Protein kinase inhibitors
A compound of formula (I), wherein R 3 , R 4 , G, B, M, and Z are as defined in the claims, and pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (I) possess utility as FGFR inhibitors and are useful in the treatment of a condition, where FGFR kinase inhibition is desired, such as cancer.
1. A compound of formula (I)
wherein
Z is CH or N;
G is a group of formula
wherein ring A is a phenyl ring or a 5-12 membered heterocyclic ring, and
R 1 is H, C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkyl carbonyl, amino, hydroxy, hydroxy C 1-7 alkyl, C 1-7 alkylamino C 1-7 alkyl, phenyl C 1-7 alkoxy, —NHC(O)—R 21 , —R 12 —C(O)—R 13 , —SO 2 —R 14 or -E-R 6 , and
R 2 is H, halogen, C 1-7 alkyl or oxo;
ring B is a 5-12 membered carbocyclic or heterocyclic ring;
R 3 is H, halogen, C 1-7 alkyl, C 1-7 alkoxy, cyano or an optionally substituted 5-6 membered heterocyclic ring;
R 4 is H, halogen, C 1-7 alkyl or oxo;
M is —NHR 5 ;
R 5 is H, —C(O)R 7 , —SO 2 R 8 , —C(O)-D-R 9 or an optionally substituted 5-6 membered heterocyclic ring;
R 6 is an optionally substituted 5-6 membered heterocyclic ring;
R 7 is C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 1-7 alkoxy, C 1-7 alkoxy C 1-7 alkyl, carboxy C 1-7 alkyl, C 1-7 alkoxy carbonyl C 1-7 alkyl, C 1-7 alkylamino C 1-7 alkyl, —NH—R 10 or —NH—X 1 —R 11 ;
R 8 is C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, hydroxy C 1-7 alkyl, —NR 18 R 19 , —NH—X 2 —R 20 , phenyl or an optionally substituted 5-6 membered heterocyclic ring;
R 9 is phenyl or an optionally substituted 5-6 membered heterocyclic ring;
R 10 is C 1-7 alkyl or C 3-7 cycloalkyl;
R 11 is phenyl or an optionally substituted 5-6 membered heterocyclic ring;
R 12 and R 21 are C 1-7 alkyl;
R 13 is C 1-7 alkoxy, amino or hydroxy;
R 14 is C 1-7 alkyl or C 3-7 cycloalkyl;
R 18 and R 19 are, independently, H, C 1-7 alkyl or C 3-7 cycloalkyl;
R 20 is phenyl or an optionally substituted 5-6 membered heterocyclic ring;
E is a bond or a C 1-7 alkyl;
D is a bond or a C 1-7 alkyl;
X 1 and X 2 are, independently, a bond or C 1-7 alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein ring A is a 5-12 membered heterocyclic ring selected from the following groups or tautomers thereof
3. The compound according to claim 1 , wherein ring B is a 5-12 membered carbocyclic or heterocyclic ring selected from the following groups or tautomers thereof
4. The compound according to claim 1 , wherein Z is CH.
5. The compound according to claim 1 , wherein Z is N.
6. The compound according to claim 1 , wherein
G is a group of formula
wherein ring A is a 5-12 membered heterocyclic ring selected from the following groups or tautomers thereof
R 1 is H, C 1-7 alkyl, C 1-7 alkoxy, hydroxy C 1-7 alkyl, C 1-7 alkylamino C 1-7 alkyl or -E-R 6 ;
R 2 is H;
ring B is a 5-12 membered carbocyclic or heterocyclic ring of formula
E is a bond or C 1-7 alkyl;
R 6 is a 5-6 membered heterocyclic ring selected from the following groups:
R 3 is H, halogen, C 1-7 alkyl, C 1-7 alkoxy or cyano;
R 4 is H or halogen;
M is —NHR 5 ;
R 5 is —C(O)R 7 , —SO 2 R 8 or —C(O)-D-R 9 or a 5-6 membered heterocyclic ring selected from the following groups:
R 7 is C 1-7 alkyl, C 2-7 alkenyl, —NH—R 10 or —NH—X 1 —R 11 ;
R 8 is C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, hydroxy C 1-7 alkyl, —NR 18 R 19 , —NH—X 2 —R 20 , phenyl or the 5-6 membered heterocyclic ring:
R 9 is phenyl or a 5-6 membered heterocyclic ring selected from the following groups or tautomers thereof:
R 10 is C 1-7 alkyl or C 3-7 cycloalkyl;
R 11 is phenyl, 4-fluorophenyl, or a 5-6 membered heterocyclic ring selected from the following groups:
R 18 and R 19 are, independently, H, C 1-7 alkyl or C 3-7 cycloalkyl;
R 20 is the 5-6 membered heterocyclic ring:
X 1 and X 2 are, independently, a bond or C 1-7 alkyl, and
D is a bond or C 1-7 alkyl.
7. The compound according to claim 1 , wherein ring B is a 5-12 membered carbocyclic or heterocyclic ring of formula
8. The compound according to claim 1 , wherein ring A is a 5-12 membered heterocyclic ring selected from the following groups or tautomers thereof
9. The compound according to claim 1 , wherein ring B is phenyl, R 3 is halogen, and R 4 is H or halogen.
10. The compound according to claim 1 , wherein M is —NHC(O)R 7 , wherein R 7 is C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, —NH—R 10 or —NH—X 1 —R 11 , wherein R 10 is C 1-7 alkyl or C 3-7 cycloalkyl, X 1 is a bond or C 1-7 alkyl, and R 11 is a 5-6 membered heterocyclic ring optionally substituted by one or two C 1-7 alkyl groups.
11. The compound according to claim 1 , wherein M is —NHSO 2 R 8 , wherein R 8 is C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, phenyl, or NR 18 R 19 , wherein R 18 and R 19 are, independently, H, C 1-7 alkyl or C 3-7 cycloalkyl.
12. The compound according to claim 1 , wherein or M is —NHC(O)-D-R 9 , wherein D is bond or C 1-7 alkyl, and R 9 is a 5-6 membered heterocyclic ring optionally substituted by one or two C 1-7 alkyl groups.
13. The compound according to claim 1 , wherein or R 5 is a 5-6 membered heterocyclic ring optionally substituted by one or two C 1-7 alkyl groups.
14. A pharmaceutical composition comprising a compound of according to claim 1 and a pharmaceutically acceptable carrier.
15. A method for inhibiting FGFR kinase comprising administering to a subject an effective amount of a compound according to claim 1 .