2-aminopyrazine derivatives as csf-1 r kinase inhibitors

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof: wherein: ring A, R 1 , R 2 , n, X, V, W, Z, ring B, [Linker] and R areas defined herein. The compounds are useful as inhibitors of CSF-1R kinase. The compounds can thus be used in medicine.

1 . A compound which is an amino acid or amino acid ester of formula (I) or a salt, N-oxide, hydrate or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         ring A is a C 6-12  aryl, 5- to 12-membered heterocyclyl or C 3-7  carbocyclyl ring; 
         R 1  and R 2  independently represent hydrogen, halogen or an unsubstituted group selected from C 1-4  alkyl, C 2-4  alkenyl, C 1-4  alkoxy, C 2-4  alkenyloxy, C 1-4  haloalkyl, C 2-4  haloalkenyl, C 1-4  haloalkoxy, C 2-4  haloalkenyloxy, hydroxyl, —SR 3 , cyano, nitro, C 1-4  hydroxyalkyl and —NR 3 R 4  groups, wherein R 3  and R 4  are the same or different and represent hydrogen or unsubstituted C 1-2  alkyl; 
         n is 0 or 1; 
         X is NH or O; 
         V and W independently represent —N═ or —C(Z)═; 
         each Z is the same or different and represents hydrogen, fluoro, chloro, bromo, iodo, cyano, unsubstituted C 1-3  fluoroalkyl or unsubstituted C 1-3 alkyl; 
         ring B is a C 6-12  aryl, 5- to 12-membered heterocyclyl or C 3-7  carbocyclyl ring; 
         [Linker] represents a group of formula —(CH 2 ) m —X 1 -L 1 -Y 1 — wherein:
 m is 0, 1, 2 or 3; 
 X 1  represents a bond, —O—, —S—, —NR 7 —, —C(═O)—, —C(═O)O—, —OC(═O)—, —S(═O) 2 —; —NR 5 C(═O)—, —C(═O)NR 5 —, —NR 5 C(═O)NR 6 —, —NR 5 S(═O) 2 —, or —S(═O) 2 NR 5 — wherein R 5  and R 6  are independently hydrogen or C 1-6  alkyl and R 7  represents hydrogen, unsubstituted C 1-4  alkyl or —C(═O)CH 3 ; 
 L 1  represents a divalent radical of formula -(Alk 1 )-(Q) y -(Het) w -(Alk 2 ) z - or -(Alk 1 ) x -(Het) w -(Q) y -(Alk 2 ) z - wherein
 x, y, w and z are independently 0 or 1; 
 Q represents a divalent C 6-12  aryl, 5- to 12-membered heterocyclyl or C 3-7  carbocyclyl ring; 
 Het represents —O—, —S— or —NR 7 — wherein R 7  represents hydrogen, unsubstituted C 1-4  alkyl or —C(═O)CH 3 ; 
 Alk 1  and Alk 2  independently represent divalent C 3-7  cycloalkyl radicals, or straight or branched, C 1-6  alkylene, C 2-6  alkenylene, or C 2-6  alkynylene radicals; 
 
 Y 1  represents a bond, —O—, —S—, —NR 7 —, —C(═O)—, —C(═O)O—, —OC(═O)—, —S(═O) 2 —, —NR 5 C(═O)—, —C(═O)NR 5 —, —NR 5 C(═O)NR 6 —, —NR 5 S(═O) 2 —, or —S(═O) 2 NR 5 —, wherein R 5  and R 6  are independently hydrogen or C 1-6  alkyl and R 7  represents hydrogen, unsubstituted C 1-4  alkyl or —C(═O)CH 3 ; 
 R represents a group of formula (X) or (Y): 
 
       
       
         
           
           
               
               
           
         
         in which:
 R 8  is a group —COOH or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a —COOH group; 
 R 9  and R 10  are the same or different and each represents the α-substituent of a natural or non-natural α-amino acid, or R 9  and R 10 , taken together with the carbon to which they are attached, form a 3- to 6-membered saturated spiro cycloalkyl or heterocyclyl ring; 
 R 11  represents a hydrogen atom or a C 1-4  alkyl group; 
 ring D is a 5- to 7-membered saturated heterocyclyl group having at least one nitrogen atom in the ring, wherein R 8  and R 11  are linked to a ring carbon adjacent to a ring nitrogen, and wherein the bond shown intersected by a wavy line may be from a nitrogen atom or a carbon atom in ring D; 
 
       
       wherein when R is (X), [Linker] is not connected to (X) via an O, N or S atom; 
       and wherein, unless otherwise stated:
 any alkyl, alkenyl and alkynyl groups and moieties in R 5 , R 6 , R 8 , R 9 , R 10 , R 11 , Alk 1  and Alk 2  are the same or different and are each unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms and C 1-4  alkoxy, C 2-4  alkenyloxy, C 1-4  haloalkoxy, C 2-4  haloalkenyloxy, hydroxyl, —SR 3 , cyano, nitro and —NR 3 R 4  groups, wherein R 3  and R 4  are the same or different and represent hydrogen or unsubstituted C 1-2  alkyl; 
 any aryl, heterocyclyl, cycloalkyl and carbocyclyl groups and moieties in rings A, B, Q, D, Alk 1  and Alk 2  and the ring formed by R 9  and R 10  are the same or different and are each unsubstituted or substituted by 1, 2, 3 or 4 unsubstituted substituents selected from halogen atoms, and cyano, nitro, C 1-4  alkyl, C 1-4  alkoxy, C 2-4  alkenyl, C 2-4  alkenyloxy, C 1-4  haloalkyl, C 2-4  haloalkenyl, C 1-4  haloalkoxy, C 2-4  haloalkenyloxy, hydroxyl, C 1-4  hydroxyalkyl, —SR 3  and —NR 3 R 4  groups wherein each R 3  and R 4  is the same or different and represents hydrogen or unsubstituted C 1-2  alkyl, or from substituents of formula —COOR 12 , —COR 12 , —SO 2 R 12 , —CONR 12 R 13 , —SO 2 NR 12 R 13 , —OCONR 12 R 13 , —NR 12 COR 13 , —NR 12 COOR 13 , —NR 12 SO 2 R 13 , —NR 12 SO 2 OR 13  or —NR 12 CONR 12 R 13  wherein R 12  and R 13  are the same or different and represent hydrogen or unsubstituted C 1-4  alkyl, or R 12  and R 13  when attached to the same nitrogen atom form a non-fused 5- or 6-membered heterocyclyl group, 
 
       with the proviso that the compound is not: 
       4-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-pyrrolidine-2-carboxylic acid methyl ester. 
     
     
         2 . A compound as claimed in  claim 1 , wherein X is NH. 
     
     
         3 . A compound as claimed in  claim 1  or  claim 2 , wherein ring A and ring B independently represent phenyl or a 5- to 6-membered heterocyclyl group, said ring A or ring B group being unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and unsubstituted C 1-4  alkyl, C 1-4  alkoxy, hydroxyl, C 1-4  haloalkyl, C 1-4  haloalkoxy, C 1-4  hydroxyalkyl, cyano, nitro, —SR 3  and —NR 3 R 4  groups, wherein R 3  and R 4  are the same or different and represent hydrogen or unsubstituted C 1-2  alkyl. 
     
     
         4 . A compound as claimed in any one of  claims 1  to  3 , wherein ring B is a 1,4-phenylene, 1,3-phenylene or pyridinyl group. 
     
     
         5 . A compound as claimed in any one of  claims 1  to  4 , wherein R 1  and R 2  independently represent hydrogen, halogen or unsubstituted C 1-4  alkyl. 
     
     
         6 . A compound as claimed in any one of  claims 1  to  5 , wherein R 8  is a group —COOH or an ester group of formula —(C═O)OR 14  wherein R 14  is R 15 R 16 R 17 C— wherein
 (i) R 15  is hydrogen, fluorine or optionally substituted C 1-3 alkyl-(Z 1 ) a —[(C 1 -C 3 )alkyl] b - or C 2-3 alkenyl-(Z 1 ) a —[C 1-3  alkyl] b - wherein a and b are independently 0 or 1 and Z 1  is —O—, —S—, or —NR 18 — wherein R 18  is hydrogen or C 1-3  alkyl; and R 16  and R 17  are independently hydrogen or C 1-3  alkyl-; 
 (ii) R 15  is hydrogen or optionally substituted R 19 R 20 N—C 1-3 alkyl—wherein R 19  is hydrogen or C 1-3 alkyl and R 20  is hydrogen or C 1-3 alkyl; or R 19  and R 20  together with the nitrogen to which they are attached form an optionally substituted monocyclic heterocyclic ring of 5- or 6-ring atoms or bicyclic heterocyclic ring system of 8 to 10 ring atoms, and R 16  and R 17  are independently hydrogen or C 1-3 alkyl-; or 
 (iii) R 15  and R 16  taken together with the carbon to which they are attached form an optionally substituted monocyclic carbocyclic ring of from 3 to 7 ring atoms or bicyclic carbocyclic ring system of 8 to 10 ring atoms, and R 17  is hydrogen; or 
 (iv) R 15  and R 15  taken together with the carbon to which they are attached form an optionally substituted monocyclic heterocyclic ring of from 3 to 7 ring atoms wherein at least one ring atom is selected from —O—, —S—, or —NR 18 — wherein R 18  is hydrogen or C 1-3 alkyl, or a bicyclic heterocyclic ring system of 8 to 10 ring atoms wherein at least one ring atom is selected from —O—, —S—, or —NR 18 — wherein R 18  is hydrogen or C 1-3 alkyl, and R 17  is hydrogen. 
 
     
     
         7 . A compound as claimed in  claim 6 , wherein either R 15  is hydrogen or C 1-3 alkyl-(Z 1 ) a —[(C 1 -C 3 )alkyl] b - wherein a and b are independently 0 or 1 and Z 1  is —O—, —S—, or —NH— and R 16  and R 17  are independently hydrogen or C 1-3  alkyl-; or R 15  and R 15  taken together with the carbon to which they are attached form a 3- to 7-membered cycloalkyl ring and R 17  is hydrogen. 
     
     
         8 . A compound as claimed in  claim 6 , wherein either R 14  is cyclopentyl or t-butyl. 
     
     
         9 . A compound as claimed in any one of the preceding claims, wherein (i) R 9  and R 10  are side chains of natural amino acids, (ii) one of R 9  and R 10  is hydrogen or unsubstituted C 1-4  alkyl and the other is an unsubstituted C 1-6  alkyl group or a C 1-6  alkyl group substituted with a C 1-4  alkoxy group, or (iii) R 9  and R 10 , taken together with the carbon to which they are attached, form a saturated spiro cyclobutyl ring. 
     
     
         10 . A compound as claimed in any one of the preceding claims, wherein R represents a group of formula (Y1): 
       
         
           
           
               
               
           
         
       
       wherein ring D is a is a 5- to 7-membered saturated heterocyclyl group having at least two nitrogen atoms in the ring, wherein R 8  and R 11  are linked to a ring carbon adjacent to a ring nitrogen, and wherein the bond shown intersected by a wavy line is from a nitrogen atom in ring D. 
     
     
         11 . A compound as claimed in any one of  claims 1  to  9 , wherein R represents a group of formula (Y2): 
       
         
           
           
               
               
           
         
       
       wherein ring D is a is a 5- to 7-membered saturated heterocyclyl group having at least one nitrogen atom in the ring, wherein R 8  and R 11  are linked to a ring carbon adjacent to a ring nitrogen, and wherein the bond shown intersected by a wavy line is from a carbon atom in ring D. 
     
     
         12 . A compound according to  claim 11 , wherein [Linker] represents —(CH 2 ) m —X 1 -(Alk 1 ) x -Y, wherein m is 0, 1, 2 or 3, x is 0 or 1, Alk 1  is an unsubstituted C 1-3  alkylene group, and X 1  and Y 1  independently represent a bond, —O—, —S—, —NR 7 —, —C(═O)— or —C(═O)NR 5 —, wherein R 5  is hydrogen or C 1-4  alkyl and R 7  represents hydrogen, unsubstituted C 1-4  alkyl or —C(═O)CH 3 . 
     
     
         13 . A compound as claimed in any one of  claims 1  to  3  or  5  to  12 , wherein:
 ring A represents phenyl or a 5- to 6-membered heterocyclyl group, said ring A group being unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and unsubstituted C 1-4  alkyl, C 1-4  alkoxy, hydroxyl, C 1-4  haloalkyl, C 1-4  haloalkoxy, C 1-4  hydroxyalkyl, cyano, nitro, —SR 3  and —NR 3 R 4  groups, wherein R 3  and R 4  are the same or different and represent hydrogen or unsubstituted C 1-2  alkyl; 
 R 1  and R 2  each represent hydrogen; 
 n is 1; 
 X is NH; 
 V is —N═; 
 W is —C(Z)═, wherein Z represents hydrogen, fluoro, chloro, or unsubstituted C 1-3  alkyl, preferably hydrogen; and 
 ring B represents phenyl or 5- to 6-membered heterocyclyl group, said ring B group being unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and unsubstituted C 1-4  alkyl, C 1-4  alkoxy, hydroxyl, C 1-4  haloalkyl, C 1-4  haloalkoxy, C 1-4  hydroxyalkyl, cyano, nitro, —SR 3  and —NR 3 R 4  groups, wherein R 3  and R 4  are the same or different and represent hydrogen or unsubstituted C 1-2  alkyl. 
 
     
     
         14 . A compound according to  claim 13 , wherein the group [Linker]-R is one of (a) to (c):
 (a) R represents a group of formula (X);
 R 8  is a group —COOH or an ester group of formula —(C═O)OR 14  wherein R 14  is R 15 R 16 R 17 C— wherein either R 15  is hydrogen or C 1-3 alkyl-(Z 1 ) a —[(C 1 -C 3 )alkyl] b - wherein a and b are independently 0 or 1 and Z 1  is —O—, —S—, or —NH— and R 16  and R 17  are independently hydrogen or C 1-3  alkyl-; or R 15  and R 16  taken together with the carbon to which they are attached form a 3- to 7-membered cycloalkyl ring and R 17  is hydrogen; 
 R 9  and R 10  are side chains of natural amino acids or one of R 9  and R 10  is hydrogen or unsubstituted C 1-4  alkyl and the other is an unsubstituted C 1-6  alkyl group; 
 R 11  represents a hydrogen atom or an unsubstituted C 1-2  alkyl group; 
 [Linker] represents —(CH 2 ) m —X 1 -(Alk 1 )- or —(CH 2 ) v —, wherein v is 1 or 2, m is 0, 1, 2 or 3; Alk 1  is an unsubstituted C 1-3  alkylene group and X 1  is a bond, —O—, —S—, —NR 7 —, —C(═O)— or —C(═O)NR 5 —, wherein R 5  is hydrogen or C 1-4  alkyl and R 7  represents hydrogen, unsubstituted C 1-4  alkyl or —C(═O)CH 3 , 
   (b) R represents a group of formula (Y1) as defined in  claim 8 ;
 R 8  is a group —COOH or an ester group of formula —(C═O)OR 14  wherein R 14  is R 15 R 16 R 17 C— wherein either R 15  is hydrogen or C 1-3 alkyl-(Z 1 ) a —[(C 1 -C 3 )alkyl] b - wherein a and b are independently 0 or 1 and Z 1  is —O—, —S—, or —NH— and R 16  and R 17  are independently hydrogen or C 1-3  alkyl-; or R 15  and R 16  taken together with the carbon to which they are attached form a 3- to 7-membered cycloalkyl ring and R 17  is hydrogen; 
 R 11  represents a hydrogen atom or an unsubstituted C 1-2  alkyl group; 
 [Linker] is —(CH 2 ) m —X 1 -(Alk 1 ) x - or —(CH 2 ) v —, wherein v is 1 or 2, m is 0, 1, 2 or 3; 
 x is 0 or 1; Alk 1  is an unsubstituted C 1-3  alkylene group; and X 1  is a bond, —O—, —S—, —NR 7 —, —C(═O)— or —C(═O)NR 5 —, wherein R 5  is hydrogen or C 1-4  alkyl and R 7  represents hydrogen, unsubstituted C 1-4  alkyl or —C(═O)CH 3 , wherein when x is 0, X 1  is a bond or C(═O), 
   (c) R represents a group of formula (Y2) as defined in  claim 9 ;
 R 8  is a group —COOH or an ester group of formula —(C═O)OR 14  wherein R 14  is R 15 R 16 R 17 C— wherein either R 15  is hydrogen or C 1-3 alkyl-(Z 1 ) a —[(C 1 -C 3 )alkyl] b - wherein a and b are independently 0 or 1 and Z 1  is —O—, —S—, or —NH— and R 16  and R 17  are independently hydrogen or C 1-3  alkyl-; or R 15  and R 16  taken together with the carbon to which they are attached form a 3- to 7-membered cycloalkyl ring and R 17  is hydrogen; 
 R 11  represents a hydrogen atom or an unsubstituted C 1-2  alkyl group; 
 [Linker] represents —(CH 2 ) m —X 1 -(Alk 1 )-Y 1 , wherein m is 0, 1, 2 or 3; x is 0 or 1; 
 X 1  is a bond or —C(═O); Alk 1  is an unsubstituted C 1-3  alkylene group; and Y 1  is a bond or —NR 7 —, preferably —NR 7 —, wherein R 7  represents hydrogen, unsubstituted C 1-4  alkyl or —C(═O)CH 3 . 
   
     
     
         15 . A compound as claimed in any one of  claims 1  to  3  and  5  to  14 , wherein:
 ring A represents a phenyl group, said ring A group being unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and unsubstituted C 1-4  alkyl, C 1-4  alkoxy, hydroxyl and —NR 3 R 4  groups, wherein R 3  and R 4  are the same or different and represent hydrogen or unsubstituted C 1-2  alkyl; 
 R 1  and R 2  each represent hydrogen; 
 n is 1; 
 X is NH; 
 V is —N═; 
 W is —C(H)═; and 
 ring B represents a 1,4-phenylene, 1,3-phenylene group or 1,3-pyrazolyl group, said ring B group being unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and unsubstituted C 1-4  alkyl, C 1-4  alkoxy, hydroxyl and —NR 3 R 4  groups, wherein R 3  and R 4  are the same or different and represent hydrogen or unsubstituted C 1-2  alkyl. 
 
     
     
         16 . A compound as claimed in  claim 15 , wherein:
 R represents a group of formula (Y1′):   
       
         
           
           
               
               
           
         
         R 8  is a group —COOH or an ester group of formula —(C═O)OR 14  wherein R 14  is R 15 R 16 R 17 C— wherein either R 15  is hydrogen or C 1-3 alkyl-(Z) a —[(C 1 -C 3 )alkyl] b - wherein a and b are independently 0 or 1 and Z 1  is —O—, —S—, or —NH— and R 16  and R 17  are independently hydrogen or C 1-3  alkyl-; or R 15  and R 16  taken together with the carbon to which they are attached form a 3- to 7-membered cycloalkyl ring and R 17  is hydrogen; 
         [Linker] is —(CH 2 ) v — and —C(═O)—, wherein v is 1 or 2. 
       
     
     
         17 . A compound as claimed in  claim 15 , wherein:
 R represents a group of formula (Y2′):   
       
         
           
           
               
               
           
         
         R 8  is a group —COOH or an ester group of formula —(C═O)OR 14  wherein R 14  is R 15 R 16 R 17 C— wherein either R 15  is hydrogen or C 1-3 alkyl-(Z 1 ) a —[(C 1 -C 3 )alkyl] b - wherein a and b are independently 0 or 1 and Z 1  is —O—, —S—, or —NH— and R 16  and R 17  are independently hydrogen or C 1-3  alkyl-; or R 15  and R 16  taken together with the carbon to which they are attached form a 3- to 7-membered cycloalkyl ring and R 17  is hydrogen; 
         [Linker] is —C(═O)NR 7 —, —CH 2 NR 7 — or —CH 2 C(═O)NR 7 —, wherein R 7  represents hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted isobutyl or —C(═O)CH 3 . 
       
     
     
         18 . A compound as claimed in  claim 1 , which is:
 Cyclopentyl (2R)-4-[(4-{5-amino-6-[(2,6-dichlorobenzyl)amino]pyrazin-2-yl}benzyl)amino]piperidine-2-carboxylate;   Cyclopentyl 4-(4-{5-amino-6-[(2,6-dichlorobenzyl)amino]pyrazin-2-yl}benzyl) piperazine-2-carboxylate;   Cyclopentyl (2S)-4-(4-{5-amino-6-[(2,6-dichlorobenzyl)amino]pyrazin-2-yl}benzyl) piperazine-2-carboxylate;   Cyclopentyl (2R)-4-(4-{5-amino-6-[(2,6-dichlorobenzyl)amino]pyrazin-2-yl}benzyl) piperazine-2-carboxylate;   Cyclopentyl (2R)-4-[(4-{5-amino-6-[(2,6-dichlorobenzyl)amino]pyrazin-2-yl}-2-chlorobenzyl)amino]piperidine-2-carboxylate;   Cyclopentyl (2R)-4-[(4-{5-amino-6-[(2,6-dichlorobenzyl)amino]pyrazin-2-yl}benzyl)(ethyl)amino]piperidine-2-carboxylate;   Cyclopentyl (2R)-4-[(4-{5-amino-6-[(2,6-dichlorobenzyl)amino]pyrazin-2-yl}benzyl)(methyl)amino]piperidine-2-carboxylate;   tert-Butyl (2R)-4-[(4-{5-amino-6-[(2,6-dichlorobenzyl)amino]pyrazin-2-yl}benzyl)(ethyl)amino]piperidine-2-carboxylate;   Cyclopentyl (2R)-4-[acetyl(4-{5-amino-6-[(2,6-dichlorobenzyl)amino]pyrazin-2-yl}benzyl)amino]piperidine-2-carboxylate;   Cyclopentyl (2R)-4-(3-{5-amino-6-[(2,6-dichlorobenzyl)amino]pyrazin-2-yl}benzyl)piperazine-2-carboxylate;   Cyclopentyl 1-[(3-{5-amino-6-[(2,6-dichlorobenzyl)amino]pyrazin-2-yl}benzyl)amino]cyclobutanecarboxylate;   Cyclopentyl N-[2-(3-{5-amino-6-[(2,6-dichlorobenzyl)amino]pyrazin-2-yl}phenyl)ethyl]-2-methylalaninate;   Cyclopentyl 4-(4-{5-amino-6-[(2,6-dichlorobenzyl)amino]pyrazin-2-yl}-2-ethylbenzyl)piperazine-2-carboxylate; or   Cyclopentyl (2S)-4-(3-{5-amino-6-[(2,6-dichlorobenzyl)amino]pyrazin-2-yl}benzyl)piperazine-2-carboxylate.   
     
     
         19 . A compound as defined in any one of the preceding claims for use in a method of treatment of the human or animal body. 
     
     
         20 . A pharmaceutical composition which comprises a compound as defined in any one of  claims 1  to  18  and one or more pharmaceutically acceptable carrier(s) and/or excipients. 
     
     
         21 . A compound as defined in any one of  claims 1  to  18  for use in the treatment of a disease or disorder mediated by CSF-1R kinase. 
     
     
         22 . A compound as defined in any one of  claims 1  to  18  for use in the treatment of a cell proliferative disease, polyglutamine disease, neurodegenerative disease, autoimmune disease, diabetes, haematological disease, inflammatory disease, cardiovascular disease, atherosclerosis, or the inflammatory sequelia of infection. 
     
     
         23 . A compound for use according to  claim 22  for use in the treatment of cancer, rheumatoid arthritis, psoriatic arthritis, Type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosis, inflammation accompanying infectious conditions, psoriasis, Crohns disease, ulcerative colitis, chronic obstructive pulmonary disease, multiple sclerosis, atopic dermatitis or graft versus host disease. 
     
     
         24 . A method of treating or preventing a disease or disorder mediated by CSF-1R kinase in a subject, which method comprises administering to said subject an effective amount of a compound as defined in any one of  claims 1  to  16 . 
     
     
         25 . Use of a compound as defined in any one of  claims 1  to  18  in the manufacture of a medicament for use in the treatment or prevention of a disease or disorder mediated by CSF-1R kinase.