IP Library › Granted Patent US 10,898,475

Granted Patent B2

US 10,898,475 · App. 16/582,499 · Granted Jan 26, 2021

Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof

Inventor: Otis Clinton Attucks (Winston-Salem, NC)

Assignee: vTv Therapeutics LLC

A61K31/437 A61K31/428 A61K31/56 Y02A50/30

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Quick Facts

Patent No.: US 10,898,475
App. No.: 16/582,499
Granted: Jan 26, 2021
Kind: B2

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Abstract

The disclosure provides pharmaceutical compositions comprising Bach1 Inhibitors and Nrf2 Activators. The disclosure also provides methods of treating diseases such as non-alcoholic steatohepatitis comprising administering a Bach1 Inhibitor and a Nrf2 Activator to a subject in need thereof.

Claims (354)

1. A method of treating non-alcoholic steatohepatitis comprising administering an Nrf2 activator and a Bach1 Inhibitor to a subject in need thereof,

wherein the Bach1 Inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof,

wherein

X 1 is ═N— or ═CH—;

G is hydrogen, —C 1-8 alkyl, —C 3-10 cycloalkyl, —C 1-6 alkylene-C 3-10 cycloaklyl, heterocyclyl, —C 1-6 alkylene-C 3-10 heterocyclyl, phenyl, heteroaryl, or NR h R k , where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R c ; or

G is —CH 2 Y 3 , —CH 2 CH 2 Y 3 , —CH 2 CH 2 CH 2 Y 3 , —CH(CH 3 )CH 2 Y 3 , —CH 2 CH(Y 3 )CH 3 , —CH(Y 3 )CH 3 , —CH 2 C(Y 3 )(CH 3 ) 2 , —C(Y 3 )(CH 3 ) 2 , or

where Y 3 is cyclopropyl, —CF 3 , —OCF 3 , —OCH 3 , —OCH 2 CH 3 , —F, —Cl, —OH, —O(CH 2 ) 2 —OH, —O(CH 2 ) 2 —F, —SCH 3 , —S(O) 2 —CH 3 , —SCH 2 CH 3 , —S(O) 2 CH 2 CH 3 , —NH—CH 3 , —NH—CH 2 CH 3 , —N(CH 3 ) 2 , tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, —NH—C(O)—CH 3 , —NH—C(O)—CH 2 CH 3 , tetrahydrofuran-2-yl-methyloxy, or —C(O)—Y 4 , where Y 4 is —OH, —OCH 3 , —OCH 2 CH 3 , —OC(CH 3 ) 3 , —NH 2 , —NH—CH 3 , —NH—CH 2 CH 3 , —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl;

L is —CH 2 —C(O)N(R 6 )—, —C(O)N(R 6 )—, —C(O)—O—, —SO 2 —, —C(O)—, heteroarylene optionally substituted one or more times with substituents independently selected from R x , or heterocyclylene optionally substituted one or more times with substituents independently selected from R x ; or the group -L-G is -cyano;

R 1 is hydrogen, R a , phenyl, or heteroaryl, where the phenyl and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R x ;

R 2 is R b ;

R 3 is hydrogen, —C 1-6 alkyl, or —C 1-6 alkylene-C 3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R z ;

R 4 is —C 1-6 alkyl or —C 1-6 alkylene-C 3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R y ;

R 6 is hydrogen, —C 1-6 alkyl, —C 1-6 alkylene-C 3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R x ;

R a is

a) -halogen,

b) —C 1-6 alkyl,

c) —C 3-10 cycloalkyl,

d) -heterocyclyl,

e) -cyano,

f) —CF 3 ,

g) —OCF 3 ,

h) —O—R d ,

i) —S(O) w —R d ,

j) —S(O) 2 O—R d ,

k) —NR d R e ,

l) —C(O)—R d ,

m) —C(O)—O—R d ,

n) —OC(O)—R d ,

o) —C(O)NR d R e ,

p) —C(O)-heterocyclyl,

q) —NR d C(O)R e ,

r) —OC(O)NR d R e ,

s) —NR d C(O)OR d , or

t) —NR d C(O)NR d R e ,

where the alkyl, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from R y ;

R b is

a) -halogen,

b) —C 1-6 alkyl,

c) —C 3-10 cycloalkyl,

d) -heterocyclyl,

e) -phenyl,

f) -heteroaryl,

g) -cyano,

h) —CF 3 ,

i) —OCF 3 ,

j) —O—R f ,

k) —S(O) w —R f ,

l) —S(O) 2 O—R f ,

m) —NR f R g ,

n) —C(O)—R f ,

o) —C(O)—O—R f ,

p) —OC(O)—R f ,

q) —C(O)NR f R g ,

r) —C(O)-heterocyclyl,

s) —NR f C(O)R g ,

t) —OC(O)NR f R g ,

u) —NR f C(O)OR f , or

v) —NR f C(O)NR f R g ,

where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R z ;

R c is

a) -halogen,

b) —C 1-6 alkyl,

c) —C 3-10 cycloalkyl,

d) -heterocyclyl,

e) -cyano,

f) —CF 3 ,

g) —OCF 3 ,

h) —O—R h ,

i) —S(O) w —R h ,

j) —S(O) 2 O—R h ,

k) —NR h R k ,

l) —C(O)—R h ,

m) —C(O)—O—R h ,

n) —OC(O)—R h ,

o) —C(O)NR h R k ,

p) —C(O)-heterocyclyl,

q) —NR h C(O)R k ,

r) —OC(O)NR h R k ,

s) —NR h C(O)OR k ,

t) —NR h C(O)NR h R k ,

u) —NR h S(O) w R k ,

v) -phenyl,

w) -heteroaryl, or

x) —O—(C 1-4 alkylene)-O—(C 1-4 alkylene)-N(R h )C(O)—OR k ,

where the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R x ;

R d and R e are independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl, where the alkyl and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R y ; or, if R d and R e are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from R y ;

R f and R g are independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R z ; or, if R f and R g are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from R z ;

R h and R k are independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R x ; or, if R h and R k are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from R x ;

R y is

a) -halogen,

b) —NH 2 ,

c) -cyano,

d) -carboxy,

e) -hydroxy,

f) -thiol,

g) —CF 3 ,

h) —OCF 3 ,

i) —C(O)—NH 2 ,

j) —S(O) 2 —NH 2 ,

k) oxo,

l) —C 1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

m) -heterocyclyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

n) —C 3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

o) —O—C 1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

p) —O—C 3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

q) —NH—C 1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

r) —N(C 1-6 alkyl) 2 optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

s) —C(O)—C 1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

t) —C(O)—O—C 1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

u) —S—C 1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

v) —S(O) 2 —C 1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

w) —C(O)—NH—C 1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

x) —C(O)—N(C 1-6 alkyl) 2 , optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

y) —S(O) 2 —NH—C 1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

z) —S(O) 2 —N(C 1-6 alkyl) 2 , optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

aa) —NH—C(O)—C 1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 , or

bb) —NH—S(O) 2 —C 1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ;

R x is

a) —R y

b) -phenyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

c) -heteroaryl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

d) —O-phenyl,

e) —O-heteroaryl,

f) —C(O)-phenyl,

g) —C(O)-heteroaryl,

h) —C(O)—O-phenyl, or

i) —C(O)—O-heteroaryl;

R z is

a) —R y

b) -phenyl,

c) -heteroaryl;

d) —O-phenyl,

e) —O-heteroaryl,

f) —C(O)-phenyl,

g) —C(O)-heteroaryl,

h) —C(O)—O-phenyl, or

i) —C(O)—O-heteroaryl;

v is an integer from 0 to 4, and

w is an integer from 0 to 2.

2. The method of claim 1 , wherein the Nrf2 Activator is selected from the group consisting of: 2-trifluoromethyl-2′-methoxychalcone, auranofin, ebselen, 1,2-naphthoquinone, cynnamic aldehyde, caffeic acid, curcumin, reservatrol, artesunate, tert-butylhydroquinone, and -quinone, (tBHQ, tBQ), vitamins K1, K2 and K3, menadione, monoalkyl hydrogen fumarate, dialkyl fumarate, 2-cyclopentenones, ethacrynic acid and its alkyl esters, bardoxolone methyl (methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate) (CDDO-Me), ethyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oic acid (CDDO), 1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), (2-cyano-N-methyl-3,12-dioxooleana-1,9(11)-dien-28 amide (CDDO-methyl amide, CDDO-MA), sulforaphane, oltipraz, 3,5-di-tert-butyl-4-hydroxytoluene, 3-hydroxycoumarin, 4-hydroxynonenal, 4-oxononenal, malondialdehyde, (E)-2-hexenal, capsaicin, allicin, allylisothiocyanate, 6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate, 8-methylthiooctyl isothiocyanate, dexamethasone, 8-iso prostaglandin A2, methyl and ethyl pyruvate, diethyl or dimethyl oxaloproprionate, 2-acetamidoacrylate, methyl or ethyl-2-acetamidoacrylate, hypoestoxide, parthenolide, eriodictyol, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, geranial, zerumbone, aurone, isoliquiritigenin, xanthohumol, [10]-Shogaol, eugenol, 1′-acetoxychavicol acetate, allyl isothiocyanate, benzyl isothiocyanate, phenethyl isothiocyanate, 4-(methylthio)-3-butenyl isothiocyanate, 6-methylsulfinylhexyl isothiocyanate, ferulic acid ferulic acid ethyl ester, ferulic acid methyl ester, sofalcone, 4-methyl daphnetin, imperatorin, auraptene, poncimarin, bis[2-hydroxybenzylidene]acetones, alicylcurcuminoid, 4-bromo flavone, β-naphthoflavone, sappanone A, benzylidene-indolin-2-ones, perillaldehyde, quercetin, fisetin, koparin, genistein, tanshinone HA, BHA, BHT, avicin D, gedunin, fisetin, andrographolide, and tricyclic bis(cyano enone) TBE-31 [(+/−)-(4b S,8aR,10aS)-10a-ethynyl-4-b,8,8-trimethyl-3,7-dioxo-3,4-b,7,8,-8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile].

3. The method of claim 1 , wherein the Nrf2 activator is a selected from the group consisting of monomethyl hydrogen fumarate, dimethyl fumarate (DMF), monoethyl hydrogen fumarate, and diethyl fumarate.

4. The method of claim 1 , wherein the Nrf2 activator is methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate.

5. The method of claim 1 , wherein the Bach1 Inhibitor is a compound selected from the group consisting of:

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl amino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl amino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl amino)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl amino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-2-methyl-propyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide;

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide;

6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ethylamide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-fluoro-ethoxy)-ethyl]-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((S)-2-hydroxy-propyl)-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl amino)-1H-benzoimidazole-5-carboxylic acid ((R)-2-hydroxy-propyl)-amide;

6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl amino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide;

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (2-ethanesulfonyl-ethyl)-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (3-methanesulfonyl-propyl)-amide;

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl amino)-1H-benzoimidazole-5-carboxylic acid ((S)-1-dimethylcarbamoyl-ethyl)-amide;

1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide;

1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide;

2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (2-fluoro-ethyl)-amide;

2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((R)-2-hydroxy-propyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((S)-2-hydroxy-propyl)-amide;

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl amino)-1H-benzoimidazole-5-carboxylic acid [2-(2-methoxy-ethoxy)-ethyl]-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-methoxy-ethoxy)-ethyl]-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl amino)-1H-benzoimidazole-5-carboxylic acid [2-(2-dimethylamino-ethoxy)-ethyl]-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide;

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (3-morpholin-4-yl-3-oxo-propyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylcarbamoylmethyl-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((R)-3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-((R)-3-methoxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-((S)-3-methoxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((S)-3-methoxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((R)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((S)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-2-oxo-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((R)-3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((S)-3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid ((S)-1-dimethylcarbamoyl-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((S)-1-dimethylcarbamoyl-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((S)-1-methyl-2-morpholin-4-yl-2-oxo-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((R)-1-dimethylcarbamoyl-ethyl)-amide; and

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [(R)-1-methyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 , wherein the Bach1 Inhibitor is:

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl amino)-1H-benzoimidazole-5-carboxylic acid methyl amide or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the Bach1 Inhibitor is:

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the Bach1 Inhibitor is:

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , wherein the Bach1 Inhibitor is

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-methoxy-ethyl)-amide or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the Bach1 Inhibitor is

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid dimethylcarbamoylmethyl-amide or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the Bach1 Inhibitor is

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-morpholin-4-yl-ethyl)-amide or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein the Bach1 Inhibitor is

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-hydroxy-propyl)-amide or a pharmaceutically acceptable salt thereof.

13. A method of treating non-alcoholic steatohepatitis comprising administering an Nrf2 activator and a Bach1 Inhibitor to a subject in need thereof,

wherein the Bach1 Inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof,

wherein

X 1 is ═N— or ═CH—;

G is hydrogen, —C 1-8 alkyl, —C 3-10 cycloalkyl, —C 1-6 alkylene-C 3-8 cycloaklyl, heterocyclyl, or NR h R k , where the alkyl, alkylene, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from R c ; or G is —CH 2 Y 3 , —CH 2 CH 2 Y 3 , —CH 2 CH 2 CH 2 Y 3 , —CH(CH 3 )CH 2 Y 3 , —CH 2 CH(Y 3 )CH 3 , —CH(Y 3 )CH 3 , —CH 2 C(Y 3 )(CH 3 ) 2 , —C(Y 3 )(CH 3 ) 2 , or

where Y 3 is -cyclopropyl, —CF 3 , —OCF 3 , —OCH 3 , —OCH 2 CH 3 , —F, —Cl, —OH, —O(CH 2 ) 2 —OH, —O(CH 2 ) 2 —F, —SCH 3 , —S(O) 2 —CH 3 , —SCH 2 CH 3 , —S(O) 2 CH 2 CH 3 , —NH—CH 3 , —NH—CH 2 CH 3 , —N(CH 3 ) 2 , tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, —NH—C(O)—CH 3 , —NH—C(O)—CH 2 CH 3 , tetrahydrofuran-2-yl-methyloxy, or —C(O)—Y 4 , where Y 4 is —OH, —OCH 3 , —OCH 2 CH 3 , —OC(CH 3 ) 3 , —NH 2 , —NH—CH 3 , —NH—CH 2 CH 3 , —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl;

L is —C(O)N(R 6 )—;

R 1 is hydrogen;

R 2 is is -halogen, -methyl, —CF 3 , —OCF 3 , —SCF 3 , —O-heteroaryl, or —S(O) 2 —CH 3 , and R 2 is attached at either the 5-position or the 6-position of the benzothiazole ring;

R 3 is hydrogen;

R 4 is -methyl, -ethyl, -isopropyl, -isobutyl, —CH 2 CH 2 —OCH 3 , —CH 2 CH 2 —F, or —CH 2 CH 2 —NH 2 ;

R 6 is hydrogen;

R c is

a) -halogen,

b) —C 1-6 alkyl,

c) —C 3-10 cycloalkyl,

d) -heterocyclyl,

e) -cyano,

f) —CF 3 ,

g) —OCF 3 ,

h) —O—R h ,

i) —S(O) w —R h ,

j) —S(O) 2 O—R h ,

k) —NR h R k ,

l) —C(O)—R h ,

m) —C(O)—O—R h ,

n) —OC(O)—R h ,

o) —C(O)NR h R k ,

p) —C(O)-heterocyclyl,

q) —NR h C(O)R k ,

r) —OC(O)NR h R k ,

s) —NR h C(O)OR k ,

t) —NR h C(O)NR h R k , or

u) —O—(C 1-4 alkylene)-O—(C 1-4 alkylene)-N(R h )C(O)—OR k ,

where the alkylene, alkyl, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from R x ;

R h and R k are independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl, where the alkyl, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R x ; or, if R h and R k are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from R x ; and

R x is R y ;

R y is

a) -halogen,

b) —NH 2 ,

c) -cyano,

d) -carboxy,

e) -hydroxy,

f) -thiol,

g) —CF 3 ,

h) —OCF 3 ,

i) —C(O)—NH 2 ,

j) —S(O) 2 —NH 2 ,

k) oxo,

m) -heterocyclyl optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

n) —C 3-10 cycloalkyl optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

o) —O—C 1-6 alkyl optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

v is 1; and

w is an integer from 0 to 2.

14. The method of claim 13 , wherein

G is —CH 2 —R c , —CH 2 CH 2 —R c , —CH 2 CH 2 CH 2 —R c , —CH(CH 3 )CH 2 R c , —CH 2 CH(R c )CH 3 , —CH(R c )CH 3 , or —CH 2 C(R c )(CH 3 ) 2 .

15. The method of claim 13 , wherein

G is —CH 2 —C(O)—NR h R k , where NR h R k is 3-hydroxy-pyrrolidino, 3-(dimethyl-amino)-pyrrolidino, morpholino, 4-hydroxy-piperidino, 4-methoxy-piperidino, 4-(hydroxymethyl)-piperidino, 3-hydroxy-piperidino, 3-methoxy-piperidino, 3-(hydroxymethyl)-piperidino, 4,4-difluoropiperidino, or dimethylamino.

16. The method of claim 13 , wherein

G is —(CH 2 ) 2 —NR h R k , —(CH 2 ) 3 —NR h R k , or —(CH 2 ) 4 —NR h R k .

17. The method of claim 13 , wherein the Nrf2 Activator is selected from the group consisting of: 2-trifluoromethyl-2′-methoxychalcone, auranofin, ebselen, 1,2-naphthoquinone, cynnamic aldehyde, caffeic acid, curcumin, reservatrol, artesunate, tert-butylhydroquinone, and -quinone, (tBHQ, tBQ), vitamins K1, K2 and K3, menadione, monoalkyl hydrogen fumarate, dialkyl fumarate, 2-cyclopentenones, ethacrynic acid and its alkyl esters, bardoxolone methyl (methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate) (CDDO-Me), ethyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oic acid (CDDO), 1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), (2-cyano-N-methyl-3,12-dioxooleana-1,9(11)-dien-28 amide (CDDO-methyl amide, CDDO-MA), sulforaphane, oltipraz, 3,5-di-tert-butyl-4-hydroxytoluene, 3-hydroxycoumarin, 4-hydroxynonenal, 4-oxononenal, malondialdehyde, (E)-2-hexenal, capsaicin, allicin, allylisothiocyanate, 6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate, 8-methylthiooctyl isothiocyanate, dexamethasone, 8-iso prostaglandin A2, methyl and ethyl pyruvate, diethyl or dimethyl oxaloproprionate, 2-acetamidoacrylate, methyl or ethyl-2-acetamidoacrylate, hypoestoxide, parthenolide, eriodictyol, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, geranial, zerumbone, aurone, isoliquiritigenin, xanthohumol, [10]-Shogaol, eugenol, 1′-acetoxychavicol acetate, allyl isothiocyanate, benzyl isothiocyanate, phenethyl isothiocyanate, 4-(methylthio)-3-butenyl isothiocyanate, 6-methylsulfinylhexyl isothiocyanate, ferulic acid ferulic acid ethyl ester, ferulic acid methyl ester, sofalcone, 4-methyl daphnetin, imperatorin, auraptene, poncimarin, bis[2-hydroxybenzylidene]acetones, alicylcurcuminoid, 4-bromo flavone, β-naphthoflavone, sappanone A, benzylidene-indolin-2-ones, perillaldehyde, quercetin, fisetin, koparin, genistein, tanshinone HA, BHA, BHT, avicin D, gedunin, fisetin, andrographolide, and tricyclic bis(cyano enone) TBE-31 [(+/−)-(4b S,8aR,10aS)-10a-ethynyl-4-b,8,8-trimethyl-3,7-dioxo-3,4-b,7,8,-8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile].

18. A method of treating non-alcoholic steatohepatitis comprising administering an Nrf2 activator and a Bach1 Inhibitor to a subject in need thereof,

wherein the Nrf2 Activator is selected from the group consisting of: monomethyl hydrogen fumarate, dimethyl fumarate (DMF), monoethyl hydrogen fumarate, and diethyl fumarate, bardoxolone methyl (methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate) (CDDO-Me), ethyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oic acid (CDDO), 1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), and (2-cyano-N-methyl-3,12-dioxooleana-1,9(11)-dien-28 amide (CDDO-methyl amide, CDDO-MA), and

wherein the Bach1 Inhibitor is selected from the group consisting of: