Heteroaryl compounds useful as inhibitors of E1 activating enzymes
View Patent ↗This invention relates to compounds that inhibit E1 activating enzymes, pharmaceutical compositions comprising the compounds, and methods of using the compounds. The compounds are useful for treating disorders, particularly cell proliferation disorders, including cancers, inflammatory and neurodegenerative disorders; and inflammation associated with infection and cachexia.
1. A method for treating lung cancer or colorectal cancer in a patient in need thereof, comprising administering to the patient a compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein:
X is —NH— or —O—;
R a is hydrogen or —OH;
R c is hydrogen or —OH;
W is —NH—, —N(R 1 )— or —O—, wherein R 1 is C 1-4 aliphatic;
one of D and E is —N═ and the other is —C(R h )═;
each R h is independently hydrogen, halo or C 1-4 aliphatic;
R 8 is hydrogen or C 1-4 aliphatic;
each R p is independently halo or C 1-4 aliphatic;
each R 8p is independently halo; C 1-4 aliphatic optionally substituted with —OR 5x or —C(O)—N(R 4x )(R 4y ), wherein R 5x is hydrogen or C 1-4 alkyl, R 4x is hydrogen or C 1-4 alkyl, and R 4y is hydrogen or C 1-4 alkyl; —OR 5x wherein R 5x is hydrogen or C 1-4 alkyl; or —C(O)—N(R 4x )(R 4y ) wherein R 4x is hydrogen or C 1-4 alkyl and R 4y is hydrogen or C 1-4 alkyl;
s is 0, 1 or 2; and
t is 0, 1 or 2.
2. The method of claim 1 , wherein the compound is administered orally.
3. The method of claim 1 , wherein the compound administered to the patient in need thereof is:
or a pharmaceutically acceptable salt thereof, wherein:
R a is hydrogen or —OH;
R p is hydrogen or —OH;
W is —NH— or —O—;
each R p is independently halo or C 1-4 aliphatic;
each R 8p is independently halo; C 1-4 aliphatic optionally substituted with —OR 5x or —C(O)—N(R 4x )(R 4y ), wherein R 5x is hydrogen or C 1-4 alkyl, R 4x is hydrogen or C 1-4 alkyl, and R 4y is hydrogen or C 1-4 alkyl; —OR 5x wherein R 5x is hydrogen or C 1-4 alkyl; or —C(O)—N(R 4x )(R 4y ) wherein R 4x is hydrogen or C 1-4 alkyl and R 4y is hydrogen or C 1-4 alkyl;
s is 0, 1 or 2; and
t is 0, 1 or 2.
4. The method of claim 3 , wherein W is —O—.
5. The method of claim 3 , wherein each R p is independently —F or —Cl.
6. The method of claim 3 , wherein each R p is independently halo; and each R 8p is independently C 1-4 aliphatic or —OR 5x wherein R 5x is hydrogen or C 1-4 alkyl.
7. The method of claim 1 , wherein X is O.
8. The method of claim 1 , wherein W is NH or O.
9. The method of claim 1 , wherein each R h is independently hydrogen, halo or CH 3 .
10. The method of claim 1 , wherein R 8 is hydrogen.
11. The method of claim 3 , wherein W is NH.
12. The method of claim 3 , wherein each R p is independently halo.
13. The method of claim 3 , wherein each R 8p is independently C 1-4 aliphatic or OR 5x wherein R5x is hydrogen or C 1-4 alkyl.
14. The method of claim 13 , wherein each R 8p is independently CH 3 or OCH 3 .