THIOPYRIMIDINE-BASED COMPOUNDS AND USES THEREOF
The present invention relates to thiopyrimidine-based compounds that are inhibitors of protein kinases including JAK kinases. In particular, the compounds are selective for JAK1, JAK2 or JAK3 kinases and combinations thereof such as JAK1 and JAK2. The kinase inhibitors can be used in the treatment of kinase associated diseases such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases and vascular diseases.
1 . A compound of formula I:
wherein:
X is CR 3 and Y is N;
wherein each R 3 is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, hydroxyl, halogen, nitro, substituted or unsubstituted amino, cyano, trifluoromethyl, methoxy, trifluoromethoxy, aryl and substituted or unsubstituted 5 or 6 membered heterocyclyl containing 1 to 2 N atoms;
R 1 is hydrogen, C 1-6 alkyl, C 1-6 alkylCN, C 3-8 cycloalkyl, C 1-6 alkylenecycloalkyl, aryl, C 1-6 alkylenearyl, heterocyclyl or C 1-6 alkyleneheterocyclyl, wherein said C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl and aryl groups are optionally substituted with 1 to 3 substituents selected from R and R 9 ;
wherein each R 9 is independently halogen, substituted or unsubstituted C 1-6 alkyl, OH, (O), OCN, substituted or unsubstituted OC 1-6 alkyl, CN, CF 3 , CF 2 CN, SCN, SO 2 NR 5 R 6 , SR 7 , CHO, CO 2 R 7 , COR 7 , CONR 5 R 6 , CONR 5 R 7 , NR 5 COR 7 , NO 2 , NR 5 R 6 , NR 5 CN, CH(CN)NR 5 R 6 , NR 5 SO 2 R 7 , COCF 3 , COCH 2 F, NR 5 COCOR 7 , NR 5 COOR 7 , NR 5 CONR 6 R 7 , heterocyclyl and COheterocyclyl, wherein each heterocyclyl may be optionally substituted with 1 to 4 substituents selected from NH 2 , CN, OH, CO 2 R 7 , CH 2 CN and 5 membered N-containing heterocyclyl; and
wherein R 5 and R 6 are each independently H, C 1-6 alkyl, C 1-6 alkylCN, C 3-8 cycloalkyl, aryl, heterocyclyl, cycloalkyl, substituted or unsubstituted C 1-6 alkylene, SO 2 C 1-6 alkyl, or C 1-6 alkylene heterocyclyl; or
R 5 and R 6 together with the nitrogen to which they are attached form a 4 to 8 membered ring having 1 to 3 heteroatoms independently selected from the group consisting of NR 8 , O, and S(O) m , wherein m is 0, 1, or 2, and wherein the ring may be optionally substituted with C 1-6 alkyl or NR 5 R 6 ;
wherein R 8 is H, C 1-6 alkyl, C 2-6 alkyleneOH, C 2-6 alkyleneNR 5 R 6 , C 3-8 cycloalkyl, aryl, heterocyclyl, C 1-6 alkylenecycloalkyl, C 1-6 alkylenearyl, C 1-6 alkyleneheterocyclyl, or C 1-6 alkyleneCN;
R 7 is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted OC 1-6 alkyl, substituted or unsubstituted SC 1-6 alkyl, CNOH, C 1-6 alkyleneCN, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, C 1-6 alkylenecycloalkyl, C 1-6 alkylenearyl, C 1-6 alkyleneheterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, NR 5 R 6 , C 1-6 alkyleneNR 5 R 6 or C 1-6 alkyleneOR 5 ;
each R is C 1-6 alkyleneR 9 or OC 1-6 alkyleneR 9 (except when R 9 is NR 5 R 6 or OC 1-6 alkyl, then R is OC 2-6 alkyleneR 9 ); or
R 9 and R together with the groups to which they are attached form a substituted or unsubstituted 5 or 6 membered N-containing heterocyclyl;
W is absent, CO, SO 2 or C 1-6 alkylene; and
R 2 is H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heterocyclyl, each of which is optionally substituted with 1 to 4 substituents selected from R and R 9 ;
wherein each alkenyl or alkynyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6 alkyl, CO 2 R 7 , CONR 5 R 6 , aryl, heterocyclyl, C 1-6 alkylene OH, and C 1-6 alkyleneNH 2 ;
or salts and/or isomers thereof.
2 . The compound according to claim 1 , wherein W is absent, CO or C 1-6 alkylene.
3 . The compound according to claim 1 , wherein R 1 is aryl; heterocyclyl; C 1-6 alkyl; or aryl substituted with 1 to 3 substituents selected from NR 5 R 6 , NR 5 COR 7 , CN, OC 1-6 alkyl, OH, CO 2 R 7 , CONR 5 R 7 , CONR 5 R 6 , NR 5 CO 2 R 7 , substituted or unsubstituted C 1-6 alkyl, SR 7 , CHO and substituted or unsubstituted heterocyclyl.
4 . The compound according to claim 1 , wherein R 2 is aryl, imidazolyl; (methylenedioxy)phenyl; or aryl substituted with 1 to 4 substituents selected from an N-containing 5 or 6 membered heterocyclyl; substituted or unsubstituted OC 1-6 alkyl; NR 5 COR 7 , wherein in this instance only R 5 is H, and R 7 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or CN; NH 2 ; halo; CO 2 R 7 ; SO 2 NR 5 R 6 ; NO 2 ; NHSO 2 Me; CHOHCF 3 CH 3 ; CH 2 NHSO 2 Me; OH; and SH.
5 . The compound according to claim 1 , wherein R 3 is H; C 1-6 alkyl; halogen; C 2-6 alkenyl; substituted or unsubstituted amino; cyano; nitro; methoxy; aryl; or 5 or 6 membered heterocyclyl containing 1 or 2 N atoms.
6 . The compound according to claim 1 , wherein a substituent of one of R 1 and R 2 is selected from
wherein
D is O or N;
R 10 is selected from H and substituted or unsubstituted C 1-4 alkyl;
R 11 and R 12 are each independently selected from H, substituted or unsubstituted C 1-4 alkyl, C 1-4 alkylNR 14 R 15 , C 1-4 alkylOR 8 , substituted or unsubstituted aryl, or may be joined to form a substituted or unsubstituted 5 to 8 membered ring optionally containing one or more heteroatoms selected from O, S, SO 2 and NR 10 ;
R 13 is OH, OC 1-4 alkyl or NR 14 R 15 ;
p is 0, 1, 2, 3 or 4; and
R 14 and R 15 are independently selected from H and substituted or unsubstituted C 1-4 alkyl, or may be joined to form a substituted 3 to 8 membered ring optionally containing one or more heteroatoms selected from O, S, SO 2 and NR 10 .
7 . A process for the preparation of the compound of formula I according to claim 1 which comprises the steps of:
(a) adding S—R 1 wherein R 1 is as defined in claim 1 to a compound of formula II
wherein X, Y and R 3 are as defined in claim 1 and LG is a leaving group, to prepare a compound of formula III
wherein X, Y, LG, R 1 and R 3 are as defined above; and
(b) coupling the compound of formula III with a source of NH—W—R 2 wherein W and R 2 are as defined in claim 1 .
8 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
9 . An implant comprising a compound of claim 1 .
10 . A method for the treatment of a kinase associated disease which comprises administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition comprising a compound of claim 1 to a human in need thereof.
11 . The method according to claim 10 , wherein the kinase associated disease is an immunological disease; inflammatory disease; hyperproliferative disease; viral disease; metabolic disease; or vascular disease.
12 . A method for suppressing the immune system of a human in need thereof which comprises administering to the human a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition comprising a compound of claim 1 .
13 . A method of inhibiting a kinase in a cell comprising contacting the cell with a compound of claim 1 .