Heterocycle amines and uses thereof

1. A method of treating an inflammatory disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

is a single or double bond;

W is O or S;

Y is N;

Z is C;

R 4 is selected from hydrogen, halogen, OR 6 , CN, NR 7 R 8 , CH 2 OR 6 , an optionally substituted aryl, an optionally substituted three to nine membered heteroaryl, an optionally substituted three to nine membered non-aromatic ring, an optionally substituted three to nine membered carbocycle, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 alkenyl, an optionally substituted C 1 -C 6 alkynyl, CO 2 R 6 , SO 3 R 6 , SO 2 R 6 and SO 2 NR 7 R 8 ;

R 5 is selected from hydrogen, halogen, OR 6 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 alkenyl, and an optionally substituted C 1 -C 6 alkynyl;

or R 4 and R 5 are linked to form an optionally substituted three to nine membered non-aromatic ring;

each R 6 is independently selected from an optionally substituted aryl, an optionally substituted three to nine membered heteroaryl, and an optionally substituted three to nine membered non-aromatic ring, each optionally fused with a substituted aryl or a substituted three to nine membered heteroaryl, hydrogen, an optionally substituted C 1 -C 10 alkyl, and an optionally substituted C 1 -C 10 haloalkyl;

each R 7 and R 8 is independently selected from an optionally substituted aryl, an optionally substituted three to nine membered heteroaryl, an optionally substituted three to nine membered non-aromatic ring, each optionally fused with a substituted aryl or a substituted three to nine membered heteroaryl, hydrogen, an optionally substituted C 1 -C 10 alkyl, an optionally substituted C 1 -C 10 haloalkyl, an optionally substituted C 1 -C 10 alkenyl, and an optionally substituted C 1 -C 10 alkynyl, or R 7 and R 8 are linked to form an optionally substituted three to nine membered non-aromatic ring;

R 9 is selected from hydrogen, halogen, OR 6 , CN, NR 7 R 8 , CH 2 OR 6 , an optionally substituted aryl, an optionally substituted three to nine membered heteroaryl, an optionally substituted three to nine membered non-aromatic ring, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 alkenyl, an optionally substituted C 1 -C 6 alkynyl, CO 2 R 6 , SO 3 R 6 , and SO 2 NR 7 R 8 ;

A is an optionally substituted aryl or an optionally substituted three to nine membered heteroaryl group; and

each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, haloalkyl, heterohaloalkyl, aryl, arylalkyl, three to nine membered heteroaryl, three to nine membered non-aromatic ring, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, —C(═O)R, —C(═S)R, —O(C═O)NR 2 , ROC(═O)NH—, —O(C═S)NR 2 , ROC(═S)NH—, —(C═O)NR 2 , RC(═O)NH—, —S(═O) 2 NR, RS(═O) 2 NH—, —C(═O)OR, RC(═O)O—, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, ═O, ═S, and amino, wherein each R is independently selected from the group consisting of alkyl, cycloalkyl, aryl, three to nine membered heteroaryl, and three to nine membered non-aromatic ring.

2. The method of claim 1 , wherein R 4 is selected from hydrogen, halogen, OR 6 , CN, NR 7 R 8 , CH 2 OR 6 , an optionally substituted aryl, an optionally substituted three to nine membered heteroaryl, an optionally substituted three to nine membered non-aromatic ring, an optionally substituted three to nine membered carbocycle, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 alkenyl, an optionally substituted C 1 -C 6 alkynyl, CO 2 R 6 , SO 3 R 6 , SO 2 R 6 and SO 2 NR 7 R 8 .

3. The method of claim 1 , wherein R 4 is pyrazolyl or pyrimidinyl.

4. The method of claim 1 , wherein R 4 is selected from oxazolyl, isoxazolyl, or imidazoyl.

5. The method of claim 1 , wherein the compound has the structure of Formula (I-A):

or a pharmaceutically acceptable salt thereof, wherein:

X is N or CR 5′ , wherein R 5′ is selected from hydrogen, halogen, OR 6 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 alkenyl, and an optionally substituted C 1 -C 6 alkynyl;

R 1 is selected from hydrogen, halogen, OR 6 , CN, NR 7 R 8 , CH 2 OR 6 , CH 2 NR 7 R 8 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 alkenyl, an optionally substituted C 1 -C 6 alkynyl, CO 2 R 6 , CONR 7 R 8 , SO 3 R 6 , and SO 2 NR 7 R 8 ; and

R 2 and R 3 are independently selected from hydrogen, halogen, OR 6 , NR 7 R 8 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 alkenyl, and an optionally substituted C 1 -C 6 alkynyl.

6. The method of claim 1 , wherein the compound has the structure of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

X is N or CR 5′ , wherein R 5′ is selected from hydrogen, halogen, OR 6 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 alkenyl, and an optionally substituted C 1 -C 6 alkynyl;

R 1 is selected from hydrogen, halogen, OR 6 , CN, NR 7 R 8 , CH 2 OR 6 , CH 2 NR 7 R 8 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 alkenyl, an optionally substituted C 1 -C 6 alkynyl, CO 2 R 6 , CONR 7 R 8 , SO 3 R 6 , and SO 2 NR 7 R 8 ; and

R 2 and R 3 are independently selected from hydrogen, halogen, OR 6 , NR 7 R 8 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 alkenyl, and an optionally substituted C 1 -C 6 alkynyl.

7. The method of claim 6 , wherein W is S.

8. The method of claim 6 , wherein X is N.

9. The method of claim 1 , wherein the compound has the structure of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

X is N or CR 5′ , wherein R 5′ is selected from hydrogen, halogen, OR 6 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 alkenyl, and an optionally substituted C 1 -C 6 alkynyl;

R 1 is selected from hydrogen, halogen, OR 6 , CN, NR 7 R 8 , CH 2 OR 6 , CH 2 NR 7 R 8 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 alkenyl, an optionally substituted C 1 -C 6 alkynyl, CO 2 R 6 , CONR 7 R 8 , SO 3 R 6 , and SO 2 NR 7 R 8 ; and

R 2 and R 3 are independently selected from hydrogen, halogen, OR 6 , NR 7 R 8 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 alkenyl, an optionally substituted C 1 -C 6 alkynyl.

10. The method of claim 9 , wherein X is N.

11. The method of claim 1 , wherein the inflammatory disorder is selected from the group consisting of osteoarthritis, rheumatoid arthritis, multiple sclerosis, corneal ulcers, uveitis, and inflammatory bowel disease.

12. The method of claim 6 , wherein R 1 is NR 7 R 8 , CH 2 NR 7 R 8 , or an optionally substituted C 1 -C 6 alkyl.

13. The method of claim 6 , wherein R 1 is selected from NR 7 R 8 , or CH 2 NR 7 R 8 .

14. The method of claim 6 , wherein R 2 and R 3 are each hydrogen.

15. The method of claim 6 , wherein R 4 is selected from an optionally substituted three to nine membered heteroaryl selected from C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and an optionally substituted three to nine membered heteroaryl selected from pyridine, pyrazole, pyridazine, pyrimidine, wherein the three to nine membered heteroaryl is optionally substituted with 1-2 substituents selected from C 1 -C 6 alkyl and CN.

16. The method of claim 6 , wherein R 4 is selected from the group consisting of pyridyl, pyrazolyl, pyrimidinyl, and pyridazinyl.

17. The method of claim 6 , wherein R 5 is hydrogen and C 1 -C 6 alkyl.

18. The method of claim 6 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

19. The method of claim 6 , wherein the compound is:

or pharmaceutically acceptable salt thereof.