Heteroaryls and uses thereof
View Patent ↗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 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 is 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-membered heterocyclyl or an optionally substituted 5-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 compound of claim 1 , having a structure according to 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 is 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, and
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)—, —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-membered heterocyclyl or an optionally substituted 5-membered heteroaryl.
3. The compound or a pharmaceutically acceptable salt of claim 1 , wherein L 1 is —N(R 8 )C(O)—, —N(R 10 )S(O) 2 —, —C(O)—, or —S(O) 2 —.
4. The compound or a pharmaceutically acceptable salt of claim 3 , wherein each of R 8 and R 10 , independently, is hydrogen, methyl or ethyl.
5. The compound or a pharmaceutically acceptable salt 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.
6. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein R 1 is
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 is 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 —, —C(O)NR x —, —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 o )S(O) 2 —, —S(O) 2 NR 11 —, —C(O)—, —C(S)—, —S(O) 2 —, —N(R 12 )—, —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 or optionally substituted 5-6-membered heteroaryl;
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.
7. The compound or a pharmaceutically acceptable salt of claim 1 , wherein X is a bond, methylene, or ethylene.
8. The compound or a pharmaceutically acceptable salt of claim 1 , wherein R 2 is hydrogen.
9. The compound or a pharmaceutically acceptable salt of claim 1 , wherein L 2 is a bond, —C(O)— or —C(O)—O—.
10. The compound or a pharmaceutically acceptable salt of claim 1 , wherein R 3 is methyl, cyclopropyl, or 6-membered heteroaryl that is optionally substituted with 1-2 R 6 .
11. The compound or a pharmaceutically acceptable salt 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;
wherein one R 4 , if present, is located at the ring carbon between the ring nitrogen and the ring carbon to which —X-L 1 -R 1 is substituted.
12. The compound or a pharmaceutically acceptable salt of claim 1 ,
wherein:
X is a bond;
L 1 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;
wherein one R 4 , if present, is located 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
13. The compound of claim 1 with formula (II) below:
wherein (m-1) is 0 or 1;
or a pharmaceutically acceptable salt thereof.
14. The compound or a pharmaceutically acceptable salt of claim 13 , wherein:
L 1 is —N(R 8 )C(O)— or —N(R 10 )S(O) 2 —;
each of R 8 and R 10 , independently, is hydrogen, methyl, or ethyl;
R 1 is C 1-4 aliphatic, phenyl, naphthyl, 3-6-membered cycloaliphatic, 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;
R 3 is C 1-3 alkyl or cyclopropyl, each of which being optionally substituted with 1-2 R 6 ;
each R 6 is C 1-4 alkyl or halo; and
R 4 is halo or -L 4 -R 17 wherein:
L 4 is C 1-4 alkylene, —O—, or —N(R z )—;
R z is hydrogen or methyl; and
R 17 is hydrogen or C 1-3 aliphatic.
15. The compound or a pharmaceutically acceptable salt of claim 14 , wherein R 4 is methyl, ethyl, fluoro, chloro, —NH 2 , methoxy, or ethoxy.
16. The compound or a pharmaceutically acceptable salt of claim 14 , wherein (m-1) is 0.
17. The compound of claim 1 with formula (VIII) below:
wherein (m-1) is 0 or 1;
or a pharmaceutically acceptable salt thereof.
18. A compound or a pharmaceutically acceptable salt thereof selected from
19. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of claim 1 , and a pharmaceutically acceptable carrier.
20. The pharmaceutical composition of claim 19 , further comprising a second therapeutic agent.
21. The pharmaceutical composition of claim 20 , wherein the second therapeutic agent is a tyrosine kinase inhibitor.
22. The compound or a pharmaceutically acceptable salt of claim 17 , wherein:
L 1 is —N(R 11 )S(O) 2 —; and
R 10 optionally joins with R 4 to form an optionally substituted 5-membered heterocyclyl or an optionally substituted 5-membered heteroaryl.
23. The compound or a pharmaceutically acceptable salt of claim 22 , wherein:
R 4 is halo or -L 4 -R 17 ; wherein
L 4 is C 1-4 alkylene, —O—, or —N(R z )—; R z is hydrogen or methyl,
R 17 is hydrogen or C 1-3 aliphatic; and
R 6 is cyano, fluoro, chloro, C 1-6 alkyl, 3-6-membered cycloalkyl, or phenyl.
24. The compound or a pharmaceutically acceptable salt of claim 23 , wherein R 4 is methyl, ethyl, fluoro, chloro, —NH 2 , methoxy, or ethoxy.
25. The compound or a pharmaceutically acceptable salt of claim 24 , wherein (m-1) is 0.
26. The compound or a pharmaceutically acceptable salt of claim 24 , wherein:
the compound is represented by formula VIII-B
wherein the R 4 located at the para position with respect to the ring nitrogen is methyl.
27. The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 27 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 27 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.