HMOX1 INDUCERS

1 . A compound represented by structural formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is 5-7 membered monocyclic cycloalkyl, 5-7 membered monocyclic heterocyclyl, 5-6 membered heteroaryl, or phenyl;

X is —S—, —O—, or —NR b —;

when X is —S— and ring A is phenyl, then R is 3-7 membered monocyclic heterocyclyl optionally substituted with one or more groups selected from the group consisting of halo, —CN, —OH, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )hydroxyalkyl, —(C 1 -C 4 )alkoxy, —(C 1 -C 4 )haloalkoxy, and —NR a R a ;

when X is —S— and ring A is 5-7 membered monocyclic cycloalkyl, 5-7 membered monocyclic heterocyclyl, or 5-6 membered heteroaryl; or when X is —O— or —NR b —; then R is —H, —(C 1 -C 4 )alkyl, or —(CH 2 ) i 3-7 membered monocyclic heterocyclyl, wherein the —(C 1 -C 4 )alkyl or 3-7 membered monocyclic heterocyclyl represented by R is optionally substituted with one or more groups selected from the group consisting of halo, —CN, —OH, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )hydroxyalkyl, —(C 1 -C 4 )alkoxy, —(C 1 -C 4 )haloalkoxy, —SO 2 R a , and —NR a R a ;

each R 1 is independently —H, halogen, —(CH 2 ) k COOH, —(CH 2 ) k CO(C 1 -C 4 )alkyl, —(CH 2 ) k COO(C 1 -C 4 )alkyl, —(CH 2 ) p C(═O)NR a R 3 , —CH(CF 3 )NR a R 3 , —C(═NOH)CF 3 , or —CH(CF 3 )OR 3 , wherein the (C 1 -C 4 )alkyl in the group represented by R 1 is optionally substituted with one or more groups selected from the group consisting of halo, —CN, —OH, —(C 1 -C 4 )hydroxyalkyl, —(C 1 -C 4 )alkoxy, —(C 1 -C 4 )haloalkoxy, and —NR a R a ;

each R 2 is independently —H, halo, CN, —(C 1 -C 4 )alkyl, —OH, —(C 1 -C 4 )alkoxy, —COOH, —C(═O)(C 1 -C 4 )alkyl, —C(═O)O(C 1 -C 4 )alkyl, —C(═O)NR a (C 1 -C 4 )alkyl, —NR a R a , 3-6 membered monocyclic cycloalkyl, —O(CH 2 ) i 3-7 membered monocyclic heterocyclyl, 3-7 membered monocyclic heterocyclyl, or 5-6 membered heteroaryl, wherein the —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkoxy, heterocyclyl, or heteroaryl represented by R 2 or in the group represented by R 2 is optionally substituted with one or more groups selected from the group consisting of halo, —CN, —OH, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkoxy, —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )hydroxyalkyl, —(C 1 -C 4 )haloalkoxy, and —NR a R a ;

each R 3 is independently H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, —(CH 2 ) p1 3-7 membered monocyclic heterocyclyl, —(CH 2 ) p1 NH3-7 membered monocyclic heterocyclyl, 5-6 membered heteroaryl, —O(CH 2 ) p2 NR a C(═O)(C 1 -C 4 )alkyl, —(CH 2 ) p2 O(CH 2 ) p2 O(C═O)(C 1 -C 4 )alkyl, or (CH 2 ) p2 NR a C(═O)(C 1 -C 4 )alkyl, wherein the alkyl, alkoxy, heteroaryl, or heterocyclyl represented by R 3 or in the group represented by R 3 is optionally substituted with one or more groups selected from the group consisting of halo, —CN, —OH, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )alkoxy, —(C 1 -C 4 )hydroxyalkyl, —(C 1 -C 4 )haloalkoxy, —(C 1 -C 4 )carboxyalkoxy, —S(O) 2 (C 1 -C 4 )alkyl, —(C 1 -C 4 )hydroxyalkoxy, and —NR a R a ;

each R a is independently —H or —(C 1 -C 4 )alkyl;

each R b is independently —H or —(C 1 -C 4 )alkyl; wherein the —(C 1 -C 4 )alkyl represented by R b is optionally substituted with one or more groups selected from halo, —CN, —OH, —(C 3 -C 6 )cycloalkyl, phenyl, 3-7 membered monocyclic heterocyclyl, and 5-6 membered heteroaryl;

i is 0 or 1;

k is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3, or 4;

p 1 is 0, 1, 2, 3, or 4; and

p 2 is 2, 3, or 4.

2 . The compound of claim 1 , wherein the compound is represented by structural formula (II) or formula (II′):

or a pharmaceutically acceptable salt thereof.

3 . (canceled)

4 . The compound of claim 1 , wherein the compound is represented by structural formula (II-A):

or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 1 , wherein the compound is represented by structural formula (II-B) or formula (II-C):

or a pharmaceutically acceptable salt thereof, wherein R b is —H or —(C 1 -C 4 )alkyl, wherein the —(C 1 -C 4 )alkyl represented by R b is optionally substituted with one or more groups selected from halo, —CN, and —OH.

6 - 8 . (canceled)

9 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R is —(C 1 -C 4 )alkyl optionally substituted with —(C 1 -C 4 )alkoxy; or —(CH 2 ) i 3-6 membered monocyclic heterocyclyl optionally substituted with one or more groups selected from the group consisting of halo, —CN, —OH, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )hydroxyalkyl, —(C 1 -C 4 )alkoxy, —(C 1 -C 4 )haloalkoxy, and —NR a R a .

10 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R is azetidinyl, azepanyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which is optionally substituted with one or more groups selected from the group consisting of halo, —OH, —(C 1 -C 4 )alkyl, and —NH 2 .

11 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein

R 1 is —(CH 2 ) k COOH, —(CH 2 ) k CO(C 1 -C 4 )alkyl optionally substituted with halo, —(CH 2 ) p C(═O)NR a R 3 , —C(═NOH)CF 3 , or —CH(CF 3 )NR a R 3 ; and

R 2 is H; halogen; CN; —(C 1 -C 4 )alkyl optionally substituted with halo; —(C 1 -C 4 )alkoxy optionally substituted with halo, hydroxy, methoxy, or ethoxy; —C(═O)(C 1 -C 4 )alkyl; 3-4 membered monocyclic cycloalkyl; —O(CH 2 ) i 3-7 membered monocyclic heterocyclyl, 3-7 membered monocyclic heterocyclyl, or 5-6 membered heteroaryl, wherein the heterocyclyl, or heteroaryl represented by R 2 or in the group represented by R 2 is optionally substituted with halo, hydroxy, or —(C 1 -C 4 )alkoxy.

12 . (canceled)

13 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R is —(C 1 -C 4 )alkyl optionally substituted with methoxy or —SO 2 CH 3 ; —(CH 2 )tetrohydrofuranyl; —(CH 2 )oxetanyl optionally substituted with hydroxy; pyrrolidinyl; piperidinyl; or tetrahydropyranyl; wherein the pyrrolidinyl or piperidinyl is optionally substituted with —(C 1 -C 4 )alkyl.

14 . The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein

R 1 is —COOH, —C(═O)CF 3 , —CH(CF 3 )(NH 2 ), —C(═NOH)CF 3 , or —C(═O)NHR 3 ;

R 3 is (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (CH 2 ) p1 3-6 membered monocyclic heterocyclyl, or (CH 2 ) p2 NHC(═O)(C 1 -C 4 )alkyl, wherein the alkyl, alkoxy, or heterocyclyl represented by R 3 or in the group represented by R 3 is optionally substituted with one or more groups selected from the group consisting of halo, —OH, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )hydroxyalkyl, —(C 1 -C 4 )alkoxy, —(C 1 -C 4 )haloalkoxy, —S(O) 2 (C 1 -C 4 )alkyl, —(C 1 -C 4 )hydroxyalkoxy, and —NR a R a ; and

R 2 is H; halogen; CN; —(C 1 -C 4 )alkyl optionally substituted with halo; —(C 1 -C 4 )alkoxy optionally substituted with halo, hydroxy, methoxy, or ethoxy; —C(═O)(C 1 -C 4 )alkyl; cyclopropyl; O-tetrahydropyranyl; N-pyrolidinyl; or thiazolyl.

15 - 16 . (canceled)

17 . The compound of claim 5 , wherein the compound is represented by structural formula (III-B):

or a pharmaceutically acceptable salt thereof.

18 . The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein

R 1 is —COOH or —C(═O)NHR 3 ,

R 3 is —(C 1 -C 4 )alkyl, -hydroxy(C 1 -C 4 )alkyl, -methoxy(C 1 -C 4 )alkyl, -amino(C 1 -C 4 )alkyl, —(C 1 -C 4 )hydroxyalkoxy(C 1 -C 4 )alkyl, or —(CH 2 ) p2 NHC(═O)(dimethylamino(C 1 -C 4 )alkyl); and

R 2 is H, halo, —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )haloalkoxy, —(C 1 -C 4 )alkoxy optionally substituted with methoxy, or —N-pyrrolidinyl.

19 - 20 . (canceled)

21 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein

R 2 is H, R 1 is —C(═O)NH(C 1 -C 4 )alkyl optionally substituted with —OH, NH 2 , oxetanyl, or —(C 1 -C 4 )hydroxyalkoxy; or —C(═O)NH(CH 2 ) p2 NHC(═O)(dimethylamino(C 1 -C 4 )alkyl); or

R 2 is F, R 1 is —C(═O)NH(methoxy(C 1 -C 4 )alkyl); or

R 2 is —N-pyrrolidinyl, R 1 is —C(═O)NH((C 1 -C 4 )hydroxyalkoxy(C 1 -C 4 )alkyl), or

R 2 is CF 3 , OCHF 2 , or OCF 3 , R 1 is —COOH; or

R 2 is OCH 2 CH 2 OCH 3 , R 1 is —C(═O)NH((C 1 -C 4 )hydroxyalkoxy(C 1 -C 4 )alkyl), —C(═O)NH(hydroxy(C 1 -C 4 )alkyl), —C(═O)NH(methoxy(C 1 -C 4 )alkyl), or —C(═O)NH(hydroxy(C 1 -C 4 )alkoxy).

22 . The compound of 14 , or a pharmaceutically acceptable salt thereof, wherein

R 1 is —C(═O)NH(C 1 -C 4 )alkyl optionally substituted with —OH, NH 2 , —(C 1 -C 4 )— alkoxy, or —(C 1 -C 4 )hydroxyalkoxy, and

R 2 is H, or OCH 2 CH 2 OCH 3 .

23 . The compound of 22 , or a pharmaceutically acceptable salt thereof, wherein

(i) R 2 is H and R 1 is —C(═O)NH(C 1 -C 4 )alkyl substituted with —(C 1 -C 4 )hydroxyalkoxy; or

(ii) R 2 is OCH 2 CH 2 OCH 3 and R 1 is —C(═O)NH(C 1 -C 4 )alkyl substituted with —(C 1 -C 4 )alkoxy.

24 - 26 . (canceled)

27 . The compound of 26 , wherein the compound is: 2-((6-(2-methoxyethoxy)benzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide or a pharmaceutically acceptable salt thereof.

28 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is

29 . (canceled)

30 . A method of increasing the activity of or the amount of HMOX-1 in a human subject comprising: administering to a human subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

31 . A method of activating transcription factor Nrf2 in a human subject comprising: administering to a human subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

32 . A method of reducing the amount of ROS in a human subject comprising: administering to a human subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

33 . A method of treating a disease, disorder, or condition comprising administering to a human subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 1 or a pharmaceutically acceptable salt thereof wherein the disease, disorder, or condition is: (i) a fibrotic disease, including a fibrotic disease of the lung, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, sarcoidosis, a fibrotic disease of the liver including those caused by alcoholic cirrhosis, steatosis, cholestasis, drug side effect, and viral infection, a fibrotic diseases of the skin, scleroderma, or psoriasis; (ii) a neurodegenerative disease, including Friedreich's ataxia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, cerebral nerve degenerative disease, or Charcot-Marie-Tooth syndrome; (iii) a cardiovascular disease, including hypertension, hypercholesterolaemia, atherosclerosis, arteriosclerosis, thrombosis, acute coronary thrombosis, deep vein thrombosis, peripheral vascular disease, congestive heart failure, acute coronary syndrome, failure of arterial fistula for dialysis, ischemia-reperfusion injury, primary pulmonary hypertension, primary pulmonary arterial hypertension, or secondary pulmonary arterial hypertension; (iv) a renal disease, including acute kidney injury, polycystic kidney disease, Alport syndrome, diabetic nephropathy, glomerular nephritis, lupus nephritis, sickle cell nephropathy, and acute tubular necrosis; (v) an inflammatory disease, including asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, inflammatory bowel syndrome, Crohn's disease, celiac disease, ulcerative colitis, chronic inflammatory bowel disease, scleroderma, dermatitis, systemic lupus erythematosus, esophagitis, vasculitis, pancreatitis, tendonitis, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, or chronic inflammation of the brain; (vi) a liver disease, including drug induced liver toxicity, nonalcoholic steatohepatitis, hepatitis B infection, or hepatitis C infection; (vii) an eye disease, including conjunctivitis, glaucoma, uveitis, an eye wound, eye trauma, corneal grafts, Fuchs' endothelial corneal dystrophy, macular degeneration, cataracts, light retinopathy, retinitis pigmentosa, diabetic retinopathy, and retinopathy of prematurity; (viii) a thyroid disease, including Graves' disease, follicular adenoma, or papillary and follicular carcinomas; (ix) a viral infection, including infections from human immunodeficiency virus, hepatitis B, hepatitis C, or herpesvirus; (x) osteoporosis; (xi) a pregnancy disorder; (xii) endometriosis; (xiii) diabetes, including type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes, pre-diabetes, hyperglycemia, metabolic syndrome, or a secondary condition resulting from a diabetic condition; (xiv) cancer; (xv) a skin disease, including dermatitis, scleroderma, or psoriasis; (xvi) a mitochondrial diseases such as mitochondrial myopathies, Leber's hereditary optic neuropathy (LHON), myoclonic epilepsy with ragged red fibers (MERFF), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) or Leigh's Syndrome; (xvii) a hematological disorder such as Diamond Blackfan anemia, myelodysplasic syndrome, sickle cell disease and beta-thalessemia; or (xviii) a muscle diseases, such as Duchenne muscular dystrophy, limb girdle muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy and rhabdomyolysis.

34 .- 36 . (canceled)

37 . A method of treating sickle cell disease, comprising administering to a human subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 1 or a pharmaceutically acceptable salt thereof.