Naphthridine derivatives as PI3K inhibitors for the treatment of cancer and immune-inflammatory disease
Compounds of formulae (I) and (II): or a pharmaceutically acceptable salt thereof, wherein: R 1 is a nitrogen-containing 5 to 7-membered heteroaryl or heterocycle; R 2 and R 3 are each independently (LQ) m Y, are described. The compounds are PI3K inhibitors and are useful for the treatment of cancer and immune-inflammatory diseases.
1. A compound of formula I or II
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of:
R 2 is (LQ) m Y;
each L is independently selected from the group consisting of: a direct bond, C 1 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, arylene and C 3 -C 10 cycloalkylene;
each Q is independently selected from the group consisting of: a direct bond, heteroarylene, —O—, —NR 6 —, —C(O)—, —C(O)NR 6 —, —SO 2 —, —SO 2 —NR 6 —, —N H —C(O)—NR 6 —, —N H —SO 2 —NR 6 , —C(halogen) a (R 6 (2-a) )—, —NR 4 R 5 —, and —C(O)NR 4 R 5 , where R 4 and R 5 together with the nitrogen to which they are attached form a 5 to 7-membered heterocycle linker;
m is from 0 to 5;
Y is independently selected from the group consisting of: H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, aryl, C 3 -C 10 cycloalkyl, heteroaryl, —OR 6 , —N(R 6 ) 2 , —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —SO 2 —R 6 , —SO 2 —N(R 6 ) 2 , —N H —C(O)—N(R 6 ) 2 , —N H —SO 2 —N(R 6 ) 2 , halogen, —C(halogen) b R 6 (3-b) ;
b is from 1 to 3;
a is 1 or 2;
R 3 is selected from the group consisting of:
(a) aryl substituted with from one to five substituents independently selected from the group of C 1 -C 3 hydroxyalkyl, —N(benzyl) 2 , C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, aryl, C 3 -C 10 cycloalkyl, heteroaryl, —OR 6 , —N(R 6 ) 2 , —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —SO 2 —R 6 , —SO 2 —N(R 6 ) 2 , —N H —C(O)—N(R 6 ) 2 , —N H —SO 2 —N(R 6 ) 2 , halogen, and —C(halogen) b R 6 (3-b) ;
(b) (C 1 -C 10 alkylene)-NR 6 -aryl; and
(c) a bicyclic heteroaryl containing at least one nitrogen atom; and
each R 6 is independently selected from the group consisting of H, C 1 -C 10 alkyl, aryl or heteroaryl.
2. The compound according to claim 1 , wherein R 1 is
3. The compound according to claim 1 , wherein R 2 is H.
4. The compound according to claim 1 , wherein R 3 is aryl substituted with from one to five substituents each independently selected from the group consisting of: C 1 -C 3 hydroxyalkyl, —N(benzyl) 2 , C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, aryl, C 3 -C 10 cycloalkyl, heteroaryl, —OR 6 , —N(R 6 ) 2 , —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —SO 2 —R 6 , —SO 2 —N(R 6 ) 2 , —N H —C(O)—N(R 6 ) 2 , —N H —SO 2 —N(R 6 ) 2 , halogen, and —C(halogen) b R 6 (3-b) .
5. The compound according to claim 4 , wherein R 3 is aryl substituted with at least one C 1 -C 3 hydroxyalkyl.
6. The compound according to claim 4 , wherein R 3 is aryl substituted with at least one (NR 6 ) 2 group.
7. The compound according to claim 1 , wherein R 3 is (C 1 -C 10 alkylene)-NR 6 -aryl.
8. The compound according to claim 1 , which has a structure selected from:
9. The compound according to claim 1 , which is compound G:
or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1 , wherein R 3 is a bicyclic heteroaryl containing at least one nitrogen atom.
11. The compound according to claim 1 , wherein R 3 is indolyl.
12. A compound of formula I or II
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is
R 2 is (LQ) m Y;
each L is independently selected from the group consisting of: a direct bond, C 1 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, arylene and C 3 -C 10 cycloalkylene;
each Q is independently selected from the group consisting of: a direct bond, heteroarylene, —O—, —NR 6 —, —C(O)—, —C(O)NR 6 —, —SO 2 —, —SO 2 —NR 6 —, —N H —C(O)—NR 6 —, —N H —SO 2 —NR 6 , —C(halogen) a (R 6 (2-a) )—, —NR 4 R 5 —, and —C(O)NR 4 R 5 , where R 4 and R 5 together with the nitrogen to which they are attached form a 5 to 7-membered heterocycle linker;
m is from 0 to 5;
Y is independently selected from the group consisting of: H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, aryl, C 3 -C 10 cycloalkyl, heteroaryl, —OR 6 , —N(R 6 ) 2 , —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —SO 2 —R 6 , —SO 2 —N(R 6 ) 2 , —N H —C(O)—N(R 6 ) 2 , —N H —SO 2 —N(R 6 ) 2 , halogen, —C(halogen) b R 6 (3-b) , and —NR 4 R 5 —C(O)NR 4 R 5 , where R 4 and R 5 together with the nitrogen to which they are attached form a 5- to 7-membered heterocycle;
b is from 1 to 3;
a is 1 or 2;
R 3 is a bicyclic heteroaryl containing at least one nitrogen atom; and
each R 6 is independently selected from the group consisting of H, C 1 -C 10 alkyl, aryl or heteroaryl.
13. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable excipient.