Amido compounds as RORγt modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-9492439-B2
Application number	US-201113634073-A
Country	US
Kind code	B2
Filing date	Mar 11, 2011
Priority date	Mar 11, 2010
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

Amido compounds are disclosed that have a formula represented by the following:

and wherein n1, n2, R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , and R 6 are as described herein. The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment 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.

First claim

What is claimed is:

1. A compound according to formula III:

wherein
A is C, N, O, or S; m is 0 or 1;
n1 is 1, 2, 3, 4 or 5; n2 is 1, 2, or 3;
each R 1a and R 1b is independently H, or substituted or unsubstituted C 1 -C 6 alkyl; or R 1a and R 1b joined together to form cycloalkyl ring;
R 2 is H, substituted or unsubstituted C 1 -C 6 alkyl, or aryl;
or one of R 1a and R 1b is joined to the C of CR 2 to form a cyclopropyl ring; or R 2 is joined to the C of CR 1a R 1b to form a cyclopropyl ring;
each R 3 and R 4 is independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, 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 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, nitro, and thiol; or any two adjacent R 3 groups, any two adjacent R 4 groups, or any two adjacent R 4 and R 7b groups, may joined together to form a substituted or unsubstituted carbocyclic or heterocyclic ring;
each R 5a is alkyl, substituted alkyl, halo, haloalkyl, hydroxyalkyl, heteroaryl, CN, alkoxyalkyl, amido, hydroxyl, alkoxy or substituted alkoxy; and t is 2 or 3;
each of R 7a and R 7b is independently OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, CN, halo, amido, or haloalkyl;

or a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers, isotopic variants and tautomers thereof;

provided that (R 3 ) n1 -Ph- group is other than substituted or unsubstituted benzopyranyl.

2. The compound according to claim 1 , wherein R 1a and R 1b is independently H or Me.

3. The compound according to claim 1 , wherein R 4 is H, alkyl, substituted alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, amido, hydroxyl, cyano, or alkoxy.

4. The compound according to claim 1 , wherein the compound is according to formula IVa, IVb, IVe, or IVf:

and wherein n1, R 2 , and R 3 are as in claim 1 ; each R 5a is alkyl, substituted alkyl, halo, haloalkyl, hydroxyalkyl, heteroaryl, CN, alkoxyalkyl, amido, hydroxyl, alkoxy or substituted alkoxy; and t is 2 or 3.

5. The compound according to claim 1 , wherein n1 is 1, 2 or 3; and each R 3 is independently selected from halo, amino, substituted amino, substituted or unsubstituted C 1 -C 6 alkyl, CN, OH, carboxyl, and substituted or unsubstituted C 1 -C 6 alkoxy.

6. The compound according to claim 1 , wherein the compound is according to formula Va, Vb, Ve, or Vf:

and wherein R 2 , t and R 5a are as in claim 1 ; and n3 is 1, 2 or 3.

7. The compound according to claim 1 , wherein R 2 is H, Me, OH, or Ph.

8. The compound according to claim 1 , wherein
t is 2; and each R 5a is independently OH, benzyl, Me, Et, n-Pr, or n-Bu; or
t is 2; and one R 5a is 3-Me and the other is 5-Me.

9. A compound according to formula VIa, VIb, VIc, VId, VIe, VIf, VIIIa, VIIIb, VIIIc, VIIId, IXa, IXb, or IXc:

and wherein R 5b is Me;
or a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers, isotopic variants and tautomers thereof.

10. A compound

or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof.

11. A pharmaceutical composition of the compound according to any one of claim 1 , 9 or 10 .

12. A method for treating or ameliorating in a mammal a disease or condition that is causally related to RORyt activity in vivo, which comprises administering to the mammal an effective disease-treating or condition-treating amount of the compound according to any one of claim 1 , 9 , or 10 or a composition thereof, wherein the disease or condition is autoimmune disease, inflammatory disease, arthritis, diabetes, multiple sclerosis, uveitis, rheumatoid arthritis, psoriasis, asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, atherosclerosis, H. pylori infections, ulcers resulting from such infection, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, sprue, food allergies, experimental autoimmune encephalomyelitis (EAE), and collagen-induced arthritis (CIA).

13. The compound of claim 1 , wherein:
A is CH 2 ; m is 1;
n1 is 1; n2 is 1;
R 1a and R 1b is H;
R 2 is H;
R 3 is cyano;
R 4 is unsubstituted alkoxy;
R 5a is alkyl; and t is 2;
R 7a is unsubstituted alkoxy; and
R 7b is unsubstituted alkoxy.

14. The compound of claim 13 , wherein the unsubstituted alkoxy is methoxy and alkyl is methyl.

15. The compound of claim 1 , wherein:
A is CH 2 ; m is 1;
n1 is 1; n2 is 1;
R 1a and R 1b is H;
R 2 is H;
R 3 is cyano;
R 4 is H;
R 5a is alkyl; and t is 2;
R 7a is unsubstituted alkoxy; and
R 7b is unsubstituted alkoxy.

16. The compound of claim 15 , wherein the unsubstituted alkoxy is methoxy; and alkyl is methyl.

17. The compound of claim 1 , wherein:
A is CH 2 ; m is 1;
n1 is 1; n2 is 1;
R 1a and R 1b is H;
R 2 is H;
R 3 is unsubstituted carbamoyl;
R 4 is unsubstituted alkoxy
R 5a is alkyl; and t is 2;
R 7a is unsubstituted alkoxy; and
R 7b is unsubstituted alkoxy.

18. The compound of claim 17 , wherein the unsubstituted alkoxy is methoxy; alkyl is methyl; and unsubstituted carbamoyl is —C(O)N(R 42 ) 2 where R 42 is hydrogen.

19. The compound of claim 1 , wherein:
A is CH 2 ; m is 1;
n1 is 1; n2 is 1;
R 1a and R 1b is H;
R 2 is H;
R 3 is unsubstituted alkylsulfonyl;
R 4 is unsubstituted alkoxy
R 5a is alkyl; and t is 2;
R 7a is unsubstituted alkoxy; and
R 7b is unsubstituted alkoxy.

20. The compound of claim 19 , wherein the unsubstituted alkoxy is methoxy; alkyl is methyl; and unsubstituted alkylsulfonyl is methylsulfonyl.

Assignees

• Littman Dan
• Huh Jun R
• Huang Wenwei
• Huang Ruili
• Englund Erika Elaine
• Univ New York
• Us Health

Inventors

• Littman Dan
• Huh Jun R
• Huang Wenwei
• Huang Ruili
• Englund Erika Elaine

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K31/4525 Primary

  containing a five-membered ring with oxygen as a ring hetero atom · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title