Amido compounds as RORγt modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-9765063-B2
Application number	US-201214343410-A
Country	US
Kind code	B2
Filing date	Sep 10, 2012
Priority date	Sep 9, 2011
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

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

and wherein Cy 1 , Cy 2 , 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 IIIa:

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

wherein
each R 1a and R 1b is independently H, substituted or unsubstituted C 1 -C 6 alkyl, or CN, 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 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 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, or any two adjacent R 4 groups may join together to form a substituted or unsubstituted carbocyclic or heterocyclic ring;
n1 is 1, 2, 3, 4 or 5;
n2 is 1, 2, or 3;
A is CR 8a R 8b , NR 8a , O, or S; m is 0 or 1;
each R 5a is alkyl, substituted alkyl, halo, haloalkyl, hydroxyalkyl, aryl, heteroaryl, CN, alkoxyalkyl, amido, hydroxyl, alkoxy or substitituted alkoxy; and t is 0, 1, 2, or 3;
R 7a is 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 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 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, nitro, and thiol;
R 7b is R 4 ; or any two adjacent R 4 and R 7b groups may join together to form a substituted or unsubstituted carbocyclic or heterocyclic ring; and
each R 8a and R 8b is independently H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
provided that
i) at least one R 3 is selected from CO 2 H, CH 2 CO 2 H, COR 3a , CONR 3a R 3b , SO 3 H, SOR 3a , SO 2 R 3a , and heteroaryl;
and wherein each R 3a and R 3b is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R 3a and R 3b may join together to form a substituted or unsubstituted heterocyclic ring;
ii) when R 3 is CONR 3a R 3b , R 3a and R 3b joined together to form a morpholino ring, m is 1, and A is O; then R 7a is other than H;
iii) when the compound is

 then the compound is in the form of a sodium, potassium, calcium, or ammonium salt; and
iv) the compound is other than

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

2. The compound according to claim 1 , wherein
each of R 7a and R 7b is independently OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, CN, halo, amido, or haloalkyl; or
each of R 7a and R 7b is independently halo, C 1 -C 6 alkyl, CN, OH, or C i -C 6 alkoxy; or
each of R 7a and R 7b is independently Cl, F, Me, CF 3 , CN, OH, or OMe; or
one of R 7a and R 7b is OH; and the other is alkoxy; or
each of R 7a and R 7b is OH or alkoxy; or
one of R 7a and R 7b is OH; and the other is OMe.

3. The compound according to claim 1 , wherein R 1a and R 1b is independently H, CN, or Me; or
each of R 1a and R 1b is H or Me; or
one of R 1a and R 1b is H; and the other is CN.

4. The compound according to claim 1 , wherein R 4 is H, alkyl, substituted alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, amido, hydroxyl, cyano, or alkoxy; or
R 4 is H, halo, C 1 -C 6 alkyl, CN, OH, or C 1 -C 6 alkoxy; or
R 4 is H, Cl, F, Me, CF 3 , CN, OH, or OMe.

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

or a pharmaceutically acceptable salt, solvate or prodrug thereof;
or stereoisomers, isotopic variants and tautomers thereof;
and wherein R 2 , R 5 , and R 6 are as in claim 1 ;
R 3 is selected from CO 2 H, CH 2 CO 2 H, COR 3a , CONR 3a R 3b , SO 3 H, SOR 3a , SO 2 R 3a , and heteroaryl; wherein each R 3a and R 3b is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R 3a and R 3b may join together to form a substituted or unsubstituted heterocyclic ring;
each R 5a is alkyl, substituted alkyl, halo, haloalkyl, hydroxyalkyl, aryl, heteroaryl, CN, alkoxyalkyl, amido, hydroxyl, alkoxy or substitituted alkoxy; t is 0, 1, 2, or 3;
provided that
i) when the compound is

then the compound is in the form of a sodium, potassium, calcium, or ammonium salt; and
ii) the compound is other than

6. The compound according to claim 1 , wherein R 3 is CO 2 H, SO 3 H, or CH 2 CO 2 H; or
R 3 is pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl; or
R 3 is 1,3,4-triazolyl or tetrazol-5-yl; or
R 3 is CONR 3a R 3b ; wherein each R 3a and R 3b is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

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 0; or
t is 1 or

Assignees

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

Inventors

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

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title