Heteroaryls and uses thereof
The present invention provides a compound of formula I: and pharmaceutically acceptable salts thereof, wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , m, and n, are as described in the specification. Such compounds are inhibitors of VPS34 and thus useful for treating proliferative, inflammatory, or cardiovascular disorders.
1. A method of treating a proliferative disorder in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, C 1-6 aliphatic, 3-10-membered cycloaliphatic, phenyl, naphthyl, 3-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which being optionally substituted with 1-5 R 6 ;
R 3 is C 1-6 aliphatic, 3-10-membered cycloaliphatic, phenyl, naphthyl, 3-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which being optionally substituted with 1-5 R 6 ;
wherein:
each R 6 independently is —CN, halo or -L 3 -R 7 wherein:
L 3 is a bond, C 1-4 alkylene, —O—, —N(R x )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —CO 2 —, N(R x )C(O)—, —N(R x )CO 2 —, —S(O) 2 NR x —, —N(R x )S(O) 2 —, —OC(O)N(R x )—, —N(R x )C(O)N(R x ), —N(R x )S(O) 2 N(R x )— or —OC(O)—;
each R x , independently, is hydrogen or C 1-4 alkyl;
R 7 is hydrogen, C 1-6 aliphatic, 3-10-membered cycloaliphatic, phenyl, naphthyl, or 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
X is a bond or C 1-4 aliphatic;
L 1 is —N(R 8 )C(O)—, —C(O)—N(R 9 )—, —N(R 10 )S(O) 2 —, —S(O) 2 NR 11 —, —C(O)—, —C(S)—, —S(O) 2 —, —O—C(O)—, —C(O)—O—, —O—S(O) 2 —, —S(O) 2 —O—, —N(R 13 )C(O)N(R 14 )—, or —N(R 15 )S(O) 2 N(R 16 )—; and wherein
each of R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , and R 16 , independently, is hydrogen or C 1-4 alkyl; or X or L 1 optionally joining with R 1 to form an optionally substituted 5-6-membered heterocyclyl;
R 2 is hydrogen or C 1-4 alkyl;
L 2 is a bond, —C(O)—, —S(O) 2 —, —C(O)—O—, —C(O)N(R y )—, or —S(O) 2 N(R y )—; wherein each R y , independently, is hydrogen or C 1-4 alkyl;
each occurrence of R 4 and R 5 , independently, is —CN, halo or -L 4 -R 17 wherein
L 4 is C 1-4 alkylene, —O—, —N(R z )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —CO 2 —, —C(O)N(R z )—, —N(R z )C(O)—,
—N(R z )C(O)O—, —S(O) 2 N(R z )—, —N(R z )S(O) 2 —, —OC(O)N(R z )—, —N(R z )C(O)N(R z )—, —N(R z )S(O) 2 N(R z )— or —OC(O)—;
each R z , independently, is hydrogen or C 1-4 alkyl, and
R 17 is hydrogen or C 1-6 aliphatic; and
each of m and n, independently, is 0-3;
provided that
if one R 4 is located at the ring carbon between the ring nitrogen and the ring carbon to which —X-L 1 -R 1 is located, X or L 1 optionally joining with said R 4 to form an optionally substituted 5-7-membered heterocyclyl or an optionally substituted 5-6-membered heteroaryl; or
if one R 4 is located at either ring carbon adjacent to the ring nitrogen, said R 4 optionally joining with the ring nitrogen to form an optionally substituted 5-7-membered heterocyclyl or an optionally substituted 5-6-membered heteroaryl; or
if L 2 is a bond and R 3 is phenyl, naphthyl, or heteroaryl, R 2 optionally joining with a substituent of R 3 to form an optionally substituted 5-7-membered heterocyclyl or an optionally substituted 5-6-membered heteroaryl.
2. The method of claim 1 , wherein L 1 is —N(R 8 )C(O)—, —N(R 10 )S(O) 2 —, —C(O)—, or —S(O) 2 —.
3. The method of claim 2 , wherein each of R 8 and R 10 , independently, is hydrogen, methyl or ethyl.
4. The method of claim 1 , wherein R 1 is C 1-4 aliphatic, 3-6-membered cycloaliphatic, phenyl, naphthyl, 3-6-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.
5. The method of claim 1 , wherein R 1 is
6. The method of claim 1 , wherein X is a bond, methylene, or ethylene.
7. The method of claim 1 , wherein R 2 is hydrogen.
8. The method of claim 1 , wherein L 2 is a bond, —C(O)— or —C(O)—O—.
9. The method of claim 1 , wherein R 3 is methyl, cyclopropyl, or 6-membered heteroaryl that is optionally substituted with 1-2 R 6 .
10. The method of claim 1 , wherein R 4 is fluoro, chloro, unsubstituted C 1-3 aliphatic, trifluoromethyl, hydroxyl, methoxy, NH 2 or NH—C 1-3 aliphatic; m is 0-2; and one R 4 is substituted at the ring carbon between the ring nitrogen and the ring carbon to which —X-L 1 -R 1 is substituted.
11. The method of claim 1 , wherein X is a bond; C is —N(R 8 )C(O)—, —N(R 10 )S(O) 2 —, —C(O)—, or —S(O) 2 —; R 2 is hydrogen, methyl, ethyl, or cyclopropylmethyl; L 2 is a bond, —C(O)— or —C(O)—O—; R 3 is C 1-3 alkyl, cyclopropyl, or 6-membered heteroaryl, each of which being optionally substituted with 1-2 R 6 ; R 4 is fluoro, chloro, C 1-3 alkyl, trifluoromethyl, hydroxyl, methoxy, —NH 2 or —NH—C 1-3 aliphatic; m is 0-2; and one R 4 is substituted at the ring carbon between the ring nitrogen and the ring carbon to which —X-L 1 -R 1 is substituted: n is 0 or 1; and R 1 is
12. The method of claim 1 , wherein the compound has formula (II) below:
wherein the value of (m−1) is 0 or 1; and a first R 4 is substituted at the ring carbon between the ring nitrogen and the ring carbon to which —X-L 1 -R 1 is substituted, or a pharmaceutically acceptable salt thereof.
13. The method of claim 1 , wherein the compound has formula (VIII) below:
wherein the value of (m−1) is 0 or 1; and a first R 4 is substituted at the ring carbon between the ring nitrogen and the ring carbon to which —X-L 1 -R 1 is substituted, or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
15. The method of claim 14 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
16. The method of claim 14 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
17. The method of claim 14 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein the proliferative disorder is breast cancer, bladder cancer, colon cancer, glioma, glioblastoma, lung cancer, hepatocellular cancer, gastric cancer, melanoma, thyroid cancer, endometrial cancer, renal cancer, cervical cancer, pancreatic cancer, esophageal cancer, prostate cancer, brain cancer, head and neck cancer, squamous cell carcinoma, or ovarian cancer.
19. The method of claim 15 , wherein the proliferative disorder is breast cancer, bladder cancer, colon cancer, glioma, glioblastoma, lung cancer, hepatocellular cancer, gastric cancer, melanoma, thyroid cancer, endometrial cancer, renal cancer, cervical cancer, pancreatic cancer, esophageal cancer, prostate cancer, brain cancer, head and neck cancer, squamous cell carcinoma, or ovarian cancer.
20. The method of claim 16 wherein the proliferative disorder is breast cancer, bladder cancer, colon cancer, glioma, glioblastoma, lung cancer, hepatocellular cancer, gastric cancer, melanoma, thyroid cancer, endometrial cancer, renal cancer, cervical cancer, pancreatic cancer, esophageal cancer, prostate cancer, brain cancer, head and neck cancer, squamous cell carcinoma, or ovarian cancer.
21. The method of claim 17 , wherein the proliferative disorder is breast cancer, bladder cancer, colon cancer, glioma, glioblastoma, lung cancer, hepatocellular cancer, gastric cancer, melanoma, thyroid cancer, endometrial cancer, renal cancer, cervical cancer, pancreatic cancer, esophageal cancer, prostate cancer, brain cancer, head and neck cancer, squamous cell carcinoma, or ovarian cancer.
22. The method of claim 1 , wherein a second therapeutic agent is administered to the patient.
23. The method of claim 22 , wherein the second therapeutic agent is an EGFR inhibitor.