Heteroaryls and uses thereof
View Patent ↗The present invention provides a compound of formula I: wherein R 1 , X 1 , X 2 , R 2 , R 3 , R 4 , R 5 , n, and m 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:
each of X 1 and X 2 , independently, is CH or CR 4 ;
L 1 is a bond, —C(O)—, —C(O)—O—, —S(O) 2 —, —C(O)N(R a )—, or —S(O) 2 N(R a )—; wherein each R a , independently, is hydrogen or C 1-4 alkyl;
R 1 is hydrogen or -L 2 -R 6 wherein:
L 2 is C 1-4 alkylene, —C(O)—, —C(O)—O—, —S(O)—, —S(O) 2 —, —C(O)N(R b )—, or —S(O) 2 N(R b )—; wherein each R b , independently, is hydrogen or C 1-4 alkyl; and
R 6 is hydrogen, C 1-6 aliphatic, 3-10-membered cycloaliphatic, phenyl, or naphthyl; each of which being optionally substituted with 1-5 R 7 ;
R 2 is hydrogen or C 1-4 alkyl;
R 3 is hydrogen, C 1-6 aliphatic, 3-10-membered cycloaliphatic, phenyl, or naphthyl; provided that if R 3 is hydrogen, then L 1 is a bond; each of R 3 being optionally substituted with 1-5 R 7 wherein:
each R 7 independently is CN, halo, or L 3 -R 8 wherein:
L 3 is a bond, C 1-4 aliphatic, —O—, —N(R c )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R c )—, —N(R c )C(O)—, —N(R c )C(O)O—, —S(O) 2 NR c —, —N(R c )S(O) 2 —, —OC(O)N(R c )—, —N(R c )C(O)N(R d )—, —N(R c )S(O) 2 N(R d )—, or —OC(O)—;
each occurrence of R c and R d , independently, is hydrogen or C 1-4 alkyl, and
R 8 is hydrogen, C 1-6 aliphatic, 3-10-membered cycloaliphatic, phenyl, or naphthyl;
each occurrence of R 4 and R 5 , independently, is —CN, halo, or -L 4 -R 9 wherein:
L 4 is C 1-4 alkylene, —O—, —N(R e )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —CO 2 —, —C(O)N(R e )—, —N(R e )C(O)—, —N(R e )C(O)O—, —S(O) 2 N(R e )—, —N(R e )S(O) 2 —, —OC(O)N(R e )—, —N(R e )C(O)N(R f )—, —N(R e )S(O) 2 N(R f )—, or —OC(O)—;
each occurrence of R e and R f , independently, is hydrogen or C 1-4 alkyl; and
R 9 is hydrogen, —NH 2 , or C 1-6 aliphatic;
m is 0-2; and
n is 0-3.
2. The compound or a pharmaceutically acceptable salt of claim 1 , wherein R 1 is -L 2 -R 6 .
3. The compound or a pharmaceutically acceptable salt of claim 2 , wherein L 1 is —C(O)— or —C(O)O—.
4. The compound or a pharmaceutically acceptable salt of claim 2 , wherein X 1 and X 2 are both CH.
5. The compound or a pharmaceutically acceptable salt of claim 2 , wherein L 2 is —C(O)— or —S(O) 2 —.
6. The compound or a pharmaceutically acceptable salt of claim 2 , wherein R 6 is methyl, ethyl, or phenyl optionally substituted with 1-3 groups selected from halo or C 1-3 alkyl.
7. The compound or a pharmaceutically acceptable salt of claim 2 , wherein R 2 is hydrogen.
8. The compound or a pharmaceutically acceptable salt of claim 2 , wherein R 3 is C 1-3 alkyl.
9. The compound or a pharmaceutically acceptable salt of claim 2 , wherein L 1 is a bond.
10. The compound or a pharmaceutically acceptable salt of claim 2 , wherein R 4 is substituted at the ring position between the ring nitrogen and the ring carbon connected to —N(R 1 )—.
11. The compound or a pharmaceutically acceptable salt of claim 1 with formula (II) below:
12. The compound or a pharmaceutically acceptable salt of claim 11 , wherein R 6 is C 1-4 alkyl, 3-6-membered cycloaliphatic, phenyl, or naphthyl; R 3 is C 1-3 alkyl; and R 4 is halo or -L 4 -R 9 , wherein L 4 is C 1-4 alkylene chain, —O—, or —N(R e )—, and wherein R e is hydrogen or methyl, and R 9 is hydrogen or C 1-3 alkyl.
13. The compound or a pharmaceutically acceptable salt of claim 11 , wherein R 6 is methyl, ethyl, cyclopropyl, or phenyl optionally substituted with C 1-3 alkyl, fluoro, or chloro.
14. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is one of:
15. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of claim 1 , and a pharmaceutically acceptable carrier.