APOPTOSIS SIGNAL-REGULATING KINASE INHIBITORS AND USES THEREOF

Title:

APOPTOSIS SIGNAL-REGULATING KINASE INHIBITORS AND USES THEREOF

Document Type and Number:

WIPO Patent Application WO/2019/051265

Kind Code:

Abstract:

Described herein are ASK1 inhibitors and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of blood disease, autoimmune disorders, pulmonary disorders, hypertension, inflammatory diseases, fibrotic diseases, diabetes, diabetic nephropathy, renal diseases, respiratory diseases, cardiovascular diseases, acute lung injuries, acute or chronic liver diseases, and neurodegenerative diseases.

Inventors:

JIN BOHAN (US)
DONG QING (US)
HUNG GENE (US)

Application Number:

PCT/US2018/050013

Publication Date:

March 14, 2019

Filing Date:

September 07, 2018

Export Citation:

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Assignee:

FRONTHERA U S PHARMACEUTICALS LLC (US)

International Classes:

A61K31/437; C07D401/12; C07D413/14

Domestic Patent References:

WO2011008709A1	2011-01-20
WO2018148204A1	2018-08-16

Foreign References:

US20170204116A1	2017-07-20
US20170174671A1	2017-06-22
US20110009410A1	2011-01-13

Other References:

See also references of EP 3678662A4

Attorney, Agent or Firm:

BONNEFOUS, Celine M. (US)

Download PDF:

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Claims:

CLAIMS

WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:

(Formula I)

wherein:

Ring A is aryl or heteroaryl;

Ring B is aryl or heteroaryl;

L is a saturated or unsaturated linear aliphatic chain having 4-10 carbon atoms optionally substituted with 1-6 R⁷, wherein 1, 2, or 3 carbon atoms are optionally replaced with -NR⁷-, -0-, -S-, -S(=0)-, or -S(=0)₂-

X¹ is N or CR¹;

X² is N or CR²;

X³ is N or CR³;

each R¹, R², and R³ is independently hydrogen, halogen, -CN, -OR^a, -SR^a, -S(=0)R^b, -N0₂, -NR^cR^d, - S(=0)₂R^d, -NR^aS(=0)₂R^d, -S(=0)₂NR^cR^d, -C(=0)R^b, -OC(=0)R^b, -C0₂R^a, -OC0₂R^a, -C(=0)NR^cR^d, - OC(=0)NR^cR^d, -NR^aC(=0)NR^cR^d, -NR^aC(=0)R^b, -NR^aC(=0)OR^a, optionally substituted d-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substituted Ci-C₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted

heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R⁴ is independently hydrogen, halogen, -CN, -OR^a, -SR^a, -S(=0)R^b, -N0₂, -NR^cR^d, -S(=0)₂R^d, - NR^aS(=0)₂R^d, -S(=0)₂NR^cR^d, -C(=0)R^b, -OC(=0)R^b, -C0₂R^a, -OC0₂R^a, -C(=0)NR^cR^d, - OC(=0)NR^cR^d, -NR^aC(=0)NR^cR^d, -NR^aC(=0)R^b, -NR^aC(=0)OR^a, optionally substituted d-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substituted Ci-C₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted

heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

or two R⁴ are taken together to form an optionally substituted cycloalkyl, optionally substituted

heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

R⁵ is hydrogen, -S(=0)R^b, -S(=0)₂R^d, -S(=0)₂NR^cR^d, -C(=0)R^b, -OC0₂R^a, -C(=0)NR^cR^d, optionally substituted Ci-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substituted Ci-C₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R⁶ is independently hydrogen, halogen, -CN, -OR^a, -SR^a, -S(=0)R^b, -N0₂, -NR^cR^d, -S(=0)₂R^d, - NR^aS(=0)₂R^d, -S(=0)₂NR^cR^d, -C(=0)R^b, -OC(=0)R^b, -C0₂R^a, -OC0₂R^a, -C(=0)NR^cR^d, - OC(=0)NR^cR^d, -NR^aC(=0)NR^cR^d, -NR^aC(=0)R^b, -NR^aC(=0)OR^a, optionally substituted d-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substituted Ci-C₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted

heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R⁷ is independently hydrogen, halogen, -CN, -OR^a, -SR^a, -S(=0)R^b, -N0₂, -NR^cR^d, -S(=0)₂R^d, - NR^aS(=0)₂R^d, -S(=0)₂NR^cR^d, -C(=0)R^b, -OC(=0)R^b, -C0₂R^a, -OC0₂R^a, -C(=0)NR^cR^d, - OC(=0)NR^cR^d, -NR^aC(=0)NR^cR^d, -NR^aC(=0)R^b, -NR^aC(=0)OR^a, optionally substituted d-Q, alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substituted Ci-C₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted

heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

or two R⁷ on the same carbon atom are taken together to form an oxo;

R^a is hydrogen, optionally substituted Ci-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionally

R^b is optionally substituted Ci-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substituted Ci-C₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R^c and R^d is independently hydrogen, optionally substituted Ci-C₆ alkyl, optionally substituted C₂- C<5 alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substituted Ci-C₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

or R^c and R^d, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;

s is 1-3; and

t is 1-3.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

Ring A is phenyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, tautomer, or

stereoisomer thereof, wherein:

Ring B is pyridyl.

4. The compound of any one of claims 1 -3, wherein the compound of Formula (I) is of Formula (la), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof: Formula (la).

5. The compound of any one of claims 1 -4, wherein the compound of Formula (I) or (la) is of Formula (lb), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:

Formula (la').

The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

R³ is halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

The compound of any one of claims 1 -4, wherein the compound of Formula (I) or (la) is of Formula (lb), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

each R⁴ is independently hydrogen, halogen, -CN, -OR^a, -NR^cR^d, -C0₂R^a, -C(=0)NR^cR^d, optionally substituted Ci-C₆ alkyl, optionally substituted C₂-C₆ alkynyl, optionally substituted Ci-C₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

each R⁴ is independently hydrogen, halogen, -CN, -OR^a, optionally substituted Ci-C₆ alkyl,

optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

each R⁴ is independently hydrogen, -OR^a, or optionally substituted heteroaryl.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

each R⁴ is independently substituted heteroaryl.

12. The compound of claim 11, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

each R⁴ is independently heteroaryl substituted with halogen, -OR^a, -NR^cR^d, Ci-C₆ alkyl, Ci-C₆ haloalkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

13. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

two R⁴ are taken together to form an optionally substituted heterocycloalkyl.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

s is 1 or 2.

15. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

s is 1.

16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

each R⁶ is hydrogen.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

R⁵ is hydrogen or optionally substituted Ci-C₆ alkyl.

19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

hydrogen.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

each R⁷ is independently hydrogen, halogen, or optionally substituted Ci-C₆ alkyl.

21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

two R⁷ are taken together to form an optionally substituted cycloalkyl.

22. The compound of any one of claims 1-19 or 21, or a pharmaceutically acceptable salt, solvate,

tautomer, or stereoisomer thereof, wherein:

two R⁷ are taken together to form a cyclopropyl, a cyclobutyl, a cyclopentyl, or a cyclohexyl.

23. The compound of any one of claims 1 -22, or a pharmaceutically acceptable salt, solvate, tautomer, or

wherein

each R^7a and R^¾ is independently hydrogen, halogen, -CN, -OR^a, -SR^a, -S(=0)R^b, -N0₂, -NR^cR^d, - S(=0)₂R^d, -NR^aS(=0)₂R^d, -S(=0)₂NR^cR^d, -C(=0)R^b, -OC(=0)R^b, -C0₂R^a, -OC0₂R^a, - C(=0)NR^cR^d, -OC(=0)NR^cR^d, -NR^aC(=0)NR^cR^d, -NR^aC(=0)R^b, -NR^aC(=0)OR^a, optionally substituted Ci-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substituted Ci-C₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or R^7a and R^7b on the same carbon atom are taken together to form an oxo;

or two R^7a are taken together to form an optionally substituted cycloalkyl;

each Y is independently -NR^7c-, -0-, -S-, -S(=0)-, or -S(=0)₂-;

each R^7c is independently hydrogen, -S(=0)R^b, -S(=0)₂R^d, -S(=0)₂NR^cR^d, -C(=0)R^b, -C0₂R^a, -

C(=0)NR^cR^d, optionally substituted Ci-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substituted Ci-C₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

a is 4-10; b is 0-9 and c is 0-9; provided that 3 < b + c < 9;

d is 0-8; e is 2-8; and f is 0-8; provided that 2 < d + e + f < 8;

g is 0-8 and h is 0-8; provided that 2 < g + h < 8;

i is 0-7; j is 0-7; and k is 0-7; provided that l≤i + j + k < 7;

1 is 0-6; m is 0-6; and n is 0-6; provided that 0 < l + m + n < 6.

24. The compound of claim 23, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

Y is -0-.

25. The compound of claim 23 or 24, or a pharmaceutically acceptable salt, solvate, tautomer, or

stereoisomer thereof, wherein:

each R^7a and R^ is independently hydrogen, halogen, or optionally substituted Ci-C₆ alkyl.

26. The compound of any one of claims 23-25, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

each R^7a and R^ is hydrogen.

27. The compound of any one of claims 23-25, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

two R^7a are taken together to form an optionally substituted cycloalkyl.

28. The compound of any one of claims 1 -27, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

. I— (CR^7aR^7b)_a-| I— (CR^7aR^7b) Y— (CR^7aR^7b)_c-j l-Y— (CR^7aR^7b)_c-|

L· IS , , ,

|— (CR^7aR^7b)g-=— (CR^7aR^7b)_h-| |-Y— (CR^7aR^7b)j— =— (CR^7aR^7b)_k-j

29. The compound of any one of claims 1 -27, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

|— (CR^7aR^7b) Y— (CR^7aR^7b)_c-|

30. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

31. The compound of any one of claims 1 -28, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

32. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, tautomer, or rein:

33. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-32, and a pharmaceutically acceptable excipient.

34. The pharmaceutical composition of claim 33, wherein the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration.

35. A method for treating a disease in a mammal comprising administering to the mammal a

therapeutically effective amount of the compound of any one of claims 1-32, or the pharmaceutical composition of claims 33 or 34.

36. The method of claim 35, wherein the disease is selected from the group consisting of a blood disease, an autoimmune disorder, a pulmonary disorder, hypertension, an inflammatory disease, a fibrotic disease, diabetes, diabetic nephropathy, a renal disease, a respiratory disease, a cardiovascular disease, acute lung injury, acute or chronic liver disease, and a neurodegenerative disease.

37. The method of claim 36, wherein the liver disease is selected from the group consisting of

fascioliasis, hepatitis, non-alcoholic steatohepatitis (NASH) with or without fibrosis, hepatic steatosis, fatty liver disease (FLD), non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, Alagille syndrome, biliary atresia, galactosemia, gallstones, hemochromatosis, liver cancer, lysosomal acid lipase deficiency (LALD), porphyria, acetaminophen hepatotoxicity, Reye's syndrome, sarcoidosis, tyrosinemia, Wilson disease, Gilbert's syndrome, cirrhosis, and primary sclerosing cholangitis.

38. The method of claim 36, wherein the pulmonary disorder is selected from the group consisting of chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), asthma, bronchitis, emphysema, lung cancer, pneumonia, cystic fibrosis, pulmonary embolism, pulmonary arterial hypertension, pulmonary edema, and pulmonary hemorrhage.

39. The method of claim 36, wherein the autoimmune disorder is selected from the group consisting of alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, diabetes (type 1), idiopathic arthritis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, myocarditis, multiple sclerosis, pemphigus/pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma/systemic sclerosis, Sjogren's syndrome, systemic lupus erythematosus, thyroiditis, uveitis, vitiligo, and granulomatosis with polyangiitis (Wegener's).

40. The method of claim 36, wherein the inflammatory disease is selected from the group consisting of Alzheimer's, ankylosing spondylitis, arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis), atherosclerosis, arteriosclerosis, cholestasis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, irritable bowel syndrome (IBS), systemic lupus erythematous (SLE), nephritis, Parkinson's disease, cardiac inflammation, and ulcerative colitis.

41. The method of claim 36, wherein the renal disease is selected from the group consisting of Alport syndrome, renal fibrosis, kidney disease, diabetic nephropathy, fabry disease, diabetic kidney disease, diabetic nephropathy, renal inflammation, renal fibrosis focal segmental glomerulosclerosis, glomerulonephritis, IgA nephropathy (Berger's disease), kidney stones, minimal change disease, nephrotic syndrome, and polycystic kidney disease (PKD).

42. The method of claim 36, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, dementia, multiple sclerosis, optical neuritis, amyotrophic lateral sclerosis, Friedreich's ataxia, amyotrophic lateral sclerosis (ALS), Huntington's disease, Lewy body disease, Parkinson's disease, and spinal muscular atrophy.

43. The method of claim 36, wherein the cardiovascular disease is selected from the group consisting of endothelial dysfunction, metabolic syndrome, atherosclerosis, coronary artery disease, heart failure, peripheral artery disease, cardiac inflammation, cardiac fibrosis, cerebrovascular disease, and coronary syndrome.

44. The method of claim 36, wherein the blood disease is sickle cell disease.

45. A method for reducing neuronal cell death following ischemic injury in a mammal comprising

administering to the mammal a therapeutically effective amount of the compound of any one of claims 1 -32, or the pharmaceutical composition of claims 33 or 34.

46. A method for modulating platelets in a mammal comprising administering to the mammal a

therapeutically effective amount of the compound of any one of claims 1 -32, or the pharmaceutical composition of claims 33 or 34.

47. The method of claim 46, wherein the compound modulates platelet activation, platelet granule

secretion, thromboxane A2 generation, or thrombosis modulation.

48. A method for modulating the level of a reactive oxidative species in a mammal comprising

administering to the mammal a therapeutically effective amount of the compound of any one of claims 1 -32, or the pharmaceutical composition of claims 33 or 34.

49. The method of claim 48, wherein the reactive oxidative species is a reactive oxygen species.

50. The method of claim 49, wherein the reactive oxidative species contains a radical on the oxygen atom.

Description:

APOPTOSIS SIGNAL-REGULATING KINASE INHIBITORS AND USES THEREOF

CROSS-REFERENCE

[0001] This patent application claims the benefit of U.S. Provisional Application No. 62/555,961, filed September 8, 2017, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases, disorders or conditions associated with apoptosis signal-regulating kinase 1 such as blood diseases, autoimmune disorders, pulmonary disorders, hypertension, inflammatory diseases, fibrotic diseases (such as idiosyncratic pulmonary fibrosis, chronic kidney disease/kidney fibrosis, irritable bowel disease, scleroderma, and liver fibrosis), diabetes, diabetic nephropathy, renal diseases, respiratory diseases, cardiovascular diseases, acute lung injuries, acute or chronic liver diseases, and neurodegenerative diseases.

BACKGROUND OF THE INVENTION

[0003] Apoptosis signal -regulating kinase 1 (ASKl) activation and signaling have been reported to play an important role in a broad range of diseases including neurodegenerative, cardiovascular,

inflammatory, autoimmune, and metabolic disorders. In addition, ASKl has been implicated in mediating organ damage following ischemia and reperfusion of the heart, brain, and kidney.

[0004] ASKl has also been identified as an important signaling pathway in non-alcoholic steatohepatitis (NASH), a type of non-alcoholic fatty liver disease (NAFLD), chronic obstructive pulmonary disease (COPD), hypertension, multiple sclerosis, Alzheimer's disease, Parkinson's disease, platelet activation, sickle cell disease, kidney disease, and oxidative stress. Therefore, therapeutic agents that function as inhibitors of ASKl have potential to remedy or improve the lives of patients suffering from such conditions.

BRIEF SUMMARY OF THE INVENTION

[0005] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:

(Formula I)

wherein:

Ring A is aryl or heteroaryl;

Ring B is aryl or heteroaryl; L is a saturated or unsaturated linear aliphatic chain having 4-10 carbon atoms optionally substituted with 1-6 R ⁷, wherein 1, 2, or 3 carbon atoms are optionally replaced with -NR ⁷-, -0-, -S-, -S(=0)-, or -S(=0) ₂-

X ¹ is N or CR ¹;

X ² is N or CR ²;

X ³ is N or CR ³;

each R ¹, R ², and R ³ is independently hydrogen, halogen, -CN, -OR ^a, -SR ^a, -S(=0)R ^b, -N0 ₂, -NR ^cR ^d, - S(=0) ₂R ^d, -NR ^aS(=0) ₂R ^d, -S(=0) ₂NR ^cR ^d, -C(=0)R ^b, -OC(=0)R ^b, -C0 ₂R ^a, -OC0 ₂R ^a, -C(=0)NR ^cR ^d, - OC(=0)NR ^cR ^d, -NR ^aC(=0)NR ^cR ^d, -NR ^aC(=0)R ^b, -NR ^aC(=0)OR ^a, optionally substituted d-C ₆ alkyl, optionally substituted C ₂-C ₆ alkenyl, optionally substituted C ₂-C ₆ alkynyl, optionally substituted Ci-C ₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted

heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R ⁴ is independently hydrogen, halogen, -CN, -OR ^a, -SR ^a, -S(=0)R ^b, -N0 ₂, -NR ^cR ^d, -S(=0) ₂R ^d, - NR ^aS(=0) ₂R ^d, -S(=0) ₂NR ^cR ^d, -C(=0)R ^b, -OC(=0)R ^b, -C0 ₂R ^a, -OC0 ₂R ^a, -C(=0)NR ^cR ^d, - OC(=0)NR ^cR ^d, -NR ^aC(=0)NR ^cR ^d, -NR ^aC(=0)R ^b, -NR ^aC(=0)OR ^a, optionally substituted d-C ₆ alkyl, optionally substituted C ₂-C ₆ alkenyl, optionally substituted C ₂-C ₆ alkynyl, optionally substituted Ci-C ₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted

heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

or two R ⁴ are taken together to form an optionally substituted cycloalkyl, optionally substituted

heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R ⁶ is independently hydrogen, halogen, -CN, -OR ^a, -SR ^a, -S(=0)R ^b, -N0 ₂, -NR ^cR ^d, -S(=0) ₂R ^d, - NR ^aS(=0) ₂R ^d, -S(=0) ₂NR ^cR ^d, -C(=0)R ^b, -OC(=0)R ^b, -C0 ₂R ^a, -OC0 ₂R ^a, -C(=0)NR ^cR ^d, - OC(=0)NR ^cR ^d, -NR ^aC(=0)NR ^cR ^d, -NR ^aC(=0)R ^b, -NR ^aC(=0)OR ^a, optionally substituted d-C ₆ alkyl, optionally substituted C ₂-C ₆ alkenyl, optionally substituted C ₂-C ₆ alkynyl, optionally substituted Ci-C ₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted

heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R ⁷ is independently hydrogen, halogen, -CN, -OR ^a, -SR ^a, -S(=0)R ^b, -N0 ₂, -NR ^cR ^d, -S(=0) ₂R ^d, - NR ^aS(=0) ₂R ^d, -S(=0) ₂NR ^cR ^d, -C(=0)R ^b, -OC(=0)R ^b, -C0 ₂R ^a, -OC0 ₂R ^a, -C(=0)NR ^cR ^d, - OC(=0)NR ^cR ^d, -NR ^aC(=0)NR ^cR ^d, -NR ^aC(=0)R ^b, -NR ^aC(=0)OR ^a, optionally substituted d-C ₆ alkyl, optionally substituted C ₂-C ₆ alkenyl, optionally substituted C ₂-C ₆ alkynyl, optionally substituted Ci-C ₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted

heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

or two R ⁷ on the same carbon atom are taken together to form an oxo;

or two R ⁷ are taken together to form an optionally substituted cycloalkyl; R ^a is hydrogen, optionally substituted Ci-C ₆ alkyl, optionally substituted C ₂-C ₆ alkenyl, optionally substituted C ₂-C ₆ alkynyl, optionally substituted Ci-C ₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

R ^b is optionally substituted Ci-C ₆ alkyl, optionally substituted C ₂-C ₆ alkenyl, optionally substituted C ₂-C ₆ alkynyl, optionally substituted Ci-C ₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R ^c and R ^d is independently hydrogen, optionally substituted Ci-C ₆ alkyl, optionally substituted C ₂- C ₆ alkenyl, optionally substituted C ₂-C ₆ alkynyl, optionally substituted Ci-C ₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

or R ^c and R ^d, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;

s is 1-3; and

t is 1-3.

[0006] Disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein, and a pharmaceutically acceptable excipient.

[0007] Also disclosed herein is a method for treating a disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein.

INCORPORATION BY REFERENCE

[0008] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0009] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of or "consist essentially of the described features.

[0010] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0011] "Aliphatic chain" refers to a linear chemical moiety that is composed of only carbons and hydrogens. In some embodiments, the aliphatic chain is saturated. In some embodiments, the aliphatic chain is unsaturated. In some embodiments, the unsaturated aliphatic chain contains one unsaturation. In some embodiments, the unsaturated aliphatic chain contains more than one unsaturation. In some embodiments, the unsaturated aliphatic chain contains two unsaturations. In some embodiments, the unsaturated aliphatic chain contains one double bond. In some embodiments, the unsaturated aliphatic chain contains two double bonds.

[0012] "Alkyl" refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms, wherein a sp3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl- 1-propyl, 2-methyl-2 -propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l- propyl, 2-methyl-l -pentyl, 3 -methyl- 1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as "Ci-C ₆ alkyl" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, the alkyl is a Ci-Cio alkyl, a C ₁-C9 alkyl, a Ci-C ₈ alkyl, a C ₁-C7 alkyl, a Ci-C ₆ alkyl, a C ₁-C5 alkyl, a C ₁-C4 alkyl, a C ₁-C3 alkyl, a Ci-C ₂ alkyl, or a Ci alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF ₃, -OH, -OMe, -NH ₂, or -N0 ₂. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF ₃, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0013] "Alkenyl" refers to an optionally substituted straight-chain, or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein a sp2-hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH ₂), 1-propenyl (-CH ₂CH=CH ₂), isopropenyl [-C(CH ₃)=CH ₂], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as "C ₂-C ₆ alkenyl" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl" where no numerical range is designated. In some embodiments, the alkenyl is a C ₂-Ci ₀ alkenyl, a C ₂-C ₉ alkenyl, a C ₂-C ₈ alkenyl, a C ₂-C ₇ alkenyl, a C ₂-C ₆ alkenyl, a C ₂-C ₅ alkenyl, a C ₂-C ₄ alkenyl, a C ₂-C ₃ alkenyl, or a C ₂ alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, - CF ₃, -OH, -OMe, -NH ₂, or -N0 ₂. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF ₃, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0014] "Alkynyl" refers to an optionally substituted straight-chain or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as "C ₂-C ₆ alkynyl" means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl" where no numerical range is designated. In some embodiments, the alkynyl is a C ₂-Ci ₀ alkynyl, a C ₂-C ₉ alkynyl, a C ₂-C ₈ alkynyl, a C ₂-C ₇ alkynyl, a C ₂-C ₆ alkynyl, a C ₂-C ₅ alkynyl, a C ₂-C ₄ alkynyl, a C ₂-C ₃ alkynyl, or a C ₂ alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, - CF ₃, -OH, -OMe, -NH ₂, or -N0 ₂. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF ₃, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0015] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, - CN, -CF ₃, -OH, -OMe, -NH ₂, or -N0 ₂. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF ₃, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0016] "Alkoxy" refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF ₃, -OH, -OMe, -NH ₂, or -N0 ₂. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF ₃, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0017] "Aryl" refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as- indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF ₃, -OH, -OMe, -NH ₂, or -N0 ₂. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0018] "Cycloalkyl" refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C ₃-C ₈ cycloalkyl), from three to six carbon atoms (C ₃-C ₆ cycloalkyl), from three to five carbon atoms (C ₃-C ₅ cycloalkyl), or three to four carbon atoms (C ₃-C ₄ cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5 - to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and

7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF ₃, -OH, -OMe, -NH ₂, or -N0 ₂. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. [0019] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0020] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0021] "Heterocycloalkyl" refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl,

decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,

1-oxo-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-l,3- dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF ₃, -OH, -OMe, -NH ₂, or -N0 ₂. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0022] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-C ₆ heteroalkyl. Unless stated otherwise specifically in the specification, a Heteroalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃, -OH, -OMe, -NH ₂, or -N0 ₂. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0023] "Heteroaryl" refers to a 5 - to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5 - to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl

(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl -lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF ₃, -OH, -OMe, -NH ₂, or -N0 ₂. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0024] The terms "treat," "prevent," "ameliorate," and "inhibit," as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease. Also, for purposes herein, "treatment," "prevention," "amelioration," or "inhibition" encompass delaying the onset of the disorder, or a symptom or condition thereof.

[0025] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate "effective" amount in any individual case is determined using techniques, such as a dose escalation study.

Compounds

[0026] Described herein are compounds that are ASKl inhibitors. These compounds, and compositions comprising these compounds, are useful for the treatment of blood diseases, autoimmune disorders, pulmonary disorders, hypertension, inflammatory diseases, fibrotic diseases (such as idiosyncratic pulmonary fibrosis, chronic kidney disease/kidney fibrosis, irritable bowel disease, scleroderma, and liver fibrosis), diabetes, diabetic nephropathy, renal diseases, respiratory diseases, cardiovascular diseases, acute lung injuries, acute or chronic liver diseases, and neurodegenerative diseases.

[0027] Diclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:

(Formula I)

wherein:

Ring A is aryl or heteroaryl;

Ring B is aryl or heteroaryl;

L is a saturated or unsaturated linear aliphatic chain having 4-10 carbon atoms optionally substituted with 1-6 R ⁷, wherein 1, 2, or 3 carbon atoms are optionally replaced with -NR ⁷-, -0-, -S-, -S(=0)-, or - S(=0) ₂-;

X ¹ is N or CR ¹;

X ² is N or CR ²;

X ³ is N or CR ³; each R ¹, R ², and R ³ is independently hydrogen, halogen, -CN, -OR ^a, -SR ^a, -S(=0)R ^b, -N0 ₂, -NR ^cR ^d, - S(=0) ₂R ^d, -NR ^aS(=0) ₂R ^d, -S(=0) ₂NR ^cR ^d, -C(=0)R ^b, -OC(=0)R ^b, -C0 ₂R ^a, -OC0 ₂R ^a, -C(=0)NR ^cR ^d, - OC(=0)NR ^cR ^d, -NR ^aC(=0)NR ^cR ^d, -NR ^aC(=0)R ^b, -NR ^aC(=0)OR ^a, optionally substituted d-C ₆ alkyl, optionally substituted C ₂-C ₆ alkenyl, optionally substituted C ₂-C ₆ alkynyl, optionally substituted Ci-C ₆ heteroalkyl, optionally substituted cycloalkyl, optionally substituted