RU2465275C2 - Bicyclic amine derivatives as tyrosine kinase inhibitors - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel bicyclic heterocyclic derivatives, which are compounds of formula

where values of X₁-X₅, A, B, R¹, R², q are given in claim 1, as well as pharmaceutical compositions containing said compounds, and use of said compounds to treat cancer.

EFFECT: high efficiency of treatment.

22 cl, 43 ex

Description

Field of Invention

The present invention relates to new compounds, which are bicyclic heterocyclic derivatives, to pharmaceutical compositions comprising these compounds, and to the use of these compounds for the treatment of diseases, for example cancer.

SUMMARY OF THE INVENTION

In accordance with a first aspect of the present invention, there is provided a compound of formula (I):

,

,

Where

X ₁ , X _2, and X ₃ are each independently selected from carbon or nitrogen, so that at least one of X ₁ -X ₃ is nitrogen;

X ₄ represents CR ³ or nitrogen;

X ₅ represents CR ⁶ , nitrogen, or C = O;

provided that no more than three of X ₁ -X ₅ are nitrogen;

представляет собой простую или двойную связь, так чтобы, по меньшей мере, одна связь в 5-членной кольцевой системе представляла собой двойную связь;

represents a single or double bond, so that at least one bond in 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, halogen C _1-6 alkyl, haloC _1-6 alkoxy or = O;

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

B represents an -V-carbocyclic group or a -W-heterocyclyl group, wherein said carbocyclic and heterocyclyl groups may optionally be substituted with one or more (e.g., 1, 2 or 3) R ^a 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 R ^W , -CH = N-OR ^W , an aryl or heterocyclyl group, wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl and heterocyclyl groups may optionally be substituted one or more R ^b groups, provided that R ² and R ⁶ both cannot simultaneously be hydrogen;

R ^e , R ^f and R ^W independently represent hydrogen or C _1-6 alkyl;

R ^a represents halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , - (CH ₂ ) _n -OC _{1- 6} alkyl, -O- (CH ₂ ) _n -OR ^x , halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkanol, = O, = S, nitro, Si (R ^x ) ₄ , - ( CH ₂ ) _s -CN, -SR ^x , -SO-R ^x , -SO ₂ -R ^x , -COR ^x , - (CR ^x R ^y ) _s -COOR ^z , - (CH ₂ ) _s -CONR ^x R ^y , - (CH ₂ ) _s -NR ^x R ^y , - (CH ₂ ) _s -NR ^x COR ^y , - (CH ₂ ) _s -NR ^x SO ₂ -R ^y , - (CH ₂ ) _s -NH- SO ₂ -NR ^x R ^y , -OCONR ^x R ^y , - (CH ₂ ) _s -NR ^x CO ₂ R ^y , -O- (CH ₂ ) _s -CR ^x R ^y - (CH ₂ ) _t -OR ^z or - (CH ₂ ) _s —SO ₂ NR ^x R ^y groups;

R ^x , R ^y and R ^z independently represent hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkanol, hydroxy, C _1-6 alkoxy, halogen C _1-6 alkyl , -CO- (CH ₂ ) _n -C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 cycloalkenyl;

R ¹ and R ^b independently represent an R ^a group or an -Y-carbocyclyl or -Z-heterocyclyl group, wherein said carbocyclyl and heterocyclyl groups may optionally be substituted with one or more (eg, 1, 2 or 3) R ^a groups;

V and W independently represent a bond or - (CR ^e R ^f ) _n is a group;

Y and Z independently represent a bond, -CO- (CH ₂ ) _s -, -COO-, - (CH ₂ ) _n -, -NR ^x - (CH ₂ ) _n -, - (CH ₂ ) _n -NR ^x , -CONR ^x -, -NR ^x CO-, -SO ₂ NR ^x , -NR ^x SO ₂ -, -NR ^x CONR ^y -, -NR ^x CSNR ^y -, -O- (CH ₂ ) _s -, - (CH ₂ ) _s —O—, —S—, —SO— or - (CH ₂ ) _s —SO ₂ -;

n is an integer having a value of 1-4;

s and t independently represent an integer having a value of 0-4;

q is an integer of 0-2;

or a pharmaceutically acceptable salt, solvate or derivative thereof, provided that the compound of formula (I) cannot be:

6-chloro-4- [3- (7-methylimidazo [1,2-a] pyridin-3-yl) phenyl] pyridin-3-ylamine; or

N- [3- (7-methylimidazo [1,2-a] pyridin-3-yl) phenyl] -N- (2-nitrophenyl) amine.

WO 01/38326 (Merck), WO 2003/048132 (Merck), WO 02/080914 (Gruenenthal), WO 01/14375 (Astra Zeneca), WO 2004/052286 (Merck), WO 00/53605 (Merck), WO 03/101993 (Neogenesis), WO 2005/075470 (SmithKline Beecham), WO 2005/054230 (Cytopia), WO 2002/46168 (Astra Zeneca), WO 01/66098 (Aventis), WO 97/12613 (Warner Lambert), WO 2006/094235 (Sirtris Pharmaceuticals) and US 2006/0035921 (OSI Pharmaceuticals), EP 1790650 (Banyu), US 2005/021531 (OSI Pharmaceuticals), WO 02/066481 (Astra Zeneca), WO 01/00214 (Merck), WO 01/00213 (Merck), WO 01/00207 (Merck), FR 2851248 (Aventis) and Clark et al. (2007) Bioorganic & Medicinal Chemistry Letters 17, 1250-1253, each discloses a number of heterocyclic derivatives.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with a first aspect of the present invention, there is provided a compound of formula (I):

,

,

Where

X ₁ , X _2, and X ₃ are each independently selected from carbon or nitrogen, so that at least one of X ₁ -X ₃ is nitrogen;

X ₄ represents CR ³ or nitrogen;

X ₅ represents CR ⁶ , nitrogen, or C = O;

provided that no more than three of X ₁ -X ₅ are nitrogen;

представляет собой простую или двойную связь, так чтобы, по меньшей мере, одна связь в 5-членной кольцевой системе представляла собой двойную связь;

represents a single or double bond, so that at least one bond in 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, halogen C _1-6 alkyl, haloC _1-6 alkoxy or = O;

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

B represents an -V-carbocyclic group or a -W-heterocyclyl group, wherein said carbocyclic and heterocyclyl groups may optionally be substituted with one or more (e.g., 1, 2 or 3) R ^a 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 R ^W , -CH = N-OR ^W , an aryl or heterocyclyl group, wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl and heterocyclyl groups may optionally be substituted one or more R ^b groups, provided that R ² and R ⁶ both cannot simultaneously be hydrogen;

R ^e , R ^f and R ^W independently represent hydrogen or C _1-6 alkyl;

R ^a represents halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^W , - (CH ₂ ) _n -OC _{1- 6} alkyl, -O- (CH ₂ ) _n -OR ^x , halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkanol, = O, = S, nitro, Si (R ^x ) ₄ , - ( CH ₂ ) _s -CN, -SR ^x , -SO-R ^x , -SO ₂ -R ^x , -COR ^x , - (CR ^x R ^y ) _s -COOR ^z , - (CH ₂ ) _s -CONR ^x R ^y , - (CH ₂ ) _s -NR ^x R ^y , - (CH ₂ ) _s -NR ^x COR ^y , - (CH ₂ ) _s -NR ^x SO ₂ -R ^y , - (CH ₂ ) _s -NH- SO ₂ -NR ^x R ^y , -OCONR ^x R ^y , - (CH ₂ ) _s -NR ^x CO ₂ R ^y , -O- (CH ₂ ) _s -CR ^x R ^y - (CH ₂ ), - OR ^z or - (CH ₂ ) _s —SO ₂ NR ^x R ^y groups;

R ^x , R ^y and R ^z independently represent hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkanol, hydroxy, C _1-6 alkoxy, halogen C _1-6 alkyl , -CO- (CH ₂ ) _n -C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 cycloalkenyl;

R ¹ and R ^b independently represent an R ^a group or an -Y-carbocyclyl or -Z-heterocyclyl group, wherein said carbocyclyl and heterocyclyl groups may optionally be substituted with one or more (eg, 1, 2 or 3) R ^a groups;

V and W independently represent a bond or - (CR ^e R ^f ) _n is a group;

Y and Z independently represent a bond, -CO- (CH ₂ ) _s -, -COO-, - (CH ₂ ) _n -, -NR ^x - (CH ₂ ) _n -, - (CH ₂ ) _n -NR ^x , -CONR ^x -, -NR ^x CO-, -SO ₂ NR ^x , -NR ^x SO ₂ -, -NR ^x CONR ^y -, -NR ^x CSNR ^y -, -O- (CH ₂ ) _s -, - (CH ₂ ) _s —O—, —S—, —SO— or - (CH ₂ ) _s —SO ₂ -;

n is an integer having a value of 1-4;

s and t independently represent an integer having a value of 0-4;

q is an integer of 0-2;

or a pharmaceutically acceptable salt, solvate or derivative thereof, provided that the compound of formula (I) cannot be:

6-chloro-4- [3- (7-methylimidazo [1,2-a] pyridin-3-yl) phenyl] pyridin-3-ylamine; or

N- [3- (7-methylimidazo [1,2-a] pyridin-3-yl) phenyl] -N- (2-nitrophenyl) amine.

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

,

,

Where

X ₁ , X _2, and X ₃ are each independently selected from carbon or nitrogen, so that at least one of X ₁ -X ₃ is nitrogen;

X ₄ represents CR ³ or nitrogen;

X ₅ represents CR ⁶ , nitrogen, or C = O;

with the proviso that not more than three of X ₁ -X ₅ are nitrogen;

представляет собой простую или двойную связь, так чтобы, когда X₅ представляет собой C=O, X₄ и X₅ были соединены простой связью, и так чтобы, по меньшей мере, одна связь в 5-членной кольцевой системе представляла собой двойную связь;

represents a single or double bond, so that when X ₅ is C = O, X ₄ and X ₅ are connected by a single bond, and so that at least one bond in 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, halogen C _1-6 alkyl, haloC _1-6 alkoxy or = O;

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

B represents an -V-carbocyclic group or a -W-heterocyclyl group, wherein said carbocyclic and heterocyclyl groups may optionally be substituted with one or more (e.g., 1, 2 or 3) R ^a 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 R ^W , -CH = N-OR ^W , an aryl or heterocyclyl group, wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl and heterocyclyl groups may optionally be substituted one or more R ^b groups, provided that R ² and R ⁶ both cannot simultaneously be hydrogen;

R ^e , R ^f and R ^W independently represent hydrogen or C _1-6 alkyl;

R ^a represents halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , -O- (CH ₂ ) _n -OR ^x , halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkanol, = O, = S, nitro, Si (R ^x ) ₄ , - (CH ₂ ) _s -CN, -SR ^x , -SO -R ^x , -SO ₂ -R ^x , -COR ^x , - (CR ^x R ^y ) _s -COOR ^z , - (CH ₂ ) _s -CONR ^x R ^y , - (CH ₂ ) _s -NR ^x R ^y , - (CH ₂ ) _s -NR ^x COR ^y , - (CH ₂ ) _s -NR ^x SO ₂ -R ^y , - (CH ₂ ) _s -NH-SO ₂ -NR ^x R ^y , -OCONR ^x R ^y , - (CH ₂ ) _s -NR ^x CO ₂ R ^y , -O- (CH ₂ ) _s -CR ^x R ^y - (CH ₂ ) _t -OR ^z or - (CH ₂ ) _s -SO ₂ NR ^x R ^y groups;

R ^x , R ^y and R ^z independently represent hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkanol, hydroxy, C _1-6 alkoxy, halogen C _1-6 alkyl , -CO- (CH ₂ ) _n -C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 cycloalkenyl;

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

V and W independently represent a bond or - (CR ^e R ^f ) _n is a group;

Y and Z independently represent a bond, -CO- (CH ₂ ) _s -, -COO-, - (CH ₂ ) _n -, -NR ^x - (CH ₂ ) _n -, - (CH ₂ ) _n -NR ^x , -CONR ^x , -NR ^x CO-, -SO ₂ NR ^x -, -NR ^x SO ₂ -, -NR ^x CONR ^y -, -NR ^x CSNR ^y -, -O- (CH ₂ ) _s -, - (CH ₂ ) _s —O—, S—, —SO— or - (CH ₂ ) _s —SO ₂ -;

n is an integer having a value of 1-4;

s and t independently represent an integer having a value of 0-4;

q is an integer of 0-2;

aryl is a carbocyclic ring;

heterocyclyl is a heterocyclic ring;

or a pharmaceutically acceptable salt, solvate or derivative thereof, provided that the compound of formula (I) cannot be:

6-chloro-4- [3- (7-methylimidazo [1,2-a] pyridin-3-yl) phenyl] pyridin-3-ylamine; or

N- [3- (7-methylimidazo [1,2-a] pyridin-3-yl) phenyl] -N- (2-nitrophenyl) amine.

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

,

,

Where

X ₁ , X _2, and X ₃ are each independently selected from carbon or nitrogen, so that at least one of X ₁ -X ₃ is nitrogen;

X ₄ represents CR ³ or nitrogen;

X ₅ represents CR ⁶ , nitrogen, or C = O;

provided that no more than three of X ₁ -X ₅ are nitrogen;

представляет собой простую или двойную связь;

represents a single or 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, halogen C _1-6 alkyl, haloC _1-6 alkoxy or = O;

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

B represents an aromatic or non-aromatic carbocyclic or heterocyclic 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, an aryl or heterocyclyl group, wherein said aryl and heterocyclyl the groups may optionally be substituted with one or more R ^b groups, provided that when R ⁶ is a heterocyclyl group, said heterocyclyl group is not pyrazolyl;

R ^a represents halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , -O- (CH ₂ ) _n -OR ^x , halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkanol, = O, = S, nitro, - (CH ₂ ) _s —CN, —SR ^x , —SO — R ^x , —SO ₂ -R ^x , -COR ^x , - (CR ^x R ^y ) _s -COOR ^z , - (CH ₂ ) _s -CONR ^x R ^y , - (CH ₂ ) _s -NR ^x R ^y , - (CH ₂ ) _s -NR ^x COR ^y , - (CH ₂ ) _s -NR ^x SO ₂ -R ^y , -OCONR ^x R ^y , - (CH ₂ ) _s -NR ^x CO ₂ R ^y , -O- (CH ₂ ) _s - CR ^x R ^y - (CH ₂ ) _t -OR ^z or - (CH ₂ ) _s -SO ₂ NR ^x R ^y groups;

R ^x , R ^y and R ^z independently represent hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkanol, hydroxy, C _1-6 alkoxy, halogen C _1-6 alkyl , -CO- (CH ₂ ) _n -C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 cycloalkenyl;

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

with the proviso that when R ² is a group other than hydrogen, X ₅ is CH or C = O, and when R ² is hydrogen, R ⁸ is a group other than hydrogen;

Y and Z independently represent a bond, -CO- (CH ₂ ) _s -, -COO-, - (CH ₂ ) _n -, -NR ^x - (CH ₂ ) _n -, - (CH ₂ ) _n -NR ^x , -CONR ^x -, -NR ^x CO-, -SO ₂ NR ^x -, -NR ^x SO ₂ -, -NR ^x CONR ^y -, -NR ^x CSNR ^y -, -O- (CH ₂ ) _s -, - (CH ₂ ) _s —O—, S—, —SO— or - (CH ₂ ) _s —SO ₂ -;

m and n independently represent an integer having a value of 1-4;

s and t independently represent an integer having a value of 0-4;

q is an integer of 0-2;

aryl is a carbocyclic ring;

heterocyclyl is a heterocyclic ring;

or a pharmaceutically acceptable salt, solvate or derivative thereof.

The term 'C _1-6 alkyl', as used herein, as a group or part of a group, refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, 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 an —OC _1-6 alkyl group, wherein C _1-6 alkyl has the meaning defined in this application. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like.

The term 'C _1-6 alkanol', as used herein, refers to a C _1-6 alkyl group substituted with one or more hydroxy groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.

The term 'C _3-8 cycloalkyl, as used herein, refers to a saturated monocyclic hydrocarbon ring of 3-8 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 saturated monocyclic hydrocarbon ring consisting of 3-6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term 'halogen' as used in this application 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, where at least one hydrogen atom is substituted with halogen. Examples of such groups include fluoroethyl, trifluoromethyl or trifluoroethyl and the like.

The term 'haloC _1-6 alkoxy', as used herein, refers to a C _1-6 alkoxy group as defined herein, wherein at least one hydrogen atom is substituted with halogen. Examples of such groups include difluoromethoxy or trifluoromethoxy and the like.

The terms “carbocyclic” and “heterocyclic” groups, as used herein, unless the context requires otherwise, should include both aromatic and non-aromatic ring systems. For example, the term “carbocyclic and heterocyclic groups” includes aromatic, non-aromatic, unsaturated, partially saturated, and fully saturated carbocyclic and heterocyclic ring systems. Typically, such groups may be monocyclic or bicyclic and may contain, for example, 3-12 ring members, mainly 5-10 ring members. Examples of monocyclic groups include groups containing 3, 4, 5, 6, 7 and 8 ring members, mainly 3-7 and preferably 5 or 6 ring members. Examples of bicyclic groups include groups containing 8, 9, 10, 11 and 12 ring members, mainly 9 or 10 ring members. When reference is made in this application to carbocyclic and heterocyclic groups, a carbocyclic or heterocyclic ring, unless the context otherwise indicates, may be unsubstituted or may be substituted with one or more substituents, for example, molecular fragments, molecular fragments of side chains or functional groups, such as discussed in this application. It should be understood that references to “carbocyclic” and “heterocyclic” groups include reference to carbocyclic and heterocyclic groups, which may optionally be substituted with one or more (eg, 1, 2 or 3) R ^a or R ^b groups.

Carbocyclic or heterocyclic groups can be aryl or heteroaryl groups containing from 5 to 12 ring members, mainly from 5 to 10 ring members. The term “aryl”, as used herein, refers to a carbocyclic group having an aromatic character, the term “heteroaryl” is used in this application to refer to a heterocyclic group having an aromatic character. The terms “aryl” and “heteroaryl” encompass polycyclic (eg, bicyclic) ring systems where one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, a group may be linked via an aromatic ring or non-aromatic ring.

The term “non-aromatic group” embraces unsaturated ring systems having no aromatic nature, partially saturated, and fully saturated carbocyclic and heterocyclic ring systems. The terms “unsaturated” and “partially saturated” refer to rings, where the ring structure (s) contain atoms having more than one valence bond common to them, i.e. the ring contains at least a multiple bond, for example a C = C, C≡C or N = C bond. The term "fully saturated" refers to rings where there are no multiple bonds between the ring atoms. Saturated carbocyclic groups include cycloalkyl groups as defined below. Partially saturated carbocyclic groups include cycloalkenyl groups as defined below, for example cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Saturated heterocyclic groups include piperidine, morpholine, thiomorpholine. Partially saturated heterocyclic groups include pyrazolines, for example 2-pyrazoline and 3-pyrazoline.

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

Examples of five-membered heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups. 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, for example, be 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 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

f) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 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;

l) a furan ring fused to a 5- or 6-membered 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 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; and

p) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms.

Specific 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).

Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, indole, indole, isoindole, indole, iso-indole , purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g., pyrazolo [1,5-a] pyrimidine), triazolopyrimidine (e.g., [1,2,4] triazolo [1,5-a] pyrimidine), benzodioxol and feast olopiridina (e.g., 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.

Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinoline, isoquinoline, chroman, thiochroman, chromene, isochromen, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxoline groups cinnoline, phthalazine, naphthyridine and pteridine.

Examples of polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzene, dihydrobenzofuran, 2,3-dihydro-benzo [1,4] dioxin, benzo [1,3] dioxole, 4 groups 5,6,7-tetrahydrobenzofuran, indoline and indan. Another example of a polycyclic heteroaryl group containing an aromatic ring and a non-aromatic ring includes tetrahydrotriazolopyrazine (for example, 5,6,7,8-tetrahydro [1,2,4] triazolo [4,3-a] pyrazine).

The nitrogen-containing heteroaryl ring must contain at least one ring nitrogen atom. Each ring may further contain up to about four other heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring contains up to 3 heteroatoms, for example 1, 2 or 3, basically up to 2 nitrogen atoms, for example one nitrogen atom. Nitrogen atoms in heteroaryl rings can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of indole or pyrrole. As a rule, the number of basic nitrogen atoms present in the heteroaryl group, including any substituents of the amino groups of the ring, should be less than five.

Examples of nitrogen-containing heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, pyrazolyl, pyrazinyl, pyrimazinyl, pyrimazinyl, pyrimazinyl, pyrimazinyl, , 3-triazolyl, 1,2,4-triazolyl), tetrazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzthiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl, indolisinyl, isoindinyl, aminopurine], guanine [2-am foreign-6-hydroxypurin]), indazolyl, quinolisinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl.

Examples of nitrogen-containing polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydroisoquinolinyl, tetrahydroquinolinyl and indolinyl.

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

Examples of non-aromatic heterocyclic groups include groups containing from 3 to 12 ring members, mainly from 5 to 10 ring members. Such groups may be monocyclic or bicyclic, for example, and typically contain from 1 to 5 heteroatoms as ring members (mainly 1, 2, 3 or 4 heteroatoms as ring members), typically selected from nitrogen, oxygen and sulfur. Heterocyclic groups may contain, for example, cyclic ether moieties (e.g., as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g., as tetrahydrothiophene and dithian), cyclic amine moieties (e.g., as pyrrolidine), cyclic amide moieties (e.g., as in pyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ureas (for example, as in imidazolidin-2-one), cyclic ester fragments (for example, as in butyrolactone), cyclic sulfones (for example, as in sul folane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and their combinations (for example, thiomorpholine).

Specific examples include morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), piperidone, pyrrolidine (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, azetidine, (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydropyranyl), imidazoline, pyrazole, pyrazole, pyrazole, pyrazole, and N-alkylpiperazines, such as N-methylpiperazine. Typically, preferred non-aromatic heterocyclic groups include saturated groups such as piperidine, pyrrolidine, azetidine, morpholine, piperazine and N-alkyl piperazines.

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

Specific examples of nitrogen-containing non-aromatic heterocyclic groups include aziridine, morpholine, thiomorpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl) pyrrolidine (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 2-pyrrolidinyl) , pyrrolidone, dihydrothiazole, imidazoline, imidazolidinone, oxazoline, thiazoline, 6H-1,2,5-thiadiazine, 2-pyrazoline, 3-pyrazoline, pyrazolidine, piperazine and N-alkylpiperazines such as N-methylpiperazine.

Heterocyclic groups may be polycyclic fused ring systems or bridged ring systems such as bicycloalkanes, tricycloalkanes and their oxo and aza analogues (e.g., adamantane and oxa-adamantane). For an explanation of the differences between fused 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, cyclooctatetraen, tetrahydronaphthenyl and decalinyl.

Each of the heterocyclic groups may be unsubstituted or may be substituted with one or more groups of substituents. For example, heterocyclic groups may be unsubstituted or may be substituted with 1, 2, 3 or 4 substituents. When a heterocyclic group is monocyclic or bicyclic, it is typically unsubstituted or contains 1, 2 or 3 substituents.

представляет собой простую или двойную связь. Специалистам в данной области должно быть понятно, что когда X₅ представляет собой C=O или R³ представляет собой =О, X₄ и X₅ соединены простой связью.As mentioned above,

represents a single or double bond. Specialists in this field should be clear that when X ₅ represents C = O or R ³ represents = O, X ₄ and X _{5 are} connected by a simple bond.

Specific Embodiments

Examples of ring systems covered by definitions X ₁ -X ₅ are presented in the following formulas (I) a- (I) t:

Additional examples of ring systems covered by definitions X ₁ -X ₅ are presented in the following formulas (I) u- (I) v:

In one embodiment, the two bonds in the 5-membered ring system are double bonds.

In one embodiment, X ₁ is C.

In one embodiment, X ₁ , X _3, and X ₅ are C, and X ₂ and X ₄ are nitrogen (i.e., a ring system of formula (I) a).

In an alternative embodiment, X ₁ , X ₃ , X _4, and X ₅ are C and X ₂ is nitrogen (i.e., a ring system of formula (I) e).

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

In an alternative embodiment, X ₁ and X ₂ are C, X ₃ is nitrogen, X ₄ is CR ³ (e.g., CH), and X ₅ is CR ⁶ (e.g., C-Me) (i.e. ring system of formula (I) h).

In an alternative embodiment, X ₁ , X ₂ , X _4, and X ₅ are C and X ₃ is nitrogen (i.e., a ring system of formula (I) j).

In an alternative embodiment, X ₁ , X _2, and X ₄ are C, and X ₃ and X ₅ are nitrogen (i.e., a ring system of formula (I) k).

In an alternative embodiment, X ₂ , X ₃ , X _4, and X ₅ are C and X ₁ is nitrogen (i.e., a ring system of formula (I) q).

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

In one embodiment, X ₁ -X ₅ are a ring system of formulas (I) a, (I) e, (I) j or (I) q. In a further embodiment, X ₁ -X ₅ are a ring system of formula (I) a or (I) j. In a further embodiment, X ₁ -X ₅ are a ring system of formula (I) j.

In one embodiment, when X ₁ , X _2, and X ₅ are C, X ₃ is nitrogen, and A is phenyl, B is a group other than a heterocyclic group.

In one embodiment, when X ₁ , X ₂ , X _4, and X ₅ are C, X ₃ is nitrogen, and A is pyrimidinyl, B is a group other than a heterocyclic group.

In one embodiment, when X ₁ , X ₃ , X _4, and X ₅ are C, X ₂ is nitrogen, and A is pyrimidinyl, B is a group other than a heterocyclic group.

In one embodiment, when X ₁ , X ₃ and X ₅ are C and X ₂ and X ₄ are nitrogen, R ^a is a group other than = O.

In one embodiment, when X ₂ , X ₃ , X _4, and X ₅ are C, X ₁ is nitrogen, A is thiazolyl, R ^a is a group other than —CONR ^x R ^y .

In one embodiment, when X ₂ and X ₃ are C and X ₁ is nitrogen, A is a group other than pyrazinyl.

In one embodiment, when X ₂ , X ₃ , X _4, and X ₅ are C and X ₁ is nitrogen, B is a group other than phenyl.

In one embodiment, when X ₄ is nitrogen, X ₁ is a group other than nitrogen.

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

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

In one embodiment, when X ₁ is carbon, at least one of X ₂ , X ₃ , X _4, and X ₅ is other than carbon.

In one embodiment, when X ₁ is carbon and A is pyrimidinyl, B is a group other than phenyl.

In one embodiment, when X ₁ is nitrogen, A is pyrimidinyl, V is - (CR ^e R ^f ) -, B is a group other than piperazinyl, morpholinyl, thiomorpholinyl, thioxomorpholinyl or thiodioxomorpholinyl.

In one embodiment, when X ₁ is nitrogen, A is pyrimidinyl, V is - (CR ^e R ^f ) -, B is a non-aromatic ring system.

In one embodiment, when X ₁ is nitrogen, X ₂ and X ₃ are carbon, A is pyrimidinyl, V is - (CReR ^f ) -, B is an aromatic ring system.

In one embodiment, when X ₁ is nitrogen, A is a group other than purin-2-yl.

Examples of ring systems covered by Definition A are represented by the following formulas (I) A- (I) O:

Group (I) L may be any imidazole tautomer, for example (I) L2.

In one embodiment, A is a group selected from any of the formulas (I) A- (I) J and (I) L- (I) O.

In one embodiment, A is a group other than pyrazolyl.

In one embodiment, A is selected from (I) B, (I) N and (I) O.

In one embodiment, A is a monocyclic aromatic carbocyclic or heterocyclic ring system containing, for example, a 5-, 6- or 7-membered ring. In a further embodiment, A is a 6 membered carbocyclic ring. In yet another embodiment, A is a phenyl group (i.e., a ring system of formula (I) A) optionally substituted with one or more (e.g., 1, 2, or 3) R ^a groups. In one embodiment, A is unsubstituted phenyl or phenyl substituted with - (CH ₂ ) _s —CONR ^x R ^y (eg, —CONH ₂ ), - (CH ₂ ) _s —CN (eg, —CN), C _{1 -6} alkyl (e.g. methyl) or C _1-6 alkoxy (e.g. methoxy).

In one embodiment, A is a monocyclic aromatic carbocyclic or heterocyclic ring system containing, for example, a 5-, 6- or 7-membered ring. In a further embodiment, A is a 6 membered carbocyclic ring. In yet another embodiment, A is a phenyl group (i.e., a ring system of formula (I) A) or a pyridyl group (i.e., a ring system of formula (IB) or (IC)) optionally substituted with one or more (e.g. , 1, 2 or 3) R ^a groups. In one embodiment, A is unsubstituted phenyl or phenyl substituted with - (CH ₂ ) _s —CONR ^x R ^y (e.g., —CONH ₂ ), - (CH ₂ ) _s —CN (eg, —CN), halogen ( e.g. fluorine), C _1-6 alkyl (e.g. methyl), C _1-6 alkanol (e.g. -CH ₂ OH) or -OR ^x (e.g. methoxy or -OCH (Me) ₂ ).

It should be understood that in an embodiment where X ₁ is nitrogen, ring A is attached to said group X ₁ via a carbon atom.

In one embodiment, A is a 6-membered monocyclic aromatic carbocyclic or heterocyclic ring system (e.g., phenyl or pyridyl) substituted with an NH-B group at the 3-position or 5-position. When A is phenyl, in one embodiment, NH-B is present at the 3-position of phenyl relative to the position of attachment to X ₁ .

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

In a further embodiment, A is unsubstituted phenyl.

When V and W are in bond, examples of aromatic ring systems covered by the definition of B-NH- are represented by the following formulas B1-B47, in particular B1-B45:

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

When V is - (CR ^e R ^f ) _n - (e.g., CH ₂ ), one example of an aromatic ring system encompassed by the definition of B-NH- is represented by the following formula B48:

.

.

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

Table 1

In one embodiment, B is -V-aryl. In one embodiment, V is a bond or CH ₂ . In a further embodiment, V is a bond. In one embodiment, the aryl group B is a phenyl group.

In one embodiment, B is -W-heterocyclyl.

In one embodiment, W is a bond.

In one embodiment, B is an aromatic or non-aromatic carbocyclic or heterocyclic group.

In one embodiment, the aryl or heterocyclyl group B is a monocyclic aromatic carbocyclic or heterocyclic ring system containing, for example, a 5-, 6- or 7-membered ring (e.g. phenyl, pyridyl, pyrazinyl, triazolyl or thiadiazolyl). In a further embodiment, the heterocyclyl group B is a 5- or 6-membered heterocyclic ring (e.g., pyridyl, pyrazinyl, triazolyl or thiadiazolyl). In a further embodiment, the heterocyclyl group B is a 5- or 6-membered heterocyclic ring (e.g., pyridyl, pyrazinyl, triazolyl, oxadiazolyl, imidazolyl or thiadiazolyl). In yet another embodiment, the heterocyclyl group B is a 5-membered heterocyclic ring group selected from compounds of formula B ^a , B ^b and B ^c :

,

, (In ^a )

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

представляет собой точку присоединения к NH;

represents the point of attachment to NH;

,

, (B ^b )

может представлять собой простую или двойную связь;where is the dashed line

may be a single or double bond;

Xa is selected from NH, CH, and S; Xb is selected from C, N, O, and S; Xc is selected from C, S, and N; Xd is selected from C, N, O, and S; Xe is selected from C and N; and

представляет собой точку присоединения к NH;

represents the point of attachment to NH;

,

, (B ^c )

может представлять собой простую или двойную связь;where is the dashed line

may be a single or double bond;

Xa is selected from NH, CH, and S; Xb is selected from C, N, O, and S; Xc is selected from C, N, O, and S; Xd is selected from C, N, O, and S; Xe is selected from C and N; and

представляет собой точку присоединения к NH.

represents the point of attachment to NH.

In a further embodiment, the heterocyclyl group B is oxadiazolyl, imidazolyl, triazolyl or thiadiazolyl. In a further embodiment, the heterocyclyl group B is triazolyl or thiadiazolyl. In yet another embodiment, the heterocyclyl group B is thiadiazolyl.

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

In one embodiment, q is 0 or 1. When q is 1, in one embodiment, R ¹ is C _1-6 alkyl (e.g. methyl). When q is 1, in an alternative embodiment, R ¹ is or - (CH ₂ ) _s —NR ^x R ^y (eg, —NH ₂ ). In a further embodiment, q is 0.

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

In one embodiment, when R ² is hydrogen, X ₅ is CR ⁶ , where R ⁶ is a group other than hydrogen.

In one embodiment, when X ₅ is CH or nitrogen, R ² is a group other than hydrogen.

In one embodiment, when R ² is a group other than hydrogen, X ₅ is CH, nitrogen, or C = O.

In one embodiment, when X ₅ is CR ⁶ , where R ⁶ is a group other than hydrogen, R ² is hydrogen.

When R ² or R ⁶ is a heterocyclyl group, in one embodiment, the heterocyclyl group is other than pyrazolyl (for example, optionally substituted pyrazolyl).

In one embodiment, R ² is C _1-6 alkyl (e.g. methyl).

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

In one embodiment, R ² is an aryl or heterocyclyl group optionally substituted with one or more R ^a groups.

In one embodiment, R ² is an aryl or heterocyclyl group optionally substituted with one or more R ^b groups.

In one embodiment, R ² is phenyl optionally substituted with R ^b .

In one embodiment, R ² is an aryl (eg, phenyl) group optionally substituted with one or more (eg, 1, 2 or 3) R ^b groups selected from halogen (eg, fluorine), halo C _1-6 alkoxy (eg , -OCF ₃ ), -OR ^x (e.g., methoxy or -OCH ₂ OHCH ₂ OH), C _1-6 alkanol (e.g., -CH ₂ OH), - (CR ^x R ^y ) _s -COOR ^z (e.g. -COOH, -COOMe, -C (Me) ₂ -COOH, -CH ₂ -COOH or -C (Me) ₂ -COOMe), - (CH ₂ ) _s -CN (e.g. -CH ₂ CN), - ( CH ₂ ) _s -NR ^x R ^y (e.g., -NMe ₂ , - (CH ₂ ) ₂ -NH ₂ , - (CH ₂ ) ₂ -NMe ₂ or -NH-CO-CH ₂ methoxy) or -O- (CH ₂ ) _n -OR ^x (e.g., -O- (CH ₂ ) _2- ethoxy).

In one embodiment, R ² is an aryl (eg, phenyl) group optionally substituted with one or more (eg, 1, 2 or 3) R ^b groups selected from halogen (eg, fluorine), halo C _1-6 alkoxy (eg , -OCF ₃ ), -OR ^x (e.g., methoxy or -OCH ₂ OHCH ₂ OH), C _1-6 alkanol (e.g., -CH ₂ OH), - (CR ^x R ^y ) _s -COOR ^z (e.g. -COOH, -COOMe, -C (Me) ₂ -COOH, -CH ₂ -COOH or -C (Me) ₂ -COOMe), - (CH ₂ ) _s -CN (e.g. -CH ₂ CN), - ( CH ₂ ) _s -NR ^x R ^y (e.g., -NH ₂ , -NMe ₂ , - (CH ₂ ) ₂ -NH ₂ , - (CH ₂ ) ₂ -NMe ₂ or -NH-CO-CH ₂ methoxy) , - (CH ₂ ) _s -CONR ^x R ^y (e.g. -CONHMe or -CH ₂ -CONHMe), - (CH ₂ ) _s -NR ^x SO ₂ -R ^y (e.g. -CH ₂ -NHSO ₂ Me) or -O- (CH ₂ ) _n -OR ^x (e.g., -O- (CH ₂ ) ₂ -ethoxy).

In a further embodiment, R ² represents an aryl (e.g., phenyl) group optionally substituted with one or more (e.g., 1, 2 or 3) R ^b groups selected from halogen (e.g., fluorine), C _1-6 alkanol (e.g. , -CH ₂ OH), - (CH ₂ ) _s -NR ^x R ^y (e.g. -NH ₂ ), - (CR ^x R ^y ) _s -COOR ^z (e.g. -CH ₂ -COOH), - (CH ₂ ) _s -CONR ^x R ^y (e.g., -CONHMe or -CH ₂ -CONHMe), - (CH ₂ ) _s -NR ^x SO ₂ -R ^y (e.g., -CH ₂ -NHSO ₂ Me).

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

In one embodiment, Y is —O— (CH ₂ ) _s - (eg, —O — CH ₂ -).

In one embodiment, R ² is an aryl (e.g., phenyl) group optionally substituted with a -Z-heterocyclyl group (e.g., -Z-morpholinyl, -Z-azetidinyl, -Z-pyrrolidinyl, -Z-tetrazolyl, -Z-piperidinyl , -Z-piperazinyl), wherein said heterocyclyl group may optionally be substituted with one or more (e.g., 1, 2 or 3) R ^a groups selected from C _1-6 alkyl (e.g. methyl) or - (CR ^x R ^y ) _s -COOR ^z (e.g., -COOH, -COOMe or -COOtBu) groups.

In one embodiment, R ² is an aryl (e.g., phenyl) group optionally substituted with a -Z-heterocyclyl group (e.g., -Z-morpholinyl, -Z-azetidinyl, -Z-pyrrolidinyl, -Z-tetrazolyl, -Z-piperidinyl , -Z-piperazinyl), wherein said heterocyclyl group may optionally be substituted with one or more (e.g. 1, 2 or 3) R ^a groups selected from C _1-6 alkyl (e.g. methyl), = O (e.g. piperazine -2-one) or - (CR ^x R ^y ) _s -COOR ^z (e.g., -COOH, -COOMe or -COOtBu) groups.

In a further embodiment, R ² represents an aryl (e.g., phenyl) group optionally substituted with a halogen (e.g., fluorine), a -Z-heterocyclyl group (e.g., -CH ₂ -morpholinyl, -CH ₂ -piperazinyl, -CH ₂ -piperidinyl , -CH ₂ -azetidinyl), - (CR ^x R ^y ) _s -COOR ^z (e.g., -COOH or -C (Me) ₂ -COOH), wherein said heterocyclyl group may optionally be substituted with a C _1-6 alkyl (e.g. , methyl) or - (CR ^x R ^y ) _s —COOR ^z (e.g., —COOH) group.

In a further embodiment, R ² represents an aryl (e.g., phenyl) group optionally substituted with a halogen (e.g., fluorine), a -Z-heterocyclyl group (e.g., -CH ₂ -morpholinyl, -CO-morpholinyl, -CH ₂ -piperazinyl, -CH ₂ -piperidinyl, -CH ₂ -azetidinyl), - (CR ^x R ^y ) _s -COOR ^z (for example, -COOH or -C (Me) ₂ -COOH), wherein said heterocyclyl group may optionally be substituted with C _{1 -6} alkyl (e.g. methyl) or - (CR ^x R ^y ) _s -COOR ^z (e.g. -COOH) group.

In one embodiment, R ² is an aryl (e.g., phenyl) group optionally substituted with a -Z-heterocyclyl group (e.g., -CH ₂ -morpholinyl, -CO-morpholinyl, -CH ₂ -piperidinyl or -CH ₂ -piperazinyl), wherein said heterocyclyl group may optionally be substituted with one or more (e.g., 1, 2 or 3) R ^a groups selected from C _1-6 alkyl (e.g. methyl) or = O (e.g. piperazin-2-one).

In yet another embodiment, R ² is an aryl (e.g., phenyl) group optionally substituted with a halogen atom (e.g., fluorine) or a -Z-heterocyclyl group (e.g., -CH ₂ -morpholinyl or -CH ₂ -piperazinyl), wherein the heterocyclyl group may optionally be substituted with a C _1-6 alkyl (e.g. methyl) group.

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

In one embodiment, R ² is a 5 membered heterocyclyl group optionally substituted with one or more R ^a groups.

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

In one embodiment, R ² is a heterocyclyl group optionally substituted with an R ^b group.

In one embodiment, R ² is a heterocyclyl group optionally substituted with a —Z-heterocyclyl or - (CH ₂ ) _s —NR ^x R ^y group.

In one embodiment, R ² is a heterocyclyl group (e.g., morpholinyl, piperazinyl, pyridyl, thienyl, pyrazinyl, benzothienyl, furanyl or pyrimidinyl) optionally substituted with one or more (e.g. 1, 2 or 3) R ^b groups selected from groups = O (e.g., pyridinone), C _1-6 alkyl (e.g., methyl), - (CH ₂ ) _s -NR ^x R ^y (e.g., -NH ₂ ), -OR ^x (e.g., methoxy), -COR ^x (e.g., -COMe) or C _1-6 alkanol (e.g., -CH ₂ OH).

In one embodiment, R ² is a heterocyclyl group (e.g., morpholinyl, piperazinyl, pyridyl, thienyl, pyrazinyl, benzothienyl, furanyl, imidazolyl, pyrazolyl, benzodioxolyl, pyrrolidinyl, azetidinyl, piperidinyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl , oxadiazolyl, isoxazolyl, benzodioxolyl, tetrahydrotriazolopyrazinyl or pyrimidinyl) optionally substituted with one or more (e.g. 1, 2 or 3) R ^b groups selected from = O groups (e.g. pyridinone or 5-oxo-4,5-dihydro [1,3,4] oxadi azolyl), = S (for example, thioxo-4,5-dihydro- [1,3,4] oxadiazole), halogen (for example fluorine), C _1-6 alkyl (for example methyl, ethyl, propyl, i-Pr or t-Bu), haloC _1-6 alkyl (e.g. -CH ₂ -F, -CF ₃ or -CH ₂ CF ₃ ), C _3-8 cycloalkyl (e.g. cyclopropyl), - (CH ₂ ) _s -NR ^x R ^y (e.g., -NH ₂ ), -OR ^x (e.g., hydroxy, methoxy or -Oi-Pr), - (CH ₂ ) _n -OC _1-6 alkyl (e.g., -CH ₂ -O-Me) , -COR ^x (e.g. -COMe), - (CR ^x R ^y ) _s -COOR ^Z (e.g. -COOH, -COOEt or -COOt-Bu), -SR ^x (e.g. -S-Me), - SO ₂ —R ^x (e.g., -SO ₂ -Et), - (CH ₂ ) _s -NR ^x R ^y (e.g., -NH ₂ ), - (CH ₂ ) ₃ -SO ₂ NR ^x R ^y (e.g. -SO ₂ -NMe ₂ ) or C _1-6 alkanol (e.g., -C (OH) (Me) ₂ or -CH ₂ OH).

In one embodiment, R ² is a heterocyclyl group (e.g., morpholinyl, piperazinyl, pyridyl, thienyl, pyrazinyl, pyrazolyl, piperidinyl, benzodioxolyl, benzothienyl, furanyl or pyrimidinyl) optionally substituted with one or more (e.g. 1, 2 or 3) R ^{b by} groups selected from the groups = O (e.g., pyridinone), C _1-6 alkyl (e.g. methyl), - (CH ₂ ) _s -NR ^x R ^y (e.g. -NH ₂ ), -OR ^x (e.g. , methoxy), -COR ^x (e.g., -COMe), - (CR ^x R ^y ) _s -COOR ^z (e.g., -COOEt), -SO ₂ -R ^x (e.g., -SO ₂ Et), or C _{1- 6} alkanol (e.g. -CH ₂ OH).

In one embodiment, R ² is a heterocyclyl group (e.g., morpholinyl, piperazinyl, pyridyl, pyrazinyl, pyrazolyl, piperidinyl, benzodioxolyl or pyrimidinyl) optionally substituted with one or more (e.g. 1, 2 or 3) R ^b groups selected from groups C _1-6 alkyl (e.g. methyl), - (CH ₂ ) _s -NR ^x R ^y (e.g. -NH ₂ ), -COR ^x (e.g. -COMe), - (CR ^x R ^y ) _s - COOR ^z (e.g., -COOEt) or -SO ₂ -R ^x (e.g., -SO ₂ Et).

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

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

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

In yet another embodiment, R ² is a heterocyclyl (eg, pyridyl) group, optionally substituted with a group - (CH ₂ ) _s —NR ^x R ^y (eg, —NH ₂ ).

In a further embodiment, R ² is oxazole, oxadiazole, triazole, tetrazole, pyrazole, thiadiazole, thiazole, imidazole or oxathiadiazole optionally substituted with one or more R ^a groups.

In a further embodiment, R ² is oxazole, oxadiazole, triazole, tetrazole, thiadiazole or oxathiadiazole optionally substituted with one or more R ^a groups.

In a further embodiment, R ² is thiadiazole, thiazole or imidazole optionally substituted with one or more R ^a groups.

In a further embodiment, R ² is a 5-membered heterocyclyl group (e.g., oxazole, oxadiazole, triazole (e.g., 1,2,3-triazole or 1,2,4-triazole), tetrazole, thiadiazole or oxathiadiazole), optionally substituted C _1-6 alkyl (e.g. methyl or ethyl) or -SR ^x (e.g. -S-Me) group.

In a further embodiment, R ² is oxadiazole (e.g., 1,3,4-oxadiazole), tetrazole or thiadiazole (e.g., 1,3,4-thiadiazole), optionally substituted with C _1-6 alkyl (e.g. methyl or ethyl) or -SR ^x (e.g., -S-Me) group.

In a further embodiment, R ² is pyrazole optionally substituted with one or more R ^a groups, for example one or two optionally substituted C _1-4 alkyl groups (e.g. CH ₃ , CH ₂ OH, (CH ₂ ) ₂ OH or (CH ₂ ) ₂ NH ₂ ).

In a further embodiment, R ² is pyrazole optionally substituted with one or more R ^a groups, for example one or two C _1-4 alkyl groups (for example, methyl groups).

In a further embodiment, R ² is an 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 = O group.

In a further embodiment, R ² is oxazole, oxadiazole, triazole, tetrazole, thiadiazole or oxathiadiazole substituted with one or two optionally substituted C _1-4 alkyl groups (e.g. CH ₃ , CH ₂ OH).

In a further embodiment, R ² is an aryl (eg, phenyl) group optionally substituted with a halogen atom (eg, fluorine), or R ² is a 5-membered heterocyclyl group (eg, oxadiazole, tetrazole or thiadiazole), optionally substituted with C _{1 -6} alkyl (e.g. methyl or ethyl) or -SR ^x (e.g. -S-Me) group.

In a further embodiment, R ² is a heterocyclyl (e.g., pyridyl or pyrimidinyl) group optionally substituted with a -Z-heterocyclyl group (e.g., -Z-azetidinyl, -Z-piperazinyl, -Z-morpholinyl or -Z-piperidinyl).

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

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

In yet another embodiment, R ² is a heterocyclyl (eg, pyridyl) group, optionally substituted with a - (CH ₂ ) _s —NR ^x R ^y (eg, —NH ₂ ) group.

In one embodiment, R ² is halogen (e.g., fluorine or chlorine). In a further embodiment, R ² is halogen (e.g., chlorine).

In one embodiment, R ² is C _1-6 alkyl (e.g., methyl or ethyl) optionally substituted with one or more R ^b groups (e.g., -CH ₂ OH, -C (OH) (Me) ₂ or -CF ₃ )

In one embodiment, R ² is C _3-8 cycloalkyl (e.g., cyclopropyl).

In one embodiment, R ² is —CH = N — OR ^W (eg, —CH = N — OH or —CH = N-OMe).

In one embodiment, R ² is —NHSO ₂ R ^W (eg, —NHSO ₂ Me).

In one embodiment, R ² is C _1-6 alkoxy (e.g., methoxy or ethoxy).

In one embodiment, R ² is C _2-6 alkynyl (e.g., ethynyl or propynyl) optionally substituted with an R ^b group (e.g., -C≡C-Si (Me) ₄ ). In a further embodiment, R ² is C _2-6 alkynyl (e.g., ethynyl) optionally substituted with an R ^b group (e.g., -C≡C-Si (Me) ₄ ). In a further embodiment, R ² is C _2-6 alkynyl (eg, ethynyl) optionally substituted with an R ^b group (eg, cyclopropyl).

In one embodiment, R ² is —C≡N.

In one embodiment, R ² is C _2-6 alkenyl optionally substituted with R ^b group (for example, -CH = CH-COOEt or -CH = CHCONHMe).

In one embodiment, R ⁶ is 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 R ^W , —CH = N — OR ^W, or a 3-6 membered monocyclic heterocyclyl group, wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and heterocyclyl groups be substituted by one or more groups R ^a .

In one embodiment, R ² and R ⁶ may optionally be substituted with an R ^b group. In a further embodiment, R ^b includes a group R ^a , or —Y-aryl or —Z-heterocyclyl.

In one embodiment, Y and Z are independently —CO—, —O— (CH ₂ ) _s - or —NH— (CH ₂ ) _n -.

In one embodiment, Z is a bond, CO, - (CH ₂ ) _n - (e.g., -CH ₂ -, - (CH ₂ ) ₂ or - (CH ₂ ) ₃ ) or -O-. In a further embodiment, Z is —O—, CO or - (CH ₂ ) _n - (for example, —CH ₂ -). In yet another embodiment, Z is - (CH ₂ ) _n - (e.g., -CH ₂ -).

In one embodiment, Y and Z independently represent a bond, CO, —CH ₂ -, - (CH ₂ ) ₂ , - (CH ₂ ) _3, or —O—.

In one embodiment, Z is a bond, CO, - (CH ₂ ) _n - (e.g., -CH ₂ -, - (CH ₂ ) ₂ or - (CH ₂ ) ₃ ) or -O-. In a further embodiment, Z is - (CH ₂ ) _n (e.g., -CH ₂ -).

In one embodiment, Z is a bond, CO, - (CH ₂ ) _n - (e.g., -CH ₂ -, - (CH ₂ ) ₂ or - (CH ₂ ) ₃ ) or -O-.

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

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

In one embodiment, R ^e , R ^f and R ^{W are} independently hydrogen or methyl. In a further embodiment, R ^e , R ^f and R ^W are hydrogen.

In one embodiment, n is 1.

In one embodiment, the compound of formula (I) is a compound of formula (Ia) or (Ib):

,

,

where A represents an aromatic carbocyclic or heterocyclic group, which optionally can be substituted by one or more (for example, 1, 2 or 3) R ^a groups;

B represents an aromatic or non-aromatic carbocyclic or heterocyclic group;

R ⁴ and R ⁵ independently represent hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-6 cycloalkenyl, C _1-6 alkanol, halogen C _1-6 alkyl, - (CH ₂ ) _n —NR ^x R ^y , - (CH ₂ ) _s —COOR ^z , - (CH ₂ ) _n —O— (CH ₂ ) _m —OH, - (CH ₂ ) _n aryl, - (CH ₂ ) _n -O-aryl, - (CH ₂ ) _n -heterocyclyl or - (CH ₂ ) _n -O-heterocyclyl, wherein said C _{1-6 is} alkyl, C _{2-6 is} alkenyl, C _{2-6 is} alkynyl , C _3-8 cycloalkyl, C _3-8 cycloalkenyl, aryl and heterocyclyl groups may optionally be substituted with one or more (e.g. 1, 2 or 3) R ^a groups;

R ^x , R ^y and R ^z independently represent hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkanol, hydroxy, C _1-6 alkoxy, halogen C _1-6 alkyl , -CO- (CH ₂ ) _n -C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 cycloalkenyl;

R ² independently represents hydrogen, an aryl or heterocyclyl group, wherein said aryl and heterocyclyl groups may optionally be substituted with one or more R ^b groups;

R ^a represents halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , -O- (CH ₂ ) _n - OR ^x , halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkanol, = O, = S, nitro, - (CH ₂ ) _s —CN, —SR ^x , —SO — R ^x , —SO ₂ -R ^x , -COR ^x , - (CR ^x R ^y ) _s -COOR ^z , - (CH ₂ ) _s -CONR ^x R ^y , - (CH ₂ ) _s -NR ^x R ^y , - (CH ₂ ) _s -NR ^x COR ^y , - (CH ₂ ) _s -NR ^x SO ₂ -R ^y , -OCONR ^x R ^y , - (CH ₂ ) _s -NR ^x CO ₂ R ^y , -O- (CH ₂ ) _s -CR ^x R ^y - (CH ₂ ) _t -OR ^z or - (CH ₂ ) _s -SO ₂ NR ^x R ^y ;

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

Y and Z independently represent a bond, -CO- (CH ₂ ) _s -, -COO-, - (CH ₂ ) _n -, -NR ^x - (CH ₂ ) _n -, - (CH ₂ ) _n -NR ^x -, -CONR ^x , -NR ^x CO-, -SO ₂ NR ^x -, -NR ^x SO ₂ -, -NR ^x CONR ^y -, -NR ^x CSNR ^y -, -O- (CH ₂ ) _s -, - (CH ₂ ) _s —O—, S—, —SO— or - (CH ₂ ) _s —SO ₂ -;

m and n independently represent an integer having a value of 1-4;

s and t independently represent an integer having a value of 0-4;

q is an integer of 0-2;

aryl is a carbocyclic ring;

heterocyclyl is a heterocyclic ring;

or a pharmaceutically acceptable salt, solvate or derivative thereof.

It should be understood that specific embodiments of groups A, B, R ¹ , q, and R ² in formula (Ia) and (Ib) above are those described above for formula (I).

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

In one embodiment, the compound of formula (I) is a compound of formula (Ia) or (Ib), wherein:

A represents phenyl or pyridine (for example, pyridin-4-yl);

B represents benzyl, thiadiazole (for example, [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 represents an optionally substituted 6-membered ring, such as phenyl or pyridine, or an optionally substituted 5-membered nitrogen-containing heterocycle, such as pyrazole or tetrazole, where optional substituents are selected from halogen, for example fluorine, amino and C _1-6 alkyl, for example methyl.

In a further embodiment, the compound of formula (I) is a compound of formula (Ia) or (Ib), wherein

A represents phenyl or pyridine (for example, pyridin-4-yl);

B represents benzyl, thiadiazole (for example, [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 phenyl optionally substituted with halogen, for example fluorine (such as 4-fluorophenyl), pyridine optionally substituted with amino (such as 4-aminopyridin-2-yl), pyrazole optionally substituted with methyl (such as 1- methyl-1H-pyrazol-4-yl), or tetrazole optionally substituted with methyl (such as 2-methyl-2H-tetrazol-5-yl).

In one embodiment, the compound of formula (I) is a subgroup having the formula (Ia), and is defined as a compound of formula (Ic):

,

,

where R ^a , R ¹ , R ² , B, and q are as defined above, n is an integer of 0-3, and L is a carbon or nitrogen atom.

Specific preferred values of the variables R ^a , R ¹ , R ² , B, and q are defined herein.

In particular, R ² is an optionally substituted phenyl or a 5-6 membered monocyclic heterocycle. Specific preferred values of R ^{2 are} defined herein.

In one embodiment, the compound of formula (I) is a subgroup having the formula (Ia), and is defined as a compound of formula (Id):

,

,

where R ^a , R ¹ , R ² , B, L, n and q have the meanings defined in this application.

Specific preferred values of the variables R ^a , R ¹ , R ² , B, and q are defined herein.

In particular, in one embodiment, R ² is phenyl optionally substituted with R ^b . In another embodiment, R ² is phenyl optionally substituted with R ^a . In one embodiment, the group R ^a or R ^b is at the 3- or 4-position of the phenyl ring. In one embodiment, when the phenyl ring is substituted with a group R ^a , in this case the group R ^a is at the 4-position of the phenyl ring. In one embodiment, when the phenyl ring is substituted with an R ^b group, where the R ^b group is a —Y-carbocyclyl (eg, Y-aryl) group or a —Z-heterocyclyl group, in which case the R ^b group is at the 3-position of the phenyl rings.

In one embodiment, the groups R ^b are selected from halogen (e.g., fluorine or chlorine), deuterium (e.g., D ₅ ), haloC _1-6 alkyl (e.g., -CF ₃ ), haloC _1-6 alkoxy (e.g., -OCF ₃ ), -OR ^x (e.g. methoxy or -OCH ₂ OHCH ₂ OH), C _1-6 alkyl (e.g. i-Pr), C _1-6 alkanol (e.g. -CH ₂ OH), - (CR ^x R ^y ) _s -COOR ^z (e.g. -COOH, -COOMe, -C (Me) ₂ -COOH, -CH ₂ -COOH or -C (Me) ₂ -COOMe), - (CH ₂ ) _s -CN (e.g. , -CN or -CH ₂ CN), - (CH ₂ ) _s -NR ^x R ^y (e.g., -NMe ₂ , - (CH ₂ ) ₂ -NH ₂ , - (CH ₂ ) ₂ -NMe ₂ or -NH -CO-CH ₂ -methoxy), -O- (CH ₂ ) _n -OR ^x (e.g., -O- (CH ₂ ) _2- ethoxy), - (CH ₂ ) _s -CONR ^x R ^y (e.g., - CONH ₂ , -CONHMe, -CONHEt, -CONH-iPr, -CH ₂ -CONHMe, -CONH- (CH ₂ ) ₂ -OMe or -CONH- (CH ₂ ) ₂ -NH ₂ ), -SO ₂ - R ^x (e.g., -SO ₂ Me), - (CH ₂ ) _s -SO ₂ NR ^x R ^y (e.g., -SO ₂ NH ₂ ), - (CH ₂ ) _s -NR ^x -SO ₂ -R ^y ( e.g., -NHSO ₂ Me or -CH ₂ -NHSO ₂ Me), - (CH ₂ ) _s -NH-SO ₂ -NR ^x R ^y (e.g. -NH-SO ₂ -NMe ₂ ).

In one embodiment, the R ^b groups are selected from halogen (e.g., fluorine), halo C _1-6 alkoxy (e.g., -OCF ₃ ), -OR ^x (e.g., methoxy or -OCH ₂ OHCH ₂ OH), C _1-6 alkanol (e.g. -CH ₂ OH), - (CR ^x R ^y ) _s -COOR ^z (e.g. -COOH, -COOMe, -C (Me) ₂ -COOH, -CH ₂ -COOH or -C (Me) ₂ -COOMe), - (CH ₂ ) _s -CN (e.g. -CH ₂ CN), - (CH ₂ ) _s -NR ^x R ^y (e.g. -NMe ₂ , - (CH ₂ ) ₂ -NH ₂ , - (CH ₂ ) ₂ —NMe ₂ or —NH — CO — CH ₂ methoxy) or —O— (CH ₂ ) _n —OR ^x (e.g., —O— (CH ₂ ) ₂ ethoxy).

In one embodiment, the R ^b groups are selected from a halogen (e.g., fluorine), a -Y-aryl (e.g., -Y-phenyl) group, or a -Z-heterocyclyl group (e.g., -Z-morpholinyl, -Z-azetidinyl, -Z -pyrrolidinyl, -Z-tetrazolyl, -Z-piperidinyl, -Z-piperazinyl), wherein said heterocyclyl group may optionally be substituted with one or more (e.g., 1, 2 or 3) R ^a groups selected from C _1-6 alkyl (e.g. methyl) or - (CR ^x R ^y ) _s -COOR ^z (e.g. -COOH, -COOMe or -COOtBu) groups, and wherein Z represents CO, CH ₂ or a bond.

In one embodiment, R ^b groups are selected from a -Z-heterocyclyl group (e.g., -Z-morpholinyl, -Z-azetidinyl, -Z-pyrrolidinyl, -Z-pyrazolyl, -Z-tetrazolyl, -Z-piperidinyl, -Z- piperazinyl, -Z-diazepanyl or -Z-tetrahydropyranyl), wherein said heterocyclyl group may optionally be substituted with one or more (e.g., 1, 2 or 3) R ^a groups selected from C _1-6 alkyl groups (e.g. methyl or ethyl), = O, -COR ^x (e.g. -COMe) or - (CR ^x R ^y ) _s -COOR ^z (e.g. -COOH, -COOMe or -COOtBu), and where Z is CH ₂ or a bond.

In yet another embodiment, R ² is an aryl (eg, phenyl) group optionally substituted with a halogen atom (eg, fluorine). In yet another embodiment, R ² is 4-fluorophenyl.

In one embodiment, the compound of formula (I) is a subgroup having the formula (Ib), and is defined as a compound of formula (Ie):

,

,

where R ^a , R ¹ , R ² , B, L, n and q have the meanings defined in this application.

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

,

,

where R ^a , R ¹ , R ² , B, L, n and q have the meanings defined in this application.

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], starting material of the A4c procedure [3- (7-chloro-imidazo [1,2-a] pyridin-3-yl) phenyl] - [1,3,4] thiadiazol-2-yl-amine] and the product of procedure G1 [[3- (7-chloro-imidazo [1,2-a] pyridin-3-yl) phenyl] - (3H- [1,2,3] triazol-4-yl) -amine] )

In one embodiment, the compound of formula (I) is a compound selected from Examples 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, of the product of the 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 G1 [[3- (7-chloro-imidazo [1,2-a] pyridine -3-yl) phenyl] - (3H- [1,2,3] triazol-4-yl) -amine]).

In one embodiment, the compound of formula (I) is a compound selected from Examples 2, 3, 4, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 20, 24, 25, 26, 28, 30, 32, 43 and the starting material of procedure A4c [3- (7-chloro-imidazo [1,2-a] pyridin-3-yl) phenyl] - [1,3,4] thiadiazol-2-yl -amine]).

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

Methods for producing compounds of formula (I)

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

Compounds of formula (I) can be prepared according to synthetic methods well known to those skilled in the art. In particular, compounds of formula (I) are readily prepared using the chemistry of palladium-mediated binding processes between aromatic chlorine, bromine, iodine or pseudo-halogen compounds, such as trifluoromethanesulfonate (triflate) or tosylate compounds, and aromatic boronic acids or stannane derivatives. In particular, the chemistry of the Suzuki coupling reaction is widely used for the synthesis of such compounds. The Suzuki reaction can be carried out under typical conditions in the presence of a palladium catalyst such as bis (tri-tert-butylphosphine) palladium, tetrakis (triphenylphosphine) palladium or a palladium catalyst (e.g., the palladium catalyst described in Bedford, RB and Cazin, CSJ (2001 ) Chem. Commun., 1540-1541), and a base (e.g., a carbonate such as potassium carbonate), as discussed in more detail below. The reaction can be carried out in a polar solvent, for example an aqueous solvent system, including an aqueous solution of ethanol, or an ether, such as dimethoxyethane or dioxane, and the reaction mixture is typically subjected to heating, for example to a temperature of 80 ° C or higher, for example to a temperature above 100 ° C .

As shown in Scheme 1, the imidazo [1,2-a] pyridine nucleus can be synthesized based on commercially available starting materials, using Way A (to obtain a 3.7 disubstituted ring) or C (to obtain a 3.6 disubstituted ring).

4-Chloro-pyridin-2-ylamine or 4-bromo-pyridin-2-ylamine in a suitable solvent and base can be cyclized at reflux with chloroacetaldehyde to give an imidazopyridine ring. 7-Chloro-imidazo [1,2-a] pyridine in a suitable solvent can then be iodinated, for example using N-iodosuccinimide at room temperature.

You can then add a suitable functional group at the halogenation positions, for example, using a number of metal-catalyzed reactions. In particular, functionalized boronic acids are suitable, or their boronate esters can be reacted with an aryl halide. This transformation, commonly known as the Suzuki reaction, is described in Rossi et al. (2004), Synthesis 15, 2419.

The Suzuki reaction is often carried out in mixtures of water and organic solvents. Examples of suitable organic solvents include toluene, 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 carried out in the presence of a base. Examples of suitable bases include sodium carbonate, potassium carbonate, cesium carbonate and potassium phosphate. Examples of suitable catalysts include bis (tri-tert-butylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0) , bis (tricyclohexylphosphine) palladium (0), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), dichlorbis (tri-o-tolylphosphine) palladium (II), complex 2 '- (dimethylamino) -2 -biphenylyl-palladium (II) chloride · dinorbornylphosphine and a complex of 2- (dimethylamino) ferrocene-1-yl-palladium (II) chloride · dinorbornylphosphine. In some cases, you can add additional ligands that contribute to the coupling reaction. Examples of suitable ligands include tri-tert-butylphosphine, 2,2-bis (diphenylphosphino) -1,1-binaphthyl, triphenylphosphine, 1,2-bis (diphenylphosphino) ethane, 1,1'-bis (diphenylphosphino) ferrocene, tricyclohexylphosphine, 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene, 1,3-bis (diphenylphosphino) propane, 2- (di-tert-butylphosphino) biphenyl, 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino ) -biphenyl, tri-o-tolylphosphine, 2- (dicyclohexylphosphino) biphenyl, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, tri (2-furyl) phosphine, 2-dicyclohexylphosphino-2 ', 6'- dimethoxybiphenyl and 2-di-tert-butylphosphino-2 ', 4', 6'-triiso propylbiphenyl.

Scheme 1

Other examples of the preparation of possible metal-catalyzed functionalization of the halide are reactions with organotin reagents (Stille reaction), with Grignard reagents, and reaction with nitrogen nucleophiles. A general overview of these transformations, as well as additional references, can be found in the 'Palladium Reagents and Catalysts' [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and in the Handbook of OrganoPalladium Chemistry for Organic Synthesis [Volume 1, Edited by Ei- ichi Negishi, Wiley, ISBN 0-471-31506-0].

In particular, one reaction that can be used is the Buchwald-Hartwig reaction (see review: JF Hartwig (1998), Angew. Chem. Int. Ed. 37, 2046-2067), which allows palladium-catalyzed synthesis of arylamines. The starting materials are aryl halides or pseudo-halides (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- (dibenzylideneacetone) -di-palladium (Pd ₂ (dba) ₃ ) or 2,2'-bis (diphenylphosphino) -1'1-binaphthyl (BINAP).

In particular, to synthesize compounds of formula (I), the aryl halide can be reacted with 3-aminobenzeneboronic acid using a suitable metal catalyst, for example bis (triphenylphosphine) palladium (II) chloride, to form an amine precursor to form secondary amine bonds.

This reaction sequence shown in Path A may have an alternative, as shown in Path B. Alternatively, the halogen functional group at the 7-position of imidazo [1,2-a] pyridine can be converted to boronic acid or ester and used to synthesize alternative motives, as shown in Scheme 2. This substance can then be used directly in any of the metal-catalyzed reactions shown in this section of the description. For example, to convert the halide to boronate, the halide is reacted with a palladium catalyst and a phosphine ligand in a suitable solvent, for example dioxane, and a base, for example KOAc, and a suitable substituted boron-containing compound.

General path E

Scheme 2

After completion of the synthesis, a number of functional group transformations can be carried out in di-aryl-substituted imidazopyridine compounds to give additional compounds of formula (I). For example, you can use some of the following hydrogenation reactions, for example, using a Raney nickel-based catalyst, hydrolysis, deprotection, and oxidation.

Scheme 3

In particular, as shown in Scheme 3, the introduced amine functional group can be used for the synthesis of cyclic amine compounds.

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

Compounds of formula (I) containing a secondary amine group can be prepared from amino compounds in various ways. Reductive amination using a suitable substituted aldehyde or ketone can be carried out in the presence of various reducing agents (see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, 1992, p. 898-900). For example, reductive amination can be carried out in the presence of sodium triacetoxyborohydride in the presence of an aprotic solvent, such as dichloromethane, at or near ambient temperature. They can also be obtained by reducing the amino compound in a nucleophilic substitution reaction, where the reagent contains a leaving group, such as a halogen.

In addition, the thiadiazolylamino compound can be synthesized using a suitable substituted boronic acid in the Suzuki reaction, for example 3 - ([1,3,4] thiadiazol-2-ylamino) phenylboronic acid pinacol ester or 3- (5-methyl- pinacol ester [1,3,4] thiadiazol-2-ylamino) phenylboronic acid. They can be synthesized as described in this application.

Alternatively, a secondary amine can be formed by cyclizing a suitable group to form a ring. Aminothiadiazole compounds can be synthesized as described in Scheme 4.

Scheme 4

This route involves reacting an amino compound in an anhydrous solvent, for example toluene, with 1,1'-thiocarbonyldi-2 (1H) -pyridone. Typical reaction conditions include heating for 1 hour, bringing the reaction to completion, and then treating with hydrazine hydrate to give thiosemicarbazide. This compound is then cyclized under conditions such as the addition of diethyl chlorophosphate dropwise. It may also give an alternative cyclization product, and therefore separation may be required.

Alternative heterocyclic groups may be formed by known heterocyclic ring formation reactions. For example, amino-triazole (for example, 3H- [1,2,3] triazol-4-yl) -amine) can be formed by reacting sodium nitrite in H ₂ O with an amine in an acid, for example 2 N. HCl solution, followed by the addition of aminoacetonitrile hydrosulfate in H ₂ O. At the end of a suitable period of time, NaOAc is added and rearranged to the desired heterocycle by heating in a solvent, for example ethanol, for 16 hours.

Suitable starting materials and reagents for these reactions can be obtained commercially or by any of numerous standard synthetic methods well known to those skilled in the art, for example, see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, 1992, and Organic Synthesis, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8), 1995, and also see the methods described in the experimental part below. For example, many suitable functionalized aniline and aminopyridine starting materials and metal catalysts are commercially available.

Many boronates, for example boronic acids or esters, or trifluoroborates suitable for use in preparing the compounds of the present invention, are commercially available, for example, from Boron Molecular Limited of Noble Park, Australia, or from Combi-Blocks Inc. of San Diego, USA. When a suitable substituted boronate is not commercially available, it can be obtained by methods known in the art, for example, as described in a review article by Miyaura, N. and Suzuki, A. (1995) Chem. Rev, 95, 2457. Thus, boronates can be prepared by reacting the corresponding bromide compound with an alkyl lithium, such as butyllithium, and then reacting with a borate ester, for example (PrO) ₃ B. The reaction is typically carried out in an anhydrous polar solvent such as tetrahydrofuran, at low temperatures (e.g. -78 ° C). Boronate esters (e.g., pinacolate-boronate) can also be obtained from the bromine compound by reaction with a diboronate ester, such as bis (pinacolato) dibor, in the presence of phosphine, such as tricyclohexylphosphine, and a palladium (0) reagent, such as tris (dibenzylidene acetone) - dipalladium (0). The formation of the boronate ester is typically carried out in an anhydrous polar aprotic solvent, such as dioxane or DMSO, with heating to a temperature of about 100 ° C, for example about 80 ° C. The resulting boronate ester derivative, if desired, can be hydrolyzed to produce the corresponding boronic acid or converted to trifluoroborate.

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

Pyrazolo [1,5-a] pyrimidines

The basic structure of pyrazolo [1,5-a] pyrimidines can be synthesized based on a suitable substituted aminopyrazole (VI) and fragments (VII), as shown in Scheme 5A, where R ^a may be hydrogen or R ₁ . This can be accomplished using a one-step or two-step method, where X ₁ and X ₂ are electrophilic carbons (i.e. carbonyl, protected carbonyl, i.e. acetal, enamine, conjugated alkenes or alkynes) (Perkin I, JCS (1979 ), 3085-3094). X ₃ is a suitable substituent of either an R ² group or groups, such as halogen or pseudo-halogens, which enable the introduction of R ₂ as described herein. Cyclization of pyrazole (VI) using a suitable substituted free or protected 1,3-dicarbonyl derivative can be used to produce substituted pyrazolo [1,5-a] pyrimidines. The cyclization typically occurs in an alcohol solvent, or in toluene, or in acetic acid, and additives such as piperidine, sodium ethoxide, HCl, AcOH, pTsOH or ZnCl ₂ may be present (J. Med. Chem. (2001), 44 (3 ), 350-361; Bull. Korean Chem. Soc. (2002), 23 (4), 610-612; Australian Journal of Chemistry (1985), 38 (1), 221-30).

5A circuit

A specific synthesis scheme for the preparation of 3,7-disubstituted pyrazolo [1,5-a] pyrimidines is shown in scheme 5B. The formation of the pyrazolopyrimidine ring is carried out by reacting substituted malonaldehyde as fragment VII with aminopyrazole. The substituted malonaldehyde can be substituted with the desired cyclic functional group, for example 2- (4-fluoro-phenyl) -malonaldehyde, or with a latent functional group, for example, with halogen, as in 2-bromo-malonaldehyde, which allows further derivatization in this position, as shown in the diagram below using the reactions described.

5V circuit

In the cyclization reaction, malonaldehyde in a solvent is added to 3-aminopyrazole followed by an acid, for example glacial acetic acid. The reagents are then cyclized by heating under reflux. The compound of formula (I) can then be synthesized using halogenation and the metal catalyzed reactions described in this application.

The compounds of formula (VI) and (VII) are known compounds, or can be obtained by analogy with known methods. Many pyrazoles of formula (VI) are commercially available. Alternatively, they can be prepared by known methods, for example, from ketones in the method described in EP308020 (Merck), or by methods discussed by Schmidt in Helv. Chim. Acta. (1956), 39, 986-991 and Helv. Chim. Acta. (1958), 41, 1052-1060, or by converting the pyrazoles of formula (VI) or a compound of formula (I), where R ^a is hydrogen, halogen, nitro, ester or amide, into the desired R ¹ functional group by standard methods, well-known specialists in this field. For example, when R ¹ is halogen, coupling reactions using tin or palladium can be carried out as described in this application.

Pyrazolo [1,5-a] pyrazines

Scheme 6

Reaction of a mixture of 2-bromo-5-iodo-pyrazine and copper (I) iodide under inert conditions in a suitable solvent and base, for example DMF / Et ₃ N, with ethynyl-trimethylsilane using a palladium catalyst, for example Pd (PPh ₃ ) ₄ , at room temperature gives 2-bromo-5-trimethylsilanylethinyl-pyrazine. This material can be used without further purification and used in the reaction to form 6-bromo-2-trimethylsilanyl-pyrazolo [1,5-a] pyrazine using O- (mesitylenesulfonyl) hydroxylamine to give an N-amino adduct. This substance can then be cyclized by reaction with a base, for example K ₂ CO ₃ , to give a pyrazolopyrazine core (Scheme 6).

You can then enter the appropriate groups at positions 3 and 7 by halogenation and the interaction of the latent functional groups at 3 and 7 positions in the metal-catalyzed reactions described in this application.

Pyrazolo [1,5-a] pyridines

3-bromopyridine is reacted with a suitable substituted boronic acid in a solvent such as DME, under inert conditions, in the presence of a base (Na ₂ CO ₃ ) and a palladium catalyst, to give 3-substituted pyridine (Scheme 7). O- (mesitylenesulfonyl) hydroxylamine is then reacted with 3-substituted pyridine under inert conditions to give N-aminopyridine, which can be used without further purification. Cyclization of the N-adduct using a base (K ₂ CO ₃ ) and 2-benzenesulfonyl-3-dimethylamino-acrylic acid methyl ester in an inert atmosphere gives the pyrazolo [1,5-a] pyridine compound in the form of a 3-carboxylic acid ester. The carboxylic acid ester can be removed, for example, by saponification using sodium hydroxide to give an acid, followed by decarboxylation in polyphosphoric acid.

Scheme 7

N-iodosuccinimide iodination and metal-catalyzed interaction of aryl halides can be used to introduce the desired functional group at the 3-position, as shown in this application.

Imidazo [4,5-b] pyridines

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

Scheme 8

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

Scheme 9

As described herein, aryl halides similar to those shown above can be subjected to a series of metal-catalyzed reactions to form the desired compounds of formula (I).

Imidazo [4,5-c] pyridines

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

Pattern 10

As indicated, regioisomeric products can be separated by chromatography. A possible way of further processing this substance to obtain the desired substitution pattern is illustrated below (Scheme 11).

Scheme 11

Interaction with an oxidizing agent, such as 3-chloroperbenzoic acid, can be used to produce N-oxide, which can be rearranged to produce disubstituted 3H-imidazo [4,5-c] pyridine using certain reagents, for example POCl ₃ , SOCl ₂ . The regioisomeric products can then be separated by chromatography. Substitution X to produce aryl and amino substituted products can be carried out by reacting a suitable nucleophile in the presence of a metal catalyst, for example 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 Chem. (1965), 2 (2), 196-201. The chlorine group may be substituted by a nucleophile in the presence of a metal catalyst (e.g., palladium) to give aryl and amino substituted products. A protective group such as a carbamate or benzyl group can be used for this conversion. Subsequent conversion to N-aryl compounds can then be carried out in accordance with the conditions shown in Scheme 10.

Pattern 12

1,5-diaryl-1H-benzoimidazole

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

Pattern 13

Substitution of fluorine in 4-bromo-1-fluoro-2-nitrobenzene with suitable aniline followed by reduction and cyclization using triethylorthoformate gives bromo-benzoimidazole with the desired substitution pattern. The product can be further processed by metal-catalyzed reaction of bromide to obtain 1,5-disubstituted benzoimidazoles.

Imidazo [1,2-c] pyrimidines

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

Scheme 14

The method is carried out starting from 7-chloro-imidazo [1,2-c] pyrimidine, the synthesis of which is described in Yanai et al., Heterocyclic compounds. Xviii. Synthesis imidazo [1,2-c] - and pyrimido [1,2-c] pyrimidine derivatives, Yakugaku Zasshi (1974), 94 (12), 1503-14. This substance can then be further processed using any of the reactions described above.

Alternatively, when the 7-position is an N-linked saturated heterocycle, for example morpholine, the S _N Ar reaction (for example, the S _N Ar reaction, see "Advanced Organic Chemistry" by Jerry March, 4th edition, pages 641-644), , for example, as described in US4503050 (Scheme 15).

Scheme 15

When the 7-position is an aryl or heteroaryl group,

The S _N Ar group can be substituted using a standard cross-linking reaction using palladium using a chemistry similar to that described in this application (Scheme 16).

Pattern 16

Imidazo [1,2-c] pyrimidin-5-one

3,7 disubstituted imidazo [1,2-c] pyrimidin-5-ones can be obtained from 7-chloro-6H-imidazo [1,2-c] pyrimidin-5-one (CAS number 56817-09-5), the synthesis of which is described in Maggiali et al. (1982), Acta Naturalia de I'Ateneo Parmense, 18 (3), 93-101 and Bartholomew et al. (1975) Journal of Organic Chemistry, 40 (25), 3708-13.

One can derivatize 7-chloro-6H-imidazo [1,2-c] pyrimidin-5-one using nucleophilic substitution reactions, such as S _N Ar, or undergo a Suzuki reaction to attach a functional group at position 7 (Scheme 17). This compound can then be iodinated, as described above, before its further functionalization using the Suzuki reaction.

Scheme 17

Alternatively, 7-chloro-6H-imidazo [1,2-c] pyrimidin-5-one can be directly iodinated to give an intermediate, as shown below, for use in the reactions described herein (Scheme 18).

Scheme 18

In addition, other oxo heterocycles can be synthesized based on a suitable chlorine-substituted derivative by hydrolysis. The protected compound can be subjected to alkaline hydrolysis to obtain pyridone. This can be accomplished using NaOH (or NaOH / H ₂ O ₂ ) in H ₂ O / MeOH or H ₂ O / dioxane, following the procedures described in the literature for the hydrolysis of chloropyridines (e.g. Australian J. Chem. (1984), 37 (12), 2469-2477).

Imidazo [1,2-b] pyridazine

Scheme 19

The synthesis of the imidazo [1,2-b] pyridazine nucleus can be carried out as shown in Scheme 19 using the pyridazin-3-ylamine derivative as described in J. Heterocyclic Chem. (2002), 39 (4), p. 737-742. The introduction of substituents at position 3 is described in J. Med. Chem. (2006), 49 (4), p. 1235-1238 to give 3,7-substituted compounds.

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

In many of the reactions described above, it may be necessary to protect one or more groups to prevent interaction on undesired portions of the molecule. Examples of protecting groups and methods for protecting functional groups and removing deprotection can be found in Protective Groups in Organic Synthesis (Green, T. and Wuts, P. (1999); 3rd Edition; John Wiley and Sons).

The hydroxy group may be protected, for example, in the form of an ether (-OR) or an ester (-OC (= O) R), for example, in the form of: a tert-butyl ether; benzyl, benzhydryl (diphenylmethyl) or trityl (triphenylmethyl) ether; trimethylsilyl or tert-butyldimethylsilyl ether; or acetyl ester (-OC (= O) CH ₃ , -OAc). The aldehyde or ketone group can be protected, for example, as acetal (R-CH (OR) ₂ ) or ketal (R ₂ C (OR) ₂ ), respectively, where the carbonyl group (> C = O) is converted to diester (> C (OR) ₂ ) by reaction, for example, with a primary alcohol. The aldehyde or ketone group is easily reduced by hydrolysis using a large excess of water in the presence of acid. The amine group may be protected, for example, in the form of an amide (-NRCO-R) or urethane (-NRCO-OR), for example, in the form of: methylamide (-NHCO-CH ₃ ); benzyloxyamide (-NHCO-OCH ₂ C ₆ H ₅ , -NH-Cbz); as tert-butoxyamide (-NHCO-OC (CH ₃ ) ₃ , -NH-Boc); as 2-biphenyl-2-propoxyamide (-NHCO-OC (CH ₃ ) ₂ C ₆ H ₄ C ₆ H ₅ , -NH-Bpoc), as 9-fluorenylmethoxyamide (-NH-Fmoc), as 6- nitroveratryloxyamide (-NH-Nvoc), as 2-trimethylsilylethyloxyamide (-NH-Teoc), as 2,2,2-trichlorethyloxyamide (-NH-Troc), as allyloxyamide (-NH-Alloc), or as 2 ( phenylsulfonyl) ethyloxyamide (-NH-Psec). Other protecting groups for amines, such as cyclic amines and heterocyclic NH groups, include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups and benzyl groups such as a para-methoxybenzyl (PMB) group. The carboxylic acid group may be protected as an ester, for example, as: a C _1-7 alkyl ester (for example methyl ester, tert-butyl ether); C _1-7 haloalkyl ester (e.g. C _1-7 trihaloalkyl ester); a complex of C _1-7 alkylsilyl-C _1-7 alkyl ether; or a C _5-20 aryl-C _1-7 alkyl ester (e.g., benzyl ester, nitrobenzyl ester); or in the form of an amide, for example, in the form of methylamide. The thiol group may be protected, for example, in the form of a thioether (-SR), for example, in the form of: a benzyl thioether; acetamidomethyl ether (-S-CH ₂ NHC (= O) CH ₃ ).

Key intermediates for preparing compounds of formula (I) are compounds of formula (XX). New chemical intermediates of formula (XX) constitute another aspect of the present invention.

A further aspect of the present invention is a process for preparing a compound of formula (I) as defined herein, the process comprising:

(i) the interaction of the compounds of formula (XX) or (XXI):

,

,

or a protected form of such a compound with a suitable substituted aldehyde or ketone; or

(ii) the interaction of the compounds of formula (XX) or (XXI):

,

,

or a protected form of such a compound with hydrazine hydrate, followed by cyclization;

and subsequent removal of any protective groups present; or

where X _1-5 , A and R ₂ have the meanings defined in this application;

and optional subsequent conversion of one compound of formula (I) to another compound of formula (I).

Pharmaceutically acceptable salts, solvates or derivatives

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

Unless otherwise indicated, reference to a particular compound also includes ionic forms, salts, solvates, isomers, tautomers, N-oxides, esters, prodrugs, isotopes and their protected forms, for example, as discussed below; preferably their ionic forms or salts, or tautomers, or isomers, or N-oxides, or solvates; and more preferably ionic forms or salts, or tautomers, or solvates, or their protected forms. Many compounds of formula (I) may exist in the form of salts, for example acid addition salts, or in some cases, salts of organic and inorganic bases, such as carboxylate, sulfonate and phosphate salts. All such salts are included within the scope of the present invention, and references to compounds of formula (I) include salt forms of these compounds.

The salts of the present invention can be synthesized starting from a starting compound that contains a basic or acidic group using conventional chemical methods, such as those 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. Typically, such salts can be obtained by reacting the free acid form or base of these compounds with a suitable base or acid in water or in an organic solvent or in a mixture of water and a solvent; typically a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used. Acid addition salts can be formed with many different acids, both inorganic and organic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butane, (+) camphor, camphor-sulfonic, (+) - (1S) -camphor-10-sulfonic, capric, capron, caprylic, cinnamon, lemon cyclamine, dodecylser, ethane-1,2-disulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, formic, fumaric, galacturonic, gentisine, hl Yugohepton, D-gluconic, glucuronic (e.g. O-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, iodide-hydrogen, isethionic, lactic (e.g., + ( milk, (±) -DL-milk), lactobionic, maleic, apple, (-) - L-apple, malonic, (±) -DL-almond, methanesulfonic, naphthalenesulfonic (e.g., naphthalene-2-sulfonic), naphthalene- 1,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamo hydrophobic, phosphoric, propionic, L-pyroglutamine, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tartaric, (+) - L-tartaric, thiocyanic, toluenesulfonic and valine, for example acids, as well as acylated amino acids and cation exchange resins.

One specific group of salts consists of salts formed from acetic, hydrochloric, hydroiodic, phosphoric, nitric, sulfuric, citric, dairy, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic, mesylsulfonic, mesylsulfonic, mesylsulfonic, mesylsulfonic, , acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids.

Another group of acid addition salts includes salts of acetic, adipic, ascorbic, aspartic, citric, DL-lactic, fumaric, gluconic, glucuronic, hippuric, hydrochloric, glutamic, DL-malic, methanesulfonic, sebacic, stearic yanic,.

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

If the compound is anionic or contains a functional group that may be anionic (for example, —COOH may be —COO ^- ), then the 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 Ca ²⁺ and Mg ²⁺ , and other cations such as Al ³⁺ . Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH ⁴⁺ ) and substituted ammonium ions (e.g., NH ₃ R ⁺ , NH ₂ R ₂ ⁺ , NHR ₃ ⁺ , NR ₄ ⁺ ).

Examples of some suitable substituted ammonium ions include ions derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids such as lysine. An example of a common quaternary ammonium ion is N (CH ₃ ) ⁺ .

When the compounds of formula (I) contain an amine functional group, they can form quaternary ammonium salts, for example, by reaction with an alkylating agent, in accordance with methods well known to those skilled in the art. Such quaternary ammonium compounds are encompassed by formula (I).

Salt forms of the compounds of the present invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al. (1977) "Pharmaceutically Acdceptable Salts", J. Pharm. Sci, Vol. 66, p. 1-19. However, salts that are not pharmaceutically acceptable can also be prepared as forms of intermediates, which can then be converted to pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which may be useful, for example, in the purification or separation of the compounds of the present invention, also form part of the present invention.

Compounds of formula (I) containing an amine functional group may also form N-oxides. The indication in the present application of a compound of formula (I) which contains an amine functional group also includes an N-oxide.

When the compound contains several functional amino groups, one or more of one nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides include N-oxides of a tertiary amine or nitrogen atom of a nitrogen-containing heterocycle.

N-oxides can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or peracid (e.g. peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be formed using the LW Deady procedure (Syn. Comm. (1977), 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane. Specific examples of N-oxides include morpholine N-oxides and pyridine N-oxides.

Compounds of formula (I) may exist in various geometric isomeric and tautomeric forms, and references to compounds of formula (I) include all such forms. For the avoidance of doubt, when a compound can exist in one of several geometric isomeric or tautomeric forms, and only one is specifically described or shown, all other forms are nevertheless encompassed by formula (I).

Other examples of tautomeric forms include, for example, keto, enol and enolate forms, as, for example, in the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / etiol and nitro / acinitro.

When the compounds of formula (I) contain one or more chiral centers and can exist in the form of two or more optical isomers, references to compounds of formula (I) include all optical isomeric forms of these compounds (e.g., enantiomers, epimers and diastereoisomers), or as individual optical isomers, or mixtures (for example, racemic mixtures) of two or more optical isomers, unless the context requires otherwise.

Optical isomers can be characterized and identified by their optical activity (ie, as + and-isomers or d and l isomers), or they can be characterized by 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 see also Cahn, Ingold & Prelog (1966) Angew. Chem. Int. Ed. Engl., 5, 385-415.

Optical isomers can be separated in various ways, including chiral chromatography (chromatography on a chiral carrier), and such methods are well known to specialists in this field.

As an alternative to chiral chromatography, optical isomers can be resolved by the formation of diastereoisomeric salts with chiral acids, such as (+) - tartaric acid, (-) - pyroglutamic acid, (-) - di-toluoyl-L-tartaric acid, (+) - mandelic acid, (-) - malic acid and (-) - camphorsulfonic acid, separating the diastereoisomers by selective crystallization followed by dissociation of salts to give an individual enantiomer of the free base.

When the compounds of formula (I) exist in two or more optical isomeric forms, one enantiomer in a pair of enantiomers may show advantages over the other enantiomer, for example, in terms of biological activity. Thus, in some 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 present invention provides compositions comprising a compound of formula (I) containing one or more chiral centers, where at least 55% (e.g., at least 60%, 65%, 70%, 75%, 80% , 85%, 90% or 95%) of the compound of formula (I) is present as a single optical isomer (e.g., enantiomer or diastereoisomer). In one general embodiment, 99% or more (e.g., substantially all) of the total amount of a compound of formula (I) may be present as a single optical isomer (e.g., enantiomer or diastereoisomer).

Compounds of the present invention include compounds with one or more isotopic substitutions, and reference to a particular element includes all isotopes of that element. For example, a reference to hydrogen includes ¹ H, ² H (D) and ³ H (T). Similarly, references to carbon and oxygen include ¹² C, ¹³ C and ¹⁴ C, and ¹⁶ O and ¹⁸ O, respectively.

Isotopes may be radioactive or non-radioactive. In one embodiment of the present invention, the compounds do not contain any radioactive isotopes. Such compounds are preferably intended for therapeutic use. However, in another embodiment, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful for diagnostic purposes.

Esters such as carboxylic acid esters and acyloxy esters of compounds of formula (I) containing a carboxylic acid group or a hydroxyl group are also encompassed by formula (I). In one embodiment of the present invention, formula (I) includes esters of compounds of formula (I) containing a carboxylic acid group or a hydroxyl group. In another embodiment of the present invention, formula (I) does not include esters of compounds of formula (I) containing a carboxylic acid group or a hydroxyl group. Examples of esters include compounds containing a —C (═O) OR group, where R is an ester substituent, for example a C _1-7 alkyl group, a C _3-20 heterocyclyl group, or a C _5-20 aryl group, preferably a C _1-7 an alkyl group. Specific 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) OPh. Examples of the acyloxy (reversible ester) group are represented by the group —OC (= O) R, where R is an acyloxy substituent, for example a C _1-7 alkyl group, a C _3-20 heterocyclyl group or a C _5-20 aryl group, preferably C _{1 7} alkyl group. Specific examples of acyloxy groups include, but are not limited to, -OC (= O) CH ₃ (acetoxy), -OC (= O) CH ₂ CH ₃ , -OC (= O) C (CH ₃ ) ₃ , -OC (= O) Ph and -OC (= O) CH ₂ Ph.

Formula (I) also encompasses polymorphic forms of compounds, solvates (e.g. hydrates), complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of compounds and prodrugs of compounds. By "prodrugs" is meant, for example, any compound that is converted in vivo to a biologically active compound of formula (I).

For example, some prodrugs are esters of the active compound (for example, a physiologically acceptable metabolically labile ester). In the process of metabolism, the ester group (-C (= O) OR) is cleaved to form an active drug. Such esters can be formed by esterification, for example, of any carboxylic acid group (-C (= O) OH) in the parent compound, with preliminary protection, where appropriate, of any other reactive groups present in the parent compound, followed by deprotection if necessary.

Examples of such metabolically labile esters include esters of the formula —C (═O) OR, where R is:

C _1-7 alkyl (e.g.-Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);

C _1-7 aminoalkyl (e.g. aminoethyl; 2- (N, N-diethylamino) ethyl; 2- (4-morpholino) ethyl); and acyloxy-C _1-7 alkyl (e.g. acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1- (1-methoxy-1-methyl) ethyl-carbonyloxyethyl; 1- (benzoyloxy) ethyl; isopropoxy-carbonyloxymethyl;

1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl;

1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl; 1- (4-tetrahydropyranyloxy) carbonyloxyethyl;

(4-tetrahydropyranyl) carbonyloxymethyl; and 1- (4-tetrahydropyranyl) carbonyloxyethyl).

Also, some prodrugs are activated enzymatically to form an active compound or compound that, through further chemical interactions, gives the active compound (for example, as in antigen-directed enzymatic prodrug therapy (ADEPT), gene-directed enzymatic prodrug therapy (GDEPT) and ligand-directed enzymatic prodrug therapy (LIDEPT), etc.). For example, the prodrug may be a sugar derivative or other glycosidic conjugate, or may be an amino acid ester derivative.

It should be understood that references to “derivatives” include references to ionic forms, salts, solvates, isomers, tautomers, N-oxides, esters, prodrugs, isotopes and their protected forms.

In accordance with one aspect of the present invention, there is provided a compound as defined herein, or a salt, tautomer, N-oxide or solvate thereof.

In accordance with a further aspect of the present invention, there is provided a compound as defined herein, or a salt or solvate thereof.

References to compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) and (If) and the subgroups of such compounds defined herein include salts or solvates or tautomers or N- oxides of compounds.

Tyrosine protein kinases (PTK)

The compounds of the present invention described herein inhibit or modulate the activity of certain tyrosine kinases, and thus, the compounds will be useful for the treatment or prevention of diseases or conditions mediated by such tyrosine kinases, in particular FGFR.

Fgfr

The FGF (fibroblast growth factor) family of tyrosine protein kinase (PTK) receptors regulates a wide range of physiological functions, including mitogenesis, wound healing, cell differentiation and angiogenesis and development. The growth of both normal and malignant cells, as well as proliferation, is affected by changes in the local concentration of FGF, extracellular signaling molecules that act as autocrine as well as paracrine factors. The autocrine signaling activity of FGF can be especially important in the progression of steroid hormone-dependent cancers to a hormone-independent state (Powers, et al. (2000) Endocr. Relat. Cancer, 7, 165-197).

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

Two prototypical members are acidic fibroblast growth factor (aFGF or FGF1) and primary fibroblast growth factor (bFGF or FGF2), and at least twenty different members of the FGF family have been identified to date. The cellular response to FGF is transmitted through four types of high affinity transmembrane tyrosine protein kinase fibroblast growth factor receptors (FGFR), numbered from 1 to 4 (FGFR1-FGFR4). When bound to a ligand, these receptors dimerize and auto- or transphosphorylate specific cytoplasmic tyrosine residues to transmit an intracellular signal, which ultimately regulates the effect of nuclear transcription factor effectors.

Interruption of the FGFR1 pathway affects the proliferation of tumor cells, since this kinase is activated in many types of tumors, in addition to proliferating endothelial cells. Excessive expression and activation of FGFR1 in the tumor-associated vasculature suggests the role of these molecules in tumor angiogenesis.

Fibroblast growth factor receptor 2 has a high affinity for acidic and / or basic fibroblast growth factor, as well as keratinocyte growth factor ligands. The fibroblast growth factor receptor 2 also propagates the strong osteogenic effects of FGF during the growth and differentiation of osteoblasts. Mutations in the receptor for fibroblast growth factor 2, leading to complex functional changes, have been shown to induce abnormal ossification of cranial sutures (craniosynostosis), which indicates the main role of FGFR signal transmission in intramembrane osteogenesis. For example, in Aper syndrome (AP), characterized by premature ossification of the cranial sutures, most cases are associated with point mutations that generate the fibroblast growth factor receptor 2 with acquired function (gain-of-function) (Lemonnier, et al. (2001), J. Bone Miner. Res., 16, 832-845). In addition, a study of mutations in patients with craniosynostosis syndrome shows that severe Pfeiffer syndrome is explained by a series of recurring FGFR2 mutations (Lajeunie et al., European Journal of Human Genetics (2006) 14, 289-298). Specific FGFR2 mutations include W290C, D321A, Y340C, C342R, C342S, C342W, N549H, K641R in FGFR2.

Some severe abnormalities in the development of the human skeleton, including Aper, Cruson, Jackson-Weiss, cutis gyrata Beer-Stevenson and Pfeiffer syndromes, are associated with the occurrence of mutations in the fibroblast growth factor receptor 2. Most, if not all, cases of Pfeiffer syndrome (PS) are also caused de novo mutation of the fibroblast growth factor receptor gene 2 (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 mutations in the fibroblast growth factor receptor 2 destroy one of the cardinal rules governing specific Stu ligands. Namely, two mutant spliced forms of the fibroblast growth factor receptor, FGFR2c and FGFR2b, have acquired the ability to bind to and be activated by atypical FGF ligands. This loss of ligand specificity leads to aberrant signal transduction and suggests that severe phenotypes of these painful syndromes are the result of ectopic ligand-dependent activation of fibroblast growth factor receptor 2 (Yu, et al. (2000), Proc. Natl. Acad. Sci. USA 97, 14536-14541).

Genetic aberrations of the FGFR3 receptor tyrosine kinase, such as chromosomal translocations or point mutations, produce ectopically expressed or unregulated, constitutively active FGFR3 receptors. Such abnormalities are associated with a subgroup of multiple myelomas and carcinomas of the bladder, hepatocellular, squamous cell intraoral carcinomas and cervical carcinomas (Powers, CJ (2000), et al., Endocr. Rel. Cancer, 7, 165; Qiu, W. et. al. (2005), World Journal Gastroenterol, 11 (34)). Accordingly, FGFR3 inhibitors should be useful in the treatment of multiple myeloma, bladder carcinomas and cervical carcinomas. FGFR3 is also overexpressed in bladder cancer, in particular invasive bladder cancer. FGFR3 is often activated as a result of a mutation in urothelial carcinoma (UC) (Journal of Pathology (2007), 213 (1), 91-98). Increased expression was associated with a mutation (85% of mutant tumors showed a high level of expression), but also 42% of tumors without a detectable mutation showed overexpression, including many muscle-invasive tumors.

As such, compounds that inhibit FGFR will be useful in providing agents to prevent the growth or induction of apoptosis in tumors, especially by inhibiting angiogenesis. Therefore, it is expected that the compounds will be useful in the treatment or prevention of proliferative disorders, such as cancers. In particular, tumors with activating mutants of tyrosine kinase receptors or upregulation of tyrosine kinase receptors may be particularly sensitive to inhibitors. Patients with activating mutants of any specific RTK isoform discussed herein can also take treatment with RTK inhibitors as particularly favorable.

Excessive expression of FGFR4 is associated with poor prognosis for prostate and thyroid carcinomas (Ezzat, S., et al. (2002) The Journal of Clinical Investigation, 109, 1; Wang et al. (2004) Clinical Cancer Research, 10). In addition, germ cell line polymorphism (Gly388Arg) has been associated with an increased incidence of lung, breast, colon and prostate cancers (Wang et al. (2004) Clinical Cancer Research, 10). In addition, it was also found that a truncated form of FGFR4 (including the kinase domain) is present in 40% of pituitary tumors, but is not present in normal tissue.

Recent studies have shown a relationship between FGFR1 expression and oncogenicity in Classical Lobular Carcinomas (CLC). CLCs make up 10-15% of all breast cancers, and, as a rule, they lack p53 and Her2 expression, while the expression of estrogen receptor is preserved. Amplification of the 8p12-p11.2 gene was demonstrated in ~ 50% of cases of CLC, and it was shown that this is associated with increased expression of FGFR1. Preliminary studies using siRNA directed against FGFR1 or a small molecule of a receptor inhibitor showed that cell lines containing 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, is possibly the result of abnormal proliferation and differentiation during skeletal myogenesis. Overexpression of FGFR1 occurs in primary rhabdomyosarcomas and is associated with hypomethylation of the 5'CpG island and abnormal expression of the AKT1, NOG, and BMP4 genes (Genes, Chromosomes & Cancer (2007), 46 (11), 1028-1038).

Fibrous conditions are a serious medical problem that occurs as a result of abnormal or excessive deposition of fibrous tissue. This occurs in many diseases, including cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, as well as the natural healing process of wounds. The mechanisms of pathological fibrosis are not fully understood, but they believe that this is the result of various cytokines (including tumor necrosis factor (TNF), fibroblast growth factors (FGF), platelet-derived growth factor (PDGF), and transforming growth factor beta). (TGFβ) is involved in the proliferation of fibroblasts and the deposition of extracellular matrix proteins (including collagen and fibronectin). This results in a change in the structure and function of the tissue and subsequent pathology.

Various preclinical trials have demonstrated increased regulation of fibroblast growth factors in preclinical models of pulmonary fibrosis (Inoue, et al. (1997 &2002); Barrios, et al. (1997)). TGFβ1 and PDGF have been reported to be involved in the fibrogenic process (Atamas & White, 2003 review), and another publication suggests that an increase in FGF's levels and the associated increase in fibroblast proliferation may occur in response to elevated levels of TGFβ1 (Khalil, et al ., 2005). The potential therapeutic relevance of this pathway in fibrotic conditions is suggested in the report of the clinical effect of pirfenidone (Arata, et al., 2005) in idiopathic pulmonary fibrosis (IPF).

Idiopathic pulmonary fibrosis (also called cryptogenic fibrosing alveolitis) is a progressive condition involving shrinkage of the lung. Gradually, the alveolar sacs of the lungs are replaced by fibrous tissue, which thickens, causing an irreversible loss of tissue's ability to transfer oxygen to the bloodstream. Symptoms of this condition include shortness of breath, chronic dry cough, weakness, chest pain and loss of appetite, resulting in rapid weight loss. This condition is extremely serious, with approximately 50% mortality after 5 years.

Vascular Endothelial Growth Factor (VEGFR)

Chronic proliferative diseases are often accompanied by severe angiogenesis, which can support or contribute to the inflammatory and / or proliferative state, or which 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).

The term “angiogenesis” is generally used to describe the development of new or replacement blood vessels or neovascularization. This is a necessary and physiologically normal process by which the formation of the vasculature in the embryo occurs. Angiogenesis, as a rule, does not occur in most normal adult tissues, with the exception of areas of ovulation, menstruation and wound healing. Many diseases, however, are characterized by persistent and increased angiogenesis. For example, in arthritis, new capillary blood vessels extend into the joint and destroy cartilage (Colville-Nash and Scott (1992), Ann. Rhum. Dis., 51, 919). In diabetes (and many different eye diseases), new vessels extend into the spot or retina or other structures of the eye and can lead to blindness (Brooks, et al. (1994) Cell, 79, 1157). The process of atherosclerosis is associated with angiogenesis (Kahlon, et al. (1992) Can. J. Cardiol., 8, 60). Tumor growth and metastases 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 the role of angiogenesis in underlying diseases has been accompanied by studies aimed at identifying and developing angiogenesis inhibitors. These inhibitors are generally classified according to specific targets in the cascade of angiogenesis, such as activation of endothelial cells by an angiogenic signal; synthesis and release of cleaving enzymes, migration of endothelial cells, proliferation of endothelial cells and the formation of capillary vessels. Therefore, angiogenesis takes place at many stages, and attempts are made to find and develop compounds that work as blockers of angiogenesis at these various stages.

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

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

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

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

Of particular interest is VEGFR-2, which is a transmembrane PTK receptor expressed primarily in endothelial cells. Activation of VEGFR-2 by VEGF is a critical step in the signal transduction pathway that initiates tumor angiogenesis. VEGF expression may be constitutive for tumor cells and may also be activated in response to certain stimuli. One such stimulus is hypoxia, where VEGF expression is activated in both tumor and associated host tissues. The VEGF ligand activates VEGFR-2 by binding to its extracellular VEGF binding site. This leads to dimerization of VEGFR receptors and autophosphorylation of tyrosine residues on the intracellular kinase domain of VEGFR-2. The kinase domain performs the function of transferring phosphate from ATP to tyrosine residues, thus providing binding sites for signal proteins below VEGFR-2, resulting in initiation of angiogenesis (McMahon, G. (2000), The Oncologist, 5 (90001), 3-10).

Inhibition of VEGFR-2 at the kinase domain binding site blocks the phosphorylation of tyrosine residues and serves to interrupt the initiation of angiogenesis.

Angiogenesis is a physiological process of the formation of new blood vessels, mediated by various cytokines, which are called angiogenic factors. Although its potential pathophysiological role in solid tumors has been extensively studied for more than 3 decades, increased angiogenesis in chronic lymphocytic leukemia (CLL) and other malignant hematologic disorders has only recently been recognized. An increased level of angiogenesis has been documented using various experimental methods in both the bone marrow and lymph nodes of patients with CLL. Although the role of angiogenesis in the pathophysiology of this disease has not yet been fully elucidated, experimental data suggest that several angiogenic factors play a role in the progression of the disease. Biological markers of angiogenesis have also been shown to be prognostic in CLL. This shows that VEGFR inhibitors may also be beneficial for patients with leukemia, such as CLL.

In order for the tumor mass to reach a size higher than critical, it must develop a vasculature connected with it. It has been suggested that targeted action on the vasculature of a tumor may limit the spread of the tumor and may be useful for treating cancer. Observations of the growth of tumors showed that tumors with a small mass can be stably present in the tissue without any tumor-specific vasculature. The arrest of nevascularized tumors is attributed to the effects of hypoxia in the center of the tumor. Recently, various pro-angiogenic and anti-angiogenic factors have been identified, and the concept of “angiogenic switching” has appeared, a process in which a violation of the normal ratio of angiogenic stimuli and inhibitors in the tumor mass makes autonomous vascularization possible. As it turned out, angiogenic switching is controlled by the same genetic changes that drive the malignant transformation: activation of oncogenes and loss of tumor suppressor genes. Some growth factors act as positive regulators of angiogenesis. The main factors include vascular endothelial growth factor (VEGF), major fibroblast growth factor (bFGF), and angiogenin. Proteins, such as thrombospondin (Tsp-1), angiostatin and endostatin, act as negative regulators of angiogenesis.

Inhibition of VEGFR2, but not VEGFR1, significantly interrupts angiogenic switching, persistent angiogenesis, and initial tumor growth in a mouse model. In the late stages of tumors, phenotypic resistance to VEGFR2 blockade arises, since tumors resume growth during treatment after the initial period of growth suppression. This resistance to VEGF blockade includes reactivation of tumor angiogenesis independent of VEGF and associated with hypoxia-mediated induction of other pro-angiogenic factors, including members of the FGF family. These other pro-angiogenic signals are functionally involved in revascularization and resumption of tumor growth in the deflection phase, since FGF blockade disrupts progression in light of VEGF inhibition. Inhibition of VEGFR2, but not VEGFR1, significantly interrupts angiogenic switching, persistent angiogenesis, and initial tumor growth. In the late stages of tumors, phenotypic resistance to VEGFR2 blockade arises, since tumors resume growth during treatment after the initial period of growth suppression. This resistance to VEGF blockade includes reactivation of tumor angiogenesis independent of VEGF and associated with hypoxia-mediated induction of other pro-angiogenic factors, including members of the FGF family. These other pro-angiogenic signals are functionally involved in revascularization and resumption of tumor growth in the deflection phase, since FGF blockade disrupts progression in light of VEGF inhibition.

It was previously reported that FGF-trap adenovirus binds to and blocks various ligands of the FGF family, including FGF1, FGF3, FGF7 and FGF10, thus effectively inhibiting angiogenesis in vitro and in vivo. Indeed, the addition of FGF-trap treatment in the phase of resumption of growth in the mouse model provided a significant decrease in tumor growth compared to using only anti-VEGFR2. This decrease in tumor load was carried out by reducing angiogenesis, which was observed as a decrease in intratumoral density of blood vessels.

Batchelor et al. (Batchelor et al., 2007, Cancer Cell, 11 (1), 83-95) provide evidence of normalization of the blood vessels of glioblastoma in patients who were treated with the pan-VEGF receptor tyrosine kinase inhibitor, AZD2171, in a phase 2 study. The rationale for using AZD2171 was based in part on results showing a decrease in perfusion and vascular density in an in vivo model of breast cancer (Miller et al., 2006, Clin. Cancer Res. 12, 281-288). In addition, using the orthotopic glioma model, the optimal time window for the delivery of anti-VEGFR2 antibodies to achieve a synergistic effect with radiation was previously determined. In the normalization window, improved oxygenation, increased pericytic coating, and activation of angiopoietin-1 were observed, leading to a decrease in interstitial pressure and tumor permeability (Winkler et al., 2004, Cancer Cell 6, 553-563). The normalization window can be quantified by magnetic resonance imaging (MRI) using MRI gradient echo, spin echo and contrast enhancement to measure blood volume, vascular size, and vascular permeability.

The authors showed that progression with AZD2171 treatment was associated with increased levels of CEC, SDF1 and FGF2, while progression after drug intervention was correlated with increased levels of circulating progenitor cells (CPC) and plasma FGF2 levels. An increase in plasma levels of SDF1 and FGF2 correlated with MRI measurements showing an increase in vascular density and size. Thus, the MRI definition of vascular normalization in combination with circulating biomarkers provides an effective tool for assessing the response to antiangiogenic agents.

PDGFR

A malignant tumor is a product of uncontrolled cell proliferation. Cellular growth is controlled by a delicate balance between growth promoting and growth inhibiting factors. In normal tissue, the production and activity of these factors leads to differentiated cell growth in a controlled and regulated manner, which maintains the normal integrity and functioning of the organ. The malignant cell evades this control; the natural balance is disturbed (through various mechanisms) and activated aberrant cell growth occurs. A growth factor that plays an important role in tumor development is platelet-derived growth factor (PDGF), which includes a family of peptide growth factors that transmit signals through cell surface tyrosine kinase receptors (PDGFRs) and stimulate a variety of cellular functions, including growth, proliferation and differentiation. PDGF expression has been demonstrated in a number of different solid tumors, including glioblastomas and prostate carcinomas. The tyrosine kinase inhibitor imatinib mesylate, which has the chemical name 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3-pyridinyl) -2-ylpyridinyl] amino] - phenyl] benzamide methanesulfonate blocks the activity of Oncoprotein Bcr-Abl and the c-Kit cell surface tyrosine kinase receptor and, as such, is approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib mesylate is also a potent inhibitor of PDGFR kinase and is currently being evaluated for the treatment of chronic myelomonocytic leukemia and glioblastoma multiforme, based on evidence that activating mutations in PDGFR occur in these diseases. In addition, sorafenib (BAY 43-9006), which has the chemical name 4- (4- (3- (4-chloro-3 (trifluoromethyl) phenyl) ureido) phenoxy) -N2-methylpyridin-2-carboxamide, specifically acts as to the Raf signaling pathway for inhibiting cell proliferation; and to the VEGFR / PDGFR signaling cascades for inhibiting tumor angiogenesis. Sorafenib is undergoing research to treat a number of cancers, including liver and kidney cancer.

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

Benefits of Selective Inhibitor

The development of inhibitors of FGFR kinases with a differentiated selectivity profile provides a new opportunity for the use of these targeted drugs in subgroups of patients where the disease is controlled by impaired regulation of FGFR. Compounds that exhibit a reduced inhibitory effect on additional kinases, in particular VEGFR2 and PDGFR-beta, provide a differentiated profile of side effects or toxicity and, as such, provide the possibility of more effective treatment of these indications. VEGFR2 and PDGFR-beta inhibitors are associated with toxicity, such as hypertension or edema, respectively. In the case of VEGFR2 inhibitors, such a hypertensive effect is often dose-limiting, may be contraindicated for some groups of patients, and requires clinical regulation.

Biological activity and therapeutic applications

The compounds of the present invention and subgroups of such compounds have an activity of inhibiting or modulating a fibroblast growth factor receptor (FGFR) and / or a vascular endothelial growth factor receptor (VEGFR), an activity of inhibiting or modulating a platelet-derived growth factor receptor (PDGFR), and will be useful for prevention or treatment of diseases or conditions described in this application. In addition, the compounds of the present invention and subgroups of such compounds will be useful for the prevention or treatment of diseases or conditions mediated by kinases. References to the prevention or prevention or treatment of a disease or condition such as cancer include alleviating or reducing the incidence of cancer.

As used herein, the term “modulation”, as applied to kinase activity, means a change in the level of biological activity of a protein kinase. Thus, modulation encompasses physiological changes that affect the increase or decrease in the activity of the corresponding protein kinase. In the latter case, modulation can be described as "inhibition." Modulation can occur directly or indirectly and can be mediated by any mechanism and at any physiological level, including, for example, the level of gene expression (including, for example, transcription, translation and / or post-translational modification), at the level of expression of genes encoding regulatory elements that act directly or indirectly on kinase activity levels. Thus, modulation may mean increased / decreased expression or over or under kinase expression, including gene amplification (i.e. multiple copies of genes) and / or increased or decreased expression through a transcriptional effect, as well as hyper- (or hypo) activity and (de) activation of protein kinases (protein kinases) (including (de) activation as a result of mutations (mutations)). The terms “modulated”, “modulation” and “modulate” should be interpreted accordingly.

As used in this application, the term "mediated", as used, for example, in connection with a kinase, as described in this application (and applicable, for example, to various physiological processes, diseases, conditions, therapies, treatments or interventions), is intended for limited use, to indicate that the various processes, diseases, conditions, treatments, and interventions to which this term applies are those where the kinase plays a biological role. In cases where the term is applied to a disease or condition, the biological role played by the kinase may be direct or indirect and may be necessary and / or sufficient to manifest the symptoms of the disease or condition (or its etiology or progression). Thus, kinase activity (and, in particular, aberrant levels of kinase activity, for example, over-expression of kinase) does not have to be the direct cause of the disease or condition: it is more likely that kinase-mediated diseases or conditions include those that have multifactorial etiologies and complex development , where the kinase in question takes only partial participation. In cases where the term is used for treatment, prophylaxis or intervention, the role played by the kinase may be direct or indirect and may be necessary and / or sufficient for the effect of the treatment, prophylaxis or result of the intervention. Thus, a disease or condition mediated by a kinase includes the development of resistance to any particular anti-cancer drug or cancer treatment.

For example, it is contemplated that the compounds of the present invention will be useful in alleviating or reducing the incidence of cancer.

More specifically, the compounds of formula (I) and subgroups of such compounds are FGFR inhibitors. For example, the compounds of the present invention have activity against FGFR1, FGFR2, FGFR3 and / or FGFR4 and, in particular, FGFR 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 present invention are those which have IC ₅₀ values of less than 0.1 μM.

The compounds of the present invention also have anti-VEGFR activity.

The compounds of the present 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 compounds of the present invention exhibit selectivity for FGFR1, 2 and / or 3 kinases and / or FGFR4 compared to VEGFR (in particular VEGFR2) and / or PDGFR, and such compounds represent one preferred embodiment of the present invention . In particular, the compounds exhibit selectivity for VEGFR2. For example, many compounds of the present invention have IC ₅₀ values against FGFR1,2 and / or 3 and / or FGFR4, which are a tenth to a hundredth of an IC ₅₀ value against VEGFR (in particular VEGFR2) and / or PDGFR B. In particular, preferred compounds of the present invention have at least 10 times greater activity against, or inhibition of, FGFR, in particular FGFR1, FGFR2, FGFR3 and / or FGFR4, compared to VEGFR2. More preferably, the compounds of the present invention have at least 100 times greater activity against, or inhibition of, FGFR, in particular FGFR1, FGFR2, FGFR3 and / or FGFR4, compared to VEGFR2. This can be determined using the methods described in this application.

As a result of their activity in modulating or inhibiting FGFR, VEGFR and / or PDGFR kinases, the compounds will be useful in providing a means of preventing the growth or induction of tumor apoptosis, in particular by inhibiting angiogenesis. Therefore, it is expected that the compounds will be useful for the treatment or prevention of proliferative disorders such as cancer. In addition, the compounds of the present invention could be useful in the treatment of diseases in which proliferation, apoptosis or differentiation is impaired.

In particular, tumors with activating VEGFR mutants or activation of VEGFR and patients with elevated serum lactate dehydrogenase levels may be especially sensitive to the compounds of the present invention. Patients with activating mutants of any of the specific RTK isoforms discussed herein can also take treatment with RTK inhibitors as particularly favorable. For example, over-expression of VEGFR in acute leukemia cells, where the clonal precursor can express VEGFR. Also, specific tumors with activating mutants or activation or over-expression of any of the FGFR isoforms, such as FGFR1, FGFR2, or FGFR3, or FGFR4, may be particularly sensitive to the compounds of the present invention, and thus patients as discussed herein with specific tumors, the application may also take treatment with RTK inhibitors as particularly favorable. It may be preferable when the treatment is associated with or directed to the mutant form of one of the tyrosine kinase receptors, such as those discussed in this application. Diagnosis of tumors with such mutations can be carried out using methods known to specialists in this field, and those described in this application, for example RTPCR and FISH.

Examples of cancers that can be treated (or inhibited) include, but are not limited to, carcinoma, such as carcinoma of the bladder, breast, colon (e.g. colorectal carcinoma, such as colon adenocarcinoma and colon adenoma), kidneys, epidermis, liver, lung, such as adenocarcinoma, small cell lung cancer, and non-small cell carcinomas of the lung, esophagus, gall bladder, ovary, pancreas, such as exocrine carcinoma of the pancreas, stomach, cervix and, endometrium, thyroid, prostate or skin, for example squamous cell carcinoma; a hematopoietic tumor of the lymphoid line, for example, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, fibrous cell lymphoma or Berket's lymphoma; a hematopoietic tumor of the myelogenous line, such as leukemia, acute and chronic myelogenous leukemia, myeloproliferative syndrome, myelodysplastic syndrome or promyelocytic leukemia; multiple myeloma; follicular thyroid cancer; a tumor of mesenchymal origin, for example fibrosarcoma or rhabdomyosarcoma; a tumor of the central or peripheral nervous system, for example, astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; Xeroderma pigmentosa; keratocanthantom; follicular thyroid cancer or Kaposi’s sarcoma.

Some cancers are drug resistant drugs. This may be caused by a type of tumor or may result from treatment with a compound. In this regard, references to multiple myeloma include bortezomib-sensitive multiple myeloma or refractory multiple myeloma. Similarly, references to chronic myelogenous leukemia include imitanib-sensitive chronic myelogenous leukemia and refractory chronic myelogenous leukemia. Chronic myelogenous leukemia is also known as chronic myeloid leukemia, chronic granulocytic leukemia, or CML. Similarly, acute myelogenous leukemia is also called acute myeloid leukemia, acute granulocytic leukemia, acute non-lymphocytic leukemia, or AML.

The compounds of the present invention can also be used to treat hematopoietic diseases with abnormal cell proliferation, precancerous or stable, such as myeloproliferative diseases. Myeloproliferative diseases ("MPD") are a group of bone marrow diseases where an excess of cells is produced. They are associated with myelodysplastic syndrome and can develop into myelodysplastic syndrome. Myeloproliferative diseases include true polycythemia, essential thrombocythemia, and primary myelofibrosis.

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

Other T-cell lymphoproliferative diseases include diseases originating from natural killer cells. The term B-cell lymphoma includes diffuse large-B-cell lymphoma.

In addition, the compounds of the present invention can be used in gastrointestinal (also known as gastric) cancer, for example gastrointestinal stromal tumors. Gastrointestinal cancer refers to malignant conditions of the gastrointestinal tract, including the esophagus, stomach, liver, bile system, pancreas, intestines and anus.

Another example of a tumor of mesenchymal origin is Ering's sarcoma.

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

Specific subgroups of cancer include multiple myeloma, bladder carcinomas, cervical, prostate and thyroid glands, lung, breast and colon cancers.

The following subgroup of cancers includes multiple myeloma, bladder carcinomas, hepatocellular, oral squamous cell carcinoma, and cervical carcinomas.

Another subgroup of cancers includes multiple myeloma, bladder carcinomas and cervical carcinomas.

In addition, it is contemplated that a compound of the present invention having FGFR inhibitory activity, such as FGFR1, will be particularly useful for the treatment or prophylaxis of breast cancer, in particular classic lobular carcinomas (CLC).

Since the compounds of the present invention are active against FGFR4, they will also be useful in the treatment of prostate cancer or pituitary gland.

In particular, the compounds of the present invention as FGFR inhibitors are useful for the treatment of multiple myeloma, myeloproliferative disorders, endometrial cancer, prostate cancer, bladder cancer, lung cancer, ovarian cancer, breast cancer, gastric cancer, colorectal cancer and oral squamous cell carcinoma.

The following subgroups of cancers are multiple myeloma, endometrial cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer, colorectal cancer, and thyroid carcinomas.

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

In particular, the compounds are useful for the treatment of lobular carcinomas, such as CLC (classical lobular carcinoma).

Since the compounds have anti-FGFR3 activity, they will be useful in treating multiple bladder myeloma.

In particular, the compounds are useful for treating t (4; 14) translocation-positive multiple myeloma.

Since the compounds have activity against FGFR2, they will be useful for the treatment of endometrial cancer, ovarian cancer, gastric and colorectal cancer. FGFR2 is also overexpressed in epithelial ovarian cancer, therefore, the compounds of the present invention can be particularly useful for treating ovarian cancer, such as epithelial ovarian cancer.

The compounds of the present invention may also be useful for treating tumors that have previously been treated with a VEGFR2 inhibitor or a VEGFR2 antibody (e.g., Avastin).

In particular, the compounds of the present invention may be useful for the treatment of VEGFR2-resistant tumors. VEGFR2 inhibitors and antibodies are used to treat thyroid carcinoma and renal cell carcinoma, therefore, the compounds of the present invention may be useful for the treatment of VEGFR2-resistant thyroid carcinoma and renal cell carcinoma.

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

Whether or not a particular cancer is susceptible to inhibition of FGFR, VEGFR or PDGFR, signaling activity can be determined by cell growth analysis as described in Examples 79 and 80 below, or by the method described in the section entitled “Diagnostic Methods”.

It is also contemplated that the compounds of the present invention, and in particular those having FGFR, VEGFR, or PDGFR inhibitory activity, will be particularly useful for treating or preventing cancer — a type associated with or characterized by elevated levels of FGFR, VEGFR or PDGFR, for example cancer, indicated in this context in the introductory part of this application.

It has been found that some FGFR inhibitors can be used in combination with other anti-cancer agents. For example, a combination of an inhibitor that induces apoptosis with another agent that acts through a different mechanism to regulate cell growth can provide a favorable result, thus treating two of the characteristic signs of cancer. Examples of such combinations are described below.

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

One subgroup of diseases and conditions for which, as provided, the compounds of the present invention will be useful, consists of inflammatory diseases, cardiovascular diseases and wound healing.

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

In addition, FGFR2 mutations are associated with some serious disorders in the development of the human skeleton, and thus, the compounds of the present invention could be useful for treating disorders of the development of the human skeleton, including abnormal ossification of cranial sutures (craniosynostosis), Aper syndrome (AR), Cruson syndrome, Jackson-Weiss syndrome, Beer-Stevenson cutis gyrata syndrome and Pfeiffer syndrome.

It is also contemplated that a compound of the present invention having FGFR inhibitory activity, such as FGFR2 or FGFR3, will be particularly useful for the treatment or prevention of skeletal diseases. Specific skeletal diseases are achondroplasia or lethal dwarfism (also known as lethal dysplasia).

In addition, it is contemplated that a compound of the present invention having FGFR inhibitory activity, such as FGFR1, FGFR2, or FGFR3, will be particularly useful for treating or preventing pathologies in which progressive fibrosis is a symptom. Fibrous conditions for the treatment of which the compounds of the present invention may be useful include diseases in which abnormal or excessive deposition of fibrous tissue occurs, for example cirrhosis of the liver, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, as well as the natural healing process of wounds. In particular, the compounds of the present invention may also be useful in the treatment of pulmonary fibrosis, in particular idiopathic pulmonary fibrosis.

Excessive expression and activation of FGFR and VEGFR in the tumor-associated vasculature also suggests the role of the compounds of the present invention in the prevention and interruption of the onset of tumor angiogenesis. In particular, the compounds of the present invention may be useful for the treatment of cancer, metastases, leukemia, such as CLL, eye diseases such as age-related macular degeneration, especially wet forms of age-related macular degeneration, ischemic proliferative retinopathies, such as early retinopathy (ROP ) and diabetic retinopathy, rheumatoid arthritis and hemangiomas.

Since the compounds of the present invention inhibit PDGFR, they can also be useful for the treatment of a number of tumors and leukemias, including glioblastomas, such as glioblastoma multiforme, prostate carcinomas, gastrointestinal stromal tumors, liver cancer, kidney cancer, chronic myelogenous leukemia, chronic myelomonocytic leukemia (CMML), as well as hypereosinophilic syndrome, a rare proliferative hematological disorder and tuberous dermatofibrosarcoma, an infiltrating skin tumor.

The activity of the compounds of the present invention as inhibitors of FGFR1-4, VEGFR and / or PDGFR A / B can be measured using the assays described in the examples below, and the level of activity exhibited by a particular compound can be determined as an IC ₅₀ value. Preferred compounds of the present invention are compounds having an IC ₅₀ value of less than 1 μM, more preferably less than 0.1 μM.

The present invention provides compounds that have FGFR inhibition or modulation activity and which are believed to be useful in the prevention or treatment of diseases or conditions mediated by FGFR kinases.

In one embodiment, a compound as defined herein is provided for use in therapy. In a further embodiment, a compound as defined herein is provided for use in the prophylaxis or treatment of a disease or condition mediated by an FGFR kinase.

For example, it is contemplated that the compounds of the present invention will be useful in alleviating or reducing the incidence of cancer.

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

In one embodiment, the invention provides the use of a compound as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a disease or condition described herein.

In a further embodiment, the use of a compound defined herein is provided for the manufacture of a medicament for the prevention or treatment of cancer.

Accordingly, the present invention provides, inter alia:

a method for preventing or treating a disease or condition mediated by an FGFR kinase, the method comprising administering to a subject in need thereof a compound of formula (I) as defined herein.

In one embodiment, a method is provided for preventing or treating a disease or condition described herein, the method comprising administering to a subject in need thereof a compound of formula (I) as defined herein.

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

A method of alleviating or reducing the incidence of diseases or conditions mediated by the FGFR kinase, the method comprising administering to a subject in need thereof a compound of formula (I) as defined herein.

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

A method for modulating a cellular process (e.g., cell division) by inhibiting the activity of 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 FGFR kinase.

A compound of formula (I) as defined herein for use as a modulator (eg, inhibitor) of FGFR.

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

The use of a compound of formula (I), as defined herein, for the manufacture of a medicament for modulating a cell process (e.g., cell division) by inhibiting the activity of 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 increased regulation of FGFR kinase (e.g., FGFR1, or FGFR2, or FGFR3, or FGFR4).

The use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prevention or treatment of cancer, wherein the cancer is a cancer of the type characterized by increased regulation of FGFR kinase (e.g., FGFR1, or FGFR2, or FGFR3, or FGFR4) .

Use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prevention or treatment of cancer in a patient selected from a subpopulation having genetic aberrations of the FGFR3 kinase.

The use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prevention or treatment of cancer in a patient who, according to the diagnosis, is part of a subpopulation having genetic aberrations of the FGFR3 kinase.

A method for preventing or treating a disease or condition characterized by increased regulation of FGFR kinase (e.g., FGFR1, or FGFR2, or FGFR3, or FGFR4), the method comprising administering a compound of formula (I) as defined herein.

A method of alleviating or reducing the incidence of diseases or conditions characterized by increased regulation of 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 preventing or treating (alleviating or reducing the incidence) of cancer in a patient suffering from or suspected of having cancer; wherein the method includes (i) passing the patient a diagnostic test to determine whether the patient has genetic aberrations of the FGFR3 gene; and (ii) thereafter, if the patient does not have this option, administering to the patient a compound of formula (I) as defined herein having FGFR3 kinase inhibitory activity.

A method for preventing or treating (alleviating or reducing the number of cases) a disease or condition characterized by increased regulation of FGFR kinase (eg, FGFR1, or FGFR2, or FGFR3, or FGFR4); wherein the method includes (i) a patient undergoing a diagnostic study to detect a marker that is indicative of the activation of the FGFR kinase (e.g., FGFR1, or FGFR2, or FGFR3, or FGFR4), and (ii) thereafter, if the diagnostic study shows activation of FGFR kinases, administering to a patient a compound of formula (I) as defined herein having FGFR kinase inhibitory activity.

Mutant Kinases

Drug-resistant kinase mutations can occur in patients who have been treated with kinase inhibitors. This occurs, in part, in portions of a protein that binds to or interacts with a specific inhibitor used in therapy. Such mutations decrease or increase the ability of an inhibitor to bind to and inhibit a kinase of interest. This can occur on any of the amino acid residues that interact with the inhibitor or are important for maintaining the binding of the indicated inhibitor to the target. An inhibitor that binds to a target kinase without requiring interaction with a mutated amino acid residue will most likely not be affected by the mutation and will remain an effective enzyme inhibitor (Carter et al. (2005), PNAS, 102 (31), 11011-110116).

There are mutations that have been observed in PDGFR in patients treated with imatinib, in particular the T674I mutation. The clinical significance of these mutations can increase significantly, since, as it now turns out, they represent the main mechanism of resistance to src / Abl inhibitors in patients.

In addition, there are chromosomal translocations or point mutations that have been observed in FGFR that cause gain-of-function, are overexpressed, or cause constitutively active biological states.

The compounds of the present invention, therefore, may be particularly applicable to cancers that express a mutated molecular target, such as FGFR or PDGFR, including PDGFR-beta and PDGFR-alpha, in particular the T674I PDGFR mutation. The diagnosis of tumors with such mutations can be carried out using methods known to specialists in this field and those described in this application, for example RTPCR and FISH.

It has been suggested that mutations of the conserved threonine residue at the ATP binding site in FGFR will lead to resistance to the inhibitor. The amino acid Valin 561 mutated to methionine in FGFR1, which corresponds to the previously described mutations found in AbI (T315) and EGFR (T766), which have been shown to confer resistance to selective inhibitors. Analytical data for FGFR1 V561M showed that this mutation reported resistance to a tyrosine kinase inhibitor, in contrast to the wild type.

Pharmaceutical Compositions

Although it is possible to administer only the active compound, it is preferable when it is presented in the form of a pharmaceutical composition (eg, composition) comprising at least one active compound of the present invention together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, excipients buffers, stabilizers, preservatives, lubricants or other substances well known to specialists in this field, and optionally other therapeutic or other prophylactically means.

Thus, the present invention also provides pharmaceutical compositions, as described above, and methods for producing a pharmaceutical composition, comprising admixing at least one active compound as defined above, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers or other substances described in this application.

The term "pharmaceutically acceptable", as used herein, refers to compounds, substances, compositions and / or dosage forms which, according to a weighted medical assessment, being suitable for use in contact with the tissues of a subject (eg, human) without excessive toxicity, irritations, allergic reactions, or other problems or complications correspond to a reasonable benefit / risk ratio. Each carrier, excipient, etc. should also be "acceptable" in the sense that it must be compatible with other ingredients of the composition.

Formulation of pharmaceutical compositions containing compounds of formula (I) can be carried out in accordance with known methods, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

Accordingly, in a further aspect, the present invention provides compounds of formula (I) and subgroups of such compounds as defined herein in the form of pharmaceutical compositions.

The pharmaceutical compositions may be in any form suitable for oral, parenteral, topical, intranasal, intraocular, intraocular, rectal, intravaginal or transdermal administration. When the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration, or for direct delivery to the target organ or tissue by injection, infusion, or other delivery means. Delivery can be accomplished by bolus injection, short-term infusion or continuous infusion, and it can be accomplished by passive delivery or using a suitable infusion pump.

Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostatic substances, cosolvents, organic solvent mixtures, cyclodextrin complexing agents, emulsifiers (for the formation and stabilization of emulsion compositions), liposome components for liposome formations, gelling polymers for the formation of polymer gels, protective substances for lyophilization and combinations of substances for, among other things, stabilizing the active ingredient in a soluble form and making the composition isotonic with the blood of the intended recipient. Pharmaceutical compositions for parenteral administration may also take the form of aqueous and non-aqueous sterile 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 spheroidal vesicles consisting of external lipid bilayer membranes and an internal aqueous core, and have a total diameter of <100 μm. Depending on the level of hydrophobicity, moderately hydrophobic drugs can be solubilized by liposomes if the drug is encapsulated or included in the liposome. Hydrophobic drugs can also be solubilized by liposomes if the drug molecule becomes part of the whole with the lipid bilayer membrane, in which case the hydrophobic drug is dissolved in the lipid part of the lipid bilayer.

The compositions may be presented in single dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored as a freeze-dried (lyophilized) product requiring only the addition of a sterile liquid carrier, for example water for injection, immediately before use.

A pharmaceutical composition can be prepared by lyophilization of a compound of formula (I) or a subgroup of such compounds. Lyophilization refers to the procedure of drying a composition by freezing. Therefore, freeze drying and lyophilization are used in this application as synonyms.

Solutions and suspensions for injection can be obtained in situ from sterile powders, granules and tablets.

The pharmaceutical compositions of the present invention for parenteral injection also include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols (such as glycerin, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures of such substances, vegetable oils (such as olive oil) and organic esters for injection, such as ethyl oleate. The necessary fluidity, for example, can be maintained by the use of coating agents, such as lecithin, while maintaining the required particle size in the case of dispersions, and by the use of surfactants.

The compositions of the present invention may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersing agents. Prevention of the action of microorganisms can be achieved by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenolsorbic acid, etc. It may also be desirable to include isotonic substances such as sugars, sodium chloride, and the like. Prolonged absorption of the pharmaceutical form for injection can be obtained by the inclusion of substances that slow down absorption, such as aluminum monostearate and gelatin.

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

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

Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, cachets or patches, as well as buccal patches.

Thus, tablet compositions may contain a unit dose of the active compound together with an inert diluent or carrier, such as sugar or sugar alcohol, for example lactose, sucrose, sorbitol or mannitol; and / or a non-sugar based diluent, such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or a derivative thereof, such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches, such as corn starch. Tablets may also contain standard ingredients such as binders and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g., swellable crosslinked polymers, such as crosslinked carboxymethylcellulose), lubricants (e.g. stearates), preservatives (e.g. parabens), antioxidants ( e.g. BHT), buffering agents (e.g. phosphate or citrate buffers) and effervescent substances such as citrate / bicarbonate mixtures. Such excipients are well known and do not require detailed discussion in this application.

Capsule compositions may be hard gelatin or soft gelatin capsule formulations and may contain the active ingredient in solid, semi-solid or liquid form. Gelatin capsules can be obtained from animal gelatin or its synthetic or vegetable equivalents.

Solid dosage forms (e.g., tablets, capsules, etc.) may be coated or uncoated, but typically have a coating, for example a protective film coating (e.g., wax or varnish) or a release control coating. The coating (for example, the type of polymer Eudragit ™) can be designed in such a way as to release the active component in the desired area of the gastrointestinal tract. Thus, the coating can be selected so that it decomposes under certain pH conditions in the gastrointestinal tract, with selective release in this way of the compound in the stomach, or in the ileum, or in the duodenum.

Instead of, or in addition to, coatings, the drug can be presented in a solid matrix comprising a release controlling substance, for example a slowing release substance that can be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or the release retardant coating may be in the form of a degradable polymer (for example, maleic anhydride polymer), which essentially breaks down as the dosage form passes through the gastrointestinal tract. As a further alternative, the active compound can be formulated into a delivery system that provides osmotic control of the release of the compound. Compositions with osmotic release and other delayed release or delayed release can be obtained in accordance with methods well known to specialists in this field.

Pharmaceutical compositions comprise from about 1% to about 95%, preferably from about 20% to about 90%, of the active ingredient. The pharmaceutical compositions in accordance with the present invention can be presented, for example, in unit dosage form, for example, in the form of ampoules, vials, suppositories, dragees, tablets or capsules.

Pharmaceutical compositions for oral administration can be prepared by combining the active ingredient with solid carriers, if desired, granulating the resulting mixture and processing the mixture, if desired or necessary, after adding suitable excipients to tablets, dragee cores or capsules. It is also possible to incorporate them into plastic carriers that allow diffusion or release of the active ingredients in measured amounts.

The compounds of the present invention can also be formulated as solid dispersions. Solid dispersions are homogeneous, extremely finely divided phases of two or more solids. Solid solutions (molecular dispersion systems), one 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 for increasing the dissolution rate and increasing the bioavailability of poorly water-soluble drugs.

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

The pharmaceutical compositions may be provided to patients in a “patient package” containing a complete course of treatment in one package, usually in a blister pack. Patient packs have an advantage over traditional prescription drugs, where the pharmacist separates the pharmaceutical dosage for the patient from the total amount, where the patient always has access to the insert contained in the patient packaging, which is usually not available in the medicines prescribed to the patient. The inclusion of the package insert, as shown, contributes to the patient's instructions of the attending physician.

Topical compositions include ointments, creams, sprays, patches, gels, liquid drops, and liners (e.g., intraocular liners). Such compositions may be formulated in accordance with known methods.

Examples of compositions for rectal or intravaginal administration include pessaries and suppositories, which can, for example, be obtained from a moldable or waxy material containing the active compound.

Compositions for administration by inhalation can be presented in the form of powder compositions for inhalation or liquid or powder sprays, and they can be entered in standard form using a device for inhalation of powder or aerosol dispenser. Such devices are well known. For administration by inhalation, the powder compositions typically include the active compound together with an inert solid powder diluent, such as lactose.

The compounds of formula (I) can typically be presented in unit dosage form and, as such, typically contain a sufficient amount of the compound to provide the desired level of biological activity. For example, a composition may contain from 1 nanogram to 2 grams of active ingredient, for example from 1 nanogram to 2 milligrams of active ingredient. Within this range, specific sub-doses of the compound range from 0.1 milligrams to 2 grams of active ingredient (generally from 10 milligrams to 1 gram, for example from 50 milligrams to 500 milligrams) or from 1 microgram to 20 milligrams (for example, from 1 microgram to 10 milligrams, for example from 0.1 milligram to 2 milligrams of the active ingredient).

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

The active compound is administered to a patient in need thereof (eg, a patient such as a human or animal) in an amount sufficient to achieve the desired therapeutic effect.

Examples of pharmaceutical compositions

(i) Composition of tablets

A tablet composition containing a compound of formula (I) is prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as a diluent and 3 mg of magnesium stearate as a lubricant and pressing to obtain a tablet in a known manner.

(ii) Capsule Composition

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

(iii) Composition for injection I

A parenteral composition for administration by injection can be prepared by dissolving a compound of formula (I) (for example, in salt form) in water containing 10% propylene glycol to obtain a concentration of the active compound of 1.5% wt. The solution is then sterilized by filtration, filled in ampoules and sealed.

(iv) Composition for injection II

A parenteral composition for injection by injection is prepared by dissolving in water a compound of formula (I) (for example, in salt form) (2 mg / ml) and mannitol (50 mg / ml), sterilely filtering the solution and filling it with hermetically sealed 1 ml vials or ampoules.

v) Composition for injection III

A composition for intravenous delivery by injection or infusion can be prepared by dissolving a compound of formula (I) (e.g., in salt form) in water at a concentration of 20 mg / ml. The vial is then sealed and autoclaved.

vi) Composition for injection IV

A composition for intravenous delivery by injection or infusion can be prepared by dissolving a compound of formula (I) (e.g., in salt form) in water containing a buffer (e.g., 0.2M acetate, pH 4.6) at a concentration of 20 mg / ml. The vial is then sealed and autoclaved.

(vii) Composition for subcutaneous injection

A hypodermic composition is prepared by mixing a compound of formula (I) with a pharmaceutical corn oil to obtain a concentration of 5 mg / ml. The composition is sterilized and administered to fill in a suitable container.

viii) Lyophilized composition

Aliquots of the compound of formula (I) formulated in the composition are added to 50 ml vials and lyophilized. During the lyophilization process, the composition is frozen using a single-stage freezing protocol at (-45 ° C). The temperature is raised to -10 ° C for annealing, then lowered to freeze at -45 ° C, followed by primary drying at + 25 ° C for about 3400 minutes, and then secondary drying with a more rapid increase in temperature to 50 ° C. The pressure during the primary and secondary drying is set to 80 mTorr.

Treatment methods

It is envisaged that the compounds of formula (I) and subgroups of such compounds as defined herein will be useful for the prevention or treatment of a number of diseases or conditions mediated by FGFR. Examples of such diseases and conditions are described above.

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

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

However, in some situations (for example, in the case of life-threatening diseases), the benefits of administering the compounds of formula (I) may outweigh their disadvantages associated with any toxic effects or side effects, in which case it may be desirable to administer the compounds in amounts that are associated with the level of toxicity.

The compounds can be administered over an extended period of time to maintain beneficial therapeutic effects, or they can be administered only for a short period of time. Alternatively, they can be administered at intervals or in a continuous manner.

A typical daily dose of a compound of formula (I) may range from 100 picograms to 100 milligrams per kilogram of body weight, more typically from 5 nanograms to 25 milligrams per kilogram of body weight, and generally from 10 nanograms to 15 milligrams per kilogram (e.g., from 10 nanograms to 10 milligrams and more typically from 1 microgram per kilogram to 20 milligrams per kilogram, for example from 1 microgram to 10 milligrams per kilogram) per kilogram of body weight, although if necessary, you can enter higher or lower to s. The compound of formula (I) can be administered daily or repeatedly, for example, every 2, or 3, or 4, or 5, or 6, or 7, or 10, or 14, or 21, or 28 days.

The compounds of the present invention can be administered orally at doses in the range of, for example, from 1 to 1500 mg, from 2 to 800 mg or from 5 to 500 mg, for example from 2 to 200 mg or from 10 to 1000 mg, with specific examples of doses include 10, 20, 50 and 80 mg. The compound may be administered once or more than once daily. The compound can be administered continuously (i.e., taken every day without any interruption during the treatment program). Alternatively, the compound may be administered intermittently, i.e. take continuously for a certain period of time, such as a week, then take a break for a certain time, such as a week, and then take continuously for the next period of time, such as a week, and so on during the treatment program. Examples of treatment programs, including intermittent administration, include programs where the administration is carried out in cycles, for example, administration within one week, interruption within one week; or an introduction within two weeks, a break for one week; or an introduction within three weeks, a break for one week; or an introduction within two weeks, a break for two weeks; or an introduction within four weeks and a break for two weeks; or administration for one week and a break for three weeks — for one or more cycles, for example 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more cycles.

According to one specific administration schedule, the patient receives an infusion of a compound of formula (I) for one hour daily for up to ten days, in particular up to five days for one week, and the treatment is repeated at desired intervals, such as from two to four weeks, in particular every three weeks.

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

According to another specific administration schedule, the patient receives an infusion of a compound of formula (I) for 30 minutes to 1 hour, followed by maintenance of the infusions for a different period of time, for example 1 to 5 hours, for example for 3 hours.

According to another specific administration schedule, the patient receives a continuous infusion of a compound of formula (I) for a period of from 12 hours to 5 days, in particular a continuous infusion over a period of time from 24 hours to 72 hours.

Ultimately, however, the amount of compound administered and the type of composition used must be consistent with the nature of the disease or physiological condition to be treated and depend on the decision of the attending physician.

The compounds defined herein can be administered as a single therapeutic agent, or they can be administered as a combination therapy with one or more other compounds to treat a particular disease condition, for example a tumor, such as cancer, as described above in this application. Examples of other therapeutic agents or treatments that can be administered together (either simultaneously or at different time intervals) with the compounds of formula (I) include, but are not limited to:

topoisomerase I inhibitors;

antimetabolites;

means of targeted action on tubulin;

DNA binder and topoisomerase II inhibitors;

alkylating agents;

monoclonal antibodies;

antihormones;

signal transduction inhibitors;

proteasome inhibitors;

Methyltransferase DNA;

cytokines and retinoids;

chromatin-targeted therapeutic agents;

radiotherapy and

other therapeutic or prophylactic agents; for example, drugs that reduce or alleviate some of the side effects associated with chemotherapy. Specific examples of such agents include antiemetics and agents that prevent or shorten the duration of chemotherapy-related neutropenia and prevent complications that result from decreased levels of red blood cells or white blood cells, such as erythropoietin (EPO), granulocyte macrophage colony stimulating factor (GM-CSF), and granulocyte colony stimulating factor (G-CSF). Also included are agents that inhibit bone resorption, such as bisphosphonate agents, for example, zoledronate, pamidronate, and ibandronate, agents that suppress inflammatory responses (such as dexamethasone, prednisone, and prednisone), and agents used to lower growth hormone and IGF- I in the blood of patients with acromegaly, such as synthetic forms of the brain hormone somatostatin, which include octreotide acetate, which is a long-acting octapeptide with pharmacological properties Tvam simulating properties of the natural hormone somatostatin. Also included are agents, such as leucovorin, which is used as an antidote to drugs that lower folic acid or folic acid levels, and drugs, such as megestrol acetate, that can be used to treat side effects, including edema and thromboembolic events.

Each of the compounds present in the combinations of the present invention can be administered in individually varying doses and using different routes of administration.

When a 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 can be administered simultaneously or sequentially. When administered sequentially, they can be administered at small intervals (for example, over a period of 5-10 minutes) or at longer intervals (for example, at intervals of 1, 2, 3, 4 or more hours, or even at even longer intervals between their administration, if necessary), while the specific mode of administration should correspond to the properties of the therapeutic agent (s).

The compounds of the present invention can also be administered in combination with non-chemotherapeutic treatment, such as radiation therapy, photodynamic therapy, gene therapy; surgical treatment and controlled diets.

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

A person skilled in the art, based on his or her general knowledge, should know the dosage regimens and combination therapies that can be used.

Diagnostic Methods

Prior to administering a compound of formula (I), a patient study may be performed to determine whether the disease or condition that the patient suffers or may suffer from is one that will respond to treatment with a compound having activity against FGFR, VEGFR and / or PDGFR.

For example, a biological sample taken from a patient can be analyzed to determine whether a condition or disease, such as cancer, that a patient suffers or may suffer from, is characterized by genetic abnormality or abnormal expression of a protein, resulting in increased levels or activity of FGFR , VEGFR and / or PDGFR, or to sensitize the pathway to normal FGFR, VEGFR and / or PDGFR activity, or to activate signaling pathways of these growth factors, such as growth factor ligand levels or factor p ligand activity hundred, or the activation of a biochemical pathway by further activation of FGFR, VEGFR and / or PDGFR.

Examples of such disorders that lead to activation or sensitization of the FGFR, VEGFR and / or PDGFR signal include the loss or inhibition of apoptotic pathways, upregulation of receptors or ligands, or the presence of mutant receptor or ligand variants, for example, PTK variants. Tumors with mutants FGFR1, FGFR2, or FGFR3, or FGFR4, or increased regulation, in particular over-expression of FGFR1, or mutants with acquired gain-of-function FGFR2 or FGFR3 may be especially sensitive to FGFR inhibitors.

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

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

In addition, amplification of the 8p12-p11.2 gene was demonstrated in ~ 50% of cases of lobular breast cancer (CLC), and it was shown that this is associated with increased expression of FGFR1. Preliminary studies using siRNA directed against FGFR1 or a small molecule of a receptor inhibitor showed that cell lines containing this amplification are particularly sensitive to inhibition of this signaling pathway (Reis-Filho et al. (2006) Clin Cancer Res. 12 (22 ): 6652-6662).

Alternatively, a biological sample taken from a patient can be tested for the loss of a negative regulator or suppressor of FGFR, VEGFR or PDGFR. As used herein, the term “loss” encompasses deletion of a gene encoding a regulator or suppressor, truncation of a gene (eg, by mutation), truncation of a transcribed product of a gene, or inactivation of a transcribed product (eg, by point mutation) or sequestration by another gene product.

The term “up-regulation” includes increased expression or over-expression, including amplification of a gene (ie, multiple copies of a gene) and increased expression as a result of the transcription effect, and hyperactivity and activation, including activation caused by mutations. Thus, the patient can undergo a diagnostic study to detect a marker that is indicative of the activation of FGFR, VEGFR and / or PDGFR. The term diagnosis includes screening. By marker is meant genetic markers, including, for example, determining the composition of DNA to detect mutations of FGFR, VEGFR and / or PDGFR. The term marker also includes markers that are specific for the activation of FGFR, VEGFR and / or PDGFR, including enzyme activity, enzyme levels, enzyme status (for example, phosphorylated or not) and mRNA levels of these proteins.

Diagnostic studies and screening are typically performed on a biological sample selected from tumor biopsy samples, blood samples (isolation and enrichment of radiating tumor cells), stool, sputum, chromosome analysis, pleural fluid, peritoneal fluid, buccal scrapings, biopsy or urine.

Methods of identification and analysis of mutations and upregulation of proteins are known to those skilled in the art. Screening methods may 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 having a mutation in FGFR, VEGFR and / or PDGFR may mean that the patient may be particularly suitable for treatment with an inhibitor of FGFR, VEGFR and / or PDGFR. Tumors can preferably be screened for the presence of the FGFR, VEGFR and / or PDGFR variant prior to treatment. A screening method typically involves direct sequencing, analysis of a micropanel of oligonucleotides or a mutant-specific antibody. In addition, the diagnosis of tumors with such mutations can be carried out using methods known to specialists in this field and described in this application, such as RT-PCR and FISH.

In addition, mutant forms, for example FGFR or VEGFR2, can be identified by direct sequencing, for example, tumor biopsies using PCR and sequencing methods for PCR products directly, as described above. One skilled in the art will appreciate that all such well-known methods for detecting excessive expression, activation, or mutations of the above proteins may be applicable in this case.

When screened by RT-PCR, the level of mRNA in the tumor is estimated by creating a cDNA copy of the mRNA followed by amplification of the cDNA by PCR. PCR amplification methods, selection of primers, and amplification conditions are known to those skilled in the art. Nucleic acid manipulations and PCR are carried out 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. Nucleic acid reactions and manipulations 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) or the methodology described in US Pat. Nos. 4,666,828, 4,683,202, 4,801,531, 5,192,659, 5,272,057, 5882864 and 6218529 and incorporated herein by reference can be used. An example of an in-situ hybridization method for evaluating mRNA expression is fluorescence in-situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152: 649).

Typically, in situ hybridization involves the following main steps: (1) fixing the tissue to be analyzed; (2) prehybridization processing of the sample to increase the availability of the target nucleic acid and to reduce non-specific binding; (3) hybridization of a mixture of nucleic acids with nucleic acid in a biological structure or tissue; (4) post-hybridization washes to remove nucleic acid fragments that remained unbound in hybridization; and (5) detection of hybridized nucleic acid fragments. The probes used for such applications are typically labeled, for example, with radioactive isotopes or fluorescent labels. Preferred probes are long enough, for example, from about 50, 100 or 200 nucleotides to about 1000 or more nucleotides, so that specific hybridization with specific target nucleic acid (s) can be achieved under stringent conditions. Standard methods for implementing FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc. and Fluorescence in situ Hybridization: Technical Overview by John M.S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed .; ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine.

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

Alternatively, protein products expressed from mRNA can be investigated using immunohistochemical analysis of tumor samples, solid phase immunoassay using microtiter plates, Western blotting, 2-dimensional SDS-polyacrylamide gel, ELISA, flow cytometry and other methods known from the level techniques for detecting specific proteins. Detection methods typically include the use of site-specific antibodies. One skilled in the art will appreciate that all such well-known methods for detecting the activation of FGFR, VEGFR and / or PDGFR, or for detecting variants or mutants of FGFR, VEGFR and / or PDGFR, may be applicable in this case.

Abnormal levels of proteins, such as FGFR or VEGFR, can be measured using standard enzyme assays, for example, assays that are described in this application. Activation or overexpression can also be determined in a tissue sample, such as tumor tissue. Measurement of tyrosine kinase activity can be performed using an assay, such as an assay from Chemicon International. Tyrosine kinase of interest is isolated from the sample lysate by immunoprecipitation and its activity is measured.

Alternative methods for measuring the overexpression or activation of FGFR or VEGFR, including their isoforms, include measuring the density of microvessels. This can be measured, for example, using the 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 CD105 (Mineo et al. (2004) J. Clin. Pathol. 57 (6), 591-7).

Therefore, all of these methods can also be used to identify tumors that are particularly suitable for treatment with the compounds of the present invention.

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

Therefore, in a further aspect, the present invention includes the use of a compound of the present invention for the manufacture of a medicament for the treatment or prophylaxis of a disease or condition in a patient who has been screened, and has been determined to be suffering from, or has such a risk of, a disease or condition, which will respond to treatment with a compound having anti-FGFR activity.

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

In another aspect, the present invention includes a compound of the present invention for use in the prophylaxis or treatment of cancer in a patient selected from a subpopulation having a variant FGFR gene (e.g., G697C mutation in FGFR3 and Gly388Arg polymorphism in FGFR4).

MRI determination of vascular normalization (e.g., using MRI of gradient echo, spin echo and contrast enhancement to measure blood volume, vascular size and vascular permeability) in combination with circulating biomarkers (circulating progenitor cells (CPC), CEC, SDF1 and FGF2) can also be used to identify VEGFR2-resistant tumors for treatment with the compounds of the present invention.

EXPERIMENTAL PART

Description of the analytical system and method LC-MS

In the examples, the compounds that were obtained are characterized by liquid chromatography and mass spectroscopy using commercially available systems (Waters Platform LC-MS system, Waters Fractionlynx LC-MS system), standard operating conditions, and commercially available columns (Phenomenex, Waters and etc.), but it will be understood by those skilled in the art that alternative systems and methods may be used. When atoms with different isotopes are present and only one mass value is indicated, the indicated mass for the compound is a monoisotopic mass (i.e. 35Cl; 79Br, etc.).

LC-MS mass-directed cleaning system

Preparative LC-MS (or HPLC) is a standard and effective method used to purify small organic molecules, such as the compounds described in this application. The methods of liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of the crude substances and better detection of samples using MS. Optimization of the preparative gradient LC method involves the use of different columns, volatile eluents and modifiers and gradients. Such methods are well known in the art for optimizing preparative LC-MS, followed by their use for the purification of compounds. 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 compound libraries; J. Comb. Chem .; 2003; 5 (3); 322-9.

Two such systems for purifying compounds by preparative LC-MS are Waters Fractionlynx or preparative LC-MS Agilent 1100, but those skilled in the art will appreciate that alternative systems and methods can be used. In particular, reverse phase methods were used for preparative HPLC for the compounds described in this application, but preparative LC methods with normal phase can be used instead of reverse phase methods. Most preparative LC-MS systems use reversed-phase LC and volatile acid modifiers, since this approach is extremely effective for the purification of small molecules and since eluents are compatible with mass spectrometry where positive electrospray ionization is used. In accordance with the analytical trace obtained, the most suitable preparative chromatography method is chosen. A typical routine method involves performing analytical LC-MS using the type of chromatography (low or high pH) most suitable for the structure of the compound. If the analytical trace showed good chromatography, choose the appropriate preparative method of the same type. For the purification of compounds, various chromatographic solutions can be used, for example, normal or reverse phase LC; acidic, basic, polar or lipophilic buffered mobile phase; basic modifiers. Based on the information presented, a person skilled in the art will be able to purify the compounds described in this application using preparative LC-MS.

All compounds, as a rule, were dissolved in 100% MeOH or 100% DMSO.

General synthesis routes

General path A

Procedure A1 - General Procedure for the Formation of the Imidazopyridine Ring

To a solution of 4-chloropyridin-2-ylamine (12.8 g, 100 mmol, 1.0 eq.) In EtOH (170 ml) was added NaHCO ₃ (16.8 g, 200 mmol, 2.0 eq.) Followed by the addition of chloroacetaldehyde (19.0 ml, 150 mmol, 1.5 equiv.). The mixture was refluxed for 6 hours. The 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 (SiO ₂ , 50% EtOAC-gasoline was eluted) to obtain 13.2 g of the product.

Procedure A2 - General iodination procedure

To a solution of 7-chloro-imidazo [1,2-a] pyridine (30.9 g, 186 mmol, 1.0 equiv.) In DMF (280 ml) was added N-iodosuccinimide (43.6 g, 194 mmol, 1 , 05 equiv.) And the resulting mixture was stirred overnight at room temperature. The brown suspension was diluted with water (840 ml), brine (280 ml) and extracted with EtOAc (560 ml). The aqueous layer was then extracted with EtOAc (3 × 280 ml). The combined organic phases were washed with water (2 × 280 ml), 10% w / v. sodium thiosulfate (280 ml), brine (280 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo to give a brown residue. The residue was triturated with ether (200 ml), filtered and the solid was washed with ether (2 × 50 ml) and dried on a filter to obtain 39 g of product.

Procedure A3 - General 3-Position Suzuki Reaction Procedure

Procedure A3a - Suzuki Reaction

To a solution of 7-chloro-3-iodo-imidazo [1,2-a] pyridine (2.8 g, 10 mmol) in acetonitrile (100 ml) was added 3-aminobenzene boronic acid (2.5 g, 10.57 mmol) , 2M Na ₂ CO ₃ (21.6 ml) [the reaction was degassed by bubbling N ₂ ] followed by the addition of bis (triphenylphosphine) palladium (II) chloride (0.35 g, 0.49 mmol). The mixture was heated at 70 ° C. overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure and purified by column chromatography on a Biotage system (SiO ₂ , eluted with 80% EtOAC in gasoline to 100% EtOAC) to give 1.9 g of product. MS: [M + H] ⁺ 244.

Procedure A3b - Suzuki Reaction

To a solution of 3-iodo-7- (3-morpholin-4-ylmethylphenyl) -imidazo [1,2-a] pyridine (1.55 g, 3.72 mmol) in DME (20 ml) was added 3-aminobenzene boronic acid ( 0.69 g, 4.8 mmol) and 2M Na ₂ CO ₃ (6.93 ml) [the reaction was degassed by bubbling N ₂ ] followed by the addition of tetrakis (triphenylphosphine) palladium (0) (0.139 g, 0.12 mmol) . The mixture was heated at 75 ° 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 0.56 g of product . MS: [M + H] ⁺ 385.

Procedure A4 - General procedure for the palladium-mediated attachment cycle in position 7

Procedure A4a - Suzuki Reaction

To a suspension of suitable 7-chloro-imidazo [1,2-a] pyridin-3-yl (0.3 mmol) in toluene (0.5 ml) was added 4- (4,4,5,5-tetramethyl- [1 , 3.2] dioxaborolan-2-yl) -pyridine (0.078 g, 0.36 mmol), K ₂ CO ₃ (0.25 g, 1.8 mmol), MeOH (0.5 ml), EtOH (0 5 ml), H ₂ O (0.75 ml) [the reaction was degassed by bubbling N ₂ ] followed by the addition of bis (tri-tert-butylphosphine) palladium (0) (0.003 g, 0.0058 mmol). The mixture was heated using microwave irradiation in a CEM discover microwave synthesizer (50 W) at 140 ° C. until the reaction was completed. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO ₄ ), filtered, concentrated under reduced pressure, and purified using preparative HPLC to give the desired product.

Procedure A4b - Suzuki Reaction

To a solution of a suitable 7-chloro-imidazo [1,2-a] pyridin-3-yl (0.35 mmol) in DME (4 ml) was added 4-fluorophenylboronic acid (0.059 g, 4.2 mmol) and 2M Na ₂ CO ₃ (1.2 ml) [the reaction was degassed by bubbling N ₂ ] followed by the addition of tetrakis (triphenylphosphine) palladium (0) (0.018 g, 0.015 mmol, 5 mol%). 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, concentrated under reduced pressure, and purified using preparative HPLC to give the desired product.

Procedure A4c - Suzuki Reaction with Fluorophenylboronic Acid

To a solution of [3- (7-chloro-imidazo [1,2-a] pyridin-3-yl) phenyl] [1,3,4] thiadiazol-2-ylamine (prepared according to A, 226 mg, 0.69 mmol) in DME (8 ml) was added 4-fluorophenylboronic acid (125 mg, 0.90 mmol) and 2M Na ₂ CO ₃ (3 ml). The reaction mixture was deoxygenated and tetrakis (triphenylphosphine) palladium (0) (42 mg) was added. The mixture was again deoxygenated 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 (MgSO ₄ ), filtered and the solvent was removed in vacuo. The residue was purified using preparative HPLC to give the desired product (78 mg) MS: [M + H] ⁺ 388.

A4d procedure - Suzuki combination

A solution of a suitable 7-chloro-imidazo [1,2-a] pyridin-3-yl (1 equivalent), 1-methylpyrazole-4-boronic acid pinacol ester (commercially available, 2 equivalents), potassium carbonate (6 equivalents) and bis (tri-tert-butylphosphine) palladium (0) (0.05 equivalents) in ethanol (10 ml), toluene (10 ml) and water (10 ml) were heated at 75 ° C for 3 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried (MgSO ₄ ), filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography to give the desired product.

General path B

Procedure B1 - General Procedure for Palladium-Mediated 7-Position Cycle Addition

Procedure B1a - Suzuki reaction for aryl cycles

The same method was used as described for general path A, procedure 4a or 4b.

Procedure B1b - Buchwald reaction for saturated cycles

To a solution of a suitable 7-chloro-imidazo [1,2-a] pyridin-3-yl (0.32 mmol) in anhydrous dioxane (4 ml) was added a suitable amine (0.35 mmol), NaO ^t Bu (0.096 g, 0.96 mmol) [the reaction was degassed by bubbling N ₂ ] followed by the addition of BINAP (0.021 g, 0.033 mmol) and Pd ₂ dba ₃ (tris- (dibenzylideneacetone) dipalladium (0)) (0.016 g, 0.017 mmol). 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, concentrated under reduced pressure, and purified using preparative HPLC or chromatography on silica to give the desired product.

Procedure B1c - Suzuki combination for heterocycles.

A solution of 7-bromo-imidazole [1,2-a] pyridine (0.5 g, 2.54 mmol, 1 equivalent) was prepared according to General Procedure A1 using 4-bromopyridin-2-ylamine instead of 4-chloropyridin-2 -ylamine), 1-methyl-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole (1.1 g, 5.08 mmol, 2 equivalent), bis (tri-tert-butylphosphine) palladium (0) (66 mg, 0.13 mmol, 0.05 equivalents) and potassium carbonate (2.1 g, 15.24 mmol, 6 equivalents) in ethanol (10 ml), toluene (10 ml) and water (10 ml) were heated at 75 ° C for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was then washed with brine, dried (MgSO ₄ ), filtered and the solvent was removed by evaporation in vacuo. The residue was purified by column chromatography (Biotage SP4, 25S system, flow rate 25 ml / min, gradient from 0% to 20% methanol in ethyl acetate) to obtain 7- (2-methyl-2H-pyrazol-3-yl) -imidazo [1,2, a] pyridine as a colorless oil (350 mg, 70%). MS: [M + H] ⁺ 199.

Procedure B1d - Synthesis of 7- [3- (4-methylpiperazin-1-ylmethyl) phenyl] imidazo [1,2-a] pyridine

The same method was used as described for General Path A, Procedure A4a, using 3-formylphenylboronic acid.

To a solution of 3-imidazo [1,2-a] pyridin-7-yl-benzaldehyde (1.889 g, 8.5 mmol, 1.0 eq.) In toluene (30 ml) and methanol (10 ml) was added N-methylpiperazine (1.1 ml, 10.2 mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature for 3 hours, 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 eq.) Was added portionwise. The reaction mixture was stirred overnight and the solvents were removed in vacuo. The reaction was quenched very slowly by the addition of 2 N. aqueous NaOH solution (20 ml). Ethyl acetate 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 (eluted with 5% methanol: dichloromethane) to give the desired compound.

Procedure B2 - Iodization

Used the same method as described for general path A, procedure A2.

Procedure B3a - General Suzuki Position 3 Reaction Procedure

Used the same method as described for general path A, procedure A3a or A3b.

Procedure B3b - General Suzuki Position 3 Reaction Procedure

The same method was used as described for general path B, procedure 1c.

General modifications D to position 7

A latent functional group at the 7-position of imidazo [1,2-a] pyridine can be used to synthesize alternative motifs.

Procedure D3 - Removal of the Boc protecting group

Boc-protected compound (0.39 mmol) in CH ₂ Cl ₂ (10 ml) was added 4M HCl in dioxane (0.5 ml, 5 equiv.). The reaction mixture was allowed to stir at room temperature for 18 hours, after which the solvent was removed in vacuo. The residue was purified using preparative HPLC to give the desired amino derivative.

In an alternative procedure, tert-butyl carboxylic acid ester (0.027 mmol) can be treated with saturated EtOAc / HCl solution, with stirring at ambient temperature for 3 hours, concentration under reduced pressure, followed by drying to obtain the desired compound.

Procedure D3b - Removal of the Boc Protective Group

To a solution of tert-butyl ether (3- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} phenyl) β-carbamic acid (190 mg, 0.39 mmol) in CH ₂ Cl ₂ (10 ml) was added 4M HCl in dioxane (0.5 ml, 2 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours, after which the solvent was removed in vacuo. The residue was purified using preparative HPLC to give the desired compound (120 mg). MS: [M + H] ⁺ 385.

Procedure E

To a solution of 7-chloro-imidazo [1,2-a] pyridine (1.0 g, 6.58 mmol) in anhydrous dioxane (60 ml) was added morpholine (0.64 ml, 6.58 mmol), NaO ^t Bu (1.9 g, 19.74 mmol) [the reaction was degassed by bubbling N ₂ ] followed by the addition of BINAP (0.43 g, 0.69 mmol) and Pd ₂ dba ₃ (tris- (dibenzylideneacetone) dipalladium (0)) (0.32 g, 0.36 mmol). 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 chromatography on silica to give the desired product (0.55 g). MS: [M + H] ⁺ 204.

General modifications F to position 3

A latent functional group at the 3-position of imidazo [1,2-a] pyridine can be used to synthesize alternative motifs.

Procedure F4 - Arylation

{3- [7- (4-Fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} pyridin-4-ylamine

Mixture of 3- [7- (4-fluoro-phenyl) -imidazo [1,2-a] pyridin-3-yl] phenylamine (200 mg, 0.65 mmol), 4-bromopyridine. HCl (130 mg, 0 , 67 mmol), (±) -Binap (63 mg, 0.1 mmol) and NaO ^t Bu (250 mg, 2.6 mmol) in anhydrous dioxane (3 ml) were deoxygenated by pumping gas / refilling N ₂ (x3 ) Pd ₂ (dba) ₃ (30 mg, 0.03 mmol) was added and the mixture was again deoxygenated (x3). The reaction mixture was stirred and heated at 100 ° C for 18 hours in an atmosphere of N ₂ . The mixture was partitioned between CH ₂ Cl ₂ / H ₂ O, then filtered. The layers were separated and the solid was combined with an organic layer, which was then evaporated. The residue was purified by chromatography on silica and then preparative HPLC to give the title compound (40 mg, solid). ¹ H NMR (400 MHz, Me-d ₃ -OD): 8.63 (1H, d), 8.44 (1H, s), 8.22 (2H, d), 7.87-7.79 ( 4H, m), 7.70 (1H, t), 7.63-7.59 (2H, m), 7.48-7.43 (1H, m), 7.37 (1H, dd), 7 31-7.24 (2H, m); 7.17 (2H, d).

Procedure F5 - Synthesis of triazole-3-thiones and amino-thiadiazoles

To a suspension of 3- [7- (3-morpholin-4-ylmethyl-phenyl) -imidazo [1,2-a] pyridin-3-yl] -phenylamine (0.25 g, 0.65 mmol) in anhydrous toluene ( 20 ml) 1,1'-thiocarbonyldi-2 (1H) -pyridone (0.51 g, 0.65 mmol) was added, stirred and heated at 110 ° C for 1 hour. The reaction mixture was cooled to ambient 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. The residue was taken up in THF (4 ml), cooled in an ice bath, and treated with hydrazine hydrate (0.05 ml, 9.7 mmol). After complete addition, the reaction mixture was stirred at the indicated temperature for 15 minutes and concentrated under reduced pressure. This material was used without further purification in the next step.

Diethyl chlorophosphate (0.23 ml, 1.58 mmol) was added dropwise to a solution of thiosemicarbazide (0.305 g, 0.66 mmol) in anhydrous DMF (5 ml) so that the internal temperature remained <25 ° C. After 30 minutes, additional diethyl chlorophosphate was added. The reaction mixture was poured into H ₂ O and extracted with EtOAc. The aqueous fraction was concentrated under reduced pressure, the residue was triturated with hot ethanol, and the solid was filtered. The filtrate was concentrated under reduced pressure and purified using preparative HPLC to give 0.08 g of product. MS: [M + H] ⁺ 469.

Procedure F8 - Alkylation

Sodium hydride was added to a solution of 3- (7-chloro-imidazo [1,2-a] pyridin-3-yl) phenylamine (0.20 g, 0.82 mmol) in anhydrous DMF (5 ml) at 0 ° C. as a 60% dispersion (0.04 g, 0.99 mmol) and the reaction mixture was stirred for 5 minutes. Benzyl bromide (0.10 ml, 0.82 mmol) was added, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. The reaction was quenched using NH ₄ Cl (aq) (10 ml) and then partitioned between EtOAc and H ₂ O. The aqueous layer was then extracted with EtOAc, the organic fractions were combined, dried (MgSO ₄ ), filtered and the solvent was removed in vacuo. . The crude residue was purified using an SCX cartridge and then reverse phase HPLC to give the product. MS: [M + H] ⁺ 333.

General Procedure G — Examples of 1,2,3-triazoles

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

A solution of sodium nitrite (285 mg, 4.1 mmol) in H ₂ O (2 ml) was added to a stirred suspension of 3- (7-chloro-imidazo [1,2-a] pyridin-3-yl) phenylamine (1 g , 4.1 mmol) in 2 N. HCl solution (8 ml) so as to maintain an internal temperature <5 ° C. Upon completion of the addition, the reaction mixture was stirred for 15 minutes at the indicated temperature before the addition of aminoacetonitrile bisulfate (635 mg, 4.1 mmol) in H ₂ O (2 ml) [maintained internal temperature <5 ° C]. After 1 hour, NaOAc (14 g) was added. The mixture was stirred for 1 hour while cooling in an ice bath, then the solid was collected by filtration. Direct absorption of this substance was carried out in EtOH (~ 20 ml). The resulting solution was stirred and heated at 90 ° C for 18 hours in an atmosphere of N ₂ . After cooling to room temperature, volatiles were removed in vacuo and the residue was purified by chromatography on silica (100% CH ₂ Cl ₂ → 5% 2M NH ₃ -MeOH / CH ₂ Cl ₂ ) to give the title compound (318 mg, solid). ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.94 (1H, s), 8.58 (1H, d), 7.84 (1H, d), 7.77 (1H, s), 7 58 (1H, s), 7.48 (1H, s), 7.40 (1H, t), 7.33 (1H, d), 7.07-7.02 (2H, m).

Procedure G2:

3- {7- [4- (4-Methylpiperazin-1-ylmethyl) phenyl] imidazo [1,2-a] pyridin-3-yl} phenyl) - (3H- [1,2,3] triazole -4-yl) aminformate

Mixture of [3- (7-chloro-imidazo [1,2-a] pyridin-3-yl) phenyl] - (3H- [1,2,3] triazol-4-yl) amine (60 mg, 0 , 19 mmol), 4- (4-methyl-piperazin-1-ylmethyl) phenylboronic acid pinacol ester (80 mg, 0.25 mmol), 2 '- (dimethylamino) -2-biphenyl-palladium (II) chloride complex Dinorbornylphosphine (10 mg, 0.02 mmol) in DME (1 ml) and 2 N. a solution of Na ₂ CO ₃ (aq., 1 ml) in a microwave vessel was deoxygenated by sparging N ₂ for 30 seconds. The vessel was sealed and then stirred and heated at 150 ° C. in the microwave for 25 minutes. After cooling to room temperature, the mixture was partitioned between CH ₂ Cl ₂ / H ₂ O and filtered. The layers were separated using a phase separation cartridge. The organic layer was evaporated and combined with the solid obtained above. This material was purified using preparative HPLC to give the title compound (30 mg, solid). ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.95 (1H, s), 8.64 (1H, d), 8.27 (2H, s), 7.98 (1H, s), 7 86-7.75 (2H, m), 7.63 (1H, broad s), 7.48 (1H, s), 7.46-7.28 (6H, m), 7.09 (1H d) 3.52 (2H, s), 2.48-2.20 (8H, broad m), 2.17 (4H, broad s).

Synthesis of boronic acids and esters

Boronic acid I4

3 - ([1,3,4] thiadiazol-2-ylamino) phenylboronic acid pinacol ester

Stage 1: 3-Bromophenylthiosemicarbazide

A solution of 3-bromophenylisothiocyanate (10 g, 47 mmol) in THF (20 ml) was added to a stirred solution of hydrazine hydrate (4.54 ml, 94 mmol) in THF (80 ml) so as to maintain an internal temperature of <5 ° C. Upon completion of the addition, the reaction mixture was stirred at the indicated temperature for 1 hour. Volatiles were removed in vacuo and the residue was triturated with gasoline. The solid was collected by filtration and then dried to give 3-bromophenylthiosemicarbazide (12.5 g, solid). This substance was used without further purification.

Stage 2: (3-Bromophenyl) - [1,3,4] thiadiazol-2-yl-amine

Diethyl chlorophosphate (16.3 ml, 117 mmol) was slowly added to a stirred solution of 3-bromophenylthiosemicarbazide (from the previous step, 12.5 g) in anhydrous DMF (120 ml) so as to maintain an internal temperature of <25 ° C. After 1 hour, the reaction mixture was poured into H ₂ O and stirred at the indicated temperature for 20 minutes. The solid was collected by filtration, then dried in vacuo at 50 ° C to give the title compound (7.4 g, solid).

¹ H NMR (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).

Stage 3: Pinacol ester of 3 - ([1,3,4] thiadiazol-2-ylamino) phenylboronic acid

A mixture of (3-bromophenyl) - [1,3,4] thiadiazol-2-ylamine (7.3 g, 29 mmol), bis (pinacolato) dibor (14.5 g, 57 mmol) and KOAc (8.5 g , 87 mmol) in anhydrous DMSO (50 ml) was deoxygenated by gas evacuation / refill N ₂ (x3). PdCl ₂ ddpf (1.05 g, 1.4 mmol) was added and the mixture was deoxygenated again (x3), then stirred and heated at 100 ° C. under N ₂ for 16 hours. The following amount of PdCl ₂ dppf (1.05 g) was added, the reaction mixture was deoxygenated (x3) and heated at 100 ° C for another 20 hours. After cooling to room temperature, the mixture was partitioned between EtOAc / H ₂ O, then filtered through Celite®. The layers were separated and the aqueous layer was extracted with EtOAc (x1). The combined organic extracts were washed with water (x1), brine (x1), then dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by chromatography on silica (20 → 60% EtOAc / gasoline) to obtain the title compound (4.1 g, solid after trituration with gasoline). ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.37 (1H, br s), 8.91 (1H, s), 8.03 (1H, d), 7.73 (1H, ddd) 7.42-7.27 (2H, m); 1.31 (12H, s).

Boronic acid I5

3- (5-Methyl- [1,3,4] thiadiazol-2-ylamino) phenylboronic acid pinacol ester

Stage 1: (3-Bromophenyl) - (5-methyl- [1,3,4] thiadiazol-2-yl) -amine

3-Bromophenylthiosemicarbazide (1.0 g, 4.0 mmol) was added to a stirred mixture of concentrated H ₂ SO ₄ (1 ml) and AcOH (280 μl, 4.9 mmol) at room temperature (exotherm was observed). The suspension was stirred and heated at 80 ° C for 2 hours. After cooling to room temperature, the mixture was cooled in an ice bath and carefully neutralized with a concentrated aqueous solution of NH ₃ . The pH was adjusted to ~ pH 10 and the solid was collected by filtration, then dried to obtain the title compound (732 mg, solid). ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.01 (1H, t), 7.45 (1H, dd), 7.28 (1H, t), 7.16 (1H, d), 2 57 (3H, s).

Stage 2: Pinacol ester of 3- (5-methyl- [1,3,4] thiadiazol-2-ylamino) phenylboronic acid

A mixture of (3-bromophenyl) - (5-methyl- [1,3,4] thiadiazol-2-yl) -amine (680 mg, 2.5 mmol), bis (pinacolato) dibor (1.27 g, 5, 0 mmol) and KOAc (740 mg, 7.5 mmol) in anhydrous DMSO (5 ml) were deoxygenated by gas evacuation / refill N ₂ (x3). PdCl ₂ ddpf (91 mg, 0.12 mmol) was added and the mixture was deoxygenated again (x3), then stirred and heated at 100 ° C. under N ₂ for 3 hours. After cooling to room temperature, the mixture was partitioned between EtOAc / H ₂ O, then filtered through Celite®. The layers were separated and the aqueous layer was extracted with EtOAc (x1). The combined organic extracts were washed with brine (x1), then dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by chromatography on silica (30 → 80% EtOAc / gasoline) to give the title compound (211 mg, oil). MS: [M + H] ⁺ 318.

Boronic acid I16

(1-Methyl-1H-imidazol-2-yl) - [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] -amine

A solution of 3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenylamine (0.5 g, 2.28 mmol) in 2-bromo-1-methyl-1H -imidazole (0.367 g, 2.28 mmol) was heated in a CEM discover microwave synthesizer (50 W) at 125 ° C until the reaction was completed. The reaction mixture was cooled and used directly in the following procedure. MS: [M + H] ⁺ 300.

Boron analogue I17 (trifluoroborates)

[3 - ([1,3,4] Thiadiazol-2-ylamino) phenyl] potassium trifluoroborate

A solution of KHF ₂ in H ₂ O (4.5 M, 36 ml) was added to a stirred solution of [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] - [1,3,4] thiadiazol-2-ylamine and phenyl- [1,3,4] thiadiazol-2-ylamine (~ 1: 1, 10 g) in MeOH (90 ml) at room temperature. After 15 minutes, the reaction mixture was evaporated to dryness. The residue was suspended in acetone (150 ml). The resulting mixture was stirred and heated at reflux for 1 hour, then filtered while hot. The filtrate was evaporated and the residue was suspended in EtOAc (50 ml). The solid was collected by filtration and dried to obtain the title compound (3.0 g) as a cream-colored solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.00 (1H, s), 8.78 (1H, s), 7.43 (1H, d), 7.35 (1H, s), 7 07 (1H, t); 7.00 (1H, d).

Boronic acid I18

N-Methyl-2- [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenylacetamide

To a solution of [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] acetic acid (0.60 g, 2.28 mmol) in DMF (15 ml ) a solution of 1-hydroxybenzotriazole (0.37 g, 2.73 mmol) and TBTU of tetrafluoroborate 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (0.88 g, 2.73) was added mmol) in DMF (15 ml). Triethylamine (0.95 ml) and methylamine (1.2 ml) were added and the reaction mixture was allowed to stir for 18 hours at room temperature. The reaction mixture was concentrated in vacuo and purified using reverse phase chromatography to give a mixture of boronic acid / acid ester, which was used crude. MS: [MH ⁺ ] 276 (ether), [MH ⁺ ] 194 (acid).

Boronic acid I19

(3-methylpiperazinone) phenylboronic acid

To a solution of piperazin-2-one (0.2 g, 2 mmol) in anhydrous THF / DMSO (10 ml: 2.5 ml) was added neopentyl glycol ether (3-bromomethylphenyl) boronic acid (0.45 g, 1.6 mmol) ), NaHCO ₃ (0.34 g, 4 mmol) and NaI (0.01 g, 0.74 mmol). The reaction mixture was heated at reflux for 12 hours, cooled and passed through a C18 reverse phase chromatography column to give a colorless gum which was used crude. MS: [MH ⁺ ] 235.

Boronic acid I21

2- (tetrahydropyran-4-yloxy) -4-pyridinylboronic acid

To a suspension of NaH (0.4 g, 10 mmol) in THF (20 ml) at 0 ° C was added 4-hydroxytetrahydropyran (1.02 ml, 10 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes, and then 4-bromo-2-chloropyridine (0.89 ml, 8.0 mmol) was added dropwise. The reaction mixture was stirred for 18 hours, then quenched with EtOH (1 ml), partitioned between CH ₂ Cl ₂ and H ₂ O and extracted with CH ₂ Cl ₂ (x2). The organic layers were combined, dried (MgSO ₄ ), filtered and the solvent was removed in vacuo. Purified by column chromatography to give 4-bromo-2- (tetrahydropyran-4-yloxy) -pyridine. MS: [MH] ⁺ 258, 260.

To 4-bromo-2- (tetrahydropyran-4-yloxy) -pyridine (0.2 g, 0.77 mmol) in DMSO (5 ml) (degassed by sparging with N ₂ ) 4,4,5,5,4 was added ', 4', 5 ', 5'-octamethyl-2,2'-bi-1,3,2-dioxaborolan (0.39 g, 1.55 mmol) and potassium acetate (0.27 g, 2.31 mmol). PdCl ₂ ddpf (0.028, 0.04 mmol) was added, the reaction mixture was degassed again and then heated at 100 ° C for 5 hours. The compound was passed through a reverse phase C18 chromatography column to obtain the desired product, which was used crude. MS: [MH] ⁺ 224.

Boronic acid I23

3 - ([1,3,4] Thiadiazol-2-ylamino) -benzeneboronic acid

LiOH (340 mg, 14 mmol) was added to a stirred solution of [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] potassium trifluoroborate (1.15 g, 4 mmol) in CH ₃ CN (20 ml ) and H ₂ O (10 ml) at room temperature. The reaction mixture was stirred at room temperature for 20 hours. The mixture was treated with saturated aqueous NH ₄ Cl (32 ml) and 2 N. HCl solution (5 ml) to obtain ~ pH 5. EtOAc was added and the precipitate was collected by filtration. The aqueous layer was extracted with CH ₂ Cl ₂ (x2). The combined extracts were evaporated and the residue was combined with the solid from the previous step. This substance was suspended in EtOAc. The solid was collected by filtration and then dried to obtain the title compound (1.1 g) as a beige solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) → a mixture of possibly boronic acid and cyclic particles. This substance was used without further purification.

Boronic acid I24

3 - ([1,2,4] thiadiazol-5-ylamino) phenylboronic acid pinacol ester

Stage 1: 1- (3-Bromophenyl) -3- [1-dimethylamino-meth- (E) -ilidene] thiourea

(3-Bromophenyl) thiourea (2.1 g, 9.1 mmol) was suspended in N, N-dimethylformamide dimethyl acetal and heated to 100 ° C for 2 days. The cooled mixture was diluted with ether and filtered, and the solid was washed with ether to give the title compound (2.42 g).

Stage 2: (3-Bromophenyl) - [1,2,4l-thiadiazol-5-ylamine

To a suspension of 1- (3-bromophenyl) -3- [1-dimethylamino-meth- (E) -ilidene] thiourea (570 mg, 2.0 mmol) in anhydrous dichloromethane (4 ml) was added mesityl sulfonylhydroxylamine (475 mg, 2 , 2 mmol) in anhydrous dichloromethane (4 ml). The reaction mixture was stirred at room temperature for 2 hours under nitrogen, then diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate. The organic fraction was dried by passing it through a phase separation cartridge and concentrated in vacuo. The residue was purified by column chromatography (10-40% EtOAc / gasoline) to give bromide (135 mg) as a colorless solid. MS: [M + H] @ ⁺ = 256.

Stage 3: Pinacol ester of 3 - ([1,2,4] thiadiazol-5-ylamino) phenylboronic acid

(3-Bromophenyl) - [1,2,4] -thiadiazol-5-ylamine was converted to the title product using the method described in step 3 of the synthesis of boronate I4. The product was used without purification.

Procedure J - Formation of HCl Salt

To a suspension of the imidazo [1,2-a] pyridin-3-yl derivative (58 μM) in dioxane (1 ml) was added 4M HCl in dioxane and stirred until complete dissolution. The solvent was removed in vacuo to give the hydrochloride salt.

Alternatively, a suspension of a suitable compound in EtOH can be treated with a saturated EtOAc / HCl solution with stirring until it is completely dissolved, followed by concentration under reduced pressure, trituration of the residue into ether powder and drying to give the desired product as the HCl salt.

General scheme for the synthesis of pyrazolo [1,5-a] pyrimidines

Procedure K - General Ring Formation Procedure

To a solution of 2-bromo-malonaldehyde (12.8 g, 80 mmol) in EtOH (150 ml) was added 3-aminopyrazole (6 g, 37 mmol) followed by glacial acetic acid (10 ml). The mixture was refluxed for 4 hours, then allowed to cool, the solid was filtered off and the filtrate was evaporated under reduced pressure. The residue was partitioned between 1M NaOH (50 ml) and EtOAc (200 ml) [some insoluble matter present was filtered off]. The organic layer was washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The solid was recrystallized from MeOH, filtered warm, washed also with MeOH and dried to give 4.5 g of product. MS: [M + H] ⁺ 198.

Receiving (or procedure) K1

The same conditions were used as in the preparation of K (above), but replacing 2-bromo-malonaldehyde with 2- (4-fluorophenyl) -malonaldehyde.

Receiving (or procedure) L - Suzuki Reaction

To a solution of 6-bromopyrazolo [1,5-a] pyrimidine (0.5 g, 2.5 mmol) in DME (10 ml) was added 4-fluorophenylboronic acid (0.46 g, 3.25 mmol) and 2M Na ₂ CO ₃ (10 ml) [the reaction was degassed by bubbling N ₂ ] followed by the addition of tetrakis (triphenylphosphine) palladium (0) (0.130 g, 0.11 mmol). 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. The residue was triturated with EtOAc, filtered and the solid was washed with additional EtOAc, then dried to give (0.16 g) of the product. The filtrate was concentrated under reduced pressure. The product was purified by column chromatography on a Biotage system (SiO ₂ , eluted with 5% EtOAC-gasoline-50% EtOAC-gasoline) to give another 0.223 g of the product. MS: [M + H] ⁺ 214.

Receiving (or procedure) M - Iodination

The method described in General Path A, Procedure 2 (A2).

Receiving (or Procedure) N - Suzuki Reaction at Position 3

The method described in General Path A, Procedure 3b (A3b).

General Procedure O, benzimidazole matrix

Procedure O1: N- (4-Bromo-2-nitrophenyl) benzene-1,3-diamine

A mixture of 4-bromo-1-fluoro-2-nitrobenzene (1.14 ml, 9.25 mmol), benzene-1,3-diamine (1.96 g, 18.1 mmol) and DIPEA (1.93 ml, 11.1 mmol) in anhydrous NMP (5 ml) was deoxygenated by gas evacuation / refilling N ₂ (x3), then stirred and heated at 120 ° C in an N ₂ atmosphere for 18 hours. After cooling to room temperature, the mixture was partitioned between EtOAc and 0.5N. HCl solution. The organic layer was washed with H ₂ O (x1), brine (x1), then dried (MgSO ₄ ), filtered and evaporated. The residue was purified by chromatography on silica (10 → 40% EtOAc / gasoline) to give the title compound (1.8 g) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 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 O2: N- (4'-Fluoro-3-nitro-biphenyl-4-yl) benzene-1,3-diamine

To a mixture of PdCl ₂ dppf (210 mg, 0.29 mmol), N- (4-bromo-2-nitrophenyl) benzene-1,3-diamine (procedure O1, 1.8 g, 5.8 mmol) and 4 -fluorophenylboronic acid (975 mg, 7.0 mmol) in DME (10 ml) was added 2 N. Na ₂ CO ₃ solution (10 ml). The reaction mixture was deoxygenated by gas evacuation / refilling N ₂ (x3), then stirred and heated at 90 ° C under N ₂ atmosphere for 18 hours. After cooling to room temperature, the mixture was partitioned between EtOAc / H ₂ O and then filtered through celite. The organic layer was washed with H ₂ O (x1), brine (x1), then dried (MgSO ₄ ), filtered and evaporated. The residue was purified by chromatography on silica (10 → 50% EtOAc / gasoline) to give the title compound (1.66 g) as a dark red-brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 9.30 (1H, s), 8.32 (1H, d), 7.85 (1H, dd), 7.72 (1H, dd), 7 35-7.24 (3H, m), 7.08 (1H, t), 6.54 (1H, s), 6.47 (2H, t), 5.25 (2H, s).

Procedure O3: N * 4 * - (3-Aminophenyl) -4'-fluorobiphenyl-3,4-diamine

N- (4'-Fluoro-3-nitrobiphenyl-4-yl) benzene-1,3-diamine (procedure O2, 1.66 g, 5.1 mmol) was hydrogenated at atmospheric pressure over 10% Pd / C (300 mg) in EtOH / AcOH (3: 1, 40 ml) until the absorption of hydrogen ceased. The catalyst was removed by filtration-washing with EtOH. Volatiles were removed in vacuo and the residue was azeotroped with PhMe to give the title compound. This substance was used directly in the next step.

Procedure O4: 3- [5- (4-Fluorophenyl) benzoimidazol-1-yl] phenylamine

A solution of N * 4 * - (3-aminophenyl) -4'-fluorobiphenyl-3,4-diamine (procedure O3, ~ 5.1 mmol) in trimethylorthoformate (30 ml) was stirred and heated at 120 ° C in an atmosphere of N ₂ in within 10 hours. Volatiles were removed in vacuo and the residue was taken up in EtOH (30 ml), treated with concentrated HCl (2 ml), then stirred and heated at reflux for 3 hours. After cooling to room temperature, the mixture was concentrated to a volume of ~ 2 ml, then diluted with H ₂ O. NaHCO ₃ (sat.) Was added to ~ pH 7.5. The resulting solid was absorbed in CH ₂ Cl ₂ . The organic layer was dried and evaporated. The residue was purified by chromatography on silica (0% → 1% → 2% 2M NH ₃ -MeOH / CH ₂ Cl ₂ ). The resulting material was then triturated with Et ₂ O to give the title compound (890 mg) as an off-white solid).

Getting O7a:

Solution of 3- [5- (4-fluoro-phenyl) -benzoimidazol-1-yl] phenylamine (300 mg, 1 mmol) and 1,1'-thiocarbonyldi-2- (1H) -pyridone (240 mg, 1 mmol ) in anhydrous toluene was stirred and heated at the boiling temperature under reflux in an atmosphere of N ₂ for 2 hours. After cooling to room temperature, the volatiles were removed in vacuo, the residue was taken up in THF (5 ml) and cooled in an ice bath. Hydrazine hydrate (300 μl) was added and the mixture was stirred at 0 ° C for 1 hour and then evaporated. The residue was used without further purification.

Getting O7b

{3- [5- (4-Fluorophenyl) benzoimidazol-1-yl] phenyl} - [1,3,4] thiadiazol-2-ylamine

Diethyl chlorophosphate (350 μl, 2.4 mmol) was added slowly to a stirred solution of N-arylthiosemicarbazide (preparation of O7a, ~ 1 mmol) in anhydrous DMF (5 ml) at room temperature under N ₂ atmosphere. After 90 minutes, the mixture was poured into a saturated aqueous solution of NaHCO ₃ . The solid was collected by filtration and the filtrate was extracted with EtOAC (x2). This solid was added to the combined extracts, which were dried, filtered and evaporated. The residue was purified on an SCX cartridge, eluting with MeOH and then with 2M NH ₃ -MeOH. NH ₃ -MeOH fractions were combined and evaporated and the residue was purified using preparative HPLC to give the title compound (30 mg).

General modification Q (formation of triazole)

N * 3 * - {3- [7- (4-Fluorophenyl) -imidazo [1,2-a] pyridin-3-yl] phenyl} -1H- [1,2,4] triazole-3,5- diamine

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

Received using General Path B, Procedure B1a using 4-fluorophenylboronic acid, Procedure B2, Procedure B3a using 3-aminobenzeneboronic acid.

To a solution of 3- [7- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenylamine (0.1 g, 0.33 mmol) in 2-propanol (3 ml) was added diphenylcyanocarbone diimidate (0.078 g, 0.33 mmol). The reaction mixture was stirred at ambient temperature overnight, the resulting solid was filtered and dried to give 0.12 g of intermediate. MS: [M + H] ⁺ 448.

This compound was dissolved in MeOH (2 ml) and treated with hydrazine hydrate (0.013 ml), stirred at ambient temperature for 30 minutes, the solid was filtered and purified using preparative LC to give 0.013 g of the product. MS: [M + H] ⁺ 386.

General Procedure S: Formation of 1,3,4 oxadiazole

{3- [7- (4-Fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,3,4] oxadiazol-2-ylamine

Procedure S1:

Solution of 3- [7- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenylamine (320 mg, 1.05 mmol) and 4-nitrophenyl chloroformate (225 mg, 1.12 mmol) in anhydrous THF (10 ml) was stirred and heated at 60 ° C for 2 hours. After cooling to room temperature, DIPEA (550 μl, 3.2 mmol) and hydrazine hydrate (102 μl, 2.1 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, then partitioned between NaHCO ₃ (aq) and CH ₂ Cl ₂ . The precipitate was collected by filtration and dried in vacuo to give semicarbazide. MS: [M + H] ⁺ 362. This material was used without further purification.

Procedure S2:

A suspension of semicarbazide (procedure S1, 130 mg, 0.35 mmol) and ethyl glyoxylate (50% in PhMe, 120 μl, ~ 0.6 mmol) in EtOH / H ₂ O (2: 1, 3 ml) was stirred and heated at 80 ° C for 90 minutes. After cooling to room temperature, the precipitate was collected by filtration. The filtrate was concentrated in vacuo and the next batch of product was collected. Two batches were combined and used without further purification. MS: [M + H] ⁺ 446.

Procedure S3:

5- {3- [7- (4-Fluorophenyl) -imidazo [1,2-a] pyridin-3-yl] phenylamino} - [1,3,4] oxadiazole-2-carboxylic acid ethyl ester

Bromine (20 μl, 0.39 mmol) in AcOH (1 ml) was added to a stirred suspension of imine (procedure S2, ~ 0.35 mmol) in AcOH (2 ml) at room temperature. The mixture was stirred at room temperature for 1 hour at 40 ° C for 30 minutes, then allowed to stand at room temperature overnight. The reaction mixture was then heated at 120 ° C for 10 minutes. After cooling to room temperature, the mixture was diluted with water. The solid was collected by filtration, washed with Et ₂ O and then dried in vacuo to give the title compound (120 mg). [M + H] ⁺ 444. This material was used without further purification.

Procedure S4: {3- [7- (4-Fluorophenyl) -imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,3,4] oxadiazol-2-ylamine

5- {3- [7- (4-Fluorophenyl) -imidazo [1,2-a] pyridin-3-yl] phenylamino} ethyl - [1,3,4] oxadiazole-2-carboxylic acid ethyl ester (120 mg 0.27 mmol) and 5 n. a solution of NaOH (0.5 ml, 2.5 mmol) in dioxane (2 ml) was stirred and heated at 100 ° C for 1 hour. After cooling to room temperature, 5 N was added. HCl solution (0.5 ml). The mixture was diluted with Et ₂ O and the liquid was drained. The residue was treated with EtOH and the solid was collected by filtration. This solid was suspended in EtOH (3 ml) and heated at reflux for 15 minutes. Volatiles were removed in vacuo and the residue was purified using preparative HPLC to give the title compound (12 mg).

Procedure U: Halogenated Monomer Formation

U1: Synthesis of (2-chloropyridin-4-yl) - [1,3,4] thiadiazol-2-ylamine

Stage 1:

To 4-amino-2-chloropyridine (0.50 g, 3.89 mmol) in toluene (20 ml) was added 1,1'-thiocarbonyldi-2 (1H) -pyridone (0.91 g, 3.90 mmol) and the mixture was heated at 110 ° C in an atmosphere of N ₂ for 1 hour. The reaction mixture 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 following reaction.

Stage 2:

To 2-chloro-4-isothiocyanatopyridine (0.66 g, 3.90 mmol) in THF (20 ml) at 0 ° C was added NH ₂ NH _{2 ·} H ₂ O (0.21 ml, 4.3 mmol) and the reaction mixture was stirred at 0 ° C for 40 minutes. The reaction mixture was concentrated in vacuo and the product was used crude.

Stage 3:

Diethyl chlorophosphate (1.35 ml, 9.3 mmol) was added dropwise to thiosemicarbazide (0.79 g, 3.89 mmol) in anhydrous DMF (15 ml) at room temperature. The reaction mixture was stirred for 1 hour. The pH of the reaction mixture was adjusted to pH 7 using a saturated solution of NaHCO ₃ and 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 again extracted with CH ₂ Cl ₂ (2 × 15 ml). The combined 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 path V

Procedure V1 - Iodization

The method described in General Path A, Procedure 2 (A2).

Procedure V2 - Formation of 6- (4-fluorophenyl) -3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) pyrazolo [1,5-a] pyrimidine

To 6- (4-fluorophenyl) -3-iodo-pyrazolo [1,5-a] pyrimidine (0.69 g, 2.02 mmol) in anhydrous DMSO (4 ml) was added bis (pinacolato) dibor (1.03 g, 4.07 mmol) and KOAc (0.63 g, 6.38 mmol). The reaction flask was purged with N ₂ and PdCl ₂ dppf (82 mg, 0.11 mmol) was added. The reaction flask was purged again with N ₂ and then heated at 100 ° C for 3 hours. After cooling to room temperature, EtOAc (30 ml) and H ₂ O (30 ml) were added and the insoluble matter was filtered off. The filtrate was retained and the organic and aqueous phases were separated. The aqueous phase was extracted again with EtOAc (25 ml). The combined organic phases were dried over MgSO ₄ , 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 Procedure

K 6- (4-fluorophenyl) -3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) pyrazolo [1,5-a] pyrimidine (70 mg, 0 , 21 mmol) and (2-chloropyridin-4-yl) - [1,3,4] thiadiazol-2-ylamine (57 mg, 0.27 mmol) in dioxane (5 ml) was added 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (3.4 mg, 0.008 mmol), 1M K ₃ PO ₄ (0.62 ml, 0.62 mmol) and Pd ₂ (dba) ₃ (3.8 mg, 0.004 mmol). The reaction mixture was heated at 90 ° C for 18 hours. The reaction mixture was concentrated in vacuo and partitioned between CH ₂ Cl ₂ (15 ml) and H ₂ O (15 ml). The aqueous phase was again extracted with CH ₂ Cl ₂ (15 ml). The combined organic phases were dried over MgSO ₄ , filtered and concentrated in vacuo. The product was purified using preparative HPLC to give the desired product as a yellow solid (3.9 mg).

Procedure W

Stage 1: Imidazo [1,2-a] pyridin-7-carbonitrile

Chloroacetaldehyde (~ 50% in H ₂ O, 3.24 ml, 26 mmol) was added to a stirred mixture of 2-amino-isonicotinonitrile (1.6 g, 3.4 mmol) and NaHCO ₃ (2.23 g, 26.5 mmol) in ethanol (20 ml) at room temperature in an atmosphere of N ₂ . The reaction mixture was stirred and heated at 80 ° C for 18 hours. After cooling to room temperature, volatiles were removed in vacuo and the residue was partitioned between EtOAc / H ₂ O. The resulting mixture was filtered to remove some insoluble dark 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 chromatography on silica: 100% DCM → 1% 2M NH ₃ -MeOH / DCM to give the title product. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.74 (1H, dd), 8.35 (1H, s), 8.19 (1H, s), 7.86 (1H, s), 7 21 (1H, dd).

Stage 2: 7- (2H-Tetrazol-5-yl) -imidazo [1,2-a] pyridine

Sodium azide (97 mg, 1.45 mmol) was added to a stirred mixture of NH ₄ Cl (82 mg, 1.53 mmol) and imidazo [1,2-a] pyridine-7-carbonitrile (200 mg, 1.4 mmol) in anhydrous DMF (5 ml) at room temperature in an atmosphere of N ₂ . The reaction mixture was stirred and heated at 80 ° C in a sealed vessel for 10 hours [3 identical reactions were carried out in parallel]. After cooling to room temperature, the reaction mixtures were combined and diluted with Et ₂ O. The solid was collected by filtration and dried to obtain the title compound (860 mg) as a light brown solid [presumably containing NaCl]. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.55 (1H, dd), 8.02 (1H, s), 7.94 (1H, s), 7.57 (1H, d), 7 54 (1H, dd).

Stage 3: 7- (2-Methyl-2H-tetrazol-5-yl) -imidazo [1,2-a] pyridine + isomer

Methyl iodide (580 μl, 9.4 mmol) was added to a stirred mixture of 7- (2H-tetrazol-5-yl) -imidazo [1,2-a] pyridine (~ 4.5 mmol) and K ₂ CO ₃ (1, 3 g, 9.4 mmol) in anhydrous DMSO (5 ml) at room temperature in an atmosphere of N ₂ . After 5 hours, the reaction mixture was partitioned between EtOAc / H ₂ O. The aqueous layer was extracted with EtOAc (x2). The combined EtOAc extracts were dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by chromatography on silica: 100% DCM → 4% 2M NH ₃ -MeOH / DCM to give two regioisomers. [To assign regiochemistry used nOe analyzes]:

7- (2-Methyl-2H-tetrazol-5-yl) -imidazo [1,2-a] pyridine (less polar): ¹ H NMR (400 MHz, DMSO-d ₆ ): 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).

Stage 4: 3-Iodo-7- (2-methyl-2H-tetrazol-5-yl) -imidazo [1,2-a] pyridine

N-iodosuccinimide (300 mg, 1.3 mmol) was added in one portion to a stirred suspension of 7- (2-methyl-2H-tetrazol-5-yl) -imidazo [1,2-a] pyridine (240 mg, 1.2 mmol) in anhydrous DMF (2 ml) at room temperature in an atmosphere of N ₂ . After 5 hours, the reaction mixture was quenched with saturated aqueous sodium thiosulfate / saturated aqueous NaHCO ₃ (1: 1, 2 ml). Then water (2 ml) was added and the mixture was stirred at room temperature for 15 minutes. The solid was collected by filtration and dried in vacuo to give the title compound (360 mg) as a cream-colored solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.51 (1H, dd), 8.20 (1H, dd), 7.86 (1H, s), 7.65 (1H, dd), 4 47 (3H, s).

Step 5: {3- [7- (2-Methyl-2H-tetrazol-5-yl) -imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,3,4] thiadiazole- 2-ylamine

A mixture of 3-iodo-7- (2-methyl-2H-tetrazol-5-yl) -imidazo [1,2-a] pyridine (300 mg, 0.92 mmol), pinacol ether 3 - ([1,3, 4] thiadiazol-2-ylamino) -phenylboronic acid (I4, 350 mg, 1.15 mmol) and 2 N. Na ₂ CO ₃ (4.5 ml) in anhydrous DME (4.5 ml) was deoxygenated by gas evacuation / refill N ₂ (x2). PdCl ₂ dppf (70 mg, 0.10 mmol) was added and the mixture was again deoxygenated (x3). The reaction mixture was stirred and heated at 85 ° C for 3 hours. After cooling to room temperature, the mixture was partitioned between EtOAc / H ₂ O and stirred for 20 minutes. The solid that remained was collected by filtration and purified by column chromatography on silica (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 common path

Procedure AA1 - Imidazopyridine Ring Formation

To a solution of 4-substituted pyridin-2-ylamine (1.0 eq.) In EtOH was added NaHCO ₃ (2.0 eq.) Followed by the addition of chloroacetaldehyde (1.5 eq.). The mixture was refluxed for 2 hours. The 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.

R R ' Product MS: [M + H] ⁺ CH ₃ N 7-methyl-imidazo [1,2-a] pyridine 133

Procedure AA2 - Iodization

To a solution of 7-substituted imidazo [1,2-a] pyridine (1.0 eq.) In DMF was added N-iodosuccinimide (1.2 eq.), And the resulting mixture was stirred for 2 hours at room temperature. A brown liquid suspension was diluted with water, 10% w / v. sodium thiosulfate and sodium carbonate (1M) and was extracted with CH ₂ Cl ₂ . The aqueous phase was again extracted with CH ₂ Cl ₂ . The combined organic phases were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the product. If necessary, the product was further purified by trituration or column chromatography on silica.

R R ' Product MS: [M + H] ⁺ CH ₃ N 3-iodo-7-methyl-imidazo [1,2-a] pyridine 259

Procedure AA3b - Suzuki Reaction with 3 - ([[1,3,4] thiadiazol-2-ylamino) phenylboronic acid pinacol ester (I4)

To a solution of 7-substituted 3-iodo-imidazo [1,2-a] pyridine (1 equiv.) In DME was added pinacol ester of 3 - ([1,3,4] -thiadiazol-2-ylamino) -phenylboronic acid (I4 ) (1.2 equiv.), 1M Na ₂ CO ₃ (8 equiv.) [The reaction was degassed by sparging N ₂ ] followed by the addition of tetrakis (triphenylphosphine) 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, column chromatography on silica, or reverse phase HPLC. Suitably, the product was dissolved in HCl / dioxane, the solvent was removed, and the product was recrystallized from MeOH to give hydrochloride.

R R ' Product CH ₃ N [3- (7-Methyl-imidazo [1,2-a] pyridin-3-yl) phenyl] - [1,3,4] thiadiazol-2-ylamine hydrochloride

EXAMPLES 1-9

Following the methods described above, the compounds of Examples 1-9 were prepared, presented in the table below.

Etc. No. Compound Chemical name Procedure NMR data MS one

{3- [7- (4-Fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} pyrazin-2-ylamine General path B, procedure B1a using 4-fluorophenylboronic acid, procedure B2, procedure B3a using 3-aminobenzene-boronic acid, general modification F4 using 2-chloropyrazine ¹ H NMR (400 MHz, DMSO-d ₆ ): 9.71 (1H, s), 8.71 (1H, d), 8.28 (1H, s), 8.20 (1H, s), 8 10 (1H, s), 8.04-7.89 (4H, m), 7.84 (1H, s), 7.72 (1H, d), 7.51 (1H, t), 7, 47-7.25 (4H, m). MS: [M + H] ⁺ 382

2

{3- [7- (3-Morpholin-4-ylmethyl-phenyl) -imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,3,4] thiadiazol-2-ylamine General path B; Procedure B1a using 4- [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl] morpholine; procedure B2; Procedure B3a using 3 - ([1,3,4] thiadiazol-2-ylamino) phenylboronic acid pinacol ester (I4) ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.63 (1H, s), 8.95 (1H, s), 8.67 (1H, d), 8.04 (1H, t), 7 99 (1H, broad s), 7.84 (1H, s), 7.81-7.72 (2H, m), 7.68 (1H, dd), 7.56 (1H, t), 7.48 (1H, t), 7.44-7.36 (2H, m), 7.34 (1H, dt), 3.66-3.53 (6H, m), 2.47-2, 33 (4H, m). MS: [M + H] ⁺ 469 3

(5-Methyl- [1,3,4] thiadiazol-2-yl) - {3- [7- (3-morpholin-4-ylmethyl-phenyl) -imidazo [1,2-a] pyridin-3-yl ] phenyl} amine General path A;
procedure A1 and A2, procedure A3b using 3- (5-methyl- [1,3,4] thiadiazol-2-ylamino) phenylboronic acid pinacol ester (I5), procedure A4b using 4- [3- (4, 4,5,5-dioxaboron-2-yl) benzyl] morpholine ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.44 (1H, s), 8.66 (1H, d), 8.04-7.95 (2H, m), 7.83 (1H, s), 7.81-7.71 (2H, m), 7.63 (1H, broad d), 7.54 (1H, t), 7.48 (1H, t), 7.44-7 , 35 (2H, m), 7.31 (1H, d), 3.66-3.54 (6H, m), 2.58 (3H, s), 2.46-2.35 (4H, m ) MS: [M + H] ⁺ 483

four

(3- {7- [4- (4-Methyl-piperazin-1-ylmethyl) -
phenyl] imidazo [1,2-a] pyridin-3-yl} phenyl) - (3H- [1,2,3] thiadiazol-4-yl) amine, formate salt General procedure G; procedures G1 and G2 ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.95 (1H, s), 8.64 (1H, d), 8.27 (2H, s), 7.98 (1H, s), 7 86-7.75 (2H, m), 7.63 (1H, broad s), 7.48 (1H, s), 7.46-7.28 (5H, m), 7.09 (1H d) 3.52 (2H, s), 2.28-2.46 (8H, broad m), 2.17 (3H, s). MS: [M + H] ⁺ 465 5

{3- [7- (4-Fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} phenylamine, formate salt General path B, procedure B1a using 4-fluorophenylboronic acid, procedure B2, procedure B3a using 3-aminobenzene boronic acid, general modification F4 using bromobenzene ¹ H NMR (400 MHz, Me-d ₃ -OD): 8.55 (1H, d), 8.21 (1H, s), 7.85-7.74 (3H, m), 7.70 ( 1H, s), 7.40 (1H, t), 7.36-7.12 (9H, m), 7.07 (1H, d), 6.91 (1H, t). MS: [M + H] ⁺ 380

6

{3- [7- (4-Fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} pyridin-4-ylamine, formate salt General route B, procedure B1a using 4-fluorophenylboronic acid, procedure B2, procedure B3a using 3-aminobenzene boronic acid, general modification F4 using bromopyridine hydrochloride ¹ H NMR (400 MHz, Me-d ₃ -OD): 8.63 (1H, d), 8.44 (1H, s), 8.22 (2H, d), 7.87-7.79 ( 4H, m), 7.70 (1H, t), 7.63-7.59 (2H, m), 7.48-7.43 (1H, m), 7.37 (1H, dd), 7 31-7.24 (2H, m); 7.17 (2H, d). MS: [M + H] ⁺ 381 7

{3- [7- (4-Fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,3,4] thiadiazol-2-ylamine General route B, procedure B1a using 4-fluorophenylboronic acid, procedure B2, procedure B3a using pinacol ester of 3 - ([1,3,4] thiadiazol-2-ylamino) phenylboronic acid (I4) ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.69 (1H, s), 9.00 (1H, s), 8.72 (1H, d), 8.10-8.06 (2H, m), 8.01-7.96 (2H, m), 7.89 (1H, s), 7.74 (1H, dd), 7.61 (1H, t), 7.45-7.37 (4H, m). MS: [M + H] ⁺ 388

8

{3- [7- (3-Morpholin-4-ylmethyl-phenyl) -imidazo [1,2-a] pyridin-3-yl] phenyl} -phenylamine General route B, procedure B1a using 4- [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl] morpholine, procedure B2, procedure B3a using 3-aminobenzeneboronic acids, general modification of F4 using bromobenzene ¹ H NMR (400 MHz, Me-d ₃ -OD): 8.59 (1H, d), 7.89-7.82 (1H, m), 7.78 (1H, s), 7.76- 7.65 (2H, m), 7.52-7.46 (1H, m), 7.46-7.39 (2H, m), 7.35 (1H, dd), 7.33-7, 25 (3H, m), 7.25-7.14 (3H, m), 7.11 (1H, d), 6.97-6.87 (1H, m), 3.78-3.68 ( 4H, m), 3.64 (2H, s), 2.59-2.48 (4H, m). MS: [M + H] ⁺ 461 9

(3- {7- [3- (4-Methyl-piperazin-1-ylmethyl) -
phenyl] imidazo [1,2-a] pyridin-3-yl} phenyl) - [1,3,4] thiadiazol-2-yl-amine, formate salt General Route B Procedure B1d, B2, B3a using 3 - ([1,3,4] thiadiazol-2-ylamino) phenylboronic acid pinacol ester (I4) ¹ H NMR (400 MHz, Me-d ₃ -OD): 8.83 (1H, s), 8.72 (1H, d), 8.38 (3H, s), 8.19 (1H, s) 7.87 (1H, s), 7.79 (2H, s), 7.73 (1H, d), 7.57-7.32 (6H, m), 3.76 (2H, s), 3.23 (4H, s); 2.81 (7H, m). MS: [M + H] ⁺ 482

EXAMPLES 10-11

Following the methods described above, were obtained pyrazolo [1,5-a] pyrimidine compounds of examples 10-11, are presented in the table below.

Etc. No. Compound Chemical name Method NMR data MS 10

{3- [6- (4-Fluorophenyl) pyrazolo [1,5-a] pyrimidin-3-yl] phenyl} - [1,3,4] thiadiazol-2-ylamine Procedure K1, M, then N using 3 - ([1,3,4] thiadiazol-2-ylamino) phenylboronic acid pinacol ester (I4) ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.52 (1H, br s), 9.54 (1H, d), 9.04 (1H, d), 8.91 (1H, s) 8.74 (1H, s), 8.31 (1H, t), 8.01-7.91 (2H, m), 7.79-7.67 (2H, m), 7.48-7 35 (3H, m). MS: [M + H] ⁺ 389 eleven

5- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] pyrazolo [1,5-a] pyrimidin-6-yl} pyridin-2-ylamine, hydrochloride salt Procedure L using 2-amino-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine, Procedure M, then Procedure N using pinacol ether 3 - ([1 , 3,4] thiadiazol-2-ylamino) phenylboronic acid (I4) ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.57-10.52 (1H, m), 9.59 (1H, d), 9.01 (1H, d), 8.92 (1H, s), 8.77 (1H, s), 8.51 (1H, d), 8.45 (1H, dd), 8.36 (1H, s), 7.74 (1H, d), 7, 71-7.62 (1H, m), 7.45 (1H, t), 7.14 (1H, d). MS: [M + H] ⁺ 387

Example 12 {3- [6- (4-Fluorophenyl) pyrazolo [1,5-a] pyridin-3-yl1-phenyl} - [1,3,4] thiadiazol-2-ylamine

Stage 1: 3- (4-Fluorophenyl) -pyridine

A solution of 3-bromopyridine (2.5 g, 15.8 mmol) and 4-fluorophenylboronic acid (2.8 g, 20.0 mmol) in DME (20 ml) and 2 N. Na ₂ CO ₃ (aq., 20 ml) was deoxygenated by gas evacuation / refilling N ₂ (x2). PdCl ₂ dppf (600 mg, 0.8 mmol) was added and the mixture was deoxygenated again (x3). The reaction mixture was stirred and heated at 80 ° C. under N ₂ for 16 hours. After cooling to room temperature, the mixture was partitioned between EtOAc / H ₂ O. The aqueous layer was extracted with EtOAc (x2). The combined extracts were washed with brine (x1), dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by chromatography on silica (10 → 40% EtOAc / gasoline) to give the title compound (3.0 g, oil). ¹ H NMR (400 MHz, CDCl ₃ ): 8.83 (1H, broad s), 8.61 (1H, broad s), 7.85 (1H, d), 7.54 (2H, dd) 7.39 (1H, broad s); 7.18 (2H, t).

Stage 2: 6- (4-Fluorophenyl) -pyrazolo [1,5-a] pyridine-3-carboxylic acid methyl ester

O- (mesitylenesulfonyl) hydroxylamine (3.5 g, 16.2 mmol) was added in one portion to a stirred solution of 3- (4-fluorophenyl) pyridine (2.8 g, 16 mmol) in anhydrous CH ₂ Cl ₂ at 0 ° C in an atmosphere of N ₂ . After 30 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 16 hours. Volatiles were removed in vacuo and N-aminopyridine was used without further purification. To a stirred solution of the obtained N-aminopyridine (~ 16 mmol) was added K ₂ CO ₃ (4.4 g, 32 mmol) and 2-benzenesulfonyl-3-dimethylamino-acrylic acid methyl ester (4.3 g, 16 mmol) in anhydrous DMF (48 ml) at room temperature in an atmosphere of N ₂ . After 3 hours at room temperature, the reaction mixture was heated at 100 ° C for 2 hours. After cooling to room temperature, the mixture was partitioned between EtOAc / H ₂ O. The aqueous layer was extracted with EtOAc (x2). The combined extracts were washed with water (x1), brine (x1), then dried (MgSO ₄ ), filtered and evaporated. The residue was purified by trituration with CH ₂ Cl ₂ / gasoline to give the title compound (2.7 g, solid). ¹ H NMR (400 MHz, CDCl ₃ ): 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).

Stage 3: 6- (4-Fluorophenyl) pyrazolo [1,5-a] pyridine

A mixture of 6- (4-fluorophenyl) pyrazolo [1,5-a] pyridine-3-carboxylic acid methyl ester (1.08 g, 4 mmol) and an aqueous solution of NaOH (2N, 4 ml) and EtOH (16 ml) was stirred and heated at 85 ° C in an atmosphere of N ₂ for 30 minutes. The reaction mixture was allowed to cool to room temperature, then placed in an ice bath. Slowly added 2 N. hydrochloric acid solution (5 ml). The solid was collected by filtration, washed with Et ₂ O, then dried in vacuo. The acid was used without further manipulation. A suspension of the obtained acid in polyphosphoric acid (~ 15 ml) was stirred and heated at 150 ° C in an atmosphere of N ₂ . After 3 hours, the reaction mixture was allowed to cool to room temperature, then carefully poured onto ice water. The solid was isolated by filtration, then dissolved in CH ₂ Cl ₂ . The resulting solution was passed through a phase separation cartridge, then evaporated to give the title compound (582 mg, solid). ¹ H NMR (400 MHz, CDCl ₃ ): 8.66 (1H, s), 7.98 (1H, s), 7.63-7.51 (3H, m), 7.34 (1H, d) 7.17 (2H, t); 6.55 (1H, s).

Stage 4: 6- (4-Fluorophenyl) -3-iodo-pyrazolo [1,5-a] pyridine

N-iodosuccinimide (630 mg, 2.8 mmol) was added in one portion to a stirred solution of 6- (4-fluorophenyl) pyrazolo [1,5-a] pyridine (500 mg, 2.4 mmol) in anhydrous DMF (6 ml ) at room temperature in an atmosphere of N ₂ . After 45 minutes, the reaction was quenched with saturated aqueous sodium thiosulfate / saturated NaHCO ₃ solution (1: 1, 40 ml). The mixture was stirred at room temperature for 15 minutes, then partitioned between EtOAc / H ₂ O. The organic layer was washed with water (x1), brine (x1), then dried (MgSO ₄ ), filtered and evaporated. The residue was purified by trituration with gasoline to give the title compound (635 mg, solid). ¹ H NMR (400 MHz, CDCl ₃ ): 8.61 (1H, s), 7.98 (1H, s), 7.57-7.51 (3H, m), 7.42 (1H, dd) 7.22-7.13 (2H, m).

Step 5: {3- [6- (4-Fluorophenyl) pyrazolo [1,5-a] pyridin-3-yl] phenyl [1,3,4] thiadiazol-2-yl amine

A mixture of 6- (4-fluorophenyl) -3-iodo-pyrazolo [1,5-a] pyridine (150 mg, 0.44 mmol), pinacol ether 3 - ([1,3,4] thiadiazol-2-ylamino) α-phenylboronic acid (190 mg, 0.62 mmol) and PdCl ₂ ddpf (32 mg, 0.04 mmol) in DME (1.5 ml) and 2 N. Na ₂ CO ₃ (aq., 1.5 ml) in a microwave vessel was deoxygenated by sparging N ₂ through the mixture for 30 seconds. The vessel was sealed and then stirred and heated at 150 ° C. in the microwave for 30 minutes. After cooling to room temperature, the mixture was partitioned between CH ₂ Cl ₂ / H ₂ O. The organic layer was evaporated and the residue was purified using preparative HPLC to give the title compound (15 mg, solid).

Etc. No. Compound Chemical name Method NMR data MS 12

{3- [6- (4-Fluorophenyl) pyrazolo [1,5-a] pyridin-3-yl] phenyl} - [1,3,4] thiadiazol-2-ylamine Separate example described above ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.52 (1H, s), 9.12 (1H, s), 8.94 (1H, s), 8.42 (1H, s), 8 12-8.06 (2H, m), 7.93-7.87 (2H, m), 7.74 (1H, dd), 7.54 (1H, d), 7.45 (1H, t) ), 7.41-7.30 (3H, m). MS: [M + H] ⁺ 388

EXAMPLES 13-43

Etc. No. Compound Chemical
title Method Data
NMR Data
Ms 13

{3- [3- (3-benzylamin-o-phenyl) -imidazo [1,2-a] pyridin-7-yl] phenyl} -acetic acid General path A, procedure A3 using 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline and the conditions described in A4d, modification F8, procedure A4e using 2- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) acetic acid ¹ H NMR (400 MHz, Me-d ₃ -OD): 8.26 (1H, d), 7.83 (1H, s), 7.72 (1H, s), 7.66 (1H, d) 7.64-7.58 (1H, m), 7.53-7.25 (9H, m), 7.22 (1H, dd), 6.86 (1H, d), 6.78 (2H d) 4.43 (2H, s), 3.73 (2H, s). [M + H] ⁺ 434

fourteen

{3- [7- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,3,4] thiadiazol-2-ylamine General route B, procedure B1c using 7-bromo-imidazole [1,2-a] pyridine and 1-methylpyrazole-4-boronic acid pinacol ester, B2 and then B3b using 3 - pinacol ester ([1,3,4 ] thiadiazol-2-ylamino) phenyl-boronic acid (I4) ¹ H NMR (DMSO-d ₆ ): 10.60 (1H, s), 8.94 (1H, s), 8.59 (1H, d), 8.37 (1H, s), 8.09 ( 1H, s), 8.00 (1H, s), 7.39 (1H, s), 7.73 (1H, s), 7.65 (1H, dd), 7.54 (1H, t), 7.30 (1H, dd), 7.25 (1H, dd), 3.90 (3H, s). [M + H] ⁺ 374 fifteen

[3- (6-pyrimidin-4-yl-pyrazolo [1,5-a] pyrimidin-3-yl) phenyl] - [1,3,4] thiadiazol-2-ylamine Procedure K using 2- (4-pyrimidyl) malondialdehyde, procedure B2, procedure B3a using I17 ¹ H NMR (400 MHz, DMSO-d ₆ ): 9.99 (1H, d), 9.43 (1H, d), 9.33 (1H, s), 9.00-8.93 (1H, m), 8.85 (2H, d), 8.35 (1H, d), 8.28 (1H, s), 7.76-7.64 (2H, m), 7.43 (1H, t) ) [M + H] ⁺ 373

16

{3- [6- (1-methyl-1H-pyrazol-4-yl) -pyrazolo [1,5-a] pyrimidin-3-yl] phenyl} - [1,3,4] thiadiazol-2-ylamine Procedure K, B1c using 1-methylpyrazole-4-boronic acid pinacol ester, M and then B3b using 3 - ([1,3,4] thiadiazol-2-ylamino) phenylboronic acid pinacol ester (I4) ¹ H NMR (DMSO-d ₆ ): 10.50 (1H, s), 9.47 (1H, m), 8.98 (1H, m), 8.91 (1H, s), 8.66 ( 1H, s), 8.39 (1H, s), 8.30 (1H, s), 8.12 (1H, s), 7.70 (2H, m), 7.43 (1H, t), 3.92 (3H, s). [M + H] ⁺ 375 17

[3- (6-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-3-yl) phenyl] - [1,3,4] thiadiazol-2-ylamine Procedure K using 2- (4-pyridyl) malondialdehyde,
procedure B2,
procedure B3a using I17 ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.58-10.50 (1H, m), 9.77 (1H, d), 9.16 (1H, d), 8.92 (1H, s), 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). [M + H] ⁺ 372 eighteen

[3- (6-pyrazin-2-yl-pyrazolo [1,5-a] pyrimidin-3-yl) phenyl] - [1,3,4] thiadiazol-2-ylamine Procedure K using 2- (2-pyrazinyl) malondialdehyde, procedure B2, procedure B3a using I17 ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.55 (1H, s), 9.93 (1H, d), 9.49 (1H, d), 9.39 (1H, d), 8 92 (1H, s), 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). [M + H] ⁺ 373

19

[3- (7-morpholin-4-yl-imidazo [1,2-a] pyridin-3-yl) phenyl] - [1,3,4] thiadiazol-2-ylamine General pathway B, procedure B1b using morpholine (as described in procedure E), procedure B2, procedure B3a using 3 - ([1,3,4] thiadiazol-2-ylamino) -phenyl-boronic acid pinacol ester (I4) ¹ H NMR (400 MHz, Me-d ₃ -OD): 8.82 (1H, s), 8.47 (1H, d), 8.05 (1H, s), 7.57-7.48 ( 3H, m), 7.33-7.25 (1H, m), 6.96 (1H, dd), 6.80 (1H, d), 3.88 (4H, t), 3.32-3 30 (4H, m). [M + H] ⁺ 379 twenty

[3- (7-benzo [1,3] -dioxol-5-yl-imidazo [1,2-a] pyridin-3-yl) phenyl] - [1,3,4] thiadiazol-2-ylamine, formate General path A, procedure A1, procedure A2, procedure A3b using pinacol ether 3 - ([1,3,4] thiadiazol-2-ylamino) -phenyl-
boronic acid (I4), procedure A4b using 3,4-methylenedioxyphenylboronic acid pinacol ester ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.62 (1H, s), 8.95 (1H, s), 8.61 (1H, d), 8.02 (1H, s), 7 95 (1H, s), 7.81 (1H, s), 7.73-7.59 (2H, m), 7.59-7.46 (2H, m), 7.42-7.28 (3H, m), 7.05 (1H, d), 6.11 (2H, s). [adduct] ⁺ 414

21

{3- [7- (4-ethanesulfonyl-piperazin-1-yl) -imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,3,4] thiadiazol-2-ylamine, hydrochloride General route B, procedure B1b using ethanesulfonyl piperazine, procedure B2, procedure B3a using 3 - ([1,3,4] thiadiazol-2-ylamino) -phenyl-boronic acid pinacol ester (I4), procedure J ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.89-10.82 (1H, m), 8.96 (1H, s), 8.14 (1H, s), 8.09 (1H, s), 7.71 (1H, d), 7.59 (1H, d), 7.33 (1H, dd), 7.30 (1H, d), 6.97 (1H, d), 3, 65 (4H, m), 3.37 (4H, m), 3.18-3.11 (2H, m), 1.25 (3H, t). [adduct] ⁺ 470 22

morpholin-4-yl- (3- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} phenyl) - methanone hydrochloride General path A, procedure A1, procedure A2, procedure A3b using 3 - ([1,3,4] thiadiazol-2-ylamino) phenyl-boronic acid pinacol ester (I4), procedure A4b using 3- (morpholine- 4-carbonyl) phenylboronic acid, procedure J ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.94 (1H, s), 8.97 (1H, s), 8.87 (1H, d), 8.49 (1H, s), 8 34 (1H, s), 8.22 (1H, s), 8.05 (1H, d), 7.99 (1H, s), 7.92 (1H, d), 7.79 (1H, d), 7.76-7.56 (3H, m), 7.39 (1H, d), 3.64 (6H, broad m), 3.42 (2H, d). [M + H] ⁺ 483

23

{3- [5- (4-fluorophenyl) benzoimidazol-1-yl] phenyl} - [1,3,4] thiadiazol-2-ylamine General procedure O, procedures O1, O2, O3, O4, procedures O7a and O7b H NMR (400 MHz, DMSO-d ₆ ): 10.77 (1H, s), 8.98 (1H, s), 8.65 (1H, s), 8.17 (1H, t), 8, 06 (1H, d), 7.83-7.75 (3H, m), 7.71-7.56 (3H, m), 7.38-7.25 (3H, m). [M + H] ⁺ 388 24

[3- (7-piperidin-1-yl-imidazo [1,2-a] pyridin-3-yl) phenyl] - [1,3,4] thiadiazol-2-ylamine General route B, procedure B1b using piperidine, procedure B2, procedure B3a using pinacol ether 3 - ([1,3,4] thiadiazol-2-ylamino) phenyl-
boronic acid (I4) ¹ H NMR (400 MHz, Me-d ₃ -OD): 8.85 (1H, s), 8.48 (1H, d), 8.41 (1H, s), 8.24 (1H, s) 7.72 (1H, s), 7.56 (2H, d), 7.36-7.27 (1H, m), 7.27-7.12 (1H, m), 6.83 (1H d), 3.58 (4H, m), 1.75 (6H, m). [M + H] ⁺ 377 25

{5- [6- (4-fluorophenyl) pyrazolo [1,5-a] pyrimidin-3-yl] pyridin-3-yl} - [1,3,4] thiadiazol-2-ylamine General path K1, general path V, procedure V1, procedure V2, procedure V3 using the halogen monomer from procedure U in which 5-bromo-pyridin-3-ylamine was used ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.72 (1H, s), 9.59 (1H, d), 9.09 (1H, d), 8.99 (1H, s), 8 95 (1H, s), 8.88 (1H, s), 8.82 (2H, s), 7.97 (2H, dd), 7.41 (2H, t). [M + H] ⁺ 390

26

N-methyl-2- (3- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} phenyl) - acetamide hydrochloride General path A, procedure A1, procedure A2, procedure A3b using pinacol ether 3 - ([1,3,4] thiadiazol-2-ylamino) -phenyl-
boronic acid (I4), procedure A4b using I18, procedure J ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.04 (1H, s), 8.96 (1H, s), 8.88 (1H, d), 8.48 (1H, s), 8 23 (2H, d), 8.12 (1H, m), 7.90-7.76 (4H, m), 7.65 (1H, t), 7.54 (1H, t), 7, 45 (1H, d), 7.39 (1H, d), 3.55 (2H, s), 2.60 (3H, s). [M + H] ⁺ 441 27

N * 3 * - {3- [7- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} -1H- [1,2,4] thiazole-3,5- diamine General route B, procedure B1a using 4-fluorophenyl boronic acid, procedure B2, procedure B3 using 3-aminobenzene-
boronic acid, general modification Q ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.17 (1H, s), 8.84 (1H, s), 8.64 (1H, d), 7.98 (1H, s), 7 94-7.90 (3H, m), 7.76 (1H, s), 7.52 (1H, d), 7.39-7.33 (4H, m), 7.03 (1H, d) ), 5.89 (2H, s). [M + H] ⁺ 386

28

4- (3- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} benzyl) piperazin-2 -on, formate General path A, procedure A1, procedure A2, procedure A3b using pinacol ether 3 - ([1,3,4] thiadiazol-2-ylamino) -phenyl-
boronic acid (I4), procedure A4b using I19 ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.65 (1H, s), 8.95 (1H, s), 8.68 (1H, d), 8.20 (2H, s), 8 , 07-7.97 (2H, m), 7.84 (1H, s), 7.83-7.72 (3H, m), 7.68 (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). [M + H] ⁺ 482 29th

{3- [7- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,3,4] oxadiazol-2-ylamine General route B, procedure B1a using 4-fluorophenyl boronic acid, procedure B2, procedure B3a using 3-aminobenzene-
boronic acid procedure S ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.69 (1H, s), 8.78 (1H, s), 8.65 (1H, dd), 8.01 (1H, d), 7 99-7.87 (3H, m), 7.83 (1H, s), 7.65-7.61 (1H, m), 7.56 (1H, t), 7.44-7.29 (4H, m). [M + H] ⁺ 372

thirty

N-methyl-3- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} benzamide, hydrochloride General path A, procedure A1, procedure A2, procedure A3b using pinacol ether 3 - ([1,3,4] thiadiazol-2-ylamino) -phenyl-
boronic acid (I4), procedure A4b using 3- (N-methylamino-carbonyl) -benzeneboronic acid, procedure J ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.00 (1H, s), 8.96 (1H, s), 8.90 (1H, d), 8.77 (1H, m), 8 50 (1H, s), 8.38 (2H, d), 8.23 (1H, s), 8.11 (1H, d), 8.02 (1H, d), 7.96 (1H, dd), 7.81 (1H, dd), 7.76-7.60 (2H, m), 7.39 (1H, d), 2.85 (3H, d). [M + H] ⁺ 427 31

{2- [6- (4-fluorophenyl) pyrazolo [1,5-a] pyrimidin-3-yl] pyridin-4-yl} - [1,3,4] thiadiazol-2-ylamine General path K1, general path V, procedure V1, procedure V2, procedure V3 using halogen monomer U1 ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.06 (1H, s), 9.59 (1H, d), 9.10 (1H, d), 9.06 (1H, s), 8 85 (1H, s), 8.51 (1H, s), 8.50-8.47 (1H, m), 8.03-7.94 (2H, m), 7.80 (1H, dd ), 7.47-7.36 (2H, m). [M + H] ⁺ 390

32

{3- [7- (3-aminophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,3,4] thiadiazol-2-ylamine, hydrochloride General path A, procedure A1, procedure A2, procedure A3b using pinacol ether 3 - ([1,3,4] thiadiazol-2-ylamino) -phenyl-
boronic acid (I4), procedure A4b using (3-Boc-aminophenyl) -boronic acid, procedure D3b ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.98 (1H, s), 8.96 (1H, s), 8.89 (1H, d), 8.48 (1H, s), 8 20 (2H, d), 7.85-7.74 (2H, m), 7.69-7.50 (4H, m), 7.39 (1H, d), 7.28-7.19 (1H, m). [M + H] ⁺ 385 33

(3- {7- [2- (tetrahydropyran-4-yloxy) -pyridin-4-yl] imidazo [1,2-a] pyridin-3-yl} phenyl) - [1,3,4] thiadiazole -2-ylamine General path A, procedure A1, procedure A2, procedure A3b using pinacol ether 3 - ([1,3,4] thiadiazol-2-ylamino) -phenyl-
boronic acid (I4), procedure A4b using I21 ¹ H NMR (400 MHz, Me-d ₃ -OD): 8.83 (1H, s), 8.73 (1H, d), 8.27-8.17 (1H, m), 8.15 ( 1H, s), 8.00 (1H, s), 7.83 (1H, s), 7.62-7.54 (2H, m), 7.42 (1H, d), 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). [M + H] ⁺ 471

34

{3- [7- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} - (1-methyl-1H-imidazol-2-yl) -amine, hydrochloride General path B, procedure B1a using
4-fluorophenyl
boronic acid, procedure B2,
procedure B3a using (1-methyl-1H-imidazol-2-yl) - [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] amine (I16) ¹ H NMR (400 MHz, Me-d ₃ -OD): 8.87-8.79 (1H, m), 8.19 (2H, d), 8.01-7.92 (2H, m), 7.87-7.72 (2H, m), 7.70-7.62 (2H, m), 7.52 (1H, d), 7.37 (2H, t), 7.20 (1H, d), 7.09 (1H, d), 3.75 (3H, s). [M + H] ⁺ 384 35

(3- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} phenyl) methanol General path A, procedure A1, procedure A2, procedure A3b using pinacol ether 3 - ([1,3,4] thiadiazol-2-ylamino) -phenyl-
boronic acid (I4), procedure A4b using (3-hydroxymethylphenyl) -boronic acid ¹ H NMR (400 MHz, Me-d ₃ -OD): 8.83 (1H, s), 8.72 (1H, d), 8.13 (1H, s), 7.88 (1H, s) 7.79 (2H, d), 7.71 (1H, d), 7.65-7.48 (3H, m), 7.48-7.33 (3H, m), 4.74 (2H , from). [M + H] ⁺ 400

36

4- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} piperazine-1-carboxylic acid ethyl ester General path B,
procedure B1b using ethyl piperazine-1-carboxylate, procedure B2, procedure B3a using pinacol ether 3 - ([1,3,4] thiadiazol-2-ylamino) -phenyl-
boronic acid (I4) ¹ H NMR (400 MHz, Me-d ₃ -OD): 8.84 (1H, s), 8.51 (1H, d), 8.42 (1H, s), 8.21 (1H, s) 7.72 (1H, s), 7.63-7.49 (2H, m), 7.30 (1H, d), 7.18 (1H, d), 6.92-6.82 (1H , m), 4.19 (2H, q), 3.68 (4H, s), 3.54 (4H, s), 1.31 (3H, t). [M + H] ⁺ 450 37

5- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} pyridin-2-ylamine, hydrochloride General path A,
procedure A1,
A2 procedure
A3b procedure using 3 - ([1,3,4] thiadiazol-2-ylamino) phenyl- pinacol ester
boronic acid (I4), procedure A4b using 2-amino-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine, procedure J ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.91 (1H, s), 8.96 (1H, s), 8.85 (1H, d), 8.67 (1H, d), 8 45 (1H, d), 8.40 (1H, m), 8.21 (2H, m), 8.15 (2H, br s), 7.84-7.71 (2H, m), 7.63 (1H, t), 7.37 (1H, d), 7.10 (1H, m). [M + H] ⁺ 386

38

1- (4- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} piperazin-1-yl) ethanone General path B,
procedure B1b using N-acylpiperazine,
procedure B2,
procedure B3a using 3 - ([1,3,4] thiadiazol-2-ylamino) phenyl- pinacol ester
boronic acid (I4) ¹ H NMR (400 MHz, Me-d ₃ -OD): 9.11 (1H, s), 8.53 (1H, d), 7.99 (1H, s), 7.88 (1H, s) 7.79-7.67 (2H, m), 7.62 (1H, d), 7.33 (1H, d), 6.98 (1H, s), 3.83 (4H, m), 3.73 (4H, m); 2.22 (3H, s). [M + H] ⁺ 420 39

{3- [7- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,2,4] thiadiazol-5-ylamine General path B,
procedure B1a using
4-fluorophenyl
boronic acid, procedure B2,
procedure B3b using 3 - ([1,2,4] thiadiazol-5-ylamino) phenyl- pinacol ester
boronic acid (I24), K ₃ PO ₄ instead of Na ₂ CO ₃ ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.18 (1H, s), 8.70 (1H, d), 8.26 (1H, s), 8.06-7.89 (4H, m), 7.86 (1H, s) , 7.65-7.54 (2H, m), 7.46-7.30 (4H, m). [M + H] ⁺ 388

40

N- (3- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} benzyl) methanesulfonamide General path A,
procedure A1,
A2 procedure
A3b procedure using 3 - ([1,3,4] thiadiazol-2-ylamino) phenyl- pinacol ester
boronic acid (I4), procedure A4b using (3-methanesulfonyl-aminomethyl) -benzeneboronic acid ¹ H NMR (400 MHz, Me-d ₃ -OD): 8.81 (1H, s), 8.58 (1H, d), 8.30 (1H, s), 8.07 (1H, s) 7.78 (1H, s), 7.72 (2H, d), 7.62 (1H, d), 7.55-7.37 (4H, m), 7.30 (1H, d), 7.25 (1H, d), 4.33 (2H, s), 2.94 (3H, s). [M + H] ⁺ 477 41

[3- (7-methyl-imidazo [1,2-a] pyridin-3-yl) phenyl] - [1,3,4] thiadiazol-2-ylamine, hydrochloride Procedure AA1 using 4-methyl-2-aminopyridine,
AA2 procedure
Procedure AA3b using 3 - ([1,3,4] thiadiazol-2-ylamino) phenyl- pinacol ester
boronic acid (I4) procedure J ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.04-7.95 (1H, m), 7.70 (1H, d), 7.23 (1H, s), 6.83 (1H, s), 6.78 (1H, d), 6.76-6.70 (1H, m), 6.60 (1H, s), 6.50 (1H, d), 6.09 (1H, d) ), 1.65 (3H, s). [adduct] ⁺ 308

42

benzyl- {3- [7- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-a] pyridin-3-yl] phenyl} -amine General path A,
Procedure A3 using 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline and the conditions described in A4d, modification F8,
A4b procedure using
1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole and K ₃ PO ₄ instead of Na ₂ CO ₃ ¹ H NMR (400 MHz, Me-d ₃ -OD): 8.21-8.10 (2H, m), 7.97 (1H, s), 7.69 (1H, s), 7.60- 7.48 (1H, m), 7.47-7.21 (7H, m), 7.08 (1H, d), 6.87-6.78 (1H, m), 6.75 (2H, d) 4.41 (2H, s), 3.97 (3H, s). [M + H] ⁺ 380 43

{3- [7- (2-methyl-2H-tetrazol-5-yl) -imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,3,4] thiadiazol-2-ylamine Procedure W ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.64 (1H, s), 8.95 (1H, s), 8.78 (1H, d), 8.29 (1H, s), 8 02 (1H, s), 7.94 (1H, s), 7.73 (1H, dd), 7.61-7.55 (2H, m), 7.35 (1H, d), 4, 48 (3H, s). [M + H] ⁺ 376

Biological tests

In vitro kinase activity inhibition assays of FGFR3 and PDGFR

Enzymes (from Upstate) were obtained at 2x final concentration in 1x kinase assay buffer (as described below). Enzymes were then incubated with test compounds, biotinylated Flt3 substrate (Biotin-DNEYFYV) (Cell Signaling Technology Inc.) and ATP. The reaction mixture was allowed to react for 3 hours (FGFR3) or 2.5 hours (PDGFR-beta) at room temperature on a plate shaker at 900 rpm, then the reaction was stopped with 20 μl of 35 mm EDTA, pH 8 (FGFR3) or 55 mM EDTA, pH 8 (PDGFR-beta). Then, twenty μl of a 5x detection mixture (50 mM HEPES, pH 7.5, 0.1% BSA, 2 nM Eu-anti-pY (PY20) (PerkinElmer), 15 nM SA-XL665 (Cisbio) for FGFR3 and 50 mM HEPES, pH 7.5, 0.5 M KF, 0.1% BSA, 11.34 nM Eu-anti-pY (PT66) (PerkinElmer), 94 nM SA-XL665 (Cisbio) for PDGFR- beta) and the plate were sealed and incubated at room temperature for one hour on a plate shaker at 900 rpm. The tablet was then read on a Packard Fusion tablet reader in TRF mode.

Enzyme 1x Buffer for analysis Substrate concentration Flt3 ATP concentration FGFR3 BUT 0.125 μM 8 μM PDGFR beta B 0.15 μM 30 μm

Kinase analytical buffers were as follows:

A: 50 mM HEPES, pH 7.5, 6 mM MnCl ₂ , 1 mM DTT, 0.1% TritonX-100;

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

The compounds of the present invention (for example, examples 1-14 and 16-43) have IC ₅₀ values of less than 10 μM or provide at least 50% inhibition of FGFR3 activity at a concentration of 10 μM. Preferred compounds of the present invention (for example, examples 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23 , 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 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- il) phenyl] - [1,3,4] thiadiazol-2-yl-amine] and the product of procedure G1 [[3- (7-chloro-imidazo [1,2-a] pyridin-3-yl) phenyl ] - (3H- [1,2,3] triazol-4-yl) -amine]) have IC ₅₀ values of less than 1 μM in the FGFR3 assay.

In vitro analysis of the inhibition of kinase activity of VEGFR2

In the analysis, reactions containing VEGFR2 enzyme (purchased from Upstate) and 250 μM Poly (Glu, Tyr) 4: 1 substrate (CisBio) in 50 mM HEPES, pH 7.5, 6 mM MnCl ₂ , 1 mM DTT, 0.01 % TritonX-100, 5 μM ATP (2.8 Ci / mmol) was carried out in the presence of a compound. Reactions were stopped after 15 minutes by adding excess phosphoric acid. The reaction mixture was then transferred to a Millipore MAPH filter plate, where the peptide binding and unused ATP were removed by washing. After washing, a scintillator was added and the incorporated activity was measured by scintillation counting using a Packard Topcount.

In vitro kinase activity inhibition assays 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 10x final concentration in enzyme buffer (20 mM MOPS, pH 7.0, 1 mM EDTA, 0.1% B-mercaptoethanol, 0.01% Brij-35, 5% glycerol, 1 mg / ml BSA). Enzymes were then incubated in assay buffer with various substrates and ³³ P-ATP (~ 500 cpm (pulses per minute) / pmol) as described in the table.

The reaction was initiated by the addition of Mg / ATP. The reaction mixture was allowed to react for 40 minutes at room temperature, then the reaction was stopped with 5 μl of a 3% phosphoric acid solution. Ten μl of the reaction mixture was transferred to filters, either filtermatA or P30 filtermat, and washed three times with 75 mM phosphoric acid and once in methanol, then dried for scintillation counting.

Compounds were tested at the concentrations indicated below, in duplicate against all kinases, and the percent activity was calculated compared to the control. When inhibition was high, an IC _{50 was} determined.

Enzyme Analysis buffer Substrate ATP Concentration (μM) FGFR1 BUT 250 μM KKKSPGEYVNIEFG 200 μm FGFR2 AT 0.1 mg / ml Poly (Glu, Tyr) 4: 1 90 μM FGFR4 FROM 0.1 mg / ml Poly (Glu, Tyr) 4: 1 155 μm VEGFR1 BUT 250 μM KKKSPGEYVNIEFG 200 μm VEGFR3 BUT 500 μm GGEEEEYFELVKKKK 200 μm

Enzyme buffer A: 8 mM MOPS, pH 7.0, 0.2 mM EDTA, 10 mM MgAcetate.

Enzyme buffer B: 8 mM MOPS, pH 7.0, 0.2 mM EDTA, 2.5 mM MnCl ₂ , 10 mM MgAcetate.

Enzyme buffer C: 8 mM Mops, pH 7.0, 0.2 mM EDTA, 10 mM MnCl ₂ , 10 mM MgAcetate.

Cell analysis of pERK by ELISA

Multiple myeloma LP-1 or JIM-1 cells were seeded in 96-well plates at a density of 1x10 ⁶ cells / ml in 200 μl per well in serum-free medium. HUVEC cells were seeded at a density of 2.5 x 10 ⁵ cells / ml and allowed to recover for 24 hours before being transferred to serum-free medium. Cells were incubated for 16 hours at 37 ° C before the test compound was added for 30 minutes. Test compounds were added at a final DMSO concentration of 0.1%. After a 30-minute incubation, a FGF-1 / heparin mixture (FGF-1 at a final concentration of 100 ng / ml and heparin at 100 μg / ml) or VEGF ¹⁶⁵ (100 μg / ml) was added to each well over the next 5 minutes. The medium was removed and 50 μl of ERK ELISA lysis buffer (R and D Systems DuoSet ELISA for pERK and total ERK # DYC-1940E, DYC-1018E) was added. ELISA plates and standards were prepared according to standard DuoSet protocols and the relative amounts of pERK relative to the total amount of ERK in each sample were calculated according to a standard curve.

In particular, the compounds of the present invention were tested against an LP-1 cell line (DSMZ no .: ACC 41) isolated from human multiple myeloma cells. Many compounds of the present invention were found to have IC ₅₀ values of less than 20 μM 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 starting material of procedure A4c [3- (7-chloro-imidazo [1,2-a] pyridin-3-yl) phenyl] - [1,3,4] thiadiazol-2-ylamine]) had an IC ₅₀ value of less than 1 μM.

HUVEC Cell Selectivity Assays

HUVEC cells were seeded in 6-well plates at a density of 1x10 ⁵ cells / ml and allowed to recover for 24 hours. Cells were transferred to serum-free medium for 16 hours before being treated with the test compound for 30 minutes at a final DMSO concentration of 0.1%. After incubation of the compounds for 5 minutes, FGF-1 (100 ng / ml) and heparin (100 μg / ml) or VEGF ¹⁶⁵ (100 ng / ml) were added. The medium was removed, the cells were washed with ice-cold PBS and lysed in 100 μl TG lysis buffer (20 mM Tris, 130 nM NaCl, 1% Triton-X-100, 10% glycerol, protease and phosphatase inhibitors, pH 7.5). Samples containing equivalent amounts of protein were combined with LDS sample buffer and analyzed by SDS PAGE and then by Western blotting for the number of downstream VEGFR and FGFR target pathways, including phospho-FGFR3, phospho-VEGFR2 and phospho-ERK1 / 2.

In vivo hypertension models

There are a number of animal models for measuring the potential hypertensive effects of small inhibitor molecules. They can be divided into two main types: indirect and direct measurement. The most widely used indirect method is the cuff method. Such methods have an advantage since are non-invasive, and, as such, they are applicable to a larger group of experimental animals, although this method only allows periodic determination of blood pressure and requires that the animals be limited in some way. The use of limiting agents can cause stress in the animal and means that it is difficult to determine changes in blood pressure associated with a specific drug action.

Direct methods include those that use radio telemetry or inserted catheters connected to external transducers. Such methods require a high level of specialized knowledge for the initial surgical intervention associated with implantation and high costs. However, a key advantage is that they make it possible to continuously monitor blood pressure without restricting the animal during the experiment. These methods are described in Kurz et al. (2005) Hypertension. 45: 299-310.

results

Biological data from an in vitro analysis of the inhibition of the kinase activity of FGFR3 and cell analysis of pERK by ELISA described above, for these examples are presented below.

Example Number FGFR3 IC ₅₀ (μM) LP-1 pERK
ELISA (μM) 7 0.00220 0,069 10 0,00482 0,0390 eleven 0,00603 0,0400 fourteen 0.0160 0.00850 37 0,00255 27 0.130 29th 0.0110 31 0.350 39 0.115 34 0.480 43 0,0339 0.140

Claims (22)

1. The compound of formula (I):

where X ₁ represents carbon;
X ₂ and X ₃ are each independently selected from carbon or nitrogen, such that at least one of X ₂ —X ₃ is nitrogen;
X ₄ represents CR ³ or nitrogen;
X ₅ represents CR ⁶ ;
with the proviso that not more than three of X ₂ —X ₄ are nitrogen;

represents a single or double bond, so that at least one bond in the 5-membered ring system is a double bond;
R ³ represents hydrogen;
A represents a phenyl or pyridinyl group, which optionally can be substituted with one or more (for example, 1, 2 or 3) R ^a groups;
B represents a -V-carbocyclic group, where the carbocyclic group represents a phenyl group, or a -W-heterocyclyl group, where the heterocyclic group represents a 5, 6 or 7-membered monocyclic aromatic heterocyclic group and contains 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein said carbocyclic and heterocyclyl groups may optionally be substituted with one or more (e.g., 1, 2 or 3) R ^a groups;
R ² and R ⁶ independently represent hydrogen, an aryl or heterocyclyl group, wherein said aryl group is phenyl and said heterocyclyl group is a 5-10 membered group and contains 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, and said aryl and heterocyclyl groups may optionally be substituted with one or more R ¹³ groups, provided that R ² and R ⁶ both cannot simultaneously be hydrogen;
R ^e , R ^f and R ^w independently represent hydrogen or C _1-6 alkyl;
R ^a represents halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , - (CH ₂ ) _n -OC _{1- 6} alkyl, -O- (CH ₂ ) _n -OR ^x , haloC _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkanol, = O, = S, nitro, Si (R ^x ) ₄ , - ( CH ₂ ) _s -CN, -SR ^x , -SO-R ^x , -SO ₂ -R ^x , -COR ^x , - (CR ^x R ^y ) _s -COOR ^z , - (CH ₂ ) _s -CONR ^x R ^y , - (CH ₂ ) _s -NR ^x R ^y , - (СН ₂ ) _s -NR ^x COR ^y , - (CH ₂ ) _s -NR ^x SO ₂ -R ^y , - (CH ₂ ) _s -NH- SO ₂ —NR ^x R ^y , —OCONR ^x R ^y , - (CH ₂ ) _s —NR ^x CO ₂ R ^y , —O— (CH ₂ ) _s —CR ^x R ^y - (CH ₂ ) _t —OR ^z or - (CH ₂ ) _s —SO ₂ NR ^x R ^y groups;
R ^x , R ^y and R ^z independently represent hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkanol, hydroxy, C _1-6 alkoxy, halogen C _1-6 alkyl , -CO- (CH ₂ ) _n -C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 cycloalkenyl;
R ¹ and R ^b independently represent a R ^a group or an -Y-carbocyclyl or -Z-heterocyclyl group, wherein said carbocyclyl group represents a 5- or 6-membered monocyclic carbocyclyl group and said heterocyclyl group represents a 5 or 6-membered monocyclic heterocyclyl group and contains 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein said carbocyclyl and said heterocyclyl groups may optionally be substituted with one or more (e.g., 1, 2 or 3) R ^a groups ;
V and W independently represent a bond or - (CR ^a R ^f ) _n group;
Y and Z independently represent a bond, —CO— (CH ₂ ) _s -, COO—, - (CH ₂ ) _n -, —NR ^x - (CH ₂ ) _n -, - (CH ₂ ) _n —NR ^x , -CONR ^x , -NR ^x CO-, SO ₂ NR ^x , -NR ^x SO ₂ -, -NR ^x CONR ^y -, -NR ^x SNR ^y -, -O- (CH ₂ ) _s -, - (СН ₂ ) _s —O—, —S—, —SO— or - (CH ₂ ) _s —SO ₂ -;
n is an integer having a value of 1-4;
s and t independently represent an integer having a value of 0-4;
q is an integer of 0-2;
or a pharmaceutically acceptable salt or solvate thereof. 2. The compound of formula (I) according to claim 1, where
X ₁ represents carbon;
X ₂ and X ₃ are each independently selected from carbon or nitrogen, such that at least one of X ₂ —X ₃ is nitrogen;
X ₄ represents CR ³ or nitrogen;
X ₅ represents CH;
with the proviso that not more than three of X ₁ -X ₅ are nitrogen;

represents a single or double bond;
R ³ represents hydrogen;
A represents a phenyl or pyridinyl group, which optionally can be substituted with one or more (for example, 1, 2 or 3) R ^a groups;
B is an aromatic heterocyclic group, wherein the heterocyclic group is a 5, 6 or 7 membered monocyclic heterocyclic group, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur;
R ² represents an aryl or heterocyclyl group optionally substituted with one or more R ^b groups, wherein said aryl group represents a phenyl group and said heterocyclyl group represents a 5-10 membered group and contains 1, 2 or 3 heteroatoms independently selected from nitrogen oxygen or sulfur;
R ^a represents halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , -O- (CH ₂ ) _n -OR ^x , haloC _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkanol, = O, = S, nitro, - (CH ₂ ) _s —CN, —SR ^x , —SO — R ^x , —SO ₂ -R ^x , -COR ^x , - (CR ^x R ^y ) _s -COOR ² , - (CH ₂ ) _s -CONR ^x R ^y , - (CH ₂ ) _s -NR ^x R ^y , - (СН ₂ ) _s -NR ^x COR ^y , - (CH ₂ ) _s -NR ^x SO ₂ -R ^y , - (CH ₂ ) _s -NH-SO ₂ -NR ^x R ^y , -OCONR ^x R ^y , - (СН ₂ ) _s -NR ^x CO ₂ R ^y , -O- (CH ₂ ) _s -CR ^x R ^y - (CH ₂ ) _t -OR ^z or - (CH ₂ ) _s -SO ₂ NR ^x R ^y groups;
R ^x , R ^y and R ^z independently represent hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkanol, hydroxy, C _1-6 alkoxy, halogen C _1-6 alkyl , -CO- (CH ₂ ) _n -C _1-6 alkoxy, C _3-8 cycloalkyl or C _3-8 cycloalkenyl;
R ¹ and R ^b independently represent a R ^a group or an -Y-aryl or -Z-heterocyclyl group, wherein said aryl group is a phenyl group and said heterocyclyl group is a 5- or 6-membered monocyclic heterocyclyl group and contains 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein said aryl and heterocyclyl groups may optionally be substituted with one or more (eg, 1, 2 or 3) R ^a groups;
Y and Z independently represent a bond, —CO—, - (CH ₂ ) -, - (CH ₂ ) ₂ -, - (CH ₂ ) ₃ -, —O— (CH ₂ ) _s - or —NH— (CH ₂ ) _n -;
n independently represents an integer having a value of 1-4;
s and t independently represent an integer having a value of 0-4;
q is an integer of 0-2. 3. The compound according to claim 1 or 2, where A represents a phenyl group optionally substituted by one or more R ^a groups. 4. The compound according to claim 1, where B is a -W-heterocyclyl group, where the heterocyclyl group is a 5- or 6-membered monocyclic heterocyclyl group. 5. The compound according to claim 1, where W is a bond. 6. The compound according to claim 1, where the heterocyclyl group is a pyridyl, pyrazinyl, triazolyl, oxadiazolyl, imidazolyl or thiadiazolyl. 7. The compound according to claim 1, where b is a thiadiazolyl. 8. The compound according to claim 1, where q has a value of 0. 9. The compound according to claim 1, where R ² represents an aryl or heterocyclyl group, optionally substituted by one or more R ^a groups, where the specified aryl group represents a phenyl group, and said heterocyclyl group represents a 5- or 6-membered monocyclic heterocyclyl group and contains 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. 10. The compound according to claim 1, where R ² is phenyl optionally substituted with halogen, - (CR ^x R ^y ) _s —COOR ^z or —Z-heterocyclyl group, wherein said heterocyclyl group is a 5- or 6-membered monocyclic heterocyclyl a group and contains 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, and said heterocyclic group may optionally be substituted with one or more R ^a groups selected from C _1-6 alkyl or - (CR ^x R ^y ) _s —COOR ^z groups, or R ² represents morpholinyl, piperazinyl, pyridyl, pyrazine yl, pyrazolyl, piperidinio, benzodioxolyl or pyrimidinyl optionally substituted with one or more R ^b groups selected from C _1-6 alkyl, - (CH ₂ ) _s —Nr ^x R ^y , COR ^x , - (CR ^x R ^y ) _s —COOR ^z or SO ₂ —R ^x . 11. The compound according to claim 1, where R ² represents a phenyl group, optionally substituted by one or more R ^b groups selected from halogen, C _1-6 alkanol, - (CH ₂ ) _s -NR ^x R ^y , - (CR ^x R ^y ) _s —COOR ^z , - (CH ₂ ) _s —CONR ^x R ^y or - (CH ₂ ) _s —NR ^x SO ₂ —R ^y , or R ² represents morpholinyl, piperazinyl, pyridyl, pyrazinyl, thienyl , benzothienyl, furanyl or pyrimidinyl optionally substituted with one or more groups = O, C _1-6 alkyl, - (CH ₂ ) _s —NR ^x R ^y , —OR ^x , —COR ^x or C _1-6 alkanol. 12. The compound according to claim 1, where X ₁ -X _{5 are} determined by the following ring systems:

13. The compound according to claim 1, where X ₁ -X _{5 are} determined by the following ring system:

14. The compound according to claim 1, where the compound is a compound of formula (Id):

where R ^a R ¹ , R ² , B and q have the meanings defined in claim 1, n is an integer having a value from 0 to 3. 15. The compound according to claim 1, which is a compound selected from the following compounds:
{3- [7- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} pyrazin-2-ylamine;
morpholin-4-yl- (3- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} phenyl) - methanone hydrochloride;
[3- (7-piperidin-1-yl-imidazo [1,2-a] pyridin-3-yl) phenyl] - [1,3,4] thiadiazol-2-ylamine;
{5- [6- (4-fluorophenyl) pyrazolo [1,5-a] pyrimidin-3-yl] pyridin-3-yl} - [1,3,4] thiadiazol-2-ylamine;
N-methyl-2- (3- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} phenyl) - acetamide hydrochloride;
N * 3 * - {3- [7- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} -1H- [1,2,4] thiazole-3,5- diamine;
4- (3- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} benzyl) piperazin-2 -one, formate;
{3- [7- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,3,4] oxadiazol-2-ylamine;
N-methyl-3- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} benzamide, hydrochloride;
{2- [6- (4-fluorophenyl) pyrazolo [1,5-a] pyrimidin-3-yl] pyridin-4-yl} - [1,3,4] thiadiazol-2-ylamine;
{3- [7- (3-aminophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,3,4] thiadiazol-2-ylamine, hydrochloride;
(3- {7- [2- (tetrahydropyran-4-yloxy) -pyridin-4-yl] imidazo [1,2-a] pyridin-3-yl} phenyl) - [1,3,4] thiadiazole -2-ylamine;
{3- [7- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} - (1-methyl-1H-imidazol-2-yl) -amine, hydrochloride;
(3- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} phenyl) methanol;
4- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} piperazine-1-carboxylic acid ethyl ester;
5- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} pyridin-2-ylamine, hydrochloride;
1- (4- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} piperazin-1-yl) ethanone;
{3- [7- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,2,4] thiadiazol-5-ylamine;
N- (3- {3- [3 - ([1,3,4] thiadiazol-2-ylamino) phenyl] imidazo [1,2-a] pyridin-7-yl} benzyl) methanesulfonamide;
benzyl- {3- [7- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-a] pyridin-3-yl] phenyl} -amine; and
{3- [7- (2-methyl-2H-tetrazol-5-yl) -imidazo [1,2-a] pyridin-3-yl] phenyl} - [1,3,4] thiadiazol-2-ylamine . 16. The compound according to claim 1, where X ₁ -X _{5 are} determined by the following ring system:

where R ² represents an aryl or heterocyclyl group optionally substituted with one or more R ^a groups, where said aryl group represents a phenyl group, and said heterocyclyl group represents a 5- or 6-membered monocyclic heterocyclyl group and contains 1, 2 or 3 heteroatoms, independently selected from nitrogen, oxygen or sulfur. 17. The compound according to claim 1, where B is a -W-heterocyclyl group, where the heterocyclyl group is a 5- or 6-membered monocyclic heterocyclyl group, and R ² is an aryl or heterocyclyl group, wherein said aryl group is a phenyl group and said heterocyclyl group represents a 5- or 6-membered monocyclic aromatic heterocyclic group and contains 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, and said aryl or heterocycles te a group optionally substituted by one or more groups R ^a. 18. The method of obtaining the compounds of formula (I) according to claim 1, including:
(i) the interaction of the compounds of formula (XX) or (XXI):

or a protected form of such a compound with a suitable substituted aldehyde or ketone; or
(ii) the interaction of the compounds of formula (XX) or (XXI):

or a protected form of such a compound with hydrazine hydrate, followed by cyclization;
and then removing any protecting groups present; or where X _1-5 , A and R ₂ have the meanings defined above. 19. A pharmaceutical composition for the prevention or treatment of cancer, comprising a compound of formula (I) according to claim 1. 20. A method for the prevention or treatment of cancer, which comprises administering to a subject in need thereof a compound of formula (I) according to claim 1. 21. The compound according to claim 1, intended for the prevention or treatment of cancer. 22. The use of a compound according to claim 1 for the manufacture of a medicament for the prevention or treatment of cancer.