Substituted quinoxaline DNA-PK inhibitors
The present invention relates to Provided are compounds of Formula (I): wherein R 1 , R 2 , X, Ring A, Ring B, and Ring C are as defined herein. Compounds of Formula (I) are useful as inhibitors of DNA-PK. Also provided are pharmaceutical compositions comprising said compounds and methods of using the compounds and compositions in the treatment of various diseases, conditions, and disorders.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
Ring A is:
Ring B is:
each optionally substituted with one, two, three, or four fluoro, one or two hydroxy, or one or two C 1-4 alkyl, wherein the C 1-4 alkyl is further optionally substituted with one, two, or three fluoro, one or two hydroxy, or one or two OC 1-2 alkyl;
Ring C is cyclohexyl;
X is —NH—, —O—, or —OC 1-4 alkylene-;
R 1 is hydrogen, C 0-4 alkyl-NHR 4 , C(O)NHR 4 , C(O)OR 4 , NHC(O)R 4 , NHC(O)NHR 4 , NHC(O)OR 4 , NHS(O) 2 R 4 , or OR 4 ;
R 2 is hydrogen, C 0-4 alkyl-NHR 4 , C(O)NHR 4 , C(O)OR 4 , NHC(O)R 4 , NHC(O)NHR 4 , NHC(O)OR 4 , NHS(O) 2 R 4 , or OR 4 ; or
R 1 and R 2 , together with the intervening carbon atom(s) to which they are attached, form a dioxane or dioxolane ring;
R 3 is hydrogen, fluoro, chloro, cyano, C 1-4 alkyl, C(O)H, C(O)NH 2 , C(O)NHC 1-2 alkyl, C(O)OH, C(O)OC 1-2 alkyl, or OC 1-2 alkyl, wherein each C 1-4 alkyl, C(O)NHC 1-2 alkyl, C(O)OC 1-2 alkyl, and OC 1-2 alkyl is optionally substituted with one, two, or three fluoro, one or two hydroxy, or one or two OC 1-2 alkyl;
each R 4 is independently hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, or phenyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl and phenyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of:
(a) one, two, three, or four fluoro, chloro, bromo, or C 1-4 alkyl;
(b) one, two, or three cyano;
(c) one or two OR 5 ;
(d) NO 2 , CH 2 OR 5 , C 0-4 alkyl-C(O)R 5 , C 0-4 alkyl-C(O)NH 2 , C 0-4 alkyl-C(O)N(R 5 ) 2 , C 0-4 alkyl-C(O)OR 5 , C 0-4 alkyl-N(R 5 )2, C 0-4 alkyl-NHC(O)R 5 , C 0-4 alkyl-O—C 1-4 alkyl, C 0-4 alkyl-O—C 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-C 3-5 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NH(C 0-4 alkyl-C 3-5 cycloalkyl), C(O)OC 1-4 alkyl, C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, or C 3-6 cycloalkyl;
(e) a heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, piperazinyl, and morpholinyl; and
(f) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, and oxadiazolyl;
wherein each C 1-4 alkyl, CH 2 OR 5 , C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl-C(O)R 5 , C 1-4 alkyl-C(O)NH 2 , C 1-4 alkyl-C(O)N(R 5 ) 2 , C 1-4 alkyl-NHC(O)R 5 , C 1-4 alkyl-N(R 5 ) 2 , C 0-4 alkyl-O—C 1-4 alkyl, C 0-4 alkyl-O—C 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 1-4 alkyl, C(O)NH(C 0-4 alkyl-C 3-5 cycloalkyl), C(O)N(C 1-4 alkyl) 2 , C 1-4 alkyl-C(O)OR 5 , C(O)OC 1-4 alkyl, C(O)OC 1-4 alkyl-C 3-5 cycloalkyl, C 3-6 cycloalkyl, heterocyclyl, and heteroaryl substituent is optionally and independently substituted with one, two, three, or four fluoro, one or two C 1-4 alkyl, one C(O)C 1-4 alkyl, one C(O)OC 1-4 alkyl, one C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, one or two hydroxy, one or two OC 1-4 alkyl, or one or two SC 1-4 alkyl; or
each R 4 is independently selected from the group consisting of:
(i) a heterocyclyl selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydroisoxazolyl, pyrimidine-2,4-(1H,3H)-dionyl, dihydropyrrolopyrimidinyl, dihydrofuropyrimidinyl, dihydropyranopyrimidinyl, tetrahydropteridinyl, and tetrahydropyridopyrimidinyl; and
(ii) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrimidinonyl, pyrazinyl, and quinolinyl;
wherein each heterocyclyl and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of:
(a) one, two, three, or four fluoro, chloro, bromo, or C 1-4 alkyl;
(b) one, two, or three cyano;
(c) one or two OR 5 ;
(d) NO 2 , CH 2 OR 5 , C 2-4 alkenyl, C 2-4 alkynyl, C 0-4 alkyl-C(O)R 5 , C 0-4 alkyl-C(O)N(R 5 ) 2 , C 0-4 alkyl-NHC(O)R 5 , C 0-4 alkyl-C(O)OR 5 , C 0-4 alkyl-N(R 5 ) 2 , C 0-4 alkyl-O—C 1-4 alkyl, C 0-4 alkyl-O—C 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NH(C 0-4 alkyl-C 3-5 cycloalkyl), C(O)OC 1-4 alkyl, C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, or C 3-6 cycloalkyl;
(e) a heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, piperazinyl, and morpholinyl; and
(f) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, and oxadiazolyl;
wherein each C 1-4 alkyl, CH 2 OR 5 , C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl-C(O)R 5 , C 1-4 alkyl-C(O)NH 2 , c 1-4 alkyl-C(O)N(R 5 )2, C 1-4 alkyl-NHC(O)R 5 , C 1-4 alkyl-N(R 5 ) 2 , C 0-4 alkyl-O—C 1-4 alkyl, C 0-4 alkyl-O—C 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 1-4 alkyl, C(O)NH(C 0-4 alkyl-C 3-5 cycloalkyl), C(O)N(C 1-4 alkyl) 2 , C 1-4 alkyl-C(O)OR 5 , C(O)OC 1-4 alkyl, C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, C 3-6 cycloalkyl, heterocyclyl, and heteroaryl substituent is optionally and independently substituted with one, two, three, or four fluoro, one or two C 1-4 alkyl, one C(O)C 1-4 alkyl, one C(O)OC 1-4 alkyl, one C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, one or two hydroxy, one or two OC 1-4 alkyl, or one or two SC 1-4 alkyl; and
each R 5 is independently hydrogen, C 1-4 alkyl, imidazolyl, triazolyl, thiazolyl, pyridinyl, pyrimidinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, wherein the C 1-4 alkyl, imidazolyl, triazolyl, thiazolyl, pyridinyl, pyrimidinyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl are each optionally and independently substituted with one, two, or three fluoro, one chloro, one cyano, one or two C 1-2 alkyl, one hydroxymethyl, one or two hydroxy, one or two OC 1-2 alkyl, one pyrrolidinyl, one spirooxetanyl, or one triazolyl; or
two R 5 , together with the intervening nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
with the proviso that R 1 and R 2 are not simultaneously hydrogen.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, C 1-4 alkyl, C(O)H, C(O)NH 2 , or OC 1-2 alkyl, wherein each C 1-4 alkyl and OC 1-2 alkyl is optionally substituted with one hydroxy.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
4. The compound of claim 1 , wherein the compound is of Formula (III):
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4 , wherein the compound is of Formula (III-A-1):
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 0-4 alkyl-NHR 4 or OR 4 .
7. The compound of claim 4 , wherein the compound is of Formula (III-B-1):
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 0-4 alkyl-NHR 4 or OR 4 .
9. The compound of claim 4 , wherein the compound is of Formula (III-C-1):
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 0-4 alkyl-NHR 4 or OR 4 .
11. The compound of claim 4 , wherein the compound is of Formula (III-D-1):
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 0-4 alkyl-NHR 4 or OR 4 .
13. The compound of claim 11 , wherein the compound is of Formula (III-D-3):
or a pharmaceutically acceptable salt thereof,
wherein:
Y is —NH— or —O—.
14. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein Ring B is:
15. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein X is —NH—.
16. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein X is —O—.
17. The compound of claim 16 , wherein the compound is of Formula (IV):
or a pharmaceutically acceptable salt thereof,
wherein:
R 3 is hydrogen, fluoro, chloro, cyano, C 1-4 alkyl, C(O)H, C(O)NH 2 , or OC 1-2 alkyl, wherein each C 1-4 alkyl and OC 1-2 alkyl is optionally substituted with one, two, or three fluoro or one hydroxy; and
R 4 is:
wherein:
X 1 is CH, CF, CCl, CC 1-2 alkyl, or N, wherein the CC 1-2 alkyl is optionally substituted with one, two, or three fluoro;
X 2 is CR 4c or N;
each of R 4a , R 4b , and R 4c is independently hydrogen; or
each of R 4a , R 4b , and R 4c is independently one or more substituents independently selected from the group consisting of:
(a) fluoro, chloro, bromo, or C 1-4 alkyl;
(b) cyano;
(c) NO 2 , C 0-4 alkyl-O—C 1-4 alkyl, C 0-4 alkyl-O—C 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-C 3-5 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NH(C 0-4 alkyl-C 3-5 cycloalkyl), C(O)OC 1-4 alkyl, or C(O)OC 0-4 alkyl-C 3-5 cycloalkyl;
(d) a heterocyclyl selected from the group consisting of azetidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, piperazinyl, and morpholinyl; and
(e) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, and oxadiazolyl;
wherein each heterocyclyl and heteroaryl substituent is optionally and independently substituted with one, two, three, or four fluoro, one or two C 1-4 alkyl, one C(O)C 1-4 alkyl, one C(O)OC 1-4 alkyl, one C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, or one or two hydroxy; and
wherein each C 1-4 alkyl, C 0-4 alkyl-O—C 1-4 alkyl, C 0-4 alkyl-O—C 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 1-4 alkyl, C(O)NH(C 0-4 alkyl-C 3-5 cycloalkyl), C(O)N(C 1-4 alkyl) 2 , C(O)OC 1-4 alkyl, and C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, substituent is optionally and independently substituted with one, two, or three fluoro, or one or two non-geminal hydroxy; or
R 4a and R 4c , together with the intervening atoms to which they are attached, form an optionally substituted heterocyclyl selected from the group consisting of:
with the proviso that X 1 and X 2 are not simultaneously N.
18. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
22. A method for inhibiting cancer cell growth in a patient, comprising administering to the patient an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21 .
23. The method of claim 22 , wherein the method further comprises administering to the patient one or more additional therapeutic agents.