 g, prepared as described in WO2004005284) in THF (60 mL) at -78 ° C and the mixture was stirred for 20 minutes. DMF (0.9 ml) was added and the solution allowed to warm to room temperature. A solution of saturated aqueous sodium bicarbonate (75 ml) was added and the solution was extracted with ethyl acetate, dried and concentrated. The residue was purified by chromatography using hexane to hexane-ethyl acetate (2: 3) as eluent to give the title compound as a white solid (1.9 g, 76%); NMR spectrum (300 MHz, DMSO) 1.45 (s, 9H), 6.18 (s, 2H), 7.17 (d, 1H), 7.68 (s, 1H), 9.14 (s, 1H), 9.78 (s, 1H) : Mass Spectrum M * 265.09. Method 19 N-f6- (hydroxymethyl) benzon, tere-butyl-3-dioxol-4-yl-carbamate Sodium borohydride (306 mg) was added to a solution of tere-butyl N- (6-formylbenzo [1, 3] dioxol-4-yl) carbamate (1.79 g-Method 18) in methanol (50 ml) and the The reaction was stirred at room temperature for 2 hours then concentrated in vacuo. The residue was partitioned between water and ethyl acetate, dried and concentrated to give the title compound as a white foam (1.8 g, 100%); NMR spectrum (300 MHz, DMSO) 1.43 (s, 9H), 4.35 (m, 2H), 5.08 (t, 1H), 5.96 (s, 2H), 6.62 (s, 1H), 6.89 (s, 1H) 8.75 (s, 1H). Method 20 N-r6-r (E / Z) 2-methoxyethenyl-1-benzori, tert-butyl-3-oxo-4- l-carbamate Potassium tert-butoxide (0.75 mL, 1M in THF) was added dropwise to a stirred suspension of (methoxymethyl) triphenylphosphonium chloride (288 mg) in THF (3 mL) and cooled in an ice bath. The red solution was then stirred at room temperature for 30 minutes, N- (6-formylbenzo [1,3] dioxol-4-yl) tere-butyl carbamate (100 mg -Method 18) in THF (3 ml) was added and the reaction was stirred at room temperature for 12 hours. The reaction was partitioned between a solution of saturated aqueous ammonium chloride and diethyl ether. The combined organic extracts were washed with water, dried and concentrated and the residue was purified by chromatography using iso-hexane to iso-hexane-10% ethyl acetate as eluent to give the title compound as a pale yellow oil ( 65 mg, 59%); NMR spectrum (300 MHz, DMSO) 1.44 (d, 9H), 3.60 (s, 1.5H), 3.72 (s, 1.5H), 5.11 (d, 0.5H), 5.74 (d, 0.5H), 5.95 (d, 2H) ), 6.18 (d, 0.5H), 6.74 -6.77 (d, 1H), 56.95-6.97 (m, 1H), 7.10 (d, 0.5H), 8.72 (d, 1H); Mass Spectrum M + 292.43. Method 21 N- [6 - [(E) -2-methoxyethenyl] benzo [1,3] dioxol-4-yl] N-f6- (2-methoxyethyl) benzon. 31-dioxol-4-illcarbamate tere-butyl] tere-butyl carbamate (0.9 g - Method 20) and 10% Pd / C (90 mg) in ethanol (90 ml) under a hydrogen atmosphere overnight. The solution was filtered and concentrated in vacuo to give the title compound as a pale brown oil (0.8 g, 88%); NMR spectrum (300 MHz, DMSO) 1.44 (s, 9H), 2.68 (t, 2H), 3.30 (s, 3H), 3.40 - 3.47 (m, 2H), 5.95 (s, 2H), 6.58 - 6.59 ( m, 1H), 6.76 (s, 1H), 8.72 (s, 1H); Mass Spectrum? -? - G 294.5. Method 22 6- (2-methoxyethyl) benzof 1, 31-dioxol-4-amine N- [6- (2-methoxyethyl) benzo [1, 3] dioxol-4-yl] tere-butyl carbamate (0.8 g - Method 21) and HCl c. (0.25 ml) in methanol (10 ml) were heated at 70 ° C for 2 hours then cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and the combined organic layers were dried and concentrated and the residue was purified by chromatography using 1: 1 DCM-ethyl acetate as eluent to give the title compound as a pale brown oil (0.4 g, 76%); NMR spectrum (300 MHz, DMSO) 3.29 (S, 3H), 3.44 (t, 2H), 4.79 (d, 2H), 5.84 (s, 2H), 6.07 (s, 1H), 6.11 (s, 1H); Mass Spectrum MhP 196.49. The procedure described above was prepared using the appropriate tere-butyl carbamate. Thus, the compound described below was obtained: Method 23 7-r (2-chloropyrimidin-4-ilaminolbenzof 1, 31-dioxol-5-carbonitrile Sodium hydride (67 mg, 60% dispersion in mineral oil) was added to 7-aminobenzo [1,3] dioxol-5-carbonitrile (109 mg -Method 17) in DMA (1 ml) at room temperature. 2,4-Dichloropyrimidine (100 mg) was added and the reaction was stirred overnight. The reaction was quenched rapidly with water and the solution was concentrated. The residue was triturated with water to give a solid which was filtered and dried in vacuo to give the title compound as a beige solid (83 mg, 45%); Mass Spectrum MH + 275.37. The procedure described above was prepared using the appropriate aniline. Thus, the compounds described below were obtained: Method 24 r7-r (2-chloropyrimidin-4-yl) ammolbenzoH, 31dioxol-5-i II methane! A mixture of DIPEA (0.07 ml), 2,4-dichloropyrimidine (50 mQ) Y (7-aminobenzo [1,3] dioxol-5-yl) methanol (56 mg - Method 22a) in n-butanol (1 ml) it was heated at 115 ° C overnight and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water, and the organic solution was concentrated. The residue was purified by chromatography using ethyl acetate as eluent to give the title compound as a white solid (37 mg, 39%); Mass Spectrum MH + 280.42.

Claims

1. A compound of formula (I)

(I) wherein R1 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more substituent groups selected from cyano, nitro, -OR2, -NR2aR2b, -C (0) NR2aR2b, or -N (R2a) C (0) R2, halo or haloalkyl of 1 to 6 carbon atoms, where R2, R2a and Rb are selected from hydrogen or alkyl of 1 to 6 carbon atoms such as methyl, or R2a and R2 together with the nitrogen atom to which they are attached can form a 5- or 6-membered heterocyclic ring, optionally containing a additional heteroatom selected from N, O or S; ring A is a 5 or 6 membered carbocyclic or heterocyclic fused ring, which is saturated or unsaturated, and is optionally substituted on any available carbon atom with one or more substituent groups selected from halo, cyano, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -S (0) Z-alkyl of 1 to 6 carbon atoms (where z is 0, 1 or 2), or -NRaRb (where Ra and Rb each is independently selected from hydrogen, alkyl of 1 to 4 carbon atoms, or alkylcarbonyl of 1 to 4 carbon atoms), and wherein any nitrogen atom in the ring is optionally substituted by an alkyl of 1 to 6 carbon atoms or a alkylcarbonyl of 1 to 6 carbon atoms; n is 0, 1, 2 or 3 and each R3 group is independently selected from halo, trifluoromethyl, cyano, nitro or a sub-formula group (i): -XI-Rn (i) where X1 is selected from a bond direct or O, S, SO, S02, OS02, NR13, CO, CH (OR13), CONR13, N (R13) CO, S02N (R13), N (R13) S02, C (R13) 20, C (R13) 2S, C (R 3) 2N (R 13) and N (R 3) C (R 13) 2, wherein R 3 is hydrogen or alkyl of 1 to 6 carbon atoms and R 11 is selected from hydrogen, alkyl from 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl or heterocyclyl, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 atoms of carbon, aryl-1-C6-alkyl or heterocyclyl-C 1-6 -alkyl, any of which may be optionally substituted with one or more groups selected from halo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy , carbamoyl, alkoxy of 1 to 6 carbon atoms, alkenexMo 2 to 6 carbon atoms, alkynyloxy of 2 to 6 atoms, alkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms , di- (alkyl of 1 to 6 carbon atoms) amino, alkoxycarbonyl of 1 to 6 carbon atoms, N-alkylcarbamoyl of 1 to 6 carbon atoms, N, N-di- (alkyl of 1 to 6 carbon atoms) ) carbamoyl, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, alkanoylamino of 2 to 6 carbon atoms, N-alkyl of 1 to 6 carbon atoms-alkanoylamino of 2 to 6 carbon atoms, alkanoylamino of 3 to 6 carbon atoms, N-alkyl of 1 to 6 carbon atoms-alkenoylamino of 3 to 6 carbon atoms, alkynylamino of 3 to 6 carbon atoms, N-alkyl of 1 to 6 carbon atoms-alkynylamino of 3 to 6 carbon atoms, N-alkylsulfamoyl of 1 to 6 carbon atoms, N, N-di- (alkyl of 1 to 6 carbon atoms) sulfamoyl, alcansulfonyl 1 to 6 carbon atoms and N-alkyl of 1 to 6 carbon atoms-alcansulfonylamino of 1 to 6 carbon atoms, and any heterocyclyl group within R 11 optionally has 1 or 2 oxo or thioxo substituents; and R4 is a group of sub-formula (iii) (iii) wherein R5, R6, R7, R8, and R9 are each independently selected from: (fj) the groups hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, of 3 to 12 carbon atoms carbocyclyl, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-alkyl of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) and wherein any aryl, carbocyclyl of at 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-alkyl of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) are optionally substituted on the any available carbon atom by halo, hydroxy, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms carbon, N-alkylamino of 1 to 6 carbon atoms, or?,? - dialkylamino of 1 to 6 carbon atoms, and any nitrogen atom present in a heterocyclyl group may, depending on valence considerations, be replaced by a group selected from hydrogen, alkyl d and 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and where any sulfur atom can optionally be oxidized to sulfur oxide; (ii) a group of sub-formula (iv): -X2-R14 (iv) where X2 is selected from O, NR16, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR16), CON (R16), N (R6) CO,

-N (R 6) C (0) N (R16) -, -N (R16) C (0) 0-, SON (R16), N (R16) SO, S02N (R16), N (R16) S02, C (R16) 20, C (R6) 2S and N (R16) C (R16) 2, wherein each R16 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, R14 is hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 6 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, or heterocyclyl ring mono- or bicyclic 4- to 8-membered (including 5- or 6-membered heteroaryl rings) or heterocyclyl-alkyl groups of 1 to 6 bicyclic carbon atoms of 4 to 8 carbon atoms (including alkyl groups of 1 to 6 atoms carbon of 5 or 6 members) and wherein any aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-alkyl groups of 1 to 6 atoms of carbon (including heteroaryl-alkyl d and 1 to 6 carbon atoms) are optionally substituted at any available carbon atom by oxo, halo, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms carbon, alkylcarbonyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or?,? - dialkylamino of 1 to 6 carbon atoms and any nitrogen atom present in the heterocyclic portions may, depending on the valence considerations, substituted by a selected group of hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and where any sulfur atom can optionally be oxidized to a sulfur oxide; (iii) to the group of the sub-formula (v): -X3-R15-Z (v) where X3 is a direct bond or is selected from O, NR17, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR17), CON (R17), N (R17) CO, -N (R17) C (0) N (R17) -, -N (R17) C (0) 0-, S02N (R17), N (R17) S02, C (R17) 20, C (R17) 2S and N (R17) C (R17) 2l where each R7 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; R15 is an alkylene of 1 to 6 carbon atoms, 2 to 6 carbon atoms alkenylene or alkynylene of 2 to 6 carbon atoms, arylene, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl (including heteroaryl), any of which which may be optionally substituted by one or more groups selected from halo, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, amino, alkylamino of 1 to 6 carbon atoms or of di- (C 1-6 alkyl) amino, Z is halo, trifluoromethyl, cyano, nitro, aryl, carbocyclyl of 3 to 12 carbon atoms or heterocyclyl (including heteroaryl), optionally having 1 or 2 substituents, which may be same or different, selected from halo, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and alkoxy of 1 to 6 carbon atoms and wherein any heterocyclyl group within of Z optionally has 1 or 2 substituents oxo, or Z is a group of sub-formula (vi) -X4-R18 (vi) where X4 is selected from O, NR19, S, SO, S02, OS02, CO, C (0) 0, OC (O) , CH (OR19), CON (R19), N (R19) CO, S02N (R19), -N (R19) C (0) N (R19) -, -N (R19) C (0) 0-N ( R19) S02, C (R19) 20, C (R19) 2S and N (R9) C (R19) 2, wherein each R19 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; and R 8 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl) or heterocyclyl-alkyl of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) optionally having 1 or 2 substituents, which may be the same or different, selected of halo, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and alkoxy of 1 to 6 carbon atoms, and wherein any heterocyclyl group within R18 optionally carries 1 or 2 oxo substituents; or (iv) R5 and R6, R6 and R7, R7 and R8 or R8 and R9 are joined together to form a 5, 6 or 7 membered fused ring, wherein the ring is unsaturated or partially or completely saturated and is optionally substituted at any available carbon atom by halo, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, amino, N-alkylamino of 1 to 6 carbon atoms, or?,? - dialkylamino of 1 to 6 carbon atoms, and the ring may contain one or more heteroatoms selected from oxygen, sulfur or nitrogen, where the sulfur atoms may optionally be oxidized to a sulfur oxide, where any CH2 group may be replaced by a C (O) group , and wherein the nitrogen atoms, depending on the valence considerations, can be substituted where R21 is selected from hydrogen or alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that if ring A, together with the phenyl ring to which it is attached, forms an indazol-4-yl group, then R1 is not hydrogen. 2. A compound of formula (IA) where A, R1, R3 and R4 according to claim 1, R3a is a group R3 as defined in claim 1, and m is 0, 1 or 2. 3. A compound according to claim 2, wherein R3a It is halo.

4. A compound according to claim 2 or 3, wherein m is 0.

5. A compound according to any of claims 1 to 4, wherein ring A is selected from -CR22 = CR22-CR22 = CR22- , -N = CR22-CR22 = CR22-, CR22 = N- CR22 = CR22-, -CR22 = CR22-N = CR22-, -CR22 = CR22-CR22 = N-, -N = CR22-N = CR22-, -CR22 = N-CR22 = N-, -N = CR22-CR22 = N-, -N = N-CR22 = CR22-, -CR2 = CR22-N = N-, -CR22 = CR2 -0-, -0 -CR22 = CR22 -, - CR2 = CR22-S-, -S-CR22 = CR22-, -CR22H-CR 2H-0-, -0-CR22H-CR22H-, -CR22H-CR22H-S-, -S- CR22H-CR22H-, -0-CR22H-0-, -0-CF2-0-, -0-CR22H-CR22H-0-, -S-CR22H-S-, -S-CR22H-CR22H-S-, - CR22 = CR22-NR22-, -NR20-CR22 = CR22-, D-CR22H-CR 2H-NR20-, -NR20-CR22H-CR22H-, -N = CR22-NR20-, -NR20-CR22 = N-, D-NR20-CR H-NR20-, -OCR22 = N-, -N = CR22-0-, -S-CR22 = N-, -N = CR22-S-, -0-CR22H-N R20-, - NR20-CR2 H-0-, -S-CR22H-NR20-, -N R20-CR22H-S-, -0-N = CR22-, CR22 = NO, -SN = CR22-, -CR22 = NS-, - O-NR20-CR22H-,, -CR22H-N R20-O-,? -S-NR20-CR22H-, -CR H-NR20-S-, -N R20-N = CR22-, -CR2 = N-NR20-, -NR20-NR20-CR22H-, -CR22H-NR20-NR20-, -N = N-NR20- or -NR20-N = N-, wherein each R20 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and where each R is independently selected of hydrogen, halo cyano, hydroxy, alkyl 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, - S (0) z-alkyl of 1 to 4 carbon atoms (where z is 0, 1 or 2), or -NRaRb (where Ra and Rb are each independently selected from hydrogen, alkyl of 1 to 2 carbon atoms, or alkanoyl of 1 to 2 carbon atoms).

6. A compound according to any of claims 1 to 4, wherein ring A is selected from -0-CR22H-0-, -0-CF2-0-, -OCR22 = N-, -N = CR22- 0-, -S-CR = N-, -N = CR 2-S-, -NR 20 -N = CR 22-, or -CR 22 = N-NR 20-, and each R 20 is independently selected from hydrogen, or alkyl from 1 a 2 carbon atoms, and each R22 is independently selected from hydrogen, halo or methyl.

7. A compound according to the claims 1 to 6, wherein R1 is hydrogen or a 1 to 2 carbon alkyl group, which is optionally substituted with one or more substituents selected from cyano, -OR2, -NR2aR2b, C (0) NR2aR b, or -N ( R2a) C (0) R2, halo or haloalkyl 1 to 4 carbon atoms, wherein R2, R2a and R2b are selected from hydrogen or alkyl of 1 to 2 carbon atoms.

8. A compound according to any of claims 1 to 6, wherein R1 is methyl.

9. A compound according to any of the preceding claims, wherein each R3 group present is independently selected from halo, trifluoromethyl, cyano, nitro or a group of sub-formula (I): -X1-R11 (I) where X1 is selected from a direct bond or O, CONR13, wherein R13 is hydrogen or alkyl of 1 to 6 carbon atoms and R11 is selected from hydrogen or alkyl of 1 to 6 carbon atoms, which may optionally be substituted with one or more alkoxy groups 1 to 2 carbon atoms.

10. A compound according to claim 1 or any of claims 5 to 9, wherein n is 0 or 1.

11. A compound according to any of the preceding claims, wherein R4 is a group of the sub- formula (iiib). (iiib) wherein at least one of R6 and R8 is a 5-, 6- or 7-membered heterocyclic ring that binds to nitrogen and the other is independently selected from: (a) hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl 1 to 6 carbon atoms, alkenyl 2 to 8 carbon atoms, alkenyl 2 to 8 carbon atoms, aryl, heterocyclyl (including heteroaryl), and wherein any aryl or heterocyclyl group (including heteroaryl) is optionally substituted at any carbon atom by halo, hydroxy, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and any nitrogen atom present in the heterocyclyl portions, depending on the considerations of valence, can be substituted by a selected group of hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms; (b) a group of sub-formula (iv) -X2-R14 (iv) where X2 is selected from O, NR16, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR16), CON (R16), N (R16) CO, SON (R16), N (R16) SO, S02N (R16), and N (R16) S02, wherein each R16 is independently selected from hydrogen or alkyl 1 to 6 carbon atoms, R14 is hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, or a heterocyclyl ring mono- or bicyclic 4 to 8 members (including 5 or 6 membered heteroaryl rings) and wherein any aryl, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl groups (including heteroaryl) are optionally substituted at any carbon atom by oxo, halo , cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, or N, N-dialkylamino of 1 to 6 carbon atoms and any nitrogen atom present in the heterocyclyl portions, depending on the valence considerations, can be substituted by a group selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and wherein any sulfur atom can optionally be oxidized to a sulfur oxide; (c) a group of sub-formula (v): -X3-R15-Z (v) where X3 is a direct bond or is selected from O, NR17, S, SO, S02, OS02, CO, C (0) 0, OC (O), CON (R17), N (R7) CO, S02N (R17), and N (R17) S02, wherein each R7 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; R15 is a C1-C6alkylene, alkenylene of 2 to 6 carbon atoms or alkynylene of 2 to 6 carbon atoms, arylene, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl (including heteroaryl), any of which it may be optionally substituted by one or more groups selected from halo, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, amino, alkylamino of 1 to 6 carbon atoms or di- (alkyl) from 1 to 6 carbon atoms) amino; Z is halo, trifluoromethyl, cyano, nitro, aryl, or heterocyclyl (including heteroaryl) optionally having 1 or 2 substituents, which may be the same or different, selected from halo, alkyl of 1 to 6 atoms of qarbon and alkoxy of 1 to 6 carbon atoms and wherein any heterocyclyl group within Z optionally has 1 or 2 oxo substituents, or, Z is a group of sub-formula (vi) -X4-R18 (vi) wherein X4 is selected from O, NR 9, S, SO, S02, OS02, CO, C (0) 0, OC (O), CON (R19), N (R19) CO, S02N (R19), and N (R19) S02, where each R19 is independently selected of hydrogen or alkyl of 1 to 6 carbon atoms; and R 8 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, aryl, or heterocyclyl (including heteroaryl) optionally having 1 or 2 substituents, which may be the same or different, selected from halo, alkyl of 1 to 6 atoms of carbon, and alkoxy of 1 to 6 carbon atoms, and wherein any heterocyclyl group within R18 optionally has 1 or 2 oxo substituents.

12. A compound according to any of the preceding claims, wherein R4 is a sub-formula group (iiib) (iiib) wherein at least one of R6 and R8 is a 5- or 6-membered heterocyclic ring that binds to nitrogen and the other is independently selected from: (a) hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, aryl, heterocyclyl (including heteroaryl), and wherein any aryl or heterocyclyl group (including heteroaryl) is optionally substituted on any atom carbon per halo, hydroxy, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and any nitrogen atom present in the heterocyclic portions, depending on the valence considerations, it can be substituted by a selected group of hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms; (b) a group of sub-formula (iv) -X2-R14 (iv) where X2 is selected from O, NR16, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR16), CON (R16), N (R16) CO, SON (R16), N (R16) SO, S02N (R16), and N (R6) S02, where each R6 is independently selected from hydrogen or alkyl 1 to 6 carbon atoms, R14 is hydrogen, alkyl of 1 to 6 carbon atoms.

13. A compound according to claim 1, wherein the compound has the general structural formulas (ID) wherein R1 is an alkyl group of 1 to 6 carbon atoms, which is optionally substituted with one or more substituents selected from cyano, -OR2, -NR2aR2b, wherein R2, R2a and R2b are selected from hydrogen or alkyl of 1 to 2 carbon atoms; R22 is as defined in claim 5 or 6; R3, is as defined in claim 1 or 9; n is as defined in claim 1 or 10, and R4 is as defined by any one of claims 1, 11 or 12.

14. A compound according to claim 1, wherein the compound has the general structural formula ( IE) as shown below (IE) wherein R1 is as defined by any of claims 1, 7, 8 or 13; R22 is as defined in claim 5 or 6; R3, is as defined in claim 1 or 9; n is as defined in claim 1 or 10, and R 4 is as defined by any one of claims 1, 11 or 12.

15. A compound according to claim 1, wherein the compound has one of the structural formulas General (IF) or (IG) shown below where X is S or O; R1 is as defined in any of claims 1, 7, 8 or 13; R22 is as defined in claim 5 or 6; R3 is as defined in claim 1 or 9; n is as defined in claim 1 or 10, and R4 is as defined in any of claims 1, 11 or 12.

16. A according to any of claims 14 or 15, wherein R is hydrogen or an alkyl group of 1 to 2 carbon atoms, which is optionally substituted with one or more substituents selected from cyano, -OR2, -N R2aR2b, where R2, R2a and R2b are selected from hydrogen or alkyl of 1 to 2 carbon atoms.

17. A compound according to any of claims 13 to 15, wherein R1 is an alkyl group of 1 to 2 carbon atoms, which is optionally substituted with one or more substituents selected from cyano, -OR2, -NR2aR2b, where R2, R2a and R2b are selected from hydrogen or alkyl of 1 to 2 carbon atoms.

18. A compound according to any of claims 13 to 15, wherein R is methyl.

19. A compound according to any of claims 13 to 18, wherein n is 0.

20. A compound according to any of claims 13 to 19, wherein R22 is hydrogen, halo, alkyl of 1 to 2 atoms. of carbon.

21. A compound according to any of claims 13 to 20, wherein R4 is as defined in claim 12.

22. A compound according to any of claims 13 to 20, wherein R4 is a group of the sub-formula (iiib) (iiib) wherein wherein R6 and R8 are n heterocyclic rings bonded to the 5 or 6 membered nitrogen.

23. A compound according to any of claims 13 to 20, wherein R4 is a group of the sub-formula (iiib) (iiib) wherein R6 and R8 are morpholin-4-yl.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or diluent.

25. A process for preparing a compound of formula (I) by reacting a compound of formula (II): wherein R4 is as defined in claim 1, with the proviso that any of the functional groups are optionally protected, and L is a leaving group, "with a compound of formula (iii) where A, R1, R3 and n are as defined in the claim, with the proviso that any of the functional groups are pionally protected; or by reacting a compound of formula (vii) where A, R3, R and n are as defined in claim 1, with the proviso that any of the functional groups are optionally protected and L is a leaving group as defined in relation to formula (ii), with a compound of formula (vi) as defined above; and then if it is desired or necessary to perform one or more of the following steps: (i) removing any protecting groups, or (ii) converting a compound of formula (i) obtained into a different compound of formula (I); (iii) form a salt.

26. The use of a compound of formula (IH) (IH) wherein R1 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more substituent groups selected from cyano, nitro, -OR2, -NR2aR2b, -C (0) NR2aR2b, or -N (R2a) C (0) R2, halo or haloalkyl of 1 to 6 carbon atoms, wherein R2, R2a and R2b they are selected from hydrogen or alkyl of 1 to 6 carbon atoms such as methyl, R2a and R2b together with the nitrogen atom to which they are attached can form a 5- or 6-membered heterocyclic ring, optionally containing an additional heteroatom selected from N, O or S; ring A is a 5 or 6 membered carbocyclic or heterocyclic fused ring, which is saturated or unsaturated, and is optionally substituted at any available carbon atom with one or more substituent groups selected from halo, cyano, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy 1 to 6 carbon atoms, -S (0) Z-alkyl of 1 to 6 carbon atoms (where z is 0, 1 or 2), or -NRaRb (where Ra and Rb each are independently selected from hydrogen, alkyl from 1 to 4 carbon atoms, or alkylcarbonyl of 1 to 4 carbon atoms), and wherein any nitrogen atom in the ring is optionally substituted by an alkyl of 1 to 6 carbon atoms or an alkylcarbonyl of 1 to 6 carbon atoms. carbon; n is 0, 1, 2 or 3 and each R3 group is independently selected from halo, trifluoromethyl, cyano, nitro or a sub-formula group (i): -Xl-Rn (i) where X1 is selected from a direct link or O, S, SO, S02, OS02, NR13, CO, CH (OR13), CONR13, N (R13) CO, S02N (R13), N (R3) S02, C (R13) 20, C (R13) 2S, C (R13) 2N (R13) and N (R13) C (R13) 2, wherein R13 is hydrogen or alkyl of 1 to 6 carbon atoms and R1 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl or heterocyclyl, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms carbon or heterocyclyl-alkyl of 1 to 6 carbon atoms, any of which may be optionally substituted with one or more groups selected from halo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, alkoxy of 1 to 6 atoms carbon, alkennioxyl of 2 to 6 carbon atoms, alkynyloxy of 2 to 6 atoms, alkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 atoms carbon, di- (C 1-6 alkyl) amino, alkoxycarbonyl of 1 to 6 carbon atoms, N-alkylcarbamoyl of 1 to 6 carbon atoms, N, N-di- (alkyl of 1 to 6 atoms carbon) carbamoyl, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, alkanoylamino of 2 to 6 carbon atoms, N-alkyl of 1 to 6 carbon atoms-alkanoylamino of 2 to 6 carbon atoms carbon, alkanoylamino of 3 to 6 carbon atoms, N-alkyl of 1 to 6 carbon atoms-alkenoylamino of 3 to 6 carbon atoms, alkynylamino of 3 to 6 carbon atoms, N-alkyl of 1 to 6 carbon atoms -alkanoylamino of 3 to 6 carbon atoms, N-alkylsulfamoyl of 1 to 6 carbon atoms, N, N-di- (alkyl of 1 to 6 carbon atoms) sulfamoyl, C 1 -C 6 alkanesulfonylamino and C 1 -C 6 alkanesulfonylamino N-alkyl of 1 to 6 carbon atoms, and any heterocyclyl group within R 11 optionally has 1 or 2 oxo or thioxo substituents; and R4 is a group of sub-formula (iii) wherein R5, R6, R7, R8, and R9 are each independently selected from: (i) the groups hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, 3 to 12 carbon atoms carbocyclyl, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-alkyl of 1 to 6 carbon atoms carbon (including heteroaryl-alkyl of 1 to 6 carbon atoms) and wherein any aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-alkyl of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) are optionally substituted at any available carbon atom by halo, hydroxy, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, alkoxy 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, or α, β-dialkylamino of 1 to 6 carbon atoms, and any nitrogen atom present in a group heterocyclyl can, depending on the valence considerations, be replaced by a group selected from hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and where any sulfur atom can optionally be oxidized to sulfur oxide; (ii) a group of sub-formula (v): -X2-R14 (iv) where X2 is selected from O, NR16, S, SO, S02, OS02, CO, C (0) 0, OC (O) , CH (OR16), CON (R16), N (R16) CO, -N (R16) C (0) N (R16) -, -N (R16) C (0) 0-, SON (R16), N (R16) SO, S02N (R16), N (R16) S02, C (R16) 20, C (R6) 2S and N (R6) C (R16) 2, wherein each R16 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms, R14 is hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 6 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, or mono- or bicyclic heterocyclyl ring of 4 to 8 members (including heteroaryl rings of 5 or 6 members) or heterocyclyl alkyl groups of 1 to 6 bicyclic carbon atoms of 4 to 8 carbon atoms (including alkyl groups of 1 to 6 carbon atoms of 5 or 6 members) and wherein any aryl, carbocyclyl of at 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl), heterocyclyl-alkyl groups of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) are substituted optionally at any available carbon atom by oxo, halo, cyano, amino, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms carbon, alkylamino of 1 to 6 carbon atoms, or?,? - d C 1 -C 6 -alkylamino and any nitrogen atom present in the heterocyclyl portions can, depending on the valence considerations, be replaced by a selected group of hydrogen, alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms, and wherein any sulfur atom may optionally be oxidized to a sulfur oxide; (c) to the group of the sub-formula (v): -X3-R15-Z (v) where X3 is a direct bond or is selected from O, NR17, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR17), CON (R17), N (R17) CO, -N (R7) C (0) N (R17) -, -N (R17) C (0) 0- , S02N (R17), N (R17) S02, C (R17) 20, C (R17) 2S and N (R7) C (R7) 2, wherein each R17 is independently selected from hydrogen or alkyl from 1 to 6 carbon atoms; R15 is an alkylene of 1 to 6 carbon atoms, 2 to 6 carbon atoms alkenylene or alkynylene of 2 to 6 carbon atoms, arylene, carbocyclyl of 3 to 12 carbon atoms, heterocyclyl (including heteroaryl), any of which which can optionally be replaced by one or more selected halo groups, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, amino, alkylamino of 1 to 6 carbon atoms or di- (alkyl of 1 to 6 carbon atoms) amino, Z is halo, trifluoromethyl, cyano, nitro, aryl, carbocyclyl of 3 to 12 carbon atoms or heterocyclyl (including heteroaryl), optionally having 1 or 2 substituents, which may be the same or different, selected from halo, alkyl from 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and alkoxy of 1 to 6 carbon atoms and wherein any heterocyclyl group within Z optionally has 1 or 2 oxo substituents, or Z is a group of sub-formula (vi) -X4-R18 (vi) where X4 is selected from O, NR19, S, SO, S02, OS02, CO, C (0) 0, OC (O), CH (OR19) , CON (R19), N (R19) CO, S02N (R19), -N (R19) C (0) N (R19) -, -N (R9) C (0) 0-N (R19) S02, C (R19) 20, C (R19) 2S and N (R19) C (R19) 2, wherein each R19 is independently selected from hydrogen or alkyl of 1 to 6 carbon atoms; and R18 is selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, aryl, carbocyclyl of 3 to 12 carbon atoms, aryl-alkyl of 1 to 6 carbon atoms, heterocyclyl (including heteroaryl) or heterocyclyl-alkyl of 1 to 6 carbon atoms (including heteroaryl-alkyl of 1 to 6 carbon atoms) optionally having 1 or 2 substituents, which may be the same or different, selected from halo, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and alkoxy of 1 to 6 carbon atoms, and wherein any heterocyclyl group within R18 carries optionally 1 or 2 oxo substituents; or (iv) R5 and R6, R6 and R7, R7 and R8 or R8 and R9 are joined together to form a 5, 6 or 7 membered fused ring, wherein the ring is unsaturated or partially or completely saturated and is optionally substituted at any available carbon atom by halo, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, amino, N-alkylamino of 1 to 6 carbon atoms, or N, N-dialkylamino of 1 to 6 carbon atoms, and the ring may contain one or more heteroatoms selected from oxygen, sulfur or nitrogen, where the sulfur atoms may optionally be oxidized to a sulfur oxide, where any CH2 group may be replaced by a C (O) group , and wherein the nitrogen atoms, depending on the valence considerations, can be substituted where R21 is selected from hydrogen or alkyl of 1 to 6 carbon atoms or alkylcarbonyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that if ring A, together with the phenyl ring to which it is attached, forms an indazol-4-yl group, then R1 is not hydrogen.

27. The use of a compound according to any one of claims 1 to 23 or 26, in the preparation of a medicament for use in the production of an EphB4 inhibitory effect in a warm-blooded animal such as a human.

28. A method for producing an inhibitory effect of EphB4 in a warm-blooded animal, such as human, in need of such treatment comprising administering to the animal an effective amount of a compound according to any of claims 1 to 23 or 26, or a pharmaceutically acceptable salt thereof.

29. The use of a compound according to any one of claims 1 to 23 or 26, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the production of an anti-angiogenic effect in an animal of warm blood such as a human.

30. A method for producing an anti-angiogenic effect in a warm-blooded animal, such as a human, in need of such treatment comprising administering to the animal an effective amount of a compound according to any of claims 1 to 23 or 26, or a pharmaceutically acceptable salt thereof.

31. A method for treating cancer in a warm-blooded animal, such as a human, in need of such treatment comprising administering to the animal an effective amount of a compound according to any of claims 1 to 23 or 26, or a pharmaceutically acceptable salt thereof.

32. A compound according to any of claims 1 to 23, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as a medicament.

33. The use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of cancer.