# US 11,078,216 B2 · Bisaryl amides as NRF2 activators

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- Number: US 11,078,216 B2
- Document ID: US11078216B2
- Status: Granted
- Kind: B2
- Application number: 16/467,538
- Filed: 2017-12-11
- Published: 2019-10-31
- Granted: 2021-08-03
- Earliest claimed: 2016-12-14
- Assignees: GlaxoSmithKline Intellectual Property Development Limited
- Applicants: Glaxosmithkline Intellectual Property Development Limited
- Inventors: James Francis Callahan; Vincent J. Colandrea; Anthony William James Cooper; Nicole Cathleen Goodwin; Chelsea Ariane Huff; Joel Karpiak; Jeffrey K. Kerns; Hong Nie
- Web page: https://patentgrep.com/patent/US11078216B2

## CPC

- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- C07D 515/04: Ortho-condensed systems
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/06: Antipsoriatics
- A61P 35/00: Antineoplastic agents
- C07D 401/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 498/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to bisaryl amide analogs, pharmaceutical compositions containing them and their use as NRF2 activators. In particular, the invention relates to bisaryl heterocycles of Formula (I),

## Claims

### Claim 1

A compound of Formula (I)
wherein:
B is benzotriazolyl, phenyl, triazolopyridinyl, —O—(CH2)-triazolyl, or —(CH2)2-triazolyl, wherein each of benzotriazolyl, phenyl, triazolopyridinyl, —O—(CH2)-triazolyl, or —(CH2)2-triazolyl is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl, —C3-7cycloalkyl, —O—C1-3alkyl, —CN, —(CH2)2—O—(CH2)2—OR3 and halo;
D is —C(O)—NR4R5, —NR4—C(O)—R5, —NR3—C(O)—NR4R5, or —NR4—C(O)—O—R5;
R1 is hydrogen, —C1-3alkyl, F, oxetanyl, or the two R1 groups together with the carbon to which they are attached form a cyclopropyl group;
R2 is hydrogen, methyl, —CF3, or halo;
R3 is hydrogen or —C1-5alkyl;
R4 is hydrogen or —C1-5alkyl;
R5 is hydrogen, —C1-5alkyl, —C3-7cycloalkyl, —C4-8heterocycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-NH—C(O)R3, —C1-3alkyl-SO2C1-3alkyl, —C1-3alkyl-C4-8heterocycloalkyl, —C1-3alkyl-C(O)NR3R4, aryl, —C1-5alkylheteroaryl, or heteroaryl, wherein each of —C1-5alkyl, —C3-7cycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-C(O)NR3R4, aryl, —C1-5alkylheteroaryl, or heteroaryl is unsubstituted or substituted by one or two substituents independently selected from —C1-3alkyl, —C1-3alkylaryl, —C1-3alkylheteroaryl, aryl, —C1-3alkylC(O)R3, —C1-3alkylC(O)OH, —C1-3alkylNHC(O)OR4, —C1-3alkylOSi(R3)3, —C1-3alkylOH, —C1-3alkylNH2, —SCH3, —C4-8heterocycloalkyl (optionally substituted with R3), —NH—(CH2)n-CH—(OH)2, —O—CH2—CH—(NH2)—CH2—OH, —SO2R3, —SO2NR3R4, —OH, —C1-3alkoxy, oxo, —CO2H, —C(O)NR3R4, —C(O)OR3, —NH—C(O)—C1-3alkyl, F, Cl, —CN, —CH—F2, —CF3, —(CH2)n—O—(CH2)m—CH3, —O(CH2)n—OH, —O(CH2)nC(O)OR3, —O(CH2)nOR3, —O(CH2)nNHC(O)OR3, —O(CH2)nNH2, —C3-7cycloalkyl, and a 5-6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from O, N and S;
or R4 and R5 together with the nitrogen atom to which they are attached form a 5-8-membered heterocyclic ring, an 8-11-membered bicyclic heterocyclic ring or a 9-10-membered bridged bicyclic heterocyclic ring, wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally includes one —C(O) or one —S(O)2, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally independently contains one, two or three oxygen ring atoms, one, two or three sulfur ring atoms or one, two or three nitrogen ring atoms, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring is unsubstituted or substituted by one, two or three substituents independently selected from —C1-5alkyl, —C3-7cycloalkyl, —C4-7heterocycloalkyl, —(CH2)phenyl, halogen, —NR3R4, —CHF2, —CF3, and —(CH2)n—O—(CH2)m—CH3;
Linker is —CH2—, —CH2—N(-cyclopropyl)-CH2—, —CH2—N(CH3)—CH2— or —N—(CH3)—CH2—;
A is
Y is independently selected from N or CH;
Z is O or CH2;
R6 is independently selected from hydrogen or —C1-4alkyl;
wherein A is unsubstituted or substituted with one, two or three substituents independently selected from halo, —CF3, —C1-4alkyl, —CN, —OMe, —C(O)NH2, —OCF3, —C1-4alkylNR8R9;
R8 is hydrogen or —C1-4alkyl;
R9 is —C1-3alkyl, aryl, heteroaryl, —C(O)C1-3alkyl, —SO2C1-3alkyl, —C(O)aryl, —C(O)heteroaryl, —SO2aryl, —SO2heteroaryl, —C3-7cycloalkyl, —C1-3alkylC3-7cycloalkyl, —C1-3alkylC3-7heterocycloalkyl, —C1-3alkylheteroaryl or —C1-3alkylaryl, wherein each of —C1-3alkyl, aryl, heteroaryl, —C(O)C1-3alkyl, —SO2C1-3alkyl, —C(O)aryl, —C(O)heteroaryl, —SO2aryl, —SO2heteroaryl, —C3-7cycloalkyl, —C1-3alkylC3-7cycloalkyl, —C1-3alkylC3-7heterocycloalkyl, —C1-3alkylheteroaryl or —C1-3alkylaryl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo, —CN, —CF3, —OCF3, —OCH3, —C1-3alkyl, —OC1-3alkyl, —OC3-7cycloalkyl, —OC3-7hetercycloalkyl, —O-aryl and —O-heteroaryl;
X is independently CH or N;
m is 1, 2 or 3; and
n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein:
B is benzotriazolyl or —(CH2)2 triazolyl, wherein each of benzotriazolyl or —(CH2)2 triazolyl is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl and halo;
D is —C(O)—NR4R5;
R1 is hydrogen;
R2 is methyl or halo;
R4 is hydrogen;
R5 is hydrogen, —C1-5alkyl, —C3-7cycloalkyl, —C4-8heterocycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-NH—C(O)R3, —C1-3alkyl-SO2C1-3alkyl, —C1-3alkyl-C4-8heterocycloalkyl, —C1-3alkyl-C(O)NR3R4, aryl, —C1-5alkylheteroaryl, or heteroaryl, wherein each of —C1-5alkyl, —C3-7cycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-C(O)NR3R4, aryl, —C1-5alkylheteroaryl, or heteroaryl is unsubstituted or substituted by one or two substituents independently selected from —C1-3alkyl, —C1-3alkylaryl, —C1-3alkylheteroaryl, aryl, —C1-3alkylC(O)R3, —C1-3alkylC(O)OH, —C1-3alkylNHC(O)OR4, —C1-3alkylOSi(R3)3, —C1-3alkylOH, —C1-3alkylNH2, —SCH3, —C4-8heterocycloalkyl (optionally substituted with R3), —NH—(CH2)n-CH—(OH)2, —O—CH2—CH—(NH2)—CH2—OH, —SO2R3, —SO2NR3R4, —OH, —C1-3alkoxy, oxo, —CO2H, —C(O)NR3R4,—C(O)OR3, —NH—C(O)—C1-3alkyl, F, Cl, —CN, —CH—F2, —CF3, —(CH2)n—O—(CH2)m—CH3, —O(CH2)n—OH, —O(CH2)nC(O)OR3, —O(CH2)nOR3, —O(CH2)nNHC(O)OR3, —O(CH2)nNH2, —C3-7cycloalkyl, and a 5-6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from O, N and S;
or R4 and R5 together with the nitrogen atom to which they are attached form a 5-8-membered heterocyclic ring, an 8-11-membered bicyclic heterocyclic ring or a 9-10-membered bridged bicyclic heterocyclic ring, wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally includes one —C(O) or one —S(O)2, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally independently contains one, two or three oxygen ring atoms, one, two or three sulfur ring atoms or one, two or three nitrogen ring atoms, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring is unsubstituted or substituted by one, two or three substituents independently selected from —C1-5alkyl, —C3-7cycloalkyl, —C4-7heterocycloalkyl, —(CH2)phenyl, halogen, —NR3R4, —CHF2, —CF3, and —(CH2)n—O—(CH2)m—CH3;
Linker is —CH2—;
A is
Y is independently selected from N or CH;
Z is O or CH2;
R6 is independently hydrogen or —C1-4alkyl;
wherein A is unsubstituted or substituted with one, two or three substituents independently selected from halo, —CF3, —C1-4alkyl, —CN, —OMe, —C(O)NH2, —OCF3, —C1-4alkylNR8R9;
R8 is hydrogen or —C1-4alkyl;
R9 is —C1-3alkyl, aryl, heteroaryl, —C(O)C1-3alkyl, —SO2C1-3alkyl, —C(O)aryl, —C(O)heteroaryl, —SO2aryl, —SO2heteroaryl, —C3-7cycloalkyl, —C1-3alkylC3-7cycloalkyl, —C1-3alkylC3-7heterocycloalkyl, —C1-3alkylheteroaryl or —C1-3alkylaryl, wherein each of —C1-3alkyl, aryl, heteroaryl, —C(O)C1-3alkyl, —SO2C1-3alkyl, —C(O)aryl, —C(O)heteroaryl, —SO2aryl, —SO2heteroaryl, —C3-7cycloalkyl, —C1-3alkylC3-7cycloalkyl, —C1-3alkylC3-7heterocycloalkyl, —C1-3alkylheteroaryl or —C1-3alkylaryl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo, —CN, —CF3, —OCF3, —OCH3, —C1-3alkyl, —OC1-3alkyl, —OC3-7cycloalkyl, —OC3-7hetercycloalkyl, —O-aryl and O-heteroaryl;
X is independently CH or N;
m is 1, 2 or 3; and
n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein:
B is benzotriazolyl wherein benzotriazolyl is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl and halo;
D is —C(O)—NR4R5;
R1 is independently selected from hydrogen or methyl;
R2 is methyl or halo;
R3 is hydrogen, methyl or ethyl;
R4 is hydrogen;
R5 is hydrogen, —C1-5alkyl, —C3-7cycloalkyl, —C4-8heterocycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3 alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-NH—C(O)R3, —C1-3alkyl-SO2C1-3alkyl, —C1-3alkyl-C4-8heterocycloalkyl, —C1-3alkyl-C(O)NR3R4, aryl, —C1-5alkylheteroaryl, or heteroaryl, wherein each of —C1-5alkyl, —C3-7cycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-C(O)NR3R4, aryl, —C1-5alkylheteroaryl, or heteroaryl is unsubstituted or substituted by one or two substituents independently selected from —C1-3alkyl, —C1-3alkylaryl, —C1-3alkylheteroaryl, aryl, —C1-3alkylC(O)R3, —C1-3alkylC(O)OH, —C1-3alkylNHC(O)OR4, —C1-3alkylOSi(R3)3, —C1-3alkylOH, —C1-3alkylNH2, —SCH3, —C4-8heterocycloalkyl (optionally substituted with R3), —NH—(CH2)n-CH—(OH)2, —O—CH2—CH—(NH2)—CH2—OH, —SO2R3, —SO2NR3R4, —OH, —C1-3alkoxy, oxo, —CO2H, —C(O)NR3R4, —C(O)OR3, —NH—C(O)—C1-3alkyl, F, Cl, —CN, —CH—F2, —CF3, —(CH2)n—O—(CH2)m—CH3, —O(CH2)n—OH, —O(CH2)nC(O)OR3, —O(CH2)nOR3, —O(CH2)nNHC(O)OR3, —O(CH2)nNH2, —C3-7cycloalkyl, and a 5-6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from O, N and S;
or R4 and R5 together with the nitrogen atom to which they are attached form a 5-8-membered heterocyclic ring, an 8-11-membered bicyclic heterocyclic ring or a 9-10-membered bridged bicyclic heterocyclic ring, wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally includes one —C(O) or one —S(O)2, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally independently contains one, two or three oxygen ring atoms, one, two or three sulfur ring atoms or one, two or three nitrogen ring atoms, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring is unsubstituted or substituted by one, two or three substituents independently selected from —C1-5alkyl, —C3-7cycloalkyl, —C4-7heterocycloalkyl, —(CH2)phenyl, halogen, —NR3R4, —CHF2, —CF3, and —(CH2)n—O—(CH2)m—CH3;
Linker is —CH2—;
A is
Y is independently selected from N or CH;
Z is O or CH2;
R6 is hydrogen or —C1-4alkyl;
wherein A is unsubstituted or substituted with one, two or three substituents independently selected from halo, —CF3, —C1-4alkyl, —CN, —OMe, —C(O)NH2, —OCF3, —C1-4alkylNR8R9;
R8 is hydrogen or —C1-4alkyl;
R9 is —C1-3alkyl, —C(O)C1-3alkyl, —SO2C1-3alkyl, —C(O)aryl, —C(O)heteroaryl, —SO2aryl, —SO2heteroaryl, —C3-7cycloalkyl, —C1-3alkylC3-7cycloalkyl, —C1-3alkylC3-7heterocycloalkyl, wherein each of —C1-3alkyl, —C(O)C1-3alkyl, —SO2C1-3alkyl, —C(O)aryl, —C(O)heteroaryl, —SO2aryl, —SO2heteroaryl, —C3-7cycloalkyl, —C1-3alkylC3-7cycloalkyl, —C1-3alkylC3-7heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo, —CF3, —OCF3 and —OCH3;
X is independently CH or N;
m is 1, 2 or 3; and
n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1, wherein:
B is benzotriazolyl wherein benzotriazolyl is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl and halo;
D is —C(O)—NR4R5;
R1 is independently selected from hydrogen or methyl;
R2 is methyl or halo;
R3 is hydrogen or —C1-5alkyl;
R4 is hydrogen;
R5 is hydrogen, —C1-5alkyl, —C3-7cycloalkyl, —C4-8heterocycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3 alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-NH—C(O)R3, —C1-3alkyl-SO2C1-3alkyl, —C1-3alkyl-C4-8heterocycloalkyl, —C1-3alkyl-C(O)NR3R4, aryl, —C1-5alkylheteroaryl, or heteroaryl, wherein each of —C1-5alkyl, —C3-7cycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-C(O)NR3R4, aryl, —C1-5alkylheteroaryl, or heteroaryl is unsubstituted or substituted by one or two substituents independently selected from —C1-3alkyl, —C1-3alkylheteroaryl, aryl, —C1-3alkylC(O)R3, —C1-3alkylC(O)OH, —C1-3alkylNHC(O)OR4, —C1-3alkylOSi(R3)3, —C1-3alkylOH, —C1-3alkylNH2, —SCH3, —C4-8heterocycloalkyl (optionally substituted with R3), —NH—(CH2)n-CH—(OH)2, —O—CH2—CH—(NH2)—CH2—OH, —SO2R3, —SO2NR3R4, —OH, —C1-3alkoxy, oxo, —CO2H, —C(O)NR3R4,—C(O)OR3, C(O)—C1-3alkyl, F, Cl, —CN, —CF3, —(CH2)n—O—(CH2)m—CH3, —O(CH2)n—OH, —O(CH2)nC(O)OR3, —O(CH2)nOR3, —O(CH2)nNHC(O)OR3, —O(CH2)nNH2, —C3-7cycloalkyl, and a 5-6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from O, N and S;
Linker is —CH2—;
A is
Y is independently selected from N or CH;
Z is O or CH2;
R6 is independently hydrogen or —C1-4alkyl;
wherein A is unsubstituted or substituted with one, two or three substituents independently selected from halo, —CF3, —C1-4alkyl, —CN, —OMe, —C(O)NH2, —OCF3, —C1-4alkylNR8R9;
R8 is hydrogen or —C1-4alkyl;
R9 is —C1-3alkyl, —C(O)C1-3alkyl, —SO2C1-3alkyl, —C(O)aryl, —C(O)heteroaryl, —SO2aryl, —SO2heteroaryl, —C3-7cycloalkyl, —C1-3alkylC3-7cycloalkyl, —C1-3alkylC3-7heterocycloalkyl, wherein each of —C1-3alkyl, —C(O)C1-3alkyl, —SO2C1-3alkyl, —C(O)aryl, —C(O)heteroaryl, —SO2aryl, —SO2heteroaryl, —C3-7cycloalkyl, —C1-3alkylC3-7cycloalkyl, —C1-3alkylC3-7heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo, —CF3, —OCF3 and —OCH3;
X is CH;
m is 1, 2 or 3; and
n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 4)

The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein A is

### Claim 6 (depends on 5)

The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Z is O.

### Claim 7 (depends on 5)

The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Z is CH2.

### Claim 8 (depends on 4)

The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein A is

### Claim 9 (depends on 8)

The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein Z is O.

### Claim 10 (depends on 8)

The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein Z is CH2.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

### Claim 12 (depends on 1)

A method of treating a respiratory disorder selected from COPD, asthma, ALI, ARDS, fibrosis, chronic asthma, acute asthma, lung disease secondary to environmental exposures, acute lung infection or chronic lung infection which comprises administering to a human in need thereof, a therapeutically effective amount of the compound of claim 1.

### Claim 13 (depends on 12)

The method of claim 12 wherein the disorder is COPD.

### Claim 14 (depends on 13)

The method of claim 13, wherein the compound is administered by inhalation.

### Claim 15 (depends on 1)

A method of treating a disease or disorder selected from atherosclerosis, hypertension, heart failure, acute coronary syndrome, myocardial infarction, myocardial repair, cardiac remodeling, cardiac arrhythmias, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction or diabetic cardiomyopathy which comprises administering to a human in need thereof, a therapeutically effective amount of the compound of claim 1.

### Claim 16 (depends on 15)

The method of claim 15 wherein the disorder is heart failure.

### Claim 17 (depends on 16)

The method of claim 16, wherein the compound is administered orally.

### Claim 18 (depends on 1)

A method of treating a disease or disorder selected from Parkinson's disease, Alzheimer's disease, Friedreich's Ataxia, amyotrophic lateral sclerosis or multiple sclerosis which comprises administering to a human in need thereof, a therapeutically effective amount of the compound of claim 1.