Steroid compounds as RORyt modulators and uses thereof
Steroid compounds are disclosed that have a formula represented by the following: and wherein m, n, t, u1, u2, v1, v2, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 3c , R 3d , and Y are as described herein. The compounds may be prepared as pharmaceutical compositions, and may be used for the treatment or prevention of a variety of conditions in mammals including humans, including by way of non-limiting example, inflammatory conditions, autoimmune disorders, cancer, and graft-versus-host disease.
1. A method for treating or ameliorating in a mammal a disease or condition that is causally related to RORγt activity in vivo, wherein the disease or condition is arthritis, diabetes, multiple sclerosis, uveitis, psoriasis, asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, atherosclerosis, H. pylori infections, ulcers, inflammatory bowel disease, Crohn's disease, ulcerative colitis, sprue, food allergies or, experimental autoimmune encephalomyelitis (EAE), which comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to formula III:
wherein
Y is CO 2 R 8 , CH 2 OH,
* denotes the attachment point; the subscript w is 0, 1, or 2;
the subscript x is 1, 2, or 3;
each R 5 and R 7 is independently H, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 8 is H or substituted or unsubstituted alkyl;
each R 1a and R 1b is independently OH, or O-acyl; or R 1a and R 1b together form
* denote the attachment points;
each R 6a and R 6b is independently H, substituted or unsubstituted alkyl, cycloalkyl, aryl or heteroaryl;
each subscript n is independently 0, 1, 2, 3, 4, or 5; and
each dotted bond is independently a single or a double bond;
or a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers, isotopic variants and tautomers thereof.
2. The method according to claim 1 , wherein Y is CH 2 OH, CO 2 H, CO 2 Me, CO 2 Et,
* denotes the attachment point; the subscript w is 0, 1, or 2;
the subscript x is 1, 2, or 3; and R 5 and R 7 are as in claim 1 .
3. The method according to claim 1 , wherein Y is
* denotes the attachment point; and the subscript w is 0, 1, or 2.
4. The method according to claim 1 , wherein Y is
and R 5 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl, and * denotes the attachment point.
5. The method according to claim 1 , wherein Y is
and R 5 is
alkyl, unsubstituted, or substituted with halo, phenyl, hydroxyl or methoxy;
alkenyl, unsubstituted, or substituted with alkyl, or phenyl;
cycloalkyl, unsubstituted, or substituted with hydroxyl or methoxy; or
aryl, unsubstituted, or substituted with substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted amino, substituted or unsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, nitro, and thiol, and * denotes the attachment point.
6. The method according to claim 1 , wherein Y is
* denotes the attachment point;
the subscript x is 1, 2, or 3; and R 5 and R 7 are as in claim 1 .
7. The method according to claim 6 , wherein R 5 is alkyl, unsubstituted, or substituted with halo, phenyl, hydroxyl or methoxy,
alkenyl, unsubstituted, or substituted with alkyl, or phenyl;
cycloalkyl, unsubstituted, or substituted with hydroxyl or methoxy; or
aryl, unsubstituted, or substituted with substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted amino, substituted or unsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, nitro, and thiol.
8. The method according to claim 6 , wherein R 7 is H.
9. The method according to claim 1 , wherein the compound is according to formula IVa, IVb, Va, Vb, VIa, VIb, VIc, or VId:
wherein
R 1a and R 1b are as in claim 1 ; z is 0, 1, 2, 3, 4, or 5; and each R 4 is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy; substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted amino, substituted or unsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkyl sulfonyl, substituted or unsubstituted aryl sulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, nitro, hydroxyl, and thiol;
or a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers, isotopic variants and tautomers thereof.
10. The method according claim 9 , wherein z is 1 or 2; and each R 4 is independently selected from F, Br, Cl, I, OH, Me, Et, CF 3 , OCF 3 , CF 3 , NMe 2 , OMe, OEt, NO 2 , OPh, and SMe.
11. The method according to claim 1 , wherein each R 1a and R 1b is independently OH or OAc.
12. The method according to claim 1 , wherein R 1a and R 1b together form
* denote the attachment points;
each R 6a and R 6b is independently H, substituted or unsubstituted alkyl, cycloalkyl, aryl or heteroaryl.
13. The method according to claim 1 , wherein the compound is according to formula VIIa, VIIb, VIIc, VIIIa, VIIIb, VIIIc, IXa, IXb, IXc, Xa, Xb, Xc, XIa, XIb, XIc, XIIa, XIIb, or XIIc:
or a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers, isotopic variants and tautomers thereof.
14. The method according to claim 1 , wherein the compound is according to formula XIIIa, XIIIb, or XIIIc:
wherein Y is CO 2 H, CO 2 Me, CO 2 Et, CO 2 -i-Pr, or CH 2 OH;
or a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers, isotopic variants and tautomers thereof.
15. The method according to claim 1 , wherein the compound is according to formula III;
and wherein
or a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers, isotopic variants and tautomers thereof.
16. The method of claim 1 , wherein the arthritis is rheumatoid arthritis or collagen-induced arthritis (CIA).
17. The method according claim 9 , wherein z is 1 or 2; and each R 4 is independently selected from F, Br, Cl, I, OH, Me, Et, CF 3 , OCF 3 , CF 3 , NMe 2 , OMe, OEt, NO 2 , OPh, and SMe.