Amido compounds as RORγt modulators and uses thereof

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 2; and each R 5a is independently OH, Ph, benzyl, or Me; or

t is 1; and R 5a is Me, Et, n-Pr, or n-Bu; or

t is 1; and R 5a is 3-Me, 3-Et, 3-n-Pr, or 3-n-Bu; or

t is 2; and one R 5a is 3-Me and the other is 5-Me.

9. The compound according to claim 1 , wherein the compound is according to formula VIIa, VIIb, VIIc, VIId, VIIe, or VIIf:

and wherein R 5b is H or Me;

or a pharmaceutically acceptable salt, solvate or prodrug thereof;

or stereoisomers, isotopic variants and tautomers thereof.

10. The compound according to claim 1 , wherein the compound is according to formula VIIIa, VIIIb, or VIIIc:

or a pharmaceutically acceptable salt, solvate or prodrug thereof;

or stereoisomers, isotopic variants and tautomers thereof.

11. The compound according to claim 1 , wherein the compound is according to formula IXa, IXb, or IXc:

or a pharmaceutically acceptable salt, solvate or prodrug thereof;

or stereoisomers, isotopic variants and tautomers thereof.

12. A compound selected from

Compd #

Structure

202

401

402

403

404

405

407

408

409

410

411

412

413

414

416

417

418

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

13. A pharmaceutical composition of the compound according to either one of claim 1 or 12 .