BRPI0721151A2 - COMPOUND OR AN ACCEPTABLE SALT, SOLVATE OR DERIVED PHARMACEUTICAL THEREOF, PROCESS FOR PREPARATION OF A COMPOUND, PHARMACEUTICAL COMPOSITION, USE OF A COMPOUND, AND METHODS FOR PROPHYLAXIS OR TREATMENT OF A DISEASE OR CONDITION OF THE CONDITION ) FOR A FGFR KINASE AND FOR PROPHYLAXY OR CANCER TREATMENT - Google Patents

Description

“COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT, SOLV ACT OR DERIVATIVE THEREOF, PROCESS FOR PREPARATION OF A COMPOUND, PHARMACEUTICAL COMPOSITION, USE OF A COMPOUND, AND METHODS FOR PROPHYLAXY OR TREATMENT OF A CONDITION OF A DISEASE OR CONDITION (A) FOR FGFR KINASE AND FOR PROPHYLAXY OR CANCER TREATMENT ”

FIELD OF 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

According to a first aspect of the invention a compound of formula (I) is produced:

H

being that

Xi, X2 and X3 are each independently selected from carbon or nitrogen, such that at least one of X1-X3 represents nitrogen;

3 Λ ·

X4 represents CR or nitrogen;

X5 represents CR6, nitrogen or C = zO;

provided no more than three of X1-X5 represent nitrogen;

------ represents a single or double bond, such that

that a bond within the 5-membered ring system is a double bond;

R3 represents hydrogen, halogen, C1-6 alkyl, C2-6

alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, cyano, haloC 1-6 alkyl, haloC 1-6 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 wherein said carbocyclic and heterocyclyl groups may be optionally substituted by one or more (e.g. 1,2 or 3) Ra groups;

R 2 and R 6 independently represent halogen, hydrogen, C 1-6 alkyl, CV 6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -C = N, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, -NHSO 2 Rw, -CH = N-ORw, an aryl or heterocyclyl group wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl and heterocyclyl groups may be optionally substituted by one or more Rb groups provided that both R2 and R6 do not represent hydrogen; Re, Rf and Rw independently represent hydrogen or Cw

alkyl;

Ra represents halogen, C1-6 alkyl, C2.6 alkenyl, C2 groups.

6 alkynyl, C3.8 cycloalkyl, C3-8 cycloalkenyl, -ORx, - (CH 2) n -0-C 1-6 alkyl, -0- (CH 2) n -0Rx, haloC 1-6 alkyl, halo C 6 alkoxy, Q6 alkanol, = 0.25 = S, nitro, Si (Rx) 4, - (CH2) sCN, -S-Rx, -SO-Rx, -SO2-Rx5 -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;

R 1, R 2 and R 2 independently represent hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkanol, hydroxyl, C 1-6 alkoxy, halo C 1-6 alkyl, -CO- (CH 2) n C 1-6 alkoxy, C 3. b cycloalkyl or C 3-8 cycloalkenyl;

R1 and Rb independently represent a Ra group or a -Y-carbocyclyl or Z-heterocyclyl group wherein said carbocyclyl and

heterocyclyl may optionally be substituted with one or more (e.g.

1,2 or 3) Ra groups;

VeW independently represent a bond or a group - (CReRf) n-;

YeZ 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;

s and t independently represent an integer from 0-

4;

q represents an integer from 0-2;

or a pharmaceutically acceptable salt, solvate or derivative thereof.

same,

provided that the compound of formula (!) is not:

6-chloro-4- [3- (7-methyl-imidazo [1,2-a] pyridin-3-yl) -phenyl] -benzamide

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 25 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 discloses a series of heterocyclic derivatives

DETAILED DESCRIPTION OF THE INVENTION According to a first aspect of the invention a compound of formula (I) is produced:

THE)

being that

X1, X2 and X3 are each independently selected from

carbon or nitrogen, such that at least one of Xi-X3 represents nitrogen;

3 · *

X4 represents CR or nitrogen;

X5 represents CR6, nitrogen or C = O;

provided no more than three of XpX5 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, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, cyano, haloC 1-6 alkyl, haloC 1-6 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 wherein said carbocyclic and heterocyclyl groups may be optionally substituted by one or more (e.g. 1,2 or 3) Ra groups;

R2 and R6 independently represent halogen, hydrogen, C1-6 alkyl, C1-6 alkoxy, C2.6 alkenyl, C2.6 alkynyl, -C = N, C3.8 cycloalkyl, C3.8 cycloalkenyl, -NHSO2 Rw, - CH = N-ORw, an aryl 10 or heterocyclyl group wherein said C 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl and heterocyclyl groups may be optionally substituted by one or more R b groups provided that both R 2 and R 6 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) n -0-C 1-6 alkyl, -0- (CH 2) n-0Rx, haloQ.6 alkyl haloC 1-6 alkoxy, C 1-6 alkanol, = O, = S, nitro, Si (Rx) 4, - (CH 2) sCN, -S-Rx, -SO-Rx, -SO 2 -Rx, -CORx, - (CRxRy ) s- COORz, - (CH2) s-CONRxRy, - (CH2) s-NRxRy, - (CH2) s-NRxCory, - (CH2) s-20 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, C2-6 alkynyl, C1-6 alkanol, hydroxyl, C1-6 alkoxy, halo C1-6 alkyl, -CO- (CH2) n- C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 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 by one or more (e.g.

1,2 or 3) Ra groups; VeW independently represent a bond or a group - (CReRt) n-;

YeZ 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 - (CH 2) s -SO 2 -;

n represents an integer from 1-4;

s and t independently represent an integer of O-

4;

q represents an integer from 0-2;

or a pharmaceutically acceptable salt, solvate or derivative thereof.

same,

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 the mine; or

N- [3- (7-methyl-imidazo [1,2-a] pyridin-3-yl) -phenyl] -N- (2-nitro)

phenyl) -amine.

In one embodiment, a compound of formula (I) is produced:

H

(!)

being that

X1, X2 and X3 are each independently selected from

carbon or nitrogen such that at least one of Xj-X3 represents nitrogen; ο

X4 represents CR or nitrogen;

X5 represents CR6, nitrogen or C = O;

provided no more than three of Xi-X5 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 5-membered ring system is a double bond;

R 3 represents hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-6 cycloalkenyl, cyano, haloC 1-6 alkyl, haloC 1-6 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 wherein said carbocyclic and heterocyclyl groups may be optionally substituted by one or more (e.g. 1,2 or 3) Ra groups;

R 2 and R 6 independently represent halogen, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -C = N, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, -NHSO 2 Rw, -CH = N-ORw, an aryl or heterocyclyl group wherein said C1-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, aryl and heterocyclyl groups may be optionally substituted by one or more Rb groups provided that both R2 and R6 do not represent hydrogen;

Re, Rf and Rw independently represent hydrogen or C} _6

alkyl;

Ra represents halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2 groups.

6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, -ORx, -0- (CH 2) n -ORx, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkanol, = O, = S, nitro, Si (Rx) 4, - (CH2) sCN, -S-Rx, -SO-Rx, -SO2-Rx, -CORx, - (CRxRy) s-COORz, - (CH2) s-CONRxRy, - (CH2) s-NRxRv, - (CH2) s-NRxCORy, - (CH2) s-NRxSO2-Ry, - (CH2) s-NH-SOrNRxRy, -OCONRxRy, - (CH2) s. NRxCO2Ry, -O- (CH2) s-CRxRy- (CH2) r OR7 or - (CH2) s-SO2NRxRy;

Rx, Ry and Rz independently represent hydrogen, C1.5 alkyl, C2- and alkenyl, C2.6 alkynyl, C1-6 alkanol, hydroxyl, C1-6 alkoxy, C1-6 alkyl, -CO- (CH2) n-C1.6 alkoxy C3-8 cycloalkyl or C3-3 cycloalkenyl;

R 1 and R b independently represent a Ra group or a -Y-aryl or -Z-heterocyclyl group wherein said aryl and heterocyclyl groups may be optionally substituted by one or more (e.g. 1,2 or 3) Ra groups;

VeW independently represent a bond or a group - (CReRf) n-;

YeZ 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 from 1-4;

s and t 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.

same,

provided that the compound of formula (!) 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.

(I):

being that

Xi, X2 and X3 are each independently selected from

carbon or nitrogen, such that at least one of Xi-X3 represents nitrogen;

Ί

X4 represents CR or nitrogen;

X5 represents CR6, nitrogen or C = O;

provided no more than three of Xi-X5 represent

nitrogen;

------ represents a single or double bond; R represents

hydrogen, halogen, C6 alkyl, C2.6 alkenyl, C2-6 alkynyl, Cw alkoxy, Cw cycloalkyl, C3.6 cycloalkenyl, cyano, haloCw alkyl, haloCw 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;

R 2 and R 6 independently represent hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl,

In one embodiment, a compound of formula is produced.

0) an aryl or heterocyclyl group wherein said aryl and heterocyclyl groups may be optionally substituted by one or more Rb groups provided that when R6 represents a heterocyclyl group, said heterocyclyl group is not pyrazolyl;

Ra represents halogen, C1-6 alkyl, C2.e alkenyl, C2-

8 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkenyl, -ORx, -0- (CH2) n -ORx, C1-6 alkyl, halo C1-6 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, halo C1-6 alkyl, -CO- (CH2) n-C1-6 alkoxy, C3.8 cycloalkyl or C 3-8 cycloalkenyl;

R1 and Rb independently represent a group Ra or a

-Y-aryl or -Z-heterocyclyl group wherein said aryl and heterocyclyl groups may be optionally substituted by one or more (e.g. 1,2 or 3) Ra groups;

provided that when R2 represents a different hydrogen group, X5 represents CH or C = O and when R2 represents hydrogen, R6 represents a different hydrogen group;

YeZ 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-;

m and n independently represent an integer from 1-4; s and t 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.

same.

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 'C 1-6 alkoxy' as used herein refers to a -O-C 1-6 alkyl group wherein C 1-6 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like.

The term 'C1-6 alkanol' as used herein refers to a C1-6 alkyl group substituted with one or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.

The term 'C3-S 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 'C 3-6 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 substituted by halogen. Examples of such groups include fluoroethyl, trifluoromethyl or trifluoroethyl and the like. The term haloC3 alkoxy as used herein refers to a C1-6 alkoxy group as defined herein wherein at least one hydrogen atom is substituted by halogen. Examples of such groups include difluoro methoxy or trifluoro methoxy and the like.

References to the "carbocyclic" and "heterocyclic" groups as used herein should, unless the context otherwise indicates, include both aromatic and nonaromatic ring systems. Thus, for example, the term "carbocyclic and heterocyclic groups" includes within its scope aromatic, nonaromatic, unsaturated, partially saturated, and fully saturated heterocyclic ring systems. In general, such groups may be monocyclic or bicyclic and may 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 commonly 9 or 10 ring members. Where 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 e.g. 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 by one or more (e.g. 1,2 or 3) Ra or Rb groups.

Carbocyclic or heterocyclic groups may 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 may be attached by the aromatic ring, or by a non-aromatic ring.

5 The term "non-aromatic group" includes ring systems

unsaturated unsaturated, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. The terms "saturated" and "partially saturated" refer to the rings wherein the ring structure (s) contain atoms sharing bond of more than 10 valence ie the ring contains at least one multiple bond eg one bond a C = C, C = C or N = C. The term "fully saturated" refers to rings where there are no multiple bonds between 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 may be, for example, a five-membered six-membered monocyclic ring or a bicyclic structure formed of two fused five- and six-membered rings or two fused six-membered rings, or two fused five-membered 25 rings. Each ring can contain up to about four typically selected nitrogen, sulfur and oxygen heteroatoms. 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. Nitrogen atoms in heteroaryl rings may be basic, as in the case of an imidazole or pyridine nitrogen, or essentially nonbasic as in the case of an indole or pyrrol nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group 5, including any ring amino group substituents, will be less than five.

Examples of five membered heteroaryl groups include but are not limited to pyrrol, furan, thiophene, imidazole, furrazane, 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 may 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- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

c) a pyrimidine ring fused to a ring of 5 or 6

members 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 ring heteroatoms;

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) an isothiazole ring fused to 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 5 or 6 membered ring fused furan ring containing 1, 2 or 3 ring heteroatoms;

m) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

n) an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

o) a cyclohexyl ring fused to a ring of 5 or 6

members 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 25 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-ajpyrimidine), 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, isochroman, benzodioxane, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, groups. quinazoline, cinolin, phitalazine, naphthyridine and pteridine.

Examples of polycyclic aryl and heteroaryl groups containing an aromatic ring and a nonaromatic ring include tetrahydro-naphthalene, tetrahydro-isoquinoline, tetrahydro-quinoline, dihydro-benzothiophene, dihydro-benzofuran, 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 nonaromatic 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 typically selected nitrogen, sulfur and oxygen heteroatoms. Typically the heteroaryl ring will contain up to 3 heteroatoms, for example 1,2 or 3, more usually up to 2 nitrogen, for example a single nitrogen. Nitrogen atoms in heteroaryl rings may be basic, as in the case of an imidazole or pyridine nitrogen, or essentially nonbasic as in the case of an indole or pyrrol 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, furazolyl, pyrazinyl, pyrimidinyl, triazinyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl, indolizinyl, isoindolinyl, purinyl (eg, adenine [6-amino-purine], guanine [2-amino-6-hydroxy-purine]), indazolyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, phthalazinyl, naphthyridinyl and pteridinyl.

Examples of polycyclic heteroaryl groups containing

Nitrogen containing an aromatic ring and a nonaromatic ring include tetrahydro-isoquinolinyl, tetrahydro-quinolinyl, and indolinyl.

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

Examples of nonaromatic heterocyclic groups are groups

having from 3 to 12 ring members, more usually 5 to 10 ring members. Such groups may be monocyclic or bicyclic, for example, and typically have heteroatomic ring members (more commonly 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-fiane and dioxane), cyclic thioether groups (eg as in tetrahydro-furan and dithian), cyclic amine groups (eg as in pyrrolidine), cyclic amide groups (eg as in pyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ureas (eg as in imidazolidin-2-one) cyclic ester groups (eg as in butyrolactone), cyclic sulfones (eg as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and combinations thereof (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, 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, 5-imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazone, piperazine, and N-alkyl piperazine 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 piperazine.

In a non-aromatic nitrogen-containing heterocyclic ring 10 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 pyrrolidinone, piperidone or caprolactam), cyclic sulfonamides (such as 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 heterocyclic groups

Nitrogen-containing compounds 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, -hydro-thiazole, imidazoline, imidazolidinone, oxazoline, thiazoline, 6H-1,2,5-thiadiazine, 2-pyrazoline, 3-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazine such as N-methyl piperazine.

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

As mentioned above, ----- represents a simple bond

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

Particular Modes of the Invention

Examples of ring systems included by the definitions of Xi-X5 are shown in the following formulas (I) to - (I) t: Other examples of ring systems included by the definitions of X1-X5 are shown in the following formulas (I) (I) v: In one embodiment, two bonds within the 5-membered ring system are double bonds.

In one embodiment, Xi represents C.

In one embodiment, X1, X3 and X5 represent C and X2 and X4 represent nitrogen (i.e. a ring system of formula (I) a).

In an alternative embodiment, X1, X3, X4 and X5 represent C and X2 represents nitrogen (i.e. a ring system of formula (I) e).

In an alternative embodiment, X1, X3 and X4 represent C and X2 and X5 represent nitrogen (i.e. a ring system of formula (I) f).

In an alternative embodiment, X1 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, X1, X2, X4 and X5 represent C and X3 represents nitrogen (i.e. a ring system of formula (I) j).

In an alternative embodiment, X1, X2 and X4 represent C and X3 and X5 represent nitrogen (i.e. a ring system of formula (I) k).

In an alternative embodiment, X 2, X 3, X 4 and X 5 represent C and X 1 represents nitrogen (i.e. a ring system of formula (I) q).

In an alternative embodiment, X 2, X 3 and X 5 represent C and X 1, and X 4 represent nitrogen (i.e. a ring system of formula (I) r).

In one embodiment, XrX5 represents a ring system of formulas (I) a, (I) and, (I) j or (I) q. In another embodiment, X1-X5 represents a ring system of formula (I) a or (I) j. In another embodiment, X1 -X5 represents a ring system of formula (I) j.

In one embodiment, when X1, X2 and X5 represent C, X3 represents nitrogen and A represents phenyl, B is a different group than a heterocyclic group.

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

In one embodiment, when X 1, X 3, X 4 and X 5 represent C, X 2 represents nitrogen and A represents pyrimidinyl, B represents a different group than a heterocyclic group.

In one embodiment, when Xj, X3 and X5 represent C and X2 and X4 represent nitrogen, Rd is a different group from = O.

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

In one embodiment, when X 2 and X 3 represent C and X 1 represents nitrogen, A represents a different group of pyrazinyl.

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

In one embodiment, when X4 represents nitrogen, X represents a different group of nitrogen.

In one embodiment, when X 5 represents CR 6 and R 6 represents a heterocyclyl group, said heterocyclyl group is different from pyrazole (e.g. optionally substituted pyrazole).

In one embodiment, when X1 and X2 represent carbon and X3 represents nitrogen, A represents a different group of pyridinyl or pyrimidinyl.

In one embodiment, when X 1 represents carbon, at least one of X 2, X 3, X 4 and X 5 is different from carbon. In one embodiment, when X 1 represents carbon and A represents pyrimidinyl, B represents a different group of phenyl.

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

In one embodiment, when Xj represents nitrogen, A represents pyrimindinyl, V represents - (CReRf) -, B represents a nonaromatic ring system.

In one embodiment, when Xj represents nitrogen, X2 and X3

represent carbon, A represents pyrimindinyl, V represents - (CReRf) -, B represents an aromatic ring system.

In one embodiment, when X1 represents nitrogen, A represents a different group of purin-2-yl.

Examples of ring systems included by definition A are

shown in the following formulas (I) A- (I) O:

(I) B Cr "rV (I) A (I) C (I) D ^ R1 ^ _ ^ R1 R1 R1 Il] (I) F (I) G (I) H (III) (I) E R1 R1 (I) K R1 r (T- (r- (4Vnh (I) J mVh (I) I (I) L (I) MT qr H1 (I) N (I) O ri nV ^ nh 0) L2 Group (I) L may be an imidazole tautomer eg (I) L2.

In one embodiment, A represents a group selected from any of formulas (I) A to (I) J and (I) L to (1) 0.

In one embodiment, A is a different group of 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 group - (CH2) sCONRxRy (eg -CONH2), - (CH2) sCN (eg -CN), C1-6 alkyl (eg methyl) or C1-6 alkoxy ( eg methoxy).

In one embodiment, A represents a ring system.

monocyclic aromatic carbocyclic or heterocyclic 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), C1-6 alkyl (eg methyl) ), C 1-6 alkanol (eg -CH 2 OH) 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 X1 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 the 5-position. When A represents phenyl, in one embodiment NH-B is present at the phenyl position-3 with respect to the binding position at X 1.

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 optionally further substituted with a single Ra group at the 3-position.

In another embodiment, A represents unsubstituted phenyl.

When VeW represents 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:

OO 0 0 HN ", ■ HN ΗΓ | \ B2 \ B4 B1 B3 to N ---, V, NO HN -0 / = H HN \ HN HN \ 85 \ B8 B6 B7 N ---, .0- ° »OH OH HN HN 0 HN \ \ HN Y B9 B10 \ B12 B11 £> · ί> 0 ΗΝ ^ \ ^ ί $ HN HN W / ^ 0 ΗΝ \ \ \ HN Β16 BI 3 Β14 \ Β15 V% 0 ί > / N HN HN H \ BI 7 Β18 S ^ ns "Xi HN O. Vn \ / NΒ19 HN Β21 HN • \ \ Β20 Β22 "Q Pnh HN ^ w hO HN HN HN HN Ν \ \ \ \ Β23 Β25 Β26 hO χ> HN ^ w HN Hl ^. ./~Ν" I \ Β2Θ HN Β30 Β27 \ Β29 ΗΝ ^ \. , Gn 1 / O0 k: 'HN HN / N / ~~ Ν • \ \ HN HN Β32 Β33 \ ■ \ Β34 Β31 OX) M Ο¬ A “N HN HN χ' N HN \ '\ HN \ Β36 Β37 Y Β35 Β38 X> HN & JQ- HN \ HN HN \ B40 \ \ B39 B41 842 HN Ü η H \ HN B45 HN B43 i ■ \ B44 B46 Ú HN \ B47 When VeW represent a bond, particular examples of B-rings include BI , 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 - (CReRt) n- (e.g. CH2), an example of an aromatic ring system included by the definition of B-NH- is shown in the following formula B48:

When VeW represents 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:

Table 1 H g ^ NH ..... 1 I> = ° HN ^ N xr O / N \ HN X HN H \ \ Λ ^ / ^ N f> ° Z = ^ s HN HI ^ / N Z- " In one embodiment, B represents -V-aryl. 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.

In 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 (e.g. phenyl, pyridyl, pyrazinyl, triazolyl or thiadiazolyl). In another embodiment, the heterocyclyl group of B represents a 5- or 6-membered heterocyclic ring (e.g. pyridyl, pyrazinyl, triazolyl or thiadiazolyl). In another embodiment, the heterocyclyl group of B represents a 5- or 6-membered heterocyclic ring (e.g. 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 Ba, Bb and Bc:

XaW

Xc

Xb

IO)

X Xd

*

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;

^ Xb

Xa- '\

V * V _

J Xc = O1S * ■> /

Xe ^ //

X Xd

*

Bb

where the dashed line ----- can represent a bond

single or double;

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; and

; represents the point of attachment in NH;

--Xb Xa ^ 'A I * Λ

:; xc

11 Sf

S ^ Xd

*

where the dashed line ----- can represent a bond

single or double;

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; and

Λ

4 *

represents the NH binding point. 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 O or 1. When q represents

1, in one embodiment, R 1 represents C 1-6 alkyl (e.g. methyl). When q represents 1, in an alternative embodiment, R1 represents or - (CH2) s-NRxRy (e.g. -NH2). In another embodiment, q represents 0.

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

In one embodiment, when R2 represents hydrogen, X5 represents CR6 wherein R6 represents a different group of hydrogen.

In one embodiment, when X 5 represents CH or nitrogen, R represents a different group of 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 different hydrogen group, R2 represents hydrogen.

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

In one embodiment, R 2 represents C 1-6 alkyl (e.g. methyl).

In one embodiment, R 2 represents halogen (e.g. chlorine).

In one embodiment, R 2 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 by one or more Rb groups.

In one embodiment, R 2 represents phenyl optionally substituted by an Rb group.

In one embodiment, R 2 represents an aryl (eg phenyl) group optionally substituted by one or more (eg 1,2 or 3) R groups selected from halogen (eg fluorine), haloC 4 alkoxy (eg -OCF 3), -ORx (eg methoxy or -OCH 2 OHCH 2 OH), C 1-6 alkanol (eg -CH 2 OH), - (CR x R y) s -COORZ 10 (eg -COOH, -COOMe, -C (Me) 2-COOH, -CH 2 -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-CH 2 -methoxy) or -0- (CH 2) n -ORx (eg -O- (CH 2) 2 -ethoxy).

In one embodiment, R 2 represents an aryl (eg phenyl) group optionally substituted with one or more (eg 1,2 or 3) Rb groups selected from halogen (eg fluorine), haloC 1-6 alkoxy (eg -OCF 3), -ORx (eg methoxy or -OCH2OHCH2OH), C1-4 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 -NH2, -NMe2, - (CH2) 2-NH2, -20 (CH2) 2-NMe2 or - NH-CO-CH2-methoxy), - (CH2) s -CONRxRy (eg -CONHMe or -CH2-CONHMe), - (CH2) s-NRxSO2-Ry (eg -CH2-NHSO2Me) or -0- (CH

2) n-ORx (e.g. -O- (CH 2) 2-ethoxy).

In another embodiment, R 2 represents an aryl (eg phenyl) group optionally substituted with one or more (eg 1,2 or 3) Rb 25 groups selected from halogen (eg fluorine), C 1-6 alkanol (eg -CH 2 OH), - (CH 2 ) s- NRxRy (eg -NH2), - (CRxRy) s-COORz (eg -CH2-COOH), - (CH2) s-CONRxRy (eg -CONHMe or -CH2-CONHMe), - (CH2) s-NRxSO2 -Ry (eg -CH 2 -NHSO 2 Me).

In one embodiment, R 2 represents an aryl (e.g. phenyl) group optionally substituted with a -Y-aryl (e.g. -Y-phenyl) group.

In one embodiment, Y represents -O- (CH 2) s- (e.g. -O-CH 2 -).

In one embodiment, R 2 represents an aryl (eg phenyl) group optionally substituted with a -Z-heterocyclyl group (eg -Z-morpholinyl, 5-Z-azetidinyl, -Z-pyrrolidinyl, -Z-tetrazolyl, -Z-piperidinyl, Z-piperazinyl) wherein said heterocyclyl group may be optionally substituted by one or more (eg 1,2 or 3) Ra groups selected from C 1-6 alkyl (eg methyl) or - (CRxRy) s-COORz (eg -COOH, -COOMe or -COOtBu).

In one embodiment, R 2 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 by one or more groups (eg 1,2 or 3) Ra groups selected from C 1-6 alkyl (eg methyl), = O (eg piperazin-2-one ) or - (CRxRy) s -COOR7 (eg -COOH, -COOMe or -COOtBu).

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

In another embodiment, R2 represents an aryl (eg phenyl) group optionally substituted with a halogen (eg fluorine), -Z-heterocyclyl (eg -CH2-morpholinyl, -CO-morpholinyl, -CH2-piperazinyl, -25 CH2- piperidinyl, -CH 2 -azetidinyl), - (CRxRy) s -COORz (eg -COOH or -C (Me) 2-COOH), wherein said heterocyclyl group may be optionally substituted by a C1-6 alkyl (eg methyl) group, or - (CRxRj) s -COORz (eg -COOH).

In one embodiment, R2 represents an aryl (eg phenyl) group optionally substituted with a -Z-heterocyclyl group (eg -CH2-morpholinyl, -CO-morpholinyl, -CH2-piperidinyl or -CH2-piperazinyl) wherein said heterocyclyl group may be substituted. 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).

2

In yet another embodiment, R represents an aryl (eg phenyl) group 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 substituted with a C1-6 alkyl (eg methyl) group.

In yet another embodiment, R 2 represents an aryl (e.g. phenyl) group optionally substituted with a halogen (e.g. fluorine) atom.

In one embodiment, R 2 represents a membered heterocyclyl group optionally substituted by one or more Ra groups.

In one embodiment, R 2 represents a 5 membered heteroaryl group optionally substituted with one or more Ra groups.

In one embodiment, R 2 represents a heterocyclyl group optionally substituted with an Rb group.

In one embodiment, R 2 represents a heterocyclyl group optionally substituted with a -Z-heterocyclyl group or - (CH 2) s -NR x R y.

In one embodiment, R 2 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, thiazolyl, thiazolyl, thiazolyl, thiazole, , isoxazolyl, benzodioxolyl, tetrahydro-triazolopyrazinyl or pyrimidinyl) optionally substituted with one or more (eg 1,2 or 3) Rb groups selected from groups = O (eg pyridinone or 5-oxo-4,5-dihydro 5 [1,2,4] oxadiazolyl) = S (eg thioxo-4,5-dihydro- [1,2,4] oxadiazole), halogen (eg fluorine), C 1-6 alkyl (eg methyl, ethyl, propyl , i-Pr or t-Bu), haloCw alkyl (eg -CH2-F, -CF3 or -CH2CF3), C3-8 cycloalkyl (eg cyclopropyl), - (CH2) s-NRxRy (e: g. NH 2), -ORx (eg hydroxyl, methoxy or -Oi-Pr), - (CH 2) n-

O-C1-6 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 (eg -NH2), - (CH2) 3-SO2NRxRy (eg -SO2-NMe2) or Cu6 alkanol ( eg -C (OH) (Me) 2 or -CH 2 OH).

In one embodiment, R 2 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) Rb groups. selected from groups = O (eg pyridinone), C1-6 alkyl (eg methyl), - (CH2) s-NRxRy (eg -NH2), -ORx (eg methoxy), -CORx (eg -COMe), - (CRxRy ) s-COORz (eg -COOEt), -SO2-Rx (eg -SO2Et) or Cu6 alkanol (eg -20 CH2OH).

2 · ·

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) R 6 groups selected from Cu 6 alkyl (eg methyl), - (CH 2) s-NRxRy (eg -NH2), -CORx (eg -COMe), - (CRxRy) s-COORz (eg -COOEt) or -SO2-Rx (eg -SO2Et).

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

In yet another embodiment, R 2 represents a heterocyclyl (e.g. pyridyl) group optionally substituted with a -Z-heterocyclyl group (e.g. -O-tetrahydro-pyranyl).

In yet another embodiment, R 2 represents a heterocyclyl (e.g. pyridyl) group optionally substituted with a - (CH 2) s -NRxR y (e.g. -NH 2) group.

In another embodiment, R represents oxazole, oxadiazole, triazole, tetrazole, pyrazole, thiadiazole, thiazole, imidazole or oxathiazole

optionally substituted with one or more groups Ra.

• 2 ·

In another embodiment, R 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 groups.

'y

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

2 .

In another embodiment, R represents oxadiazole (e.g. 1,3,4-

oxadiazole), tetrazole or thiadiazole (e.g. 1,3,4-thiadiazole) optionally substituted with a C 1-6 alkyl (e.g. methyl or methyl) or -S-Rx (e.g.-S-Me) group.

In another embodiment, R represents pyrazol 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, R 2 represents pyrazol optionally substituted with one or more Ra groups, for example one or two C 1-4 alkyl groups (e.g. methyl groups).

In another embodiment, R 2 represents oxazole, oxadiazole, triazole, tetrazole, imidazole, thiadiazole or oxathiadiazole substituted with one or two optionally substituted C 1-4 alkyl groups (e.g. CH 3, CH 2 OH) or a = O group.

In another embodiment, R 2 represents oxazole, oxadiazole, triazole, tetrazole, thiadiazole or oxathiazole substituted with one or two optionally substituted C 1-6 alkyl groups (e.g. CH 3, CH 2 OH).

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

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

In another embodiment, R 2 represents a heterocyclyl (e.g. pyridyl) group optionally substituted with a -Z-heterocyclyl group (e.g. -Z-piperazinyl, -Z-morpholinyl or -Z-piperidinyl).

In another embodiment, R 2 represents a heterocyclyl (e.g. pyridyl) group optionally substituted with a -Z-heterocyclyl group (e.g. -Z-piperazinyl, -Z-morpholinyl, Z-tetrahydro-pyranyl or -Z-piperidinyl).

In yet another embodiment, R 2 represents a heterocyclyl (e.g. pyridyl) group optionally substituted with a - (CH 2) s -NRxR y (e.g. -NH 2) group.

In one embodiment, R 2 represents halogen (e.g. fluorine or chlorine). In another embodiment, R2 represents halogen (e.g. chlorine).

In one embodiment, R2 represents C1-6 alkyl (e.g. methyl or

methyl) optionally substituted with one or more Rb groups (e.g. -CH 2 OH, -C (OH) (Me) 2 or -CF 3).

In one embodiment, R 2 represents C 3-8 cycloalkyl (e.g.

cyclopropyl).

In one embodiment, R 2 represents -CH = N-ORw (e.g. -CH = N-

OH or -CH = N-OMe).

In one embodiment, R2 represents -NHSO2Rw (e.g. -

NHSO 2 Me).

In one embodiment, R2 represents C1-6 alkoxy (e.g. methoxy or

ethoxy).

In one embodiment, R2 represents C2.6 alkynyl (e.g. ethinyl

• · B

or propynyl) optionally substituted with an R group (e.g. -C = C-

Si (Me) 4). In another embodiment, R 2 represents C 2-6 alkynyl (e.g. ethinyl) optionally substituted with an Rb group (e.g. -C 2 -C-Si (Me) 4). In another embodiment, R represents C 2-6 alkynyl (e.g. ethinyl) optionally substituted with an Rb (e.g. cyclopropyl) group.

In one embodiment, R represents -C = N.

In one embodiment, R 2 represents C 2-6 alkenyl optionally substituted with a group R b (e.g. -CH = CH-COOEt or -CH = CHCONHMe).

In one embodiment R 6 represents halogen, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2,6 alkenyl, C 2,6 alkynyl, -C = N, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, -NHSO 2 Rw, -. CH = N-ORw, or a 3-6 membered monocyclic heterocyclyl group wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and heterocyclyl groups may be optionally substituted by one or more Ra groups.

2 6

In a ReR embodiment they may be optionally substituted by an Rb group. In another embodiment R b includes a group Ra or -Y-aryl or -Z-heterocyclyl.

In one embodiment, YeZ 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, YeZ independently represent a bond, CO, -CH 2 -, - (CH 2) 2, - (CH 2) 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, - (CH 2) n - (e.g. -CH 2 -, - (CH 2) 2 or - (CH 2) 3) or -O-.

In one embodiment, Z represents a bond or -CH 2 -.

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

In one embodiment, Re, R1 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): (Ia) (Ib)

being that

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

B represents a non-heterocyclic or carbocyclic group.

aromatic or aromatic;

R4 and R5 independently represent hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 alkynyl, C3.8 cycloalkyl, C3-8 cycloalkenyl, C1-6 alkanol, haloC6-6 alkyl, - (CH2) n -NRxRy, - (CH 2) s -COORz, - (CH 2) n -0- (CH 2) m -OH, - (CH 2) n -aryl, - (CH 2) n-0-aryl, - (CH 2) n-heterocyclyl or - (CH

2) n-O-heterocyclyl wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, aryl and heterocyclyl groups may be optionally substituted by one or more (eg 1 , 2 or 3) Ra groups;

Rx, Ry and Rz independently represent hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkanol, hydroxyl, C1-6 alkoxy, halo C1-6 alkyl, -CO- (CH2) n-C1-6 alkoxy, C3.8 cycloalkyl or C3.8 cycloalkenyl;

R 2 independently represent hydrogen, an aryl or heterocyclyl group wherein said aryl and heterocyclyl groups may be optionally substituted by one or more Rb groups;

R d represents halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2 groups.

6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, -ORx, -0- (CH 2) n -ORx, haloC 1-6 alkyl, haloCw alkoxy, C 1-6 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) 1-ORzO- (CH2) s-SO2NRxRy;

R1 and Rb represent a group Ra or a group -Y-aryl or -Z-

heterocyclyl wherein said aryl and heterocyclyl groups may be optionally substituted by one or more (e.g. 1,2 or 3) Ra groups;

YeZ 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 -;

m and n independently represent an integer of

1-4;

4;

s and t independently represent an integer of O-

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.

same.

• 12 It will be appreciated that specific modalities of A, B, R, q and R

groups in formulas (Ia) and (Ib) above are as outlined here 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 (e.g. pyridin-4-yl);

B is benzyl, thiadiazol (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;

R 2 is an optionally substituted 6-membered ring such as phenyl, or pyridine, or an optionally substituted nitrogen-containing 5-membered heterocycle such as pyrazole or tetrazole, with optional substituents being selected from halogen eg fluorine, amino and C 1-4 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 (e.g. pyridin-4-yl);

B is benzyl, thiadiazol (e.g. [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 [1,2,4] oxadiazol-2-yl ;

R 2 is optionally halogen-substituted phenyl eg fluorine (such as 4-fluoro-phenyl), optionally amino-substituted pyridine (such as 4-amino-pyridin-2-yl), optionally methyl-substituted pyrazole (such as 1-methyl). 1H-pyrazol-4-yl) or tetrazol optionally substituted with methyl (such as 2-methyl-2H-tetrazol-5-yl).

In one embodiment, the compound of formula (I) is a sub-formula of (Ia) and is defined by a compound of formula (Ic):

(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, Beq are here

defined.

In particular R 2 is optionally substituted phenyl or a 5-6 membered monocyclic heterocycle. Particular preferences of R are as outlined above.

In one embodiment, the compound of formula (I) is a sub-formula of (Ia) and is defined by a compound of formula (Id):

(Id)

wherein Ra, R1, R2, B, L, n and q are as defined herein.

Particular preferences of variables Ra, R1, R2, Beq are here

defined.

In particular, in one embodiment R2 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 position 3 or position 4 of the phenyl ring. In one embodiment where the phenyl ring is substituted with Ra, the Ra group is at the 4-position of the phenyl ring. In one embodiment where the phenyl ring is substituted with Rb, where 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 Rb groups are selected from halogen (eg fluorine or chlorine), deuterium (eg D5), haloC1-f, alkyl (eg -CF3), haloCN6 alkoxy (eg -OCF3), -ORx (eg methoxy or -OCH2OHCH2OH ), C 1-6 alkyl (eg i-Pr), C 1-6 alkanol (eg -CH 2 OH), - (CR x R y) s -COOR 7 '(eg - COOH, -COOMe, -C (Me) 2-COOH, -CH 2 - COOH or -C (Me) 2-COOMe), - (CH2) sCN (eg -CN or -CH2CN), - (CH2) s-NRxRy (eg -NMe2, - (CH2) 2-NH2, -5 (CH2 ) 2-NMe2 or -NH-CO-CH2-methoxy), -0- (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- 10 NMe2).

In one embodiment R groups are selected from halogen (eg fluorine), haloCN6 alkoxy (eg -OCF3), -ORx (eg methoxy or -OCH2OHCH2OH), Cn6 alkanol (eg -CH2OH), - (CRxRy) s-COOR2 (eg -COOH, -COOMe, -C (Me) 2-COOH, -CH2-COOH or -C (Me) 2-COOMe), -15 (CH2) sCN (eg -CH2CN), - (CH2) s-NRxRy ( eg -NMe2, - (CH2) 2-NH2, - (CH2) 2-NMe2 or -NH-CO-CH2-methoxy) or -0- (CH2) n-ORx (eg -0- (CH2) 2- ethoxy).

In one embodiment Rb 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 by one or more (eg 1,2 or 3) Ra groups selected from CN 6 alkyl (eg methyl) groups or - (CRxRy) s -COORz (eg -COOH, -COOMe or -COOtBu) and where Z is CO, CH2 or a bond.

In one embodiment Rb groups are selected from the group -25 Z-heterocyclyl (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 by one or more (eg 1,2 or 3) Ra groups selected from CN 6 alkyl groups (eg methyl or methyl) , = O, -CORx (eg - COMe) or - (CRxRy) s-COOR2 (eg -COOH, -COOMe or -COOtBu) and where Z is CH2 or a bond.

In yet another embodiment, R 2 represents an aryl (e.g. phenyl) group optionally substituted with a halogen (e.g. fluorine) atom. In yet another embodiment, R 2 represents 4-fluoro-phenyl.

In one embodiment, the compound of formula (I) is a sub-formula of (Ib) and is defined by a compound of formula (Ie):

(Ie)

wherein Ra, R1, R2, B, L, n and q are as defined herein.

In one embodiment, the compound of formula (I) is a compound of formula (If):

(If)

wherein Ra, R1, R2, B, L, n and q 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 of 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 Gl [[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 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, o Procedure F8 [Benzyl- [3- (7-chloroimidazo [1,2-a] pyridin-3-yl) -phenyl] -amine], the starting material of Procedure A4c [3- (7-Chloro] imidazo [1,2-a] pyridin-3-yl) -phenyl] - [1,2,4] thiadiazol-2-yl-amine] and the procedure product Gl [[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] - [1,2,4] thiadiazole 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 preparing compounds of formula (!)

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

Compounds of formula (1) may be prepared according to synthesis methods well known to the skilled person. In particular compounds of formula (I) are readily prepared by palladium-mediated copulation chemicals between chlorine, bromine, iodine, or aromatic pseudohalogens such as trifluoromethanesulfonate (triflate) or tosylate compounds, and aromatic boronic acids or stanane derivatives. In particular, Suzuki copulation chemistry is widely applicable for synthesis of these compounds. The Suzuki reaction may be carried out under typical conditions in the presence of a palladium catalyst such as bis (tri-t-butylphosphine) palladium, tetrakis (triphenylphosph) palladium (0) or a paladacyclic catalyst. (eg the paladacyclic 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 dimethoxyethane or dioxane, and the reaction mixture is typically subjected to heating, for example to a temperature of 10 ° C. 80 ° 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 Route 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 may be cyclized under reflux with chloro-acetaldehyde to give the imidazopyridine ring. 7-Chloro-imidazo [1,2-a] pyridine in an appropriate solvent can then be iodinated for example using N-iodo succinimide at RT.

Appropriate functionality may then be added at the halogenated positions, for example using a variety of metal catalyzed reactions. In particular, suitably functionalized boronic acids or their boronane esters may react with aryl halide. This transformation, commonly known as the Suzuki reaction, has been reviewed by Rossi et al. (2004), Synthesis 15, 2419).

Suzuki's reaction is often performed in mixtures of water and organic solvents. Examples of suitable organic solvents include toluene, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile, N-methylpyrrolidinone, ethanol, methanol and dimethylformamide. The reaction mixture is typically subjected to heating, for example to a temperature above 100 ° C. The reaction is performed 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-butylphosphine) palladium (O), tris (dibenzylidene acetone) diaipaladium (O), bis (triphenylphosphine) palladium (II) chloride, 10% acetate. palladium (II), tetrakis (triphenylphosph) palladium (0), bis (tricyclohexylphosph) palladium (O), [1,1'-bis (diphenylphosph) ferrocene] dichloro palladium (II), dichloro-bis (tri-o-tolyl-phosphine) -palladium (II), 2 '- (dimethyl-amino) -2-biphenylyl-palladium (II) / dinorbonyl urea chloride complex and 2- (dimethylamino) -phenOcen-1-yl-palladium (II) chloride / dinorbonyl urea chloride. In some cases additional binders may be added to facilitate the copulation reaction. Examples of suitable binders include tri-t-butylphosphine, 2,2-bis (diphenylphosphino) -1,1-bisphenyl, triphenylphosphine, 1,2-bis (diphenylphosphino) ethane, 1,1 '- bis (diphenylphosphino) ferrocene, tricyclohexyl phosphine, 9,9-dimethyl-4,5-bis (diphenylphosph) xanthene, 1,3-bis (diphenylphosph) propane, 2 - (di-t-butylphospho) biphenyl, 2-dicyclohexylphosphino-2 '- (n, n-dimethylamino) biphenyl, tri-o-tolylphosphine, 2- (dicyclo hexylphosphino) biphenyl, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl biphenyl, tri (2-furyl) phosphine, 2-dicyclohexylphosph-2 ', 6'-dimethoxy-biphenyl and 2-di-tert-butyl-phosphino-2 ', 4', 6'-triisopropyl-biphenyl. General Route A

General Route B

Air / CYC

Air / CYC

Route

GeneralC

, B (OH).

Air / CYC

Scheme 1

Other examples of possible metal catalyzed functionalizations are reactions with organotin reagents (Stille reaction), Grignard reagents and reaction with nitrogen nucleophiles. An overview, and other key references, of these transformations are given 5 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 Hey-ichi Negishi, Wiley, ISBN 0-471-31506-0].

In particular, one reaction that can be used is the Buchwald-Hartwig type reaction (see Revision: J. F. Hartwig (1998), Angew. Chem.

Int. Ed. 37, 2046-2067) which provides a palladium catalyzed aryl amine synthesis medium. The starting materials are aryl halides or pseudohalides (e.g. 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 (Pd 2 (dba) 3), or 2,2'-bis (diphenylphosph) -1'-bisphenyl (BINAP).

In particular, for synthesis of compounds of formula (I) aryl halide may be reacted with 3-amino-benzene boronic acid using a suitable metal catalyst eg bis (triphenylphosphine) palladium (II) chloride to form the amino precursor for secondary amine binding formations.

This reaction sequence outlined in Route A can be alternated as outlined in Route B. Alternatively the halogen functionality at the 7-position of imidazo [1,2-a] pyridine can be converted to a 10 ester or boronic acid and used to synthesize motifs. alternatives as outlined in Scheme 2. This can then be used directly in any of the metal catalyzed reactions outlined herein. For example, for conversion of a halide to a boronate, the halide is reacted with a palladium catalyst and a phosphine binder in an appropriate solvent e.g. dioxane, and base e.g. KOAc, and the appropriate substituted boron compound.

General Route E,

Air

“-Q

The

Scheme 2

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

Scheme 3

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

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

Compounds of formula (I) containing a secondary amine group may be prepared from amino compounds by numerous methods. Reductive termination with an appropriately substituted aldehyde or ketone (a) may be performed 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 may be carried out in the presence of sodium triacetoxy borohydride in the presence of an aprotic solvent, such as dichloromethane, at or near ambient temperatures. They may also be prepared by reacting the amino compound in nucleophilic displacement reaction, wherein the reagent contains a leaving group such as a halogen.

In addition thiadiazolyl amino compound can be synthesized

by the use of appropriate substituted boronic acid in the Suzuki reaction eg 3 - ([1,2,4] thiadiazol-2-yl-amino) phenyl boronic acid pinacol-ester or 3- (5- methyl- [1,2,3,4-thiadiazol-2-yl-amino) -phenyl boronic acid. These can be synthesized as described herein. Alternatively the secondary amine may be formed by cyclizing an appropriate group to form a ring. Amino thiadiazole compounds can be synthesized as described in Scheme 4.

η

Scheme 4

This involves reaction of the amino compound in anhydrous solvent 5 e.g. toluene with 1,1-thiocarbonyl-di-2 (1H) -pyridone. Typical reaction conditions are heating for 1 hour, processing and then treatment with hydrazine hydrate to form thiosemicarbazide. It is then cyclized under conditions such as by the addition of diethyl chlorophosphate droplets. This can also generate the alternative cyclization product and as a consequence separation may be required.

Alternative heterocyclic groups may be formed by known heterocyclic ring formation reactions. For example amino-triazole (eg 3H- [1,2,3] triazol-4-yl) -amine) may be formed by the reaction of sodium nitrite in H 2 O with the amine in acid eg 2 H HCl, followed by 15 addition of amino acetonitrile hydrogen sulfate in H2O. After an appropriate period of time NaOAc is added and rearrangement to the desired heterocycle is performed by heating in solvent e.g. ethanol for 16 hours.

Suitable reagents and starting materials for these reactions may be obtained commercially or by any of numerous standard synthesis 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.

5 Many boronates, eg boronic acids or esters

Suitable boronic or trifluoro borates for use in the preparation of compounds of the invention are commercially available, for example from Boron Molecular Limited of Noble Park, Australia, or Combi-Blocks Inc. of San Diego, USA. Where the appropriately substituted boronate is not commercially available, they may 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 may be prepared by reaction of the corresponding bromine compound with an alkyl lithium such as butyllithium and then reaction with a borate ester e.g. 15 (1PrO) 3B. The reaction is typically carried out in a dry polar solvent such as tetrahydrofuran at a reduced temperature (e.g. -78 ° C). Boronate esters (for example a pinacolatoboronate) may also be prepared from a bromine compound by reaction with a diboronate ester such as tris (pinacolate) diboron in the presence of a phosphine such as tricyclohexyl phosphine and a reagent. of palladium (O) such as tris (dibenzylidene acetone) -dipaladium (0). Formation of the boronate ester is typically performed 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 may, if desired, be hydrolyzed to give the corresponding boronic acid or converted to trifluoro borate.

All of the reactions described above can be used to functionalize alternative heterocyclic models of formula (I), the synthesis of which is outlined below. PyrazoloT 1,5-alpyrimidines

The pyrazolo [1,5-a] pyrimidine model can be synthesized to

from the appropriately substituted amino pyrazole (VI) and fragments (VII) as shown in Scheme 5A, where Ra may be hydrogen or R1.

This can occur by a one-step or two-step process, where Xi and X2 are electrophilic carbons (ie carbonyl, masked carbonyl ie acetal, enamine, conjugated alkynes or alkenes) (Perkin I, JCS (1979), 3085-3094). . X 3 is a suitable substituent that a group R 2 either groups such as halogen or pseudohalogens which will allow reaction to introduce R2 10 as described herein. Cyclization of pyrazole (VI) with an appropriately substituted masked or free 1,3-carbonyl derivative may be used to prepare substituted pyrazolo [1,5-a] pyrimidines. Cyclization typically occurs in an alcohol or toluene or acetic acid solvent, and may have additives present such as piperidine, sodium ethoxide, HCl, AcOH, pTsOH, or

ZnCl 2 (J. Med. Chem. (2001), 44 (3), 350-361; Buli. Korean Chem. Soc. (2002), 23 (4), 610-612; Australian Journal of Chemistry (1985), 38 (1), 221-30).

Scheme 5A

A particular synthesis scheme for the preparation of 3,7-disubstituted pyrazolo [1,5-a] pyrimidines is outlined in Scheme 5B. THE

replaced as fragment VII with amino pyrazole. The substituted malonaldehyde may be substituted with the desired cyclic functionality e.g.

2- (4-fluoro-phenyl) -malonaldehyde, or with a latent functionality e.g. a halogen as in 2-bromo-malonaldehyde, which allows additional derivation

X »

(Vile)

(SAW)

Pyrazolopyrimidine ring is formed by the reaction of a malonaldehyde at this position as in the scheme shown below using the reactions outlined here.

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

or they may be prepared by analogy to known methods. Many pyrazoles of formula (VI) are commercially available. Alternatively they may be obtained by known methods e.g. 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) wherein Ra is hydrogen, halogen, nitro, ester, or amide to the desired R1 functionality by standard methods known as "R". A person

THE

H

Br

.0

Air

THE

Air

Air

Scheme 5B

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

Compounds of formula (VI) and (VII) are compounds known to those skilled in the art. For example, where R1 is halogen, copulation reactions with tin or palladium chemistry could be performed as described herein.

PyrazoloT 1,5-Alpyrazines

Scheme 6

Reaction of a mixture of 2-bromo-5-iodo-pyrazine and iodide

of copper (I) under inert conditions in a suitable solvent and base eg DMF / Et3N with ethinyl trimethyl silane 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-trimethylsilanyl-pyrazolo [1,5-a] pyrazine using O- (Mesitylene-sulfonyl) -hydroxyl-amine to form N-amino. -aduct. This can then be cyclized by reaction based e.g. on K 2 CO 3 to form the pyrazolopyrazine nucleus (Scheme 6).

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

Pyrazolo [1,5-alpyridines

3-Bromo-pyridine is reacted with the appropriately substituted boronic acid in a solvent such as in DME under inert conditions based (Na 2 CO 3) and a palladium catalyst to form 3-substituted pyridine (Scheme 7). 0- (Mesitylene sulfonyl) hydroxy amine is 10

15

It is then reacted with 3-substituted pyridine under inert conditions to form the N-amino pyridine which may be used without further purification. Cyclization of the N-adduct using base (K2CO3) and 2-benzenesulfonyl-3-dimethylamino acrylic acid methyl ester in an inert atmosphere gives the 3- acid ester pyrazolo [1,5-a] pyridine carboxylic acid. The carboxylic ester may be removed for example by saponification using sodium hydroxide to form the acid and then decarboxylation to polyphosphoric acid.

Scheme 7

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

Imidazo T4,5-bl pyridines

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 ).

^ ci

GC

N NHPh

CC.

Ph \ N

CO

Scheme 8

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

10 more

N

NH,

NaNO,

c HCI

AfNHj

EtjN1 NMP

100 “C

XX

NHPh

Air

Ai-B (OH) 3.

v € l

HCOjH

SO0C

Na2S

NH4Cl

MeOH

over there,

NHPh

Ac * Pd (PPfij) 4

1,3-propanediol

NaiCO3 (aqy

DMe

Scheme 9

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

Imidazor4,5-clpyridines

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

Cul1 KiCOs

1,10-phenanthroline

CHWlF 110 * 0

Air

\

CO

Figure 10

It is reported that regioisomeric products may be separated by chromatography. A possible way to further elaborate this material to give the desired substitution pattern is illustrated below (Scheme 11). R '= aryl, NR1R2 χ = Halogen, OR

Scheme 11

Reaction with an oxidizing agent, such as 3-chloroperbenzoic acid, could be used to prepare N-oxide that can be rearranged to 3 H -imidazo [4,5-c] pyridine with various reagents e.g. POCl 3, SOCl 2. The regioisomeric products could then be separated by chromatography. Displacement of X to give aryl- and amino-substituted products could be accomplished by reacting 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 chlorine group may 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 may be used in conversion such as a carbamate or benzyl group. Subsequent elaboration for the N-aryl compounds could then be performed according to the 15 conditions shown in Scheme 10.

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

I. AfNH2 NMP HOaC -: -

Br Z Zinc OH. 60 eC

3. HG (OEt) j, 100 ° C

Ar Ò

Br

Ar1B (OH) 1

--- J ».

P (HPPhj) 4 NaiCps Dioxane / HjO oil

Ar \ N

ih

N

Ouch1

Figure 13

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

Imidazof 1,2-clpyrimidines

Disubstituted imidazo [1,2-c] pyrimidines may be prepared as outlined in Scheme 14.

J Ar

____ / Kn ^ n _ ^ h ^ h

'Cl NiNAcl

Air / C VC

H

■ N

Air / CYC

Ar N '

-N

Air / CYC Figure 14

It starts from 7-chloro-imidazo [1,2-c] pyrimidine, the synthesis of which has been described in Yanai et al., Heterocyclic 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 US4503050 (Scheme 15).

N - ^ = N

THE

Air

N

THE

The

Figure 15

Where the 7-position is an aryl or heteroaryl group the S1 Ar group may be substituted with a standard palladium cross-coupling reaction using similar chemicals as described herein (Scheme 16).

^ '^' Ν

H2N Cl H2N ^ Ar

I. Air

N

ImidazoT 1,2-clpyrimidin-5-one

3,7-Disubstituted Ar 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 IAteneo 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 at position 7 (Scheme 17). This compound can then be iodinated as described above prior to further functionalization using the Suzuki reaction.

iodation

SwAr

I °

iodination L.A.

NH

'CYC N CYC

Scheme 17

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 herein (Scheme 18).

! i? k. THE

iNation “N NH

Figure 18

In addition, other oxoheterocycles could be synthesized from the appropriate chloro-derivative by hydrolysis. The protected compound would be subjected to basic hydrolysis to give the pyridone. This could be performed with NaOH (or NaOH / H2O2) in H20 / Me0H or H2OAdioxane following H2N '

Air

'Air

Air

Air

Air

Scheme 19

The synthesis of the Imidazo [1,2-b] pyridazine nucleus can be

performed as described in Scheme 19 using a pyridazin-3-ylamine derivative as reported in J. Heterocyclic Chem. (2002), 39 (4), p737-742. Introduction of substituents at position 3 is exemplified in J. Med. Chem (2006), 49 (4), p2335-1238 to give 3,7-substituted compounds.

well known, 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).

protect one or more groups to prevent reaction from occurring at an undesirable location in the molecule. Examples of protecting groups, and methods of protecting and unprotecting functional groups, can be found.

rd

in "Protective Groups in Organic Synthesis" (Green, T. and Wuts, P. (1999); 3 Edition; John Wiley and Sons).

A hydroxyl group may be protected, for example, as

an (-OR) ether or (-OC (= O) R) ester, for example as: a t-butyl ether;

Other heterocycles may be synthesized using reactions

In many of the reactions described above, a benzyl, benzhydryl (diphenyl methyl), or trityl (triphenyl methyl) ether may be required; a trimethyl silyl or t-butyl dimethyl silyl ether; or an acetyl ether (-O C (= O) CH 3, -OAc). An aldehyde or acetone group may be protected, for example, as an acetal (R-CH (OR) 2) or ketal (R2C (OR) 2), respectively, in which the carbonyl group (> C = 0) is converted in 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 amino group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example as: a methyl amide (-NHCO-CH3); a benzyloxy amide (-NHCO-OCH 2 C 6 H 5, -NH-Cbz); as a t-butoxy amide (-NHCO-OC (CH3) 3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC (CH3) 2C6H4CeH5, -NH-Bpoc), such as a 9-fluorenyl methoxy-amide (-NH-Fmoc), such as a 6-nitro-veratryloxy- (-NH-Nvoc) amide as a 2-trimethylsilyl methyl oxide amide (-NH-Teoc), 15 as a 2,2,2-trichloro methyl oxide amide (-NH-Troc) as an allyl oxyamide (-NH-Alloc) or as a 2- (phenylsulfonyl) methyloxy amide (-NH-Psec). Other amine protecting groups, such as cyclic amines and heterocyclic N-H groups, include toluenesulfonyl (tosyl) group and methanol sulfonyl (mesyl) and benzyl groups such as a para-methoxy benzyl 20 (PMB) group. A carboxylic acid group may be protected as an ester for example as: a C1-7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a C1-7 alkyl ester (e.g., C1-7 trihaloalkyl ester); tri C1-7 alkyl silyl-C1-7 alkyl ester; or a C 5-20 aryl-C 1-7 alkyl ester (e.g., a benzyl ester; a nitro-benzyl ester); or as an amide, for example as a methyl amide. A thiol group may be protected, for example, as a thioether (- SR), for example as: a benzylthioether; an acetamido methyl ether (-S-CH 2 NHC (4 O) CH 3).

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

Another aspect of the invention is a process for the preparation of a compound of formula (I) as defined herein, which process comprises:

(i) the reaction of a compound of formula (XX) or (XXI):

H2N-A

Y

H2N-A

X1-

<f f3>

R2

R2

(XX) <xxd

or a protected form thereof with an appropriately substituted aldehyde or ketone (a); or

(ii) the reaction of a compound of formula (XX) or (XXI):

H2N-A

X y

40χ

</ I3 I5

R2

(XX) (XXi)

or a protected form thereof with hydrazine hydrate and then cyclization; and then removal of any protecting groups present; or wherein X1, A and R2 are as defined herein; and optionally thereafter converting a compound of formula (I) into another compound of formula (I).

Pharmaceutical salts, solvates or derivatives thereof

acceptable

In this section, as in all other sections of this application, the

Unless the context otherwise indicates, references to formula (I) include references to all of its other subgroups, preferences and examples 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, down, beneath, underneath, downwards, downhill; preferably their ionic forms, or salts or tautomers or isomers or N-oxides or solvates; and more preferably ionic forms, or salts or tautomers or solvates or protected forms thereof. Many compounds of formula (I) may exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of the invention, and references to the compounds of formula (I) include salt forms of the compounds.

Salts of the present invention may be synthesized from the parent compound containing 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 may be prepared by reacting the free base or acid forms of these compounds with the appropriate acid or base. (a) in water or an organic solvent, or a mixture of both; 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 both organic and inorganic acids. 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, benzene sulfonic, benzoic acids , 4-acetamido-benzoic, butanoic, (+) - camphoric, camphor sulfonic, (+) - (lS) - camphor-10-sulfonic, caprioco, caprylic, caprylic, cinnamic, cyclic, dodecyl sulfuric, ethane -1,2-disulfonic, ethanesulfonic, 2-hydroxy-ethanesulfonic, formic, fumaric, galactaric, gentisic, glycoheptenoic, D-glucuronic (eg D-glucuronic), glutamic (eg L-glutamic), α -oxo-glutaric, glycolic, hyperuric, hydrobromic, hydrochloric, hydroiodic, isethionic, lactic (eg (+) - L-lactic, (±) -L-lactic), lactobionic, maleic, malic, (-) - L-malic , malonic, (±) -DL-mandelic, methanesulfonic, naphthalene sulfonic (egnaphthalene-2-sulfonic), naphthalene-1,5-disulfonic, 1-hydroxy-2-naphthoic, ni cotinic, nitric, oleic, orotic, oxalic, palmitic, pamic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+) - L-tartaric, thio- cyanic, toluene sulfonic (eg p-toluenesulfonic), undecylenic and valeric, as well as acetylated amino acids and cation exchange resins.

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

Another group of acid addition salts includes salts formed from the acetic, adipic, ascorbic, aspartic, citric, DL-Lactic, fumaric, glyconic, glucuronic, hyperuric, glutamic, DL-malic, methanesulfonic, sebacic acids. , stearic, succinic and tartaric.

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

If the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO '), then a salt may 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 + NR4 +).

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, 5 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 may 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).

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 that are not pharmaceutically acceptable may also be prepared as intermediate forms which may 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 (!) Containing an amino function may also form N-oxides. A reference herein to a compound of formula (I) which contains an amino function also includes N-oxide.

Where a compound contains several amine functions, one or more

than a nitrogen atom can be oxidized to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or nitrogen atom of a nitrogen-containing heterocycle.

N-Oxides may 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 may be prepared by the LW Deady procedure (Syn. Comm. (1977), 7, 509-514) in which the amino compound is reacted with m-chloro peroxy 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 however 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 (shown below), imine / enamine, amide / imino alcohol, amidine / amidine, nitrous / oxime, thio ketone / enetiol, and nitro / aci-nitro.

01 OH

keto

enol enolate

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 (I) include all their optical isomeric forms (eg, enantiomers, epimers and diastereoisomers) either as individual optical isomers, as mixtures (eg racemic mixtures) or as two or more optical isomers, unless context 25 requires otherwise.

Optical isomers can be characterized and identified by their optical activity (ie + and - isomers, or 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, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and also see Cahn, Ingold & Prelog (1966) Angew. Chem. Int. Ed. Engl., 5, 385-415.

Optical isomers may 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 may be separated by the formation of diastereoisomeric salts with chiral acids such as (+) - tartaric acid, (-) - pyroglutamic acid, (-) - di-toluoyl-L-tartaric acid, (+) - Mandelic, (-) - malic acid, and (-) - camphorsulfonic acid, separation of diastereoisomers by preferential crystallization, and then dissociation of salts to give the individual free base enantiomer.

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 diastereoisomers. Accordingly, the invention provides compositions containing a compound of formula (I) having one or more chiral centers, 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 diastereoisomer). 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). The 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

12 3

Reference to hydrogen includes within its scope H, H (D), and H (T). Similarly, references to carbon and oxygen include within their scope 12C, 13C and 14C and 16O and 18O respectively.

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 may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.

Esters such as carboxylic acid and acyloxy 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) 0R, wherein R is an ester substituent, for example a C1-7 alkyl group, a C3.20 heterocyclyl group, or a C5-aryl group, preferably a C1-7 alkyl group . Particular examples of ester groups include, but are not limited to, -C (= O) OCH 3, -C (= O) OCH 2 CH 3, -C (= O) OC (CH 3) 3, and -C (= O) 0Ph. Examples of acyl oxyl (inverse ester) groups are represented by -OC (zO) R, where R is an acyl oxyl substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5.20 aryl group preferably a C1-7 alkyl group. Particular examples of acyloxy groups include, but are not limited to, -OC (= <)) CH 3 (acetoxy), -OC (^ O) CH 2 CH 3, -0 C (= 0) C (CH 3) 3, -0C ( = 0) Ph, and - 0C (= 0) CH 2 Ph. 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 metal complexes) of the compounds, and prodrugs of the compounds. "Prodrugs" has for example the meaning 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 (= 0) 0R) is cleaved to give the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid (-C (= O) OH) groups in the parent compound, with, where appropriate, prior to the protection of any other reactive groups present in the parent compound, followed by by unprotection if required.

Examples of such metabolically labile esters include those of formula -C (= 0) 0R where R is:

C 1.7 alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);

C 1-7 aminoalkyl (e.g., amino methyl; 2- (N, N-dimethylamino) methyl; 2- (4-morpholino) methyl); and

acyl-C 1-7 alkyl (eg, acyl-oxymethyl; acyl-oxymethyl; pivaloyl-oxymethyl; acetoxy-methyl; 1-acetoxy-methyl; 1- (1-methoxy-1-methyl) methyl-methyl carbonyoxymethyl; - (benzoyloxy) methyl; isopropoxycarbonyloxymethyl;

1-isopropoxycarbonyloxyoxymethyl; cyclohexylcarbonyloxy-

methyl;

1-cyclohexylcarbonyloxymethyl;

cyclohexyloxycarbonyloxyoxymethyl;

1-cyclohexyloxycarbonyloxyoxymethyl; (4-tetrahydro-pyranyloxy) carbonyloxymethyl; 1- (4-Tetrahydro-pyranyloxy) -carbonyloxy-methyl;

(4-tetrahydro-pyranyl) carbonyl-oxymethyl; and 1- (4-tetrahydropyranyl) carbonyloxyethyl).

Also, some prodrugs are enzymatically activated 5 to give the active compound, a compound that, under another chemical reaction, gives the active compound (for example as an antigen-directed enzyme prodrug therapy (ADEPT)). gene-directed enzyme prodrug (GDEPT) and ligand-directed enzyme prodrug therapy (LIDEPT), etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may 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 a

compound as defined herein or a salt, tautomer, N-oxide or solvate thereof.

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

References to the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) 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 disease conditions or conditions mediated by those particular tyrosine kinases FGFR.

FGFR

The protein tyrosine kinase receptor (PTK) fibroblast growth factor (FGF) family regulates a diverse variety of physiological functions including mitogenesis, wound healing, cell differentiation and angiogenesis, and development. Both growth and proliferation of normal and malignant cells 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 hormone-dependent cancers to a hormone-independent state (Powers, et al. (2000) Endocr. Cancer Report, 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. In addition, numerous oncogenes are homologous to growth factor receptor coding genes, and there is potential for aberrant FGF-dependent signaling activation in human pancreatic cancer (Ozawa, et al. (2001), Teratog. Carcinog. Mutagen., 21,27-44).

The two prototypic members are acid 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) receptor tyrosine high affinity transmembrane protein tyrosine numbered 1 through 4 (FGFR1 to FGFR4). Under ligand binding, the receptors dimerize and auto- or trans-phosphorylate specific cytoplasmic tyrosine residues to transmit an intracellular signal that ultimately regulates nuclear transcription factor effectors.

FGFR1 pathway disruption should affect tumor cell proliferation because this kinase is activated in many tumor types in addition to endothelial cell proliferation. 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. Fibroblast growth factor receptor 2 mutations, it has been shown that fibroblast growth factor receptor 2 mutations, leading to complex functional changes, 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's syndrome (Lajeunie et al, European Journal of Human Genetics (2006) 14, 289-298). Particular mutations of FGFR2 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 25 fibroblast growth factor receptor 2 mutations. Most, if not all, Pfeiffer's Syndrome (PS) cases 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 has recently been shown that fibroblast growth factor receptor 2 mutations break down. one of the cardinal rules governing ligand specificity. Namely, two forms of fibroblast growth factor receptor mutant publishing, 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 fibroblast growth factor receptor 2 ectopic ligand-dependent activation (Yu, et al. (2000), Proc. Natl. Acad Sci USA 97,14536-14541).

Genetic aberrations of FGFR3 receptor tyrosine kinase such as point mutations or chromosomal translocations result in constitutively active ectopically expressed or dysregulated FGFR3 receptors. Such abnormalities are linked to a subset of multiple myelomas and in oral, squamous cell, hepatocellular, and bladder carcinomas (Powers, CJ (2000), et al., Endocr. King. 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 overexpressed in bladder cancer, particularly invasive bladder cancer. FGFR3 is often 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 without detectable mutation showed overexpression, including many muscle-invasive tumors.

As such, FGFR inhibiting compounds will be useful in providing means of preventing growth or inducing apoptosis in tumors, particularly by inhibiting angiogenesis. Therefore the compounds are expected to prove useful in treating or preventing proliferative disorders such as cancers. In particular tumors with receptor tyrosine kinase activating mutants or receptor tyrosine kinase over-regulation 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, I; Wang et al. (2004) Clinical Cancer Research, 10). In addition a germline polymorphism (Gly388Arg) is associated with an increasing incidence 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 are generally lacking p53 and FIer2 expression while maintaining estrogen receptor expression. 8pl2-pll.2 gene amplification has been demonstrated in -50% of CLC cases and has been shown to be linked to increased expression of FGFR1. Preliminary studies with siRNA directed against FGFR1, or a small molecule receptor inhibitor, have shown 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.

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma probably results from abnormal proliferation and differentiation during skeletal mitogenesis. FGFR1 is overexpressed in primary rhabdomyosarcoma tumors and is associated with 5'CpG island hypomethylation 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 considered as a result of the actions of various cytokines (including tumor necrosis factor (TNF), fibroblast growth factors (FGFs), platelet derived growth factor (PDGF) and Transforming Growth Beta (TGFP) involved in fibroblast proliferation and deposition of cell matrix proteins (including collagen and fibronectin) This results in altered tissue function and structure and subsequent pathology.

Numerous preclinical studies have shown the over-regulation of fibroblast growth factors in preclinical models of lung fibrosis (Inoue, et al. (1997 &2002); Barrios, et al. (1997)). TGFpi and PDGF have been reported to be involved in the fibrogenetic process (reviewed by Atamas & White, 2003) and another published study suggests that elevation of FGF's and consequent increase in fibroblast proliferation may be in response to elevated TGFpi (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) on idiopathic pulmonary fibrosis (IPF).

Idiopathic pulmonary fibrosis (also called cryptogenic fibrous alveolitis) is a progressive condition involving lung healing. Gradually, the air sacs in the lungs become replaced by thicker fibrotic tissue, causing an irreversible loss of tissue capacity 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 series 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 that leads 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 replacement of blood vessels, 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, except for 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 found 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 angiogenesis involvement 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 endothelial cell activation by an angiogenic signal; synthesis and release of degrading enzymes; endothelial cell migration;

5 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, operating by various 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. 15 Natl. Cancer Inst, 87, 293).

Receptor tyrosine kinases (RTKs) are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand binding domain connected through a segment 20 in the plasma membrane into an intracellular tyrosine kinase domain. Binding of receptor at the receptor results in stimulation of receptor-associated tyrosine kinase activity that results in the phosphorylation of tyrosine residues on both the receptor and the other intracellular proteins, leading to a variety of cellular responses. To date, at least 25 nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified.

Vascular Endothelial Growth Factor (VEGF), a polypeptide, is mitogenic to in vitro endothelial cells 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.l, 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-I (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. VEGFR-2 activation by VEGF is a critical step in the signal transduction pathway that initiates tumor angiogenesis. VEGF expression may be constitutive for tumor cells and may also be up-regulated in response to certain stimuli. One such stimulus is hypoxia, where VEGF expression is overregulated in both tumor tissues and associated host tissues. VEGF ligand activates VEGFR-2 by binding to its extracellular VEGF binding site. This leads to VEGFRs receptor dimerization and auto-phosphorylation of tyrosine residues in the VEGFR-2 extracellular kinase domain. The kinase domain operates to transfer an ATP phosphate to the tyrosine residues, thereby producing binding sites for signaling. of proteins downstream of VEGFR-2 finally leading to initiation of angiogenesis (McMahon, G. (2000), The Oncologist, 5 (90001), 3-10).

Inhibition at VEGFR-Kinase domain binding site

2 would block tyrosine residue phosphorylation and serve to disrupt the initiation of angiogenesis. Angiogenesis is a physiological process of new blood vessel formation mediated by various cytokines called angiogenic factors. Although its potential pathophysiological role in solid tumors has been extensively studied for over 3 decades, intensification of angiogenesis in chronic lymphocytic leukemia (CLL) and other malignant haematological disorders has been recognized more recently. An increased level of angiogenesis has been documented by several experimental methods in both lymph nodes and bone marrow of CLL patients. 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. It has also been shown that biological markers of angiogenesis are 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. Selection of a tumor vasculature has been proposed to limit tumor expression and could be a useful cancer therapy. Tumor growth observations have indicated that small tumor masses may persist in a tissue without any tumor-specific vasculature. Growth arrest of non-vascularized tumors has been attributed to the effects of hypoxia in the center of the tumor. More recently, a variety of proangiogenic and antiangiogenic factors have been identified and have led to the concept of "angiogenic change", a process in which disruption of the normal ratio of angiogenic stimuli and inhibitors in a tumor mass allows for autonomous vascularization. Angiogenic change appears to be governed by the same genetic changes that lead to malignant conversion: oncogen activation and loss of tumor suppressor genes. Several growth factors act as positive regulators of angiogenesis. Chief among 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 markedly disrupts angiogenic change, persistent angiogenesis, and early tumor growth in a mouse model. In late-stage tumors, phenotypic resistance to VEGFR2 blockade emerged because tumors grew back 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 proangiogenic factors, including members of the FGF family. These other proangiogenic signs are functionally implicated in revascularization and tumor regrowth in the evasion phase, because FGF blockade impairs progression upon VEGF inhibition. Inhibition of VEGFR2 but not VEGFR1 notably disrupted angiogenic change, persistent angiogenesis, and early tumor growth. In end-stage tumors, phenotypic resistance to VEGFR2 blockade emerged because the tumors recurred 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 proangiogenic factors, including members of the FGF family. These other proangiogenic signs are functionally implicated in revascularization and tumor regrowth in the evasion phase, because FGF blockade impairs progression upon VEGF inhibition.

It has been previously reported that an FGF-trap adenovirus binds on and blocks several FGF family ligands, including FGFl, FGF3, FGF7, and FGF10, thereby effectively inhibiting angiogenesis in vitro and in vivo. In fact, addition of FGF-trap treatment in the growth phase of a mouse model produced a significant decrease in tumor growth compared with anti-VEGFR2 alone. This decrease in tumor burden was accompanied by a decrease in angiogenesis that 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 logical reason for the use of AZD2171 was partially based 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, with the use of 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 over-regulation leading to a decrease in interstitial pressure and permeability within the tumor (Winkler et al., 2004, Cancer Cell 6, 553-563 ). The normalization window can be quantified using magnetic resonance imaging (MRI) using gradient-echo, spin-echo, and contrast enhancement to measure blood volume, relative vessel size, and vascular permeability.

The authors showed that progression on AZD2171 treatment was associated with an increase in CPBs, SDF1, and FGF2, whereas progression after drug interruptions correlated with increases in plasma levels of FGF2 and circulating progenitor cells (CPCs). The increase in plasma SDFl and FGF2 levels correlated with MRI measurements demonstrated an increase in relative vessel size and density. Thus, MRI determination of vessel normalization in combination with circulating biomarkers provides an effective means to evaluate 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 factors and growth inhibitors. In normal tissue the production and activity of these factors results in differentiated cell growth in a controlled and regulated manner that maintains the normal integrity and functioning of the organ. 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 via surface tyrosine kinase receptors (PDGFR) and stimulate various cellular functions including growth, proliferation, and differentiation. PGDF expression has been demonstrated in numerous different solid tumors including glioblastomas and prostate carcinomas. Imatinib tyrosine kinase inhibitor, 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 activity of the Bcr-Abl oncoprotein and c-Kit surface tyrosine kinase receptor, and as such is approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Imatinib mesylate is also a potent inhibitor of PDFGR kinase and is currently being evaluated for the treatment of chronic myelomonocytic leukemia and glioblastoma multiforme, based on the evidence in these diseases of PDGFR activating mutations. In addition, soraenenib (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 Raf signaling pathway to inhibit cell proliferation and 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. PDGFR activation is also associated with other malignancies, which include chronic myelomonocytic leukemia (CMML). In another disorder, protuberant dermatofibrosarcoma, an infiltrative skin tumor, a reciprocal translocation involving the PDGF-B ligand coding gene results in constitutive chimeric ligand secretion 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 for 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 or platelet-derived growth factor receptor (PDGFR) inhibitory inhibitor, and which will be useful in preventing or treating the conditions or disease states 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 prevention or prophylaxis or treatment of an unhealthy condition or condition such as cancer influence within its scope the alleviation or reduction of cancer incidence.

As used herein, the term "modulation", as applied to the activity of a kinase, is intended to define a change in the level of protein kinase biological activity. Thus, modulation accompanies physiological changes that affect an increase or decrease in the relevant protein kinase activity. In the latter case, modulation may be described as "inhibition". Modulation may begin directly or indirectly, and may be mediated by any mechanism and at any physiological level, including for example at the level of gene expression (including for example transcription, translation and / or post-translation modification), at the expression of genes encoding regulatory elements that act directly or indirectly on kinase activity levels. Thus, modulation may imply elevated / suppressed expression or over or under expression of a kinase, including gene amplification (ie multiple gene copies) and / or expression increased or decreased by a transcriptional effect as well as hyper- ( or hypo-) activity and (dis) activation of protein kinase (s) (including (dis) activation) by mutation (s). The terms "modulated", "modulation" and "modular" 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 in a limited manner so that The various processes, diseases, states, conditions, treatments, and interventions to which the term is applied are those in which 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 the 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 diseases, states or conditions Kinase-mediated studies 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 kinase may be direct or indirect and may be necessary and / or sufficient for treatment operation, prophylaxis or intervention outcome. Thus, a kinase-mediated disease state or condition includes the development of resistance to any particular cancer treatment or drug.

Thus, for example, it is contemplated 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 FGFRs selected from FGFR1, FGFR2 and FGFR3, as well as FGFR4. Preferred compounds of the invention are those having IC 50 values less than 0.1 μΜ.

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, inhibit PDGFR A and / or PDGFR B.

In addition many of the compounds of the invention exhibit selectivity for FGFR 1,2, and / or 3 kinase, 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 which are between one tenth and one hundredth of 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-fold 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 herein.

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

In particular tumors with VEGFR activating mutants or VEGFR up-regulation and patients with elevated serum lactate dehydrogenase 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 may express VEGFR. Also, particular tumors with activating mutants or up-regulation 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. They may also find treatment with the compounds of the invention particularly beneficial. It may be preferred that the treatment be 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, ovaries, pancreas eg exocrine pancreatic carcinoma, stomach, cervix, endometrium, thyroid, prostate, or skin, for example squamous cell carcinoma; a lymphoid lineage hematopoietic tumor, for example leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or capillary lymphoma. Burkett; a hematopoietic tumor of myeloid lineage, for example leukemia, acute and chronic myelogenous leukemia, myeloproliferative syndrome, myelodysplastic syndrome, or promyelocytic 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 may be due to tumor type or may occur 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 myeloid leukemia, chronic granulocytic leukemia or CML. Also, acute myeloid leukemia, is also called acute myeloblastic leukemia, acute granulocytic leukemia, acute non-lymphocytic leukemia or AML.

The compounds of the invention may also be used in the treatment of abnormal pre-malignant or stable hematopoietic cell proliferation diseases 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 may 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 a cancer. In addition T-cell lymphoproliferative diseases 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 may 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 a cancer.

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

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

Another subset of cancers include multiple myeloma, bladder and cervical carcinomas.

It is further considered that the 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 Classic 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.

In particular the compounds of the invention as FGFR inhibitors 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, cancer

endometrial, 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 10 t translocation (4; 14) or overexpressing multiple myeloma), 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 treating lobular carcinomas such as CLC (Classic Lobular Carcinoma).

As the compounds have activity against FGFR3 they will be useful in treating multiple myeloma and bladder.

In particular the compounds are useful for the treatment of positive t (4,14) translocation multiple myeloma.

As the compounds have activity against FGFR2 they will be useful.

in the treatment of endometrial, ovarian, gastric and colorectal cancers. FGFR2 is also overexpressed in ovarian epithelial cancer, so the compounds of the invention may be specifically useful in treating ovarian cancer such as ovarian epithelial cancer.

Compounds of the invention may also be useful in

treating pre-treated tumors with VEGFR2 inhibitor or VEGFR2 antibody (e.g. Avastin).

In particular the compounds of the invention may be useful in the treatment of VEGFR2 resistant tumors. VEGFR2 antibodies and inhibitors are used in the treatment of thyroid and renal cell carcinomas, so the compounds of the invention may be useful in the treatment of VEGFR2 resistant thyroid and renal cell carcinomas.

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

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

r

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

It has been found that some FGFR inhibitors may be used in combination with other anticancer agents. For example, it may be beneficial to combine an apoptosis-inducing inhibitor with another agent that acts via a different mechanism for regulating cell growth thereby 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 treating 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 Alzheimer's disease, neuromotor disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease for example autoimmune diseases and neurodegenerative diseases.

A subset of disease conditions and conditions where it is considered that the compounds of the invention will be useful consists of inflammatory diseases, cardiovascular disease 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 treating the following different cancer diseases; 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, haematological diseases, eg 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 various severe abnormalities in human skeletal development and thus the compounds of the invention could be useful in treating 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 considered that the 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.

5 Particular skeletal diseases are achondroplasia or tanatophoric dwarfism (also known as tanatophoric 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 treating or preventing conditions in which progressive fibrosis is a symptom. Fibrotic conditions in which the compounds of the invention may be useful in 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 in idiopathic pulmonary fibrosis.

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 stopping 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, eye diseases such as age-related macular degeneration in particular wet form of age-related macular degeneration, ischemic proliferative retinopathies such as retinal disease. prematurity (ROP) and 25 diabetic retinopathy, rheumatoid arthritis and hemangioma.

Since the compounds of the invention inhibit PDGFR they can also be useful in treating numerous types of leukemia and tumor including glioblastomas such as glioblastoma multiforme, prostate carcinomas, gastrointestinal stromal tumors, liver cancer, kidney cancer, acute myeloid leukemia, myelomonocytic leukemia. (CMML) as well as hypereosinophilic syndrome, a rare proliferative haematological disorder and protuberant dermatofibrosarcoma, an infiltrative skin tumor.

The activity of the compounds of the invention as inhibitors of 5 FGFR1-4, VEGFR and / or PDGFR A7B 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 IC 50 value. Preferred compounds of the present invention are compounds having an IC 50 value of less than 1 μΜ, more preferably less than 0.1 μΜ.

The invention produces compounds that have modulatory activity.

or inhibitory effect of FGFR, and which is considered to be useful in preventing or treating 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 an unhealthy condition or an unhealthy condition mediated by an FGFR kinase.

Thus, for example, it is contemplated 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

of a compound for the manufacture of a medicament for the prophylaxis or treatment of an unhealthy condition or an unhealthy condition mediated by (a) 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 an unhealthy condition or an unhealthy condition mediated by an FGFR kinase, which method comprises administering to a subject in need thereof a compound of formula (!) As defined herein.

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

A method for alleviating or reducing the incidence of an unhealthy condition or an unhealthy 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 (e.g. 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 (e.g. cell division) by inhibiting the activity of an FGFR kinase.

A compound of formula (I) as defined herein for use as an FGFR modulator (e.g. inhibitor). 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 for modulating a cellular process (e.g. 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 over-regulation of an FGFR10 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 medicament for the prophylaxis or treatment of cancer, the cancer being one which is characterized by over-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 drug for the prophylaxis or treatment of cancer in a selected patient from a subpopulation having FGFR3 genetic kinase aberrations.

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

A method for the prophylaxis or treatment of a disease or condition characterized by over-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 alleviating or reducing the incidence of a disease or condition characterized by over-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 alleviating or reducing the incidence of) cancer in a patient suffering from or suspected of having cancer; which method comprises (i) subjecting a patient to a diagnostic test to determine if the patient has FGFR3 gene 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 of incidence of) an unhealthy condition or an unhealthy condition characterized by over-regulation of an FGFR kinase (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 FGFR kinase over-regulation (eg FGFR1 or FGFR2 or FGFR3 or FGFR4) and (ii) where the diagnostic test is indicative of supra- FGFR kinase regulation, 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 20 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 binding capacity of the inhibitor and inhibit the kinase in question. This may occur at any of the amino acid residues that interact with the inhibitor or are important to support 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 enzyme inhibitor (Carter et al. (2005), PNAS, 102 (31), 11011- 110116). Mutations have been observed in PDGFR in patients treated with imatinib, in particular the T674I mutation. The clinical significance of these mutations can grow considerably, as it seems to date 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 which cause overexpressed or biologically active biological states of function gain.

The compounds of the invention would therefore find particular application to cancers expressing 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 FISFL 15 It has been suggested that mutations of a threonine residue

conserved at the FGFR ATP binding site would result in inhibitor resistance. The amino acid valine 561 has been mutated to a methionine in FGFR1 which corresponds to previously reported mutations found in Abl (T315) and EGFR (T766) which as has been shown to confer resistance to selective inhibitors. Assay data for FGFR1 V561M showed that this mutation conferred resistance to a tyrosine kinase inhibitor compared to that of 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 additionally provides pharmaceutical compositions as defined above and methods of preparation.

5 of a pharmaceutical composition comprising mixing at least one active compound as defined above together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers, or other materials as described herein.

The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of correct medical judgment, suitable for use in contact with a subject's tissues (eg. without causing excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each vehicle, 15 excipient, etc. It must also be "acceptable" in the sense that it is compatible with the other ingredients of 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 produces 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, intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they may be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct release into a target tissue or organ by injection, infusion or other delivery medium. Release may be by bolus injection, short-term infusion or long-term infusion and may be via passive release or by use of a suitable infusion pump.

Familial formulations adapted for parenteral administration include sterile aqueous and non-aqueous injection solutions 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 polymer gels, lyophilization protectors and combinations of agents to, inter alia, stabilize the active ingredient in a soluble form and take the isotonic formulation with the intended recipient patient's blood. 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 nucleus with a total diameter of <100 μηι. Depending on the level of hydrophobicity, moderately hydrophobic drugs may be solubilized by liposomes if the drug becomes encapsulated or interspersed within the liposome. Hydrophobic drugs may 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 multiple dose containers, for example sealed vials and ampoules, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately before use.

The pharmaceutical formulation may be prepared by lyophilizing a compound of formula (I) or its subgroups. Freeze drying refers to the freeze drying procedure of a composition. Freeze drying and freeze drying are therefore used herein as synonyms.

Extemporaneous injection suspensions and solutions may 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 dispersions or solutions immediately prior to 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 flowability may be maintained, for example, by the use of coating materials such as lecithin, maintaining the required particle size in the case of dispersions, and the use of surfactants.

The 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 may be warranted by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, 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 caused by the inclusion of absorption delaying agents such as aluminum monostearate and gelatin. In a preferred embodiment of the invention, the pharmaceutical composition is in a form suitable for Lv administration, for example by injection or infusion. For intravenous administration, the solution may be dosed as such, or may 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 oral plasters.

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 derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches. such as cornstarch. 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 carboxy-methyl cellulose cross-linked), lubricating agents (eg stearates), preservatives (eg parabens) , antioxidants (eg BHT), buffering agents (e.g. phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and need not be discussed in detail herein.

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

Solid dosage forms (eg; tablets, capsules etc.) may be coated or uncoated, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a controlled release coating. The coating (e.g. an Eudragit ™ type polymer) may be designed to release the active component at a desired location within the gastrointestinal tract. Thus, the coating may be selected to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively releasing the compound into 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 retarding agent that may be adapted to selectively release the compound under acid or acid conditions. varied 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) that is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. As another alternative, the active compound may be formulated in a release system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or extended release formulations may be prepared according to methods known to those skilled in the art.

The pharmaceutical compositions comprise from about 1% to about 95%, preferably from about 20% to about 90%, of 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 may 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 the addition of appropriate excipients, in tablets, dragee cores or capsules. . They may also be incorporated into plastic vehicles that allow active ingredients to diffuse or be released in metered amounts.

The compounds of the invention may also be formulated as solid dispersions. Solid dispersions are homogeneous extremely thin 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 increasing 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 chewable tablets, capsules and tablets. Known excipients may be mixed with the solid solution to obtain the desired dosage form. For example, a capsule may contain the solid solution mixed with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. A tablet may contain the solid solution mixed with at least one disintegrant, a lubricant, a surfactant, and a sliding agent. 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 may be presented to a patient in "patient packs" containing an entire course of treatment in a single pack, usually a blister pack. Patient packages have an advantage over traditional prescriptions, where a pharmacist splits a patient supply of a drug from a bulk supply because the patient always has access to the package insert contained in the normally missing patient package. on patient prescriptions. Inclusion of a package insert has been shown to improve patient compliance with physician instructions.

Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (e.g. intraocular inserts). Such compositions may 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 molded waxy or moldable material containing the active compound.

Compositions for administration by inhalation may take the form of inhalable powder or liquid powder or spray 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.

The 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 milligrams to 2 grams of active ingredient (most commonly from 10 milligrams to 1 gram, eg 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (eg 1 microgram 10 milligrams, eg 0.1 milligrams 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 (!) Is prepared by mixing 50 mg of compound with 197 mg of lactose (BP) as diluent, and 3 mg of magnesium stearate as a lubricant and compression to form a tablet in the manner. known.

(ii) Capsule formulation

A capsule formulation is prepared by mixing 100 mg of a compound of formula (I) with 100 mg lactose and filling the standard opaque hard gelatin capsules with the resulting mixture.

Gii) Injectable formulation I

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 a concentration of active compound of 1.5% by weight. Weight. The solution is then sterile filtered, and an ampoule is filled with it and sealed. (iv) Injectable formulation II A parenteral injection composition is prepared by dissolving in water a compound of formula (I) (eg in salt form) (2 mg / ml) and mannitol (50 mg / ml) by sterile filtering the solution and 1 ml sealed ampoules or vials are filled with it.

v) Injectable formulation III

A formulation for i.v. release by injection or infusion may be prepared by dissolving the compound of formula (I) (e.g. 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 may be prepared by dissolving the compound of formula (I) (eg in a salt form) in water containing a buffer (eg 0.2 M 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 compound of formula (I) formulated are placed in 50 ml vials and lyophilized. During lyophilization, the 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 temperature increments of 50 ° C. The pressure during primary and secondary drying is set at 11 Pascal. Methods of Treatment It is contemplated that the compounds of formula (I) and their subgroups as defined herein will be useful in the prophylaxis and treatment of a variety of FGFR-mediated disease states and disease conditions. 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 which are generally non-toxic.

However, in certain situations (for example in the case of life-threatening diseases), 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 may be administered for a prolonged period to maintain beneficial therapeutic effects or may be administered for a short time only. Alternatively they may 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 body weight, more typically 5 nanograms to 25 milligrams per kilogram body weight, and more usually 10 nanograms to 15 milligrams per kilogram. 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 body weight although higher or lower doses may be administered where required. The compound of formula (1) 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 per day. example.

The compounds of the invention may be administered orally in a dose range, 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 may be administered one or more times a day. Compound can be taken continuously (ie taken daily without a break in the duration of the treatment regimen. Alternatively, compound can be taken intermittently, ie taken continuously for a given period such as one week, then discontinued for a period such as one week. and then taken continuously for another period such as a week and so on over the entire duration of the treatment regimen. Examples of treatment regimens involving intermittent administration include regimens where administration is in one week yes, one week cycles. no, or two weeks yes, one week no, or three weeks yes, one week no, or two weeks yes, two weeks no, or four weeks yes two weeks no, or one week yes three weeks no - for one or more cycles eg 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more cycles.

In a particular dosage 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 for one week, and treatment is repeated at a desired interval as two to four weeks, in particular every three weeks.

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

In another particular dosage schedule, a patient is infused 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.

Finally, however, the amount of compound administered and the type of composition used will correspond to the nature of the disease or 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 treatment of a particular disease state, for example a cancerous neoplastic disease 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 I inhibitors Antimetabolites

Tubulin Selection Agents Topoisomerase II Inhibitors and DNA Ligand

Alkylating Agents Monoclonal Antibodies Antihormones

Signal Transduction Inhibitors Protosome Inhibitors

DNA methyl transferases Cytokines and retinoids Chromatin selection therapies Radiotherapy, 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 antiemetic agents and agents that prevent or shorten the duration of chemotherapy-associated neutropenia and prevent complications resulting from reduced levels of red blood cells or white blood cells, for example erythropoietin (EPO), macrophage-granulocyte colony stimulating factor (GM-CSF), and granulocyte colony stimulating factor (G-CSF). Also included are bone resorption inhibiting agents such as biophosphonate agents eg zoldronate, pamidronate and ibandronate, agents that suppress inflammatory responses (such as dexametazone, 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 brain hormone somatostatin, which include octretide acetate which is a long-acting optapeptide with pharmacological properties that mimic those of the natural hormone somatostatin. Also included are agents such as leucovorin, which is used as an antidote for drugs that lower folic acid levels, or folinic acid itself, and agents such as megestrol acetate that can be used to treat side effects including edema and thromboembolic episodes. .

Each of the compounds present in the combinations of the invention may 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 administered sequentially, they may be administered at tightly spaced intervals (for example over a period of 5-10 minutes) or at longer intervals (for example 1,2, 3, 4 or more hours apart, or even longer periods). where required), the precise dosing regimen being commensurate with the properties of the therapeutic agent (s).

The compounds of the invention may 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 may be, for example, formulated together in a dosage form containing two, three, four or more. or more therapeutic agents. In an alternative, the individual therapeutic agents may be formulated separately and presented together as a kit, optionally with instructions for their use.

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

Diagnosis Methods

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

For example, a biological sample taken from a patient may be analyzed to determine if 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 genetic abnormality that leads to over-regulation of FGFR, VEGFR and / or PDGFR levels or activity or sensitization of a route to normal FGFR, VEGFR and / or PDGFR activity, or over-regulation of such growth factor signaling pathways such as growth factor binder levels or growth factor binder activity or the up-regulation of a biochemical pathway downstream 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, receptor or ligand up-regulation, or presence of mutant receptor or ligand variants eg PTK Tumors with FGFR1, FGFR2 or FGFR3 or FGFR4 mutants or up-regulation, in particular FGFR1 overexpression, or FGFR2 or FGFR3 gain-of-function mutants may be particularly sensitive to FGFR inhibitors.

For example, point mutations engendering gain-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, FGFR3 receptor tyrosine kinase genetic aberrations such as point mutations or chromosomal translocations resulting in constitutively active ectopically expressed or dysregulated 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 PDGF receptor mutation has been identified in patients treated with imatinib.

In addition, 8pl2-pll.2 gene amplification has been demonstrated in -50% of lobular breast cancer (CLC) cases and it has been shown to be linked to increased expression of FGFR1. Preliminary studies with siRNA directed against FGFR1, or a small molecule receptor inhibitor, have shown 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 may be assayed for loss of a FGFR, VEGFR or PDGFR negative regulator or suppressor. In the present context, the term "loss" includes deletion of a regulator or suppressor coding gene, truncation of the gene (e.g. by mutation), truncation of the transcribed product of the gene, or inactivation of the transcribed product (eg by mutation). punctuation) or sequestration by another gene product.

The term up-regulation includes elevated expression or overexpression, including gene amplification (i.e. multiple gene copies) and expression enhanced by a transcription effect, and hyperactivity and activation, including activation by mutations. Thus, the patient may undergo a diagnostic test to detect a characteristic marker of FGFR, VEGFR and / or PDGFR overregulation. The term diagnosis includes screening. With respect to the marker we include 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 up-regulation, 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 selected biological sample from tumor biopsy samples, blood samples (detached tumor cell isolation and enrichment), stool biopsies, saliva, chromosome analysis, pleural fluid, peritoneal fluid, Mouthpieces, biopsy or urine. Methods of identifying and analyzing protein mutations and over-regulation are known to one of ordinary skill 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).

Identification of an individual carrying a mutation in FGFR, VEGFR and / or PDGFR may mean that the patient would be particularly suitable for treatment with an FGFR, VEGFR and / or PDGFR inhibitor. Tumors may preferably be screened for the presence of a variant of FGFR, VEGFR and / or PDGFR 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, for example FGFR or VEGFR2, can be identified by direct sequencing of, for example, tumor biopsies using PCR and methods for sequencing PCR products directly as described hereinbefore. The skilled artisan will recognize that all such well-known techniques for detecting overexpression, activation or mutations of the above proteins could be applicable in the present case.

In RT-PCR screening, the tumor mRNA level is assessed by creating a cDNA copy of the mRNA followed by PCR amplification of the cDNA. PCR amplification methods, primer selection, and conditions for amplification are known to one of ordinary skill 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 RT-PCR kit (e.g. Roche, Molecular Biochemicals) may be used, or methodology as described in United States Patent 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 for evaluating 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 the target nucleic acid, and to reduce non-specific binding; (3) hybridizing the nucleic acid mixture to the nucleic acid in the tissue or biological structure; (4) post-hybridization washes to remove unbound nucleic acid fragments in hybridization, and (5) detecting 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 25200 nucleotides to about 1000 or more nucleotides, to allow specific hybridization to the target nucleic acid (s) under stringent conditions. Standard methods for performing FlSH 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 gene expression profiling are described in 5 (DePrimo et al. (2003), BMC Cancer, 3: 3). Briefly, the protocol is as follows: Double stranded cDNA is synthesized from total RNA using an oligomer (dT) 24 to initiate first strand cDNA synthesis, followed by second strand synthesis of cDNA with random hexamer 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, 15 mRNA expressed protein products can be assayed by immunohistochemistry of tumor samples, microtiter plate solid phase immunoassay, Western blotting, SDS-polyacrylamide two-dimensional 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 skilled person will recognize that all such well-known techniques for detecting FGFR, VEGFR and / or PDGFR over-regulation, or detecting FGFR, VEGFR and / or PDGFR Mutants or variants could be applicable in the present case.

Abnormal levels of proteins such as FGFR or VEGFR 25 may 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 from Chemicon International. Tyrosine kinase of interest would be immunoprecipitated from the sample lysate and its activity measured.

Alternative methods for measuring FGFR or VEGFR overexpression or activation including their isoforms include microvessel density measurement. This can for example be measured using 5 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 they include CD31, CD34 and CD 105 (Mineo et at. (2004) J Clin Pathol. 57 (6), 591-7).

Therefore all of 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 observed in 62% of oral squamous cell carcinomas and causes constitutive activation of kinase activity. FGFR3 activating 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, it has been found that a Gly388Arg polymorphism in FGFR4 is associated with increased incidence and aggressiveness of prostate, colon, lung and breast cancer.

Therefore in another aspect the invention includes the 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 determined as suffering from or at risk of a disease or condition that would be susceptible to treatment with a compound having activity against FGFR.

Particular mutations to 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 subpopulation having a variant of the FGFR gene (e.g. G697C mutation in FGFR3 and Gly388Arg polymorphism in FGFR4).

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

EXPERIMENTAL

LC-MS Method and Analytical System Description

In the examples, prepared compounds were characterized by liquid chromatography and mass spectroscopy using commercially available systems (Waters Platform LC-MS system), standard operating conditions and commercially available columns (Phenomenex, Waters etc) but one skilled in the art will consider which alternative systems and methods could be used. Where atoms with different isotopes are present and a single mass is cited, the cited mass for the compound is the monoisotopic mass (i.e. 35Cl; 79Br etc.).

LC-MS with mass directed purification system

Preparative 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 crude materials and improved detection of samples by MS. Optimization of the preparative gradient LC method will involve varying columns, volatile eluents and modifiers, and gradients. Methods for optimizing preparative LC - MS methods and their use for purifying compounds are well known in the art. Such methods are described in Rosentreter 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 one skilled in the art will consider that alternative systems and methods could be used. In particular, reverse phase methods were used for preparative HPLC for the compounds described herein, but normal phase preparative LC-based methods could be used in place of reverse phase methods. Preparative LC - MS systems mostly use reverse 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 preparative chromatography type is chosen. A typical routine is to operate an analytical LC-MS using the type of chromatography (low or high pH) most suitable for the structure of the compound. Once the good chromatography analytical trace has been shown, a suitable preparative method of the same type is chosen. A variety of chromatographic solutions e.g. reverse phase or normal LC; acidic, basic, polar, or buffered 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.

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

General Synthesis Routes General Route A

Cl

CXX

To a solution of 4-Chloro-pyridm-2-yl-amine (12.8 g, 100 mmol, 1.0 equiv) in EtOH (170 mL) was added NaHCO3 (16.8 g, 200 mmol, 2.0 equiv) followed by chloroacetaldehyde (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 (MgSO 4), filtered and concentrated under reduced pressure. The product was purified by column chromatography (SiO2, eluted with 50% EtOAc - petrol) to give 13.2 g of product. Procedure A2 - General Iodination 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-iodo-succinimide (43 , 6 g, 194 mmol, 1.05 equiv) and the resulting mixture was stirred overnight at RT. The thin brown slurry was diluted with water (840ml), brine 5 (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), vacuum filtered to give a brown residue. The residue was triturated with ether (200ml), filtered and the solid was washed with ether (2 x 50ml) and dried over filter to give 39g of product.

Procedure A3 - General Suzuki at Position-3

A3a Procedure - Suzuki

To a solution of 7-Chloro-3-iodoimidazo [1,2-a] pyridine 15 (2.8g, 10mmol) in acetonitrile (100ml) was added 3-amino-benzene boronic acid (2.5g, 10g). 0.5mmol), 2M Na2 CO3 (21.6ml) [reaction was degassed by bubbling N2 therethrough] followed by bis (triphenylphosphine) 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 Biotage column chromatography (SiO 2, eluted with 80%) EtOAC in 100% EtOAc petrol) to give 1.9 g of product. MS: [M + H] + 244 Procedure A3b - Suzuki In 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 3-amino-benzene-boronic acid (0.69g, 4.8mmol) and 2M Na2CO3 (6.93ml) [reaction was degassed by bubbling N2 therethrough] followed by 5 tetrakis (triphenylphosph) palladium (0) (0.139g, 0.12mmol). The mixture was heated at 750 ° 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 Biotage column chromatography (SiO 2, eluted with EtOAC - 20% MeOH / EtOAC) to give 0.56g 10 of product. MS: [M + H] + 385

Procedure A4 - General Palladium-Mediated Position-7 Cycle Addition Procedure A4a - Suzuki

To a suspension of the appropriate 7-chloro-imidazo [1,2-a] pyridin-3-yl (0.3mmol) in toluene (0.5ml) is added 4- (4,4,5,5-15 Tetramethyl). [1,2,3] dioxaborolan-2-yl) pyridine (0.078g, 0.36mmol), K 2 CO 3 (0.25g, 1.8mmol), MeOH (0.5ml), EtOH (0.5ml), H2O (0.75ml) [reaction was degassed by bubbling N2 therethrough] followed by bis (tri-t-butylphosphine) palladium (O) (0.003g, 0.0058mmol). The mixture is heated using microwave irradiation in a CEM discover 20 (50W) microwave synthesizer 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 (MgSO 4), filtered and concentrated under reduced pressure and purified by preparative HPLC to give the desired product.

A4b Procedure - Suzuki

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 (triphenylphosphine) palladium (O) (0.018g, 0.015mmol, 5 mol%). The mixture is heated at 80 ° C overnight, then diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried (MgSO 4), filtered and concentrated under reduced pressure and purified by preparative HOPLC 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) -phenyl [1,2,4] thiadiazol-2-yl-amine (prepared according to Route 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 (triphenylphosphine) palladium (0) (42mg) added. The mixture was deoxygenated again and then heated at 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

A solution of the appropriate 7-chloro-imidazo [1,2-a] pyridin-3-yl (1 equivalent), 1-methylpyrazol-4-boronic acid pinacol ester (commercially available, 2 equivalents), potassium (6

(10ml), toluene (10ml) and water (10ml) is heated at 750 ° C for 3 h. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is dried (MgSO 4), filtered and the solvent evaporated in vacuo. The residue is purified by column chromatography to give the desired product.

General Route B

Air

Air

\

equivalents), and bis (tri-t-butylphosph) palladium (0) (0.05 equivalent) in ethanol

Air / GYC

Air

Air / CYC

Air / C YC

Procedure Bl - General Palladium Mediated 7-Position Cycle Addition

Bla- Suzuki Aryl Cycle Procedure Method as described in General Route Procedure 4a or 4

Ab

Blb-Buchwald Procedure for Saturated Cycles

In a solution of the appropriate 7-chloro-imidazo [1,2-a] pyridin-5-3-yl (0.32 mmol) in anhydrous dioxane (4ml) is added the appropriate amine (0.35mmol), NaOtBu (0.096g). 0.96mmol) [reaction was degassed by bubbling N2 therethrough] followed by BINAP (0.021g, 0.033mmol) and Pd2dba3 (tris- (dibenzylidene-acetone) -dipaladium (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.

Procedure Blc- Suzuki copulation for heterocycles.

A solution of 7-Bromoimidazole [1,2-a] pyridine (0.5g, 15 2.54mmol, 1 equivalent, prepared according to general procedure Al using 4-bromo-pyridin-2-yl-amine instead 4-chloro-pyridin-2-yl-amine), 1-methyl-5- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) -1H-pyrazole (1 1 g, 5.08 mmol, 2 equivalents), bis (tri-t-butylphosphine) palladium (0) (66mg, 0.13 mmol, 0.05 equivalents) and potassium carbonate (2.1 g, 15, 24 mmol, 620 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 saturated brine solution, dried (MgSO 4), 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 [1,2,2a] pyridine as a colorless oil (350mg, 70%). MS: [M + H] + 199.

Procedure Bld - Synthesis of 7- [3- (4-Methyl-piperazin-1-ylmethyl) -pheninimidazole] 1,2-alpyridine

using 3-formyl phenyl boronic acid.

To a solution of 3-Imidazo [1,2-a] pyridin-7-yl-benzaldehyde (1.899 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 portionwise. 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 20 was added and the layers were separated. The organic layer was washed with brine, dried (MgSO 4), filtered and concentrated under reduced pressure. The compound was purified by column chromatography (eluting with 5% methanol: dichloromethane) to give the desired compound. Procedure B2 - Iodization

10

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

Method as described in Route Procedure A3a or A3b

General A

Procedure B3b - General Suzuki at Position-3

I Ar

(/ I »

Air / CYC N '^' Air / CYC

Method as described in General Route B procedure 1 c General modifications D at position 7

Latent functionality at the 7-position of imidazo [1,2-a] pyridine may be used for the purpose of synthesizing alternative motifs.

Air air

ÒCX ~ Cf

N

'Air / CYC

Procedure D3 - Boc Unprotection

'ArVCYC'

To the Boc-protected compound (0.39mmol) in CFI2Cl2 (10ml) is added 4M HCl in dioxane (0.5ml, 5equiv). 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.

Carboxylic acid (0.027mmol) may be treated with saturated EtOAc / HCl, stirred at room temperature for 3 hours, concentrated under reduced pressure then dried to give the desired compound.

Procedure D3b - Boc Unprotection

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

Procedure E

5th

In an alternative procedure the tert-butyl acid ester

10

In a solution of tert-butyl ester of (3- {3- [3-

To 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), NaOtBu (1.9g). 0.74mmol) [reaction was degassed by bubbling N2 therethrough] followed by BINAP (0.43g, 0.69mmol) and Pd2dba3 (tris- (dibenzylidene-acetone) -dipaladium (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 (MgSO 4), 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 modifications F at position-3

Latent functionality at the 3-position of imidazo [1,2-a] pyridine may 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] -phenylamine (200mg, 0.65 mmol), 4-bromo-pyridine.HCl (130mg, 0.67mmol), (±) -Binap (63mg, 0.1mmol) and NaO1Bu (250mg, 2.6mmol) in dry dioxane (3ml) was deoxygenated by evacuation / refill with N2 (x3). Pd 2 (dba) 3 (30mg, 0.03 mmol) was added and the mixture was deoxygenated again (x3). The reaction was stirred and heated at 100 ° C for 18 hours under N 2. The mixture was partitioned between CH 2 Cl 2 and H 2 O, then filtered. The layers were separated and the solid was combined with organic layers which were then evaporated. The residue was purified by silica chromatography followed by preparative HPLC to give the title compound (40mg,

imidazo [1,2-a] pyridin-3-yl] -phen-amine (0.25g, 0.65 mmol) in anhydrous toluene (20ml) was added 1,2-thiocarbonyl-di-2 (1H) -pyridone (0.5lg, 0.65mmol) stirred and heated at 1100 ° C for 1h. The reaction was cooled to room temperature, diluted with CH 2 Cl 2, washed with water and brine, dried (Na 2 SO 4), 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). After completion of the 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.

solid). 1H-NMR (400 MHz, Me-d3-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-Thionas and Amino Thiadiazoles

To a suspension of 3- [7- (3-Morpholin-4-ylmethylphenyl) - In a solution of thiosemicarbazide (0.305g, 0.66mmol) in anhydrous DMF (5ml) was added chlorine phosphate. diethyl (0.23ml, 1.5mmol) in drops such that the internal temperature remained <25 ° C. After min more diethyl chlorophosphate was added. The reaction mixture was poured into Fl 2 O and extracted with EtOAc. The aqueous fraction was concentrated under reduced pressure, the residue was triturated with hot ethanol, solid was filtered off. 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

To a solution of 3- (7-Chloro-imidazo [1,2-a] pyridin-3-yl) -phenylamine (0.20g, 0.82mmol) in dry DMF (5ml) at 0 ° C was added hydrochloride. sodium as a 60% dispersion (0.04g, 0.99mmol) and the reaction mixture stirred for 5 min. Benzyl bromide (0.1 Oml, 0.82 mmol) was added, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18 h. 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 (MgSO 4), filtered and the solvent removed in vacuo. The crude residue was purified using an SCX cartridge followed by reverse phase HPLC to give the product. MS: [M + HJ] 333.

General Procedure G Examples of 1,2,3-triazol Procedure Gl - [3- (7-Chloro-imidazo [K 2 -alPyridin-3-yl) -phenyl- (3H-1,21,2] triazol-4-yl )-the mine

A solution of sodium nitrite (285mg, 4.1 mmol) in H 2 O (2ml) was added in a stirred suspension of 3- (7-chloro-imidazo [1,2- 5 a] pyridin-3-yl) -phenyl -amine (1g, 4.1 mmol) in 2 N HCl (8ml) such that the internal temperature was <5 ° C. After completion of the addition the reaction was stirred for 15 minutes at this temperature before the addition of amino acetonitrile hydrogen sulfate (635mg, 4.1 mmol) in H 2 O (2ml) [internal temperature maintained <50 ° C]. After 1 hour NaOAc (14g) was added. The mixture 10 was stirred for 1 hour with ice bath cooling, 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 the volatiles were removed in vacuo and the residue was purified by silica chromatography (100% CH 2 Cl 2 - + 5% 2M NH 3 -15 MeOH / CH 2 Cl 2) to give the title compound (318mg, solid). 1H 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). G2 procedure:

3- {7- [4- (4-Methyl-piperazin-1-yl-methyl) -phenin-imidazo [1,2-a] pyridin-3-yl) -phenyl) - (3H- [1, 2,3] triazol-4-yl) -amine H

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-acid pinacolester boronic acid (80mg, 0.25 mmol) and 2 '- (dimethylamino) -2-biphenyl palladium (II) / dinorbomyl phosphine 5 (10mg, 0.02 mmol) chloride complex in DME (Iml) and 2N Na 2 CO 3 (aq., 1 ml) in a microwave flask was deoxygenated by bubbling N2 through it for 30 seconds. The flask 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 CH 2 Cl 2 and H 2 O 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). 1H NMR (400 MHz,

(2H, s), 2.48-2.20 (8H, brm), 2.17 (4H, brs).

Synthesis of boronic acids and esters Boronic acid 14

3-RL3,41thiadiazol-2-yl-amino) -phenyl-boronic acid pinacol-ester Step 1: 3-Bromo-phenyl-thiosemicarbazide

DMSO-d 6): 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

s

20

A solution of 3-bromo-phenylthio-isocyanate (10g, 47mmol) in THF (20ml) was added in a stirred solution of hydrazine hydrate (4.54ml, 94mmol) in THF (80ml) such that the internal temperature was <5 ° C. After completing the addition, the reaction was stirred at this temperature for 1hr. The 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) -1,3,41-thiadiazol-2-yl-amine

Diethyl chlorophosphate (16.3ml, 117mmol) was slowly added in a stirred solution of 3-bromo-phenylthio semicarbazide (from above, 12.5g) in dry DMF (120ml) such that the temperature internal

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). 1H NMR

it was <25 ° C. After 1 hour the reaction mixture was poured into H 2 O and stirred.

(400 MHz, DMSO-d 6): 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: 3- (Fl, 3,4,4thiadiazol-2-yl-amino) -phenyl-boronic acid pinacol ester

A mixture of (3-bromo-phenyl) - [1,2,4] thiadiazol-2-yl-amine (7.3g, 29 mmol), bis (pinacolato) diboro (14.5g, 57 mmol) and KOAc ( 8.5g, 87mmol) in dry DMSO (50ml) was deoxygenated by evacuation / refill with N2 (x3). PdCl 2 dpf (1.05g, 1.4 mmol) was added and the mixture was deoxygenated again (x3) then stirred and heated to 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 to 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 (xl). The combined organic extracts were washed with water (xl), brine (xl) then dried (Na 2 SO 4), filtered and evaporated. The residue was purified by silica chromatography (20% -60% EtOAc / petrol) to give the title compound (4.1 g, solid - after trituration with petrol). 1H 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- (5-Methyl-R1, 3,41-thiadiazol-2-yl-amino) -phenyl-boronic acid pinacol-ester Step 1: (3-Bromo-phenyl) - (5-methyl-R 1,3,41-thiadiazole -2 ~ iQ-amine

Hn

(X

3-Bromo-phenyl-thio semicarbazide (1.0g, 4.0 mmol) was added in a stirred mixture of H 2 SO 4 c. (Iml) and AcOH (280μ1, 4.9 mmol) at RT (observed exotherm). The suspension was stirred and heated at 20-80 ° C for 2 hours. After cooling to RT, the mixture was cooled in an ice bath and carefully neutralized with concentrated aqueous NH 3. The pH was adjusted to ~ pH10 and the solid was collected by filtration then dried to give the title compound (732mg, solid). 1H 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: 3- (5-Methyl-β, 3,41-thiadiazol-2-yl-amino) -phenyl-boronic acid pinacol ester

A mixture of (3-bromo-phenyl) - (5-methyl- [1,4,] thiadiazol-2-yl) -benzamide

amine (680mg, 2.5mmol), bis (pinacolato) diboro (1.27g, 5.0mmol) and KOAc (740mg, 7.5mmol) in dry DMSO (5ml) were evacuated deoxygenated / refilled with N2 (x3). PdCl2ddpf (91 mg, 0.12 mmol) was added and the mixture was deoxygenated again (x3) then stirred and heated to 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 (xl). The combined organic extracts were washed with brine (xl) then dried (Na 2 SO 4), filtered and evaporated. The residue was purified by silica chromatography (30-> 80% EtOAc / petrol) to give the title compound (211 mg, oil). MS: [M + H] + 318 Boronic Acid 116

(1-Methyl-1H-imidazol-2-yl-R3- (4A5,5-tetramethyl-β, 3,21dioxaborolan-2-yl) -phenylamine

yl) -phenylamine (0.5g, 2.28mmol) in 2-Bromo-1-methyl-1H-imidazole (0.367g,

A solution of 3- (4,4,5,5-Tetramethyl- [1,2,2] dioxaborolan-2- 2,28mmol) was heated on a CEM discover (50W) microwave synthesizer to 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)

Potassium [3- (R1,3,4,4 thiadiazol-2-yl-amino] phenyl] trifluoro borate

s - ^ \

Hn

N

N

K

A solution of KHF2 in H 2 O (4.5M, 36ml) was added in a stirred solution of [3- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) phenyl] - [1,2,4] thiadiazol-2-yl-amine and phenyl- [1,2,4] thiadiazol-241-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. 1H 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 118

N-Methyl-2-r3- (4,4,5,5-tetramethyl-n, 3,21dioxaborolan-2-yl) phenyl acetamide In a solution of [3- (4,4,5,5- Tetramethyl- [1,2,2] dioxaborolan-2-yl) -phenyl] -acetic (0.60g, 2.28mmol) in DMF (15ml) was added a solution of 1-hydroxy-benzotriazole (0.37g, 2 73mmol) and 2- (1H-benzotriazol-1-yl) -1,1,3-tetramethyluronium tetrafluoro borate (0.88g, 2.73mmol) tetrafluoro borate 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 (acid).

Boronic Acid 119

(3-Methyl-piperazinone) -phenyl-boronic acid

HO

To a solution of piperazine-2-one (0.2g, 2mmol) in dry THF / DMSO (10ml: 2.5ml) was added (3-bromo-methylphenyl) -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 Cl8 reverse phase chromatography column to give a colorless gum, which was used crude MS:

[MH +] 235

Boronic Acid 121

To 0 ° C was added 4-hydroxy-tetrahydropyran (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 CH 2 Cl 2 and H 2 O and extracted CH 2 Cl 2 (x 2). 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-yloxy) -pyridine MS: [MH] +258,260

0.77mmol) in DMSO (5ml) (degassed by N 2 bubbling therethrough) was 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 degassed again and then heated to 100 ° C for 5 h. The compound was passed through a Cl 8 reverse phase chromatography column to give

the desired product, used crude. MS: [MH] + 224.

2-ftetrahydro-pyran-4-yl-oxy) -4-pyridinyl-boronic acid

Br

Rr

5th

In a suspension of NaH (0.4 g, 10 mmol) in THF (20 mL)

H(

Br

In 4-Bromo-2- (tetrahydro-pyran-4-yloxy) -pyridine (0.2g, Boronic Acid 123

3- (Th3,41thiadiazol-2-yl-amino) -benzene-boronic acid

I N

S ^ s

L N

HN ^ 5rN

OH

OH

LiOH (340mg, 14 mmol) was added in a solution

potassium [3 - ([1,4,4] thiadiazol-2-yl-amino) -phenyl] trifluoroborate (1, 15g, 4 mmol) in CH 3 CN (20ml) and H 2 O (10ml) at RT . The reaction was stirred at RT for 20 hours. The mixture was treated with saturated aqueous NH 4 Cl (32ml) and 2N HCl (5ml) to give ~ pH5. EtOAc was added and the precipitate was collected by filtration. The aqueous layer was extracted with CH 2 Cl 2 (x 2). The combined extracts were evaporated and the residue was combined with the solid above. This material was suspended in EtOAc. The solid was collected by filtration and then dried to give the title compound (1.1 g) beige solid. 1H NMR (400 MHz, DMSO-d6) => mixture, possibly boronic acid and cyclic species. This material was used without further purification.

Boronic Acid 124 3- (Tl, 2,41thiadiazol-5-yl-amino) -phenyl boronic acid pinacol ester

Step 1: 1- (3-Bromo-phenyl) -3-U-dimethyl-amino-met- (E) -ylidene-1-thiourea

s

(3-Bromo-phenyl) -thiourea (2.1 g, 9.1 mmol) was suspended in Δ, Ν-dimethylformamide-dimethyl acetal and was heated at 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) -1,3,41-thiadiazol-5-yl-amine

'Br

In a suspension of dry 1- (3-Bromo-phenyl) -3- [1-dimethyl-amino-met- (E) -ylidene] -thio urea (570 mg, 2.0 mmol) dichloromethane (4 (ml) dry dithloromethane (475 mg, 2.2 mmol) dichloromethane (4 ml) was added. 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 passage through a phase separation cartridge and concentrated in vacuo. The residue was purified by column chromatography (10 → 40% EtOAc / petrol) to give bromide (135 mg) as a colorless solid. MS: [M + H] + = 256,

Step 3: 3- (T1, 2,41thiadiazol-5-yl-amino) -phenyl-boronic acid pinacol 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 boronate synthesis

14. The product was used without purification.

Procedure j - HCl Ar salt formation

To a suspension of the imidazo [1,2-a] pyridin-3-yl-derivative (58μηιο1) compound in dioxane (Iml) 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 may be treated with stirred EtOAc / saturated HCl until all in solution, concentrated under reduced pressure, and residue was triturated with dry ether to give the desired HCl salt as product.

General Scheme for synthesizing pyrazole | T, 5-a1-pyrimidines

Br

The

Air

NH,

N

N

H

Γ d.

N

H

N-Nn ^

Air

n-n ^

Br

Air

Procedure K - General Ring Formation In 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 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 (MgSO 4), 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

F

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

2.5 mmol) 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). phosphma) -

Br

F

In a solution of 6-Bromo-pyrazolo [1,5-a] pyrimidine (0.5g, palladium (O) (0.130g, 0.11 mmol) The mixture was heated at 70 ° C overnight then diluted. The organic layer was washed with brine, dried (MgSO 4), filtered and concentrated under reduced pressure Residue was triturated with EtOAc, filtered, and the solid was washed with 5 more EtOAc then dried to give (0 ° C). The filtrate was concentrated under reduced pressure The product was purified by Biotage column chromatography (SiO 2, eluted with 5% EtOAc - petrol - 50% EtOAc - petrol) to give an additional 0.223 g of product. : [M + H] +214 Preparation (or Procedure) M - Iodination

10

Method as described in General Route Procedure 2 (A2)

THE

Preparation (or Procedure) N - Suzuki in position-3

H

F

Method as described in Procedure 3b of General Route A

Procedure Ol: N- (4-Bromo-2-nitro-phenyl) -benzene-K3-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, 11.1mmol) in dry NMP (5ml) was deoxygenated by evacuating / filling with N2 (x3), then stirred and heated to 120 ° C under N 2 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. 1H 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 02: N- (4'-Fluoro-3-nitro-biphenyl-4-yl) -benzene-1,3-diamine

bromo-2-nitro-phenyl) -benzene-1,3-diamine (Procedure Ol, 1,8g, 5.8mmol) and 4-fluoro-phenyl-boronic acid (975mg, 7.0 mmol) in DME (10ml) 2N Na 2 CO 3 (10ml) was added. The reaction was deoxygenated by evacuation / filling with N 2 (x 3), then stirred and heated to 90 ° C under N 2 for 18 hours. After cooling to RT the mixture was partitioned between EtOAc and H2O 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

THE

In a mixture of PdCl 2 dppf (210mg, 0.29 mmol), N- (4-title compound (1.66g) as a brown / dark red solid. 1H NMR (400 MHz, DMSOd6): 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-diamma

(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 ceased. The catalyst was removed by filtration - washing with EtOH. 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: 3-5- (4-Fluoro-phenyl-benzoimidazol-1-yl-phenyl-amine

Γ

A solution of N * 4 * - (3-Amino-phenyl) -4'-fluoro-biphenyl-3,4-diamine (Procedure 03, —5.1 mmol) in trimethyl orthoformate (30ml)

HCl c. (2ml), then stirred and heated under reflux for 3 hours. After

F

F

N- (4'-Fluoro-3-nitro-phenyl-4-yl) -benzene-1,3-diamine

it was stirred and heated at 120 ° C under N 2 for 10 hours. The volatiles were removed in vacuo and the residue was taken up in EtOH (30ml) and cooled to RT, the mixture was concentrated to ~ 2ml, then diluted with H2O. NaHCO3 (sat) was added to give ~ pH7.5. The solid was collected in CH 2 Cl 2. The organic layer was dried and evaporated. The residue was purified by silica chromatography (0% → 1% → 2% 2M NH 3 -MeOH / CH 2 Cl 2). The material was then triturated with Et 2 O to give the title compound (890mg) as an off-white solid.

Q7a Preparation:

A solution of 3- [5- (4-fluoro-phenyl) -benzoimidazol-1-yl] -phenylamine (300mg, 1 mmol) el, thio-carbonyl-di-2- (1H) -pyridone ( 240mg, 110 mmol) in dry toluene was stirred and heated under reflux under N 2 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 μΐ) was added and the mixture was stirred at 0 ° C for 1 hour and then evaporated. The residue was used without further purification.

Preparation_Q7b_j3-R5- (4-Fiori-phenyl Vbenzoimidazol-1-yl-β-phenyl} -

Γ1,3,41thiadiazol-2-yl-amine

Diethyl chlorophosphate (350 μΐ, 2.4 mmol) was slowly added in a stirred solution of N-arylthio semicarbazide (Preparation 10

07a, ~ 1 mmol) in dry DMF (5ml) at RT under N 2. After 90 minutes the mixture was poured into saturated aqueous NaHCO 3. 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. The residue was purified on an SCX cartridge, eluting with MeOH followed by 2M NH 3 -MeOH. The NH 3 -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)

N * 3 * - (3-7- (4-Fluoro-phenyl) -imidazori, 2-β-pyridin-3-yn-phenyl-1H-

ri, 2.41 triazole-3,5-diamine

3- [7- (4-Fluoro-phenyl) -imidazo [1,2-a] pyridin-3-yl] -phenylamine

15

N NH,

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

NH2

In a solution of 3- [7- (4-Fluoro-phenyl) -imidazo [1,2-a] pyridin-3-yl] -phenyl-amine (0.1g, 0.33mmol) in 2-propanol ( 3ml) diphenylcyano-carbondiimidate (0.078g, 0.33mmol) was added. 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 hydrochloride.

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-oxadiazole {3- [7- (4-Fluoro-phenyl) -imidazor-L 2, alpyridin-3-yl-phenyl] -n, 3,41-oxadiazol-2-yl-amine Procedure S1:

yl] -phenylamine (320mg, 1.05mmol) and 4-nitro-phenylchloroformate (225mg, 1.12mmol) in dry THF (10ml) was stirred and heated at 60 ° C for 2h 15h . After cooling to RT, DIPEA (550 μΐ, 3.2 mmol) and hydrazine hydrate (102 μΐ, 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: 10

15

H n-n // ^ Í Ν-γ O

THE-/

A suspension of semicarbazide (procedure SI, 130mg, 0.35mmol) and ethyl glyoxylate (50% in PhMe, 120μ1, ~ 0.6mmol) in EtOH / H2 O (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- (347- (4-Fluoro-phenyl-1-imidazo [T, 2-Î ± -pyridin-3-yl-phenyl-amino} -Γ1,3,41oxadiazole-2-carboxylic acid ethyl ester

Bromide (20 μΐ, 0.39 mmol) in AcOH (Iml) was added in a stirred suspension of the imine (Procedure S2, -0.35 mmol) in AcOH (2ml) 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 Et 2 O 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) -imidazon, 2-alpyridin-3-yl-phenyl) -Δ1,3,41oxadiazol-2-yl-amine

a] pyridin-3-yl] phenyl-amino [1,2,4] oxadiazole-2-carboxylic acid (120mg, 0.27mmol) and 5N NaOH (0.5ml, 2.5mmol) in dioxane (2ml) were stirred and heated at 100 ° C for 1 hour. After cooling to RT, 5N HCl (0.5ml) was added. The mixture was diluted with Et 2 O and the liquid was decanted. THE

It was suspended in EtOH (3ml) and heated under reflux for 15 minutes. The volatiles were removed in vacuo and the residue was purified by preparative HPLC to give the title compound (12mg).

Procedure U: Halo Monomer Formations

Ul: Synthesis of (2-Chloro-pyridin-4-ir) -Rh3,41thiadiazol-2-ylamine

THE

5- {3- [7- (4-Fluoro-phenyl) -imidazo [1,2-acid] ethyl ester

The residue was treated with EtOH and the solid was collected by filtration. This solid

Step 1: In 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 CH 2 Cl 2 (25 mL) and H 2 O (20 mL). The organic phase was washed with brine, dried over MgSO 4, filtered and concentrated in vacuo. The product was used crude in the subsequent reaction.

THF (20 mL) at 0 ° C was added NH 2 NH 2 -H 2 O (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 gross used product.

Step 2:

s

In 2-chloro-4-isothio-cyanoate-pyridine (0.66 g, 3.90 mmol) in

Step 3:

s

In thiosemicarbazide (0.79 g, 3.89 mmol) in dry DMF (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 NaHCO 3 solution and the DMF was removed in vacuo. The residue was partitioned between H 2 O (15 mL) and CH 2 Cl 2 (25 mL) and the aqueous phase was re-extracted with CH 2 Cl 2 (2 x 15 mL). The combined 5 organic phases were dried over MgSO 4, 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 I-Iodation

Method as described in General Route Procedure 2 (A2)

THE

Procedure V2 - Formation of 6- (4-fluoro-phenyl) -3- (4,4,5,5-tetramethyl-1,3,21dioxaboyl-2-yl) -pyrazolor 1,5-alpyrimidine 10

15

T ^ "F

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) diboro (1 0.03 mmol) and KOAc (0.63 g, 6.38 mmol). The reaction vial was purged with N 2 and PdCl 2 dppf (82 mg, 0.11 mmol) added. The reaction flask was further purged with N 2 and then heated to 100 ° C for 3 h. After cooling to room temperature, EtOAc (30 mL) and H 2 O (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 reextracted with EtOAc (25 mL). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The solid was triturated with Et 2 O to give the title compound as a brown solid (0.35 g).

Procedure V3 - General Suzuki Reaction

[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) was added 2-dicyclohexylphosph-2 ', 6'-dimethoxybiphenyl (3.4 mg, 0.008 mmol), K 3 PO 4 IM (0.62 mL, 0.62 mmol) and Pd 2 (dba) 3 (3.8 mg, 0.004 mmol). The reaction was heated at 90 ° C for 18 hours. The reaction was concentrated in vacuo and partitioned between CH 2 Cl 2 (15 mL) and H 2 O (15 mL). The aqueous phase was reextracted 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 W

Step 1: Imidazori, 2-Alpyridine-7-Carbonitrile

Chloroacetaldehyde (-50% H 2 O, 3.24 mL, 26 mmol) was added in a stirred mixture of 2-aminoisonicotinonitrile (1.6g, 3.4 mmol) and NaHCO3 (2.23g, 26.5 mmol) in ethanol (20ml) at RT under N 2. The reaction was stirred and heated at 80 ° C for 18 hours. After cooling to RT the 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 (Na 2 SO 4) and filtered. MeOH washes were added and volatiles were removed in vacuo. The residue was purified by silica chromatography: 100% DCM → 1% 2M NH 3 -MeOH / DCM to give the title product. 1H 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-ID-imidazo [1,2-a] pyridine Sodium azide (97mg, 1.45 mmol) was added in a stirred mixture of NH 4 Cl (82mg, 1.53 mmol) and imidazo [1,2-a] pyridine-7-carbonitrile (200mg, 1.4 mmol) in dry DMF (5ml) at RT under N2 The reaction was stirred and heated to 80 ° C in a sealed vial for 10 hours. 3 identical reactions were performed in parallel] After cooling to RT the reaction mixtures were combined and diluted with Et 2 O. The solid was collected by filtration and dried to give the title compound (860mg) as a light brown solid, [presumably contains NaCl] 1H 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 [1,2-a] pyridine + isomer

Methyl iodide (580 pl, 9.4 mmol) was added in a stirred mixture of 7- (2H-tetrazol-5-yl) -imidazo [1,2-a] pyridine (~ 4.5 mmol) and K 2 CO 3 (1 (3g) 9.4 mmol) in dry DMSO (5ml) at RT under N 2. 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 (Na 2 SO 4) and filtered and evaporated. The residue was purified by silica chromatography: 100% DCM -> 4% 2M NH 3 -MeOH / DCM to give both regioisomers [Regiochemistry was determined using no studies]:

7- (2-Methyl-2H-tetrazol-5-yl) -imidazo [1,2-a] pyridine (less polar): 1H 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-d 6): 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-Iodo-7- (2-methyl-2H-tetrazol-5-yl) -imidazo [1,2-a] pyridine

N-Iodine Succinimide (300mg, 1.3 mmol) was added in one portion in 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 NaHCO 3 (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. 1H 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-ID-imidazo [1,2-a1-pyridin-3-yl-1-phenyl} -1,2,3,4-thiadiazol-2-yl-amine

A mixture of 3-iodo-7- (2-methyl-2H-tetrazol-5-yl) -

imidazo [1,2-a] pyridine (300mg, 0.92 mmol), 3- ([1,2,3,4] thiadiazol-2-yl-amino) -phenyl-boronic acid pinacol ester (14, 350mg, 1.15 mmol) and 2N Na 2 CO 3 (4.5ml) in dry DME (4.5ml) was deoxygenated by evacuation / N 2 (x 2) filling. PdCl2dppf (70mg, 0.10 mmol) was added, and the mixture was deoxygenated again (x3). The reaction was stirred and heated at 85 ° C for 3 hours. After cooling to RT the mixture was partitioned between EtOAc and H2O and stirred for 20 min. The remaining solid 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 (100 mg). MS: [M + H] + = 376.

AA General Route

Procedure AA1 - Imidazopyridine Ring Formation

In a solution of a 4-substituted-pyridin-2-yl-amine (1.0

equiv) in EtOH was added NaHCO 3 (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.

RR 'MS Product: [M + H] + CH 3 H 7-Methyl-imidazo [1,2-a] pyridine 133 Procedure AA2 -Iodation In a 7-substituted Imidazo [1,2-a] pyridine solution (1, The equiv) in DMF was added N-iodo-succinimide (1.2 equiv) and the resulting mixture was stirred for 2 h at room temperature. The thin brown slurry was diluted with water, 10% w / v sodium thiosulfate and sodium carbonate (IM) and extracted with CH 2 Cl 2. The aqueous phase was further extracted with CH 2 Cl 2. The combined organic phases were washed with brine, dried (MgSO 4) and concentrated in vacuo to afford the product. Where necessary, the product was further purified by trituration or silica column chromatography.

RR 'MS Product: [M + H] + CH 3 H 3-Iodo-7-methyl-imidazo [1,2- 259 a] pyridine Procedure AA3b - Suzuki reaction with 3- ([1,3-3) acid pinacolester , 4] thiadiazol-2-yl-amino) -phenyl boronic (14)

To a solution of 7-substituted-3-iodoimidazo [1,2-ajpyridine (1 equiv) in DME was added 3 - ([1,3,4] thiadiazol-2-yl-amino acid pinacolester). ) -phenyl boronic (14) (1.2 equiv.), Na2CO3 IM (8 equiv) [reaction was degassed by bubbling N2 therethrough] followed by tetrakis (triphenylphosph) 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 (MgSO 4) and concentrated under reduced pressure. The products were purified by trituration with Et 2 O, silica column chromatography or reverse phase HPLC. Where appropriate

The product was dissolved in HCl / dioxane, the solvent was removed and the product recrystallized from MeOH to give the hydrochloride.

R R1 Product CH3 H [3- (7-Methyl-imidazo [1,2-a] pyridin-3-yl) -phenyl] - [1,2,4] thiadiazol-2-yl-amine hydrochloride EXAMPLES I A 9

By the following methods described above, the compounds of

Examples 1 to 9 shown in Table below were prepared.

Eg- Compound Name Procedure N.M.R. MS Commercial No. 1 PfVy {3- [7- (4- General Route B, 'HRMN (400MHz, MS: fluorophenyl KJ) - procedure B1 to DMSO-d6): 9.71 [M + H] N = () imidazo [1,2- using 4-fluoro- (1H, s), 8.71 (1H, + 382 F ajpyridin-3-phenyl-boronic acid, d), 8.28 (1H, s), 8 , 20 yl] -phenyl} - procedure B2, (1H, s), 8.10 (1H, s), pitazin-2-yl-procedure B3a 8.04-7.89 (4H, m), amine using acid 3-amino-7.84 (1H, s), 7.72 (1H, benzene boronic d), 7.51 (1H, t), 7.47- General Modification F4 7.25 (4H, m ). using 2-chloro-pyrazine 2 µCro {3- [7- (3 General Route B; 1H NMR (400 MHz, MS: morpholin-A- Procedure Bl at DMSO-d6): 10.63 [M + H] yl methyl- using 4- [3- (4,4,5,5- (1H, s), 8.95 (1H, + 469 phenyl) tetramethyl-1,3,2-s), 8.67 ( 1H, d), 8.04 imidazo [1,2-dioxaborolan-2-yl) - (1H, t), 7.99 (1H, a] pyridin-3-benzyl] morpholine; brs), 7.84 (1H, s), yl] phenyl} - procedure B2; 7.81-7.72 (2H, m), [1,2,4] procedure B3a 7,68 (1 H.dd), 7,56 diazol-2-yl- using (1H, t), 7.48 (1H, t), amine acid 3-7.44-7.36 (2H, m), ([1,3,4] thiadiazol-2-yl-7.34 (1H, dt), 3,66-amino) phenyl boronic 3.53 (6H, m), 2.47- (14). 2.33 (4H, m). 3 JiV (5-methyl-General Route A; 1H NMR (400 MHz, MS: O [1,2,4]] procedure Al and A2, DMSO-d 6): 10.44 [M + H] diazole-2 -II) - Procedure A3b (1H, s), 8.66 (1H, d), + 483 --- O {3- [7- (3- using 8.04-7.95 pinacol ester ( 2H, morpholin-4-acid 3- (5-methyl-m), 7.83 (1H, s), 7.81-ylmethyl 1- [1,3,4] thiadiazol-2-yl-7, 71 (2H, m), 7.63 phenyl) amino) phenyl boronic (1H, brd), 7.54 imidazo [1,2- (15), Procedure A4b (1H, t), 7.48 ( 1H, t), a] pyridin-3- with 4- [3- (4,4,5,5- 7,44-7,35 (2H, m), yl] phenyl} tetramethyl-1,3 , 2. 7.31 (1H, d), 3.66-amine dioxaboron-2-yl) - 3.54 (6H, m), 2.58 benzyl-morpholine. (3H, s), 2.46-2.35 (4H, m). 4 rfà General Procedure salt G; 1H NMR (400 MHz, MS: δ procedure procedures G1 DMSO-d6): 8.95 [M + H] N (3- {7- [4- (4 and G2 (1H, s)), 8.64 ( 1H, d), + 465 (methyl-8.27 (2H, s), 7.98 piperazin-1- (1H, s), 7.86-7.75-ylmethyl) - (2H, m), 7.63 (1H, phenyl] -brs), 7.48 (1H, s), imidazo [1,2-7,46-7,28 (5H, m), a] pyridin-3-7,09 ( 1H, d), 3.52 yl} phenyl) - (2H, s), 2.28-2.46 (3H- (8H, brm), 2.17 (3H, [1,2,3]) triaz s) .ol-4-yl) amine General Route B salt, 1H NMR (400 MHz, MS: v-procedure formate B1 to Me-drOD): 8.55 [M + H] Xaf {3- [7- (4- _ using 4-fluoro acid - (1H, d), 8.21 (1H, S), + 380 fluoro-phenyl) phenyl-boronic, 7.85-7.74 (3H, imidazo [1,2-procedure B2, m), 7.70 (1H, s), 7.40 ajpiridin-3-procedure B3a (1H, t), 7.36-7.12 yl] -phenyl} - using 3-amino- (9H, m), 7 7.07 Benzene-boronic phenylamine, (1H, d), 6.91 (1H, t). General Modification F4 using bromo-benzene 6 rfO salt of General Route B, 1H NMR (400 MHz, MS: procedure formate Bla Me-d3-OD): 8.63 [M + H] / TN 6 {3- [ 7- (4- using 4-fluoro- (1H, d), 8.44 (1H, s), + 381.Xi-F-fluoro-phenyl) phenyl-boronic acid, 8.22 (2H, d) 7,87-imidazo [1,2-procedure B2, 7,79 (4H, m), 7,70 ajpyridin-3-procedure B 3a (1 H, t), 7,63-7,59 yl] phenyl } - using 3-amino- (2H, m), 7.48-7.43 pyridin-4-yl-benzene boronic acid, (1H, m), 7.37 (1H, amine General Modification F4 dd), 7.31-7.24 (2H, using 4m hydrochloride), 7.17 (2H, d). bromo-pyridine 7 Vf {3- [7- (4 General Route B, 1H NMR (400 MHz, MS: fluorophenyl) - procedure Bla DMSOd6): 10.69 [M + H] imidazofl, 2- using acid 4-fluoro- (1H, s), 9.00 (1H, + 388 a] pyridin-3-phenyl boronic, s), 8.72 (1H, d), 8,10-yl] -phenyl} - procedure B2, 8.06 (2H, m), 8.01- [1, 3,4] thia procedure B3a 7.96 (2H, m), 7.89 diazol-2-yl- using pinacol ester of ( 1H, s), 7.74 amine 3 - ([1,2,4] - (1H, dd), 7,61 (1H, t), thiadiazol-2-yl-amino) - 7,45-7 , 37 (4H, m). phenyl boronic (14) 8 OmO {3- [7- (3 General Route B, 1H NMR (400 MHz, MS: δ-q morpholin-4-procedure Bla Me-d3-OD): 8.59 [M + H] ylmethyl- using 4- [3- (4,4,5,5- (1H, d), 7,89-7,82 + 461 phenyl) tetramethyl-1,3,2- (1H m, 7.78 (1H, s), imidazofl, 2-dioxaborolan-2-yl) - 7.76-7.65 (2H, m), ajpyridin-3-benzyl] -morpholine, 7.52- 7.46 (1H, m), - yl] phenyl} - procedure B2, 7.46-7.39 (2H, m), phenyl amine procedure B3a 7.35 (1 H.dd), 7.33 - using 3-amino-7,25 (3H, m), 7,25-benzene boronic acid, 7,14 (3H, m), 7,11 General Modification F4 (1H, d), 6,97-6 , 87 using bromo-benzene (1H, m), 3.78-3.68 (4H, m), 3.64 (2H, s), 2.59-2.48 (4H, m). 9 H N. General Route salt B 1H NMR (400 MHz, MS: The procedure formate Bld, B2, Me-d3-OD): 8.83 [M + H] ry (3- {7- [3- (4-B3a using pinacol- (1H, s), 8.72 (1H, d), + 482 3-8.38 (3H, s) acid methyl ester, 8.19 piperazin-1- ([1 3,4] -thiadiazol-2-yl- (1H, s), 7.87-ylmethyl) amino) phenyl boronic (1H, s), 7.79 (2H, phenyl) - (14) s), 7.73 (1H, d), 7.57-imidazo [1.2-2.32 (6H, m), 3.76 ajpiridin-3- (2H, s), 3.23 (4H, s), yl} phenyl) - 2.81 (7H, m). [1,2,4] thia diazol-2-ylamine EXAMPLES 10 TO 11

By the following methods described above, the pyrazolo [1,5-ajpyrimidine compounds of Examples 10 to 11 shown in Table below were prepared. Eg- Compound Trade Name Method Data of N.M.R. M.S. No. «Sa. {3- [6- (4-fluoro-Procedure K, 1 H NMR (400 MHz, MS: phenyl) -M, then DMSO-d 6): 10.52 (1H, [M + pyrazolo [1,5-procedure N brs ), 9.54 (1H, d), 9.04 H] + a] pyrimidin-3-yl] - using pinacol- (1H, d), 8.91 (1H, 389 phenyl} - 3-acid ester s), 8.74 (1H, s), 8.31 [1,2,4] thiadiazole ([1,3,4] thiadiazole (1H, t), 8.01-7.91 (2H, 2 (2-yl-amino) -phenyl-m), 7.79-7.67 (2H, m), boronic (14) 7.48-7.35 (3H, m). 11 H hydrochloride salt Procedure L 1 H NMR (400 MHz, MS: 5- {3- [3-> using 2-amino-5-DMSOd 6): 10.57- [M +] / ([1, 3,4] thiadiazol- (4,4,5,5-tetramethyl-10,52 (1H, m), 9.59 H] + NN / 2-yl-amino) -1,3,2- (1H, d), 9.01 (1H, 387 N NH 1 phenyl] dioxaborolan-2-yl) - d), 8.92 (1H, s), 8.77 pyrazolo [1,5-pyridine (1H, s) , 8.51 a] pyrimidin-6-procedure M (1H, d), 8.45 (1H, dd), yl} -pyridin-2-yl-then 8.36 (1H, s), 7, 74 (1H, amine procedure N d), 7.71-7.62 (1H, m) using pinacol-7.45 (1H, t), 7.14 (1H, 3-d acid ester). ([1,4,3,4-thiadiazol-2-yl-amino) -phenyl-boronic acid ()4) Example_12- {3-6- (4-Fluoro-phenyl) -pyrazolo [T-5-Î ± -pyridin-3-1H-

phenyl Γ1,3,41thiadiazol-2-yl-amine Step 1: 3- (4-Fluoro-phenyl-pyridine

A solution of 3-bromo-pyridine (2.5g, 15.8 mmol) and 4-5-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, 0.8 mmol) was added and the mixture was deoxygenated again (x3). The reaction was stirred and heated at 80 ° C under N 2 for 16 hours. After cooling to RT the mixture was partitioned between EtOAc and H2O. The aqueous layer 10 was extracted with EtOAc (x2). The combined extracts were washed with brine (xl), dried (Na2SO4), filtered and evaporated. The residue was purified by silica chromatography (10-40% EtOAc / Petrol) to give the title compound (3.0g, oil). 1H 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) -pyrazololT.5-alpyridine-3-carboxylic acid methyl ester

0- (Mesitylene sulfonyl) hydroxylamine (3.5g, 16.2 mmol) was added in one portion in a stirred solution of 3- (4-fluoro-phenyl) -pyridine (2.8g, 16mmol) in CH 2 Cl 2 dried at 0 ° C under N 2. After 30 minutes the ice bath was removed and the reaction was stirred at RT for 16 hours. The volatiles were removed in vacuo and N-amino pyridine was used without further purification. K 2 CO 3 (4.4g, 32 mmol) was added in a stirred solution of the above N-amino pyridine (—16 mmol) and 2-benzenesulfonyl-3-dimethylamino-acrylic acid methyl ester (4.3g , 16 mmol) in dry DMF (48ml) at RT under N 2. After 3 hours at RT the reaction was heated at 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 CH 2 Cl 2 / petrol to give the title compound (2.7g, solid). 1H NMR (400 MHz, CDCl3): 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: Fluoro-phenyl-pyrazolor-US-alpyridine

A mixture of 6- (4-fluoro-phenyl) pyrazolo [1,5-a] pyridine-3-carboxylic acid methyl ester (1.08g, 4 mmol) and aqueous NaOH (2N, 4ml) and EtOH ( 16ml) was stirred and heated at 85 ° C under N 2 for 30 minutes. The reaction was allowed to cool to RT, then put in an ice bath. 2N Hydrochloric acid (5ml) was added slowly. The solid was collected by filtration, washed with Et 2 O then dried under vacuum. The acid was used without further manipulation. A suspension of the above acid in polyphosphoric acid 5 (~ 15ml) was stirred and heated to 150 ° C under N 2. After 3 hours the reaction was allowed to cool to RT then carefully poured 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). 1H 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 (1

H, s).

Step 4: 6- (4-Fluoro-phenyl) -3-iodo-pyrazolo [1,5-alpyridine

sF

N-Iodo-succinimide (630mg, 2.8 mmol) was added in one portion in a stirred solution of 6- (4-fluoro-phenyl) -pyrazolo [1,5- 15 a] pyridine (500mg, 2.4 mmol). ) in dry DMF (6ml) at RT under N2. After 45 minutes, the reaction was quenched with saturated aqueous sodium thiosulfate / saturated NaHCO 3 (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). 1H NMR (400 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 5-5- (3-6- (4-Fluoro-phenyl) -pyrazoloF-1,5-alpyridin-3-yl] -benzamide

phenyl 1,3,41 thiadiazol-2-yl-amine A mixture of 6- (4-fluoro-phenyl) -3-iodo-pyrazolo [1,5-a] pyridine (150mg, 0.44 mmol), pinacol ester of 3 - ([1,4,4] thiadiazol-2-yl-amino) -phenyl boronic acid (190mg, 0.62 mmol) and PdCl2ddpf (32mg, 0.04 mmol) in DME (1.5ml) and 2N Na 2 CO 3 (aq, 1.5ml) in a microwave flask was deoxygenated by bubbling N2 therethrough for 30 seconds. The flask 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 CH2Cl2 and H2O. The organic layer was evaporated and the residue was purified by preparative HPLC to give the title compound (15mg, 10 solid).

Eg. No. Compound Name Method Data of N.M.R. M.S. Commercial 12 Hs. {3- [6- (4-fluoro-example 1 H NMR (400 MHz, MS: NN phenyl) - single DMSO-d 6): 10.52 [M + H] + pyrazolo [1,5- described (1 H, s), 9.12 (1H, s), 8.94 388 a] pyridin-3-yl] - above (1H, s), 8.42 (1H, s), phenyl} - 8.12-8, 06 (2H, m), 7.93- [1, 3,4] thiadiazol-7.87 (2H, m), 7.74 (1H, 2-yl-amine dd), 7.54 (1H, d), 7.45 (1H, t), 7.41-7.30 (3H, m). EXAMPLES 13 TO 43

Eg- Structure Method Name NMR Data Compound No. Data MS 13 Om acid {3- [3- (3 General Route A, 1H NMR (400 [M + H] + c »benzylamino-procedure A3 MHz Me-d3-434 (phenyl) - using 3- (4,4,5,5-OD): 8,26 imidazo [1,2-tetramethyl-1,3,2- (1H, d), 7, 83 (1H, a] pyridin-7-yl] dioxaboroan-2-yl) s), 7.72 (1H, s), phenyl} acetic aniline and conditions 7.66 (1H, d), described in A4d, 7.64-7.58 (1H, modification F8, m), 7.53-7.25 procedure A4e (9H, m), 7.22 using Acid 2- (3- (1H, dd), 6.86 (4,4,5,5-tetramethyl-1,3,2- (1H, d), 6,78 (2H, dioxaborolan-2-yl ) - d), 4.43 (2H, s), phenyl) -acetic 3.73 (2H, s). 14 here {3- [7- (1-methyl-General Route B, 1H NMR (DMSC) - [M + H] + ■ 1H-pyrazol-4-Procedure B1 and d6) (1H, 374 Il) - using (1.H, imidazo [1,2-imidazole [1,2-a] pyridine s) 8.94 (1H, a] pyridin-3-yl] - and pinacol ester d) 8.59 (1H, phenyl} -1-methyl-pyrazol-4-s) acid 8.37; (1H, [1, 3,4] thiadiazo boronic acid, B2 and then s) 8.09; (1H 1-2-ylamine B3b using pinacols) 8.00 (1H, 3-acid ester ester) 7.39 (1H, ([1,3,4] thiadiazol-2-yl ) 7.73 (1H, amino) phenyl boronic dd) 7.65 (1H, t) 7.5 (1 4) 4. (1H, dd) 7.30, (1H, dd) 7.25 (3H, s) 3.90 M-trvQ [3- (6- Procedure K using 1H NMR (400 [M + H] + VV Pyrimidin-4-yl-2- (4- MHz, DMSOd 6): 373 JJ-O pyrazolo [1,5-pyrimidyl) malondialdehyde 9.99 a] pyrimidin-3, procedure B2, (1H, d ), 9.43 (1H, d) yl) -phenyl] - procedure B3a, 9.33 (1H, s), [1,2,4] thiadiazo using 117 9.00-8.93 (1H, 1- 2-ylamine m), 8.85 (2H, d), 8.35 (1H, d), 8.28 (1H, s), 7.76-7.64 (2H, m), 7.43 (1H, t). ! 16 cAs * {3- [6- (1-methyl-Procedure K, Blc 1 HRMN (I) M SO- [M + H] JNN IH-pyrazol-4 using d6-pinacol ester) 375 (yl) -1-methyl-pyrazol-4-s) 10.50, (1H, m) pyrazolo [1.5 boronic acid, M and then 9.47, (1H, ajpyrimidin-3-B3b using pinacol-m,) 8.98; (1H, yl] -phenyl} 3-acid acid ester) 8.91; (1H, [1,2,3,4] thiadiazole ([1,2,4] thiadiazole -2-yl) 8.66, (1H, 2-amino-amino) phenyl-boronic s) 8.39, (1H, (14) t) 8.30, (1H, s) 8 (2H, m) 7.70 (1H, t) 7.43 (3H, s) 3.92 [3- (6-pyridin-Procedure K using 1H NMR (400 [M + H] + PO 4-yl-2- (4 MHz, DMS0-d6): 372 pyrazolo [1,5a] pyridyl) malondialdehyde, 10.58-10.50 (1H, pyrimidin-3-procedure B2, m), 9.77 yl) -phenyl] -procedure B3a (1H, d), 9.16 (1H, d) [1,3, 4] thiadiazo using 117, 8.92 (1H, s), 1-2-ylamine 8.81 (1H, s), 8.73 (2H, d), 8.33 (1H, t), 8 .02-7.94 (2H, m), 7.79-7.67 (2H, m), 7.46 (1H, t). 18 KO [3- (6-pyrazin-Procedure K using 1 H NMR (400 [M + H] * '2-yl-2- (2-pyrazinyl) -1 MHz, DMSO-d 6): 373 pyrazolo [1,5- malondialdehyde 10.55 (1H, s), a] pyrimidin-3-procedure B2, 9.93 (1H, d), 9.49 yl) -phenyl]-procedure B3a (1H, d), 9.39 [ 1,3,4] thiadiazo using 117 (1H, d), 8.92 (1H, 1-2-ylamines), 8.84 (1H, s), 8.81 (1H, t), 8.72 (1H, d), 8.33 (1H, s), 7.78-7.71 (2H, m), 7.47 (1H, d). 19 Ortl ^ [3- (7-General Route B, 1H NMR (400 [M + H] "C» morpholin-4-yl-procedure Blb MHz, Me-dj-379 0 imidazo [1,2- using morpholine ( as OD): 8.82 (1H, s), α] pyridin-3-yl) - described in 8.47 (1H, d), 8.05 phenyl] - Procedure E), (1H, s), 7.57-7.48 [1,2,4] thiadiazo procedure B2, (3H, m), 7.33-2-2-ylamine procedure B3a 7.25 (1H, m) using pinacol ester 6.96 (1H, dd), 3-6.80 (1H, d) acid, 3.88 ([1,3,4] thiadiazol-2-yl- (4H, t), 3.32-3 .30 amino) phenyl boronic (4H, m). (14) vOR [3- General Route A, 1H NMR (400 [Adduct] 'VK5> (7-benzo [1,3] procedure Al, MHz, DMSO-d 6): 414 dioxol-5-yl-procedures A2, 10, 62 (1H, s), imidazo [1,2-procedure A3b 8.95 (1H, s), 8.61 a] pyridin-3-yl) - using (IH, d), 8, pinacol ester O (1H, phenyl] -acid 3 s), 7.95 (1H, s), [1,2,4] thiadiazol ([1,3,4] thiadiazol-2-yl-7,81 (1H, s), -2-ylamine amino) phenyl boronic 7.73-7.59 (2H, (14), procedure A4b m), 7.59-7.46 using (2H, m), 7,42-3,4-methylene-7,28 (3H, m), dioxy-phenyl boronic acid. 7.05 (1H, d), 6.11 (2H, s) 21 ■ Λ General Route B hydrochloride, 1H NMR (400 [Adduct] + {3- [7- (4 procedure Blb MHz, DMSO-d6 ): 470 ethanesulfonyl- using 1-ethanesulfonyl-10.89-10.82 (1H, piperazin-1-yl) piperazine, m), 8.96 (1H, s), imidazo [1.2 - procedure B2, 8.14 (1H, s), 8.09 a] pyridin-3-yl] - procedure B3a (1H, s), 7.71 (1H, phenyl} - using, d-pinacol ester , 7.59 (1H, t), [1,2,3,4] thiadiazol acid 3-7.33 (1H, dd), -2-yl-amine ([1,2,4] thiadiazol-2-yl] 7.30 (1H, d), amino) phenyl boronic 6.97 (1H, d), 3.65 (14). Procedure J (4H, m), 3.37 (4H, m), 3.18-3.11 (2H, m), 1.25 (3H, t). General Route Î ± -hydrochloride A, 1H NMR (400 [M + H] + morpholin-4-yl-procedure Al, MHz, DMSO-d6): 483 (3- {3- [3-procedure A2, 10 94 (1H, s), ([1, 3,4] thiadiaz procedure A3b 8.97 (1H, s), 8.87 ol-2-yl-amino) - using (1H, d ), 8.49 (1H, phenyl] -acid 3 s), 8.34 (1H, s), imidazo [1,2- ([1,2,4] thiadiazol-2-yl-8,22) (1H, s), 8.05 a] pyridin-7-yl} amino) phenyl boronic (1H, d), 7.99 (1H, phenyl) - (14), procedure A4b s), 7, 92 (1H, d), methanone using 3- 7.79 (1H, d), (morpholine-4-carbonyl) - 7.76-7.56 (3H, phenyl boronic acid, m), 7.39 ( IH, d), Procedim then 3.64 (6H, br m), 3.42 (2H, d). 23 ςΛ> {3- [5- (4- General Procedure O, 1H NMR (400 [M + H] 'cP "fluorophenyl) - Procedures Ol, 02, MHz, DMSO-d6): 388 F benzoimidazole 03, 04, Procedures 10.77 (1H, s), -1-yl] -phenyl} - 07a and 07b 8.98 (1H, s), 8.65 [1,3,4] thiadiazol- (1H, s), 8.17 (1H, 2-ylamine t), 8.06 (1H, d), 7.83-7.75 (3H, m), 7.71-7.56 (3H, m), 7 , 38-7.25 (3H, m) 240 * ϊ> [3- (7- General Route B, 1H NMR (400 [M + H] + ca piperidin-1-yl-procedure B1 b MHz, Me -d3-0D): 377 ■ imidazo [1,2- using pipe ridine, 8.85 (1H, s), a] pyridin-3-yl) - procedure B2, 8.48 (1H, d), 8.41 phenyl] -, procedure B3a (1H, s), 8, 24 (1H, [1,3,4] thiadiazole using s-pinacol ester), 7,72 (1H, s), 2-yl-amine 3 - ([1,2,4] - 7, 56 (2H, d), thiadiazol-2-yl-amino) - 7.36-7.27 (1H, phenyl boronic (14) m), 7.27-7.12 (1H, m), 6, 83 (1H, d), 3.58 (4H, m), 1.75 (6H, m). Orli * {5- [6- (4- General Route K1, 1H NMR route (400 [M + Hf cf "fluorophenyl) - general V, procedure MHz, DMSO-d6): 390 F pyrazolo [1.5 VI , procedure V2, 10.72 (1H, s), a] pyrimidin-3 procedure V3 9.59 (1H, d), 9.09 yl] pyridin-3 using halo- (1H, d) 8.99 (1H, yl) - [1,3,4] s monomer), 8.95 (1H, s), thiadiazol-2-yl U procedure 8.88 (1H, s), 8 , 82 amine used 5-bromo-pyridin-3- (2H, s), 7.97 (2H, yl-amine dd), 7.41 (2H, t) 26 Ν = λ General Route A hydrochloride, 1H NMR (400 [M + H] + δγ8 N-methyl-2- (3-procedure Al, MHz, DMSOd 6): 441 δ Cr “{3- [3-procedure A2, 11.04 (1H, s), here ( [1,2,4] thiadiaz procedure A3b 8.96 (1H, s), 8.88 ol-2-yl-amino) - using (1H, d), 8.48 (1H, phenyl] acid 3 s), pinacol ester (8.23 (2H, d), imidazo [1,2- ([1,2,4] thiadiazol-2-yl-8,12 (1H, m), a] pyridin-7-yl} amino) phenyl boronic 7.90-7.76 (4H, phenyl) - (14), procedure A4b m), 7.65 (1H, t), acetamide using 118, 7.54 (1H, t), 7.45 Procedure J (1H, d), 7.39 (1H, d) ), 3.55 (2H, s), 2.60 (3H, s). 27 JXJr N * 3 * - {3- [7- General Route B, 1H NMR (400 [M + H +] <RTIgt; (4-fluoro-procedure Bl at MHz, DMSOd6): 386 ^ Lt "phenyl) - using acid 4-fluoro-11.17 (1H, s), NH 3 imidazo [1,2-phenyl-boronic, 8,84 (1 H, s), 8,64 a] pyridin-3-yl] - procedure B2, ( 1H, d), 7.98 (1H, phenyl} -1H-procedure B3 s), 7.94-7.90 (3H, [1,2,4] triazo (using 3-amino-acid)), 7 76 (1H, s), e-3,5-benzene boronic diamine, 7.52 (1H, d), General Modification Q 7.39-7.33 (4H, m), 7.03 (1H, d), 5.89 (2H, s) .28 4-General P-formate A, 1H NMR (400 [M + Hf H δ (3- {3- [3 procedure A1, MH z, DMSO-d 6): 482 ([1,2,4] thia procedure A2, 10,65 (1H, diazol-2-yl-procedure A3b s), 8,95 (1H, s), amino) phenyl ] - using 8.68 (1H, d), 8.20 imidazo [1,2-acid 3- (2H, s), 8.07-7.97 a] pyridin-7-yl} - ([1,3,4] thiadiazol-2-yl- (2H, m), 7.84 benzyl) amino) phenyl boronic (1H, s), 7.83-7.72 piperazin-2- ( 14), procedure A4b (3H, m), 7.68 one using 119 (1H, d), 7.56 (1H, t), 7.50 (1H, t), 7.40 (2H, d), 7.34 (1H, d), 3.66 (2H, s), 3.18 (2H, s), 2.98 (2H, s). ZX I {3- [7- (4 General Route B, 1H NMR (400 [M + H] + tf fluoro-phenyl) - procedure Bla MHz, DMSO-d6): 372 imidazo [1,2- using acid 4-fluoro-10.69 (1H, s), a] pyridin-3-yl] phenylboronic, 8.78 (1H, s), 8.65 phenyl} - [1,3,4] procedure B2 , (1H, dd), 8.01 oxadiazol-2-yl-procedure B3a (1H, d), 7.99-7.87 amine using 3-amino- (3H, m), 7.83 benzene boronic acid , (1H, s), 7.65-7.61 procedure S (1H, m), 7.56 (1H, t), 7.44-7.29 (4H, m). General Route N hydrochloride A, 1H NMR (400 [M + H] + N 3 S N-methyl-3- {3-procedure Al, MHz, DMSOd 6): 427 δ 13- ([1.3, 4] procedure A2, 11.00 (1H, s), H2-thiadiazol-2-yl-procedure A3b 8.96 (1H, s), 8.90 amino) -phenyl] - using (IH pinacol ester d), 8.77 (1H, imidazo [1,2-3-m-acid), 8.50 (1H, s), a] pyridin-7-yl} - ([1,2,4] thiadiazol-1 2-yl-8.38 (2H, d), 8.23 amino) -phenyl-boronic benzamide (1H, s), 8.11 (1H, (14), procedure A4b d), 8.02 (1H, d) using 3- (N- 7.96 (1H, dd), methylamino carbonyl) - 7.81 (1H, dd), benzene boronic acid, 7.76-7.60 (2H,Procedure J m), 7.39 (1H, d), 2.85 (3H, d). 31 H {2- [6- (4- General Route K1, route 1H NMR (400 [M + H] + λ Tr T Ti fluoro-phenyl) - general V, procedure MHz, DMSO-d6): 390 NN 1 ^ N pyrazolo [1.5 VI, procedure V2, 11.06 (1H, s), L NN a] pyrimidin-3-procedure V3 9.59 (1 Hd), 9.10 Î »yl] pyridin [4-using halomer (1H, d), 9.06 (1H, F [1,2,4] thiadiazole Ul s), 8.85 (1H, s), 8.51 -2-ylamine (1H, s ), 8.50-8.47 (1H, m), 8.03-7.94 (2H, m), 7.80 (1H, dd), 7.47-7.36 (2H, m). General Route A hydrochloride 1 H NMR (400 [M + H] + {3- [7- (3 procedure Al, MHz, DMSO-d 6): 385 amino phenyl) - procedure A2, 10.98 ( 1H, imidazo [1,2-procedure A3b s), 8.96 (1H, s), a] pyridin-3-yl] - using 8.89 (IH, d), 8.48 phenyl} pinacolester - 3- (1H, s), 8.20 [1,2,4] thiadiazol ([1,2,4] thiadiazol-2-yl- (2H, d), 7,85-7,74 -2 acid -amino) -phenyl-boronic acid (2H, m), 7.69- (14), procedure A4b 7.50 (4H, m), 7.39 using (3-Boc- (1H, d) acid 7.28-7.19 amino-phenyl) boronic, (1H, m). Procedure D3b 33 (3- {7- [2- General Route A, 1H NMR (400 [M + H] + cT (tetrahydro-procedure Al, MHz, Me-d3-OD): 471 ° (Pyran-4-yloxy) - procedure A2, 8.83 (1H, s), pyridin-4-yl] - procedure A3b 8.73 (1H, d), 8,27-imidazo [1,2 - using 8.17 (1H, m), 8.15 a] pyridin-3-yl} - 3- (1H, s), 8.00 (1H, phenyl) - ([1,3) , 4] thiadiazol-2-yl), 7.83 (1H, s), [1,2,4] thiadiazol-amino) -phenyl 1-boronic 7,62-7,54 (2H, -2-yl) - amine (14), procedure A4b m), 7.42 (1H, d) using 121 7.35 (2H, d), 7.18 (1H, s), 5.34-5.23 (1H, m), 4.07- 3.95 (2H, m), 3.71-3.59 (2H, m), 2.18-2.05. (2H, m), 1.88-1.74 (2H, m). 34 ps® hydrochloride {3-General Route B, 1H NMR (400 [M + H] [α] D [4- (4-Fluoro-procedure Bla MHz, Me-d3-OD): 384 phenyl) - using 4-acid fluoro-8.87-8.79 (1H, m), imidazo [1,2-phenyl-boronic, 8.19 (2H, d), 8.01-a] pyridin-3-yl] - procedure B2, 7 , 92 (2H, m), phenyl} - (1-procedure B3a 7.87-7.72 (2H, m), methyl-1H- using (1-methyl-1H-7.70-7.62 (2H, m ), imidazol-2-yl) imidazol-2-yl) - [3- 7.52 (1H, d), 7.37 amine (4,4,5,5-tetramethyl (2H, t), 7 , 20 (1H, [1,3,2] dioxaborolan-2-d), 7.09 (1H, d), yl) phenyl] amine (116) 3.75 (3H, s). HO- {j (3- {3- [3- General Route A, 1 H NMR (400 [M + H] +) ([1,4,4] procedure Al, MHz, Me-d 3-OD): 400 diazole Procedure A2, 8.83 (1H, s), ylamino) - procedure A3b 8.72 (1H, d), 8.13 phenyl] - using (IH, s) pinacol ester, 7.88 (1H, imidazo [1,2-acid 3-s), 7.79 (2H, d), a] pyridin-7 ([1,3,4] thiadiazol-2-yl-7.71 (1H, d ), 7,65-yl} -phenyl) -amino) -phenyl-boronic 7.48 (3H, m), methanol (14), procedure A4b 7.48-7.33 (3H, m), using acid ( 3- 4.74 (2H, s), hydroxymethylphenyl) boronic 36 N = \ ethyl ester of General Route B, 1H NMR (400 [M + H] + NyS acid 4- {3- [3-procedure Blb MHz, Me-d3-OD): 450 NH ([1,2,4] thia using piperazine-1- 8,84 (1H, s), 8.51 ethyl diazol-2-yl carboxylate, (1H, d), 8.42 (1H, amino) phenyl] - procedure B2, s), 8.21 (1H , s), The imidazo [1,2-procedure B 3a 7,72 (1 H, s), 7,63-a] pyridin-7 using 7.49 (2H, m) pinacol ester, 7,30 piperazine-1-acid 3- (1H, d), 7.18 (1H, carboxylic acid ([1,3,4] thiadiazol-2-yl)), 6.92-6.82 (1H, amino) - phenyl boronic m), 4.19 (2H, q), (14). 3.68 (4H, s), 3.54 (4H, s), 1.31 (3H, t). General Route A hydrochloride 1 H NMR (400 [M + H] + H 3 N 5- {3- [3 procedure Al, MHz, DMSO-d 6): 386 ([1,2,4] thia procedure A2, 10.91 (1H, s), diazol-2-yl-procedure A3b 8.96 (1H, s), 8.85 amino) -phenyl] - using (IH, d) pinacol ester, 8.67 (1H, imidazo [1,2-acid 3-d), 8.45 (1H, d), a] pyridin-7-yl} - (1,2,4] thiadiazol-2-yl 8.40 (1H, m), 8.21 pyridin-2-yl-amino) phenyl boronic (2H, m), 8.15 (2H, amine (14), procedure A4b br.s) 7.84 -7.71 using 2-amino-5- (2H, m), 7.63 (1H, (4,4,5,5-tetramethyl-t), 7,37 (1H, d), 1,3 2,2-dioxaborolan-2-7,10 (1H, m) yl) pyridine, Procedure J 38 σ "ϊ> <1- (4- {3- [3- General Route B, 1H NMR (400 [M + H] + c" ([1,2,4] procedure Blb MHz, Me- d3-OD): 420 σ diazol-2-yl- using N-acyl-9.11 (1H, s), 8.53 - (<amino) phenyl] piperazine (1H, d), 7.99 (1H, imidazo [1,2-procedure B2, s), 7.88 (1H, s), a] pyridin-7-yl}-procedure B3a 7.79-7.67 (2H, m), piperazin -1- using 7.62 (1H, d), 7.33 yl) -ethanone pinacol ester 3- (1H, d), 6.98 (1H, ([1,2,4] thiadiazol-2-acid) (s), 3.83 (4H, m), amino) phenyl-boronic 3.73 (4H, m), 2.22 (14). (3H, s). 39, Cp {3- [7- (4 General Route B. 1H NMR (400 [M + Hf fluoro-phenyl) - Procedures B1 to MHz, DMSO-d6): 388 imidazo [1,2- using 4- Fluoro-11.18 (1H, s), 8.70 a] pyridin-3-yl] phenylboronic, (1H, d), 8.26 (1H, phenyl} - [1,2,4] procedure B2, s), 8.06-7.89 (4H, thiadiazol-5-yl-procedure B3b m), 7.86 (1H, s), amine using pinacol ester 7.65-7.54 (2H, m), 3- 7.46-7.30 (4H, m) ([1,2,4] thiadiazol-5-yl-amino) -phenyl boronic acid (124), K3PO4 in place of 40 N2 Na2CO3 s N- (3- {3- [3- General Route A, 1H NMR (400 [M + H] + C ') ([1,2,4] This procedure Al, MHz, Me-d 3 -477 os diazole-2 procedure A2, OD): 8.81 (1H, s), amino) -phenyl] - procedure A3b 8.58 (1H, d), 8.30 imidazo [1,2- using pinacol ester). (1H, s), 8.07 (1H, a] pyridin-7-yl} -acid (3s), 7.78 (1H, s), benzyl) - ([1,2,4] thiadiazole 2-yl-7.72 (2H, d), 7.62 methane-amino) -phenyl boronic (1H, d), 7.55-7.37 sulfonamide (14), procedure A4b (4H, m), 7.30 using (3- (1H, d), 7.25 (1H, methanesulfonyl-amino-d), 4.33 (2H, s), methyl) -benzene boronic 2.94 (3H, s). 41 H Procedure AA1 H hydrochloride, 1H NMR (400 [Adduct] + IYM * [3- (7-methyl- using 4-methyl-2 MHz, DMSO-d 6): 308 1W1 Nn imidazo [1,2-amino- pyridine, 8.04-7.95 (1H, b) pyridin-3-yl) - Procedure AA2, m), 7.70 (1H, d), phenyl] - procedure AA3b 7.23 (1H, s ), 6.83 [1,2,4] thiadiazole using (1H, s) pinacol ester, 6.78 (1H, -2-ylamine acid 3 d), 6.76-6.70 ( 1H, ([1,3,4] thiadiazol-2-yl), 6.60 (1H, s), amino) phenyl boronic 6.50 (1H, d), 6.09 (14) . Procedure J. (1H, d), 1.65 (3H, s). Benzyl- {3- [7- General Route A, 1H NMR (400 [M + H] + β (1-methyl 1-1H-procedure A3 MHz, Me-d3-380 pyrazol-4-yl) - using 3- (4,4,5,5-OD): 8,21-8,10 imidazo [1,2-tetramethyl-1,3,2- (2H, m), 7.97 a] pyridine- 3-yl] dioxaboroan-2-yl) - (1H, s), 7.69 (1H, phenyl} -amine aniline and conditions s), 7.60-7.48 (1H, described in A4d, m) , 7.47-7.21 modification F8, (7H, m), 7.08 procedure A4b (1H, d), 6.87-6.78 using 1-methyl 1-4- (1H, m), 6 , 75 (4,4,5,5-tetramethyl- (2H, d), 4.41 (2H, 1,3,2-dioxaborolan-2s), 3.97 (3H, s)) -1H-pyrazole and K3PO4 in place of Na 2 CO 3 43 tf * {3- [7- (2-methyl-Procedure W 1H NMR (400 [M + H] + -V 1 2H-tetrazol-5 MHz, DMSO-d 2): 376 iO-10 , 64 (1H, s), imidazo [1,2-8,95 (1H, s), 8,78 a] pyridin-3-yl] - (1H, d), 8,29 (1H, phenyl} - s), 8.02 (1H, s), [1,2,4] thiadiazole 7.94 (1H, s), 7.73 -2-ylamine (1H, dd), 7.61- 7.55 (2H, m), 7.35 (1H, d), 4.48 (3H, s). Biological Assays

FGFR3 and PDGFR in vitro kinase inhibitory activity assays

Enzymes (from Upstate) were prepared in final concentration x2 and in kinase assay buffer Ix (as described below). Enzymes were then incubated with test compounds, biotinylated Flt3 substrate (biotin-DNEYFYV) (Cell Signaling 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 900 rpm plate shaker before being stopped with 20 μΐ 35 mM EDTA, pFI 8 (FGFR3) or 55 mM EDTA, pH 8 (PDGFR-beta). Twenty μΐ of 5x detection mix (50 mM FtEPES pH 7.5, 0.1% BSA, 2nM Eu-anti-pY (PY20) SA-XL665 15nM (Cisbio) for 50 mM FGFR3 and HEPES, pH 7.5, 0.5 M KF, 0.1% BSA, Eu-anti-pY (PT66) 11.34 nM (Perkin Elmer), SA-XL665 94nM (Cisbio) for PDGFR-beta) were then added in each well and the plate was sealed and incubated at room temperature for one hour on a plate shaker at 900 rpm. The card was read on a Packard Fusion card reader in

TRF

Enzyme Assay Buffer Concentration Concentration of Ix Substrate Flt3 ATP FGFR3 A 0.125 μΜ 8 μΜ PDGFR-beta B 0.15 μΜ 30 μΜ Kinase assay buffers were:

A: 50 mM HEPES pH 7.5, 6 mM MnCl2, 1 mM DTT, Triton

X-100 0.1%

B: 20 mM MOPS pH 7.0, 10 mM MnCl 2, 0.01% Triton X-100, 1 mM DTT, 0.1 mM sodium ortho vanadate

Compounds of the invention (eg Examples 1-14 and 16-43) have IC50 values of less than 10 μΜ or provide inhibition of at least 50% of FGFR3 activity at a concentration of 10 μΜ. Preferred compounds of the invention (e.g. 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 of 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 Gl [[3- (7-Chloro-imidazo [1,2-a] pyridin-3-yl) -phenyl] - (3H- [1, 2,3] triazol-4-yl) -amine]) have IC50 values of less than 1 μΜ in the FGFR3 assay.

VEGFR2 In vitro Kinase Inhibitory Activity Assay VEGFR2-containing Enzyme Assay Reactions

(purchased from Upstate), and Poly (Glu5Tyr) 4: 1 250 μΜ (CisBio) substrate in 50 mM HEPES, pH 7.5, 6 mM MnCl2, 1 mM DTT, 0.01% Triton X-100, ATP 5 μΜ (2.8 Ci / mmol) were performed in the presence of compound. Reactions were stopped after 15 minutes by the addition of excess phosphoric acid. The reaction mixture was then transferred to a Millipore MAPH filter plate where the peptide binds and unused ATP is removed for 10 minutes.

15

20

wash. After washing, scintillation agent was added and the incorporated activity was measured by scintillation counting on a Packard Topcount. In vitro kinase inhibitory activity assays for FGFR1, FGFR2, FGFR4, VEGFR1 and VEGFR3

Inhibitory activity against FGFR1, FGFR2, FGFR4, VEGFR1 and VEGFR3 can be determined in Upstate Discovery Ltd. Enzymes were prepared at final concentration 10x in enzyme buffer (MOPS 20 mM, pH 7.0, 1 mM EDTA, B-mercapto- 0.1% ethanol, Brij-35

0.01%, 5% glycerol, 1 mg / ml BSA). Enzymes were then incubated in multi-substrate assay buffer and 33 P-ATP (-500 cpm / pmol) as described in the table.

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

Compounds were tested twice at the concentrations detailed below against all kinases and percent activity compared to control was calculated. Where inhibition was high an IC50 was determined.

Enzyme Buffer Substrate Assay ATP Concentration (MM) FGFR1 A KKKSPGEYVNIEFG 250 μΜ 200 μΜ FGFR2 B poly (Glu, Tyr) 4: 1 0.1 mg / ml 90 μΜ FGFR4 C poly (Glu, Tyr) 4: 1 0, 1 mg / ml 155 μΜ VEGFRl A KKKSPGEYVNIEFG 250 μΜ 200 μΜ VEGFR3 A GGEEEEYFELVKKK 500 μΜ 200 μΜ Enzyme Buffer A: MOPS 8 mM, pH 7.0, EDTA 0.2 mM, Mg Acetate 10 mM

Enzyme Buffer B: 8 mM MOPS, pH 7.0, 0.2 mM EDTA, 2.5 mM MnCL, 10 mM Mg Acetate C Enzyme Buffer: 8 mM MOPS, pH 7.0, 0.2 mM EDTA 10 mM MnCl 2, 10 mM Mg Acetate.

Cell-based pERK ELISA Method

LP-I or JIM-I multiple myeloma cells were seeded in 96-well plates at Ix106 cells / ml at 200μ1 per well in serum-free media. HUYEC cells were seeded at 2.5x10 5 cells / ml and allowed to recover for 24h before transfer to serum free media. Cells were incubated for 16h at 37 ° C prior to the addition of 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-I / Heparin (final 100ng / ml FGF-1 and 100μg / ml Heparin) or VEGF165 (100μg / ml) was added to each well for an additional 5 minutes. The medium was removed and 50µl of Iise ERK ELISA buffer (R and D Systems DuoSet ELISA for pERK and Total ERK # DYC-1940E, DYC-1018E) were added. ELISA plates and standards were prepared according to DuoSet standard 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 human multiple myeloma derived LP-I cell line (DSMZ no .: ACC 41). Many compounds of the invention have been found to have IC50 values of less than 20 μΜ in this assay and some compounds (e.g. Examples 2, 3, 4, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18 , 20, 24, 25, 26, 28, 30,

32, 43 and the procedural starting material A4c [3- (7-Chloro-imidazo [1,2-a] pyridin-3-yl) -phenyl] - [1,2,4] thiadiazol-2-yl-amine ]) have IC 50 values lower than 1 μΜ.

HUVEC cell-based selectivity tests

HUVEC cells were seeded in 6-well plates at 1x106 cells / well and allowed to recover for 24h. They were transferred to serum free media for 16 hours prior to treatment with test compound for 30 minutes in final concentration of 0.1% in DMSO. After incubation of compound FGF-I (100ng / ml) and Heparin (100μg / ml) or VEGF163 (100ng / ml) were added for 5 minutes. Medium was removed, 5 cells were washed in ice cold PBS and lysed in ΙΟΟμΙ of Iise TG 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 completed with LDS sample buffer and runs on SDS PAGE followed by western blotting to numerous downstream 10 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 noninvasive and as such can be applied to a larger group of experimental animals however the process allows only intermittent blood pressure sampling and requires the animal to be restricted in some way. Restriction application can stress the animal and mean that changes in blood pressure attributable to a specific drug effect can be difficult to grasp.

Direct methodologies include those using radiotelemetry technology or delay probes connected to 25 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 FGFR3 in vitro kinase inhibitory activity assay and cell-based pERK ELISA method described above for identified examples are shown below.

Example Number FGFR3 IC50 ^ M) LP-I pERK ELISA (μΜ) 7 0.00220 0.069 10 0.00482 0.0390 11 0.00603 0.0400 14 0.0160 0.00850 37 0.00255 27 0.130 29 0 0110 31 0.350 39 0.115 34 0.480 43 0.0339 0.140

Claims (41)

A compound or a pharmaceutically acceptable salt, solvate or derivative thereof, characterized in that it is of formula (I): wherein Xj, X2 and X3 are each independently. selected from carbon or nitrogen such that at least one of X1-X3 represents nitrogen; X4 represents CR3 or nitrogen; X5 represents CR6, nitrogen or C = O; provided no more than three of X1-X5 represent nitrogen; ----- represents a single or double bond, such that a bond within the 5-membered ring system is a double bond; R 3 represents hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, cyano, haloC 1-6 alkyl, haloC 1-6 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) R d groups; B represents a -V-carbocyclic group or a -W-heterocyclyl group wherein said carbocyclic and heterocyclyl groups may be optionally substituted by one or more (e.g. 1,2 or 3) Ra groups; R 2 and R 6 independently represent halogen, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -C = N, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, -NHSO 2 Rw, -CH = N- ORw, an aryl or heterocyclyl group wherein said C1-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, aryl and heterocyclyl groups may be optionally substituted by 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, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, -ORx, - (CH 2) n -O-Cu 6 alkyl, -0- (CH 2) n- ORx, haloCu6 alkyl, haloCu6 alkoxy, Cv8 alkanol, = O, = S, nitro, Si (Rx) 4, - (C12) 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) rOR2 or - (CH2) s-SO2NRxRy; R x, R y and R 7 independently represent hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cu alkanol, hydroxyl, Cu alkoxy, haloC 1-6 alkyl, -CO- (CH 2) n-C 1-6 alkoxy, C 3-8 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 by one or more (e.g. 1, 2 or 3) Ra groups; VeW independently represent a bond or a group - (CReRf) n-; YeZ 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 from 1-4; s and t independently represent an integer from 0-4; q represents an integer from 0-2; 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 the mine; or N- [3- (7-methyl-imidazo [1,2-a] pyridin-3-yl) -phenyl] -N- (2-nitro-phenyl) -amine. A compound according to claim 1, characterized in that X1, X2 and X3 are each independently selected from carbon or nitrogen, such that at least one of Xr-X3 represents nitrogen; X4 represents CR or nitrogen; X 5 represents CH, nitrogen or C = O; provided that no more than three of Xi-X5 represent nitrogen; ----- represents a single or double bond; R represents hydrogen 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 an aromatic or nonaromatic heterocyclic group; R represents an aryl or heteroaryl group optionally substituted with one or more Rb groups; R a represents halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 and alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, -ORx, -0- (CH 2) n-ORx, haloC 1-6 alkyl, IialoCu6 alkoxy, C i6 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- ORzOu - (CH 2) s -SO 2 NRxRy; R 1, R 2 and R 2 independently represent hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkanol, hydroxyl, C 1-6 alkoxy, haloC 1-6 alkyl, -CO- (CH 2) n -C 1-6 alkoxy, C 3 .8 cycloalkyl or C3-8 cycloalkenyl; ReR independently represent an R group or a -Y-aryl or -Z-heterocyclyl group wherein said aryl and heterocyclyl groups may be optionally substituted by one or more (e.g. 1,2 or 3) Ra groups; provided that when R2 represents a group other than hydrogen, X5 represents CH or C = O; YeZ independently represent a bond, -CO-, -CH2-, - (CH2) 2, - (CH2) 3-, -O- (CH2) s- or -NH- (CH2) n-; m and n independently represent an integer from 1-4; s and t independently represent an integer from 0-4; q represents an integer from 0-2; aryl represents a carbocyclic ring; heterocyclyl represents a heterocyclic ring; A compound according to claim 1 or claim 2, wherein A represents a phenyl or pyridyl group optionally substituted by one or more Ra groups. A compound according to claim 1 or claim 2, wherein A represents a phenyl group optionally substituted with one or more Ra groups. A compound according to claim 4, characterized in that A represents unsubstituted phenyl. Compound according to any one of the preceding claims, characterized in that B represents a -V-aryl group. A compound according to claim 6, wherein V represents a bond or -CH 2 -. A compound according to claim 6 or claim 7, characterized in that aryl represents phenyl. A compound according to any one of claims 1 to 5, characterized in that B represents a -W-heterocyclyl group. A compound according to claim 9, characterized in that W represents a bond. A compound according to claim 9 or claim 10, characterized in that the heterocyclyl group is a 5- or 6-membered monocyclic heterocyclyl group. A compound according to claim 11, characterized in that the heterocyclyl group is pyridyl, pyrazinyl, triazolyl, oxadiazolyl, imidazolyl or thiadiazolyl. A compound according to claim 12, characterized in that the heterocyclyl group is triazolyl or thiadiazolyl. Compound according to claim 13, characterized in that B represents thiadiazolyl. Compound according to any one of the preceding claims, characterized in that q represents 0. Compound according to any one of the preceding claims, characterized in that R2 represents an aryl or heteroaryl group optionally substituted with one or more Ra groups. Compound according to any one of the preceding claims, characterized in that R2 represents phenyl optionally substituted by a halogen group, - (CRxRy) s-COOR7 or -Z-heterocyclyl group, wherein said heterocyclyl group may be optionally substituted. with one or more Ra groups selected from C1-6 alkyl or - (CRxRy) s-COOR2 groups. A compound according to any one of claims 1 to 16, characterized in that R2 represents a phenyl group optionally substituted by one or more Rb groups selected from CN6 halogen alkanol, - (CH2) sNRxRy - (CRxRy) s-COORz , - (CH2) s -CONRxRy or - (CH2) S-NRxSO2-Ry. A compound according to any one of claims 1 to 16, characterized in that R2 represents morpholinyl, piperazinyl, pyridyl, pyrazinyl, pyrazolyl, piperidinyl, benzodioxolyl or pyrimidinyl optionally substituted with one or more R groups selected from C1-6 alkyl, - (CH2) s -NRxRy, -CORx, - (CRxRy) s-COORz or -SO2-Rx. A compound according to any one of claims 1 to 16, characterized in that R 2 represents optionally substituted morpholinyl, piperazinyl, pyridyl, thienyl, pyrazinyl, benzothienyl, furanyl or pyrimidinyl with one or more alkyl = O, C 6 alkyl groups. , - (CH2) s -NRxRy, -ORx, -CORx or Cu6 alkanol. A compound according to claim 20, characterized in that R 2 represents pyridyl optionally substituted with an NH 2 group. A compound according to any one of claims 1 to 16, characterized in that R 2 represents C 1-6 alkyl. Compound according to any one of the preceding claims, characterized in that XpXs are defined by the following ring systems: <formula> formula see original document page 191 </formula> Compound according to claim 23, characterized in that X1-X5 are defined by the following ring systems: <formula> formula see original document page 191 </formula> A compound according to claim 24, characterized in that X1-X5 are defined by the following ring system: <formula> formula see original document page 191 </formula> Compound according to any one of the preceding claims, characterized in that YeZ independently represent a bond, -CO-, -CH2-, - (CH2) 2- or - (CH2) 3-. Compound according to claim 26, characterized in that Z represents -CH 2 -. Compound, characterized in that it is of formula (Id): wherein Ra, R1, R2, Beq are as defined in claim 1, n represents an integer of 0 to 3. Compound according to any one of the preceding claims, characterized in that it is a compound selected from Examples 1-43, Benzyl- [3- (7-chloro-imidazo [1,2-a] pyridin-3-yl). ) -phenyl] -amine, 3- (7-Chloro-imidazo [1,2-a] pyridin-3-yl) -phenyl] - [1,2,4] thiadiazol-2-yl-amine and [3- (7-Chloro-imidazo [1,2-a] pyridin-3-yl) -phenyl] - (3H- [1,2,3] triazol-4-yl) -amine]. A compound as defined in any one of the preceding claims or a salt, tautomer, N-oxide or solvate thereof. A compound as defined in any one of claims 1 to 29 or a salt or solvate thereof. Process for the preparation of a compound of formula (!) As defined in any one of the preceding claims, characterized in that it comprises: (i) the reaction of a compound of formula (XX) or (XXI): formula see original document page 191 </formula> or a protected form thereof with an appropriately substituted aldehyde or ketone; or (ii) reacting a compound of formula (XX) or (XXI): <formula> formula see original document page 193 </formula> or a protected form thereof with hydrazine hydrate and then cyclization; and then removal of any protecting groups present; or wherein X15, A and R2 are as defined herein; and optionally thereafter converting a compound of formula (I) into another compound of formula (I). Pharmaceutical composition, characterized in that it comprises a compound of formula (I) as defined in any one of claims 1 to 31. Compound according to any one of claims 1 to 31, characterized in that it is for use in therapy. A compound according to any one of claims 1 to 31 for use in the prophylaxis or treatment of an unhealthy condition or an unhealthy condition mediated by an FGFR kinase. Use of a compound as defined in any one of claims I to 31, characterized in that it is for the manufacture of a medicament for the prophylaxis or treatment of an unhealthy condition or an unhealthy condition mediated by an FGFR kinase. . Use of a compound as defined in any one of claims 1 to 31, characterized in that it is for the manufacture of a medicament for the prophylaxis or treatment of an unhealthy condition or an unhealthy condition as described herein. Use of a compound as defined in any one of claims 1 to 31, characterized in that it is for the manufacture of a medicament for the prophylaxis or treatment of cancer. A method for the prophylaxis or treatment of an unhealthy condition or an unhealthy condition mediated by an FGFR kinase, comprising administering to a subject in need thereof a compound of formula (I) as defined in any one of claims 1 to 31. A method for the prophylaxis or treatment of an unhealthy condition or disease as described herein, comprising administering to a subject in need thereof a compound of formula (I) as defined in any one of claims 1. to 31. A method for the prophylaxis or treatment of cancer, comprising administering to a subject in need thereof a compound of formula (I) as defined in any one of claims 1 to 31.