Substituted imidazo[1,5-a]pYRAZINES for modulation of IRE1

1. A compound having the Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

ring A is R 41 -substituted or unsubstituted cycloalkylene, R 41 -substituted or unsubstituted heterocycloalkylene, R 41 -substituted or unsubstituted arylene or R 41 -substituted or unsubstituted heteroarylene;

L 1 is a bond or unsubstituted C 1 -C 5 alkylene;

L 2 is —NR 6a C(O)NR 6b — or —NHC(O)OCH 2 —;

R 1 is hydrogen, oxo, halogen, —CX 3 , —CN, —S(O) 2 Cl, —S(O) n R 10 , —S(O) v NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC(O)NHNH 2 , —NHC(O)NR 7 R 8 , —N(O) m , —NR 7 R 8 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 7 R 8 , —OR 10 , —NR 7 S(O) n R 10 , —NR 7 C(O)R 9 , —NR 7 C(O)OR 9 , —NR 7 OR 9 , —OCX 3 , —OCHX 2 , R 11 -substituted or unsubstituted alkyl, R 11 -substituted or unsubstituted heteroalkyl, R 11 -substituted or unsubstituted cycloalkyl, R 11 -substituted or unsubstituted heterocycloalkyl, R 11 -substituted or unsubstituted aryl or R 11 -substituted or unsubstituted heteroaryl;

R 2 is hydrogen, R 14 -substituted or unsubstituted alkyl or R 14 -substituted or unsubstituted cycloalkyl;

each R 3 is independently hydrogen, halogen, —CX b 3 , —CN, —S(O) 2 Cl, —S(O) n2 R 10b , —S(O) v2 NR 7b R 8b , —NHNH 2 , —ONR 7b R 8b , —NHC(O)NHNH 2 , —NHC(O)NR 7b R 8b , —N(O) m2 , —NR 7b R 8b , —C(O)R 9b , —C(O)OR 9b , —C(O)NR 7b R 8b , —OR 10b , —NR 7b S(O) n2 R 10b , —NR 7b C(O)R 9b , —NR 7b C(O)OR 9b , —NR 7b OR 9b , —OCX b 3 , —OCHX b 2 , R 17 -substituted or unsubstituted alkyl, R 17 -substituted or unsubstituted heteroalkyl, R 17 -substituted or unsubstituted cycloalkyl, R 17 -substituted or unsubstituted heterocycloalkyl, R 17 -substituted or unsubstituted aryl or R 17 -substituted or unsubstituted heteroaryl;

R 4 is hydrogen or unsubstituted C 1 -C 6 alkyl;

R 5 is hydrogen or unsubstituted C 1 -C 6 alkyl;

R 7 , R 8 , R 9 , R 10 , R 6a , R 6b , R 7b , R 8b , R 9b and R 10b are each independently hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)NH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF 3 , —OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl; or

R 7 and R 8 , together with the nitrogen to which they are bonded, may optionally form a unsubstituted heterocycloalkyl or unsubstituted heteroaryl; or

R 7b and R 8b , together with the nitrogen to which they are bonded, may optionally form a unsubstituted heterocycloalkyl or unsubstituted heteroaryl;

each R 11 is independently oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)NH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF 3 , —OCHF 2 , R 12 -substituted or unsubstituted alkyl, R 12 -substituted or unsubstituted heteroalkyl, R 12 -substituted or unsubstituted cycloalkyl, R 12 -substituted or unsubstituted heterocycloalkyl, R 12 -substituted or unsubstituted aryl or R 12 -substituted or unsubstituted heteroaryl;

each R 12 is independently oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)NH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF 3 , —OCHF 2 , R 13 -substituted or unsubstituted alkyl, R 13 -substituted or unsubstituted heteroalkyl, R 13 -substituted or unsubstituted cycloalkyl, R 13 -substituted or unsubstituted heterocycloalkyl, R 13 -substituted or unsubstituted aryl or R 13 -substituted or unsubstituted heteroaryl;

each R 13 is independently oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)NH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF 3 , —OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl;

each R 14 is independently oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)NH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF 3 , —OCHF 2 , R 15 -substituted or unsubstituted alkyl, R 15 -substituted or unsubstituted heteroalkyl, R 15 -substituted or unsubstituted cycloalkyl, R 15 -substituted or unsubstituted heterocycloalkyl, R 15 -substituted or unsubstituted aryl or R 15 -substituted or unsubstituted heteroaryl;

each R 15 is independently oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)NH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF 3 , —OCHF 2 , R 16 -substituted or unsubstituted alkyl, R 16 -substituted or unsubstituted heteroalkyl, R 16 -substituted or unsubstituted cycloalkyl, R 16 -substituted or unsubstituted heterocycloalkyl, R 16 -substituted or unsubstituted aryl or R 16 -substituted or unsubstituted heteroaryl;

each R 16 is independently oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)NH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF 3 , —OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl;

each R 17 is independently oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)NH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF 3 , —OCHF 2 , R 18 -substituted or unsubstituted alkyl, R 18 -substituted or unsubstituted heteroalkyl, R 18 -substituted or unsubstituted cycloalkyl, R 18 -substituted or unsubstituted heterocycloalkyl, R 18 -substituted or unsubstituted aryl or R 18 -substituted or unsubstituted heteroaryl;

each R 18 is independently oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)NH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF 3 , —OCHF 2 , R 19 -substituted or unsubstituted alkyl, R 19 -substituted or unsubstituted heteroalkyl, R 19 -substituted or unsubstituted cycloalkyl, R 19 -substituted or unsubstituted heterocycloalkyl, R 19 -substituted or unsubstituted aryl or R 19 -substituted or unsubstituted heteroaryl;

each R 19 is independently oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)NH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF 3 , —OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl;

each R 41 is independently oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)NH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF 3 , —OCHF 2 , R 42 -substituted or unsubstituted alkyl, R 42 -substituted or unsubstituted heteroalkyl, R 42 -substituted or unsubstituted cycloalkyl, R 42 -substituted or unsubstituted heterocycloalkyl, R 42 -substituted or unsubstituted aryl or R 42 -substituted or unsubstituted heteroaryl;

each R 42 is independently oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)NH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF 3 , —OCHF 2 , R 43 -substituted or unsubstituted alkyl, R 43 -substituted or unsubstituted heteroalkyl, R 43 -substituted or unsubstituted cycloalkyl, R 43 -substituted or unsubstituted heterocycloalkyl, R 43 -substituted or unsubstituted aryl or R 43 -substituted or unsubstituted heteroaryl;

each R 43 is independently oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —C(O)OH, —C(O)NH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF 3 , —OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl;

each occurrence of X and X b is independently a halogen;

each occurrence of m and m2 is independently 1 or 2;

each occurrence of n and n2 is independently 0, 1, 2, 3 or 4;

each occurrence of v and v2 is independently 1 or 2; and

z is 0, 1 or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A is R 41 substituted or unsubstituted arylene or R 41 -substituted or unsubstituted heteroarylene.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A is unsubstituted naphthalenyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —NR 6a C(O)NR 6b —.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 6a and R 6b are each independently hydrogen.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is R 11 -substituted or unsubstituted cycloalkyl, R 11 -substituted or unsubstituted heterocycloalkyl, R 11 -substituted or unsubstituted aryl or R 11 -substituted or unsubstituted heteroaryl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is R 11 -substituted phenyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is R 14 -substituted or unsubstituted alkyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is unsubstituted C 1 -C 6 alkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently hydrogen.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are each independently hydrogen.

13. The compound of claim 1 , wherein the compound has the Formula (II):

or a pharmaceutically acceptable salt thereof,

wherein:

L 3 is —NR 6b —.

14. The compound of claim 13 , wherein the compound has the Formula (III):

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

16. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. A method for modulating the activity of an inositol-requiring enzyme 1 protein, the method comprising contacting the inositol-requiring enzyme 1 protein with an effective amount a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

18. A method for modulating the activity of an inositol-requiring enzyme 1 protein in a subject, the method comprising administering to the subject a therapeutically effective amount a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19. The method of claim 18 , wherein the subject suffers from a disease selected from the group consisting of a fibrotic disease, retinitis pigmentosa and diabetes.

20. A compound selected from the group consisting of: