Cycloalkyl-linked diheterocycle derivatives
The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein A, L, D, R 1 -R 15 , w, x, y, and z are defined herein. The novel cycloalkyl-linked diheterocycle derivatives that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. The present invention also relates to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.
1. A compound of formula (IVa)
wherein
L is -(C 4 -C 10 cycloalkyl)- optionally substituted by one to three substituents selected from the group consisting of halogen, cyano, C 1 -C 4 alkyl, hydroxy, and C 1 -C 4 alkoxy;
R 1 is hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, —C(O)R 10a , or 5-6 membered heteroaryl, wherein the C 3 -C 6 cycloalkyl and the 5-6 membered heteroaryl are independently optionally substituted by one or two R 15 groups;
R 2 is hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, —C(O)R 10b , or 5-6 membered heteroaryl, wherein the C 3 -C 6 cycloalkyl and the 5-6 membered heteroaryl are independently optionally substituted by one or two R 15 groups;
R 3 and R 4 are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or C 3 -C 6 cycloalkyl;
R 7 and R 8 are each independently hydrogen, halogen, cyano, C 1 -C 2 alkyl, hydroxy, C 1 -C 2 alkoxy, or —N(R 11 )(R 12 ), wherein the C 1 -C 2 alkyl and the C 1 -C 2 alkoxy are each independently optionally substituted by halogen or hydroxy;
R 10a and R 10b are each independently hydrogen, C 1 -C 4 alkyl, —[C(R 13 )(R 14 )] z -(C 4 -C 10 cycloalkyl), —[C(R 13 )(R 14 )] z -(4-6 membered heterocycloalkyl), —[C(R 13 )(R 14 )] z -(C 6 -C 10 aryl), or —[C(R 13 )(R 14 )] z -(5-10 membered heteroaryl), wherein the C 1 -C 4 alkyl, the C 4 -C 10 cycloalkyl, the 4-6 membered heterocycloalkyl, the C 6 -C 10 aryl, and the 5-10 membered heteroaryl in R 10a and R 10b are each independently optionally substituted by one, two or three halogen, cyano, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, —(CH 2 ) w —N(R 11 )(R 12 ), —(CH 2 ) w —C(O)N(R 11 )(R 12 ), —C(O)OR 11 , —N(R 11 )C(O)R 12 , —S(O) 2 R 11 , or —S(O)N(R 11 )(R 12 ) groups;
each R 11 , R 12 , R 13 , R 14 and R 15 is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, or 3-6 membered heterocycloalkyl, wherein the C 1 -C 4 alkyl, the C 3 -C 6 cycloalkyl, and the 3-6 membered heterocycloalkyl are each independently optionally substituted by one, two or three substituents selected from the group consisting of halogen, cyano, hydroxy, and methoxy;
w is 0, 1, 2 or 3;
x is 1;
and
z is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
2. The compound or salt of claim 1 , wherein L is
optionally substituted by one to three substituents selected from the group consisting of halogen, cyano, C 1 -C 4 alkyl, hydroxy, and C 1 -C 4 alkoxy.
3. The compound or salt of claim 2 , wherein L is
optionally substituted by one to three substituents selected from the group consisting of halogen, cyano, C 1 -C 4 alkyl, hydroxy, and C 1 -C 4 alkoxy.
4. The compound or salt of claim 3 wherein L is
5. The compound or salt of claim 1 , wherein
R 1 is —C(O)R 10a and R 2 is hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, —C(O)R 10b or 5-6 membered heteroaryl, wherein the C 3 -C 6 cycloalkyl and the 5-6 membered heteroaryl are independently optionally substituted by one or two R 15 groups; or
R 2 is —C(O)R 10b and R 1 is hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, —C(O)R 10b , or 5-6 membered heteroaryl, wherein the C 3 -C 6 cycloalkyl and the 5-6 membered heteroaryl are independently optionally substituted by one or two R 15 groups; or
R 1 is —C(O)R 10a and R 2 is —C(O)R 10b .
6. The compound or salt of claim 5 , wherein R 1 is —C(O)R 10a and R 2 is —C(O)R 10b .
7. The compound or salt of claim 6 , wherein R 10a is —[C(R 13 )(R 14 )] z -(C 4 -C 10 cycloalkyl), —[C(R 13 )(R 14 )] z -(4-6 membered heterocycloalkyl), —[C(R 13 )(R 14 )] z -(C 6 -C 10 aryl), or —[C(R 13 )(R 14 )] z -(5-10 membered heteroaryl) and R 10b is —[C(R 13 )(R 14 )] z -(C 4 -C 10 cycloalkyl), —[C(R 13 )(R 14 )] z -(4-6 membered heterocycloalkyl), —[C(R 13 )(R 14 )] z -(C 6 -C 10 aryl), or —[C(R 13 )(R 14 )] z -(5-10 membered heteroaryl), wherein the C 4 -C 10 cycloalkyl, the 4-6 membered heterocycloalkyl, the C 6 -C 10 aryl, and the 5-10 membered heteroaryl in R 10a and R 10b are each independently optionally substituted by one, two or three halogen, cyano, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, —(CH 2 ) w —N(R 11 )(R 12 ), —(CH 2 ) w —C(O)N(R 11 )(R 12 ), —C(O)OR 11 , —N(R 11 )C(O)R 12 , —S(O) 2 R 11 , or —S(O)N(R 11 )(R 12 ) groups.
8. The compound or salt of claim 7 , wherein R 10a is —[C(R 13 )(R 14 )] z -(C 6 aryl) or —[C(R 13 )(R 14 )] z -(5-6 membered heteroaryl) and R 10b is —[C(R 13 )(R 14 )] z -(C 6 aryl) or —[C(R 13 )(R 14 )] z -(5-6 membered heteroaryl), wherein the C 6 aryl and the 5-6 membered heteroaryl in R 10a and R 10b are each independently optionally substituted by one or two halogen or C 1 -C 4 alkyl groups.
9. The compound or salt of claim 8 , wherein R 10a is —[C(R 13 )(R 14 )] z -(5-6 membered heteroaryl) and R 10b is —[C(R 13 )(R 14 )] z -(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl in R 10a and R 10b are each independently optionally substituted by one or two C 1 -C 4 alkyl groups.
10. The compound or salt of claim 9 , wherein each R 13 and R 14 is hydrogen and each z is 1.
11. The compound or salt of claim 10 , wherein R 10a is —CH 2 -pyridinyl and R 10b is —CH 2 -pyridinyl, wherein each pyridinyl is optionally substituted by one or two C 1 -C 4 alkyl groups.
12. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
13. A combination of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, with an anti-tumor agent or with radiation therapy, for the treatment of cancer.
14. A method of treating abnormal cell growth in a mammal comprising administering to the mammal an amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating said abnormal cell growth.
15. A compound, which is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
16. A compound, which is
or a pharmaceutically acceptable salt thereof.
17. A compound, which is
or a pharmaceutically acceptable salt thereof.
18. A compound, which is
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a compound of claim 18 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
20. A combination of a compound of claim 18 , or a pharmaceutically acceptable salt thereof, with an anti-tumor agent or with radiation therapy, for the treatment of cancer.
21. A method of treating abnormal cell growth in a mammal comprising administering to the mammal an amount of a compound of claim 18 , or a pharmaceutically acceptable salt thereof, that is effective in treating said abnormal cell growth.