Compounds and methods of use

1. A compound of Formula I or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof:

wherein:

ring A is C 4 -C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;

X is—O—, —S—, —NR 9 —, —CR 5 ═CR 5 —, or—CR 5 ═N—;

p is 0, 1 or 2;

q is 0, 1, 2 or 3;

R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, —CN, —OR 7 , —C(O)OR 6 , —C(O)N(R 7 ) 2 , —OC(O)R 6 , —S(O) 2 R 8 , —S(O) 2 N(R 7 ) 2 , —S(O)N(R 7 ) 2 , —S(O)R 8 , —N(R 7 ) 2 , —NO 2 , —C 1 -C 6 alkyl—OR 7 , or—Si(R 15 ) 3 ;

R 2 is—C 1 -C 2 haloalkyl, —C 2 -C 3 alkenyl, —C 2 -C 3 haloalkenyl, C 2 alkynyl, or—CH 2 OS(O) 2 -phenyl, wherein the C 1 -C 2 alkylhalo and—C 2 -C 3 alkenylhalo are optionally substituted with one or two—CH 3 , and the C 2 alkynyl and phenyl are optionally substituted with one—CH 3 ;

each R 3 is independently halo, —CN, —OH, —OR 8 , —NH 2 , —NHR 8 , —N(R 8 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 7 ) 2 , —S(O)N(R 7 ) 2 , —NO 2 , —Si(R 12 ) 3 , —SF 5 , —C(O)OR 6 , —C(O)N(R 7 ) 2 , —NR 12 C(O)R 8 , —NR 12 C(O)OR 8 , —OC(O)N(R 7 ) 2 , —OC(O)R 8 , —C(O)R 6 , —OC(O)CHR 8 N(R 12 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or—C 2 -C 6 alkenylheteroaryl; wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, -C 1 -C 6 alkylheteroaryl, or—C 2 -C 6 alkenylheteroaryl of R 3 is independently optionally substituted with one to three R 10 ;

each R 4 is independently halo, —CN, —OH, —OR 8 , —NH 2 , —NHR 8 , —N(R 8 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 7 ) 2 , —S(O)N(R 7 ) 2 , —NO 2 , —Si(R 15 ) 3 , —C(O)OR 6 , —C(O)N(R 7 ) 2 , —NR 12 C(O)R 8 , —OC(O)R 8 , —C(O)R 6 , —NR 12 C(O)OR 8 , —OC(O)N(R 7 ) 2 , —OC(O)CHR 8 N(R 12 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or—C 2 -C 6 alkenylheteroaryl; wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or—C 2 -C 6 alkenylheteroaryl of R 4 is independently optionally substituted with one to three R 10 ;

each R 5 is independently hydrogen, halo, —CN, —OH, —OR 8 , —NH 2 , —NHR 8 , —N(R 8 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 7 ) 2 , —S(O)N(R 7 ) 2 , —NO 2 , —Si(R 15 ) 3 , —C(O)OR 6 , —C(O)N(R 7 ) 2 , —NR 12 C(O)R 8 , —OC(O)R 8 , —C(O)R 6 , —NR 12 C(O)OR 8 , —OC(O)N(R 7 ) 2 , —OC(O)CHR 8 N(R 12 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or—C 2 -C 6 alkenylheteroaryl; wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or—C 2 -C 6 alkenylheteroaryl of R 5 is independently optionally substituted with one to three R 10 ;

each R 6 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or—C 2 -C 6 alkenylheteroaryl; wherein each R 6 is independently optionally further substituted with one to three R 11 ;

each R 7 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 6 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 6 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, —C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl, or two R 7 , together with the nitrogen atom to which they are attached, form a 4 to 7 membered heterocyclyl; wherein each R 7 or ring formed thereby is independently optionally further substituted with one to three R 11 ;

each R 8 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, —C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl; wherein each R 8 is independently optionally further substituted with one to three R 11 ;

R 9 is hydrogen or C 1 -C 6 alkyl;

each R 10 is independently halo, —CN, —OR 12 , —NO 2 , —N(R 12 ) 2 , —S(O)R 13 , —S(O) 2 R 13 , —S(O)N(R 12 ) 2 , —S(O) 2 N(R 12 ) 2 , —Si(R 12 ) 3 , —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —NR 12 C(O)R 12 , —OC(O)R 12 , —OC(O)OR 12 , —OC(O)N(R 12 ) 2 , —NR 12 C(O)OR 12 , —OC(O)CHR 12 N(R 12 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R 10 is optionally independently substituted with one to three R 11 ;

each R 11 is independently halo, —CN, —OR 12 , —NO 2 , —N(R 12 ) 2 , —S(O)R 13 , —S(O) 2 R 13 , —S(O)N(R 12 ) 2 , —S(O) 2 N(R 12 ) 2 , —Si(R 12 ) 3 , —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —NR 12 C(O)R 12 , —OC(O)R 12 , —OC(O)OR 12 , —OC(O)N(R 12 ) 2 , —NR 12 C(O)OR 12 , —OC(O)CHR 12 N(R 12 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;

each R 12 is independently hydrogen, C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl;

each R 13 is independently C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl; and

each R 15 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, heteroaryl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, —C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl; provided that at least one of the following is true:

1) R 1 is other than—C(O)OCH 3 ;

2) R 2 is—C 2 alkynyl optionally substituted with one—CH 3 ; or

3) when R 1 is—C(O)OCH 3 and R 2 is—CH 2 Cl, then the moiety

is other than 1,3-benzodioxol-5-yl, 4-nitrophenyl, 4-bromophenyl, cyclohexyl, furyl, or 4-methoxyphenyl.

2. The compound of claim 1 , represented by a compound of Formula II, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof:

3. The compound of claim 1 , represented by a compound of Formula III, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof:

wherein R 14 is halo.

4. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein ring A is C 4 -C 10 cycloalkyl.

5. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein ring A is heterocyclyl.

6. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein ring A is aryl.

7. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein ring A is heteroaryl.

8. The compound of claim 1 , represented by a compound of Formula VIII, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof:

9. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, —CN, —C(O)OR 6 , —C(O)N(R 7 ) 2 , —N(R 7 ) 2 , —OR 7 , or —C 1 -C 6 alkyl-OR 7 .

10. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R 1 is —C(O)OR 6 or—C(O)N(R 7 ) 2 .

11. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 alkyl.

12. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein p is 0 or 1.

13. The compound of claim 1 , represented by a compound of Formula IX, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof:

wherein R 16 is hydrogen or C 2 -C 5 alkyl.

14. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein q is 2 or 3.

15. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein each R 4 is independently halo, —CN, —OH, —OR 8 , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or C 3 -C 10 cycloalkyl; wherein each C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or C 3 -C 10 cycloalkyl of R 4 is independently optionally substituted with one to three R 10 .

16. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein q is 0.

17. A pharmaceutical composition comprising a compound, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, of claim 1 , and a pharmaceutically acceptable carrier.

18. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein the compound is:

19. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein the compound is:

20. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein the compound is:

21. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein the compound is:

22. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein the compound is:

23. A compound which is:

or pharmaceutically acceptable salt thereof.

24. A compound which is:

or pharmaceutically acceptable salt thereof.

25. A compound which is:

or pharmaceutically acceptable salt thereof.

26. A compound which is:

or pharmaceutically acceptable salt thereof.

27. A compound which is:

28. A compound which is:

29. A compound which is:

30. A compound which is: