BRPI0721151B1 - COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT OR SOLVATE OF THE SAME, PHARMACEUTICAL COMPOSITION, AND, USE OF A COMPOUND - Google Patents

Abstract

compound or a pharmaceutically acceptable salt or solvate thereof, pharmaceutical composition, and use of a compound The invention relates to novel bicyclic heterocyclic derivative compounds, pharmaceutical compositions comprising said compounds and the use of said compounds in the treatment of diseases, eg cancer.

Description

FIELD OF THE INVENTION

The invention relates to novel bicyclic heterocyclic derivative compounds, pharmaceutical compositions comprising said compounds and the use of said compounds in the treatment of diseases, e.g. cancer.

SUMMARY OF THE INVENTION

em queXi, X2 e X3 são cada um independentemente selecionados de carbono ou nitrogênio, de tal modo que pelo menos um de X1-X3 represente nitrogênio;X4 representa CR ou nitrogénio;X5 representa CR6, nitrogênio ou C=O;desde que não mais do que três de XrX5 representem nitrogênio;representa uma ligação simples ou dupla, de tal modo que uma ligação dentro do sistema de anel de 5 membros seja uma ligação dupla;R3 representa hidrogênio, halogênio, C].6 alquila, C2-6 alquenila, C2.6 alquinila, Ci-6 alcóxi, €3,6 ciclo-alquila, C3-6 ciclo-alquenila, ciano, haloCi-6 alquila, haloCμg alcóxi ou =O;According to a first aspect of the invention a compound of formula (I) is produced:

wherein Xi, X2 and X3 are each independently selected from carbon or nitrogen, such that at least one of X1-X3 represents nitrogen;X4 represents CR or nitrogen;X5 represents CR6, nitrogen or C=O; provided no more than three of XrX5 represent nitrogen; represents a single or double bond, such that a bond within the 5-membered ring system is a double bond; R3 represents hydrogen, halogen, C 1.6 alkyl, C2-6 alkenyl , C2.6 alkynyl, C1-6 alkoxy, €3.6 cycloalkyl, C3-6 cycloalkenyl, cyano, haloC1-6 alkyl, haloCμg alkoxy or =O;

A represents a non-aromatic or aromatic heterocyclic or carbocyclic group which may be optionally substituted by one or more (e.g. 1,2 or 3) Ra groups;

B represents a -V-carbocyclic group or a -W-heterocyclyl group, said carbocyclic and heterocyclyl groups being optionally substituted with one or more (eg 1,2 or 3) Ra groups; R2 and R6 independently represent halogen, hydrogen, C1.6 alkyl, Cμ6 alkoxy, C2.6 alkenyl, C2„6 alkynyl, -C=N, C3.8 cycloalkyl, C3.8 cycloalkenyl, -NHSO2RW, -CH=N-ORW, an aryl group or heterocyclyl wherein said C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl and heterocyclyl groups may be optionally substituted with one or more Rb groups provided that both R2 and R6 do not represent hydrogen; Re, Rf and Rw independently represent hydrogen or C1.6 alkyl;Ra represents halogen groups, Cμ6 alkyl, C2.6 alkenyl, C2. 6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkenyl, -ORX, -(CH 2)nO-C1-6 alkyl, -O-(CH 2)n-ORx, haloC1-6 alkyl, halo Cμ6 alkoxy, Cμ6 alkanol, =O, =S, nitro, Si(Rx)4, -(CH2)SCN, -S-Rx, -SO-RX, -SO2-RX, -CORX, -(CRxRy)s- COORZ , -(CH2)s-CONRxRy, -(CH2)s-NRxRy, -(CH2)s-NRxCORy, -(CH2)S-NRXSO2-Ry, -(CH2)s-NH-SO2-NRxRy, -OCONRxRy, -(CH2)s-NRxCO2Ry, -O-(CH2)s-CRxRy-(CH2)t-ORz or -(CH2)s-SO2NRxRy;Rx, Ry and Rz independently represent hydrogen, C1-6 alkyl, C2. 6 alkenyl, C 2-6 alkynyl, C 1-6 alkanol, hydroxyl, C 1-6 alkoxy, halo C 1-6 alkyl, -CO-(CH 2 )n C ]-6 alkoxy, C 3 s cycloalkyl or C 3 8 cyclo- alkenyl;R1 and Rb independently represent a Ra group or a -Y-carbocyclyl or Z-heterocyclyl group wherein said carbocyclyl and heterocyclyl groups may be optionally substituted with one or more (eg 1,2 or 3) Ra;V and W groups independently represent a bond or a group -(CReRf)n-;Y and Z independently represent a bond, -CO-(CH2)S-, -COO-, -(CH 2)n-, -NRX-(CH 2)n-, -(CH 2)n-NRx-, -CONRX-, -NRXCO-, -SO2NRX-, -NRXSO2-, -NRxCONRy-, -NRxCSNRy-, - O-(CH2)S-, -(CH2)SO-, -S-, -SO- OR -(CH2)S-SO2-;n represents an integer of 1-4;set independently represent an integer of 0 - 4;q represents an integer from 0-2;or a pharmaceutically acceptable salt, solvate or derivative thereof, provided that the compound of formula (I) is not: 6-chloro-4-[3-(7-methyl -imidazo[1,2-a]pyridin-3-yl)-phenyl]-pyridin-3-yl-amine; or N-[3-(7-methyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-N-(2-nitro-phenyl)-amine. WO 01/38326 (Merck), WO 2003 /048132 (Merck), WO 02/080914 (Gruenenthal), WO 01/14375 (Astra Zeneca), WO 2004/052286 (Merck), WO 00/53605 (Merck), WO 03/101993 (Neogenesis), WO 2005/ 075470 (SmithKline Beecham), WO 2005/054230 (Cytopia), WO 2002/46168 (Astra Zeneca), WO 01/66098 (Aventis), WO 97/12613 (Warner Lambert), WO 2006/094235 (Sirtris Pharmaceuticals) and US 2006/0035921 (OSI Pharmaceuticals), EP 1790650 (Banyu), US 2005/021531 (OSI Pharmaceuticals), WO 02/066481 (Astra Zeneca), WO 01/00214 (Merck) WO 01/00213 (Merck), WO 01/ 00207 (Merck), FR 2851248 (Aventis) and Clark et al. (2007) Bioorganic & Medicinal Chemistry Letters 17, 1250-1253 each reveal a number of heterocyclic derivatives

DETAILED DESCRIPTION OF THE INVENTION

sendo queXi, X2 e X3 são cada um independentemente selecionados de carbono ou nitrogênio, de tal modo que pelo menos um de X]-X3 represente nitrogênio;X4 representa CR ou nitrogênio;X5 representa CR6, nitrogênio ou C=O;desde que não mais do que três de XrX5 representem nitrogênio;— representa uma ligação simples ou dupla, de tal modo que uma ligação dentro do sistema de anel de 5 membros seja uma ligação dupla;R3 representa hidrogênio, halogênio, Ci-6 alquila, C2-6 alquenila, C2-6 alquinila, Cμg alcóxi, C3.6 ciclo-alquila, C3_6 ciclo-alquenila, ciano, haloCi-6 alquila, haloCi-6 alcóxi ou =O;According to a first aspect of the invention a compound of formula (I) is produced:

wherein Xi, X2 and X3 are each independently selected from carbon or nitrogen, such that at least one of X]-X3 represents nitrogen; X4 represents CR or nitrogen; X5 represents CR6, nitrogen or C=O; more than three of XrX5 represent nitrogen;— represents a single or double bond such that a bond within the 5-membered ring system is a double bond; R3 represents hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cμg alkoxy, C3-6 cycloalkyl, C3_6 cycloalkenyl, cyano, haloC1-6 alkyl, haloC1-6 alkoxy or =O;

A represents a non-aromatic or aromatic heterocyclic or carbocyclic group which may be optionally substituted by one or more (e.g. 1,2 or 3) Ra groups;

B represents a -V-carbocyclic group or a -W-heterocyclyl group, said carbocyclic and heterocyclyl groups being optionally substituted with one or more (eg 1,2 or 3) Ra groups; R and R independently represent halogen, hydrogen, Cμ6 alkyl, Cb6 alkoxy, C2-6 alkenyl, C2.6 alkynyl, -C=N, C3_8 cycloalkyl, C3.8 cycloalkenyl, -NHSO2RW, -CH=N-ORW, an aryl or heterocyclyl group where said Cµ6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl and heterocyclyl groups may be optionally substituted with one or more Rb groups provided that both R2 and R6 do not represent hydrogen; Re, Rf and Rw independently represent hydrogen or C1-6 alkyl; Ra represents halogen, C1-6 alkyl, C2.6 alkenyl, C2 groups. 6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkenyl, -OR", -(CH 2)nOC].6 alkyl, -O-(CH 2)n-ORx, haloQ.g alkyl, haloC1 - 6 alkoxy, C1-6 alkanol, =O, =S, nitro, Si(Rx)4, -(CH2)SCN, -S-RX, -SO-RX, -SO2-RX, -CORX, -(CRxRy) s- COORZ, -(CH2)s-CONRxRy, -(CH2)s-NRxRy, -(CH2)s-NRxCORy, -(CH2)S-NRXSO2-Ry, -(CH2)s-NH-SO2-NRxRy, -OCONRxRy, -(CH2)s-NRxCO2Ry, -O-(CH2)s-CRxRy-(CH2)rORz or -(CH2)s-SO2NRxRy;Rx, Ry and Rz independently represent hydrogen, C1_6 alkyl, C2. 6 alkenyl, C2.6 alkynyl, C1-6 alkanol, hydroxyl, C1-6 alkoxy, haloC1-6 alkyl, -CO-(CH2)n-C1-6 alkoxy, C3.8 cycloalkyl or C3.8 cycloalkenyl; R1 and Rb independently represent a Ra group or a -Y-carbocyclyl or Z-heterocyclyl group wherein said carbocyclyl and heterocyclyl groups may be optionally substituted with one or more (eg 1,2 or 3) Ra groups; V and W independently represent a bond or a group -(CReR')n-;Y and Z independently represent a bond, -CO-(CH2)S-, -COO-, -(C H 2)n-, -NRX-(CH 2)n-, -(CH 2)n-NRx-, -CONRX-, -NRXCO- , -SO2NRX-, -NRXSO2-, -NRxCONRy-, -NRxCSNRy- - O-(CH2)S-, -(CH2)SO-, -S-, -SO- or -(CH2)s-SO2-;n represents an integer of 1-4; set independently represent an integer of 0 - 4;q represents an integer from 0-2;or a pharmaceutically acceptable salt, solvate or derivative thereof, provided that the compound of formula (I) is not: 6-chloro-4-[3-(7-methyl -imidazo[1,2-a]pyridin-3-yl)-phenyl]-pyridin-3-yl-amine; or N-[3-(7-methyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-N-(2-nitro-phenyl)-amine.

sendo queXi, X2 e X3 são cada um independentemente selecionados de carbono ou nitrogênio, de tal modo que pelo menos um de X1-X3 represente nitrogênio;oX4 representa CR ou nitrogênio;X5 representa CR6, nitrogênio ou C=O;desde que não mais do que três de XrX5 representem nitrogênio;— representa uma ligação simples ou dupla, de tal modo que quando X5 representa C=O, X4 e X5 são unidos por uma ligação simples e de tal modo que uma ligação dentro do sistema de anel de 5 membros seja uma ligação dupla;R3 representa hidrogênio, halogênio, Cμ6 alquila, C2.6 alquenila, C2.6 alquinila, C μ6alcoxi, C3.g ciclo-alquila, C3.6 ciclo-alquenila, ciano, haloCi.6 alquila, haloCμβ alcóxi ou =O;In one embodiment, a compound of formula (I) is produced:

wherein Xi, X2 and X3 are each independently selected from carbon or nitrogen, such that at least one of X1-X3 represents nitrogen; oX4 represents CR or nitrogen; X5 represents CR6, nitrogen or C=O; than three of XrX5 represent nitrogen;— represents a single or double bond, such that when X5 represents C=O, X4 and X5 are joined by a single bond and such that a bond within the ring system of 5 members is a double bond; R3 represents hydrogen, halogen, Cμ6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C μ6alkoxy, C3.g cycloalkyl, C3.6 cycloalkenyl, cyano, haloCi.6 alkyl, haloCμβ alkoxy or =O;

A represents a non-aromatic or aromatic heterocyclic or carbocyclic group which may be optionally substituted by one or more (e.g. 1,2 or 3) Ra groups;

B represents a -V-carbocyclic group or a -W-heterocyclyl group, said carbocyclic and heterocyclyl groups being optionally substituted with one or more (eg 1,2 or 3) Ra groups; R2 and R6 independently represent halogen, hydrogen, Cμ6 alkyl, Cμ6 alkoxy, C2.6 alkenyl, C2.6 alkynyl, -ON, C3.8 cycloalkyl, C3-g cycloalkenyl, -NHSO2RW, -CH=N-ORW, an aryl or heterocyclyl group where said Cμ4 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl and heterocyclyl groups may be optionally substituted with one or more Rb groups provided that both R2 and R6 do not represent hydrogen; Re, Rf and Rw independently represent hydrogen or Cμ6 alkyl ;Ra represents halogen groups, Cμ6 alkyl, C2.6 alkenyl, C2. 6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkenyl, -ORX, -O-(CH 2)n-ORx, haloCμ6 alkyl, haloCμ6 alkoxy, Cμ6 alkanol, =O, =S, nitro, Si( Rx)4, -(CH2)SCN, -S-RX, -SO-RX, -SO2-RX, -CORX, -(CRxRy)s-COORz, -(CH2)S- CONRxRy, -(CH2)s- NRxRy, -(CH2)s-NRxCORy, -(CH2)s-NRxSO2-Ry, -(CH2)S-NH-SOrNRxRy, -OCONRxRy, -(CH2)S. NRxCO2Ry, -O-(CH2)s-CRxRy-(CH2)t-ORZ or -(CH2)s-SO2NRxRy;Rx, Ry and Rz independently represent hydrogen, C1-6 alkyl, C2-and alkenyl, C2.6 alkynyl , C1-6 alkanol, hydroxyl, C1-6 alkoxy, haloC1-6 alkyl, -CO-(CH2)n-C1-6 alkoxy, C3.8 cycloalkyl or C3.8 cycloalkenyl; R1 and Rb independently represent a Ra group or a -Y-aryl or -Z-heterocyclyl group wherein said aryl and heterocyclyl groups may be optionally substituted with one or more (eg 1,2 or 3) groups Ra;V and W independently represent a bond or a -(-group CReRf)n-;Y and Z independently represent a bond, -CO-(CH2)S-, -COO-, -(CH2)n-, -NRX-(CH2)n-, -(CH2)n -NRx-, -CONRX-, -NRXCO- , -SO2NRX-, -NRXSO2-, -NRxCONRy-, -NRxCSNRy- -O-(CH2)S-, -(CH2)SO-, S-, -SO-or -(CH2)S-SO2-;n represents an integer from 1-4;set independently represent an integer from 0-4;q represents an integer from 0-2;aryl represents a carbocyclic ring; heterocyclyl represents a heterocyclic ring; or a pharmaceutically acceptable salt, solvate or derivative thereof, provided that the compound of formula (I) is not: 6-chloro-4-[3-(7-methyl-imidazo[1,2- a]pyridin-3-yl)-phenyl]-pyridin-3-yl-amine; or N-[3-(7-methyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-N-(2-nitro-phenyl)-amine.

sendo queXi, X2 e X3 são cada um independentemente selecionados de carbono ou nitrogênio, de tal modo que pelo menos um de Xi-X3 represente nitrogênio;X4 representa CR3 ou nitrogênio;X5 representa CR6, nitrogênio ou C=O;desde que não mais do que três de Xi-X5 representem nitrogênio;representa uma ligação simples ou dupla; R representa hidrogênio, halogênio, C].6 alquila, C2.6 alquenila, C2.6 alquinila, Cμ6 alcóxi, C3.6 ciclo-alquila, C3.6 ciclo-alquenila, ciano, haloCi.6 alquila, haloCi.6 alcóxi ou =O;In one embodiment, a compound of formula (D:

wherein Xi, X2 and X3 are each independently selected from carbon or nitrogen, such that at least one of Xi-X3 represents nitrogen; X4 represents CR3 or nitrogen; X5 represents CR6, nitrogen or C=O; than three of Xi-X5 represent nitrogen; represents a single or double bond; R represents hydrogen, halogen, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Cμ6 alkoxy, C3.6 cycloalkyl, C3.6 cycloalkenyl, cyano, haloC1.6 alkyl, haloC1.6 alkoxy or =O;

A represents a non-aromatic or aromatic heterocyclic or carbocyclic group which may be optionally substituted by one or more (e.g. 1,2 or 3) Ra groups;

B represents a non-aromatic or aromatic heterocyclic or carbocyclic group; R2 and R6 independently represent hydrogen, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3-8 cycloalkyl, C3.8 cycloalkenyl, an aryl group or heterocyclyl wherein said aryl and heterocyclyl groups may be optionally substituted with one or more Rb groups provided that when R6 represents a heterocyclyl group, said heterocyclyl group is not pyrazolyl; Ra represents halogen groups, C1.6 alkyl, C2.6 alkenyl , C2. 8 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkenyl, -ORX, -O-(CH 2)n-ORx, haloC1-6 alkyl, haloCμ6 alkoxy, C1-6 alkanol, =O, =S, nitro, -(CH2)SCN, -S-Rx, -SO-RX, -SO2-RX, -CORX, -(CRxRy)s-COORz, -(CH2)s-CONRxRy, -(CH2)S-NRxRy, -( CH2)sNRxCORy, -(CH2)s-NRxSO2-Ry, -OCONRxRy, -(CH2)S-NRxCO2Ry, -O-(CH2)s-CRxRy-(CH2)t-ORz or -(CH2)s-SO2NRxRy; Rx, Ry and Rz independently represent hydrogen, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 alkanol, hydroxyl, C1-6 alkoxy, haloC1-6 alkyl, -CO-(CH2)n- C1-6 alkoxy, C3.8 cycloalkyl or C3.8 cycloalkenyl; R1 and Rb independently represent a Ra group or a -Y-aryl or -Z-heterocyclyl group wherein said aryl and heterocyclyl groups may be optionally substituted with one or more (eg 1,2 or 3) Ra groups; provided that when R2 represents a group other than hydrogen, X5 represents CH or C=O and when R2 represents hydrogen, R6 represents a group other than hydrogen; Y and Z independently represent a link. action, -CO- (CH2)S-, -COO-, -(CH 2)n-, -NRX-(CH 2)n-, -(CH 2)n-NRx-, -CONRX-, -NRXCO- , -SO2NRX-, -NRXSO2-, -NRxCONRy-, -NRxCSNRy-, -O-(CH2)S-, -(CH2)SO-, S-, -SO- or -(CH2)S-SO2-;men independently represent an integer from 1-4; set independently represent an integer from 0-4; q represents an integer from 0-2; aryl represents a carbocyclic ring; heterocyclyl represents a heterocyclic ring; or a pharmaceutically acceptable salt, solvate or derivative thereof.

The term 'C1-6 alkyl' as used herein as a group or part of the group refers to a straight or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.

The term 'C1-6 alkoxy' as used herein refers to an -O-C1-6 alkyl group wherein C1-6 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like.

The term 'C 6 alkanol' as used herein refers to a C 1-6 alkyl group substituted with one or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.

The term 'C3.8 cycloalkyl' as used herein refers to a monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like.

The term 'C3-6 cycloalkyl' as used herein refers to a monocyclic hydrocarbon ring of 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term 'halogen' as used herein refers to a fluorine, chlorine, bromine or iodine atom.

The term 'haloC 1-6 alkyl' as used herein refers to a C 1-6 alkyl group as defined herein wherein at least one hydrogen atom is replaced by halogen. Examples of such groups include fluoro-ethyl, trifluoro-methyl or trifluoro-ethyl and the like.

The term 'haloC 1-6 alkoxy' as used herein refers to a C 1-6 alkoxy group as defined herein wherein at least one hydrogen atom is replaced by halogen. Examples of such groups include difluoro-methoxy or trifluoro-methoxy and the like. References to "carbocyclic" and "heterocyclic" groups as used herein are, unless the context indicates otherwise, to include both aromatic and non-aromatic ring systems. aromatic. Thus, for example, the term "carbocyclic and heterocyclic groups" includes within its scope aromatic, non-aromatic, unsaturated, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. In general, such groups can be monocyclic or bicyclic and can contain, for example, 3 to 12 ring members, more usually 5 to 10 ring members. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7, and 8 ring members, more usually 3 to 7, and preferably 5 or 6 ring members. Examples of bicyclic groups are those containing 8, 9, 10, 11 and 12 ring members, and more usually 9 or 10 ring members. When reference is made herein to carbocyclic and heterocyclic groups, the carbocyclic or heterocyclic ring may, unless the context otherwise indicates, be unsubstituted or substituted with one or more substituents eg molecular fragments, molecular structures or functional groups such as discussed here. It will be recognized that references to "carbocyclic" and "heterocyclic" groups include reference to carbocyclic and heterocyclic groups which may be optionally substituted with one or more (e.g. 1,2 or 3) Ra or Rb groups.

Carbocyclic or heterocyclic groups can be aryl or heteroaryl groups having from 5 to 12 ring members, more usually from 5 to 10 ring members. The term "aryl" as used herein refers to a carbocyclic group having aromatic character and the term "heteroaryl" is used herein to denote a heterocyclic group having aromatic character. The terms "aryl" and "heteroaryl" include polycyclic (e.g. bicyclic) ring systems wherein one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the group can be linked by the aromatic ring, or by a non-aromatic ring.

The term "non-aromatic group" includes unsaturated ring systems without aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. The terms "saturated" and "partially saturated" refer to rings wherein the ring structure(s) contain atoms sharing bond of more than one valence ie the ring contains at least one multiple bond eg a bond to C=C, C=C or N=C. The term "fully saturated" refers to rings where there are no multiple bonds between the ring atoms. Saturated carbocyclic groups include cycloalkyl groups as defined below. Partially saturated carbocyclic groups include cycloalkenyl groups as defined below, for example cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Saturated heterocyclic groups include piperidine, morpholine, thio-morpholine. Partially saturated heterocyclic groups include pyrazolines, for example 2-pyrazoline and 3-pyrazoline.

Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a five-membered or six-membered monocyclic ring or a bicyclic structure formed from two fused five- and six-membered rings or two fused six-membered rings, or two fused five-membered rings. Each ring can contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine nitrogen, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any ring amino group substituents, will be less than five.

Examples of five membered heteroaryl groups include but are not limited to the groups a pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole. Another example of a five-membered heteroaryl group includes thiadiazole.

Examples of six-membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.

A bicyclic heteroaryl group can be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5-ring or 6-membered ring containing 1, 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5 or 6 membered ring containing 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a 5 or 6 membered ring containing 1, 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a 5 or 6 membered ring containing 1 or 2 ring heteroatoms; f) an imidazole ring fused to a 5 or 6 membered ring containing 1 or 2 heteroatoms of ring; g) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; h) an isoxazole ring fused to a 5 or 6 membered ring containing 1 or 2 ring heteroatoms; i) a thiazole ring fused to a 5 or 6 membered ring containing 1 or 2 ring heteroatoms; j) a fused isothiazole ring in a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; k) a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; 1) a furan ring fused to a ring of 5 or 6 membered containing 1, 2 or 3 ring heteroatoms; m) an oxazol ring fused to a 5 or 6 membered ring containing 1 or 2 ring heteroatoms; h) an isoxazole ring fused to a 5 or 6 membered ring containing 1 or 2 ring heteroatoms; o) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1,2 or 3 ring heteroatoms; and p) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a five-membered ring fused to another five-membered ring include but are not limited to imidazothiazole (eg imidazo[2,1-b]thiazole) and imidazoimidazole (eg imidazo[1,2-a] imidazole).

Particular examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include but are not limited to benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (eg, adenine, guanine), indazole, pyrazolopyrimidine (eg pyrazolo[1,5-a]pyrimidine), triazolopyrimidine (eg [1,2,4]triazolo[1,5-a]pyrimidine), benzodioxol and pyrazolopyridine (eg pyrazolo[1,5-a]pyridine). Another example of a bicyclic heteroaryl group containing a six-membered ring fused to a five-membered ring includes imidazopyridine.

Particular examples of bicyclic heteroaryl groups containing two fused six-membered rings include but are not limited to quinoline, isoquinoline, chroman, thio-chroman, chromene, isochromene, chroman, isochrome, benzodioxane, quinolizine, benzoxazine, benzodiazine, pyridoxaline, quino quinazoline, cinoline, phthalazine, naphthyridine and pteridine.

Examples of polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydro-naphthalene, tetrahydro-isoquinoline, tetrahydro-quinoline, dihydro-benzothiophene, dihydro-benzofuran groups, 2,3-dihydro-benzo[1,4]dioxin, benzoyl,3]dioxol, 4,5,6,7-tetrahydro-benzofuran, indoline and indane. Another example of a polycyclic heteroaryl group containing an aromatic ring and a non-aromatic ring includes tetrahydro-triazolopyrazine (eg 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3 -a]pyrazine).

A nitrogen-containing heteroaryl ring must contain at least one ring nitrogen atom. Each ring may, in addition, contain up to about four other heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, for example 1,2 or 3, more usually up to 2 nitrogens, for example a single nitrogen. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine nitrogen, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any ring amino group substituents, will be less than five.

Examples of nitrogen-containing heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl (triazolyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl, indolizinyl, isoindolinyl, purdeninyl (eg, [6-amino-purine], guanine [2-amino-6-hydroxy-purine]), indazolyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, phthalazinyl, naphthyridinyl and pteridinyl.

Examples of nitrogen-containing polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydro-isoquinolinyl, tetrahydro-quinolinyl, and indolinyl.

Examples of carbocyclic aryl groups include phenyl, naphthyl, indenyl, and tetrahydro-naphthyl groups.

Examples of non-aromatic heterocyclic groups are groups having from 3 to 12 ring members, more usually 5 to 10 ring members. Such groups can be monocyclic or bicyclic, for example, and typically have heteroatomic ring members (most usually 1,2, 3 or 4 heteroatomic ring members), usually selected from nitrogen, oxygen and sulfur. Heterocyclic groups may contain, for example, cyclic ether groups (eg as in tetrahydro-furan and dioxane), cyclic thio-ether groups (eg as in tetrahydro-furan and dithiane), cyclic amine groups (eg as in pyrrolidine), cyclic amide groups (eg as in pyrrolidone), cyclic thio-amides, cyclic thio-esters, cyclic ureas (eg as in imidazolidin-2-one) cyclic ester groups (eg as in butyrolactone), cyclic sulfones (eg as in in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and their combinations (eg thio-morpholine).

Particular examples include morpholine, piperidine (eg 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), piperidone, pyrrolidine (eg 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, azetidine, pyran (2H -pyran or 4H-pyran), dihydro-thiophene, dihydro-pyran, dihydro-furan, dihydro-thiazole, tetrahydro-furan, tetrahydro-thiophene, dioxane, tetrahydro- pyran (eg 4-tetrahydro-pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazone, piperazine, and N-alkyl-piperazines such as N-methyl-piperazine. In general, preferred non-aromatic heterocyclic groups include saturated groups such as piperidine, pyrrolidine, azetidine, morpholine, piperazine and N-alkyl-piperazines.

In a non-aromatic nitrogen-containing heterocyclic ring the ring must contain at least one ring nitrogen atom. Heterocyclic groups may contain, for example, cyclic amine groups (eg as in pyrrolidine), cyclic amides (such as a pyrrolidinone, piperidone or caprolactam), cyclic sulfonamides (such as an isothiazolidine 1,1-dioxide, [1,2]thiazinane 1,1-dioxide or [1,2]thiazepane 1,1-dioxide) and combinations thereof.

Particular examples of non-aromatic nitrogen-containing heterocyclic groups include aziridine, morpholine, thio-morpholine, piperidine (eg 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (eg 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, dihydro-thiazol, imidazoline, imidazolidinone, oxazoline, thiazoline, 6H-1,2,5-thiadiazine, 2-pyrazoline, 3-pyrazoline, pyrazolidine, piperazine, and N-alkyl-piperazines such as N-methyl-piperazine.

Heterocyclic groups can be fused polycyclic ring systems or point-linked ring systems such as bicycloalkanes, tricycloalkanes and their oxa- and aza-analogs (e.g. adamantane and oxa-adamantane). For an explanation of the distinction between fused ring and bridged ring systems, see "Advanced Organic Chemistry" by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992.

Examples of non-aromatic carbocyclic groups include cycloalkane groups such as cyclohexyl and cyclopentyl, cycloalkenyl groups such as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, as well as cyclohexadienyl, cyclooctatetraene, tetrahydro-naphthenyl and decalinyl.

Heterocyclic groups can each be unsubstituted or substituted with one or more substituent groups. For example, heterocyclic groups can be unsubstituted or substituted with 1, 2, 3 or 4 substituents. Where the heterocyclic group is monocyclic or bicyclic, it typically is unsubstituted or has 1,2 or 3 substituents.

As mentioned above, it represents a single or double bond. It will be clear to the person skilled in the art that when X5 represents C=O or R3 represents =0, X4 and X5 are joined by a single bond.

PARTICULAR MODALITIES OF THE INVENTION

Outros exemplos de sistemas de anel incluídos pelas

Examples of ring systems included by the definitions of X]-X5 are shown in the following formulas (I)a-(I)t:

Other examples of ring systems included by

In one embodiment, two bonds within the 5-membered ring system are double bonds. In one embodiment, X! represents C.

In one embodiment, Xb X3 and X5 represent C and X2 and X4 represent nitrogen (i.e. a ring system of formula (I)a).

In an alternative embodiment, X], X3, X4 and X5 represent C and X2 represents nitrogen (i.e. a ring system of formula (I)e).

In an alternative embodiment, X], X3 and X4 represent C and X2 and X5 represent nitrogen (i.e. a ring system of formula (I)f).

In an alternative embodiment, Xi and X2 represent C, X3 represents nitrogen, X4 represents CR3 (e.g. CH) and X5 represents CR6 (e.g. C-Me) (i.e. a ring system of formula (I)h).

In an alternative embodiment, Xi, X2, X4 and X5 represent C and X3 represents nitrogen (i.e. a ring system of formula (I)j).

In an alternative embodiment, Xb X2 and X4 represent C and X3 and X5 represent nitrogen (i.e. a ring system of formula (I)k).

In an alternative mode, X2, X3, X4 and X5 represent C and X! represents nitrogen (i.e. a ring system of formula (I)q).

In an alternative embodiment, X2, X3 and X5 represent C and X], and X4 represent nitrogen (i.e. a ring system of formula (I)r).

In one embodiment, XrX5 represent a ring system of formulas (I)a, (I)e, (I)j or (I)q. In another embodiment, XrX5 represent a ring system of formula (I)a or (I)j. In another embodiment, Xj -X5 represent a ring system of formula (I)j.

In one embodiment, when Xb X2 and X5 represents C, X3 represents nitrogen and A represents phenyl, B is a group other than a heterocyclic group.

In one embodiment, when Xlt X2, X4 and X5 represents C, X3 represents nitrogen and A represents pyrimidinyl, B represents a group other than a heterocyclic group.

In one embodiment, when Xb X3, X4 and X5 represents C, X2 represents nitrogen and A represents pyrimidinyl, B represents a group other than a heterocyclic group.

In one embodiment, when Xb X3 and X5 represent C and X2 and X4 represent nitrogen, Rd is a group other than =O.

In one embodiment, when X2, X3, X4 and X5 represent C, X represents nitrogen, A represents thiazolyl, Ra represents a group other than -CONRxRy.

In one embodiment, when X2 and X3 represent C and X] represent nitrogen, A represents a group other than pyrazinyl.

In one embodiment, when X2, X3, X4 and X5 represent C and X represents nitrogen, B represents a group other than phenyl.

In one embodiment, when X4 represents nitrogen, X represents a group other than nitrogen.

In one embodiment, when X5 represents CR6 and R6 represents a heterocyclyl group, said heterocyclyl group is other than pyrazole (e.g. optionally substituted pyrazole).

In one embodiment, when X 1 and X 2 represent carbon and X 3 represent nitrogen, A represents a group other than pyridinyl or pyrimidinyl.

In one embodiment, when Xi represents carbon, at least one of X2, X3, X4, and X5 is different from carbon.

In one embodiment, when Xj represents carbon and A represents pyrimidinyl, B represents a group other than phenyl.

In one embodiment, when X 1 represents nitrogen, A represents pyrimidinyl, V represents -(CReRf)-, B represents a group other than piperazinyl, morpholinyl, thio-morpholinyl, thioxo-morpholinyl, or thio-dioxo-morpholinyl.

In one embodiment, when Xi represents nitrogen, A represents pyrimidinyl, V represents -(CReRf)-, B represents a non-aromatic ring system.

In one embodiment, when Xj represents nitrogen, X2 and X3 represent carbon, A represents pyrimidinyl, V represents -(CReRf)-, B represents an aromatic ring system.

O grupo (I)L pode ser um tautômero de imidazol e.g. (I)L2.Em uma modalidade, A representa um grupo selecionado de qualquer uma das fórmulas (I)A a (I)J e (I)L a (1)0.Em uma modalidade, A é um grupo diferente de pirazolila.Em uma modalidade, A é selecionado de (I)B, (I)N, (1)0.In one embodiment, when Xi represents nitrogen, A represents a group other than purin-2-yl. Examples of ring systems included by definition A are shown in the following formulas (I)A-(I)O:

The (I)L group can be an imidazole tautomer eg (I)L2. In one embodiment, A represents a group selected from any of the formulas (I)A through (I)J and (I)L through (1) 0. In one embodiment, A is a group other than pyrazolyl. In one embodiment, A is selected from (I)B, (I)N, (1)0.

In one embodiment, A represents a monocyclic aromatic carbocyclic or heterocyclic ring system having for example a 5-, 6- or 7-membered ring. In another embodiment, A represents a 6-membered carbocyclic ring. In yet another embodiment, A represents a phenyl group (i.e. a ring system of formula (I)a) optionally substituted with one or more (e.g. 1,2 or 3) Ra groups. In one embodiment, A represents phenyl unsubstituted or substituted with a -(CH2)sCONRxRy (e.g. -CONH2), -(CH2)SCN (e.g. -CN), Cb6 alkyl (e.g. methyl) or alkoxy (e.g. methoxy) group.

In one embodiment, A represents a monocyclic aromatic carbocyclic or heterocyclic ring system having for example a 5-, 6- or 7-membered ring. In another embodiment, A represents a 6-membered carbocyclic ring. In yet another embodiment, A represents a phenyl group (ie a ring system of formula (I)A) or a pyridyl group (ie a ring system of formula (IB) or (IC)) optionally substituted with one or more ( eg 1,2 or 3) Ra groups. In one embodiment, A represents phenyl unsubstituted or substituted with a group -(CH2)s-CONRxRy (eg -CONH2), -(CH2)SCN (eg -CN), halogen (eg fluorine), Cμ6 alkyl (eg methyl ), Cµ6 alkanol (eg -CH2OH) or -ORX (eg methoxy or -OCH(Me)2).

It will be appreciated that in the embodiment in which X] represents nitrogen, ring A will be attached to said group Xj via a carbon atom.

In one embodiment, A represents a 6-membered monocyclic aromatic carbocyclic or heterocyclic ring system (e.g. phenyl or pyridyl), substituted with NH-B at the 3-position or 5-position. When 10 A represents phenyl, in an NH-B embodiment it is present in the 3-position of the phenyl with respect to the bond position in Xb

In one embodiment, A represents a 6-membered monocyclic aromatic carbocyclic or heterocyclic ring system (e.g. phenyl or pyridyl), substituted with NH-B at the 5-position and further optionally substituted with a single Ra group at the 3-position.

In another embodiment, A represents unsubstituted phenyl. When V and W represent a bond, examples of aromatic ring systems included by the definition of B-NH- are shown in the following formulas B1-B47, in particular B1-B45:

When V and W represent a bond, particular examples of B rings include B1, B4 and B9. Other particular examples of B rings include B19-21, B22, B24, B25, B27-36, B38-40, B42 and B44.

When V represents -(CReRf)n- (eg CH2), an example of an aromatic ring system included by the definition of B-NH- is shown in the following formula B48:

When V and W represent a bond, examples of saturated or partially saturated aromatic ring systems included by the definition of B-NH- are shown in the following Table 1:

In one embodiment, B represents -V-aryla. In one embodiment, V represents a bond or CH2. In another embodiment, V represents a bond. In one embodiment, the aryl group of B represents a phenyl group. In one embodiment, B represents -W-heterocyclyl. In one embodiment, W represents a bond.

In one embodiment, B represents a non-aromatic or aromatic heterocyclic or carbocyclic group.

Ba sendo que Xa é selecionado de NH, CH, e S; Xb éselecionado de C, N, O, e S; Xc é selecionado de N, e O; Xd é selecionado de C, N, O, e S; Xe é selecionado de C e N erepresenta o ponto de ligação em NH;

sendo que a linha tracejada pode representar uma ligaçãosimples, ou dupla;Xa é selecionado de NH, CH, e S; Xb é selecionado de C, N, O, e S; Xc é selecionado de C, S e N; Xd é selecionado de C, N, O, e S; Xe é selecionado de C e N; erepresenta o ponto de ligação em NH;

sendo que a linha tracejada pode representar uma ligaçãosimples, ou dupla;Xa é selecionado de NH, CH, e S; Xb é selecionado de C, N, O, e S; Xc é selecionado de C, N, O, e S; Xd é selecionado de C, N, O, e S; Xe é selecionado de C e N; erepresenta o ponto de ligação em NHIn one embodiment, the aryl or heterocyclyl group of B 10 represents a monocyclic aromatic carbocyclic or heterocyclic ring system having for example a 5-, 6- or 7-membered ring (eg phenyl, pyridyl, pyrazinyl, triazolyl or thiadiazolyl). In another embodiment, the heterocyclyl group of B represents a 5- or 6-membered heterocyclic ring (eg pyridyl, pyrazinyl, triazolyl or thiadiazolyl). In another embodiment, the heterocyclyl group of B represents a 5- or 6-membered heterocyclic ring (eg pyridyl, pyrazinyl, triazolyl, oxadiazolyl, imidazolyl or thiadiazolyl). In yet another embodiment, the heterocyclyl group of B represents a 5-membered heterocyclic ring group selected from compounds of formula Bd, B b and Bc:

Ba where Xa is selected from NH, CH, and S; Xb is selected from C, N, O, and S; Xc is selected from N, and O; Xd is selected from C, N, O, and S; Xe is selected from C and N and represents the point of attachment in NH;

the dashed line may represent a single or a double bond; Xa is selected from NH, CH, and S; Xb is selected from C, N, O, and S; Xc is selected from C, S and N; Xd is selected from C, N, O, and S; Xe is selected from C and N; erepresents the point of attachment in NH;

the dashed line may represent a single or a double bond; Xa is selected from NH, CH, and S; Xb is selected from C, N, O, and S; Xc is selected from C, N, O, and S; Xd is selected from C, N, O, and S; Xe is selected from C and N; erepresents the point of attachment in NH

In yet another embodiment, the heterocyclyl group of B represents oxadiazolyl, imidazolyl, triazolyl or thiadiazolyl. In another embodiment, the heterocyclyl group of B represents triazolyl or thiadiazolyl. In yet another embodiment, the heterocyclyl group of B represents thiadiazolyl.

In one embodiment, when B represents -NH-C(Me)-phenyl or -NH-CH 2 -phenyl, A represents a monocyclic group.

In one embodiment, q represents 0 or 1. When q represents 1, in one embodiment, R1 represents Cµ6 alkyl (e.g. methyl). When q represents 1, in an alternative embodiment, R1 represents either -(CH2)s-NRxRy (e.g. -NH2). In another modality, q represents 0.

In one embodiment, R1 and Rb independently represent a Ra group or a -Y-aryl or -Z-heterocyclyl group wherein said aryl and heterocyclyl groups may optionally be substituted with one or more (e.g. 1,2 or 3) Ra groups.

In one embodiment, when R2 represents hydrogen, X5 represents CR6 where R6 represents a group other than hydrogen.

In one embodiment, when X5 represents CH or nitrogen, R represents a group other than hydrogen.

In one embodiment, when R2 represents a group other than hydrogen, X5 represents CH, nitrogen, or C=O.

In one embodiment, when X5 represents CR6 where R6 represents a group other than hydrogen, R2 represents hydrogen.

When R2 or R6 represents a heterocyclyl group, in one embodiment the heterocyclyl group is other than pyrazolyl (e.g. optionally substituted pyrazolyl).

In one embodiment, R2 represents C1-6 alkyl (e.g. methyl). In one embodiment, R2 represents halogen (e.g. chlorine).

In one embodiment, R2 represents an aryl or heteroaryl group optionally substituted with one or more Ra groups.

In one embodiment, R2 represents an aryl or heteroaryl group optionally substituted with one or more Rb groups. In one embodiment, R2 represents phenyl optionally substituted with an Rb group.

In one embodiment, R2 represents an aryl (eg phenyl) group optionally substituted with one or more (eg 1,2 or 3) groups R selected from halogen (eg fluorine), haloC 1.6 alkoxy (eg -OCF3), -ORX ( eg methoxy or -OCH2OHCH2OH), Cμ6 alkanol (eg -CH2OH), -(CRxRy)s-COORz (eg -COOH, -COOMe, -C(Me)2-COOH, -CH2-COOH or -C(Me)2 -COOMe), -(CH2)S, CN (eg -CH2CN), -(CH2)s-NRxRy (eg-NMe2, -(CH2)2-NH2, -(CH2)2-NMe2 or -NH-CO- CH2-methoxy) or -O-(CH2)n-ORx (eg -O-(CH2)2-ethoxy).

In one embodiment, R2 represents an aryl (eg phenyl) group optionally substituted with one or more (eg 1,2 or 3) groups Rb selected from halogen (eg fluorine), haloC1-6 alkoxy (eg -OCF3), -ORX ( eg methoxy or -OCH2OHCH2OH), alkanol (eg -CH2OH), -(CRxRy)s-COORz (eg -COOH, -COOMe, -C(Me)2-COOH, -CH2-COOH or -C(Me)2- COOMe), -(CH2)SCN (eg -CH2CN), -(CH2)s-NRxRy (eg -NH', -NMe2, -(CH2)2-NH2, -(CH2)2-NMe2 or -NH-CO -CH2-methoxy), -(CH2)s-CONRxRy (eg -CONHMe or -CH2-CONHMe), -(CH2)s-NRxSO2-Ry (eg -CH2-NHSO2Me) or -O-(CH ?)n- ORx (eg -O-(CH2)2-ethoxy).

In another embodiment, R2 represents an aryl group (eg phenyl) optionally substituted with one or more (eg 1,2 or 3) groups Rb selected from halogen (eg fluorine), Cµ6 alkanol (eg -CH2OH), -(CH2) S-NRxRy (eg -NH2), -(CRxRy)s-COORz (eg -CH2-COOH), -(CH2)s-CONRxRy (eg -CONHMe or -CH2-CONHMe), -(CH2)s-NRxSO? -Ry (eg -CH?-NHSO2Me). optionally substituted with an -Y-aryl group (eg. -Y-phenyl). In one embodiment, Y represents -O-(CH2)S- (eg. -O-CH2-).

In one embodiment, R2 represents an aryl (eg phenyl) group optionally substituted with a -Z-heterocyclyl group (eg -Z-morpholinyl, -Z-azetidinyl, -Z-pyrrolidinyl, -Z-tetrazolyl, -Z-piperidinyl, - Z-piperazinyl) wherein said heterocyclyl group may be optionally substituted with one or more (eg 1,2 or 3) Ra groups selected from C 1-6 alkyl (eg methyl) or -(CRxRy)s-COORz (eg -COOH) groups , -COOMe or -COCfBu).

In one embodiment, R2 represents an aryl (eg phenyl) group optionally substituted with a -Z-heterocyclyl group (eg -Z-morpholinyl, -Z-azetidinyl, -Z-pyrrolidinyl, -Z-tetrazolyl, -Z-piperidinyl, - Z-piperazinyl) wherein said heterocyclyl group may be optionally substituted with one or more groups (eg 1,2 or 3) Ra groups selected from C1-6 alkyl (eg methyl), =O (eg piperazin-2-one) or -(CRxRy)s-COORz (eg -COOH, -COOMe or -COOlBu).

In another embodiment, R2 represents an aryl group (eg phenyl) optionally substituted with a halogen (eg fluorine), -Z-heterocyclyl group (eg -CH2-morpholinyl, -CH2-piperazinyl, -CH2-piperidinyl, -CH2-azetidinyl ), -(CRxRy)s-COORz (eg -COOH or -C(Me)2-COOH), wherein said heterocyclyl group may be optionally substituted with a C1-6 alkyl group (eg methyl), or -(CRxRy) s-COOR2 (eg -COOH).

In another embodiment, R2 represents an aryl group (eg phenyl) optionally substituted with a halogen (eg fluorine), -Z-heterocyclyl group (eg -CH2-morpholinyl, -CO-morpholinyl, -CH2-piperazinyl, -CH2-piperidinyl , -CH2-azetidinyl), -(CRxRy)s-COORz (eg -COOH or -C(Me)2-COOH), wherein said heterocyclyl group may be optionally substituted with a C 1.6 alkyl group (eg methyl) , or -(CRxRy)s-COORz (eg -COOH). optionally substituted with a -Z-heterocyclyl group (eg -CH2-morpholinyl, -CO-morpholinyl, -CH2-piperidinyl or -CH2-piperazinyl) wherein said heterocyclyl group may be optionally substituted with one or more (eg 1,2 or 3) Ra groups selected from C 1.6 alkyl (eg methyl) or =O (eg piperazin-2-one).

In yet another embodiment, R represents an aryl group (eg phenyl) optionally substituted with a halogen atom (eg fluorine) or a -Z-heterocyclyl group (eg -CH2-morpholinyl or -CH2-piperazinyl) wherein said heterocyclyl group may optionally be substituted with a C1-6 alkyl group (eg methyl).

In yet another embodiment, R2 represents an aryl (e.g. phenyl) group optionally substituted with a halogen (e.g. fluorine) atom.

In one embodiment, R2 represents a 5-membered heterocyclyl group optionally substituted with one or more Ra groups.

In one embodiment, R2 represents a 5-membered heteroaryl group optionally substituted with one or more Rd groups. In one embodiment, R2 represents a heterocyclyl group optionally substituted with an Rb group.

In one embodiment, R2 represents a heterocyclyl group optionally substituted with a -Z-heterocyclyl or -(CH2)s-NRxRy group.

In one embodiment, R2 represents a heterocyclyl group (eg morpholinyl, piperazinyl, pyridyl, thienyl, pyrazinyl, benzothienyl, furanyl or pyrimidinyl) optionally substituted with one or more (eg 1,2 or 3) Rb groups selected from =O groups (eg pyridinone), C1-6 alkyl (eg methyl), -(CH2)S NRxRy (eg -NH2), -ORX (eg methoxy), -CORX (eg -COMe) or C1-6 alkanol (eg -CH2OH).

In one embodiment, R2 represents a heterocyclyl group (eg morpholinyl, piperazinyl, pyridyl, thienyl, pyrazinyl, benzothienyl, furanyl, imidazolyl, pyrazolyl, benzodioxolyl, pyrrolidinyl, azetidinyl, piperidinyl, oxazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl , isoxazolyl, benzodioxolyl, tetrahydro-triazolopyrazinyl or pyrimidinyl) optionally substituted with one or more (eg 1,2 or 3) Rb groups selected from =O groups (eg pyridinone or 5-oxo-4,5-dihydro- [1,3,4]oxadiazolyl), =S (eg thioxo-4,5-dihydro-[1,3,4]oxadiazole), halogen (eg fluorine), C1-6 alkyl (eg methyl, ethyl, propyl, i-Pr or t-Bu), haloCμ6 alkyl (eg -CH2-F, -CF3 or -CH2CF3), C3.8 cycloalkyl (eg cyclopropyl), -(CH2)s-NRxRy (e: -NH2), -ORX (eg hydroxyl, methoxy or -Oi-Pr), -(CH2)n-O-Ci-e alkyl (eg -CH2-O-Me), -CORX (eg -COMe) , -(CRxRy)s-COORz (eg -COOH, -COOEt or -COOt-Bu), -S-Rx (eg -S-Me), -SO2-RX (eg -SO2-Et), -(CH2) s -NRxRy (e.g. -NH2), -(CH2)3-SO2NRxRy (e.g. -SO2-NMe2) or alkanol (e.g. -C(OH)(Me)2 or -CH2OH).

In one embodiment, R2 represents a heterocyclyl group (eg morpholinyl, piperazinyl, pyridyl, thienyl, pyrazinyl, pyrazolyl, piperidinyl, benzodioxolyl, benzothienyl, furanyl or pyrimidinyl) optionally substituted with one or more (eg 1,2 or 3) selected Rb groups of groups =O (eg pyridinone), C 1.6 alkyl (eg methyl), -(CH2)s-NRxRy (eg -NH2), -ORX (eg methoxy), -CORX (eg -COMe), - (CRxRy )s-COORz (eg -COOEt), -SO2-RX (eg -SO2Et) or Cµ6 alkanol (eg -CH2OH).

In one embodiment, R represents a heterocyclyl group (eg morpholinyl, piperazinyl, pyridyl, pyrazinyl, pyrazolyl, piperidinyl, benzodioxolyl or pyrimidinyl) optionally substituted with one or more (eg 1,2 or 3) Rb groups selected from Cμ6 alkyl (eg methyl ), -(CH2)S-NRxRy (eg -NH2), -CORX (eg -COMe), -(CRxRy)s-COORz (eg -COOEt) or -SO2-RX (eg -SO2Et).

In another embodiment, R represents a heterocyclyl group (eg. pyridyl) optionally substituted with a -Z-heterocyclyl group (eg. -Z-piperazinyl, -Z-morpholinyl or -Z-piperidinyl).

In another embodiment, R represents a heterocyclyl group (eg. pyridyl) optionally substituted with a -Z-heterocyclyl group (eg. -Z-piperazinyl, -Z-morpholinyl, -Z-tetrahydro-pyranyl or -Z-piperidinyl).

In yet another embodiment, R represents a heterocyclyl group (eg. pyridyl) optionally substituted with a -Z-heterocyclyl group (eg. -O-tetrahydro-pyranyl).

In yet another embodiment, R represents a heterocyclyl group (eg. pyridyl) optionally substituted with a -(CH 2 )S-NRxRy (eg. -NH 2 ) group.

In another embodiment, R2 represents oxazole, oxadiazole, triazole, tetrazole, pyrazole, thiadiazole, thiazole, imidazole or oxathiadiazole optionally substituted with one or more Ra groups.

In another embodiment, R2 represents oxazole, oxadiazole, triazole, tetrazole, thiadiazole or oxathiadiazole optionally substituted with one or more Ra groups.

In another embodiment, R represents thiadiazole, thiazole, or imidazole optionally substituted with one or more Ra'y groups

In another embodiment, R represents a 5-membered heterocyclyl group (eg oxazol, oxadiazol, triazole (eg, 1,2,3-triazol or 1,2,4-triazol), tetrazole, thiadiazol or oxathiadiazole) optionally substituted with a C1-6 alkyl group (eg methyl or methyl) or -S-Rx (eg -S-Me).

In another embodiment, R2 represents oxadiazole (eg 1,3,4-oxadiazole), tetrazole or thiadiazole (eg 1,3,4-thiadiazole) optionally substituted with a C1-6 alkyl (eg methyl or methyl) or -S group -Rx (eg -S-Me).

In another embodiment, R represents pyrazole optionally substituted with one or more Ra groups, for example one or two optionally substituted C1-6 alkyl groups (e.g. CH3, CH2OH, (CH2)2OH OR (CH2)2NH2).

In another embodiment, R2 represents pyrazole optionally substituted with one or more Ra groups, for example one or two C1-4 alkyl groups (e.g. methyl groups).

In another embodiment, R2 represents oxazole, oxadiazole, triazole, tetrazole, imidazole, thiadiazole or oxathiadiazole substituted with one or two optionally substituted C1-4 alkyl groups (e.g. CH3, CH2OH) or an =O group.

In another embodiment, R2 represents oxazole, oxadiazole, triazole, tetrazole, thiadiazole or oxathiadiazole substituted with one or two optionally substituted C1-6 alkyl groups (e.g. CH3, CH2OH).

In another embodiment, R2 represents an aryl group (eg phenyl) optionally substituted with a halogen atom (eg fluorine) or Rz represents a 5-membered heterocyclyl group (eg oxadiazole, tetrazole or thiadiazole) optionally substituted with a C1-6 group alkyl (eg methyl or methyl) or -S-Rx (eg -S-Me).

In another embodiment, R2 represents a heterocyclyl group (eg. pyridyl or pyrimidinyl) optionally substituted with a -Z-heterocyclyl group (eg. -Z-azetidinyl, -Z-piperazinyl, -Z-morpholinyl or -Z-piperidinyl).

In another embodiment, R2 represents a heterocyclyl group (eg. pyridyl) optionally substituted with a -Z-heterocyclyl group (eg. -Z-piperazinyl, -Z-morpholinyl or -Z-piperidinyl). O

In another embodiment, R represents a heterocyclyl group (eg. pyridyl) optionally substituted with a -Z-heterocyclyl group (eg. -Z-piperazinyl, -Z-morpholinyl, Z-tetrahydro-pyranyl or -Z-piperidinyl).

In yet another embodiment, R2 represents a heterocyclyl (e.g. pyridyl) group optionally substituted with a -(CH2 )S-NRxRy (e.g. -NH2 ) group.

In one embodiment, R2 represents halogen (e.g. fluorine or chlorine). In another embodiment, R2 represents halogen (eg chlorine). In one embodiment, R2 represents Cμ6 alkyl (eg methyl or methyl) optionally substituted with one or more Rb groups (eg -CH2OH, -C(OH)(Me)2 or -CF3).*2 • In one embodiment, R represents C3.8 cycloalkyl (eg cyclopropyl). In one embodiment, R2 represents -CH=N-ORW (eg -CH=N-OH or -CH =N-OMe). In one modality, R2 represents -NHSO2RW (eg - NHSO2Me). In one modality, R represents Ci.6 alkoxy (eg methoxy or ethoxy).

In one embodiment, R represents C2.6 alkynyl (e.g. ethynyl or propynyl) optionally substituted with an Rb group (e.g. -C=C-Si(Me)4). In another embodiment, R2 represents C2.6 alkynyl (e.g. ethynyl) optionally substituted with an Rb group (e.g. -C=C-Si(Me)4). In another embodiment, R represents C2.6 alkynyl (eg. ethynyl) optionally substituted with an Rb group (eg. cyclopropyl). In one embodiment, R represents -C=N.

In one embodiment, R represents C2.6 alkenyl optionally substituted with an Rb group (e.g. -CH=CH-COOEt or -CH=CHCONHMe).

In one embodiment R6 represents halogen, hydrogen, Cμ6 alkyl, Cμ6 alkoxy, C2.6 alkenyl, C2.6 alkynyl, -C=N, C3.8 cycloalkyl, C3.8 cycloalkenyl, -NHSO2RW, -CH= N-ORW, or a 3-6 membered monocyclic heterocyclyl group wherein said C1-6 alkyl, C1-6 alkenyl, C2-6 alkynyl and heterocyclyl groups may optionally be substituted with one or more Ra groups.

In one embodiment R and R may be optionally substituted with an Rb group. In another embodiment Rb includes an Ra or -Y-aryl or -Z-heterocyclyl group. In one embodiment, Y and Z independently represent -CO-, -O-(CH2)S- OR -NH-(CH2)n -,

In one embodiment, Z represents a bond, CO, -(CH 2 )n - (e.g. -CH 2 -, -(CH 2 ) 2 OR -(CH 2 ) 3 ) OR -O-. In another embodiment, Z represents -O-, CO or -(CH 2 )n- (e.g. -CH 2 -). In yet another embodiment, Z represents -(CH 2 )n - (e.g. -CH 2 -).

In one embodiment, Y and Z independently represent a bond, CO, -CH2-, -(CH2)2, -(CH2)3 or -O-.

In one embodiment, Z represents a bond, CO, -(CH 2 )n - (e.g. -CH 2 -, -(CH 2 ) 2 OR -(CH 2 ) 3 ) OR -O-. In another embodiment, Z represents -(CH 2 )n - (e.g. -CH 2 -).

In one embodiment, Z represents a bond, CO, -(CH2)n- (eg -CH2-, -(CH2)2 OR -(CH2)3) OR -O-. In one embodiment, Z represents a bond or -CH2-.

In one embodiment, Rb represents a Ra group or a -Y-aryl or -Z-heterocyclyl group wherein said aryl and heterocyclyl groups may optionally be substituted with one or more (e.g. 1,2 or 3) Ra groups.

sendo queIn one embodiment, Re, R' and Rw independently represent hydrogen or methyl. In another embodiment, Re, Rf, and Rw represent hydrogen. In one embodiment, n represents 1. In one embodiment, the compound of formula (I) is a compound of formula (Ia) or (Ib):

being that

A represents an aromatic carbocyclic or heterocyclic group which may be optionally substituted with one or more (e.g. 1,2 or 3) Ra groups;

B represents a non-aromatic or aromatic heterocyclic or carbocyclic group; R4 and R5 independently represent hydrogen, Cμ6 alkyl, C2-6 alkenyl, C6-6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkenyl, Cj- 6 alkanol, haloCμ6 alkyl, -(CH2)n-NRxRy, -(CH2)S-COORZ, -(CH2)nO-(CH2)m-OH, -(CH2)n-aryl, -(CH2 )nO-aryl, -(CH2)n-heterocyclyl or -(CH2)nO-heterocyclyl, said groups being Cμ6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3.8 cyclo -alkenyl, aryl and heterocyclyl may be optionally substituted with one or more (eg 1,2 or 3) groups Ra;Rx, Ry and Rz independently represent hydrogen, Cμ6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Cμ6 alkanol, hydroxyl, Cμ6 alkoxy, haloCμ6 alkyl, -CO-(CH 2)n-Cμ6 alkoxy, C3.8 cycloalkyl or C3.8 cycloalkenyl; R2 independently represent hydrogen, an aryl or heterocyclyl group, said aryl groups and heterocyclyl may be optionally substituted with one or more groups. s Rb;Rd represents halogen groups, Cµ6 alkyl, C2.6 alkenyl, C2. 6 alkynyl, C3-8 cycloalkyl, C3.8 cycloalkenyl, -ORX, -O-(CH2)n-ORx, haloC1-6 alkyl, haloC1-6 alkoxy, C1-6 alkanol, =O, =S , nitro, -(CH2)SCN, -S-Rx, -SO-RX, -SO2-RX, -CORX, -(CRxRy)s-COOR2, -(CH2)s-CONRxRy, -(CH2)S-NRxRy , -(CH2)s-NRxCORy, -(CH2)s-NRxSO2-Ry, -OCONRxRy, -(CH2)S-NRxCO2Ry, -O-(CH2)s-CRxRy-(CH2)rORz or -(CH2)s- SO2NRxRy;R1 and Rb represents a Ra group or a -Y-aryl or -Z-heterocyclyl group wherein said aryl and heterocyclyl groups may be optionally substituted with one or more (eg 1,2 or 3) Ra;Y and Z groups independently represent a bond, -CO-(CH2)S-, -COO-, -(CH 2)n-, -NRX-(CH 2)n-, -(CH 2)n-NRx-, -CONRX-, -NRXCO- , -SO2NRX-, -NRXSO2-, -NRxC0NRy-, -NRxCSNRy- -O-(CH2)S-, -(CH2)SO-, S-, -SO- or -(CH2)S-SO2- ; men independently represent an integer from 1-4; set independently represent an integer from 0-4; q represents an integer from 0-2; aryl represents a carbocyclic ring; heterocyclyl represents a heterocyclic ring; or a pharmaceutically acceptable salt, solvate or derivative thereof.

It will be appreciated that specific modalities of A, B, R, q and R groups in formulas (Ia) and (Ib) above are as outlined herein above for formula (I).

In one embodiment the compound of formula (I) is a compound of formula (Ia) as hereinbefore defined.

In one embodiment the compound of formula (I) is a compound of formula (Ia) or (Ib) wherein: A is phenyl or pyridine (eg pyridin-4-yl); B is benzyl, thiadiazole (eg [1,2 ,4]thiadiazol-5-yl or [1,3,4]thiadiazol-2-yl), [1,2,4]triazol-3-amine, 1-methyl-1H-imidazol-2-yl or [1 ,3,4]oxadiazol-2-yl; R2 is an optionally substituted 6-membered ring such as phenyl, or pyridine, or an optionally substituted nitrogen-containing 5-membered heterocycle such as pyrazol or tetrazole, wherein the optional substituents are selected of halogen eg fluorine, amino and C1-4 alkyl eg methyl.

In another embodiment the compound of formula (I) is a compound of formula (Ia) or (Ib) wherein A is phenyl or pyridine (eg pyridin-4-yl); B is benzyl, thiadiazole (eg [1,2, 4]thiadiazol-5-yl or [1,3,4]thiadiazol-2-yl), [1,2,4]triazol-3-amine, 1-methyl-1H-imidazol-2-yl or [1 ,3,4]oxadiazol-2-yl; R2 is phenyl optionally substituted with halogen eg fluorine (such as 4-fluoro-phenyl), pyridine optionally substituted with amino (such as 4-amino-pyridin-2-yl), pyrazol optionally substituted with methyl (such as 1-methyl-1H-pyrazol-4-yl) or tetrazole optionally substituted with methyl (such as 2-methyl-2H-tetrazol-5-yl).

sendo que Ra, R1, R2, B e q são como aqui definidos, n representa um número inteiro de 0 a 3 e L representa um átomo de carbono ou nitrogênio.Preferências particulares de variáveis Ra, R1, R2, B e q são aqui definidas.In one embodiment, the compound of formula (I) is a sub-formula of (Ia) and is defined by a compound of formula (Ic):

wherein Ra, R1, R2, B and q are as defined herein, n represents an integer from 0 to 3 and L represents a carbon or nitrogen atom. Particular preferences of variables Ra, R1, R2, B and q are defined herein.

In particular R2 is optionally substituted phenyl or a 5-6 membered monocyclic heterocycle. Particular preferences of R are as outlined above.

sendo que Ra, R1, R2, B, L, n e q são como aqui definidos.Preferências particulares de variáveis Ra, R1, R2, B e q são aqui definidas.In one embodiment, the compound of formula (I) is a sub-formula of (Ia) and is defined by a compound of formula (Id):

wherein Ra, R1, R2, B, L, neq are as defined herein. Particular preferences of variables Ra, R1, R2, B and q are defined herein.

In particular, in one embodiment R is phenyl optionally substituted with Rb. In another embodiment R2 is phenyl optionally substituted with Ra. In one embodiment the group Ra or Rb is at the 3-position or the 4-position of the phenyl ring. In an embodiment where the phenyl ring is substituted with Ra, the Ra group is at the 4-position of the phenyl ring. In an embodiment where the phenyl ring is substituted with Rb, where the Rb group is -Y-carbocycle group (e.g. Y-aryl) or -Z-heterocyclyl group the Rb group is at the 3-position of the phenyl ring.

In one embodiment the Rb groups are selected from halogen (eg fluorine or chlorine), deuterium (eg D5), haloC^f, alkyl (eg -CF3), haloCi.6 alkoxy (eg -OCF3), -ORX (eg methoxy or -OCH2OHCH2OH), Cμg alkyl (eg i-Pr), Cμ6 alkanol (eg -CH2OH), -(CRxRy)s-COOR7 (eg -COOH, -COOMe, -C(Me)2-COOH, -CH2-COOH or -C(Me)2-COOMe), -(CH2)SCN (eg -CN or -CH2CN), -(CH2)s-NRxRy (eg -NMe2, -(CH2)2-NH2, -(CH2)2- NMe2 or -NH-CO-CH2-methoxy), -O-(CH2)n-ORx (eg -O-(CH2)2-ethoxy), -(CH2)s-CONRxRy (eg -CONH2, -CONHMe, -CONHEt, -CONH-iPr, -CH2-CONHMe, -CONH-(CH2)2-OMe or -CONH-(CH2)2-NH2), -SO2-RX (eg -SO2Me), -(CH2)s- SOzNRxRy (eg -SO2NH2), -(CH2)s-NRx-SO2-Ry (eg -NHSO2Me or -CH2-NHSO2Me), -(CH2)s-NH-SO2-NRxRy (eg -NH-SO2-NMe2).

In one embodiment the R groups are selected from halogen (eg fluorine), haloCμ6 alkoxy (eg -OCF3), -ORX (eg methoxy or -OCH2OHCH2OH), C1-6 alkanol (eg -CH2OH), -(CRxRy)s-COOR2 (eg -COOH, -COOMe, -C(Me)2-COOH, -CH2-COOH or -C(Me)2-COOMe), -(CH2)SCN (eg -CH2CN), -(CH2)s-NRxRy (eg -NMe2, -(CH2)2-NH2, -(CH2)2-NMe2 or -NH-CO-CH2-methoxy) or -O-(CH2)n-ORx (eg -O-(CH2)2 -ethoxy). 1_

In one embodiment the R groups are selected from halogen (eg fluorine), -Y-aryl group (eg -Y-phenyl) or -Z-heterocyclyl group (eg -Z-morpholinyl, -Z-azetidinyl, -Z-pyrrolidinyl, -Z-tetrazolyl, -Z-piperidinyl, -Z-piperazinyl) wherein said heterocyclyl group may be optionally substituted with one or more (eg 1,2 or 3) Ra groups selected from C1-6 alkyl (eg methyl) or -(CRxRy)s-COORz (eg -COOH, -COOMe or -COO'Bu) and where Z is CO, CH2 or a bond.

In one embodiment the Rb groups are selected from the -Z-heterocyclyl group (eg -Z-morpholinyl, -Z-azetidinyl, -Z-pyrrolidinyl, -Z-pyrazolyl, -Z-tetrazolyl, -Z-piperidinyl, -Z-piperazinyl , -Z-diazepanyl or -Z-tetrahydro-pyranyl) wherein said heterocyclyl group may be optionally substituted with one or more (eg 1,2 or 3) Ra groups selected from C 1-6 alkyl groups (eg methyl or methyl ), =O, -CORX (eg -COMe) or -(CRxRy)s-COOR2 (eg -COOH, -COOMe or -COO'Bu) and where Z is CH2 OR a bond.

In yet another embodiment, R2 represents an aryl (e.g. phenyl) group optionally substituted with a halogen (e.g. fluorine) atom. In yet another embodiment, R2 represents 4-fluoro-phenyl.

sendo que Ra, Rl, R2, B, L, n e q são como aqui definidos.In one embodiment, the compound of formula (I) is a sub-formula of (Ib) and is defined by a compound of formula (le):

wherein Ra, R1, R2, B, L, neq are as defined herein.

sendo que Ra, R1, R2, B, L, n e q são como aqui definidos.In one embodiment, the compound of formula (I) is a compound of formula (If):

wherein Ra, R1, R2, B, L, neq are as defined herein.

In one embodiment, the compound of formula (I) is a compound selected from Examples 1-43, the product of Procedure F8 [Benzyl-[3-(7-chloro-imidazo[1,2-a]pyridin-3-yl) )-phenyl]-amine], the starting material from Procedure A4c [3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-[1,3,4]thiadiazol- 2-yl-amine] and the product of Procedure G1 [[3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-(3H-[1,2,3]triazole -4-yl)-amine]). In one embodiment, the compound of formula (I) is a compound selected from Examples 1-42. In one embodiment, the compound of formula (I) is a compound selected from Examples 1-13 .

In one embodiment, the compound of formula (I) is a compound selected from Examples 1,2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16,17, 18, 19, 20, 21.22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37.38, 39, 40, 41, 42, 43, the product from Procedure F8 [Benzyl-[3-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-amine], the starting material from Procedure A4c [3-(7-Chloro-imidazo) [1,2-a]pyridin-3-yl)-phenyl]-[1,3,4]thiadiazol-2-yl-amine] and the product of Procedure G1 [[3-(7-Chloro-imidazo[1 ,2-a]pyridin-3-yl)-phenyl]-(3H-[1,2,3]triazol-4-yl)-amine]).

In one embodiment, the compound of formula (I) is a compound selected from Examples 2, 3, 4, 7, 9, 10, 11, 12.13, 14, 16, 17, 18, 20, 24, 25, 26 , 28, 30, 32, 43 and the starting material of Procedure A4c [3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-[1,3,4]thiadiazol- 2-yl-amine]).

In one embodiment, the compound of formula (I) is a compound selected from Examples 7, 10, 11, 14, 27, 29, 31, 34, 37, 39 and 43.

Methods for the Preparation of Compounds of Formula (I) In this section, as in all other sections of this application unless the context indicates otherwise, references to formula (I) also include all its other subgroups and examples as defined herein.

Compounds of formula (1) can be prepared according to synthetic methods well known to the skilled person. In particular compounds of formula (I) are readily prepared by palladium-mediated coupling chemistries between chlorine, bromine, iodine, or aromatic pseudohalogens such as a trifluoromethanesulfonate (triflate) or tosylate compounds, and aromatic boronic acids or stannane derivatives. In particular, Suzuki copulation chemistry is widely applicable for synthesizing these compounds. The Suzuki reaction can be carried out under typical conditions in the presence of a palladium catalyst such as bis(tri-t-butyl-phosphine)-palladium, tetrakis(triphenyl-phosphine)-palladium(0) or a paladacycle catalyst ( eg the paladacycle catalyst described in Bedford, RB and Cazin, CSJ (2001) Chem. Commun., 1540-1541) and a base (eg a carbonate such as potassium carbonate) as discussed in more detail below. The reaction may be carried out in a polar solvent, for example an aqueous solvent system, including aqueous ethanol, or an ether such as dimethylethane or dioxane, and the reaction mixture is typically subjected to heating, for example to a temperature of 80°C. °C or higher, eg a temperature above 100°C.

As illustrated in Scheme 1, the imidazo[1,2-a]pyridine nucleus can be synthesized from commercially available starting materials using Rota A (to give a 3,7-disubstituted ring) or C (to give a 3,6- ring disubstituted). 4-Chloro-pyridin-2-yl-amine or 4-bromo-pyridin-2-yl-amine in an appropriate solvent and base can be cyclized under reflux with chloro-acetaldehyde to give the imidazopyridine ring. The 7-chloro-imidazo[1,2-a]pyridine in an appropriate solvent can then be iodinated for example using N-iodosuccinimide at RT.

Appropriate functionality then can be added at the halogenated positions, for example using a variety of metal catalyzed reactions. In particular, properly functionalized boronic acids or their boronane esters can react with the aryl halide. This transformation, commonly known as the Suzuki reaction, has been reviewed by Rossi et al. (2004), Synthesis 15, 2419). The Suzuki reaction is often carried out in mixtures of water and organic solvents. Examples of suitable organic solvents include toluene, tetrahydro-furan, 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile, N-methyl-pyrrolidinone, ethanol, methanol and dimethylformamide. The reaction mixture is typically subjected to heating, for example to a temperature above 100°C. The reaction is carried out in the presence of a base. Examples of suitable bases include sodium carbonate, potassium carbonate, cesium carbonate and potassium phosphate. Examples of suitable catalysts include bis(tri-t-butyl-phosphine)-palladium(0), tris(dibenzylidene-acetone)-dipalladium(O), bis(triphenyl-phosphine)-palladium(II) chloride, palladium acetate (II), tetrakis(triphenyl-phosphine)-palladium(0), bis(tricyclohexyl-phosphine)-palladium(O), [1,1'-bis(diphenyl-phosmo)-ferrocene]-dichloro-palladium( II), dichloro-bis(tri-o-tolyl-phosphine)-palladium(II), 2'-(dimethyl-amino)-2-biphenylyl-palladium(II) chloride complex / dinorbonyl-urea and chloride complex of 2-(dimethylamino)-ferrocen-1-yl-palladium(II) / dinorbonyl urea. In some cases, additional linkers can be added to facilitate the copulation reaction. Examples of suitable binders include tri-t-butyl-phosphine, 2,2-bis(diphenyl-phosphino)-1,1-binaphthyl, triphenyl-phosphine, 1,2-bis(diphenyl-phosphino)-ethane, 1,1 '- bis(diphenyl-phosmo)-ferrocene, tricyclohexyl-phosphine, 9,9-dimethyl-4,5-bis(diphenyl-phosmo)-xanthene, 1,3-bis(diphenyl-phosphmo)-propane, 2 -(di-t-butyl-phosphino)-biphenyl, 2-dicyclohexyl-phosmo-2'-(n,n-dimethyl-amino)-biphenyl, tri-o-tolyl-phosphine, 2-(dicyclohexyl -phosmo)-biphenyl, 2-dicyclohexyl-phosphino-2',4',6'-triiso-propyl-biphenyl, tri(2-furyl)-phosphine, 2-dicyclohexyl-phosphine-2',6 '- dimethoxy-biphenyl and 2-di-tert-butyl-phosphino-2',4',6'-triiso-propyl-biphenyl.

Other examples of possible metal-catalyzed functionalizations are reactions with organotin reagents (the Stille reaction), with Grignard reagents and reaction with nitrogen nucleophiles. An overview, and other key references, of these transformations are presented5 in 'Palladium Reagents and Catalysts' [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and Handbook of OrganoPalladium Chemistry for Organic Synthesis [Volume 1, Edited by Ei -ichi Negishi, Wiley, ISBN 0-471-31506-0].

In particular, one reaction that can be used is the Buchwald-Hartwig type reaction (see Review: JF Hartwig (1998), Angew. Chem.10 Int. Ed. 37, 2046-2067) which provides a means for aryl synthesis -amines catalyzed by palladium. Starting materials are aryl halides or pseudohalides (eg triflates) and primary or secondary amines, in the presence of a strong base such as sodium tert-butoxide and a palladium catalyst such as tris-(dibenzylidene-acetone)- di-palladium (Pd2(dba)3), or 2,2'-bis(diphenyl-phosphmo)-1'-binaphthyl (BINAP).

In particular, for synthesis of compounds of formula (I) the aryl halide can be reacted with 3-amino-benzene boronic acid using an appropriate metal catalyst eg bis(triphenyl-phosphine)-palladium(II) chloride to form the amine precursor to secondary amine bond formations.

This sequence of reactions outlined in Rota A can be alternated as outlined in Rota B. Alternatively the halogen functionality at the 7-position of imidazo[1,2-a]pyridine can be converted to an ester or boronic acid and used to synthesize alternative motifs as outlined in Scheme 2. This can then be used directly in any of the metal-catalyzed reactions outlined here. For example, for conversion of a halide to a boronate, the halide is reacted with a palladium catalyst and a phosphine linker in an appropriate solvent eg dioxane, and base eg KOAc, and the appropriate substituted boron compound.

Once synthesized, a variety of functional group conversions can be employed on di-aryl-substituted imidazopyridine compounds to produce other compounds of formula (I). For example, some of the reactions that can be used are hydrogenation eg using Raney nickel catalyst, hydrolysis, deprotection, and oxidation.

In particular, as outlined in Scheme 3, the introduced amine functionality can be used to synthesize cyclic amine compounds.

Amines can be prepared by reducing the corresponding nitro-compounds under standard conditions. The reduction can be carried out, for example, by catalytic hydrogenation in the presence of a catalyst such as palladium on carbon in a polar solvent such as ethanol or dimethylformamide at room temperature.

Compounds of formula (I) containing a secondary amine group can be prepared from amino compounds by numerous methods. Reductive amination with an appropriately substituted aldehyde or ketone can be carried out in the presence of a variety of reducing agents (see "Advanced Organic Chemistry" by Jerry March, 4th Edition, John Wiley & Sons, 1992, pp898-900). For example, reductive amination can be carried out in the presence of sodium triacetoxyborohydride in the presence of an aprotic solvent, such as dichloromethane, at or near ambient temperatures. They can also be prepared by reacting the amino compound in a nucleophilic displacement reaction, where the reactant contains a leaving group such as a halogen.

In addition the thiadiazolyl-amino-compound can be synthesized by using the appropriate substituted boronic acid in the Suzuki reaction eg pinacol-ester of 3-([1,3,4]thiadiazol-2-yl-amino)-phenyl-boronic acid or pinacol-3-(5-methyl-[1,3,4]thiadiazol-2-yl-amino)-phenyl-boronic acid ester. These can be synthesized as described herein.

Alternatively the secondary amine can be formed by cyclizing an appropriate group to form a ring. Amino-thiadiazole-compounds can be synthesized as described in Scheme 4.

This involves reaction of the amino-compound in anhydrous solvent e.g. toluene, with 1,1'-thio-carbonyl-di-2(1H)-pyridone. Typical reaction conditions are heating for 1 hour, processing and then treatment with hydrazine hydrate to form thiosemicarbazide. This is then cyclized under conditions such as by adding dropwise diethyl chlorophosphate. This may also generate the alternative cyclization product and as a consequence separation may be required.

Alternative heterocyclic groups can be formed by known heterocyclic ring formation reactions. For example the amino-triazole (eg 3H-[1,2,3]triazol-4-yl)-amine) can be formed by the reaction of sodium nitrite in H2O with the amine in acid eg 2N HCl, followed by addition of amino-acetonitrile hydrogen sulfate in H2O. After an appropriate period of time NaOAc is added and rearrangement to the desired heterocycle is carried out by heating in solvent e.g. ethanol, for 16 hours.

Suitable reagents and starting materials for these reactions can be obtained commercially or by any of numerous standard synthetic methods well known to those skilled in the art, for example see "Advanced Organic Chemistry" by Jerry March, 4th Edition, John Wiley & Sons , 1992, and Organic Syntheses, Volumes 1-8,

John Wiley, Edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8), 1995, and see also the methods described in the experimental section below. For example a variety of functionalized amino-pyridine and aniline starting materials, and metal catalysts are commercially available.

Many boronates, for example boronic acids or boronic esters or trifluoroborates, suitable for use in the preparation of compounds of the invention are commercially available, for example from Boro Molecular Limited of Noble Park, Australia, or from Combi-Blocks Inc. of San Diego , USA. Where the appropriately substituted boronate is not commercially available, they can be prepared by methods known in the art, for example as described in the review article by Miyaura, N. and Suzuki, A. (1995) Chem. Rev.95, 2457. Thus, boronates can be prepared by reacting the corresponding bromo-compound with an alkyllithium such as butyllithium and then reacting with a borate ester e.g. ('PrO)3B. The reaction is typically carried out in a dry polar solvent such as tetrahydro-furan at a reduced temperature (eg -78°C). Boronate esters (for example a pinacolatoboronate) can also be prepared from a bromo-compound by reaction with a diboronate ester such as tris(pinacolato)diboron in the presence of a phosphine such as tricyclohexyl-phosphine and a reagent of palladium(O) such as tris(dibenzylidene-acetone)-dipalladium(0). Formation of the boronate ester is typically carried out in a dry polar aprotic solvent such as dioxane or DMSO with heating to a temperature of up to about 100°C, for example around 80°C. The resulting boronate ester derivative can, if desired, be hydrolyzed to give the corresponding boronic acid or converted to the trifluoroborate.

All of the reactions described above can be used to functionalize alternative heterocyclic models of formula (I), the synthesis of which is outlined below.

Pyrazolof 1,5-a]pyrimidines

The pyrazolo[1,5-a]pyrimidine model can be synthesized from the appropriately substituted amino-pyrazole (VI) and fragments (VII) as shown in Scheme 5A, where Ra can be hydrogen or Rb. one-step or two-step, where X1 and X2 are electrophilic carbons (ie carbonyl, masked carbonyl ie acetal, enamine, alkynes or conjugated alkenes) (Perkin I, JCS (1979), 3085-3094). X3 is an appropriate substituent that an R2 group wants groups such as halogen or pseudohalogens that will allow reaction to introduce R2 as described herein. Cyclization of the pyrazole (VI) with an appropriately substituted free or masked 1,3-carbonyl derivative can be used to prepare substituted pyrazolo[1,5-a]pyrimidines. Cyclization typically occurs in an alcohol solvent or in toluene or acetic acid, and may have additives present such as piperidine, sodium ethoxide, HCl, AcOH, pTsOH, or ZnCl2 (J. Med. Chem. (2001), 44 (3 ), 350-361; Bull. Korean Chem. Soc. (2002), 23 (4), 610-612; Australian Journal de Chemistry (1985), 38(1), 221-30).

A particular synthetic scheme for the preparation of 3,7-disubstituted pyrazolo[1,5-a]pyrimidines is outlined in Scheme 5B. The pyrazolopyrimidine ring is formed by the reaction of a malonaldehyde substituted as fragment VII with amino-pyrazole. The substituted malonaldehyde may be substituted with the desired cyclic functionality eg 2-(4-fluoro-phenyl)-malonaldehyde, or with a latent functionality eg a halogen as in 2-bromo-malonaldehyde, which allows further derivation at this position as in the scheme shown below using the reactions outlined here.

In the cyclization reaction, malonaldehyde in solvent is added in 3-amino-pyrazole followed by acid e.g. glacial acetic acid.

Reagents are then cyclized under heating under reflux. The compound of formula (I) can then be synthesized using the metal catalyzed and halogenation reactions outlined herein.

Compounds of formula (VI) and (VII) are known compounds or can be prepared by analogy to known methods. Many pyrazoles of formula (VI) are commercially available. Alternatively they can be obtained by known methods eg from ketones in a process described in EP308020 (Merck), or by methods discussed by Schmidt in Helv. Chim. Minutes (1956), 39, 986-991 and Helv. Chim. Minutes (1958), 41, 1052-1060 or by converting the pyrazoles of formula (VI) or the compound of formula (I) where Ra is hydrogen, halogen, nitro, ester, or amide to the desired R1 functionality by standard methods known to a person experienced in the technique. For example, where R1 is halogen, coupling reactions with tin or palladium chemistry could be carried out as described herein.

Reaction of a mixture of 2-bromo-5-iodo-pyrazine and copper(I) iodide under inert conditions in an appropriate solvent and base eg DMF/Et3N with ethynyl-trimethylsilane using a palladium catalyst eg Pd( PPh3)4 at room temperature gives 2-Bromo-5-trimethyl-silanyl-ethynyl-pyrazine. This material can be used without further purification and reacted to form 6-bromo-2-trimethyl-silanyl-pyrazolo[1,5-a]pyrazine using O-(Mesitylenesulfonyl)-hydroxyl-amine to form the N-amino- adduct. This can then be cyclized by reaction with base e.g. K2CO3 to form the pyrazolopyrazine nucleus (Scheme 6).

Appropriate groups at positions 3 and 7 can then be introduced by halogenation and reaction of latent functionality at positions 3 and 7 in the metal catalyzed reactions outlined herein.

Pyrazolof 1,5-a]pyridines

lodação com N-iodo-succinimida e reação catalisada por metal de haletos de arila, pode ser usada para introduzir a funcionalidade exigida na 10 posição 3 como aqui esboçado.3-Bromo-pyridine is reacted with the appropriately substituted boronic acid in a solvent such as in DME under inert conditions with base (Na2CO3) and a palladium catalyst to form 3-substituted pyridine (Scheme 7). O-(Mesitylenesulfonyl)-hydroxyl-amine is then reacted with 3-substituted pyridine under inert conditions to form the N-amino-pyridine which can be used without further purification. Cyclization of the N-adduct using base (K2CO3) and 2-benzenesulfonyl-3-dimethyl-amino-acrylic acid methyl ester under an inert atmosphere gives the 3-carboxylic acid ester pyrazolo[1,5-a]pyridine . The carboxylic ester can be removed for example by saponification using sodium hydroxide to form the acid and then decarboxylation to polyphosphoric acid.

lodation with N-iodosuccinimide and metal catalyzed reaction of aryl halides can be used to introduce the required functionality at position 3 as outlined herein.

Imidazor4,5-b1pyridines

An imidazo[4,5-b]pyridine ring system can be constructed by reacting an aniline with 2-chloro-3-amino pyridine as described in J. Heterocyclic Chemistry (1983), 20(5), 1339 (Scheme 8 ).

An alternative synthesis of a more functionalized intermediate has been described in US 06723735 (Scheme 9).

As described herein aryl halides similar to that shown above can undergo a variety of metal catalyzed reactions to generate the required compounds of formula (I).

Imidazor4,5-c]pyridines

A 3-aryl-3H-imidazo[4,5-c]pyridine ring system can be constructed by reacting 3H-imidazo[4,5-c]pyridine with an aryl iodide as discussed in Biorg. Med. Chem. Letter (2004), 14, 5263 (Scheme 10).

It is reported that regioisomeric products can be separated by chromatography. A possible way to further elaborate this material to give the desired replacement pattern is illustrated below (Scheme 11).

Reaction with an oxidizing agent such as 3-chloro-perbenzoic acid could be used to prepare the N-oxide which can be rearranged to 3H-imidazo[4,5-c]pyridine with various reagents e.g. POC13, SOC12. The regioisomeric products could then be separated by chromatography. Displacement of X to give aryl- and amino-substituted products could be accomplished by the reaction of a suitable nucleophile in the presence of a metal catalyst e.g. palladium.

An alternative strategy is shown in Scheme 12. The synthesis of 6-chloro-3H-imidazo[4,5-c]pyridine is described in J. Heterocyclic 10 Chem (1965), 2(2), 196-201. The chloro group can be displaced with a nucleophile in the presence of a metal catalyst (e.g. palladium) to give aryl- and amino-substituted products. A protecting group can be used in the conversion such as a carbamate or benzyl group. Subsequent elaboration for the N-aryl compounds could then be carried out according to the 15 conditions shown in Scheme 10.

Scheme 12

A synthesis of 1,5-diaryl-1H-benzoimidazoles is reported in Biorg. Med. Chem. Lett (2003), 13, 2485-2488 (Scheme 13).

Fluorine displacement from 4-bromo-1-fluoro-2-nitro-benzene with an appropriate aniline followed by reduction and cyclization with triethyl orthoformate gives the bromo-benzoimidazole with the desired substitution pattern. The product can be further elaborated by metal catalyzed reaction of the bromide to give 1,5-disubstituted benzoimidazoles.

Imidazo1,2-c]pyrimidines

Este inicia a partir de 7-cloro-imidazo[l,2-c]pirimidina, cuja síntese tem sido descrita em Yanai et al., Eleterocyclic Compounds. XVIII. Synthesis of imidazo[l,2-c]- and pyrimido[l,2-c]pyrimidine derivatives, Yakugaku Zasshi (1974), 94(12), 1503-14. Este material então pode ser 5 adicionalmente elaborado usando qualquer uma das reações descritas acima.Disubstituted imidazo1,2-c]pyrimidines can be prepared as outlined in Scheme 14.

It starts from 7-chloro-imidazo[1,2-c]pyrimidine, the synthesis of which has been described in Yanai et al., Eleterocyclic Compounds. XVIII. Synthesis of imidazo[1,2-c]- and pyrimido[1,2-c]pyrimidine derivatives, Yakugaku Zasshi (1974), 94(12), 1503-14. This material can then be further elaborated using any of the reactions described above.

Alternatively, where the 7-position is an N-linked saturated heterocycle, for example morpholine, an SNAr reaction (for examples of SNAr reaction see "Advanced Organic Chemistry" by Jerry March, 4th edition, pages 641-644) could be performed, for example as described in 10 US4503050 (Scheme 15).

Where the 7-position is an aryl or heteroaryl group the S 1 -Ar group can be replaced with a standard palladium cross-coupling reaction using similar chemistries as described herein (Scheme 16).

3,7-disubstituted imidazo[1,2-c]pyrimidin-5-ones can be prepared from 7-Chloro-6H-imidazo[1,2-c]pyrimidin-5-one (CAS number 56817-09- 5) whose synthesis is described in Maggiali et al. (1982), Acta Naturalia de Tateneo Parmense, 18(3), 93-101 and Bartholomew et al. (1975) 5 Journal of Organic Chemistry, 40(25), 3708-13.7-Chloro-6H-imidazo[1,2-c]pyrimidin-5-ones can be derived using nucleophilic substitution reactions such as SNAr or subjected to a Suzuki reaction to add functionality in position 7 (Scheme 17). This compound can then be iodinated as described above 10 before further functionalization using the Suzuki reaction.

Alternatively 7-Chloro-6H-imidazo[1,2-c]pyrimidin-5-one could be directly iodinated to the intermediate below for use in the reactions described here (Scheme 18).

In addition, other oxo-heterocycles could be synthesized from the appropriate chlorine derivative by hydrolysis. The protected compound would undergo basic hydrolysis to give pyridone. This could be carried out with NaOH (or NaOH/H2O2) in H2O/MeOH or H2O/dioxane following procedures described in the literature for the hydrolysis of chloro-pyridines (eg Australian J. Chem. (1984), 37(12), 2469- 2477).

The synthesis of the Imidazo[1,2-b]pyridazine nucleus can be carried out as described in Scheme 19 using a pyridazin-3-yl-amine derivative as reported in J. Heterocyclic Chem. (2002), 39(4), p737-742. Introduction of 3-position substituents is exemplified in J. Med. Chem (2006), 49(4), p1235-1238 to give the 3,7-substituted compounds.

Other heterocycles can be synthesized using well known reactions, for example as described in Comprehensive Heterocyclic Chemistry I (Edited by Katritzky, AR and Rees, CW (1982) Elsevier) and Comprehensive Heterocyclic Chemistry II (Edited by Katritzky, AR, Rees, CW and EFV Scriven, EFV (1996) Elsevier, ISBN 0-08-042072-9).

In many of the reactions described above, it may be necessary to protect one or more groups to prevent the reaction from occurring at an undesirable location in the molecule. Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in "Protective Groups in Organic Synthesis" (Green, T. and Wuts, P. (1999); 3rd Edition; John Wiley and Sons).

A hydroxy group may be protected, for example, as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl-, benzhydryl-(diphenyl-methyl), or trityl-(triphenyl-methyl) ether; a trimethyl-silyl- or t-butyl-dimethyl-silyl-ether; or an acetyl ether (-OC(=O)CH3, -OAc). An aldehyde or acetone group can be protected, for example, as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=O) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid. An amine group can be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl-amide (-NHCO-CH3); a benzyl-oxy-amide (-NHCO-OCH2C6H5, -NH-Cbz); as a t-butoxy-amide (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxy-amide (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), such as a 9-fluorenyl-methoxyl-amide (-NH-Fmoc), such as a 6-nitro-veratryloxy- amide (-NH-Nvoc), as a 2-trimethyl-silyl-methyl-oxy-amide (-NH-Teoc), as a 2,2,2-trichloro-methyl-oxy-amide (-NH-Troc), as an allyl-oxy-amide (-NH-Alloc), or as a 2-(phenyl-sulfonyl)-methyl-oxy-amide (-NH-Psec). Other protecting groups for amines, such as cyclic amines and heterocyclic N-H groups, include toluene-sulfonyl group (tosyl) and methanol-sulfonyl group (mesyl) and benzyl group such as a para-methoxy-benzyl group (PMB). A carboxylic acid group can be protected as an ester for example, as: a Cμ7 alkyl-ester (e.g., a methyl-ester; a t-butyl-ester); a C 1.7 halo-alkyl-ester (e.g., the C -17 tri-halo-alkyl-ester); to triC 1.7 alkyl-silyl-C 1.7 alkyl-ester; or a C5-2o aryl-C67 alkyl-ester (e.g., a benzyl-ester; a nitro-benzyl-ester); or as an amide, for example as a methyl amide. A thiol group can be protected, for example, as a thio-ether (-SR), for example, as: a benzyl-thio-ether; an acetamido-methyl-ether (-S-CH2NHC(=O)CH3).

Key intermediates in the preparation of compounds of formula (I) are compounds of formula (XX). New chemical intermediates of formula (XX) form another aspect of the invention.

ou uma sua forma protegida, com um aldeído ou uma cetona apropriadamente substituído(a); ou(ii) a reação de um composto de fórmula (XX) ou (XXI):

ou uma sua forma protegida, com hidrato de hidrazina e então 10 ciclização; e depois remoção de qualquer grupo protetor presente; ou sendo que Xi, A e R2 são como aqui definidos; e opcionalmente depois conversão de um composto de fórmula (I) em outro composto de fórmula (I).Seus ais, solvatos ou derivados farmaceuticamente aceitáveis15 Nesta seção, como em todas as outras seções deste pedido, anão ser que o contexto indique de outra maneira, referências à fórmula (I) incluem referências a todos os seus outros sub-grupos, preferências e exemplos como aqui definidos.A não ser que seja especificado de outra maneira, uma referência a um composto particular também inclui suas formas iônicas, sais, solvatos, isômeros, tautômeros, N-óxidos, ésteres, pró-drogas, isótopos e formas protegidas, por exemplo, como discutido abaixo; preferivelmente, suas formas iônicas, ou sais ou tautômeros ou isômeros ou N-óxidos ou solvatos; e mais preferivelmente, as formas iônicas, ou sais ou tautômeros ou solvatos ou formas protegidas dos mesmos. Muitos compostos de fórmula (I) podem existir na forma de sais, por exemplo sais de adição de ácido ou, em certos casos sais de bases orgânicas e inorgânicas tal como sais de carboxilato, sulfonato e fosfato. Todos tais sais estão dentro do escopo da invenção, e referências aos compostos de fórmula (I) incluem as formas de sal dos compostos.Another aspect of the invention is a process for the preparation of a compound of formula (I) as defined herein, which process comprises: (i) reacting a compound of formula (XX) or (XXI):

or a protected form thereof, with an appropriately substituted aldehyde or ketone; or (ii) the reaction of a compound of formula (XX) or (XXI):

or a protected form thereof, with hydrazine hydrate and then cyclization; and then removing any protective groups present; or where Xi, A and R2 are as defined herein; and optionally thereafter converting a compound of formula (I) into another compound of formula (I). Pharmaceutically acceptable salts, solvates or derivatives thereof15 In this section, as in all other sections of this application, unless the context indicates otherwise , references to formula (I) include references to all other subgroups, preferences and examples thereof as defined herein. Unless otherwise specified, a reference to a particular compound also includes its ionic forms, salts, solvates , isomers, tautomers, N-oxides, esters, prodrugs, isotopes and protected forms, for example, as discussed below; preferably, their ionic forms, or salts or tautomers or isomers or N-oxides or solvates; and more preferably, the ionic forms, or salts or tautomers or solvates or protected forms thereof. Many compounds of formula (I) can exist in the form of salts, for example acid addition salts or in certain cases salts of organic and inorganic bases such as carboxylate, sulphonate and phosphate salts. All such salts are within the scope of the invention, and references to the compounds of formula (I) include the salt forms of the compounds.

The salts of the present invention can be synthesized from the parent compound which contains a basic or acidic group by conventional chemical methods such as methods described in "Pharmaceutical Salts: Properties, Selection, and Use", P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate acid or base (a) in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. Acid addition salts can be formed with a wide variety of acids, both organic and inorganic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (eg L-ascorbic), L-aspartic, benzenesulfonic, benzoic acid. , 4-acetamido-benzoic, butanoic, (+)-camphoric, camphor-sulfonic, (+)-(!S)-camphor-10-sulfonic, caproic, caproic, caprylic, cinnamic, citric, cyclamic, dodecyl-sulfuric, ethane-1,2-disulfonic, ethane-sulfonic, 2-hydroxy-ethane-sulfonic, formic, fumaric, galactaric, gentisic, glycoheptenoic, D-glucuronic (eg D-glucuronic), glutamic (eg L-glutamic), a-oxo-glutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (eg (+)-L-lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L- malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalenesulfonic (egnaphthalene-2-sulfonic), naphthalene-1,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, f osphoric, propionic, L-pyroglutamic, salicylic, 4-aminosalicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, toluene-sulfonic (e.g. p-toluenesulfonic), undecylenic and valeric, as well as acetylated amino acids and cation exchange resins.

A particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate) acids ), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic.

Another group of acid addition salts includes salts formed from acetic, adipic, ascorbic, aspartic, citric, DL-lactic, fumaric, glycolic, glucuronic, hippuric, hydrochloric, glutamic, DL-malic, methanesulfonic, sebacic acids , stearic, succinic and tartaric.

The compounds of the invention can exist as mono- or di-salts depending on the pKa of the acid from which the salt is formed.

If the compound is anionic, or has a functional group that can be anionic (e.g., -COOH can be -COO’), then a salt can be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth metal cations such as Ca2+ and Mg2+, and other cations such as Al3+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4+) and substituted ammonium ions (e.g., NH3R+, NH2R2+, NHR3+ NR/).

Examples of some suitable substituted ammonium ions are those derived from: methyl-amine, dimethyl-amine, dicyclohexyl-amine, trimethyl-amine, butyl-amine, methylene-diamine, ethanol-amine, diethanol-amine, piperazine, benzyl- amine, phenyl-benzyl-amine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+.

Where the compounds of formula (I) contain an amine function, they can form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (I).

The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al. (1977) "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. However, salts which are not pharmaceutically acceptable can also be prepared as intermediate forms which can then be converted to pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which may be useful, for example, in purifying or separating the compounds of the invention, also form part of the invention.

Compounds of formula (1) containing an amine function can also form N-oxides. A reference herein to a compound of formula (I) which contains an amine function also includes the N-oxide.

Where a compound contains multiple amine functions, one or more than one nitrogen atom can be oxidized to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or of a nitrogen atom of a nitrogen-containing heterocycle.

N-Oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (eg a peroxy-carboxylic acid), see for example "Advanced Organic Chemistry", by Jerry March, 4th Edition, Wiley Interscience , pages [sic], More particularly, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. (1977), 7, 509-514) in which the amino compound is reacted with m-chloro-peroxy acid -benzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane. Particular examples of N-oxides include morpholine-N-oxides and pyridine-N-oxides.

Compounds of formula (I) may exist in numerous tautomeric, and different geometric isometric forms and references to compounds of formula (I) include all such forms. For the avoidance of doubt, where a compound may exist in one of several geometric or tautomeric isomeric forms and only one is specifically described or shown, all others are nevertheless included by formula (I). Other examples of tautomeric forms include, for example, keto, enol, and enolate forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.

Where compounds of formula (I) contain one or more chiral centers, and may exist in the form of two or more optical isomers, references to compounds of formula (1) include all optical isomeric forms thereof (eg enantiomers, epimers and diastereoisomers) , either as individual optical isomers, or as mixtures (eg racemic mixtures) or as two or more optical isomers, unless the context requires otherwise. Optical isomers can be characterized and identified by their optical activity (ie + and - isomers, or of 1 isomers) or can be characterized in terms of their absolute stereochemistry using the "R" and "S" nomenclature developed by Cahn, Ingold and Prelog, see "Advanced Organic Chemistry" by Jerry March, 4lh Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog (1966) Angew. Chem. Int. Ed. Engl., 5, 385-415.

Optical isomers can be separated by numerous techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art.

As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-ditoluoyl-L-tartaric acid, acid (+)-mandelic, (-)-malic acid, and (-)-camphorsulfonic acid, separation of the diastereoisomers by preferential crystallization, and then dissociation of the salts to give the individual enantiomer from the free base.

Where compounds of formula (I) exist as one or more optical isomeric forms, one enantiomer in one pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a plurality of diastereomers. Accordingly, the invention provides compositions containing a compound of formula (I) having one or more chiral centers, wherein at least 55% (eg at least 60%, 65%, 70%, 75%, 80%, 85%, 90 % or 95%) of the compound of formula (I) is present as a single optical isomer (eg enantiomer or diastereomer). In a general embodiment 99% or more (e.g. substantially all) of the total amount of the compound of formula (I) may be present as a single optical isomer (e.g. enantiomer or diastereoisomer).

Compounds of the invention include compounds with one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope H, H (D), and H (T). Similarly, references to carbon and oxygen include within their scope respectively 12C, 13C and 14C and 16O and 18O.

Isotopes can be radioactive or non-radioactive. In one embodiment of the invention, the compounds do not contain radioactive isotopes. Such compounds are prepared for therapeutic use. In another embodiment, however, the compound can contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.

Esters such as carboxylic acid esters and acyl-oxy-esters of the compounds of formula (I) having a carboxylic acid group or a hydroxyl group are also included by formula (I). In one embodiment of the invention, formula (I) includes within its scope esters of compounds of formula (I) having a carboxylic acid group or a hydroxyl group. In another embodiment of the invention, formula (I) does not include within its scope esters of compounds of formula (I) having a carboxylic acid group or a hydroxyl group. Examples of esters are compounds containing the group -C(=O)OR, where R is an ester substituent, for example, a C1-7 alkyl group, a C3-2 heterocyclyl group, or a C5 group. 20 aryl, preferably a C 1.7 alkyl group. Particular examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, and -C(=O)OPh. Examples of acyloxy (reverse ester) groups are represented by -OC(=O)R, where R is an acyloxy substituent, for example, a C1.7 alkyl group, a C3.20 heterocyclyl group, or a C5.20 aryl group, preferably a C67 alkyl group. Particular examples of acyl-oxy groups include, but are not limited to, - OC(-O)CU3 (acetoxy), -OC(=O)CH2CH3, -OC(=O)C(CH3)3, -OC(= O)Ph, and - OC(=O)CH2Ph.

Also included by formula (I) are polymorphic forms of the compounds, solvates (e.g. hydrates), complexes (e.g. clathrates or inclusion complexes with compounds such as cyclodextrins, or complexes with metals) of the compounds, and prodrugs of the compounds. "Prodrugs" has the meaning for example of any compound which is converted in vivo to a biologically active compound of formula (I).

For example, some prodrugs are esters of the active compounds (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to give the active drug. Such esters can be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, before protecting any other reactive groups present in the parent compound, followed by lack of protection if required.

Examples of such metabolically labile esters include those of the formula -C(=O)OR where R is:Ci-7 alkyl (eg, -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu); C1-7 amino-alkyl (eg, amino-methyl; 2-(N,N-dimethyl-amino)-methyl; 2-(4-morpholino)-methyl); acyl-oxy-C 1.7 alkyl (eg, acyl-oxy-methyl; acyl-oxy-methyl; pivaloyl-oxy-methyl; acetoxy-methyl; 1-acetoxy-methyl; 1-(1-methoxy-1-methyl)- methyl-carbonyloxy-methyl; -(benzoyl-oxy)-methyl; isopropoxy-carbonyl-oxy-methyl; 1-isopropoxy-carbonyl-oxy-methyl; cyclohexyl-carbonyl-oxy-methyl; 1-cyclohexyl-methyl; carbonyl-oxy-methyl; cyclohexyl-oxy-carbonyl-oxy-methyl; 1-cyclohexyl-oxy-carbonyl-oxy-methyl; (4-tetrahydro-pyranyl-oxy)carbonyl-oxy-methyl; -(4-tetrahydro-pyranyl-oxy)-carbonyl-oxy-methyl; (4-tetrahydro-pyranyl)-carbonyl-oxy-methyl; and 1-(4-tetrahydro-pyranyl)-carbonyl- oxy-ethyl). Also, some prodrugs are enzymatically activated to give the active compound, or a compound that, upon another chemical reaction, gives the active compound (eg as an enzyme-antigen-targeted prodrug therapy (ADEPT) ), gene-targeted enzyme prodrug therapy (GDEPT) and enzyme ligand-targeted prodrug therapy (LIDEPT) etc.). For example, the prodrug can be a sugar derivative or other glycoside conjugate, or it can be an amino acid ester derivative.

It will be appreciated that references to "derivatives" include references to their ionic forms, salts, solvates, isomers, tautomers, N-oxides, esters, prodrugs, isotopes and protected forms.

According to one aspect of the invention there is produced a compound as defined herein or a salt, tautomer, N-oxide or solvate thereof.

According to a further aspect of the invention there is produced a compound as defined herein or a salt or solvate thereof.

References to compounds of formula (I), (Ia), (1b), (Ic), (Id), (le) and (If) and their subgroups as defined herein include within their scope salts or solvates or tautomers or N-oxides of the compounds. Protein tyrosine kinases (PTK)

The compounds of the invention described herein inhibit or modulate the activity of certain tyrosine kinases, and thus the compounds will be useful in the treatment or prophylaxis of diseased conditions or conditions mediated by those particular tyrosine kinases in particular FGFR.FGFR

The fibroblast growth factor (FGF) family of receptor protein tyrosine kinase (PTK) regulates a diverse variety of physiological functions including mitogenesis, wound healing, cell differentiation and angiogenesis, and development. Both normal and malignant cell growth and proliferation are affected by changes in local concentration of FGFs, extracellular signaling molecules that act as autocrine as well as paracrine factors. Autocrine FRF signaling may be particularly important in the progression of steroid hormone-dependent cancers to a hormone-independent state (Powers, et al. (2000) Endocr. Relat. Cancer, 7, 165-197).

FGFs and their receptors are expressed at increased levels in various tissues and cell lines and overexpression is believed to contribute to the malignant phenotype. Furthermore, numerous oncogenes are homologous to genes encoding growth factor receptors, and there is a potential for aberrant activation of FGF-dependent signaling in human pancreatic cancer (Ozawa, et al. (2001), Teratog. Carcinog. Mutagen., 21,27-44).

The two prototypic members are acidic fibroblast growth factor (aFGF or FGF1) and basic fibroblast growth factor (bFGF or FGF2), and to date, at least twenty distinct FGF family members have been identified. The cellular response to FGFs is transmitted via four types of fibroblast growth factor (FGFR) high-affinity transmembrane protein tyrosine kinase receptors numbered 1 to 4 (FGFR1 to FGFR4). Upon ligand binding, receptors dimerize and auto- or trans-phosphorylate specific cytoplasmic tyrosine residues to transmit an intracellular signal that ultimately regulates nuclear transcription factor effectors.

Disruption of the FGFR1 pathway must affect tumor cell proliferation because this kinase is activated in many tumor types in addition to endothelial cell proliferation. The overexpression and activation of FGFR1 in tumor-associated vasculature has suggested a role for these molecules in tumor angiogenesis.

Fibroblast growth factor receptor 2 has high affinity for acidic and/or basic fibroblast growth factors as well as keratinocyte growth factor ligands. Fibroblast growth factor receptor 2 also propagates the potent osteogenic effects of FGFs during osteoblast differentiation and growth. Mutations in fibroblast growth factor receptor 2, mutations in fibroblast growth factor receptor 2, leading to complex functional changes, have been shown to induce abnormal ossification of cranial sutures (craniosynostosis), implying a greater role of FGFR signaling in intramembranous bone formation. For example, in Apert syndrome (AP), characterized by premature cranial suture ossification, most cases are associated with point mutations engendering gain-of-function in fibroblast growth factor receptor 2 (Lemonnier, et al. (2001), J. Bone Miner. Res., 16, 832-845). In addition, mutation screening in patients with syndromic craniosynostosis indicates that numerous recurrent FGFR2 mutations are responsible for severe forms of Pfeiffer syndrome (Lajeunie et al, European Journal of Human Genetics (2006) 14, 289-298). Particular FGFR2 mutations include W290C, D321A, Y340C, C342R, C342S, C342W, N549H, K641R in FGFR2.

Several severe abnormalities in human skeletal development, including Apert, Crouzon, Jackson-Weiss, Beare-Stevenson cutis gyrata, and Pfeiffer syndromes are associated with the occurrence of fibroblast growth factor receptor 2 mutations. Most, if not all, cases of Pfeiffer Syndrome (PS) are also caused by de novo mutation of the fibroblast growth factor receptor 2 gene (Meyers, et al. (1996) Am. J. Hum Genet., 58, 491-498; Plomp, et al. (1998) Am. J. Med. Genet., 75, 245-251), and it was recently shown that mutations in fibroblast growth factor receptor 2 disrupt one of the cardinal rules governing ligand specificity. Namely, two mutant-editing forms of fibroblast growth factor receptor, FGFR2c and FGFR2b, have acquired the ability to bind to and be activated by atypical FGF ligands. This loss of ligand specificity leads to aberrant signaling and suggests that the various phenotypes of these disease syndromes result from ectopic ligand-dependent activation of fibroblast growth factor receptor 2 (Yu, et al. (2000), Proc. Natl. Acad. Sci. USA, 97.14536-14541).

Genetic aberrations of the FGFR3 receptor tyrosine kinase such as point mutations or chromosomal translocations result in ectopically expressed or deregulated, constitutively active FGFR3 receptors. Such abnormalities are linked to a subset of multiple myelomas and in bladder, hepatocellular, oral and cervical squamous cell carcinomas (Powers, CJ (2000), et al., Endocr. Rei. Cancer, 7, 165; Qiu, W. et al (2005), World Journal Gastroenterol, 11(34)). Accordingly, FGFR3 inhibitors would be useful in the treatment of multiple cervical, bladder, and myeloma carcinomas. FGFR3 is also over-expressed in bladder cancer, in particular invasive bladder cancer. FGFR3 is frequently activated by mutation in urothelial carcinoma (UC) (Journal of Pathology (2007), 213(1), 91-98). Increased expression was associated with mutation (85% of mutant tumors showed high-level expression) but also 42% of tumors with no detectable mutation showed overexpression, including many muscle-invasive tumors.

As such, compounds which inhibit FGFR will be useful in providing a means of preventing growth or inducing apoptosis in tumors, particularly by inhibiting angiogenesis. Therefore, the compounds are expected to prove useful in the treatment or prevention of proliferative disorders such as cancers. In particular tumors with mutants activating receptor tyrosine kinases or upregulating receptor tyrosine kinases may be particularly sensitive to inhibitors. Patients with activating mutants of any of the specific RTK isoforms discussed herein may also find treatment with RTK inhibitors particularly beneficial.

FGFR4 overexpression has been linked to poor prognosis in both thyroid and prostate carcinomas (Ezzat, S., et al. (2002) The Journal of Clinical Investigation, 109, 1; Wang et al. (2004) Clinical Cancer Research, 10). In addition, a germline polymorphism (Gly388Arg) is associated with increasing incidences of lung, breast, colon, and prostate cancers (Wang et al. (2004) Clinical Cancer Research, 10). In addition, a truncated form of FGFR4 (including the kinase domain) has also been found present in 40% of pituitary tumors but not present in normal tissue.

A recent study has shown a link between FGFR1 expression and tumorigenicity in Classical Lobular Carcinomas (CLC). CLCs account for 10-15% of all breast cancers and generally lack p53 and Her2 expression while maintaining estrogen receptor expression. A gene amplification of 8p12-pll.2 has been demonstrated in —50% of CLC cases and this has been shown to be linked to increased expression of FGFR1. Preliminary studies with siRNA directed against FGFR1, or a small molecule inhibitor of the receptor, showed that cell lines hosting this amplification are particularly sensitive to the inhibition of this signaling pathway (Reis-Filho et al. (2006) Clin Cancer Res. 12(22 ): 6652-6662.

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma likely results from abnormal proliferation and differentiation during skeletal mitogenesis. FGFR1 is overexpressed in primary rhabdomyosarcoma tumors and is associated with hypomethylation of a 5' CpG island and abnormal expression of the AKT1, NOG, and BMP4 genes (Genes, Chromosomes & Cancer (2007), 46(11), 1028 -1038).

Fibrotic conditions are a major medical problem resulting from abnormal or excessive deposition of fibrous tissue. This occurs in many diseases, including liver cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, as well as the natural wound healing process. The mechanisms of pathological fibrosis are not fully understood but are thought to result from the actions of various cytokines (including tumor necrosis factor (TNF), fibroblast growth factors (FGFs), platelet-derived growth factor (PDGF) and factor transforming growth beta (TGFβ) involved in fibroblast proliferation and deposition of cell matrix proteins (including collagen and fibronectin) This results in altered tissue structure and function and subsequent pathology.

Numerous preclinical studies have demonstrated upregulation of fibroblast growth factors in preclinical models of lung fibrosis (Inoue, et al. (1997 &2002); Barrios, et al. (1997)). It has been reported that TGFβl and PDGF are involved in the fibrogenetic process (reviewed by Atamas & White, 2003) and another published study suggests that the elevation of FGF's and consequent increase in fibroblast proliferation may be in response to elevated TGFβl (Khalila, et al. al., 2005). The potential therapeutic relevance of this route in fibrotic conditions is suggested by the reported clinical effect of Pirfenidone (Arata, et al., 2005) in idiopathic pulmonary fibrosis (IPF).

Idiopathic pulmonary fibrosis (also called cryptogenic fibrous alveolitis) is a progressive condition involving scarring of the lung. Gradually, the air sacs in the lungs become replaced by fibrotic tissue, which thickens, causing an irreversible loss of the tissue's ability to transfer oxygen into the bloodstream. Symptoms of the condition include shortness of breath, chronic dry cough, fatigue, chest pain and loss of appetite resulting in rapid weight loss. The condition is extremely serious with approximately 50% mortality after 5 years.Vascular Endothelial Growth Factor (VEGFR)

Chronic proliferative diseases are often accompanied by profound angiogenesis, which may contribute to or maintain an inflammatory and/or proliferative state, or which lead to tissue destruction through invasive proliferation of blood vessels. (Folkman (1997), 79, 1-81; Folkman (1995), Nature Medicine, 1.27-31; Folkman and Shing (1992) J. Biol. Chem., 267, 10931).

Angiogenesis is generally used to describe the development of new blood vessels or blood vessel replacement, or neovascularization. It is a normal and necessary physiological process by which vasculature is established in the embryo. Angiogenesis does not generally occur in most normal adult tissues, the exception being sites of ovulation, menstrual flow, and wound healing. Many diseases, however, are characterized by persistent and unregulated angiogenesis. For example, in arthritis, new capillary blood vessels invade the joint and destroy cartilage (Colville-Nash and Scott (1992), Ann. Rhum. Dis., 51, 919). In diabetes (and in many different eye diseases (Brooks, et al. (1994) Cell, 79, 1157) The process of atherosclerosis has been linked to angiogenesis (Kahlon, et al. (1992) Can. J. Cardiol., 8, 60) Tumor growth and metastasis have been shown to be dependent on angiogenesis (Folkman (1992), Cancer Biol, 3, 65; Denekamp, (1993) Br. J. Rad, 66,181; Fidler and Ellis (1994) , Cell, 79,185).

Recognition of the involvement of angiogenesis in major diseases has been accompanied by research to identify and develop angiogenesis inhibitors. These inhibitors are generally classified in response to discrete targets in the angiogenesis cascade, such as activation of endothelial cells by an angiogenic signal; synthesis and release of degrading enzymes; endothelial cell migration; endothelial cell proliferation; and formation of capillary tubules. Therefore, angiogenesis occurs at many stages and attempts are underway to discover and develop compounds that work to block angiogenesis at these various stages.

There are publications that teach that angiogenesis inhibitors, working by diverse mechanisms, are beneficial in diseases such as cancer and metastasis (O'Reilly, et al. (1994) Cell, 79, 315; Ingber, et al. (1990) Nature, 348, 555), eye diseases (Friedlander, et al. (1995) Science, 270,1500), arthritis (Peacock, et al. (1992), J. Exp. Med, 175, 1135; Peacock et al. (1995) ), Cell. Immun., 160,178) and hemangioma (Taraboletti, et al. (1995) J. Natl. Cancer Inst, 87, 293).

Receptor tyrosine kinases (RTKs) are important in transmitting biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Ligand binding on the receptor results in stimulation of receptor-associated tyrosine kinase activity which leads to phosphorylation of tyrosine residues in both the receptor and other intracellular proteins, leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified.

Vascular endothelial growth factor (VEGF), a polypeptide, is mitogenic for endothelial cells in vitro and stimulates angiogenic responses in vivo. VEGF has also been linked to inappropriate angiogenesis (Pinedo, H.M., et al. (2000), The Oncologist, 5(90001), 1-2). VEGFR(s) are protein tyrosine kinases (PTKs). PTKs catalyze the phosphorylation of specific tyrosine residues on proteins involved in cell function, thereby regulating cell growth, survival and differentiation. (Wilks, AF (1990), Progress in Growth Factor Research, 2, 97-111; Courtneidge, SA (1993) Dev. Supp.1, 57-64; Cooper, JA (1994), Semin. Cell Biol., 5 (6), 377-387; Paulson, RF (1995), Semin. Immunol., 7(4), 267-277; Chan, AC (1996), Curr. Opin.Immunol., 8(3), 394- 401).

Three PTK receptors for VEGF have been identified: VEGFR-1 (Flt-1); VEGFR-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4). These receptors are involved in angiogenesis and participate in signal transduction (Mustonen, T. (1995), et al., J. Cell Biol., 129, 895-898).

Of particular interest is VEGFR-2, transmembrane receptor PTK expressed primarily in endothelial cells. Activation of VEGFR-2 by VEGF is a critical step in the signal transduction pathway that initiates tumor angiogenesis. VEGF expression can be constitutive for tumor cells and can also be up-regulated in response to certain stimuli. One such stimuli is hypoxia, where VEGF expression is up-regulated in both tumor tissues and associated host tissues. The VEGF ligand activates VEGFR-2 by binding to its extracellular VEGF binding site. This leads to receptor dimerization of VEGFRs and autophosphorylation of tyrosine residues in the extracellular kinase domain of VEGFR-2. The kinase domain operates to transfer a phosphate from ATP to tyrosine residues, thus producing binding sites for signaling. of proteins downstream of VEGFR-2 ultimately leading to initiation of angiogenesis (McMahon, G. (2000), The Oncologist, 5(90001), 3-10).

Inhibition at the kinase domain binding site of VEGFR-2 would block phosphorylation of tyrosine residues and would serve to halt the initiation of angiogenesis.

Angiogenesis is a physiological process of formation of new blood vessels mediated by several cytokines called angiogenic factors. Although its potential pathophysiological role in solid tumors has been extensively studied for over 3 decades, enhancement of angiogenesis in chronic lymphocytic leukemia (CLL) and other malignant hematologic disorders has been recognized more recently. An increased level of angiogenesis has been documented by various experimental methods both in lymph nodes and bone marrow from patients with CLL. Although the role of angiogenesis in the pathophysiology of this disease remains to be fully elucidated, experimental data suggest that several angiogenic factors play a role in disease progression. Biological markers of angiogenesis have also been shown to be of prognostic relevance in CLL. This indicates that VEGFR inhibitors may also be beneficial for patients with leukemias such as CLL.

With the object of a tumor mass going beyond a critical size, it needs to develop an associated vasculature. It has been proposed that selection for a tumor vasculature would limit tumor expression and could be a useful cancer therapy. Observations of tumor growth have indicated that small tumor masses may persist in tissue without any tumor-specific vasculature. The growth arrest of non-vascularized tumors has been attributed to the effects of hypoxia in the tumor center. More recently, a variety of pro-angiogenic and anti-angiogenic factors have been identified and have led to the concept of "angiogenic shift", a process in which disruption of the normal ratio of angiogenic and inhibitory stimuli in a tumor mass allows for autonomous vascularization. Angiogenic change appears to be governed by the same genetic alterations that drive malignant conversion: the activation of oncogenes and the loss of tumor suppressor genes.

Several growth factors act as positive regulators of angiogenesis. Major of these are vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiogenin. Proteins such as thrombospondin (Tsp-1), angiostatin, and endostatin function as negative regulators of angiogenesis.

Inhibition of VEGFR2 but not VEGFR1 remarkably interrupts angiogenic shift, persistent angiogenesis, and early tumor growth in a mouse model. In late-stage tumors, phenotypic resistance to VEGFR2 blockade emerged because tumors regrow during treatment after an initial period of growth suppression. This resistance to VEGF blockade involves reactivation of tumor angiogenesis, independent of VEGF and associated with hypoxia-mediated induction of other pro-angiogenic factors, including members of the FGF family. These other pro-angiogenic signals are functionally implicated in revascularization and tumor regrowth in the evasion phase, because FGF blockade impairs progression in the face of VEGF inhibition. Inhibition of VEGFR2 but not VEGFR1 remarkably halted angiogenic change, persistent angiogenesis, and early tumor growth. In late-stage tumors, phenotypic resistance to VEGFR2 blockade emerged because tumors regrow during treatment after an initial period of growth suppression. This resistance to VEGF blockade involves reactivation of tumor angiogenesis, independent of VEGF and associated with hypoxia-mediated induction of other pro-angiogenic factors, including members of the FGF family. These other pro-angiogenic signals are functionally implicated in revascularization and tumor regrowth in the evasion phase, because FGF blockade impairs progression in the face of VEGF inhibition.

It has been previously reported that an FGF-trap adenovirus binds to and blocks several FGF family ligands, including FGF1, FGF3, FGF7, and FGF 10, thereby effectively inhibiting angiogenesis in vitro and in vivo. In fact, addition of FGF-trap treatment in the regrowth phase of a mouse model produced a significant decrease in tumor growth compared to anti-VEGFR2 alone. This decrease in tumor burden was accompanied by a decrease in angiogenesis which was observed as decreased intratumoral vessel density.

Batchelor et al. (Batchelor et al., 2007, Cancer Cell, 11(1), 83-95) provided evidence for normalization of glioblastoma blood vessels in patients treated with a pan-VEGF receptor tyrosine kinase inhibitor, AZD2171, in a study of phase 2. The rationale for using AZD2171 was based partially on results showing a decrease in perfusion and vessel density in an in vivo breast cancer model (Miller et al., 2006, Clin. Cancer Res. 12, 281- 288). Furthermore, using an orthotropic glioma model, the optimal time window for releasing anti-VEGFR2 antibody to achieve a synergistic effect with radiation had previously been identified. During the normalization window, there was improved oxygenation, increased pericyte coverage, and angiotensin-1 upregulation leading to a decrease in interstitial pressure and permeability within the tumor (Winkler et al., 2004, Cancer Cell 6, 553-563 ). The window of normalization can be quantified using magnetic resonance imaging (MRI) using gradient-echo, spin-echo, and contrast enhancement MRI to measure blood volume, relative vessel size, and vascular permeability.

The authors showed that progression over AZD2171 treatment was associated with an increase in CECs, SDF1, and FGF2, whereas progression after drug withdrawals correlated with increases in plasma FGF2 and circulating progenitor cell (CPC) levels. The increase in plasma levels of SDF1 and FGF2 correlated with MRI measurements demonstrated an increase in relative vessel size and density(a). Thus, MRI determination of vessel normalization in combination with circulating biomarkers provides an effective means to assess response to antiangiogenic agents.PDGFR

A malignant tumor is the product of uncontrolled cell proliferation. Cell growth is controlled by a delicate balance between growth-promoting and growth-inhibiting factors. In normal tissue the production and activity of these factors results in the growth of differentiated cells in a controlled and regulated manner that maintains normal organ integrity and function. The malignant cell has evaded this control; the natural balance is disturbed (via a variety of mechanisms) and unregulated, aberrant cell growth occurs. A growth factor of importance in tumor development is platelet-derived growth factor (PDGF) which comprises a family of peptide growth factors that signal through surface receptor tyrosine kinase (PDGFR) and stimulate various cell functions including growth, proliferation, and differentiation. PGDF expression has been demonstrated in numerous different solid tumors including glioblastomas and prostate carcinomas. The tyrosine kinase inhibitor imatinib mesylate, which has the chemical name 4-[(4-methyl-1-piperazinyl)-methyl]-N-[4-methyl-3-[[4-(3-) pyridinyl)-2-yl-pyridinyl]-amino]-phenyl]-benzamide, blocks the activity of the oncoprotein Bcr-Abl and the surface receptor tyrosine kinase c-Kit, and as such is approved for the treatment of chronic myeloid leukemia and of gastrointestinal stromal tumors. Imatinib mesylate is also a potent PDFGR kinase inhibitor and is currently being evaluated for the treatment of chronic myelomonocytic leukemia and glioblastoma multiforme, based on evidence in these diseases of activating mutations in PDGFR. In addition, sorafenib (BAY 43-9006) which has the chemical name 4-(4-(3-(4-chloro-3-(trifluoro-methyl)-phenyl)-ureido)-phenoxy-N2-methyl-pyridine- 2-carboxamide, selects both the Raf signaling pathway to inhibit cell proliferation and the VEGFR/PDGFR signaling cascades to inhibit tumor angiogenesis Sorafenib is being investigated for the treatment of numerous cancers including kidney and liver cancer.

There are conditions that are dependent on PDGFR activation such as hypereosinophilic syndrome. Activation of PDGFR is also associated with other malignancies, which include chronic myelomonocytic leukemia (CMML). In another disorder, bulging dermatofibrosarcoma, an infiltrating skin tumor, a reciprocal translocation involving the PDGF-B ligand-encoding gene results in constitutive secretion of the chimeric ligand and receptor activation. Imatinib which is a PDGFR inhibitor has activity against all three of these diseases.

Advantages of a selective inhibitor

Development of FGFR kinase inhibitors with a differentiated selectivity profile provides a new opportunity to use selected agents in subgroups of patients whose disease is induced by FGFR dysregulation. Compounds that exhibit reduced inhibitory action on additional kinases, particularly VEGFR2 and PDGFR-beta, offer the opportunity to have a differentiated toxicity or side effect profile and as such allow more effective treatment of these indications. VEGFR2 and PDGFR-beta inhibitors are associated with toxicities such as hypertension or edema respectively. In the case of VEGFR2 inhibitors this hypertensive effect is often dose-limiting, may be contraindicated in certain patient populations, and requires clinical supervision.

Biological activity and therapeutic uses

The compounds of the invention, and their subgroups, have fibroblast growth factor receptor (FGFR) modulatory or inhibitory activity and/or vascular endothelial growth factor receptor (VEGFR) modulatory or inhibitory activity, and/or modulatory activity or inhibitory to platelet-derived growth factor receptor (PDGFR), and which will be useful in preventing or treating the disease conditions or conditions described herein. In addition the compounds of the invention, and subgroups thereof, will be useful in preventing or treating kinase-mediated diseases and conditions. References to the prevention or prophylaxis or treatment of an unhealthy condition or condition such as cancer fall within its scope to alleviate or reduce the incidence of cancer.

As used herein, the term "modulation", as applied to the activity of a kinase, is intended to define a change in the level of biological activity of the protein kinase. Thus, modulation follows physiological changes that affect an increase or decrease in the relevant protein kinase activity. In the latter case, modulation can be described as "inhibition". Modulation can start directly or indirectly, and can be mediated by any mechanism and at any physiological level, including for example at gene expression level (including for example transcription, translation and/or post-translational modification), at the level of expression of genes encoding regulatory elements that act directly or indirectly on kinase activity levels. Thus, modulation may imply elevated/suppressed or over- or under-expression of a kinase, including gene amplification (ie multiple gene copies) and/or increased or decreased expression by a transcription effect, as well as hyper- (or hypo-)activity and (de)activation of protein kinase(s) (including (de)activation) by mutation(s). The terms "modulated", "modulation" and "modulate" are to be interpreted accordingly.

As used herein, the term "mediated", as used eg in conjunction with a kinase as described herein (and applied for example to various physiological processes, diseases, conditions, conditions, therapies, treatments and interventions) is intended to operate limitedly so that the various processes, diseases, states, conditions, treatments and interventions to which the term is applied are those in which the kinase plays a biological role. In cases where the term is applied to a disease, state, or condition, the biological role played by a kinase may be direct or indirect and may be necessary and/or sufficient for the manifestation of symptoms of the disease, state or condition (or its etiology or progression). Thus, kinase activity (and in particular aberrant levels of kinase activity, eg kinase overexpression) need not necessarily be the proximal cause of the disease, state or condition: instead, it is contemplated that the diseases, states or conditions kinase-mediated include those having multifactorial etiologies and complex progressions in which the kinase in question is only partially involved. In cases where the term is applied to treatment, prophylaxis or intervention, the role played by the kinase may be direct or indirect and may be necessary and/or sufficient for the operation of the treatment, prophylaxis or outcome of the intervention. Thus, a kinase-mediated disease state or condition includes the development of resistance to any particular cancer drug or treatment.

Thus, for example, it is considered that the compounds of the invention will be useful in alleviating or reducing the incidence of cancer.

More particularly, the compounds of formulas (I) and their subgroups are inhibitors of FGFRs. For example, compounds of the invention have activity against FGFR1, FGFR2, FGFR3, and/or FGFR4, and in particular FGFRs selected from FGFR1, FGFR2 and FGFR3.

Preferred compounds are compounds that inhibit one or more FGFR selected from FGFR1, FGFR2 and FGFR3, and also FGFR4.

Preferred compounds of the invention are those having IC50 values less than 0.1 µM. Compounds of the invention also have activity against VEGFR.

Compounds of the invention also have activity against PDGFR kinases. In particular, the compounds are PDGFR inhibitors and, for example, they inhibit PDGFR A and/or PDGFR B.

In addition many of the compounds of the invention exhibit selectivity for FGFR 1,2, and/or kinase 3, and/or FGFR4 compared to VEGFR (in particular VEGFR2) and/or PDGFR and such compounds represent a preferred embodiment of the invention. In particular, the compounds exhibit selectivity for VEGFR2. For example, many compounds of the invention have IC50 values against FGFR1,2 and/or 3 and/or FGFR4 that are between one tenth and one hundredth of the IC50 against VEGFR (in particular VEGFR2) and/or PDGFR B. In particular preferred compounds of the invention have at least 10-fold greater activity against or inhibition of FGFR in particular FGFR1, FGFR2, FGFR3 and/or FGFR4 than VEGFR2. More preferably the compounds of the invention have at least 100 times greater activity against or inhibition of FGFR in particular FGFR1, FGFR2, FGFR3 and/or FGFR4 than VEGFR2. This can be determined using the methods described here.

As a consequence of their activity in modulating or inhibiting FGFR, VEGFR and/or PDGFR kinases, the compounds will be useful in providing a means of preventing growth or inducing apoptosis of neoplasms, particularly by inhibiting angiogenesis. Therefore, the compounds are expected to prove useful in the treatment or prevention of proliferative disorders such as cancers. In addition, the compounds of the invention could be useful in the treatment of diseases in which there is a proliferation, apoptosis or differentiation disorder.

In particular tumors with VEGFR activating mutants or VEGFR upregulation and patients with elevated serum lactate dehydrogenase levels may be particularly sensitive to the compounds of the invention. Patients with activating mutants of any of the specific RKT isoforms discussed herein may also find treatment with the compounds of the invention particularly beneficial. For example, overexpression of VEGFR in acute leukemia cells where the clonal parent can express VEGFR. Also, particular tumors with activating mutants or upregulation or overexpression of any of the FGFR isoforms such as FGFR1, FGFR2 or FGFR3 or FGFR4 may be particularly sensitive to the compounds of the invention and thus patients as discussed herein with such particular tumors as well may find treatment with the compounds of the invention particularly beneficial. It may be preferred that the treatment is related to or directed to a mutant form of one of the receptor tyrosine kinases, as discussed herein. Diagnosis of tumors with such mutations could be performed using techniques known to a person skilled in the art and as described herein such as RTPCR and FISH.

Examples of cancers that can be treated (or inhibited) include, but are not limited to, a carcinoma, for example a bladder, breast, colon carcinoma (eg colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermis , liver, lung, for example adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, esophagus, gallbladder, ovary, pancreas eg exocrine pancreatic carcinoma, stomach, cervix, endometrium, thyroid, prostate, or skin , for example squamous cell carcinoma; a hematopoietic tumor of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, capillary cell lymphoma, or Burkett's lymphoma ; a hematopoietic tumor of myeloid lineage, for example leukemias, acute and chronic myelogenous leukemias, myeloproliferative syndrome, myelodysplastic syndrome, or promyeliocyte leukemia; multiple myeloma; thyroid follicular cancer; a tumor of mesenchymal origin, for example fibrosarcoma or rhabdomyosarcoma; a tumor of the peripheral or central nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratocanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

Certain cancers are resistant to treatment with particular drugs. This could be due to the type of tumor or it could be due to treatment with the compound. In this regard, references to multiple myeloma include refractory multiple myeloma or bortezomid sensitive multiple myeloma. Similarly, references to chronic myelogenous leukemia include refractory chronic myelogenous leukemia and imitanib-sensitive chronic myelogenous leukemia. Chronic Myelogenous Leukemia is also known as Chronic Myelogenous Leukemia, Chronic Granulocytic Leukemia or CML Likewise, Acute Myelogenous Leukemia is also called Acute Myeloblastic Leukemia, Acute Granulocytic Leukemia, Acute Non-lymphocytic Leukemia, or AML.

The compounds of the invention can also be used in the treatment of abnormal cell proliferative hematopoietic diseases whether premalignant or stable such as myeloproliferative diseases. Myeloproliferative diseases ("MPDs") are a group of bone marrow diseases in which excess cells are produced. They are related to, and can develop into, myelodysplastic syndrome. Myeloproliferative disorders include true polycythemia, essential thrombocytopenia, and primary myelofibrosis.

Thus, in the pharmaceutical compositions, uses or methods of this invention for treating a disease or condition comprising abnormal cell growth, the disease or condition comprising abnormal cell growth in one embodiment is cancer.

Furthermore, T-cell lymphoproliferative disorders include those derived from natural Killer cells. The term B-cell lymphoma includes diffuse large B-cell lymphoma.

In addition the compounds of the invention can be used for gastrointestinal (also known as gastric) cancer e.g. gastrointestinal stromal tumors. Gastrointestinal cancer refers to malignant conditions of the gastrointestinal tract, including the esophagus, stomach, liver, biliary system, pancreas, intestines, and anus. Another example of a tumor of mesenchymal origin is Ewing's sarcoma.

Thus, in the pharmaceutical compositions, uses or methods of this invention for treating a disease or condition comprising abnormal cell growth, the disease or condition comprising abnormal cell growth in one embodiment is cancer.

Particular subsets of cancers include multiple myeloma, bladder, cervical, prostate and thyroid carcinomas, lung, breast, and colon cancers.

Another subset of cancers includes multiple myeloma, bladder, hepatocellular, oral squamous cell, and cervical carcinomas. Another subset of cancers includes multiple myeloma, bladder and cervical carcinomas.

It is further envisaged that compound of the invention having FGFR inhibitory activity such as FGFR1 will be particularly useful in the treatment or prevention of breast cancer in particular Classical Lobular Carcinomas (CLC).

As the compounds of the invention have FGFR4 activity they will also be useful in the treatment of prostate or pituitary cancers.

FGFR, are useful in the treatment of multiple myeloma, myeloproliferative disorders, endometrial cancer, prostate cancer, bladder cancer, breast cancer, ovarian cancer, breast cancer, gastric cancer, colorectal cancer, and oral squamous cell carcinoma.

Other subsets of cancer are multiple myeloma, endometrial cancer, bladder cancer, cervical cancer, prostate cancer, breast cancer, breast cancer, colorectal cancer and thyroid carcinomas.

In particular the compounds of the invention are useful in the treatment of multiple myeloma (in particular multiple myeloma with t(4;14) translocation or overexpressing FGFR3), prostate cancer (hormone refractory prostate carcinomas), endometrial cancer (in particular endometrial tumors with activating mutations in FGFR2) and breast cancer (in particular lobular breast cancer).

In particular the compounds are useful for the treatment of lobular carcinomas such as CLC (Classic Lobular Carcinoma). As the compounds have activity against FGFR3 they will be useful in the treatment of multiple myeloma and bladder. In particular the compounds are useful for the treatment of multiple myeloma positive t(4; 14) translocation.

As the compounds have activity against FGFR2 they will be useful in the treatment of endometrial, ovarian, gastric and colorectal cancers. FGFR2 is also over-expressed in epithelial ovarian cancer, therefore compounds of the invention may be specifically useful in the treatment of ovarian cancer such as epithelial ovarian cancer.

Compounds of the invention may also be useful in treating tumors pretreated with a VEGFR2 inhibitor or VEGFR2 antibody (e.g. Avastin).

In particular the compounds of the invention may be useful in the treatment of tumors resistant to VEGFR2. Antibodies and inhibitors of

VEGFR2 are used in the treatment of renal and thyroid cell carcinomas, therefore the compounds of the invention may be useful in the treatment of VEGFR2-resistant renal and thyroid cell carcinomas.

Cancers can be cancers that are sensitive to inhibition of any one or more FGFRs selected from FGFR1, FGFR2, FGFR3, FGFR4, for example, one or more FGFRs selected from FGFR1, FGFR2 or FGFR3.

Whether or not a particular cancer is sensitive to inhibition of FGFR, VEGFR or PDGFR signaling can be determined by means of a cell growth assay described in Examples 79 and 80 below or by a method described in the section entitled "Diagnostic methods" .

It is further contemplated that compounds of the invention, and in particular those compounds having inhibitory activity on FGFR, VEGFR or PDGFR, will be particularly useful in the treatment or prevention of cancers of a type associated with or characterized by the presence of elevated levels of FGFR, VEGFR or PDGFR, for example the cancers referred to in this context in the introductory section of this application.

It has been discovered that some FGFR inhibitors can be used in combination with other anti-cancer agents. For example, it may be beneficial to combine an inhibitor that induces apoptosis with another agent that acts via a different mechanism to regulate cell growth, thus treating two of the characteristic features of cancer development. Examples of such combinations are shown below.

It is also contemplated that the compounds of the invention will be useful in the treatment of other conditions that result from proliferative disorders such as insulin-independent or type II diabetes mellitus, autoimmune diseases, head trauma, stroke, epilepsy, neurodegenerative diseases such as malaise. Alzheimer's, neuromotor disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease for example autoimmune diseases and neurodegenerative diseases.

A subgroup of conditions and disease states where it is considered that the compounds of the invention will be useful consists of inflammatory diseases, cardiovascular diseases and wound healing.

It is also known that FGFR, VEGFR and PDGFR play a role in apoptosis, angiogenesis, proliferation, differentiation and transcription and therefore the compounds of the invention could also be useful in the treatment of the following diseases other than cancer; chronic inflammatory diseases, for example systemic lupus erythematosus, autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes mellitus, hypersensitive reactions to eczema, asthma, COPD, rhinitis, and upper respiratory tract disease; cardiovascular diseases for example cardiac hypertrophy, restenosis, arteriosclerosis; neurodegenerative disorders, for example Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; glomerulonephritis; myelodysplastic syndromes, myocardial infarctions associated with ischemic injury, stroke and reperfusion injury, arrhythmia, arteriosclerosis, alcohol-related or toxin-induced liver diseases, hematologic diseases, e.g., chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system, eg osteoporosis and arthritis, aspirin sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.

In addition, FGFR2 mutations are associated with several severe abnormalities in human skeletal development and thus compounds of the invention could be useful in the treatment of abnormalities in human skeletal development, including abnormal ossification of cranial sutures (craniosynostosis), Apert syndrome ( AP), Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, and Pfeiffer syndrome.

It is further contemplated that compound of the invention having FGFR inhibitory activity such as FGFR2 or FGFR3 will be particularly useful in the treatment or prevention of skeletal diseases. Particular skeletal disorders are achondroplasia or thanatophoric dwarfism (also known as thanatophoric dysplasia).

It is further considered that the compound of the invention having FGFR inhibitory activity such as FGFR1, FGFR2 or FGFR3 will be particularly useful in the treatment or prevention of conditions in which progressive fibrosis is a symptom. Fibrotic conditions in which the compounds of the invention may be useful in the treatment include diseases exhibiting abnormal or excessive deposition of fibrous tissue for example in liver cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, as well as the natural wound healing process. In particular the compounds of the invention may also be useful in the treatment of pulmonary fibrosis in particular idiopathic pulmonary fibrosis.

The overexpression and activation of FGFR and VEGFR in tumor associated vasculature has also suggested a role for the compounds of the invention in preventing and disrupting the initiation of tumor angiogenesis. In particular the compounds of the invention may be useful in the treatment of cancer, metastasis, leukemias such as CLL, ocular diseases such as age-related macular degeneration in particular wet form of age-related macular degeneration, ischemic proliferative retinopathies such as retinopathy of prematurity (ROP) and diabetic retinopathy, rheumatoid arthritis and hemangioma.

As the compounds of the invention inhibit PDGFR they may also be useful in the treatment of numerous types of leukemia and tumors including glioblastomas such as glioblastoma multiforme, prostate carcinomas, gastrointestinal stromal tumors, liver cancer, kidney cancer, acute myelogenous leukemia, myelomonocytic leukemia (CMML) as well as hypereosinophilic syndrome, a rare proliferative hematologic disorder, and bulging dermatofibrosarcoma, an infiltrating skin tumor.

The activity of compounds of the invention as inhibitors of FGFR1-4, VEGFR and/or PDGFR A/B can be measured using the assays shown in the examples below and the level of activity exhibited by a given compound can be defined in terms of the IC50 value . Preferred compounds of the present invention are compounds having an IC50 value of less than 1 µM, more preferably less than 0.1 µM.

The invention produces compounds which have FGFR modulatory or inhibitory activity, and which are considered to be useful in the prevention or treatment of disease states or disease conditions mediated by FGFR kinases.

In one embodiment, a compound as defined herein for use in therapy is produced. In another embodiment, a compound as defined herein is produced for use in the prophylaxis or treatment of a diseased state or diseased condition mediated by an FGFR kinase.

Thus, for example, it is considered that the compounds of the invention will be useful in alleviating or reducing the incidence of cancer.

Accordingly, in one aspect, the invention provides the use of a compound for the manufacture of a medicament for the prophylaxis or treatment of a diseased state or diseased condition mediated by an FGFR kinase, the compound having formula (I ) as defined herein.

In one embodiment, there is provided the use of a compound as defined herein for the manufacture of a medicament for the prophylaxis or treatment of an unhealthy condition or an unhealthy condition as described herein.

In another embodiment, the use of a compound as defined herein for the manufacture of a medicament for the prophylaxis or treatment of cancer is provided. Accordingly, the invention provides inter alia:

A method for the prophylaxis or treatment of a diseased state or diseased condition mediated by an FGFR kinase, which method comprises administering to a subject in need thereof a compound of formula (I) as defined herein.

In one embodiment, there is provided a method for the prophylaxis or treatment of a diseased condition or a diseased condition as described herein, which method comprises administering to a subject in need thereof a compound of formula (I) as defined herein.

In another embodiment, a method for the prophylaxis or treatment of cancer is provided, which method comprises administering to a subject in need thereof a compound of formula (I) as defined herein.

A method of alleviating or reducing the incidence of a diseased state or diseased condition mediated by an FGFR kinase, which method comprises administering to a subject in need thereof a compound of formula (I) as defined herein.

A method of inhibiting an FGFR kinase, which method comprises contacting the kinase with a kinase inhibitor compound of formula (I) as defined herein.

A method of modulating a cellular process (eg cell division) by inhibiting the activity of an FGFR kinase using a compound of formula (I) as defined herein.

A compound of formula (I) as defined herein for use as a modulator of a cellular process (eg cell division) by inhibiting the activity of an FGFR kinase. A compound of formula (I) as defined herein for use as a modulator ( eg inhibitor) of FGFR.

The use of a compound of formula (I) as defined herein for the manufacture of a medicament for modulating (e.g. inhibiting) FGFR activity.

Use of a compound of formula (I) as defined herein in the manufacture of a medicament to modulate a cellular process (eg cell division) by inhibiting the activity of an FGFR kinase.

The use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a disease or condition characterized by upregulation of an FGFR kinase (e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4).

The use of a compound of formula (I) as defined herein for the manufacture of a medicine for the prophylaxis or treatment of a cancer, cancer being one that is characterized by up-regulation of an FGFR kinase (eg FGFR1 or FGFR2 or FGFR3 or FGFR4).

The use of a compound of formula (I) as defined herein for the manufacture of a medicine for the prophylaxis or treatment of cancer in a patient selected from a sub-population having FGFR3 kinase genetic aberrations.

The use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prophylaxis or treatment of cancer in a patient who has been diagnosed as forming part of a sub-population having FGFR3 kinase genetic aberrations.

A method for the prophylaxis or treatment of a disease or condition characterized by upregulation of an FGFR kinase (e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4), the method comprising administering a compound of formula (I) as defined herein.

A method of alleviating or reducing the incidence of a disease or condition characterized by up-regulation of an FGFR kinase (e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4), the method comprising administering a compound of formula (I) as defined herein.

A method for the prophylaxis or treatment of (or alleviation or reduction in the incidence of) cancer in a patient suffering from or suspected of suffering from cancer; which method comprises (i) subjecting a patient to a diagnostic test to determine whether the patient has FGFR3 gene genetic aberrations; and (ii) where the patient has said variant, then administering to the patient a compound of formula (I) as defined herein having FGFR3 kinase inhibitory activity.

A method for the prophylaxis or treatment of (or alleviation or reduction in incidence of) a diseased state or a diseased condition characterized by upregulation of an FGFR kinase (e.g. e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4); which method comprises (i) subjecting a patient to a diagnostic test to detect a characteristic marker of upregulation of an FGFR kinase (eg FGFR1 or FGFR2 or FGFR3 or FGFR4) and (ii) where the diagnostic test is indicative of upregulation of FGFR kinase, then administering to the patient a compound of formula (I) as defined herein having FGFR kinase inhibitory activity.

mutated kinases

Drug-resistant kinase mutations may begin in patient populations treated with kinase inhibitors. These occur, in part, in regions of the protein that bind to or interact with the particular inhibitor used in therapy. Such mutations reduce or increase the inhibitor's binding capacity and inhibit the kinase in question. This can occur at any of the amino acid residues that interact with the inhibitor or are important in supporting the binding of said inhibitor to the target. An inhibitor that binds to a target kinase without requiring interaction with the mutated amino acid residue is unlikely to be affected by the mutation and will remain an effective inhibitor of the enzyme (Carter et al. (2005), PNAS, 102(31), 11011- 110116).

There are mutations that have been observed in PDGFR in patients treated with imatinib, in particular the T674I mutation. The clinical importance of these mutations may grow considerably, as to date it seems to represent the primary mechanism of resistance to src/Abl inhibitors in patients.

In addition, there are point mutations or chromosomal translocations that have been observed in FGFR that give rise to biological, over-expressed, or biologically active, gain-of-function biological states.

The compounds of the invention would therefore find particular application in relation to cancers which express a mutated molecular target such as FGFR or PDGFR including PDGFR-beta and PDGFR-alpha in particular the T674I mutation of PDGFR. Diagnosis of tumors with such mutations could be performed using techniques known to a person skilled in the art and as described herein such as RTPCR and FISH.

It has been suggested that mutations of a conserved threonine residue in the ATP binding site of FGFR would result in inhibitor resistance. The amino acid valine 561 has been mutated to a methionine in FGFR1 that corresponds to previously reported mutations found in Abl (T315) and EGFR (T766) that have been shown to confer resistance to selective inhibitors. Assay data for FGFR1 V561M showed that this mutation granted resistance to a tyrosine kinase inhibitor compared to that of the wild type.

Pharmaceutical formulations

While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (eg formulation) comprising at least one active compound of the invention together with one or more carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers , preservatives, lubricants, or other pharmaceutically acceptable materials well known to those skilled in the art and optionally other prophylactic or therapeutic agents.

Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of preparing a pharmaceutical composition comprising mixing at least one active compound, as defined above, together with one or more carriers, excipients, buffers, adjuvants, stabilizers, or other pharmaceutically acceptable materials as described herein.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (eg human ) without causing excessive toxicity, irritation, allergic response, or other problem or complication, proportionate to a reasonable benefit/risk ratio. Each vehicle, excipient, etc. it also needs to be "acceptable" in the sense of being compatible with the other ingredients in the formulation.

Pharmaceutical compositions containing compounds of formula (I) may be formulated according to known techniques, see for example, "Remington's Pharmaceutical Sciences", Mack Publishing Company, Easton, PA, USA.

Accordingly, in another aspect, the invention provides compounds of formula (I) and their subgroups as defined herein in the form of pharmaceutical compositions.

The pharmaceutical compositions may be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, optical, rectal, intravaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they may be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery to a target tissue or organ by injection, infusion or other means of delivery. Delivery can be by bolus injection, short-term infusion or long-term infusion and can be via passive release or through the use of an appropriate infusion pump.

Pharmaceutical formulations adapted for parenteral administration include sterile aqueous and non-aqueous solutions for injection which may contain antioxidants, buffers, bacteriostats, co-solvents, organic solvent mixtures, cyclodextrin complexing agents, emulsifying agents (to form and stabilize emulsion formulations ), liposome components to form liposomes, gellable polymers to form polymeric gels, freeze-drying protectants and combinations of agents to, inter alia, stabilize the active ingredient in a soluble form and make the formulation isotonic with the blood of the intended recipient patient. Pharmaceutical formulations for parenteral administration may also take the form of sterile aqueous and non-aqueous suspensions which may include suspending agents and thickening agents (RG Strickly (2004), "Solubilizing excipients in oral and injectable formulations", Pharmaceutical Research, Vol 21( 2), p 201-230).

Liposomes are closed spherical vesicles composed of outer lipid bilayer membranes and an inner aqueous core and with an overall diameter of <100 μm. Depending on the level of hydrophobicity, moderately hydrophobic drugs can be solubilized by liposomes if the drug becomes encapsulated or interspersed within the liposome. Hydrophobic drugs can also be solubilized by liposomes if the drug molecule becomes an integral part of the lipid bilayer membrane, in which case the hydrophobic drug is dissolved in the lipid portion of the lipid bilayer.

The formulations may be presented in unit-dose or multi-dose containers, eg sealed vials and ampoules, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of sterile liquid vehicle, eg water for injections, immediately before use.

The pharmaceutical formulation can be prepared by lyophilizing a compound of formula (I), or its subgroups. Lyophilization refers to the procedure of freeze drying a composition. Freeze drying and lyophilization are therefore used synonymously here.

Extemporaneous injection solutions and suspensions can be prepared from sterile tablets, granules and powders.

Pharmaceutical compositions of the present invention for parenteral injection may also comprise pharmaceutically acceptable sterile aqueous or non-aqueous emulsions, suspensions or solutions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just before use. Examples of aqueous and non-aqueous vehicles, solvents, diluents or carriers include water, ethanol, polyols (such as glycerol, propylene glycol, poly(methylene glycol), and the like), carboxymethyl cellulose and mixtures thereof suitable, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

Compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Preservation against the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chloro-butanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In a preferred embodiment of the invention, the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion. For intravenous administration, the solution can be dosed as such, or it can be injected into an infusion bag (containing a pharmaceutically acceptable excipient such as 0.9% saline or 5% dextrose) prior to administration.

In another preferred embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) administration.

Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, small capsules, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and mouth patches.

Thus, tablet compositions may contain a unit dosage of active compound together with an inert carrier or diluent such as a sugar or sugar alcohol, e.g.; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar-derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or its derivative such as methyl-cellulose, ethyl-cellulose, hydroxy-propyl-methyl-cellulose, and starches such as corn starch. Tablets may also contain standard ingredients such as binding and granulating agents such as poly(vinyl-pyrrolidone), disintegrants (eg swellable cross-linked polymers such as cross-linked carboxy-methyl-cellulose), lubricating agents (eg stearates), preservatives (eg parabens) , antioxidants (eg BHT), buffering agents (eg phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are well known and need not be discussed in detail here.

Capsule formulations can be of the soft gelatin or hard gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or its synthetic or plant-derived equivalents.

Solid dosage forms (eg; tablets, capsules etc.) can be coated or uncoated, but typically have a coating, for example a protective film coating (eg a wax or a varnish) or a controlled release coating. The coating (e.g. an Eudragit™ type polymer) can be designed to release the active component at a desired location within the gastrointestinal tract. Thus, the coating can be selected to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively releasing the compound in the stomach or ileum or duodenum.

Instead of or in addition to a coating, the drug may be presented in a solid matrix comprising a release control agent, for example a release delaying agent which may be adapted to selectively release the compound under acidic or acidic conditions. varying alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating may take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. As another alternative, the active compound can be formulated in a delivery system that provides osmotic control of compound release. Osmotic release and other delayed release or extended release formulations can be prepared according to methods known to those skilled in the art.

Pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient.

Pharmaceutical compositions according to the invention may be, for example, in unit dosage form, such as in the form of ampoules, vials, suppositories, pills, tablets or capsules.

Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after addition of appropriate excipients, into tablets, dragees or capsules . It is also possible that they are incorporated into plastic vehicles that allow the active ingredients to diffuse or be released in measured amounts.

The compounds of the invention can also be formulated as solid dispersions. Solid dispersions are homogeneous, extremely fine dispersed phases of two or more solids. Solid solutions (molecularly dispersed systems), a type of solid dispersion, are well known for use in pharmaceutical technology (see (Chiou and Riegelman (1971), J. Pharm. Sci., 60,1281-1300) and are useful in augmenting dissolution rates and increase the bioavailability of poorly water-soluble drugs.

This invention also produces solid dosage forms comprising the solid solution described above. Solid dosage forms include tablets, capsules and chewable tablets. Known excipients can be mixed with the solid solution to obtain the desired dosage form. For example, a capsule can contain the solid solution mixed with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. A tablet can contain the solid solution mixed with at least one disintegrant, a lubricant, a surfactant, and a glidant. The chewable tablet may contain the solid solution mixed with a bulking agent, a lubricant, and if desired an additional sweetening agent (such as an artificial sweetener), and suitable flavorings.

Pharmaceutical formulations can be presented to a patient in "patient packages" containing an entire course of treatment in a single package, typically a blister pack. Patient packs have an advantage over traditional prescriptions, where a pharmacist splits a patient supply of a drug from a bulk supply, in that the patient always has access to the pack insert contained in the normally absent patient pack. in patient prescriptions. The inclusion of a package insert has been shown to improve patient acceptance of physician instructions.

Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (eg intraocular inserts). Such compositions can be formulated according to known methods.

Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed of a waxy or molded material containing the active compound.

Compositions for administration by inhalation may take the form of inhalable powder or liquid powder or liquid compositions, and may be administered in standard form using powder inhalation devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, powder formulations typically comprise the active compound together with an inert solid powder diluent such as lactose.

Compounds of formula (I) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient. Within this range, particular sub-ranges of compound are 0.1 milligram to 2 grams of active ingredient (more usually 10 milligrams to 1 gram, eg 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (eg 1 microgram to 10 milligrams, eg 0.1 milligram to 2 milligrams of active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof (for example an animal or human patient) in an amount sufficient to achieve the desired therapeutic effect. Examples of Pharmaceutical Formulations(i) Tablet Formulation A tablet composition containing a compound of formula (I) is prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as a diluent, and 3 mg of magnesium stearate as a lubricant and compressing to form a tablet in the known manner. (ii) Capsule formulation A formulation capsule is prepared by mixing 100 mg of a compound of formula (I) with 100 mg of lactose and filling standard opaque hard gelatin capsules with the resulting mixture. (iii) Injectable formulation A parenteral composition for administration by injection may be prepared by dissolving a compound of formula (I) (eg in a salt form) in water containing 10% propylene glycol to give an active compound concentration of 1.5% by weight. The solution is then sterilized by filtration, and an ampoule filled with it and sealed. (iv) Injectable formulation II A parenteral composition for injection is prepared by dissolving in water a compound of formula (I) (eg in salt form) (2 mg/ml) and mannitol (50 mg/ml), sterilely filtering the solution. and 1 ml sealable ampoules or vials are filled with it. (v) Injectable formulation III A formulation for iv release by injection or infusion may be prepared by dissolving the compound of formula (I) (eg in a salt form) in water at 20 mg/ml. The vial is then sealed and autoclaved. (vi) Injectable formulation IV A formulation for iv release by injection or infusion can be prepared by dissolving the compound of formula (I) (eg in a salt form) in water containing a buffer ( eg 0.2M acetate pH 4.6) at 20mg/ml. The vial is then sealed and autoclaved. (vii) Formulation for subcutaneous injection A composition for subcutaneous administration is prepared by mixing a compound of formula (I) with pharmaceutical grade corn oil to give a concentration of 5 mg/ml. The composition is sterilized and a suitable container is filled with it.viii) Lyophilized formulation

Aliquots of the formulated compound of formula (I) are placed in 50 ml vials and lyophilized. During lyophilization, compositions are frozen using a one-step freezing protocol at (-45°C). The temperature is raised to -10°C to temper, then lowered to freeze to -45°C, followed by primary drying at +25°C for approximately 3400 minutes, followed by secondary drying with 50°C temperature increments. Pressure during primary and secondary drying is set all Pascal.

treatment methods

It is contemplated that the compounds of formula (I) and its subgroups as defined herein will be useful in the prophylaxis and treatment of a variety of disease states and disease conditions mediated by FGFR. Examples of such unhealthy states or unhealthy conditions are cited above.

The compounds are generally administered to a subject in need of such administration, for example an animal or human patient, preferably a human.

The compounds will typically be administered in amounts that are therapeutically or prophylactically useful and that generally are non-toxic.

However, in certain situations (for example in the case of life-threatening illnesses), the benefits of administering a compound of formula (I) may be more important than the disadvantages of any side effects or toxic effects, in which case it may be It is considered desirable to administer compounds in amounts that are associated with a degree of toxicity.

The compounds can be administered for a prolonged period to maintain beneficial therapeutic effects or they can be administered for a short period of time only. Alternatively they can be administered in a pulsatile or continuous manner.

A typical daily dose of the compound of formula (I) may be within the range of 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of body weight, and more usually 10 nanograms to 15 milligrams per kilogram (eg 10 nanograms to 10 milligrams, and more typically 1 microgram per kilogram to 20 milligrams per kilogram, for example 1 microgram to 10 milligrams per kilogram) per kilogram of body weight although higher or lower doses may be administered where required. The compound of formula (I) may be administered on a daily basis or on a repeated basis every 2, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21, or 28 days for example.

The compounds of the invention may be administered orally in a range of doses, for example 1 to 1500 mg, 2 to 800 mg, or 5 to 500 mg, eg 2 to 200 mg or 10 to 1000 mg, particular examples of doses including 10, 20, 50 and 80 mg. The compound can be administered one or more times a day. The compound can be administered continuously (ie taken daily without a break in the duration of the treatment regimen. Alternatively, the compound can be taken intermittently, ie taken continuously for a given period such as a week, then discontinued for a period such as a week and then taken continuously for another period such as a week and so on throughout the duration of the treatment regimen. Examples of treatment regimens involving intermittent administration include regimens where administration is in cycles of one week to one week no; or two weeks on, one week off; or three weeks on, one week off; or two weeks on, two weeks off; or four weeks on two weeks off; or one week on three weeks off - for one or more cycles , eg 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more cycles.

In a particular dosing schedule, a patient will receive an infusion of a compound of formula (1) for periods of one hour daily for up to ten days in particular up to five days in a week, and the treatment is repeated at a desired interval such as two to four weeks, in particular every three weeks.

More particularly, a patient may receive an infusion of a compound of formula (1) for periods of one hour daily for 5 days and the treatment is repeated every three weeks.

In another particular dosing schedule, a patient receives an infusion for 30 minutes to 1 hour followed by maintenance infusions of varying duration, for example 1 to 5 hours, e.g. 3 hours.

In another particular dosing schedule, a patient receives a continuous infusion over a period of 12 hours to 5 days, in particular a continuous infusion from 24 hours to 72 hours.

Ultimately, however, the amount of compound administered and the type of composition used will correspond to the nature of the disease or physical condition being treated and will be at the discretion of the physician.

The compounds as defined herein may be administered as a therapeutic agent alone or may be administered in combination therapy with one or more other compounds for treating a particular disease state, for example a neoplastic disease such as a cancer as defined hereinbefore. Examples of other therapeutic agents or treatments that may be administered together (either concurrently or at different time intervals) with the compounds of formula (I) include but are not limited to: Topoisomerase II inhibitors Antimetabolites Tubulin sorting agents Topoisomerase II and ligand inhibitors DNAAlkylating AgentsMonoclonal AntibodiesAntihormonesSignal Transduction Inhibitors Proteosome InhibitorsDNA Methyl TransferasesCytokines and Retinoids Chromatin Selection TherapiesRadiotherapy, and,

Other prophylactic or therapeutic agents; for example agents that reduce or alleviate some of the side effects associated with chemotherapy. Particular examples of such agents include anti-emetic agents and agents that prevent or shorten the duration of neutropenia associated with chemotherapy and prevent complications that result from reduced levels of red blood cells or white blood cells, for example erythropoietin (EPO), granulocyte-macrophage colony stimulating factor (GM-CSF), and granulocyte colony stimulating factor (G-CSF). Also included are agents that inhibit bone resorption such as biophosphonate agents eg zoldronate, pamidronate and ibandronate, agents that suppress inflammatory responses (such as dexamethazone, prednisone, and prednisolone) and agents used to reduce blood levels of growth hormone and IGF-I in patients with acromegaly such as synthetic forms of the brain hormone somatostatin, which include octretide acetate which is a long-acting optapeptide with pharmacological properties that mimic those of the natural hormone somatostatin. Further included are agents such as leucovorin, which is used as an antidote to drugs that lower folic acid levels, or folinic acid itself, and agents such as megestrol acetate which can be used to treat side effects including edema and thromboembolic episodes. .

Each of the compounds present in the combinations of the invention can be given in individually varied dose schedules and via different routes.

Where the compound of formula (I) is administered in combination therapy with one, two, three, four or more other therapeutic agents (preferably one or two, more preferably one), the compounds may be administered simultaneously or sequentially. When given sequentially, they can be given at closely spaced intervals (eg over a period of 5-10 minutes) or at longer intervals (eg 1.2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosing regimen being commensurate with the properties of the therapeutic agent(s).

The compounds of the invention can also be administered in conjunction with non-chemotherapeutic treatments such as radiotherapy, photodynamic therapy, gene therapy, surgery and controlled diets.

For use in combination therapy with another chemotherapeutic agent, the compound of formula (I) and one, two, three, four or more other therapeutic agents can be, for example, formulated together in a dosage form containing two, three, four or more therapeutic agents. In an alternative, individual therapeutic agents can be formulated separately and presented together in the form of a kit, optionally with instructions for their use.

A person skilled in the art would know from their common general knowledge the dosage regimens and combination therapies to use.

diagnosis methods

Prior to administration of a compound of formula (I), a patient can be screened to determine whether a disease or condition the patient is suffering from or may be suffering from is one that would be amenable to treatment with a compound having activity against FGFR, VEGFR and/or PDGFR.

For example, a biological sample taken from a patient can be analyzed to determine whether a condition or disease, such as cancer, that the patient has or may suffer from is one that is characterized by an abnormal protein expression or a genetic abnormality that leads to upregulation of FGFR, VEGFR and/or PDGFR levels or activity or sensitization of a pathway to normal FGFR, VEGFR and/or PDGFR activity, or upregulation of these growth factor signaling pathways such as levels of growth factor ligand or growth factor binding activity or to upregulation of a biochemical pathway downstream of activation of FGFR, VEGFR and/or PDGFR.

Examples of such abnormalities that result in activation or sensitization of the FGFR, VEDFR and/or PDGFR signal include loss of or inhibition of apoptotic pathways, upregulation of receptors or ligands, or presence of mutant variants of the receptors or ligands eg variants of PTK. Tumors with mutants of FGFR1, FGFR2 or FGFR3 or FGFR4 or upregulation, in particular over-expression of FGFR1, or gain-of-function mutants of FGFR2 or FGFR3 may be particularly sensitive to FGFR inhibitors.

For example, point mutations engendering gain-of-function in FGFR2 have been identified under numerous conditions (Lemonnier, et al. (2001), J. Bone Miner. Res., 16, 832-845). In particular activating mutations in FGFR2 have been identified in 10% of endometrial tumors (Pollock et al., Oncogene, 2007, 26, 7158-7162).

In addition, genetic aberrations of the FGFR3 receptor tyrosine kinase such as point mutations or chromosomal translocations resulting in ectopically expressed or deregulated, constitutively active FGFR3 receptors have been identified in a subset of multiple myelomas, bladder and cervical carcinomas (Powers, CJ, et al (2000), Endocr. Rei. Cancer, 7, 165). A particular T674I mutation of the PDGF receptor has been identified in patients treated with imatinib.

In addition, 8p12-pll.2 gene amplification has been demonstrated in ~50% of lobular breast cancer (CLC) cases and this has been shown to be linked to increased expression of FGFR1. Preliminary studies with siRNA directed against FGFR1, or a small molecule inhibitor of the receptor, showed that cell lines hosting this amplification are particularly sensitive to inhibition of this signaling pathway (Reis-Filho et al. (2006), Clin Cancer Res. 12( 22), 6652-6662).

Alternatively, a biological sample taken from a patient can be analyzed for loss of an FGFR, VEGFR, or PDGFR negative regulator or suppressor. In the present context, the term "loss" includes deletion of a gene encoding a regulator or suppressor, truncation of the gene (eg by mutation), truncation of the gene transcript, or inactivation of the transcript (eg by mutation point) or sequestration by another gene product.

The term upregulation includes up-expression or over-expression, including gene amplification (i.e. multiple gene copies) and increased expression by a transcriptional effect, and hyperactivity and activation, including activation by mutations. Thus, the patient may undergo a diagnostic test to detect a characteristic marker of upregulation of FGFR, VEGFR and/or PDGFR. The term diagnosis includes screening. In relation to the marker we have included genetic markers including, for example, measuring DNA composition to identify FGFR, VEGFR and/or PDGFR mutations. The term marker also includes markers that are characteristic of FGFR, VEGFR and/or PDGFR upregulation, including enzyme activity, enzyme levels, enzyme status (e.g. phosphorylated or not) and mRNA levels of the aforementioned proteins.

Screening and diagnostic tests are typically conducted on a biological sample selected from tumor biopsy samples, blood samples (isolation and enrichment of detached tumor cells), stool biopsies, saliva, chromosome analysis, pleural fluid, peritoneal fluid, oral stylets, biopsy or urine.

Methods of identifying and analyzing mutations and protein upregulation are known to a person skilled in the art. Screening methods could include, but are not limited to, standard methods such as reverse transcriptase polymerase chain reaction (RT-PCR) or in situ hybridization such as fluorescence in situ hybridization (FISH).

Identifying an individual carrying a mutation in FGFR, VEGFR and/or PDGFR could mean that the patient would be particularly suitable for treatment with an inhibitor of FGFR, VEGFR and/or PDGFR. Tumors can preferably be screened for the presence of an FGFR, VEGFR and/or PDGFR variant prior to treatment. The screening process typically involves direct sequencing, oligonucleotide microarray analysis, or a mutant-specific antibody. In addition, diagnosis of tumors with such mutations could be performed using techniques known to a person skilled in the art and as described herein such as RT-PCR and FISH.

In addition, mutant forms of eg FGFR or VEGFR2 can be identified by direct sequencing of eg tumor biopsies using PCR and methods for directly sequencing PCR products as described herein above. The skilled person will recognize that all such well-known techniques for detecting overexpression, activation or mutations of the aforementioned proteins could be applicable in the present case.

In RT-PCR screening, the level of mRNA in the tumor is assessed by creating a cDNA copy of the mRNA followed by PCR amplification of the cDNA. PCR amplification methods, selection of primers, and conditions for amplification are known to a person skilled in the art. Nucleic acid manipulations and PCR are performed by standard methods, as described for example in Ausubel, F.M. et al., eds. (2004) "Current Protocols in Molecular Biology", John Wiley & Sons Inc., or Innis, M.A. et al., eds. (1990) "PCR Protocols: a guide to methods and applications", Academic Press, San Diego. Reaction techniques and manipulations involving nucleic acid are also described in Sambrook et al., (2001), 3rd Ed, "Molecular Cloning: A Laboratory Manual", Cold Spring Harbor Laboratory Press. Alternatively a commercially available kit for RT-PCR (for example Roche, Molecular Biochemicals) can be used, or methodology as described in U.S. Patents 4,666,828; 4,683,202; 4,801,531; 5,192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated herein by reference. An example of an in-situ hybridization technique to assess mRNA expression would be fluorescence in-situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152: 649).

Generally, in situ hybridization comprises the following main steps: (1) fixation of the tissue to be analyzed; (2) sample prehybridization treatment to increase accessibility of target nucleic acid, and to reduce non-specific binding; (3) hybridization of the mixture of nucleic acids to the nucleic acid in tissue or biological structure; (4) post-hybridization washes to remove unbound nucleic acid fragments in hybridization, and (5) detection of the hybridized nucleic acid fragments. Probes used in such applications are typically labeled, for example, with radioisotopes or fluorescent reporters. Preferred probes are long enough, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to allow specific hybridization to the target nucleic acid(s) under conditions stringent. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. (2004) "Current Protocols in Molecular Biology", John Wiley & Sons Inc and "Fluorescence In Situ Hybridization: Technical Overview" by

John M.S. Bartlett in "Molecular Diagnosis of Cancer, Methods and Protocols", 2nd ed.; ISBN: 1-59259-760-2; March 2004, pps. 077-088; "Series: Methods in Molecular Medicine".

Methods for profiling gene expression are described in (DePrimo et al. (2003), BMC Cancer, 3:3). Briefly, the protocol is as follows: Double-stranded cDNA is synthesized from total RNA using a (dT)24 oligomer to prime first strand cDNA synthesis, followed by second strand cDNA synthesis with random hexameric primers. Double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides. cRNA is chemically fragmented according to protocols described by Affymetrix (Santa Clara, CA, USA), and then hybridized overnight in Human Genome Arrays.

Alternatively, protein products expressed from mRNAs can be assayed by immunohistochemistry of tumor samples, solid phase immunoassay with microtiter plates, Western blotting, two-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and other methods known in the art for detecting specific proteins. Detection methods would include the use of site-specific antibodies. The experienced person will recognize that all such well known techniques for detecting upregulation of FGFR, VEGFR and/or PDGFR, or detection of Mutants or variants of FGFR, VEGFR and/or PDGFR could be applicable in the present case.

Abnormal levels of proteins such as FGFR or VEGFR can be measured using standard enzyme assays, for example those assays described herein. Activation or overexpression could also be detected in a tissue sample, for example a tumor tissue. By measuring tyrosine kinase activity with an assay such as that of Chemicon International. The tyrosine kinase of interest would be immunoprecipitated from the sample lysate and its activity measured.

Alternative methods for measuring the overexpression or activation of FGFR or VEGFR including their isoforms include measuring microvessel density. This can be measured for example using methods described by Orre and Rogers (Int J Cancer (1999), 84(2) 101-8). Assay methods also include the use of markers, for example in the case of VEGFR these include CD31, CD34 and CD 105 (Mineo et at. (2004) J Clin Pathol. 57(6), 591-7).

Therefore all these techniques could also be used to identify tumors particularly suitable for treatment with the compounds of the invention.

The compounds of the invention are particularly useful in treating a patient having a mutated FGFR. The G697C mutation in FGFR3 is seen in 62% of oral squamous cell carcinomas and causes constitutive activation of kinase activity. Activating FGFR3 mutations have also been identified in cases of bladder carcinoma. These mutations were of 6 types with varying degrees of prevalence: R248C, S249C, G372C, S373C, Y375C, K652Q. In addition, a Gly388Arg polymorphism in FGFR4 has been shown to be associated with increased incidence and aggressiveness of prostate, colon, lung and breast cancer.

Therefore in another aspect the invention includes use of a compound according to the invention for the manufacture of a medicament for the treatment or prophylaxis of an unhealthy condition or an unhealthy condition in a patient who has been screened and has been determined to be suffering of, or being at risk of suffering from, a disease or condition that would be amenable to treatment with a compound having activity against FGFR.

Particular mutations for which a patient is screened include mutations G697C, R248C, S249C, G372C, S373C, Y375C, K652Q in FGFR3 and Gly388Arg polymorphism in FGFR4.

In another aspect the invention includes a compound of the invention for use in the prophylaxis or treatment of cancer in a patient selected from a sub-population having an FGFR gene variant (for example G697C mutation in FGFR3 and Gly388Arg polymorphism in FGFR4).

Determination of vessel normalization by MRI (eg using gradient-echo, spin-echo, and contrast enhancement MRI to measure blood volume, relative vessel size, and vascular permeability) in combination with circulating biomarkers (circulating progenitor cells (CPCs) , CECs, SDF1, and FGF2) can also be used to identify tumors resistant to VEGFR2 for treatment with a compound of the invention.

EXPERIMENTAL

Description of LC-MS method and analytical system In the examples, the prepared compounds were characterized by liquid chromatography and mass spectroscopy using commercially available systems ("Waters Platform LC-MS system", "Waters Fractionlynx LC-MS system"), conditions operating standard and commercially available columns (Phenomenex, Waters etc) but a person skilled in the art will consider that alternative systems and methods could be used. Where atoms with different isotopes are present and a single mass is quoted, the quoted mass for the compound is the monoisotopic mass (ie 35C1; 79Br etc.). LC-MS system with targeted purification for preparative mass LC (or HPLC) - MS is an effective and standard method used for the purification of small organic molecules such as the compounds described herein. Methods for liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of raw materials and improved detection of samples by MS. Optimization of the preparative gradient LC method will involve various columns, volatile eluents and modifiers, and gradients. Methods for optimizing preparative LC-MS methods and also their use to purify compounds are well known in the art. Such methods are described in Rosenterer U, Huber U.; "Optimal fraction collecting in preparative LC/MS"; J Comb Chem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C, "Development of a custom high-throughput preparative liquid chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries" ; J Comb Chem.; 2003; 5(3); 322-9.

Two such systems for purifying compounds via preparative LC-MS are the "Waters Fractionlynx system" or the "Agilent 1100 LC-MS preparative system" although a person skilled in the art will consider that alternative systems and methods could be used. In particular, reversed-phase methods were used for preparative HPLC for the compounds described herein, but methods based on preparative normal-phase LC could be used in place of reversed-phase methods. Preparative LC-MS systems use mostly reversed-phase LC and volatile acid modifiers because the approach is very effective for small molecule purification and because the eluents are compatible with positive ion electron spray mass spectroscopy. According to the analytical trace obtained, the most appropriate type of preparative chromatography is chosen. A typical routine is to run an analytical LC-MS using the type of chromatography (low or high pH) best suited to the structure of the compound. Once having shown the analytical trace good chromatography a suitable preparative method of the same type is chosen. A variety of chromatographic solutions e.g. reversed or normal phase LC; buffered acidic, basic, polar, or lipophilic mobile phase; Basic modifiers could be used to purify the compounds. From the information obtained a person skilled in the art could purify the compounds described herein by preparative LC - MS.

Procedimento Al - formação de anel de imidazopiridina geral

All compounds were customarily dissolved in 100% MeOH or 100% DMSO.

Procedure Al - general imidazopyridine ring formation

To a solution of 4-Chloro-pyridin-2-yl-amine (12.8 g, 100 mmol, 1.0 equiv) in EtOH (170 ml) was added NaHCO3 (16.8 g, 200 10 mmol, 2, 0 equiv) followed by chloro-acetaldehyde (19.0 ml, 150 mmol, 1.5 equiv). The mixture was refluxed for 6 h. Solvents were removed under reduced pressure and the crude mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO4 ), filtered and concentrated under reduced pressure. The product was purified by column chromatography 15 (SiO 2 eluted with 50% EtOAc - petrol) to give 13.2 g of product.

Em uma solução de 7-Cloro-imidazo[l,2-a]piridina (30,9 g, 186 mmol, 1,0 equiv) em DMF (280ml) foi adicionada N-iodo-succinimida (43,6 g, 194 mmol, 1,05 equiv) e a mistura resultante foi agitada durante a noite na RT. A lama marrom fina foi diluída com água (840ml), salmoura (280 ml) e extraída com EtOAc (560 ml). A camada aquosa foi adicionalmente extraída com EtOAc (3 x 280ml). As fases orgânicas combinadas foram lavadas com água (2 x 280ml), tiossulfato de sódio 10% p/v (280 ml), salmoura (280 ml), secas (MgSO4), filtradas em vácuo para dar um resíduo marrom. O resíduo foi triturado com éter (200ml), filtrado e o sólido foi lavado com éter (2 x 50ml) e seco sobre filtro para dar 39 g de produto.Procedimento A3 - Suzuki geral na posição-3Procedimento A3a - Suzuki

Procedure A2 - general lotion

To a solution of 7-Chloro-imidazo[1,2-a]pyridine (30.9 g, 186 mmol, 1.0 equiv) in DMF (280ml) was added N-iodosuccinimide (43.6 g, 194 mmol, 1.05 equiv) and the resulting mixture was stirred overnight at RT. The fine brown slurry was diluted with water (840ml), brine (280ml) and extracted with EtOAc (560ml). The aqueous layer was further extracted with EtOAc (3 x 280ml). The combined organic phases were washed with water (2 x 280ml), 10% w/v sodium thiosulfate (280ml), brine (280ml), dried (MgSO4 ), filtered in vacuo to give a brown residue. The residue was triturated with ether (200ml), filtered and the solid washed with ether (2 x 50ml) and dried on filter to give 39 g of product.Procedure A3 - General Suzuki at position-3Procedure A3a - Suzuki

To a solution of 7-Chloro-3-iodo-imidazo[1,2-a]pyridine (2.8g, 10mmol) in acetonitrile (100ml) was added 3-amino-benzene boronic acid (2.5g, 10, 57mmol), 2M Na2CO3 (21.6ml) [reaction was degassed by bubbling N2 through it] followed by bis(triphenyl-phosphine)-palladium(II) chloride (0.35g, 0.49mmol). The mixture was heated at 70°C overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure and purified by column chromatography on Biotage (SiO 2 , eluted with 80% EtOAC in petrol to 100% EtOAc) to give 1.9g of product. MS: [M+H]+ 244 Procedure A3b - Suzuki

To a solution of 3-Iodo-7-(3-morpholin-4-yl-methyl-phenyl)-imidazo[1,2-a]pyridine (1.55g, 3.72mmol) in DME (20ml) was added acid. 3-amino-benzene-boronic (0.69g, 4.8mmol) and 2M Na2CO3 (6.93ml) [reaction was degassed by bubbling N2 through it] followed by tetrakis(triphenyl-phosphine)-palladium(0) (0.139g , 0.12mmol). The mixture was heated at 75°C overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure and purified by column chromatography on Biotage (SiO2, eluted with EtOAC - 20% MeOH/EtOAC) to give 0.56g of product. MS: [M+H]+ 385

Procedure A4 - Cycle addition at position-7 mediated by general palladium Procedure A4a - Suzuki

Em uma solução do apropriado 7-cloro-imidazo[l,2-a]piridin-5 3-il (0,35mmol) em DME (4ml) é adicionado ácido 4-fluoro-fenil-borônico (0,059g, 4,2mmol) e Na2CO3 2M (l,2ml) [reação foi desgaseificada borbulhando N2 através da mesma] seguido por tetraquis(trifenil-fosfina)- paládio(O) (0,018g, 0,015mmol, 5% em mol). A mistura é aquecida a 80°C durante a noite, então diluída com água e extraída com EtOAc. A camada10 orgânica é lavada com salmoura, seca (MgSO4), filtrada e concentrada sob pressão reduzida e purificada por HPLC preparativa para dar o produto desejado.Procedimento A4c - Suzuki com ácido fluoro-fenil-borônico

To a suspension of the appropriate 7-chloro-imidazo[1,2-a]pyridin-3-yl (0.3mmol) in toluene (0.5ml) are added 4-(4,4,5,5-Tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-pyridine (0.078g, 0.36mmol), K2CO3 (0.25g, 1.8mmol), MeOH (0.5ml), EtOH (0.5ml), H2O ( 0.75ml) [reaction was degassed by bubbling N2 through it] followed by bis(tri-t-butyl-phosphine)-palladium(O) (0.003g,0.0058mmol). The mixture is heated using microwave irradiation in a CEM discover microwave synthesizer (50W) at 140°C until the reaction is complete. The reaction is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure and purified by preparative HPLC to give the desired product.Procedure A4b - Suzuki

To a solution of the appropriate 7-chloro-imidazo[1,2-a]pyridin-5 3-yl (0.35mmol) in DME (4ml) is added 4-fluoro-phenyl-boronic acid (0.059g, 4.2mmol) ) and 2M Na2CO3 (1.2ml) [reaction was degassed by bubbling N2 through it] followed by tetrakis(triphenyl-phosphine)-palladium(O) (0.018g, 0.015mmol, 5% by mol). The mixture is heated at 80°C overnight, then diluted with water and extracted with EtOAc. Organic layer 10 is washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure and purified by preparative HPLC to give the desired product. Procedure A4c - Suzuki with fluoro-phenyl-boronic acid

In a solution of [3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-15-phenyl[1,3,4]thiadiazol-2-yl-amine (prepared according to Rota A , 226mg, 0.69mmol) in DME (8ml) was added 4-fluoro-phenyl-boronic acid (125mg, 0.90mmol) and 2M Na2CO3 (3ml). The reaction was deoxygenated and tetrakis(triphenyl-phosphine)-palladium(0) (42mg) added. The mixture was again deoxygenated and then heated to 80°C overnight. The reaction mixture was cooled, diluted with water and extracted with EtOAc (x2). The organic layers were combined, dried (MgSO4 ), filtered and the solvent removed in vacuo. The residue was purified by preparative HPLC to give the desired product (78mg) MS: [M+H]+ 388.

A4d Procedure - Suzuki Copulation

Procedimento BI - Adição de ciclo na posição-7 mediada por paládio geralProcedimento Bl a - Suzuki para ciclos arila

Método como descrito em Procedimento 4a ou 4 de Rota GeralAbProcedimento Blb - Buchwald para ciclos saturados

A solution of the appropriate 7-chloro-imidazo[1,2-a]pyridin-3-yl (1 equivalent), 1-methyl-pyrazol-4-boronic acid pinacol ester (commercially available, 2 equivalents), pine carbonate potassium (6 equivalents), and bis(tri-t-butyl-phosphine)-palladium(0) (0.05 equivalent) in 10 ethanol (10ml), toluene (10ml) and water (10ml) is heated to 75°C for 3 h. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is dried (MgSO4 ), filtered and the solvent evaporated in vacuo. The residue is purified by column chromatography to give the desired product. General Route B

Procedure BI - Cycle addition at position-7 mediated by general palladiumProcedure Bl a - Suzuki for aryl cycles

Method as described in General Route Procedure 4a or 4Ab Procedure Blb - Buchwald for saturated cycles

Into a solution of the appropriate 7-chloro-imidazo[1,2-a]pyridin-3-yl (0.32mmol) in anhydrous dioxane (4ml) is added the appropriate amine (0.35mmol), NaOlBu (0.096g, 0.96mmol) [reaction was degassed by bubbling N2 through it] followed by BINAP (0.021g, 0.033mmol) and Pd2dba3 (tris-(dibenzylidene-acetone)-dipalladium(O)) (0.016g, 0.017mmol). The mixture is heated at 80°C overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO 4 ), filtered, concentrated under reduced pressure and purified by preparative HPLC or silica chromatography to give the desired product.

Blc procedure - Suzuki copulation for heterocycles.

Método como descrito em Procedimento A4a de Rota Geral Ausando ácido 3-formil-fenil-borônico.

A solution of 7-Bromo-imidazol[1,2-a]pyridine (0.5g, 2.54mmol, 1 equivalent, prepared according to general procedure Al using 4-bromo-pyridin-2-yl-amine in place of 4-chloro-pyridin-2-yl-amine), 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1 H-pyrazole (1 .1 g, 5.08mmol, 2 equivalents), bis(tri-t-butyl-phosphine)-palladium(0) (66mg, 0.13mmol, 0.05 equivalent) and potassium carbonate (2.1g, 15, 24mmol, 6 equivalents) in ethanol (10ml), toluene (10ml) and water (10ml) was heated at 75°C for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was then washed with a saturated brine solution, dried (MgSO4 ), filtered and the solvent removed by evaporation in vacuo. The residue was purified by column chromatography (Biotage SP4, 25S, flow rate 25ml/min, gradient 0% to 20% methanol in ethyl acetate) to give 7-(2-methyl-2H-pyrazol-3-yl )-imidazo[1,2,a]pyridine as a colorless oil (350mg, 70%). MS: [M+H]+199. Bid Procedure - Synthesis of 7-r3-(4-Methyl-piperazin-1-yl-methyl)-phenyl]-imidazoT 1,2-a]pyridine

Method as described in General Route Procedure A4a Using 3-formyl-phenyl-boronic acid.

Método como descrito em Procedimento A2 de Rota Geral AProcedimento B3a - Suzuki geral na posição-3

Método como descrito em Procedimento A3 a ou A3b de Rota5 Geral AProcedimento B3b - Suzuki geral na posição-3

Método como descrito em Rota Geral B procedimento 1 cModificações gerais D na posição-7Funcionalidade latente na posição-7 da imidazo[l,2-a]piridina10 pode ser utilizada com o propósito de sintetizar motivos alternativos

Procedimento D3 - Desproteção de Boc

No composto Boc-protegido (0,39mmol) em CH2Cl2(10ml) é adicionado HC1 4M em dioxano (0,5ml, 5equiv). A mistura reacional é permitida agitar na temperatura ambiente por 18h antes de o solvente ser removido em vácuo. O resíduo é purificado por HPLC preparativa para dar o amino-derivado desejado.To a solution of 3-Imidazo[1,2-a]pyridin-7-yl-benzaldehyde (1.889 g, 8.5 mmol, 1.0 equiv) in toluene (30 ml) and methanol (10 ml) was added N -methyl-piperazine (1.1 ml, 10.2 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 3 h and the solvents were removed under reduced pressure. The resulting crude imine was dissolved in ethanol and methanol (1:1, 30 ml) and sodium borohydride (483 mg, 12.75 mmol, 1.5 equiv) was added in portions. The reaction mixture was stirred overnight and solvents were removed in vacuo. The reaction was stopped very slowly by the addition of 2N aqueous NaOH (20 ml). Ethyl acetate was added and the layers were separated. The organic layer was washed with brine, dried (MgSO4 ), filtered and concentrated under reduced pressure. The compound was purified by column chromatography (eluted with 5% methanol:dichloromethane) to give the desired compound. Procedure B2 - flooding

Method as described in General Route Procedure A2 AProcedure B3a - General Suzuki in 3-position

Method as described in Procedure A3a or A3b of Rota5 General AProcedure B3b - Suzuki General in 3-position

Method as described in General Route B procedure 1 cGeneral modifications D at position-7 Latent functionality at position-7 of imidazo[1,2-a]pyridine10 can be used for the purpose of synthesizing alternative motifs

Procedure D3 - Boc Deprotection

In the Boc-protected compound (0.39mmol) in CH2Cl2(10ml) 4M HCl in dioxane (0.5ml, 5equiv) is added. The reaction mixture is allowed to stir at room temperature for 18h before the solvent is removed in vacuo. The residue is purified by preparative HPLC to give the desired amino derivative.

In an alternative procedure the tert-butyl carboxylic acid ester (0.027mmol) can be treated with EtOAc/saturated HCl, stirred at room temperature for 3 hours, concentrated under reduced pressure then dried to give the desired compound.Procedure D3b - Deprotection of Boc

In a solution of (3-{3-[3-([1,3,4]Thadiazol-2-yl-amino)-phenyl]-imidazo[1,2-a]pyridin- acid tert-butyl ester 7-yl}-phenyl)-carbamic (190mg, 0.39mmol) in CH 2 Cl 2 (10ml) was added 4M HCl in dioxane (0.5ml, 2mmol). The reaction mixture was allowed to stir at room temperature for 18h before the solvent was removed in vacuo. The 15 residue was purified by preparative HPLC to give the desired compound (120mg) MS: [M+H]+385. Procedure E

Procedimento F4 - arilação{3-[7-(4-Fluoro-fenil)-imidazo[l,2-a]piridin-3-il]-fenil}- piridin-4-il-amina

In a solution of 7-Chloro-imidazo[1,2-a]pyridine (1.0g, 6.58mmol) in anhydrous dioxane (60ml) was added morpholine (0.64ml, 6.58mmol), NaOlBu (1.9g , 19.74mmol) [reaction was degassed by bubbling N2 through it] followed by BINAP (0.43g, 0.69mmol) and Pd2dba3 (tris-(dibenzylidene-acetone)-dipalladium(O)) (0.32g, 0 .36mmol). The mixture was heated at 80°C overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4 ), filtered and concentrated under reduced pressure. The crude residue was purified by silica chromatography to give the desired product (0.55g) MS: [M+H]+204. General F-Modifications at 3-position Latent 3-position functionality of imidazo[1,2-a]pyridine can be used for the purpose of synthesizing alternative motifs

Procedure F4 - arylation{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-pyridin-4-yl-amine

A mixture of 3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl-amine (200mg, 0.65mmol), 4-bromo-pyridine.HCl (130mg, 0.67mmol), (±)-Binap (63mg, 0.1mmol) and NaOlBu (250mg, 2.6mmol) in dry dioxane (3ml) was deoxygenated by evacuation/refilling with N2 (x3). Pd2(dba)3 (30mg, 0.03mmol) was added and the mixture was deoxygenated again (x3). The reaction was stirred and heated at 100°C for 18 hours under N2. The mixture was partitioned between CH2Cl2 and H2O, then filtered. The layers were separated and the solid was combined with organic layers which were then evaporated. The residue was purified by chromatography on silica followed by preparative HPLC to give the title compound (40mg, 5 solid). 1 H NMR (400 MHz, Me-d 3 -OD): 8.63 (1H, d), 8.44 (1H, s), 8.22 (2H, d), 7.87-7.79 (4H , m), 7.70 (1H, t), 7.63-7:59 (2H, m), 7.48-7.43 (1H, m), 7.37 (1H, dd), 7. 31-7.24 (2H, m), 7.17 (2H, d). Procedure F5 - Synthesis of triazol-3-thiones and amino-thiadiazoles

In a suspension of 3-[7-(3-Morpholin-4-yl-methyl-phenyl)-10 imidazo[1,2-a]pyridin-3-yl]-phenyl-amine (0.25g, 0.65 mmol) in anhydrous toluene (20ml) was added 1,1'-thio-carbonyl-di-2(1H)-pyridone (0.5lg, 0.65mmol) stirred and heated to 110°C for 1h. The reaction was cooled to room temperature, diluted with CH2C12, washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give a brown oil. Residue was taken up in THF (4ml), cooled in an ice bath and treated with hydrazine hydrate (0.05ml, 9.7mmol). Upon completion of addition, the reaction was stirred at this temperature for 15 min and concentrated under reduced pressure. This material was used without further purification in the step below.

To a solution of thiosemicarbazide (0.305g, 0.66mmol) in anhydrous DMF (5ml) was added diethyl chlorophosphate (0.23ml, 1.58mmol) in drops such that the internal temperature remained <25° Ç. After 30 min more diethyl chlorophosphate was added. The reaction mixture was poured into H2O and extracted with EtOAc. The aqueous fraction was concentrated under reduced pressure, the residue was triturated with hot ethanol, solid was filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to give 0.08g of product. MS: [M+H]' 469 Procedure F8 - Alkylation

Procedimento G1 - [3-(7-Cloro-imidazo[l,2-a]Piridin-3-il)-fenil]-(3H- r 1,2,3]triazol-4-il)-amina

To a solution of 3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl-amine (0.20g, 0.82mmol) in dry DMF (5ml) at 0°C was added sodium hydride as a 60% dispersion (0.04g, 0.99mmol) and the reaction mixture stirred for 5 min. Benzyl bromide (0.10ml, 0.82mmol) was added, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18h. The reaction was quenched using NH4Cl(aq) (10ml) and then partitioned between EtOAc and H2O. The aqueous layer was further extracted with EtOAc, the organic fractions were combined, dried (MgSO4 ), filtered and the solvent removed in vacuo. The crude residue was purified using an SCX cartridge followed by reversed phase HPLC to give the product. MS: [M+HJ* 333. General Procedure G Examples of 1,2,3-triazole

Procedure G1 - [3-(7-Chloro-imidazo[1,2-a]Pyridin-3-yl)-phenyl]-(3H-r1,2,3]triazol-4-yl)-amine

A solution of sodium nitrite (285mg, 4.1mmol) in H2O (2ml) was added to a stirred suspension of 3-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl- amine (1g, 4.1mmol) in 2N HCl (8ml) such that the internal temperature was <5°C. Upon completion of addition the reaction was stirred for 15 minutes at this temperature before addition of amino-acetonitrile hydrogen sulfate (635mg, 4.1mmol) in H2O (2ml) [internal temperature kept <5°C]. After 1 hour NaOAc (14g) was added. The mixture was stirred for 1 hour with cooling in an ice bath, then the solid was collected by filtration. This material was taken up in EtOH directly (~20 ml). This solution was stirred and heated at 90°C for 18 hours under N 2 . After cooling to RT volatiles were removed in vacuo and the residue was purified by silica chromatography (100% CH2C12—+ 5% 2M NH3-MeOH / CH2Cl2) to give the title compound (318mg, solid). *H NMR (400 MHz, DMSO-d6): 8.94 (1H, s), 8.58 (1H, d), 7.84 (1H, d), 7.77 (1H, s), 7. 58 (1H, s), 7.48 (1H, s), 7.40 (1H, t), 7.33 (1H, d), 7.07-7.02 (2H, m). Procedure G2: 3-{7-[4-(4-Methyl-piperazin-1-yl-methyl)-phenyl]-imidazo[1,2-a]pyridin-3-yl)-phenyl)-(3H) formate -[1,2,3]triazol-4-yl)-amine

A mixture of [3-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-(3H-[1,2,3]triazol-4-yl)-amine (60mg, 0.19 mmol) and 4-(4-methyl-piperazin-1-yl-methyl)-phenyl-boronic acid pinacol-ester (80mg, 0.25 mmol) and 2'-(dimethyl-amino chloride complex) )-2-biphenyl-palladium(II) / dinorbomyl-phosphine (10mg, 0.02mmol) in DME (1ml) and 2N Na2CO3 (aq., Iml) in a microwave flask was deoxygenated by bubbling N2 through it. for 30 seconds. The vial was sealed and then shaken and heated to 150°C in a microwave oven for 25 minutes. After cooling to RT the mixture was partitioned between CH2C12 and H2O and filtered. The layers were separated using a phase separation cartridge. The organic layer was evaporated and combined with the above solid. This material was purified by preparative HPLC to give the title compound (30mg, solid). 1 H NMR (400 MHz, DMSO-d6): 8.95 (1H, s), 8.64 (1H, d), 8.27 (2H, s), 7.98 (1H, s), 7. 86-7.75 (3H, m), 7.63 (1H, brs), 7.48 (1H, s), 7.46-7.28 (6H, m), 7.09 (1H, d) , 3.52 (2H, s), 2.48-2.20 (8H, brm), 2.17 (4H, brs).Synthesis of Boronic Acids and Esters Boronic Acid 14Pinachol-Acid 3-ri,3 ester 4]thiadiazol-2-yl-amino)-phenyl-boronicStep 1: 3-Bromo-phenyl-thio-semicarbazide

Cloro-fosfato de dietila (16,3ml, 117 mmol) foi adicionadolentamente em uma solução agitada de 3-bromo-fenil-tio-semicarbazida (from acima, 12,5g) em DMF seca (120ml) de tal modo que a temperatura interna fosse <25°C. Após 1 hora a mistura reacional foi derramada em H2O e agitada nesta temperatura por 20 minutos. O sólido foi coletado por filtração então seco sob vácuo a 50°C para dar o composto do título (7,4g, sólido). *H RMN(400 MHz, DMSO-d6): 10,59 (1H, s), 8,96 (1H, s), 8,08 (1H, t), 7,49 (1H,dd), 7,30 (1H, t), 7,18 (1H, ddd).Etapa 3: Pinacol-éster de ácido 3-(ri,3,4]tiadiazol-2-il-amino)-fenil-borônico

A solution of 3-bromo-phenyl-thio-isocyanate (10g, 47mmol) in THF (20ml) was added to a stirred solution of hydrazine hydrate (4.54ml, 94mmol) in THF (80ml) such that the internal temperature was <5°C. Upon completion of addition, the reaction was stirred at this temperature for 1hr. Volatiles were removed in vacuo and the residue was triturated with petrol. The solid was collected by filtration and then dried to give 3-bromo-phenyl-thiosemicarbazide (12.5g, solid). This material was used without further purification. Step 2: (3-Bromo-phenyl)-ri,3,4]thiadiazol-2-yl-amine

Diethyl chloro-phosphate (16.3ml, 117mmol) was added slowly to a stirred solution of 3-bromo-phenyl-thio-semicarbazide (from above, 12.5g) in dry DMF (120ml) such that the internal temperature was reached. was <25°C. After 1 hour the reaction mixture was poured into H2O and stirred at this temperature for 20 minutes. The solid was collected by filtration then dried under vacuum at 50°C to give the title compound (7.4g, solid). *H NMR (400 MHz, DMSO-d6): 10.59 (1H, s), 8.96 (1H, s), 8.08 (1H, t), 7.49 (1H,dd), 7. 30 (1H,t), 7.18 (1H,ddd).Step 3: Pinachol-ester of 3-(ri,3,4]thiadiazol-2-yl-amino)-phenyl-boronic acid

A mixture of (3-bromo-phenyl)-[1,3,4]thiadiazol-2-yl-amine(7.3g, 29mmol), bis(pinacolato)diboron (14.5g, 57mmol) and KOAc ( 8.5g, 87mmol) in dry DMSO (50ml) was deoxygenated by evacuation/refilling with N2 (x3). PdCl2ddpf (1.05g, 1.4 mmol) was added and the mixture was deoxygenated again (x3) then stirred and heated at 100°C under N2 for 16 hours. An additional amount of PdCl2dppf (1.05g) was added, the reaction was deoxygenated (x3) and the reaction was heated at 100°C for a further 20 hours. After cooling to RT the mixture was partitioned between EtOAc and H2O then filtered through Celite®. The layers were separated and the aqueous layer was extracted with EtOAc (x1). The combined organic extracts were washed with water (xl), brine (xl) then dried (Na2SO4), filtered and evaporated. The residue was purified by silica chromatography (20%-60% EtOAc/petrol) to give the title compound (4.1g, solid - after trituration with petrol), 1 NMR (400 MHz, DMSO-d6): 10 .37 (1H, brs), 8.91 (1H, s), 8.03 (1H, d), 7.73 (1H, ddd), 7.42-7.27 (2H, m), 1. 31 (12H, s).

Boronic Acid 15

3-Bromo-fenil-tio-semicarbazida (l,0g, 4,0 mmol) foiadicionada em uma mistura agitada de H2SO4 c. (Iml) e AcOH (280μl, 4,9 mmol) na RT (exoterma observada). A suspensão foi agitada e aquecida a 80°C por 2 horas. Após esfriamento para RT, a mistura foi esfriada em banho de gelo e cuidadosamente neutralizada com NH3 aquosa concentrada. O pH foi ajustado para ~ pH10 e o sólido foi coletado por filtração então seco para dar o composto do título (732mg, sólido). !H RMN (400 MHz, DMSO-d6): 8,01 (1H, t), 7,45 (1H, dd), 7,28 (1H, t), 7,16 (1H, d), 2,57 (3H, s).Pinacol-ester of 3-(5-methyl-r,3,4]thiadiazol-2-yl-amino)-phenyl-boronic acid Step 1: (3-Bromo-phenyl)-(5-methyl-r 1,3 ,4]thiadiazol-2-yl)-amine

3-Bromo-phenyl-thiosemicarbazide (1.0g, 4.0mmol) was added to a stirred mixture of H 2 SO 4 c. (Iml) and AcOH (280μl, 4.9 mmol) at RT (exotherm observed). The suspension was stirred and heated to 80°C for 2 hours. After cooling to RT, the mixture was cooled in an ice bath and carefully neutralized with concentrated aqueous NH3. The pH was adjusted to ~ pH10 and the solid was collected by filtration then dried to give the title compound (732mg, solid). 1 H NMR (400 MHz, DMSO-d6): 8.01 (1H, t), 7.45 (1H, dd), 7.28 (1H, t), 7.16 (1H, d), 2, 57 (3H, s).

Step 2: Pinacol-ester of 3-(5-methyl-ri,3,4]thiadiazol-2-yl-amino)-phenyl-boronic acid

A mixture of (3-bromo-phenyl)-(5-methyl-[1,3,4]thiadiazol-2-yl)-amine (680mg, 2.5mmol), bis(pinacolato)diboron (1.27g, 5.0mmol) and KOAc (740mg, 7.5mmol) in dry DMSO (5ml) was deoxygenated by evacuation/5 refilling with N2 (x3). PdCl2ddpf (91 mg, 0.12 mmol) was added and the mixture was deoxygenated again (x3) then stirred and heated at 100°C under N2 for 3 hours. After cooling to RT the mixture was partitioned between EtOAc and H2O then filtered through Celite®. The layers were separated and the aqueous layer was extracted with EtOAc (x1). The combined organic extracts were washed with brine (xl) then dried (Na2SO4), filtered and evaporated. The residue was purified by silica chromatography (30->80% EtOAc/petrol) to give the title compound (211mg, oil). MS: [M+H]+318 Boronic Acid 116(1-Methyl-1H-imidazol-2-yl)-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2- yl)-phenyl-amine

A solution of 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-amine (0.5g, 2.28mmol) in 2-Bromo-1-methyl -IH-imidazole (0.367g, 2.28mmol) was heated in a CEM discover microwave synthesizer (50W) at 125°C until the reaction was complete. The reaction mixture was cooled and used directly in the following procedure. MS: [M+H]+ 300. Boronic Analog 117 (trifluoro-borates)[3-(ri,3,41Thadiazol-2-yl-aminoyphenyl]-potassium trifluoroborate

A solution of KHF2 in H2O (4.5M, 36ml) was added to a stirred solution of [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] -[1,3,4]thiadiazol-2-yl-amine and phenyl-[1,3,4]thiadiazol-2-yl-amine (~1:1, 10 g) in MeOH (90 ml) at RT. After 15 minutes the reaction mixture was evaporated to dryness. The residue was suspended in acetone (150 ml). This mixture was stirred and heated under reflux for 1 hour, then filtered while still hot. The filtrate was evaporated and the residue was suspended in EtOAc (50 ml). The solid was collected by filtration and dried to give the title compound (3.0 g) as a cream solid. NMR (400 MHz, DMSO-d6): 10.00 (1H, 15 s), 8.78 (1H, s), 7.43 (1H, d), 7.35 (1H, s), 7.07 (1H,t), 7.00 (1H,d).Boronic Acid 118N-Methyl-2-[3-(4,4,5,5-tetramethyl-11,3,2]dioxaborolan-2-yl)- phenylacetamide

In a solution of [3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid (0.60g, 2.28mmol) in DMF (15ml ) a solution of 1-hydroxy-benzotriazole (0.37g, 2.73mmol) and TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate was added 5 (0.88g, 2.73mmol) in DMF (15ml). Trimethyl-amine (0.95 ml) and methyl-amine (1.2 ml) were added and the reaction mixture was allowed to stir for 18h at room temperature. The reaction mixture was concentrated in vacuo and purified using reverse phase chromatography to give an ester/boronic acid mixture, which was used crude. MS: [MH+] 276 (ester), [MH+] 194 10 (acid).Boronic Acid 119(3-Methyl-piperazinone)-phenyl-boronic acid

To a solution of piperazine-2-one (0.2g, 2mmol) in dry THF/DMSO (10ml:2.5ml) were added (3-bromo-methyl-15 phenyl)-boronic acid, neopentyl-glycol-ester ( 0.45g, 1.6mmol), NaHCO3 (0.34g, 4mmol) and NaI (0.01g, 0.74mmol). The reaction mixture was heated under reflux for 12h, cooled and passed through a C18 reverse phase chromatography column to give a colorless gum, which was used crude MS:[MH+] 235Boronic Acid 121Acid 2-(tetrahydro-pyran- 4-yl-oxy)-4-pyridinyl-boronic

Em 4-Bromo-2-(tetra-hidro-piran-4-il-óxi)-piridina (0,2g,0,77mmol) em DMSO (5ml) (desgaseificado por borbulhamento de N2 através do mesmo) foram adicionados 4,4,5,5,4',4',5',5'-Octametil-2,2'-bi- 1,3,2-dioxaborolano (0,39g, l,55mmol) e acetato de potássio (0,27g, 2,31 mmol). PdCl2ddpf (0,028, 0,04mmol) foi adicionado, a mistura reacional foi de novo desgaseificada e então aquecida a 100°C por 5 h. O composto foi passado através de uma coluna de cromatografia em fase reversa Cl 8 para dar o produto desejado, usado bruto. MS: [MH]+224. Ácido Borônico 123Ácido 3-(ri,3,4]tiadiazol-2-il-amino)-benzeno-borônico

LiOH (340mg, 14 mmol) foi adicionado em uma soluçãoagitada de [3-([l,3,4]Tiadiazol-2-il-amino)-fenil]trifluoro-borato de potássio (1,15g, 4 mmol) em CH3CN (20ml) e H2O (10ml) na RT. A reação foi agitada na RT por 20 horas. A mistura foi tratada com NH4C1 aquoso saturado (32ml) e HC1 2 N (5ml) para dar ~pH5. EtOAc foi adicionado e o precipitado foi coletado por filtração. A camada aquosa foi extraída com CH2C12 (x2). Os extratos combinados foram evaporados e o resíduo foi combinado com o sólido acima. Este material foi suspenso em EtOAc. O sólido foi coletado por filtração e então seco para dar o composto do título (l,lg) sólido bege. !H RMN (400 MHz, DMSO-dg) => mistura, possivelmente o ácido borônico e espécies cíclicas. Este material foi usado sem purificação adicional.Ácido Borônico 124Pinacol-éster de ácido 3-([l,2,4]tiadiazol-5-il-amino)-fenil-borônicoEtapa 1: l-(3-Bromo-fenil)-3-|T-dimetil-amino-met-(E)-ilideno1-tío-uréia

(3-Bromo-fenil)-tio-uréia (2,1 g, 9,1 mmol) foi suspensa emN,N-dimetil-formamida-dimetil-acetal e foi aquecida a 100°C por 2 d. A mistura esfriada foi diluída com éter e filtrada e o sólido foi lavado com éter para dar o composto do título (2,42 g).Etapa 2: (3-Bromo-fenil)-ri,2,4]-tiadiazol-5-il-amina

To a suspension of NaH (0.4 g, 10 mmol) in THF (20 ml) at 0°C was added 4-hydroxy-tetrahydro-pyran (1.02 ml, 10 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 min before 4-bromo-2-chloro-pyridine (0.89 ml, 8.0 mmol) was added dropwise. The reaction mixture was stirred for 18 h before being quenched with EtOH (1 ml), partitioned between CH2C12 and H2O and extracted with CH2C12 (x2). The organic extracts were combined, dried (MgSO4 ), filtered and the solvent removed in vacuo. Purified by column chromatography to give 4-Bromo-2-(tetrahydro-pyran-4-yl-oxy)-pyridine MS: [MH]+258, 260

In 4-Bromo-2-(tetrahydro-pyran-4-yl-oxy)-pyridine (0.2g, 0.77mmol) in DMSO (5ml) (degassed by bubbling N2 through it) were added 4, 4,5,5,4',4',5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane (0.39g, 1.55mmol) and potassium acetate (0, 27g, 2.31mmol). PdCl2ddpf (0.028, 0.04mmol) was added, the reaction mixture was again degassed and then heated to 100°C for 5 h. The compound was passed through a C18 reverse phase chromatography column to give the desired product, used crude. MS: [MH]+224. Boronic Acid 123 3-(ri,3,4]thiadiazol-2-yl-amino)-benzene-boronic acid

LiOH (340mg, 14mmol) was added to a stirred solution of potassium [3-([1,3,4]thiadiazol-2-yl-amino)-phenyl]trifluoro-borate (1.15g, 4mmol) in CH3CN (20ml) and H2O (10ml) at RT. The reaction was stirred at RT for 20 hours. The mixture was treated with saturated aqueous NH4Cl (32ml) and 2N HCl (5ml) to give ~pH5. EtOAc was added and the precipitate was collected by filtration. The aqueous layer was extracted with CH2Cl2 (x2). The combined extracts were evaporated and the residue was combined with the above solid. This material was suspended in EtOAc. The solid was collected by filtration and then dried to give the title compound (1.1g) beige solid. !H NMR (400 MHz, DMSO-dg) => mixture, possibly boronic acid and cyclic species. This material was used without further purification.Boronic Acid 124Pinacol-3-([1,2,4]thiadiazol-5-yl-amino)-phenyl-boronic acid ester Step 1: 1-(3-Bromo-phenyl)-3 -|T-dimethyl-amino-met-(E)-ylidene1-thio-urea

(3-Bromo-phenyl)-thio-urea (2.1 g, 9.1 mmol) was suspended in N,N-dimethyl-formamide-dimethyl-acetal and heated to 100°C for 2 d. The cooled mixture was diluted with ether and filtered and the solid was washed with ether to give the title compound (2.42 g). Step 2: (3-Bromo-phenyl)-ri,2,4]-thiadiazol-5 -yl-amine

(3-Bromo-fenil)-[l,2,4]-tiadiazol-5-il-amina foi convertida no 15 produto do título usando o método descrito em Etapa 3 da síntese de boronato 14. O produto foi usado sem purificação.Procedimento J - Formação de sal de HC1

In a suspension of 1-(3-Bromo-phenyl)-3-[1-dimethyl-amino-met-(E)-ylidene]-thio-urea (570 mg, 2.0 mmol) dry dichloromethane (4 ml) was added mesityl-sulfonyl-hydroxyl-amine (475 mg, 2.2 mmol) dry dichloromethane (4 ml). The reaction was stirred at room temperature for 2 h under a nitrogen atmosphere, before being diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate. The organic fraction was dried by passing through a phase separation cartridge and concentrated in vacuo. The residue was purified by column chromatography (10 —> 40% EtOAc/petrol) to give the bromide (135 mg) as a colorless solid. MS: [M+H]+ = 256, Step 3: Pinacol-3-(ri,2,4]thiadiazol-5-yl-amino)-phenyl-boronic acid ester

(3-Bromo-phenyl)-[1,2,4]-thiadiazol-5-yl-amine was converted to the title product using the method described in Step 3 of the boronate synthesis 14. The product was used without purification. Procedure J - HCl salt formation

Procedimento K - Formação de anel geral

To a suspension of the imidazo[1,2-a]pyridin-3-yl-derivative compound (58μmol) in dioxane (1ml) was added 4M HCl in dioxane and stirred until all in solution. The solvent was removed in vacuo to give the hydrochloride salt. Alternatively a suspension of the appropriate compound in EtOH could be treated with EtOAc/saturated HCl stirred until all in solution, concentrated under reduced pressure, and the residue was triturated with dry ether to give the salt of desired HCl as product.General Scheme for synthesizing pyrazolori,5-a1pyrimidines

Procedure K - General Ring Formation

Mesmas condições que as da Preparação K (acima) massubstituição de 2-bromo-maIonaldeído por 2-(4-fluoro-feniI)-malonaldeído.Preparação (ou Procedimento) L - Reação de Suzuki

To a solution of 2-Bromo-malonaldehyde (12.8 g, 80 mmol) in EtOH (150 ml) was added 3-amino-pyrazole (6 g, 37 mmol) followed by glacial acetic acid (10 ml). The mixture was refluxed for 4 h then allowed to cool, solid was filtered off and the filtrate was evaporated under reduced pressure. The residue was partitioned between IM NaOH (50ml) and EtOAc (200ml) [some insoluble material was filtered off]. The organic layer was washed with brine, dried (MgSO4 ), filtered and concentrated under reduced pressure. The solid was crystallized from MeOH, filtered hot and washed with more MeOH and dried to give 4.5g of product. MS: [M+H]+ 198 Preparation (or Procedure) Kl

Same conditions as Preparation K (above) but replacement of 2-bromo-malonaldehyde with 2-(4-fluoro-phenyl)-malonaldehyde. Preparation (or Procedure) L - Suzuki Reaction

Método como descrito em Procedimento 2 (A2) de Rota GeralAPreparação (ou Procedimento) N - Suzuki na posição-3

Método como descrito em Procedimento 3 b de Rota Geral A (A3b)15 Procedimento Geral Q: Modelo benzimidazolProcedimento OI: N-(4-Bromo-2-nitro-fenil)-benzeno-l,3-diamina

In a solution of 6-Bromo-pyrazolo[1,5-a]pyrimidine (0.5g, 2.5mmol) in DME (10ml) were added 4-fluoro-phenyl-boronic acid (0.46g, 3.25mmol) and 2M Na2CO3 (10ml) [reaction was degassed by bubbling N2 through it] followed by tetrakis(triphenyl-phosphine)-palladium(O) (0.130g, 0.11mmol). The mixture was heated at 70°C overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4 ), filtered and concentrated under reduced pressure. Residue was triturated with EtOAc, filtered, and the solid was washed with more EtOAc then dried to give (0.16g) of the product. The filtrate was concentrated under reduced pressure. The product was purified by column chromatography on Biotage (SiO 2 , eluted with 5% EtOAc - petrol - 50% EtOAc - petrol) to give an additional 0.223g of product. MS: [M+H] ' 214

Method as described in General Route Procedure 2 (A2) Preparation (or Procedure) N - Suzuki in 3-position

Method as described in General Route A Procedure 3b (A3b)15 General Procedure Q: Benzimidazole Model Procedure OI: N-(4-Bromo-2-nitro-phenyl)-benzene-1,3-diamine

A mixture of 4-bromo-1-fluoro-2-nitro-benzene (1.14ml, 9.25mmol), benzene-1,3-diamine (1.96g, 18.1mmol) and DIPEA (1.93ml, 11.1 mmol) in dry NMP (5ml) was deoxygenated by evacuation/filling with N2 (X3), then stirred and heated to 120°C under N2 for 18 hours. After cooling to RT the mixture was partitioned between EtOAc and 0.5N HCl. The organic layer was washed with H 2 O (xl), brine (xl) then dried (MgSO 4 ), filtered and evaporated. The residue was purified by silica chromatography (10->40% EtOAc/petrol) to give the title compound (1.8g) as a red solid. 1 H NMR (400 MHz, DMSO-d6): 9.28 (1H, s), 8.20 (1H, d), 7.63 (1H, dd), 7.14 (1H, d), 7. 07 (1H, t), 6.49 (1H, s), 6.48-6.39 (2H, m), 5.24 (2H, s). Procedure Q2: N-(4'-Fluoro-3 -nitro-biphenyl-4-yl)-benzene-1,3-diamine

N-(4'-Fluoro-3-nitro-bifenil-4-il)-benzeno-l,3-diamina(Procedimento 02, l,66g, 5,1 mmol) foi hidrogenada na pressão atmosférica sobre Pd 10% / C (300mg) em EtOH/AcOH (3:1, 40ml) até cessar o consumo de hidrogênio. O catalisador foi removido por filtração - lavagem com EtOH.10 Os voláteis foram removidos em vácuo e o resíduo foi azeotropado comPhMe para dar o composto do título. Este material foi usado imediatamente na etapa seguinte.Procedimento 04: 3-r5-(4-Fluoro-fenil)-benzoimidazol-l-il1-fenil-amina

In a mixture of PdCl2dppf (210mg, 0.29mmol), N-(4-bromo-2-nitro-phenyl)-benzene-1,3-diamine (Procedure Ol, 1.8g, 5.8mmol) and acid 4 -fluoro-phenyl-boronic (975mg, 7.0mmol) in DME (10ml) was added 2N Na2CO3 (10ml). The reaction was deoxygenated by evacuation/filling with N2 (x3), then stirred and heated to 90°C under N2 for 18 hours. After cooling to RT the mixture was partitioned between EtOAc and EI2O and then filtered through Celite. The organic layer was washed with H 2 O (xl), brine (xl) then dried (MgSO 4 ), filtered and evaporated. The residue was purified by silica chromatography (10->50% EtOAc/petrol) to give the title compound (1.66g) as a brown/dark red solid. 1 H NMR (400 MHz, DMSO-d6): 9.30 (1H, s), 8.32 (1H, d), 7.85 (1H, dd), 7.72 (2H, dd), 7. 35-7.24 (3H, m), 7.08 (1H, t), 6.54 (1H, s), 6.47 (2H, t), 5.25 (2H, s). Procedure 03: N*4*-(3-Amino-phenyl)-4'-fluoro-biphenyl-3,4-diamine

N-(4'-Fluoro-3-nitro-biphenyl-4-yl)-benzene-1,3-diamine (Procedure 02, 1.66g, 5.1 mmol) was hydrogenated at atmospheric pressure over 10% Pd/C (300mg) in EtOH/AcOH (3:1, 40ml) until hydrogen consumption ceases. Catalyst was removed by filtration - washing with EtOH. The volatiles were removed in vacuo and the residue azeotroped with PhMe to give the title compound. This material was used immediately in the next step. Procedure 04: 3-r5-(4-Fluoro-phenyl)-benzoimidazol-1-yl1-phenyl-amine

A solution of N*4*-(3-Amino-phenyl)-4'-fluoro-biphenyl-3,4-15 diamine (Procedure 03, ~5.1mmol) in trimethyl orthoformate (30ml) was stirred and heated to 120°C under N2 for 10 hours. Volatiles were removed in vacuo and the residue was taken up in EtOH (30ml) and treated with HCl c. (2ml), then stirred and heated under reflux for 3 hours. After cooling to RT, the mixture was concentrated to ~2ml, then diluted with H2O. NaHCO3 (sat) was added to give ~pH7.5. The solid was taken up in CH 2 Cl 2 . The organic layer was dried and evaporated. The residue was purified by chromatography on silica (0%—>1%—>2% 2M NH3-MeOH/CH2Cl2). The O5 material was then triturated with Et2O to give the title compound (890mg) as an off-white solid. Preparation O7a:

Cloro-fosfato de dietila (350 μl, 2,4 mmol) foi adicionado lentamente em uma solução agitada da N-aril-tio-semicarbazida (Preparação 07a, ~1 mmol) em DMF seca (5ml) na RT sob N2. Após 90 minutos a mistura foi derramada em NaHCO3 aquoso saturado. O sólido foi coletado por filtração e, o filtrado foi extraído com EtOAC (x2). O sólido foi adicionado nos extratos combinados que foram secos, filtrados e evaporados. O resíduo 5 foi purificado em um cartucho SCX, eluindo com MeOH seguido por NH32M-MeOH. As frações de Nff-MeOH foram combinadas e evaporada e o resíduo foi purificado por HPLC preparativa para dar o composto do título (30mg).Modificação Geral Q (formação de triazol)10 N*3 *-(3-r7-(4-Fluoro-fenil)-imidazor 1,2-a]piridin-3-il]-feniH -1H-|T,2,4]triazol-3,5-diamina3-[7-(4-Fluoro-fenil)-imidazo[l,2-a]piridin-3-il]-fenil-amina

Preparada usando Rota Geral B, procedimento Bla usandoácido 4-fluoro-fenil-borônico, procedimento B2, procedimento B3a usando15 ácido 3-amino-benzeno-borônico.

A solution of 3-[5-(4-fluoro-phenyl)-benzoimidazol-1-yl]-phenyl-amine (300mg, 1mmol) el,T-thio-carbonyl-di-2-(1H)-pyridone ( 240mg, 101 mmol) in dry toluene was stirred and heated under reflux under N2 for 2 h. After cooling to RT the volatiles were removed in vacuo and the residue was taken up in THF (5ml) and cooled in an ice bath. Hydrazine hydrate (300 µl) was added and the mixture was stirred at 0°C for 1 hour and then evaporated. The residue was used without further purification. Preparation O7b{3 - r5-(4-Fluoro-phenyl)-benzoimidazol-1-yl]-phenyl} -[1,3,4]thiadiazol-2-yl-amine

Diethyl chloro-phosphate (350 µl, 2.4 mmol) was added slowly to a stirred solution of the N-aryl-thiosemicarbazide (Preparation 07a, ~1 mmol) in dry DMF (5 ml) at RT under N2. After 90 minutes the mixture was poured into saturated aqueous NaHCO3 . The solid was collected by filtration and the filtrate was extracted with EtOAC (x2). The solid was added to the combined extracts which were dried, filtered and evaporated. Residue 5 was purified on an SCX cartridge, eluting with MeOH followed by NH32M-MeOH. The Nff-MeOH fractions were combined and evaporated and the residue was purified by preparative HPLC to give the title compound (30mg). General Modification Q (triazole formation) 10 N*3 *-(3-r7-(4- Fluoro-phenyl)-imidazor 1,2-a]pyridin-3-yl]-phenylH-1H-|T,2,4]triazol-3,5-diamine3-[7-(4-Fluoro-phenyl)-imidazo [1,2-a]pyridin-3-yl]-phenyl-amine

Prepared using General Rota B, Bla procedure using 4-fluoro-phenyl-boronic acid, procedure B2, procedure B3a using 15 3-amino-benzene-boronic acid.

To a solution of 3-[7-(4-Fluoro-phenyl)-imidazo[1,2-0.33mmol) in 2-propanol (3ml) was added diphenyl-cyano-carbondiimidate (0.078g, 0.33mmol). The reaction mixture was stirred at room temperature overnight, the resulting solid was filtered, and dried to give 0.12g of intermediate. MS: [M+H]+ 448 This was dissolved in MeOH (2ml) and treated with hydrazine hydrate (0.013ml) stirred at room temperature for 30 min, the solid was filtered and purified by preparative LC to give 0.013g of product. MS: [M+H]+386 General Procedure S: Formation 1,3,4 oxadiazol{ 3 - [7-(4-Fluoro-phenyl)-imidazor 1,2,a]pyridin-3-ill-phenyl} - f 1,3,4] oxadiazol-2-yl-amine Procedure S1:

A solution of 3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl-amine (320mg, 1.05mmol) and 4-nitro chloroformate -phenyl (225mg, 1.12mmol) in dry THF (10ml) was stirred and heated at 60°C for 2 hours. After cooling to RT, DIPEA (550 µl, 3.2 mmol) and hydrazine hydrate (102 µl, 2.1 mmol) were added. The reaction was stirred at RT for 1 hour, then partitioned between NaHCO3 (aq) and CH2Cl2. The precipitate was collected by filtration and dried under vacuum to give the semicarbazide. MS: [M+H]+ 362. This material was used without further purification. Procedure S2:

A suspension of the semicarbazide (Sl procedure, 130mg, 0.35mmol) and ethyl glyoxylate (50% in PhMe, 120μl, ~0.6mmol) in EtOH/H2O (2:1, 3ml) was stirred and heated to 80°C °C for 90min. After cooling to RT the precipitate was collected by filtration. The filtrate was concentrated in vacuo and an additional crop of product was collected. The two batches were combined and used without further purification. MS: [M+H]+ 446. Procedure S3: 5-{3-f7-(4-fluoro-phenyl]-imidazo|T,2-a]pyridin-3-yl]-phenyl-acid ethyl ester 10 amino}-[1,3,4]oxadiazole-2-carboxylic acid

Etil-éster de ácido 5-{3-[7-(4-fluoro-fenil)-imidazo[l,2- 5 a]piridin-3-il]-fenil-amino[l,3,4]oxadiazol-2-carboxílico (120mg, 0,27 mmol) e NaOH 5N (0,5ml, 2,5 mmol) em dioxano (2ml) foram agitados e aquecidos a 100°C por 1 hora. Após esfriamento para RT, HC1 5N (0,5ml) foi adicionado. A mistura foi diluída com Et2O e o líquido foi decantado. O resíduo foi tratado com EtOH e o sólido foi coletado por filtração. Este sólido 10 foi suspenso em EtOH (3ml) e aquecido sob refluxo por 15 minutos. Os voláteis foram removidos em vácuo e o resíduo foi purificado por HPLC preparativa para dar o composto do título (12mg).Procedimento U: Formações de halo-monômeroLU: Síntese de (2-cloro-piridin-4-il)-[T,3,4]tiadiazol-2-il-amina

Etapa 1:

Em 4-amino-2-cloro-piridina (0,50 g, 3,89 mmol) em tolueno (20 mL) foi adicionada l,l'-tio-carbonil-di-2(lH)-piridona (0,91 g, 3,90 mmol) e a mistura foi aquecida a 110°C sob N2 por 1 hora. A reação foi concentrada em vácuo e o resíduo foi dividido entre CH2CI2 (25 mL) e H2O 5 (20 mL). A fase orgânica foi lavada com salmoura, seca sobre MgSO4,filtrada e concentrada em vácuo. O produto foi usado bruto na reação subseqüente.Etapa 2:

Em 2-cloro-4-iso-tio-cianato-piridina (0,66 g, 3,90 mmol) em10 THF (20 mL) a 0°C foi adicionada NH2NH2.H2O (0,21 mL, 4,3 mmoL) e a reação foi agitada a 0°C por 40 minutos. A reação foi concentrada em vácuo e o produto usado bruto.Etapa 3:

Bromide (20 µl, 0.39 mmol) in AcOH (Iml) was added to a stirred suspension of the imine (Procedure S2, ~0.35 mmol) in AcOH (2 ml) at RT. The mixture was stirred at RT for 1 h, at 40°C for 30 minutes, then allowed to stand at RT overnight. The reaction was then heated to 120°C for 10 minutes. After cooling to RT the mixture was diluted with water. The solid was collected by filtration, washed with Et2O and then dried under vacuum to give the title compound (120mg). [M+H]+ 444. This material was used without further purification. Procedure S4: {3-[7-(4-Fluoro-phenyl)-imidazo[1,2-alpyridin-3-yl-phenyl)-[1] ,3,4]oxadiazol-2-yl-amine

5-{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-5a]pyridin-3-yl]-phenyl-amino[1,3,4]oxadiazol-2 acid ethyl ester -carboxylic acid (120mg, 0.27mmol) and 5N NaOH (0.5ml, 2.5mmol) in dioxane (2ml) were stirred and heated to 100°C for 1 hour. After cooling to RT, 5N HCl (0.5ml) was added. The mixture was diluted with Et2O and the liquid was decanted. The residue was treated with EtOH and the solid was collected by filtration. This solid 10 was suspended in EtOH (3ml) and heated under reflux for 15 minutes. Volatiles were removed in vacuo and the residue was purified by preparative HPLC to give the title compound (12mg).Procedure U: Halo-monomer formationsLU: Synthesis of (2-chloro-pyridin-4-yl)-[T, 3,4]thiadiazol-2-yl-amine

Step 1:

To 4-amino-2-chloro-pyridine (0.50 g, 3.89 mmol) in toluene (20 mL) was added 1,1'-thio-carbonyl-di-2(1H)-pyridone (0.91 g, 3.90 mmol) and the mixture was heated at 110°C under N 2 for 1 hour. The reaction was concentrated in vacuo and the residue was partitioned between CH2Cl2 (25 mL) and H2O5 (20 mL). The organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The product was used crude in the subsequent reaction. Step 2:

To 2-chloro-4-iso-thio-cyanato-pyridine (0.66 g, 3.90 mmol) in 10 THF (20 mL) at 0°C was added NH2NH2.H2O (0.21 mL, 4.3 mmol) ) and the reaction was stirred at 0°C for 40 minutes. The reaction was concentrated in vacuo and the product used crude. Step 3:

Procedimento V1 - lodação

Método como descrito em Procedimento 2 (A2) de Rota GeralProcedimento V2 - Formação de 6-(4-fluoro-fenil)-3-(4,4,5,5-tetrametil-F1,3,2]dioxaborolan-2-il)-pirazolor 1,5-a]pirimidina

Em 6-(4-fluoro-fenil)-3-iodo-pirazolo[l,5-a]pirimidina (0,69g,2,02 mmol) em DMSO anidro (4 mL) foram adicionados bis(pinacolato)diboro (1,03g, 4,07 mmol) e KOAc (0,63g, 6,38 mmol). O frasco de reação foi purgado com N2 e PdCl2dppf (82 mg, 0,11 mmol)5 adicionado. O frasco de reação foi adicionalmente purgado com N2 e então aquecido a 100°C por 3 h. Após esfriamento para temperatura ambiente, EtOAc (30 mL) e H2O (30 mL) foram adicionados e o material insolúvel foi filtrado. O filtrado foi retido e as fases orgânicas e aquosas foram separadas. A fase aquosa foi re-extraída com EtOAc (25 mL). As fases orgânicas10 combinadas foram secas sobre MgSO4, filtradas e concentradas em vácuo. O sólido foi triturado com Et2O para dar o composto do título como um sólido marrom (0,35 g).Procedimento V3 - Reação de Suzuki geral

Em 6-(4-fluoro-fenil)-3-(4,4,5,5-tetrametil-15 [1,3,2]dioxaborolan-2-il)-pirazolo[l,5-a]pirimidina (70 mg, 0,21 mmol) e (2-Cloro-piridin-4-il)-[l,3,4]tiadiazol-2-il-amina (57 mg, 0,27 mmol) em dioxano (5 mL) foram adicionados 2-diciclo-hexil-fosfino-2',6'-dimetóxi- bifenil (3,4 mg, 0,008 mmol), K3PO4 1M (0,62 mL, 0,62 mmol) e Pd2(dba)3 (3,8 mg, 0,004 mmol). A reação foi aquecida a 90°C por 18 horas. A reação foi concentrada em vácuo e dividido entre CH2C12 (15 mL) e H2O (15 mL). A fase aquosa foi re-extraída com CH2C12 (15 mL). As fases orgânicas combinadas foram secas sobre MgSCfo filtradas e concentradas em vácuo. O produto foi purificado por HPLC preparativa para dar o produto desejado como um sólido amarelo (3,9 mg).Procedimento WEtapa 1: Imidazoll,2-a]piridina-7-carbonitrila

Cloro-acetaldeído (-50% em H2O, 3,24 ml, 26 mmol) foiadicionado em uma mistura agitada de 2-amino-isonicotinonitrila (l,6g, 3,4 mmol) e NaHCO3 (2,23g, 26,5 mmol) em etanol (20ml) na RT sob N2. A reação foi agitada e aquecida a 80°C por 18 horas. Após esfriamento para RT os voláteis foram removidos em vácuo e o resíduo foi dividido entre EtOAc e H2O. Esta mistura foi filtrada para remover algum resíduo insolúvel escuro. O sólido foi lavado com MeOH. A camada aquosa foi extraída com EtOAc (x2).Os extratos combinados de EtOAc foram secos (Na2SO4) e filtrados. As lavagens de MeOH foram adicionadas e os voláteis foram removidos em vácuo. O resíduo foi purificado por cromatografia sobre sílica: 100% DCM —>1% NH3 2M-MeOH /DCM para dar o produto do título. ’H RMN (400 MHz, DMSO-d6): 8,74 (1H, dd), 8,35 (1H, s), 8,19 (1H, s), 7,86 (1H, s), 7,21 (1H,dd).Etapa 2: 7-(2H-Tetrazol-5-il)-imidazorL2-a]piridina

Azida de sódio (97mg, 1,45 mmol) foi adicionada em uma mistura agitada de NH4C1 (82mg, 1,53 mmol) e imidazo[l,2-a]piridina-7- carbonitrila (200mg, 1,4 mmol) em DMF seca (5ml) na RT sob N2. A reação foi agitada e aquecida a 80°C em um frasco vedado por 10 horas. [3 reações idênticas foram realizadas em paralelo] Após esfriamento para RT as misturas reacionais foram combinadas e diluídas com Et2O. O sólido foi coletado por filtração e seco para dar o composto do título (860mg) como um sólido marrom claro, [presumidamente contém NaCl] ’H RMN (400 MHz, DMSO- d6): 8,55 (1H, dd), 8,02 (1H, s), 7,94 (1H, s), 7,57 (1H, d), 7,54 (lH,dd).Etapa 3: 7-(2-Metil-2H-tetrazol-5-il)-imidazo|T,2-a]piridina + ísômero

lodeto de metila (580 p.l, 9,4mmol) foi adicionado em uma mistura agitada de 7-(2H-tetrazol-5-il)-imidazo[l,2-a]piridina (~4,5 mmol) e K2CO3 (l,3g, 9,4 mmol) em DMSO seco (5ml) na RT sob N2. Após 5 horas, a reação foi dividida entre EtOAc e H2O. A camada aquosa foi extraída com EtOAc (x2). Os extratos combinados de EtOAc foram secos (Na2SO4) e filtrados e evaporados. O resíduo foi purificado por cromatografia sobre sílica: 100% DCM -*4% NH3 2M-MeOH / DCM para dar os dois regioisômeros [Regioquímica foi determinada usando estudos nOe]:7-(2-Metil-2H-tetrazol-5-il)-imidazo[l,2-a]piridina (menos polar): *H RMN (400 MHz, DMSO-d6): 8,73 (1H, d), 8,19 (1H, s), 8,10 (1H, s), 7,72 (1H, d), 7,50 (1H, dd), 4,46 (3H, s). 7-(l-Metil-lH-tetrazol-5-il)- imidazo[l,2-a]piridina (mais polar): ’H RMN (400 MHz, DMSO-dg): 8,78 (1H, dd), 8,18-8,15 (2H, m), 7,79 (1H, d), 7,35 (1H, dd), 4,28 (3H, s).Etapa 4: 3-Iodo-7-(2-metil-2H-tetrazol-5-il)-imidazof 1,2-alpiridina

N-Iodo succinimida (300mg, 1,3 mmol) foi adicionada em5 uma porção em uma suspensão agitada de 7-(2-metil-2H-tetrazol-5-il)- imidazo[l,2-a]piridina (240mg, 1,2 mmol) em DMF seca (2ml) na RT sob N2. Após 5 horas, a reação foi extinta com tiossulfato de sódio aquoso saturado / NaHCO3 aquoso saturado (1:1,2 ml). Água (2ml) foi então adicionada e a mistura foi agitada na RT por 15 minutos. O sólido foi coletado por filtração e 10 seco em vácuo para dar o composto do título (360mg) como um sólido creme.RMN (400 MHz, DMSO-d6): 8,51 (1H, dd), 8,20 (1H, dd), 7,86 (1H, s), 7,65 (1H, dd), 4,47 (3H, s).Etapa 5: (3-r7-(2-Metil-2H-tetrazol-5-il)-imidazo[ 1,2-a]piridin-3-il]-fenil }- f 1,3,4]tiadiazol-2-il-amina

To thiosemicarbazide (0.79 g, 3.89 mmol) in dry DMF (15 15 mL) at room temperature was added diethyl chlorophosphate (1.35 mL, 9.3 mmol) dropwise. The reaction was stirred for 1 hour. The pH of the reaction mixture was adjusted to pH 7 using a saturated NaHCO3 solution and DMF was removed in vacuo. The residue was partitioned between H2O (15ml) and CH2Cl2 (25ml) and the aqueous phase re-extracted with CH2Cl2 (2x15ml). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The solids were suspended in EtOAc, filtered and washed with EtOAc to give the product as a pale brown solid (0.35 g). General Route V

Procedure V1 - flooding

Method as described in General Route Procedure 2 (A2) Procedure V2 - Formation of 6-(4-fluoro-phenyl)-3-(4,4,5,5-tetramethyl-F1,3,2]dioxaborolan-2-yl )-pyrazolor 1,5-a]pyrimidine

To 6-(4-fluoro-phenyl)-3-iodo-pyrazolo[1,5-a]pyrimidine (0.69g, 2.02 mmol) in anhydrous DMSO (4 mL) was added bis(pinacolato)diboron (1 .03g, 4.07mmol) and KOAc (0.63g, 6.38mmol). The reaction flask was purged with N2 and PdCl2dppf (82 mg, 0.11 mmol)5 added. The reaction flask was further purged with N2 and then heated to 100°C for 3 h. After cooling to room temperature, EtOAc (30 mL) and H2O (30 mL) were added and insoluble material was filtered off. The filtrate was retained and the organic and aqueous phases were separated. The aqueous phase was re-extracted with EtOAc (25 mL). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The solid was triturated with Et2O to give the title compound as a brown solid (0.35g).Procedure V3 - General Suzuki Reaction

In 6-(4-fluoro-phenyl)-3-(4,4,5,5-tetramethyl-15[1,3,2]dioxaborolan-2-yl)-pyrazolo[1,5-a]pyrimidine (70 mg, 0.21 mmol) and (2-Chloro-pyridin-4-yl)-[1,3,4]thiadiazol-2-yl-amine (57 mg, 0.27 mmol) in dioxane (5 mL) were added 2-dicyclohexyl-phosphino-2',6'-dimethoxy-biphenyl (3.4 mg, 0.008 mmol), 1M K3PO4 (0.62 mL, 0.62 mmol) and Pd2(dba)3 (3, 8mg, 0.004mmol). The reaction was heated at 90°C for 18 hours. The reaction was concentrated in vacuo and partitioned between CH2Cl2 (15 mL) and H2O (15 mL). The aqueous phase was re-extracted with CH 2 Cl 2 (15 mL). The combined organic phases were dried over MgSO4 , filtered and concentrated in vacuo. The product was purified by preparative HPLC to give the desired product as a yellow solid (3.9 mg).Procedure WStep 1: Imidazoll,2-a]pyridine-7-carbonitrile

Chloro-acetaldehyde (-50% in H2O, 3.24ml, 26mmol) was added to a stirred mixture of 2-amino-isonicotinonitrile (1.6g, 3.4mmol) and NaHCO3 (2.23g, 26.5mmol) ) in ethanol (20ml) at RT under N2. The reaction was stirred and heated to 80°C for 18 hours. After cooling to RT volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. This mixture was filtered to remove some dark insoluble residue. The solid was washed with MeOH. The aqueous layer was extracted with EtOAc (x2). The combined EtOAc extracts were dried (Na2SO4) and filtered. MeOH washings were added and volatiles were removed in vacuo. The residue was purified by silica chromatography: 100% DCM —>1% 2M NH3-MeOH /DCM to give the title product. 1 H NMR (400 MHz, DMSO-d6): 8.74 (1H, dd), 8.35 (1H, s), 8.19 (1H, s), 7.86 (1H, s), 7. 21 (1H,dd).Step 2: 7-(2H-Tetrazol-5-yl)-imidazorL2-a]pyridine

Sodium azide (97mg, 1.45mmol) was added to a stirred mixture of NH4Cl (82mg, 1.53mmol) and imidazo[1,2-a]pyridine-7-carbonitrile (200mg, 1.4mmol) in Dry DMF (5ml) at RT under N2. The reaction was stirred and heated to 80°C in a sealed flask for 10 hours. [3 identical reactions were performed in parallel] After cooling to RT the reaction mixtures were combined and diluted with Et2O. The solid was collected by filtration and dried to give the title compound (860mg) as a light brown solid, [presumably contains NaCl] 1 H NMR (400 MHz, DMSO-d6): 8.55 (1H, dd), 8 .02 (1H, s), 7.94 (1H, s), 7.57 (1H, d), 7.54 (1H,dd). Step 3: 7-(2-Methyl-2H-tetrazol-5 -yl)-imidazo|T,2-a]pyridine + isomer

Methyl iodide (580 pl, 9.4mmol) was added to a stirred mixture of 7-(2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (~4.5mmol) and K2CO3 (1 .3g, 9.4mmol) in dry DMSO (5ml) at RT under N2. After 5 hours the reaction was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (x2). The combined EtOAc extracts were dried (Na2SO4) and filtered and evaporated. The residue was purified by chromatography on silica: 100% DCM -*4% NH3 2M-MeOH / DCM to give the two regioisomers [Regiochemistry was determined using nOe studies]:7-(2-Methyl-2H-tetrazol-5-yl )-imidazo[1,2-a]pyridine (less polar): *H NMR (400 MHz, DMSO-d6): 8.73 (1H, d), 8.19 (1H, s), 8.10 ( 1H, s), 7.72 (1H, d), 7.50 (1H, dd), 4.46 (3H, s). 7-(1-Methyl-1H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (more polar): 1 H NMR (400 MHz, DMSO-dg): 8.78 (1H, dd) , 8.18-8.15 (2H, m), 7.79 (1H, d), 7.35 (1H, dd), 4.28 (3H, s). Step 4: 3-Iodine-7- (2-methyl-2H-tetrazol-5-yl)-imidazo, 1,2-alpyridine

N-Iodine succinimide (300mg, 1.3mmol) was added in 5 one portion to a stirred suspension of 7-(2-methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (240mg, 1.2 mmol) in dry DMF (2ml) at RT under N2. After 5 hours the reaction was quenched with saturated aqueous sodium thiosulfate / saturated aqueous NaHCO3 (1:1.2 ml). Water (2ml) was then added and the mixture was stirred at RT for 15 minutes. The solid was collected by filtration and dried in vacuo to give the title compound (360mg) as a cream solid. NMR (400 MHz, DMSO-d6): 8.51 (1H, dd), 8.20 (1H, dd), 7.86 (1H, s), 7.65 (1H, dd), 4.47 (3H, s). Step 5: (3-r7-(2-Methyl-2H-tetrazol-5-yl) )-imidazo[1,2-a]pyridin-3-yl]-phenyl}-(1,3,4]thiadiazol-2-yl-amine

Procedimento AA1 - Formação de anel de imidazopiridina

A mixture of 3-iodo-7-(2-methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (300mg, 0.92mmol), 3-([ 1,3,4]thiadiazol-2-yl-amino)-phenyl-boronic (14.350mg, 1.15mmol) and 2N Na2CO3 (4.5ml) in dry DME (4.5ml) was deoxygenated by evacuation/filling with N2 (x2). PdCl2dppf (70mg, 0.10mmol) was added, and the mixture was deoxygenated again (x3). The reaction was stirred and heated to 85°C for 3 hours. After cooling to RT the mixture was partitioned between EtOAc and H2O and stirred for 20 min. The solid that remained was collected by filtration and purified by silica column chromatography (100% CH 2 Cl 2 - 5% 2M NH 3 -MeOH/CH 2 Cl 2 ) to give the desired compound (100mg). MS: [M+H]+ = 376. General Route AA

Procedure AA1 - Imidazopyridine Ring Formation

Procedimento AA2 -lodação

To a solution of a 4-substituted-pyridin-2-yl-amine (1.0equiv) in EtOH was added NaHCO3 (2.0 equiv.) followed by chloroacetaldehyde (1.5 equiv). The mixture was refluxed for 2 h. Solvents were removed under reduced pressure and the crude mixture was partitioned between water and EtOAc. The products were purified using column chromatography, trituration or recrystallization.

AA2 procedure -lodation

Procedimento AA3b - Reação de Suzuki com pinacol-éster de ácido 3- ([l,3,4]tiadiazol-2-il-amino)-fenil-borônico (14)

To a solution of 7-substituted Imidazo[1,2-a]pyridine (1.0 equiv) in DMF was added N-iodosuccinimide (1.2 equiv) and the resulting mixture was stirred for 2 h at room temperature. The fine brown slurry was diluted with water, 10% w/v sodium thiosulfate and (1M) sodium carbonate, and extracted with CH 2 Cl 2 . The aqueous phase was further extracted with CH2Cl2. The combined organic phases were washed with brine, dried (MgSO4 ) and concentrated in vacuo to give the product. Where necessary, the product was further purified by trituration or silica column chromatography.

Procedure AA3b - Suzuki reaction with pinacol-ester of 3-([1,3,4]thiadiazol-2-yl-amino)-phenyl-boronic acid (14)

EXEMPLOS 1 A 9Pelos seguintes métodos descritos acima, os compostos deExemplos 1 a 9 mostrados em Tabela abaixo foram preparados.

EXEMPLOS 10 A 11Pelos seguintes métodos descritos acima, os pirazolo[l ,5- a]pirimidina-compostos de Exemplos 10 a 11 mostrados em Tabela abaixo foram preparados.

Exemplo 12{3-r6-(4-Fluoro-fenil)-pirazolor 1,5-a]piridin-3-il]- feniiri,3,4]tiadiazol-2-il-aminaEtapa 1: 3-(4-Fluoro-fenil}-piridinaTo a solution of 7-substituted-3-iodo-imidazo[1,2-a]pyridine (1 equiv) in DME was added 3-([1,3,4]-thiadiazol-2-yl acid ester) -amino)-phenyl-boronic (14) (1.2 equiv.), 1M Na2CO3 (8 equiv) 15 [reaction was degassed by bubbling N2 through it] followed by tetrakis(triphenyl-phosphine)-palladium(0) (0 .05 equiv.). The mixture was heated at 80°C overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4 ) and concentrated under reduced pressure. The products were purified by trituration with Et2O, silica column chromatography or reverse phase HPLC. Where appropriate the product was dissolved in HCl/dioxane, the solvent was removed and the product 5 recrystallized from MeOH to give the hydrochloride.

EXAMPLES 1 TO 9 By the following methods described above, the compounds of Examples 1 to 9 shown in Table below were prepared.

EXAMPLES 10 TO 11 By the following methods described above, the pyrazolo[1,5-a]pyrimidine-compounds of Examples 10 to 11 shown in Table below were prepared.

Example 12{3-r6-(4-Fluoro-phenyl)-pyrazolor 1,5-a]pyridin-3-yl]-phenyl,3,4]thiadiazol-2-yl-amine Step 1: 3-(4-Fluoro -phenyl}-pyridine

O-(Mesitileno-sulfonil)-hidroxil-amina (3,5g, 16,2 mmol) foi adicionada em uma porção em uma solução agitada de 3-(4-fluoro-fenil)- piridina (2,8g, lómmol) em CH2C12 seco a 0°C sob N2. Após 30 minutos o banho de gelo foi removido e a reação foi agitada na RT por 16 horas. Os voláteis foram removidos em vácuo e a N-amino-piridina foi usada sem purificação adicional. K2CO3 (4,4g, 32 mmol) foi adicionado em uma solução agitada da N-amino-piridina acima (~16 mmol) e metil-éster de ácido 2- benzeno-sulfonil-3-dimetil-amino-acrílico (4,3g, 16 mmol) em DMF seca (48ml) na RT sob N2. Após 3 horas na RT a reação foi aquecida a 100°C por 2 horas. Após esfriamento para a RT a mistura foi dividida entre EtOAc e H2O. A camada aquosa foi extraída com EtOAc (x2).Os extratos combinados foram lavados com água (xl), salmoura (xl), então secos (MgSO4), filtrados e evaporados. O resíduo foi purificado por trituração com CH2C12/ petrol para dar o composto do título (2,7g, sólido). ’H RMN (400 MHz, CDCfi): 8,68 (1H, s), 8,42 (1H, s), 8,22 (1H, d), 7,63 (1H, dd), 7,60-7,51 (2H, m), 7,23- 7,14 (2H, m), 3,94 (3H, s).Etapa 3: 6-(4-Fluoro-fenil)-pirazolo[l,5-a]piridina

A solution of 3-bromo-pyridine (2.5g, 15.8 mmol) and 4-fluoro-phenyl-boronic acid (2.8g, 20.0 mmol) in DME (20ml) and 2N Na2CO3 (aq, 20ml) was deoxygenated by evacuation/refilling with N2 (x2). PdCl2dppf (600mg, 0.8mmol) was added and the mixture was deoxygenated again (x3). The reaction was stirred and heated to 80°C under N2 for 16 hours. After cooling to RT the mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (x2). The combined extracts were washed with brine (xl), dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica (10→40% EtOAc/Petrol) to give the title compound (3.0g, oil). 1 H NMR (400 MHz, CDCl3 ): 8.83 (1H, brs), 8.61 (1H, brs), 7.85 (1H, d), 7.54 (2H, dd), 7.39 (1H, , brs), 7.18 (2H, t). Step 2: 6-(4-Fluoro-phenyl)-pyrazolo1,5-a]pyridine-3-carboxylic acid methyl ester

O-(Mesitylene-sulfonyl)-hydroxyl-amine (3.5g, 16.2 mmol) was added in one portion to a stirred solution of 3-(4-fluoro-phenyl)-pyridine (2.8g, 1mmol) in CH2Cl2 dried at 0°C under N2. After 30 minutes the ice bath was removed and the reaction was stirred at RT for 16 hours. Volatiles were removed in vacuo and the N-amino-pyridine was used without further purification. K2CO3 (4.4g, 32 mmol) was added to a stirred solution of the above N-amino-pyridine (~16 mmol) and 2-benzenesulfonyl-3-dimethyl-amino-acrylic acid methyl ester (4.3g , 16 mmol) in dry DMF (48 ml) at RT under N2. After 3 hours at RT the reaction was heated to 100°C for 2 hours. After cooling to RT the mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (x2). The combined extracts were washed with water (xl), brine (xl), then dried (MgSO4), filtered and evaporated. The residue was purified by trituration with CH2 Cl2 / petrol to give the title compound (2.7g, solid). 'H NMR (400 MHz, CDCl): 8.68 (1H, s), 8.42 (1H, s), 8.22 (1H, d), 7.63 (1H, dd), 7.60- 7.51 (2H, m), 7.23-7.14 (2H, m), 3.94 (3H, s). Step 3: 6-(4-Fluoro-phenyl)-pyrazolo[1,5- a]pyridine

N-iodo-succinimida (630mg, 2,8 mmol) foi adicionada em uma porção em uma solução agitada de 6-(4-fluoro-fenil)-pirazolo[l,5- a]piridina (500mg, 2,4 mmol) em DMF seca (6ml) na RT sob N2. Após 45 minutos, a reação foi extinta com tiossulfato de sódio aquoso saturado / NaHCO3 saturado (l:l,40ml). A mistura foi agitada na RT por 15 minutos então dividida entre EtOAc e H2O. A camada orgânica foi lavada com água (xl), salmoura (xl), então seca (MgSO^, filtrada e evaporada. O resíduo foi purificado por trituração com petrol para dar o composto do título (635mg, sólido). JH RMN (400 MHz, CDC13): 8,61 (1H, s), 7,98 (1H, s), 7,57-7,51 (3H, m), 7,42 (1H, dd), 7,22-7,13 (2H,m).Etapa 5;(3-r6-(4-Fluoro-fenil)-pirazolo[ 1,5-a]piridin-3-il]-fenilf 1,3,4]tiadiazol-2-il-amina

A mixture of 6-(4-fluoro-phenyl)-pyrazolo1,5-a]pyridine-3-carboxylic acid methyl ester (1.08g, 4mmol) and aqueous NaOH (2N, 4ml) and EtOH (16ml) was stirred and heated to 85°C under N2 for 30 minutes. The reaction was allowed to cool to RT, then placed in an ice bath. 2N hydrochloric acid (5ml) was added slowly. The solid was collected by filtration, washed with Et2O then dried under vacuum. The acid was used without further manipulation. A suspension of the above acid in polyphosphoric acid (~15ml) was stirred and heated to 150 °C under N 2 . After 3 hours the reaction was allowed to cool to RT then poured carefully into ice water. The solid was isolated by filtration, then dissolved in CH 2 Cl 2 . This solution was passed through a phase separation cartridge then evaporated to give the title compound (582mg, solid). 1 H NMR (400 MHz, CDCl3 ): 8.66 (1H, s), 7.98 (1H, s), 7.63-7.51 (3H, m), 7.34 (1H, d), 7.17(2H,t), 6.55(1H,s).Step 4: 6-(4-Fluoro-phenyl)-3-iodo-pyrazolor 1,5-a]pyridine

N-iodosuccinimide (630mg, 2.8mmol) was added in one portion to a stirred solution of 6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridine (500mg, 2.4mmol) in dry DMF (6ml) at RT under N2. After 45 minutes, the reaction was quenched with saturated aqueous sodium thiosulfate / saturated NaHCO3 (1:1.40ml). The mixture was stirred at RT for 15 minutes then partitioned between EtOAc and H2O. The organic layer was washed with water (xl), brine (xl), then dried (MgSO4 , filtered and evaporated.) The residue was purified by trituration with petrol to give the title compound (635mg, solid). MHz, CDCl3 ): 8.61 (1H, s), 7.98 (1H, s), 7.57-7.51 (3H, m), 7.42 (1H, dd), 7.22-7 ,13(2H,m).Step 5;(3-r6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-phenyl-1,3,4]thiadiazol-2- il-amine

Ensaios biológicosEnsaios de atividade inibitória de quinase in vitro de FGFR3 e PDGFREnzimas (de Upstate) foram preparadas em concentração final x2 e em tampão de ensaio de quinase lx (como descrito abaixo). Enzimas foram então incubadas com compostos de teste, substrato Flt3 biotinilado (biotina-DNEYFYV) (Cell Signalling Technology Inc.) e ATP. A reação foi permitida proceder por 3 horas (FGFR3) ou 2,5 h (PDGFR-beta) na temperatura ambiente sobre um agitador de placa a 900 rpm antes de ser interrompida com 20 μl de EDTA 35 mM, pH 8 (FGFR3) ou EDTA 55 mM, pH 8 (PDGFR-beta). Vinte μl de mistura de detecção 5x (F1EPES 50 mM pH 7,5, BSA 0,1%, Eu-anti-pY (PY20) 2nM (Perkin Elmer) SA-XL665 15nM (Cisbio) para FGFR3 e HEPES 50 mM, pH 7,5, KF 0,5 M, BSA 0,1%, Eu- anti-pY (PT66) 11,34 nM (Perkin Elmer), SA-XL665 94nM (Cisbio) para PDGFR-beta) foram então adicionados em cada cavidade e a placa foi vedada e incubada na temperatura ambiente por uma hora sobre um agitador de placa a 900 rpm. A placa foi lida em uma leitora de placa Packard Fusion no modo TRF.

Tampões para ensaio de quinase foram:A: HEPES 50 mM pH 7,5, MnCl2 6 mM, DTT 1 mM, TritonX-100 0,1%B: MOPS 20 mM pH 7,0, MnCl2 10 mM, Triton X-100 0,01%, DTT 1 mM, orto-vanadato de sódio 0,1 mMA mixture of 6-(4-fluoro-phenyl)-3-iodo-pyrazolo[1,5-a]pyridine (150mg, 0.44mmol), pinacol-acid 3-([1,3,4]-ester thiadiazol-2-yl-amino)-phenyl-boronic (190mg, 0.62mmol) and PdCl2ddpf (32mg, 0.04mmol) in DME (1.5ml) and 2N Na2CO3 (aq, 1.5ml) in a flask The microwave oven was deoxygenated by bubbling N2 through it for 30 seconds. The vial was sealed and then shaken and heated to 150°C in a microwave oven for 30 minutes. After cooling to RT the mixture was partitioned between CH2C12 and H2O. The organic layer was evaporated and the residue was purified by preparative HPLC to give the title compound (15mg, solid).

Biological Assays In vitro kinase inhibitory activity assays of FGFR3 and PDGFRenzymes (from Upstate) were prepared in x2 final concentration and in 1x kinase assay buffer (as described below). Enzymes were then incubated with test compounds, biotinylated Flt3 substrate (biotin-DNEYFYV) (Cell Signalling Technology Inc.) and ATP. The reaction was allowed to proceed for 3 hours (FGFR3) or 2.5 h (PDGFR-beta) at room temperature on a plate shaker at 900 rpm before being stopped with 20 μl of 35 mM EDTA, pH 8 (FGFR3) or 55 mM EDTA, pH 8 (PDGFR-beta). Twenty μl of 5x detection mix (50 mM F1EPES pH 7.5, 0.1% BSA, 2nM Eu-anti-pY (PY20) (Perkin Elmer) 15nM SA-XL665 (Cisbio) for FGFR3 and 50 mM HEPES, pH 7.5, 0.5M KF, 0.1% BSA, Eu-anti-pY (PT66) 11.34nM (Perkin Elmer), SA-XL665 94nM (Cisbio) for PDGFR-beta) were then added to each well and the plate was sealed and incubated at room temperature for one hour on a plate shaker at 900 rpm. The plate was read on a Packard Fusion plate reader in TRF mode.

Buffers for kinase assay were: A: 50 mM HEPES pH 7.5, 6 mM MnCl 2 , 1 mM DTT, 0.1% TritonX-100 B: 20 mM MOPS pH 7.0, 10 mM MnCl 2 , Triton X-100 0.01%, 1 mM DTT, 0.1 mM sodium ortho-vanadate

Compounds of the invention (for example Examples 1-14 and 16-43) have IC50 values less than 10 µM or provide at least 50% inhibition of FGFR3 activity at a concentration of 10 µM. Preferred compounds of the invention (for example Examples 1,2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, the product of Procedure F8 [Benzyl-[3 -(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-amine], the starting material from Procedure A4c [3-(7-Chloro-imidazo[1,2-a]pyridin -3-yl)-phenyl]-[1,3,4]thiadiazol-2-yl-amine] and the product of Procedure G1 [[3-(7-Chloro-imidazo[1,2-a]pyridin-3) -yl)-phenyl]-(3H-[1,2,3]triazol-4-yl)-amine]) have IC50 values less than 1 µM in the FGFR3 assay. VEGFR2 Assay reactions containing enzyme containing VEGFR2 (purchased from Upstate), and Poly (Glu,Tyr) 4:1 substrate 250 µM (CisBio) in 50 mM HEPES, pH 7.5, 6 mM MnCl2, 1 mM DTT, Triton X- 100 0.01%, 5 µM ATP (2.8 Ci/mmol) were carried out in the presence of compound. Reactions were stopped after 15 minutes by the addition of an excess of phosphoric acid. The reaction mixture was then transferred to a Millipore MAPH filter plate where the peptide binds and unused ATP is washed away. After washing, scintillation agent was added and incorporated activity was measured by scintillation counting in a Packard Topcount. In vitro kinase inhibitory activity assays of FGFR1, FGFR2, FGFR4, VEGFR1 and VEGFR3

Inhibitory activity against FGFR1, FGFR2, FGFR4, VEGFR 1 and VEGFR3 can be determined at Upstate Discovery Ltd. Enzymes were prepared at 10x final concentration in enzyme buffer (20 mM MOPS, pH 7.0, 1 mM EDTA, B-mercapto -0.1% ethanol, 0.01% Brij-35, 5% glycerol, BS A 1 mg/ml). Enzymes were then incubated in assay buffer with various substrates and 33 P-ATP (-500 cpm/pmol) as described in the table.

The reaction was started by adding Mg/ATP. The reaction was allowed to proceed for 40 minutes at room temperature before being stopped with 5 μl of a 3% phosphoric acid solution. Ten µl of the reaction mixture was transferred to a filtermatA or P30 filtermat and washed three times in 75 mM phosphoric acid and once in methanol before being dried for scintillation reading.

Tampão de enzima A: MOPS 8 mM, pH 7,0, EDTA 0,2 mM,Acetato de Mg 10 mMTampão de enzima B: MOPS 8 mM, pH 7,0, EDTA 0,2 mM, MnCL 2,5 mM, Acetato de Mg 10 mM Tampão de enzima C: MOPS 8 mM, pH 7,0, EDTA 0,2 mM, MnCl2 10 mM, Acetato de Mg 10 mM.Método de pERK ELISA baseado em célulaCélulas de mieloma múltiplo LP-1 ou JIM-1 foram semeadas em placas de 96 cavidades a 1x106 células/ml em 200μl por cavidade em meios livres de soro. Células HUVEC foram semeadas a 2,5x105 células/ml e permitidas se recuperarem por 24h antes da transferência para meios livres de soro. Células foram incubadas por 16h a 37°C antes da adição de um composto de teste por 30 minutos. Compostos de teste foram administrados em uma concentração final de 0,1% em DMSO. Após esta incubação de 30 min uma mistura de GF-l/Heparina (FGF-1 a 100ng/ml final e Heparina a 100μg/ml) ou VEGF165 (100μg/ml) foi adicionada em cada uma das cavidades por mais 5 minutos. O meio foi removido e foram adicionados 50μl de tampão de lise ERK ELISA (R and D Systems DuoSet ELISA para pERK e Total ERK #DYC-1940E, DYC-1018E). Placas de ELISA e padrões foram preparados de acordo com os protocolos padrão DuoSet e as quantidades relativas de pERK para ERK total em cada amostra foram calculadas de acordo com a curva padrão.Compounds were tested twice at the concentrations detailed below against all kinases and the percent activity compared to control was calculated. Where inhibition was high an IC50 was determined.

Enzyme Buffer A: 8 mM MOPS, pH 7.0, 0.2 mM EDTA, 10 mM Mg Acetate MTEnzyme Buffer B: 8 mM MOPS, pH 7.0, 0.2 mM EDTA, 2.5 mM MnCL, 10 mM Mg Acetate Enzyme Buffer C: 8 mM MOPS, pH 7.0, 0.2 mM EDTA, 10 mM MnCl 2 , 10 mM Mg Acetate. Cell-based method of pERK ELISA Multiple myeloma cells LP-1 or JIM -1 were seeded in 96-well plates at 1x106 cells/ml in 200μl per well in serum-free media. HUVEC cells were seeded at 2.5x105 cells/ml and allowed to recover for 24h before transfer to serum-free media. Cells were incubated for 16h at 37°C before adding a test compound for 30 minutes. Test compounds were administered at a final concentration of 0.1% in DMSO. After this 30 min incubation a mixture of GF-l/Heparin (FGF-1 at 100ng/ml final and Heparin at 100μg/ml) or VEGF165 (100μg/ml) was added to each well for another 5 minutes. The medium was removed and 50µl of ERK ELISA lysis buffer (R and D Systems DuoSet ELISA for pERK and Total ERK #DYC-1940E, DYC-1018E) was added. ELISA plates and standards were prepared according to standard DuoSet protocols and the relative amounts of pERK to total ERK in each sample were calculated according to the standard curve.

In particular, compounds of the invention were tested against the LP-1 cell line (DSMZ no.: ACC 41) derived from human multiple myeloma. It has been found that many compounds of the invention have IC50 values less than 20 µM in this assay and some compounds (eg Examples 2, 3, 4, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18 , 20, 24, 25, 26, 28, 30, 32, 43 and the starting material from Procedure A4c [3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-[ 1,3,4]thiadiazol-2-yl-amine]) have IC50 values less than 1 μM. HUVECC cell-based selectivity assays HUVEC cells were seeded in 6-well plates at 1x106 cells/well and allowed to recover per well. 24h. They were transferred to serum-free media for 16 hours before treatment with test compound for 30 minutes at a final concentration of 0.1% in DMSO. After incubation, FGF-1 compound (100ng/ml) and Heparin (100μg/ml) or VEGF163 (100ng/ml) were added for 5 minutes. Medium was removed, cells were washed in ice-cold PBS and lysed in 100μl of TG lysis buffer (20mM Tris, 130nM NaCl, 1% Triton-X-100, 10% glycerol, protease and phosphatase inhibitors, pH 7.5). Samples containing equivalent amounts of protein were topped up with LDS sample buffer and run on SDS PAGE followed by western blotting for numerous downstream VEGFR and FGFR route targets including phospho-FGFR3, phospho-VEGFR2 and phospho-ERK1/2.

In vivo hypertension models

There are numerous animal models for measuring the potential hypertensive effects of small molecule inhibitors. They can be classified into two main types; indirect and direct measures. The most common indirect method is the cuff technique. Such methods have the advantages of being non-invasive and as such can be applied to a larger group of experimental animals however the process only allows intermittent blood pressure sampling and requires the animal to be restrained in some way. Restriction application can stress the animal and mean that changes in blood pressure attributable to a specific drug effect may be difficult to capture. Direct methodologies include those that make use of radiotelemetry technology or via delay probes connected to externally mounted transducers. Such methods require a high level of technical expertise for the initial surgery involved in implantation and the costs involved are high. However a key advantage is that they allow continuous monitoring of blood pressure without restriction over the time period of the experiment. These methods are reviewed in Kurz et al. (2005) Hypertension. 45: 299-310.

Results

Biological data from the in vitro kinase inhibitory activity of FGFR3 assay and cell-based pERK ELISA method described above for identified examples are shown below.

Claims (15)

1. Compound characterized by being of formula (I):

where X1 is carbon, X2 and X3 are each independently selected from carbon or nitrogen, such that at least one of X2-X3 represents nitrogen;X4 represents CR3 or nitrogen;X5 represents CR6; three of X2-X4 represent nitrogen; represents a single or double bond, such that at least one bond in the 5-membered ring system is a double bond; R3 represents hydrogen; A represents a phenyl or pyrinidyl group which may optionally be substituted with one or more (eg 1 , 2 or 3) groups Ra;B represents a -V-carbocyclic group, where the carbocyclic group is a phenyl group, or a -W-heterocyclyl group, where the heterocyclic group is a 5,6 monocyclic aromatic heterocyclyl group or 7-membered and contains 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein said carbocyclic and heterocyclyl groups may be optionally substituted with one or more (eg 1,2 or 3) Ra;R2 groups and R6 independently represents hydrogen, an aryl group or a heterocyclyl group, wherein said aryl group is a phenyl group and said heterocyclyl group is a 5- to 10-membered group and contains 1, 2 or 3 heteroatoms independently selected from ni trogen, oxygen and sulfur, and said aryl and heterocyclyl groups may be optionally substituted by one or more Rb groups provided that R2 and R6 do not both represent hydrogen; Re, Rf and Rw independently represent hydrogen or C1-6 alkyl;Ra represents groups halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, -ORx, -(CH2)nO-C1-6 alkyl, -O-(CH2 )n-ORx, haloC1-6 alkyl, haloC1-6 alkoxy, C1-6 alkanol, =O, =S, xxxxx xy znitro, Si(R )4, -(CH2)sCN, -SR , -SO-R , -SO2-R , -COR , -(CR R )s-COOR , xy xy xyx y-(CH2)s-CONR R , -(CH2)s-NR R , -(CH2)s-NR COR , -( CH2)s-NR SO2-R, - xy xy xy xy(CH2)s-NH-SO2-NR R , -OCONR R , -(CH2)s-NR CO2R , -O-(CH2)s-CR R - (CH2)t-ORz or -(CH2)s-SO2NRxRy;Rx, Ry and Rz independently represent hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkanol, hydroxyl, C1-6 alkoxy , haloC 1-6 alkyl, -CO-(CH 2 )n -C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 cycloalkenyl; R 1 and Rb independently represent a Ra group or a -Y-carbocyclyl or Z-heterocyclyl group, wherein said carbocyclyl group is a 5- or 6-membered monocyclic carbocyclyl group and said heterocyclyl group is a 5- or 6-membered monocyclic heterocyclyl group and contains 1 , 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein said carbocyclyl and heterocyclyl groups may be optionally substituted with one or more (eg 1, 2 or 3) Ra;V and W groups independently represent a bond or a group -(CReRf)n-;Y and Z independently represent a bond, -CO-(CH2)s-, -COO-, -(CH2)n-, -NRx-(CH2)n-, -(CH2 ) )n-NRX-, -CONRx-, -NRxCO-, -SO2NRx-, -NRxSO2-, -NRxCONRy-, -NRxCSNRy- -O-(CH2)s-, -(CH2)sO-, -S-, - SO- or -(CH2)s-SO2-;n represents an integer from 1-4;set independently represent an integer from 0-4;q represents an integer from 0-2 or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, characterized in that X1 is carbon; X2 and X3 are each independently selected from carbon or nitrogen, such that at least one of X2-X3 represents nitrogen; X4 represents CR3 or nitrogen;X5 represents CH;provided that no more than three of X2-X4 represents nitrogen; represents a single or double bond; R3 represents hydrogen or =O;A represents a phenyl or pyrinidyl group which may be optionally substituted with one or more (eg 1, 2 or 3) groups Ra;B represents an aromatic heterocyclic group, wherein the heterocyclic group is a 5-, 6- or 7-membered monocyclic heterocyclyl group and each heteroatom is independently selected from nitrogen, oxygen and sulfur; R2 represents an aryl or heterocyclyl group optionally substituted with one or more Rb groups, wherein said aryl group is a phenyl group and said heterocyclyl group is a 5- to 10-membered group and contains 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ra represents halogen, C1-6 alkyl, C2- 6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, -ORx, -O-(CH2)n-ORx, haloC1-6 alkyl, haloC1-6 alkoxy, C1-6 alkanol, =O, =S, nitro, -(CH2)s-CN, -S- Rx xxx xy z xy, -SO-R , -SO2-R , -COR , -(CR R )s-COOR , -(CH2)s-CONR R , -(CH2)s-xy xyxy xyNR R , -(CH2)sNR COR , -(CH2)s-NR SO2-R , -OCONR R , -(CH2)s-NRxCO2Ry, -O-(CH2)s-CRxRy-(CH2)t-ORz or -(CH2)s-SO2NRxRy;Rx, Ry and Rz independently represent hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkanol, hydroxyl, C1-6 alkoxy, haloC1-6 alkyl, -CO-(CH2)n-C1-6 alkoxy, C3-8 cycloalkyl or C3-8 cycloalkenyl ;R1 and Rb independently represent a Ra group or a -Y-aryl or -Z-heterocyclyl group wherein said aryl group is a phenyl group and said heterocyclyl group is a 5- or 6-membered monocyclic heterocyclyl and contains 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur and said aryl and heterocyclyl groups may be optionally substituted with one or more (eg 1,2 or 3) groups Ra;Y and Z independently represent a bond, -CO-, -CH2-, -(CH2)2, -(CH2)3-, -O-(CH2)s- or -NH- (CH 2)n-;n independently represent an integer from 1-4;set independently represent an integer from 0-4;q represents an integer from 0-2. A compound according to claim 1 or claim 2, characterized in that A represents a phenyl group optionally substituted with one or more groups Ra. 4. Compound according to any one of claims 1 or 3, characterized in that B represents a -W- heterocyclyl group in which the heterocyclyl group is a 5- or 6-membered monocyclic heterocyclyl group. 5. Compound according to claim 4, characterized in that W represents a bond. 6. Compound according to any one of claims 1 to 5, characterized in that q represents 0. A compound according to any one of claims 1 to 6, characterized in that R2 represents a 5-membered heterocyclyl group optionally substituted with one or more Ra groups wherein said aryl group is a phenyl group and said heterocyclyl group is a 5- or 6-membered monocyclic heterocyclyl group and contains 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 8. A compound according to any one of claims 1 to 6, characterized in that R2 represents phenyl optionally substituted with a halogen group, -(CRxRy)s-COORz or -Z- heterocyclyl group, wherein said heterocyclyl group is a 5- or 6-membered monocyclic heterocyclyl and contains 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur and said heterocycle group may be optionally substituted with one or more Ra groups selected from C 1-6 alkyl or -( groups CRxRy)s-COORz or wherein R2 represents morpholinyl, piperazinyl, pyridyl, pyrazinyl, pyrazolyl, piperidinyl, benzodioxolyl or pyrimidinyl optionally substituted with one or more Rb groups selected from C1-6 alkyl, -(CH2)s-NRxRy, -CORx , -(CRxRy)s-COORz or -SO2-Rx. 9. Compound according to any one of claims 1 to 6, characterized in that R2 represents a phenyl group optionally substituted with one or more Rb groups selected from halogen, C1-6 alkanol, -(CH2)sNRxRy -(CRxRy) s-COORz, -(CH2)s-CONRxRy or -(CH2)s-NRxSO2-Ry, or wherein R2 represents morpholinyl, piperazinyl, pyridyl, thienyl, pyrazinyl, benzothienyl, furanyl or pyrimidinyl optionally substituted with one or more groups = O, C1-6 alkyl, -(CH2)s-NRxRy, -ORx, -CORx or C1-6 alkanol. 10. Compound according to any one of claims 1 to 9, characterized in that X1-X5 are defined by the following ring systems:

11. Compound according to claim 1, characterized in that said compound is a compound of formula (Id):

where r represents an integer from 0 to 3. 12. Compound according to any one of claims 1 to 11, characterized in that it is a compound selected from {3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl] -phenyl}-pyrazin-2-yl-amine,{3-[7-(3-Morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-[1 ,3,4]thiadiazol-2-yl-amine,(5-Methyl-[1,3,4]thiadiazol-2-yl) - {3-[7-(3-morpholin-4-ylmethyl-phenyl) - imidazo[1,2-a]pyridin-3-yl]-phenyl}-amine,(3-{7-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-imidazo formate salt [ 1,2-a]pyridin-3-yl}-phenyl)-(3H-[1,2,3]triazol-4-yl)-amine,{3-[7-(4-Fluoro-)formate salt phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-phenyl-amine,{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]formate salt ]pyridin-3-yl]-phenyl}-pyridin-4-yl-amine,{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl} - [1,3,4]thiadiazol-2-yl-amine,{3-[7-(3-Morpholin-4-ylmethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl }-phenyl-amine, Format salt of (3-{7-[3- (4-M) ethyl-piperazin-1-ylmethyl)-phenyl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-[1,3,4]thiadiazol-2-yl-amine,{3-[6 -(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-phenyl}-[1,3,4]thiadiazol-2-yl-amine, 5-{3-Hydrochloride Salt [3 - ([1,3,4] thiadiazol-2-ylamino)-phenyl]-pyrazolo [1,5-a] pyrimidin-6-yl}-pyridin-2-ylamine,{3-[6-4 -Fluoro-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-phenyl}-[1,3,4]thiadiazol-2-yl-amine,{3-[3-(3-Benzylamino) acid -phenyl)-imidazo[1,2-a]pyridin-7-yl]-phenyl}-acetic,{3-[7-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1,2- a]pyridin-3-yl]-phenyl}-[1,3,4]thiadiazol-2-yl-amine,[3-(6-Pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidin-3 -yl)-phenyl]-[1,3,4]thiadiazol-2-yl-amine,{3-[6-(1-Methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a] pyrimidin-3-yl]-phenyl}-[1,3,4]thiadiazol-2-yl-amine,[3-(6-Pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-3-yl )-phenyl]-[1,3,4]thiadiazol-2-yl-amine,[3-(6-pyrazin-2-yl-pyrazolo[1,5-a]pyrimidin-3-yl)-phenyl]- [1,3,4] thiadiazol-2-yl-amine,[ 3-(7-Morpholin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-[1,3,4]thiadiazol-2-yl-amine, [3-( 7-Benzo[1,3]dioxol-5-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-[1,3,4]thiadiazol-2-yl-amine,{3- [7-(4-Ethanesulfonyl-piperazin-1-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-[1,3,4]thiadiazol-2-yl-amine Hydrochloride, Hydrochloride of Morpholin-4-yl-(3-{3-[3-([1,3,4]thiadiazol-2-ylamino)-phenyl]-imidazo[1,2-a]pyridin-7-yl}-phenyl ) -methanone,[3-(7-Piperidin-1-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-[1,3,4]thiadiazol-2-yl-amine,{ 5-[6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-3-yl}-[1,3,4]thiadiazol-2-yl-amine, N-Methyl-2-(3-{3-[3 -([1,3,4]thiadiazol-2-ylamino)-phenyl]-imidazo[1,2-a]pyridin-7-yl}- hydrochloride phenyl)-acetamide,N * 3 * - {3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-1H-[1,2,4 ] triazole-3,5-diamine, 4-(3-{3-[3 -([1,3,4]thiadiazol-2-ylamino)-phenyl]-imidazo[1,2-a]pyridin-format 7-yl}-benzyl)-piperazi n-2-one,{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-[1,3,4]oxadiazol-2-yl -amine,N-methyl-3-{3-[3 - ([1,3,4] thiadiazol-2-ylamino)-phenyl]-imidazo[1,2-a]pyridin-7-yl}-hydrochloride benzamide (Example 30), {2-[6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-4-yl}-[1,3,4]thiadiazole -2-yl-amine,{3-[7-(3-amino-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-[1,3,4]thiadiazole-hydrochloride 2-yl-amine,(3-{7-[2-(Tetrahydro-pyran-4-yloxy)-pyridin-4-yl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)- [1,3,4]thiadiazol-2-yl-amine,{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-hydrochloride ( 1-methyl-1H-imidazol-2-yl)-amine,(3-{3-[3 -([1,3,4]thiadiazol-2-ylamino)-phenyl]-imidazo[1,2-a] pyridin-7-yl}-phenyl)-methanol, 4-{3-[3-([1,3,4]thiadiazol-2-ylamino)-phenyl]-imidazo[1,2-a] acid ethyl ester pyridin-7-yl}-piperazine-1-carboxylic acid 5-{3-[3-([1,3,4]thiadiazol-2-ylamino)-phenyl]-imidazo[1,2-a] hydrochloride pyridin-7-yl}-pyridin-2-ylamine,1. (4-{3-[3-([1,3,4]thiadiazol-2-ylamino)-phenyl]-imidazo[1,2-a]pyridin-7-yl}-piperazin-1-yl)-ethanone ,{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-[1,2,4]thiadiazol-5-yl-amine,N- (3-{3-[3-([1,3,4]Thadiazol-2-ylamino)-phenyl]-imidazo[1,2-a]pyridin-7-yl}-benzyl)-methanesulfonamide,Benzyl-{ 3-[7-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-amine,{3-[7- (2-Methyl- 2H-tetrazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-[1,3,4]thiadiazol-2-yl-amine. 13. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) as defined in any one of claims 1 to 12. 14. Compound according to any one of claims 1 to 12, characterized in that it is for use in therapy. 15. Use of a compound as defined in any one of claims 1 to 12, characterized in that it is for the manufacture of a medicine for the prophylaxis or treatment of cancer.