Pyrazolyl quinoxaline kinase inhibitors

Abstract

The invention relates to new quinoxaline derivative compounds, to pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         including any tautomeric or stereochemically isomeric form thereof, wherein 
         n represents an integer equal to 0, 1, 2, 3 or 4; 
         R 1  represents hydrogen, C 1-6 alkyl, C 2-4 alkenyl, hydroxyC 1-6 alkyl, haloC 1-6 alkyl, hydroxyhaloC 1-6 alkyl, cyanoC 1-4 alkyl, C 1-6 alkoxyC 1-6 alkyl wherein each C 1-6 alkyl may optionally be substituted with one or two hydroxyl groups, C 1-6 alkyl substituted with —NR 4 R 5 , C 1-6 alkyl substituted with —C(═O)—NR 4 R 5 , —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 -haloC 1-6 alkyl, —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —NH—S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —NH—S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —NR 12 —S(═O) 2 —NR 14 R 15 , R 6 , C 1-6 alkyl substituted with R 6 , C 1-6 alkyl substituted with —C(═O)—R 6 , hydroxyC 1-6 alkyl substituted with R 6 , C 1-6 alkyl substituted with —Si(CH 3 ) 3 , C 1-6 alkyl substituted with —P(═O)(OH) 2  or C 1-6 alkyl substituted with —P(═O)(OC 1-6 alkyl) 2 ; 
         each R 1a  is independently selected from hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkyl substituted with amino or mono- or di(C 1-4 alkyl)amino or —NH(C 3-8 cycloalkyl), cyanoC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, and C 1-4 alkyl substituted with one or more fluoro atoms; 
         each R 2  is independently selected from hydroxyl, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, hydroxyC 1-4 alkyl, hydroxyC 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, hydroxyhaloC 1-4 alkyl, hydroxyhaloC 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, haloC 1-4 alkoxyC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl wherein each C 1-4 alkyl may optionally be substituted with one or two hydroxyl groups, hydroxyhaloC 1-4 alkoxyC 1-4 alkyl, R 13 , C 1-4 alkyl substituted with R 13 , C 1-4 alkyl substituted with —C(═O)—R 13 , C 1-4 alkoxy substituted with R 13 , C 1-4 alkoxy substituted with —C(═O)—R 13 , —C(═O)—R 13 , C 1-4 alkyl substituted with —NR 7 R 8 , C 1-4 alkyl substituted with —C(═O)—NR 7 R 8 , C 1-4 alkoxy substituted with —NR 7 R 8 , C 1-4 alkoxy substituted with —C(═O)—NR 7 R 8 , —NR 7 R 8  and —C(═O)—NR 7 R 8 ; or when two R 2  groups are attached to adjacent carbon atoms they may be taken together to form a radical of formula:
 —O—(C(R 17 ) 2 ) p —O—; 
 —X—CH═CH—; or 
 —CH═N—; wherein R 17  represents hydrogen or fluorine, p represents 1 or 2 and X represents O or S; 
 
         R 3  represents hydroxyl, C 1-6 alkoxy, hydroxyC 1-6 alkoxy, C 1-6 alkoxy substituted with —NR 10 R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl optionally substituted with —O—C(═O)—C 1-6 alkyl, hydroxyC 1-6 alkyl optionally substituted with —O—C(═O)—C 1-6 alkyl, hydroxyC 2-6 alkenyl, hydroxyC 2-6 alkynyl, hydroxyhaloC 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6 alkyl substituted with carboxyl, C 1-6 alkyl substituted with —C(═O)—C 1-6 alkyl, C 1-6 alkyl substituted with —C(═O)—O—C 1-6 alkyl, C 1-6 alkyl substituted with C 1-6 alkoxyC 1-6 alkyl-O—C(═O)—, C 1-6 alkyl substituted with C 1-6 alkoxyC 1-6 alkyl-C(═O)—, C 1-6 alkyl substituted with —O—C(═O)—C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl wherein each C 1-6 alkyl may optionally be substituted with one or two hydroxyl groups or with —O—C(═O)—C 1-6 alkyl, C 2-6 alkenyl substituted with C 1-6 alkoxy, C 2-6 alkynyl substituted with C 1-6 alkoxy, C 1-6 alkyl substituted with R 9  and optionally substituted with —O—C(═O)—C 1-6 alkyl, C 1-6 alkyl substituted with —C(═O)—R 9 , C 1-6 alkyl substituted with hydroxyl and R 9 , C 2-6 alkenyl substituted with R 9 , C 2-6 alkynyl substituted with R 9 , C 1-6 alkyl substituted with —NR 10 R 11 , C 2-6 alkenyl substituted with —NR 10 R 11 , C 2-6 alkynyl substituted with —NR 10 R 11 , C 1-6 alkyl substituted with hydroxyl and —NR 10 R 11 , C 1-6 alkyl substituted with one or two halogens and —NR 10 R 11 , —C 1-6 alkyl-C(R 12 )═N—O—R 12 , C 1-6 alkyl substituted with —C(═O)—NR 10 R 11 , C 1-6 alkyl substituted with —O—C(═O)—NR 10 R 11 , —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 -haloC 1-6 alkyl, —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —NR 12 —S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —NH—S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —NR 12 —S(═O) 2 —NR 14 R 15 , R 13 , C 1-6 alkyl substituted with —P(═O)(OH) 2  or C 1-6 alkyl substituted with —P(═O)(OC 1-6 alkyl) 2 ; 
         R 4  and R 5  each independently represent hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, haloC 1-6 alkyl, hydroxyhaloC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl wherein each C 1-6 alkyl may optionally be substituted with one or two hydroxyl groups, —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 -haloC 1-6 alkyl, —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —NH—S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —NH—S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —NH—S(═O) 2 —NR 14 R 15 , R 13  or C 1-6 alkyl substituted with R 13 ; 
         R 6  represents C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, 4 to 7-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; said C 3-8  cycloalkyl, C 3-8 cycloalkenyl, phenyl, 4 to 7-membered monocyclic heterocyclyl, optionally and each independently being substituted by 1, 2, 3, 4 or 5 substituents, each substituent independently being selected from cyano, C 1-6 alkyl, cyanoC 1-6 alkyl, hydroxyl, carboxyl, hydroxyC 1-6 alkyl, halogen, haloC 1-6 alkyl, hydroxyhaloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkyl-O—C(═O)—, —NR 14 R 15 , —C(═O)—NR 14 R 15 , C 1-6 alkyl substituted with —NR 14 R 15 , C 1-6 alkyl substituted with —C(═O)—NR 14 R 15 , —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 -haloC 1-6 alkyl, —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —NH—S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —NH—S(═O) 2 -haloC 1-6 alkyl or C 1-6 alkyl substituted with —NH—S(═O) 2 —NR 14 R 15 ; 
         R 7  and R 8  each independently represent hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, haloC 1-6 alkyl, hydroxyhaloC 1-6 alkyl or C 1-6 alkoxyC 1-6 alkyl; 
         R 9  represents C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, naphthyl, or 3 to 12 membered monocyclic or bicyclic heterocyclyl containing at least one heteroatom selected from N, O or S, said C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, naphthyl, or 3 to 12 membered monocyclic or bicyclic heterocyclyl each optionally and each independently being substituted with 1, 2, 3, 4 or 5 substituents, each substituent independently being selected from ═O, C 1-4 alkyl, hydroxyl, carboxyl, hydroxyC 1-4 alkyl, cyano, cyanoC 1-4 alkyl, C 1-4 alkyl-O—C(═O)—, C 1-4 alkyl substituted with C 1-4 alkyl-O—C(═O)—, C 1-4 alkyl-C(═O)—, C 1-4 alkoxyC 1-4 alkyl wherein each C 1-4 alkyl may optionally be substituted with one or two hydroxyl groups, halogen, haloC 1-4 alkyl, hydroxyhaloC 1-4 alkyl, —NR 14 R 15 , —C(═O)—NR 14 R 15 , C 1-4 alkyl substituted with —NR 14 R 15 , C 1-4 alkyl substituted with —C(═O)—NR 14 R 15 , C 1-4 alkoxy, —S(═O) 2 —C 1-4 alkyl, —S(═O) 2 -haloC 1-4 alkyl, —S(═O) 2 —NR 14 R 15 , C 1-4 alkyl substituted with —S(═O) 2 —NR 14 R 15 , C 1-4 alkyl substituted with —NH—S(═O) 2 —C 1-4 alkyl, C 1-4 alkyl substituted with —NH—S(═O) 2 -haloC 1-4 alkyl, C 1-4 alkyl substituted with —NH—S(═O) 2 —NR 14 R 15 , R 13 , —C(═O)—R 13 , C 1-4 alkyl substituted with R 13 , phenyl optionally substituted with R 16 , phenylC 1-6 alkyl wherein the phenyl is optionally substituted with R 16 , a 5 or 6-membered aromatic monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S wherein said heterocyclyl is optionally substituted with R 16 ;
 or when two of the substituents of R 9  are attached to the same atom, they may be taken together to form a 4 to 7-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; 
 
         R 10  and R 11  each independently represent hydrogen, carboxyl, C 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6  alkyl substituted with —NR 14 R 15 , C 1-6 alkyl substituted with —C(═O)—NR 14 R 15 , haloC 1-6 alkyl, hydroxyC 1-6 alkyl, hydroxyhaloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl wherein each C 1-6 alkyl may optionally be substituted with one or two hydroxyl groups, R 6 , C 1-6 alkyl substituted with R 6 , —C(═O)—R 6 , —C(═O)—C 1-6 alkyl, —C(═O)-hydroxyC 1-6 alkyl, —C(═O)-haloC 1-6 alkyl, —C(═O)-hydroxyhaloC 1-6 alkyl, C 1-6 alkyl substituted with —Si(CH 3 ) 3 , —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 -haloC 1-6 alkyl, —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —NH—S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —NH—S(═O) 2 -haloC 1-6 alkyl or C 1-6 alkyl substituted with —NH—S(═O) 2 —NR 14 R 15 ; 
         R 12  represents hydrogen or C 1-4 alkyl optionally substituted with C 1-4 alkoxy; 
         R 13  represents C 3-8 cycloalkyl or a saturated 4 to 6-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said C 3-8 cycloalkyl or monocyclic heterocyclyl is optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, hydroxyl, C 1-6 alkyl,
 —C(═O)—C 1-6 alkyl, C 1-6 alkoxy, or —NR 14 R 15 ; 
 
         R 14  and R 15  each independently represent hydrogen, or haloC 1-4 alkyl, or C 1-4 alkyl optionally substituted with a substituent selected from hydroxyl, C 1-4 alkoxy, amino or mono- or di(C 1-4 alkyl)amino; 
         R 16  represents hydroxyl, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, —NR 14 R 15  or —C(═O)NR 14 R 15 ; 
         a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. 
       
     
     
         2 . A compound according to  claim 1  wherein R 1  represents hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl wherein each C 1-6 alkyl may optionally be substituted with one or two hydroxyl groups, C 1-6 alkyl substituted with —NR 4 R 5 , C 1-6 alkyl substituted with —C(═O)—NR 4 R 5 , —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —NH—S(═O) 2 —C 1-6 alkyl, R 6 , C 1-6 alkyl substituted with R 6 , C 1-6 alkyl substituted with —C(═O)—R 6 , hydroxyC 1-6 alkyl substituted with R 6 , or C 1-6 alkyl substituted with —Si(CH 3 ) 3 ; wherein each R 1a  is hydrogen; wherein R 10  and R 11  each independently represent hydrogen, C 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6 alkyl substituted with —NR 14 R 15 , C 1-6 alkyl substituted with —C(═O)—NR 14 R 15 , haloC 1-6 alkyl, hydroxyC 1-6 alkyl, hydroxyhaloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl wherein each C 1-6 alkyl may optionally be substituted with one or two hydroxyl groups, R 6 , C 1-6 alkyl substituted with R 6 , —C(═O)—R 6 , —C(═O)—C 1-6 alkyl, —C(═O)-hydroxyC 1-6 alkyl, —C(═O)-haloC 1-6 alkyl, —C(═O)-hydroxyhaloC 1-6 alkyl, C 1-6 alkyl substituted with —Si(CH 3 ) 3 , —S(═O) 2 —C 1-6 -alkyl, —S(═O) 2 -haloC 1-6 alkyl, —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —S(═O) 2 —C 1-6 , C 1-6 alkyl substituted with —S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —NH—S(═O) 2 —C 1-6 -alkyl, C 1-6 alkyl substituted with —NH—S(═O) 2 -haloC 1-6 alkyl or C 1-6 alkyl substituted with —NH—S(═O) 2 —NR 14 R 15 . 
     
     
         3 . A compound according to  claim 1  wherein each R 1a  is hydrogen. 
     
     
         4 . A compound according to  claim 1  wherein R 1  represents C 1-6 alkyl. 
     
     
         5 . A compound according to  claim 1  wherein R 1  represents CH 3 — or CD 3 -. 
     
     
         6 . A compound according to  claim 1  wherein R 2  is independently selected from halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, hydroxyC 1-4 alkyl, hydroxyC 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, R 13 , C 1-4 alkoxy substituted with R 13 , —C(═O)—R 13 , C 1-4 alkyl substituted with NR 7 R 8 , C 1-4 alkoxy substituted with NR 7 R 8 , —NR 7 R 8  and —C(═O)—NR 7 R 8 ; 
     
     
         7 . A compound according to  claim 6  wherein R 2  represents C 1-6 alkyloxy. 
     
     
         8 . A compound according to  claim 6  wherein R 2  represents CH 3 O— or CD 3 O—. 
     
     
         9 . A compound according to  claim 1  wherein R 3  represents C 1-6 alkyl, hydroxyC 1-6 alkyl, hydroxyhaloC 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl substituted with —C(═O)—C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl wherein each C 1-6 alkyl may optionally be substituted with one or two hydroxyl groups, C 1-6 alkyl substituted with R 9 , C 1-6 alkyl substituted with —NR 10 R 11 , C 1-6 alkyl substituted with hydroxyl and —NR 10 R 11 , C 1-6 alkyl substituted with one or two halogens and —NR 10 R 11 , C 1-6 alkyl substituted with —C(═O)—O—C 1-6 alkyl, C 1-6 alkyl substituted with —O—C(═O)—NR 10 R 11 , C 1-6 alkyl substituted with carboxyl, C 1-6 alkyl substituted with —NR 12 —S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —NR 12 —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with hydroxyl and R 9 , —C 1-6 alkyl-C(R 12 )═N—O—R 12 , C 1-6 alkyl substituted with —C(═O)—NR 10 R 11 , C 1-6 alkyl substituted with —C(═O)—R 9 , C 2-6 alkynyl substituted with R 9 , hydroxyC 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or R 13 . 
     
     
         10 . A compound according to  claim 1  wherein R 1  represents C 1-6 alkyl, each R 1a  is hydrogen, n represents an integer equal to 2 and each R 2  represents C 1-4 alkoxy, and R 3  represents C 1-6 alkyl substituted with —NR 10 R 11 . 
     
     
         11 . A compound according to  claim 10  wherein R 10  represents hydrogen or C 1-6 alkyl, and R 11  represents hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, —C(═O)—C 1-6 alkyl, —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 —NR 14 R 15 , hydroxyC 1-6 alkyl, —C(═O)-hydroxyhaloC 1-6 alkyl, —C(═O)—R 6 , cyanoC 1-6 alkyl, R 6 , C 1-6 alkyl substituted with R 6 , —C(═O)-haloC 1-6 alkyl, or C 1-6 alkyl substituted with —Si(CH 3 ) 3 . 
     
     
         12 . A compound according to  claim 10  wherein R 10  represents hydrogen, —CH 3 , —CH 2 CH 3  or —CH(CH 3 ) 2  and R 11  represents hydrogen, —CH 3 , —CH 2 CH 3  or —CH(CH 3 ) 2 , —CH 2 CF 3 , —CH 2 CHF 2  or —CH 2 CH 2 F, —C(═O)—CH 3 , —S(═O) 2 —CH 3 , —S(═O) 2 —CH 2 CH 3 , —S(═O) 2 —CH(CH 3 ) 2 , —S(═O) 2 —N(CH 3 ) 2 , —CH 2 CH 2 OH, —C(═O)—C(OH)(CH 3 )CF 3 , —C(═O)-cyclopropyl, —CH 2 CH 2 CN, cyclopropane, cyclopentane, 2,2,6,6-tetramethyl-piperidine, —CH 2 C3H 5 , —CH 2 -tetrahydrofuran, —C(═O)-(1-methyl-piperidin-3-yl), —C(═O)—CF 3 , —CH 2 Si(CH 3 ) 3 , or —CH 2 —C 6 H 5 . 
     
     
         13 . A compound according to  claim 10  wherein R 1  represents —CH 3 , each R 1a  is hydrogen, n represents an integer equal to 2 and each R 2  represents CH 3 O—, and R 3  represents —CH 2 CH 2 NHCH(CH 3 ) 2 . 
     
     
         14 . A compound according to  claim 10  wherein R 1  represents —CH 3 , each R 1a  is hydrogen, n represents an integer equal to 2 and each R 2  represents CH 3 O—, R 3  represents —CH 2 CH 2 —CH 2 —NHCH 2 CF 3 . 
     
     
         15 . A compound according to  claim 10  wherein R 1  represents —CH 3 , each R 1a  is hydrogen, n represents an integer equal to 2 and each R 2  represents CH 3 O—, R 3  represents —CH 2 CH 2 NH 2 . 
     
     
         16 . A compound as defined in  claim 1  or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         17 . A process for the preparation of a compound of formula (I) as defined in  claim 1 , which process comprises:
 (i) deprotecting a compound of formula (XXX) wherein P represents a suitable protective group, in the presence of a suitable acid,   
       
         
           
           
               
               
           
         
       
       or
 (ii) the reaction of a compound of the formula (IX) or (IX′): 
 
       
         
           
           
               
               
           
         
         or a protected form thereof, with an appropriately substituted amine or a reactive derivative thereof, such as for example NHR 10 R 11  (X), NHR 10 P (X-a) or a suitable nitrogen containing ring within the definition of R 9 : 
       
       
         
           
           
               
               
           
         
       
       for example in a sealed vessel, in the presence of a suitable base, and/or in the presence or absence of a solvent; or
 (iii) the reaction of a compound of the formula (VI): 
 
       
         
           
           
               
               
           
         
         or a protected form thereof, with a compound of formula W 6 —C 1-6 alkyl-NR 10 P wherein P represents a suitable protective group and W 6  represents a suitable leaving group, in the presence of a suitable base, and a suitable solvent, followed by removing P and optionally removing any further protecting group present; or 
         (iv) the reaction of a compound of the formula (VI): 
       
       
         
           
           
               
               
           
         
         or a protected thereof, with a compound of formula W 6 —C 1-6 alkyl-NHR 10  wherein W 6  represents a suitable leaving group, in the presence of a suitable base, and a suitable solvent; 
         (v) the reaction of a compound of formula (XXXVI) 
       
       
         
           
           
               
               
           
         
         with hydrazine in the presence of a suitable solvent; 
         (vi) the reaction of a compound of formula (IX-1) wherein R u  represents —O—S(═O) 2 —CH 3 , 
       
       
         
           
           
               
               
           
         
         with an intermediate of formula (X) in the presence of a suitable solvent; 
         (vii) the reaction of a compound of formula (VI) 
       
       
         
           
           
               
               
           
         
         with an intermediate of formula W 11 —R 3b  wherein R 3b  represents optionally substituted C 2-6 alkynyl and W 11  represents a suitable leaving group, in the presence of a suitable base and a suitable solvent; 
         (viii) the reaction of a compound of formula (VIII′) wherein R x  and R y  represent C 1-4 alkyl, and R z  represent C 1-4 alkyl or phenyl, 
       
       
         
           
           
               
               
           
         
         with a suitable acid, in the presence of a suitable solvent; 
         (viii) deprotecting a compound of formula (XXXXII) 
       
       
         
           
           
               
               
           
         
         in the presence of a suitable base and a suitable solvent; 
         (ix) the reaction of a compound of formula (VI) 
       
       
         
           
           
               
               
           
         
         with di(C 1-6 alkyl)vinylphosphonate in the presence of a suitable catalyst and a suitable solvent; 
         (x) deprotecting a compound of formula (XXXXI) 
       
       
         
           
           
               
               
           
         
         in the presence of a suitable base and a suitable solvent; 
         (xi) the reaction of a compound of formula (XIX) with a compound of formula (III) 
       
       
         
           
           
               
               
           
         
         in the presence of a suitable catalyst, a suitable ligand, a suitable base, and a suitable solvent; 
         (xii) the reaction of a compound of formula (XX) wherein R 3a  represents optionally substituted C 1-6 alkyl, with a compound of formula (XIV) 
       
       
         
           
           
               
               
           
         
         in the presence of a suitable catalyst, a suitable ligand, a suitable base, and a suitable solvent; 
         (xiii) the reaction of a compound of formula (XXXI) 
       
       
         
           
           
               
               
           
         
         with W 8 —CN, wherein W 8  represents a suitable leaving group, in the presence of a suitable base and a suitable solvent; 
         (xiv) the reaction of a compound of formula (XXXV) 
       
       
         
           
           
               
               
           
         
         with a suitable base in the presence of a suitable solvent; 
         (xv) deprotecting a compound of formula (XXVI) wherein P represents a suitable protective group, 
       
       
         
           
           
               
               
           
         
         in the presence of a suitable acid, or a suitable de-silylating agent, and a suitable solvent; 
         (xvi) the reaction of a compound of formula (XXIX) with a compound of formula (XXI) 
       
       
         
           
           
               
               
           
         
         in the presence of suitable peptide coupling reagents; 
         (xvii) the reaction of a compound of formula (XXIX) 
       
       
         
           
           
               
               
           
         
         with NHR 4 R 5  in the presence of suitable peptide coupling reagents and a suitable base, and a suitable solvent; 
         (xviii) reacting the below compound 
       
       
         
           
           
               
               
           
         
         with NHR 7 R 8  in the presence of a suitable base and a suitable solvent; 
         (xviii) deprotecting the below compound 
       
       
         
           
           
               
               
           
         
         in the presence of hydrazine monohydrate and a suitable solvent;
 wherein R 1 , R 1a , R 2 , R 3 , R 10 , and n are as defined herein; and optionally thereafter converting one compound of the formula (I) into another compound of the formula (I). 
 
       
     
     
         18 . A pharmaceutical composition comprising a compound of formula (I) as defined  claim 1 . 
     
     
         19 - 24 . (canceled) 
     
     
         25 . A method for the prophylaxis or treatment of a disease state or condition mediated by a FGFR kinase, which method comprises administering to a subject in need thereof a compound of the formula (I) as defined in  claim 1 .