Pyrido[3,2-d]pyrimidine compounds uses thereof for treating a proliferative disease
Compounds, compositions and their use in the treatment of a proliferative disease or condition such as a said proliferative disease or disorder is associated with a RAF gene mutation and/or a RAS gene mutation. The compounds disclosed are of Formula I or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 2 , R 3 , X 1 , X 2 , X 3 and X 4 are as defined herein.
1 . A compound of formula:
or a pharmaceutically acceptable salt thereof,
wherein each R 14 is, independently, selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 4-10 heterocycloalkyl, optionally substituted C 6 aryl, and optionally substituted C 5-10 heteroaryl, or each R 14 and their adjacent nitrogen atom together form an optionally substituted C 4-10 heterocycloalkyl group.
2 . The compound of claim 1 , wherein each R 14 and their adjacent nitrogen atom together form an optionally substituted C 4-10 heterocycloalkyl group.
3 . The compound of claim 2 , wherein the optionally substituted C 4-10 heterocycloalkyl group is monocyclic or bicyclic and comprises from 1 to 3 heteroatoms.
4 . The compound of claim 2 , wherein the optionally substituted C 4-10 heterocycle is substituted with at least one group selected from F, OH, oxo, CN, NH 2 , SO 2 CH 3 , COCH 3 , COOC(CH 3 ) 3 , COCH(CH 3 ) 2 , pyrrolidine, optionally substituted C 1-4 alkyl, and optionally substituted OC 1-4 alkyl.
5 . The compound of claim 4 , wherein the optionally substituted C 1-4 alkyl is substituted with at least one group selected from F, OH, and OC 1-3 alkyl.
6 . The compound of claim 1 , wherein each R 14 , their adjacent nitrogen atom, and the benzimidazolyl ring to which the adjacent nitrogen is bound together form a moiety: selected from the group consisting of:
7 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.
8 . A method of inhibiting RAS-ERK in a subject in need thereof, comprising administering to the subject a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein each R 14 is, independently, selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 4-10 heterocycloalkyl, optionally substituted C 6 aryl, and optionally substituted C 5-10 heteroaryl, or each R 14 and their adjacent nitrogen atom together an optionally substituted C 4-10 heterocycloalkyl group.
9 . The method of claim 8 , wherein each R 14 and their adjacent nitrogen atom together form an optionally substituted C 4-10 heterocycloalkyl group.
10 . The method of claim 9 , wherein the optionally substituted C 4-10 heterocycloalkyl group is monocyclic or bicyclic and comprises from 1 to 3 heteroatoms.
11 . The method of claim 9 , wherein the optionally substituted C 4-10 heterocycle is substituted with at least one group selected from F, OH, oxo, CN, NH 2 , SO 2 CH 3 , COCH 3 , COOC(CH 3 ) 3 , COCH(CH 3 ) 2 , pyrrolidine, optionally substituted C 1-4 alkyl, and optionally substituted OC 1-4 alkyl.
12 . The method of claim 11 , wherein the optionally substituted C 1-4 alkyl is substituted with at least one group selected from F, OH, and OC 1-3 alkyl.
13 . The method of claim 8 , wherein each R 14 , their adjacent nitrogen atom, and the benzimidazolyl ring to which the adjacent nitrogen is bound together form a moiety: selected from the group consisting of:
14 . A method of inhibiting RAS-ERK in a subject suffering from a melanoma, comprising administering to the subject a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein each R 14 is, independently, selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 4-10 heterocycloalkyl, optionally substituted C 6 aryl, and optionally substituted C 5-10 heteroaryl, or each R 14 and their adjacent nitrogen atom together form an optionally substituted C 4-10 heterocycloalkyl group.
15 . The method of claim 14 , wherein each R 14 and their adjacent nitrogen atom together form an optionally substituted C 4-10 heterocycloalkyl group.
16 . The method of claim 15 , wherein the optionally substituted C 4-10 heterocycloalkyl group is monocyclic or bicyclic and comprises from 1 to 3 heteroatoms.
17 . The method of claim 15 , wherein the optionally substituted C 4-10 heterocycle is substituted with at least one group selected from F, OH, oxo, CN, NH 2 , SO 2 CH 3 , COCH 3 , COOC(CH 3 ) 3 , COCH(CH 3 ) 2 , pyrrolidine, optionally substituted C 1-4 alkyl, and optionally substituted OC 1-4 alkyl.
18 . The method of claim 17 , wherein the optionally substituted C 1-4 alkyl is substituted with at least one group selected from F, OH, and OC 1-3 alkyl.
19 . The method of claim 14 , wherein each R 14 , their adjacent nitrogen atom, and the benzimidazolyl ring to which the adjacent nitrogen is bound together form a moiety: selected from the group consisting of:
20 . The compound of claim 1 , wherein each R 14 , their adjacent nitrogen atom, and the benzimidazolyl ring to which the adjacent nitrogen is bound together form a moiety: selected from the group consisting of:
21 . The method of claim 8 , wherein each R 14 , their adjacent nitrogen atom, and the benzimidazolyl ring to which the adjacent nitrogen is bound together form a moiety: selected from the group consisting of:
22 . The method of claim 14 , wherein each R 14 , their adjacent nitrogen atom, and the benzimidazolyl ring to which the adjacent nitrogen is bound together form a moiety: selected from the group consisting of: