Bicyclic oxa-lactam kinase inhibitors
View Patent ↗Provided are bicyclic oxa-lactam compounds of formula I: and pharmaceutically acceptable salts thereof which are inhibitors of JAK/Syk kinase. The present disclosure is also directed to intermediates used in making such compounds, methods for their preparation, pharmaceutical compositions thereof, methods for inhibiting JAK/Syk kinase activity, and methods for treating conditions mediated at least in part by JAK/Syk kinase activity.
1. A compound of Formula (I):
or a tautomer or a pharmaceutically acceptable salt thereof, wherein
G 1 is N and G 2 is N;
L 1 is selected from the group consisting of a bond, NH, O, and S;
Z 1 is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with 1 to 5 R 1 ;
t is 1;
R 1 is independently selected from the group consisting of halo, C 1-8 alkyl, C 2-8 alkenyl, haloC 1-8 alkyl, (CH 2 ) n SR 1a , (CH 2 ) n OR 1a , O(CH 2 ) j OR 1a , (CH 2 ) n NR 1b R 1c , (CH 2 ) n COR 1e , (CH 2 ) n CONR 1b R 1c , (CH 2 ) n NR 1b COR 1e , (CH 2 ) n CONR 1b (OR 1a ), (CH 2 ) n CO 2 R 1a , O(CH 2 ) n CO 2 R 1a , (CH 2 ) n NR 1b CO 2 R 1a , (CH) n SO 2 NR 1b R 1c , (CH 2 ) n NR 1b SO 2 R 1e , (CH 2 ) n SOR 1e , (CH 2 ) n SO 2 R 1e , oxo, (CH 2 ) n CN, N 3 , NO 2 , and -L 2 -W, where n is 0, 1, 2, 3, 4, 5, or 6 and j is 1, 2, 3, 4, 5, or 6;
L 2 is selected from the group consisting of —O(CH 2 ) b —, —SO—, —SO 2 —, —CO—, —NR 1d —, —CONR 1d (CH 2 ) b —, —NR 1d CO—, —NR 1d SO 2 —, —SO 2 NR 1d —, a bond, and —(CH 2 ) e — where b is 0, 1, 2, 3, 4, or 5 and e is 1, 2, 3, 4, or 5;
W is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclyl each optionally substituted with 1 to 3 R 2 ;
R 2 is independently selected from the group consisting of halo, C 1-8 alkyl, C 2-8 alkenyl, haloC 1-8 alkyl, (CH 2 ) m SR 2a , (CH 2 ) m OR 2a , O(CH 2 ) k OR 2a , (CH 2 ) m NR 2b R 2c , (CH 2 ) m COR 2e , (CH 2 ) m CONR 2b R 2c , (CH 2 ) m NR 2b COR 2e , (CH 2 ) m CONR 2b (OR 2a ), (CH 2 ) m CO 2 R 2a , O(CH 2 ) m CO 2 R 2a , (CH 2 ) m NR 2b CO 2 R 2a , (CH) m SO 2 NR 2b R 2c , (CH 2 ) m NR 2b SO 2 R 2e , (CH 2 ) m SOR 2e , (CH 2 ) m SO 2 R 2e , oxo, (CH 2 ) m CN, N 3 , and NO 2 , where m is 0, 1, 2, 3, 4, 5, or 6 and k is 1, 2, 3, 4, 5, or 6;
R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , and R 2c are independently selected from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, and haloC 1-8 alkyl;
R 1e and R 2e are independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and haloC 1-8 alkyl;
Y 1 is
or (CH 2 ) v (Y 2 ), wherein
v is 0, 1, 2, or 3;
Y 2 is selected from the group consisting of CH 2 CH 3 , (CH 2 ) 3 NH 2 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1 to 3 R 10 ;
R 4 is selected from the group consisting of H, halo, C 1-8 alkyl, C 2-8 alkenyl, haloC 1-8 alkyl, (CH 2 ) p SR 4a , (CH 2 ) p SOR 4a , (CH 2 ) p SO 2 R 4a , (CH 2 ) p OR 4a , (CH 2 ) p NR 4b R 4c , (CH 2 ) f CONR 4b R 4c , (CH 2 ) p NR 4b COR 4d , (CH 2 ) f CO 2 R 4a , (CH 2 ) p NR 4b CO 2 R 4a , (CH 2 ) f cycloalkyl, (CH 2 ) p (O)cycloalkyl, (CH 2 ) p (S)cycloalkyl, (CH) p SO 2 NR 4b R 4c , (CH 2 ) p NHcycloalkyl, (CH 2 ) f CN, (CH 2 ) f (aryl), (CH 2 ) f (heteroaryl), (CH 2 ) f (aryl)(heteroaryl), (CH 2 ) f (heterocyclyl), (CH 2 ) p (O)(CH 2 ) f (aryl), (CH 2 ) p (O)(CH 2 ) f (heteroaryl), (CH 2 ) p (O)(CH 2 ) f C 3-8 cycloalkyl, and (CH 2 ) p (O)(CH 2 ) f (heterocyclyl), where the aryl, heteroaryl, cycloalkyl, and heterocyclyl are each optionally substituted with 1 to 3 R 11a , f is 0, 1, 2, 3, 4, 5, or 6, and p is 1, 2, 3, 4, 5, or 6; or R 4 and R 5 together form ═O or a 3 to 8 membered carbocyclic or heterocyclic ring optionally substituted with 1 to 3 R 11a ;
R 5 is selected from the group consisting of H and C 1-8 alkyl; or R 5 is joined to the adjacent nitrogen atom to form a 4 to 6 membered heterocyclic ring optionally substituted with 1 to 3 R 11a ;
R 6 is selected from the group consisting of H, C 1-8 alkyl, OH, O(C 1-8 alkyl), CO 2 R 6a , CO(NR 6a R 6b ), and C 3-8 cycloalkyl; or R 6 together with R 7 and the atoms to which they are attached to form a heterocyclyl ring optionally substituted with 1 to 3 R 11b ;
R 7 is selected from the group consisting of H, C 1-8 alkyl, and cycloalkyl;
R 8 is selected from the group consisting of H, C 1-8 alkyl, (CH 2 ) u NR 8b R 8c , (CH 2 ) g CONR 8b R 8c , (CH 2 ) g CO(CH 2 ) u NR 8b R 8c , (CH 2 ) g CO 2 R 8a , (CH 2 ) u OR 8a , CH(C 1-8 alkyl)OR 8a , (CH 2 ) g cycloalkyl, (CH 2 ) g heterocyclyl, (CH 2 ) g aryl, (CH 2 ) g heteroaryl, and (CH 2 ) u (O)(aryl), where the aryl, cycloalkyl, heteroaryl, and heterocyclyl are each optionally substituted with 1 to 3 R 11c , g is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6; or R 8 together with R 9 and the atoms to which they are attached to form ═O, ═S, or a cycloalkyl or heterocyclyl ring optionally substituted with R 11c ;
R 9 is H or C 1-8 alkyl;
R 10 is independently selected from the group consisting of halo, C 1-8 alkyl, C 2-8 alkenyl, haloC 1-8 alkyl, (CH 2 ) q SR 10a , (CH 2 ) q OR 10a , (CH 2 ) q NR 10b R 10c , (CH 2 ) q COR 10d , (CH 2 ) q CONR 10b R 10c , (CH 2 ) q NR 10b COR 10d , (CH 2 ) q CONR 10b (OR 10a ), (CH 2 ) q CO 2 R 10a , O(CH 2 ) q CO 2 R 10a , (CH 2 ) q NR 10b CO 2 R 10a , (CH) q SO 2 NR 10b R 10c , (CH 2 ) q NR 10b SO 2 R 10d , (CH 2 ) q SOR 10d , (CH 2 ) q SO 2 R 10d , oxo, (CH 2 ) q CN, N 3 , N═CH 2 , NO 2 , C(O)heterocyclyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl, where the aryl, cycloalkyl, heteroaryl, and heterocyclyl are each optionally substituted with 1 to 3 R 11d and q is 0, 1, 2, 3, 4, 5, or 6;
R 11a , R 11b , R 11c , and R 11d are independently selected from the group consisting of halo, C 1-8 alkyl, haloC 1-8 alkyl, OH, C 1-8 alkoxy, haloC 1-8 alkoxy, C(O)C 1-8 alkyl, CO 2 C 1-8 alkyl, and SO 2 C 1-8 alkyl;
R 4a , R 4b , R 4c , R 6a , R 6b , R 8a , R 8b , R 8c , R 10a , R 10b , and R 10c are independently selected from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, and haloC 1-8 alkyl;
R 4d and R 10d are independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and haloC 1-8 alkyl; and
the wavy line indicates the point of attachment to the rest of the molecule.
2. A compound of claim 1 of Formula (Ia)
or a tautomer or a pharmaceutically acceptable salt thereof wherein HET is heteoraryl optionally substituted with 1 to 3 R 1 .
3. A compound of claim 1 a tautomer or a pharmaceutically acceptable salt thereof, wherein Z 1 is selected from the group consisting of
where the point of attachment to the rest of the molecule is at a carbon ring atom and wherein Z 1 is optionally substituted with 1 to 3 R 1 .
4. A compound of claim 3 wherein Z 1 is selected from the group consisting of
where the wavy line indicates the point of attachment to the rest of the molecule and wherein Z 1 is optionally substituted with 1 to 3 R 1 .
5. A compound of claim 3 wherein Z 1 is selected from the group consisting of
where the wavy line indicates the point of attachment to the rest of the molecule and wherein Z 1 is optionally substituted with 1 to 3 R 1 .
6. A compound of claim 3 wherein Z 1 is selected from the group consisting of
where the wavy line indicates the point of attachment to the rest of the molecule and wherein Z 1 is optionally substituted with 1 to 3 R 1 .
7. A compound of claim 3 wherein Z 1 is selected from the group consisting of
where the wavy line indicates the point of attachment to the rest of the molecule and wherein Z 1 is optionally substituted with 1 to 3 R 1 .
8. A compound of claim 3 or a tautomer or a pharmaceutically acceptable salt thereof, wherein Z 1 is selected from the group consisting of
where the point of attachment to the rest of the molecule is at a carbon ring atom and wherein Z 1 is optionally substituted with 1 to 3 R 1 .
9. A compound of claim 3 wherein Z 1 is selected from the group consisting of
where the wavy line indicates the point of attachment to the rest of the molecule and wherein Z 1 is optionally substituted with 1 to 3 R 1 .
10. A compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof, wherein Z 1 is a six-membered heteroaryl ring optionally substituted with 1 to 3 R 1 .
11. A compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof, wherein Z 1 is a five-membered heteroaryl ring optionally substituted with 1 to 3 R 1 .
12. A compound of claim 1 of Formula (Ib)
or a tautomer or a pharmaceutically acceptable salt thereof.
13. A compound of claim 1 wherein at least one R 1 is C 1-3 alkyl.
14. A compound of claim 1 having Formula (II)
or a tautomer or a pharmaceutically acceptable salt thereof.
15. A compound of claim 2 or a tautomer or a pharmaceutically acceptable salt thereof wherein HET is selected from the group consisting of:
where the wavy line indicates the point of attachment to the rest of the molecule.
16. A compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof, wherein Y 1 is
where the wavy line indicates the point of attachment to the rest of the molecule.
17. A compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof, wherein Y 1 is selected from the group consisting of
where the wavy line indicates the point of attachment to the rest of the molecule.
18. A compound or a tautomer or a pharmaceutically acceptable salt thereof selected from the group consisting of:
STRUCTURE
NAME
7-(((1R,2S)-2-aminocyclohexyl)amino)- 5-(m-tolylamino)-2H-pyrimido[5,4- e][1,3]oxazin-4(3H)-one
7-(((1R,2S)-2-aminocyclohexyl)amino)- 5-(1-methyl-1H-pyrazol-4-yl)-2H- pyrimido[5,4-e][1,3]oxazin-4(3H)-one
7-(((1R,2S)-2-aminocyclohexyl)amino)- 5-(pyridin-2-ylamino)-2H- pyrimido[5,4-e][1,3]oxazin-4(3H)-one
7-(((1R,2S)-2-aminocyclohexyl)amino)- 5-(oxazol-2-ylamino)-2H-pyrimido[5,4- e][1,3]oxazin-4(3H)-one
7-(((1R,2S)-2-aminocyclohexyl)amino)- 5-(pyrimidin-2-ylamino)-2H- pyrimido[5,4-e][1,3]oxazin-4(3H)-one
7-(((1R,2S)-2-aminocyclohexyl)amino)- 5-((4-morpholinophenyl)amino)-2H- pyrimido[5,4-e][1,3]oxazin-4(3H)-one
7-(((1R,2S)-2-aminocyclohexyl)amino)- 5-((5-morpholinopyridin-2-yl)amino)- 2H-pyrimido[5,4-e][1,3]oxazin-4(3H)- one
7-(((1R,2S)-2-aminocyclohexyl)amino)- 5-((6-morpholinopyridin-3-yl)amino)- 2H-pyrimido[5,4-e][1,3]oxazin-4(3H)- one
7-(((1R,2S)-2-aminocyclohexyl)amino)- 5-((1-isopropyl-1H-pyrazol-4- yl)amino)-2H-pyrimido[5,4- e][1,3]oxazin-4(3H)-one
7-(((1R,2S)-2-aminocyclohexyl)amino)- 5-((4-methoxy-3- (trifluoromethyl)phenyl)amino)-2H- pyrimido[5,4-e][1,3]oxazin-4(3H)-one
7-((3-aminopropyl)amino)-5-(m- tolylamino)-2H-pyrimido[5,4- e][1,3]oxazin-4(3H)-one
7-(((1R,2S)-2-aminocyclohexyl)amino)- 5-((3-fluoro-4- morpholinophenyl)amino)-2H- pyrimido[5,4-e][1,3]oxazin-4(3H)-one
7-(((1R,2S)-2-aminocyclohexyl)amino)- 5-(quinolin-6-ylamino)-2H- pyrimido[5,4-e][1,3]oxazin-4(3H)-one
7-(((1R,2S)-2-aminocyclohexyl)amino)- 5-((1-methyl-1H-pyrazol-4-yl)amino)- 2H-pyrimido[5,4-e][1,3]oxazin-4(3H)- one.
19. A pharmaceutical composition comprising a compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier or excipient.
20. A method for inhibiting Syk or JAK kinase or a signal transduction pathway mediated at least in part by Syk kinase activity comprising contacting a cell with a compound of claim 1 .