# US 10,870,630 B2 · Substituted bicyclic heteroaryl allosteric modulators of nicotinic acetylcholine receptors

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,870,630 B2
- Document ID: US10870630B2
- Status: Granted
- Kind: B2
- Application number: 16/345,903
- Filed: 2017-10-30
- Published: 2019-10-10
- Granted: 2020-12-22
- Earliest claimed: 2016-11-01
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Brendan M. Crowley; Ian M. Bell; Andrew John Harvey; William D. Shipe; Kenneth J. Leavitt; John M. Sanders; Deodial G. Guiadeen; Linda M. Suen; Thomas J. Greshock; Vanessa L. Rada
- Web page: https://patentgrep.com/patent/US10870630B2

## CPC

- C07D 263/56: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- A61K 31/416: condensed with carbocyclic ring systems, e.g. indazole
- A61K 31/4162: condensed with heterocyclic ring systems
- A61K 31/423: condensed with carbocyclic rings
- A61K 31/428: condensed with carbocyclic rings
- A61K 31/4365: the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A61K 31/502: ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
- A61K 31/5025: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/536: ortho- or peri-condensed with carbocyclic ring systems
- A61K 31/5383: ortho- or peri-condensed with heterocyclic ring systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 311/08: having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07D 217/02: with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 235/06: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D 237/28: Cinnolines
- C07D 239/74: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
- C07D 241/42: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D 263/52: condensed with carbocyclic rings or ring systems
- C07D 265/16: with only hydrogen or carbon atoms directly attached in positions 2 and 4
- C07D 265/36: condensed with one six-membered ring
- C07D 277/66: with aromatic rings or ring systems directly attached in position 2
- C07D 277/68: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D 471/04: Ortho-condensed systems
- C07D 487/02: in which the condensed system contains two hetero rings
- C07D 487/04: Ortho-condensed systems
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 495/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present disclosure relates to compounds of formula (I) that are useful as modulators of α7 nAChR, compositions comprising such compounds, and the use of such compounds for preventing, treating, or ameliorating disease, particularly disorders of the central nervous system such as cognitive impairments in Alzheimer's disease, Parkinson's disease, and schizophrenia, as well as for L-DOPA induced-dyskinesia and inflammation.

## Claims

### Claim 1

A compound having the formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from
Y is 4 substituents, each independently selected from H, (C1-C4)alkyl, halogen, and OH, wherein said alkyl is optionally substituted with one or more halogen or OH;
A is a bicyclic heteroaryl ring which is substituted with 0 to 4 R groups each independently selected from OH, oxo, amino, amido, carboxyl, keto, CN, alkoxy, S(O)m-alkyl, halogen, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, alkynyl, aryl, heteroaryl, and heterocyclyl, wherein said amino, amido, carboxyl, keto, alkoxy, S(O)m-alkyl, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, alkynyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF3, OCF3, CN, (C1-C6)alkyl, O(C1-C4)alkyl, S(O)m—(C1-C4)alkyl, C═O(C1-C4)alkyl, (C═O)NR7R8, (C═O)OR7, (C2-C4)alkynyl, (C3-C6)cycloalkyl, O(C3-C6)cycloalkyl, C═O(C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally independently substituted with one or more halogen, CF3, OH and oxo;
R1 is H or (C1-C4)alkyl;
R2 is H or (C1-C4)alkyl;
R3 is H, halogen or (C1-C4)alkyl, wherein said alkyl is optionally substituted with one or more halogen;
R4 is H, halogen or (C1-C4)alkyl, wherein said alkyl is optionally substituted with one or more halogen;
or, R3 and R4 optionally can come to together to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring wherein said ring may be optionally substituted with one or more substituents independently selected from OH, halogen, or (C1-C4)alkyl;
R5 is H or (C1-C4)alkyl;
R6 is H or (C1-C4)alkyl;
R7 is H or (C1-C4)alkyl, wherein said alkyl is optionally substituted with one or more halogen;
R8 is H or (C1-C4)alkyl, wherein said alkyl is optionally substituted with one or more halogen;
Ra is H or (C1-C4)alkyl;
Rb is H or (C1-C4)alkyl; and
m is 0, 1, or 2.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is

### Claim 3 (depends on 2)

The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is H.

### Claim 4 (depends on 3)

The compound of according to claim 3, or a pharmaceutically acceptable salt thereof, wherein A is selected from benzoxazolyl, quinazolinyl, tetrahydrobenzoxazolyl, oxazolopyridinyl, quinoxalinyl, imidazopyridazinyl, benzothiazolyl, dihydrocyclopentaoxazolyl, naphthyridinyl, pyrazolopyridinyl, cinnolinyl, isoquinolyl, thienopyridinyl, indazolyl, tetrahydropyrazolopyridinyl, furopyridinyl, dihydropyridooxazinyl, tetrahydrobenzothiazolyl, tetrahydroquinazolinyl, benzoxazinyl, benzimidazolyl, thiazolopyridinyl, quinolinyl, pyridopyrimidinyl, phthalazinyl, pyridopyrazinyl, thienoxazole, and thienothiazole each optionally substituted with 1 to 2 R groups independently selected from halogen, CN, (C1-C6)alkyl, O(C1-C6)alkyl, NR7R8, (C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, NR7R8, (C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted with one or more substituents independently selected from halogen, CN, (C1-C6)alkyl, (C═O)O(C1-C4)alkyl, and phenyl.

### Claim 5 (depends on 4)

The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R5, R6, Ra and Rb are independently H or methyl.

### Claim 6 (depends on 5)

The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are independently H, F or methyl.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula:
or a pharmaceutically acceptable salt thereof, wherein;
A is selected from benzoxazolyl, quinazolinyl, tetrahydrobenzoxazolyl, oxazolopyridinyl, quinoxalinyl, imidazopyridazinyl, benzothiazolyl, dihydrocyclopentaoxazolyl, naphthyridinyl, pyrazolopyridinyl, cinnolinyl, isoquinolyl, thienopyridinyl, indazolyl, tetrahydropyrazolopyridinyl, furopyridinyl and dihydropyridooxazinyl, each optionally substituted with 1 to 2 R groups independently selected from F, Cl, (C1-C4)alkyl, O(C1-C4)alkyl and CF3;
R3 is H, F or methyl; and
R4 is H, F or methyl.

### Claim 8 (depends on 1)

The compound of claim 1 which is selected from the group consisting of
4-[(1R,3R)-3-(1,3-Benzoxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide;
4-[(1S,3S)-3-(6-Fluoro-1,3-benzoxazol-2-yl)-2,2-dimethylcyclopropyl]benzenesulfonamide;
4-[(1R,2R)-2-(Quinazolin-2-yl)cyclopropyl]benzenesulfonamide;
4-[(1R,2R)-2-(4,5,6,7-Tetrahydro-1,3-benzoxazol-2-yl)cyclopropyl]benzenesulfonamide;
4-[(1R,2R)-2-(1,3-Benzoxazol-2-yl)cyclopropyl]benzenesulfonamide;
4-[(1R,3R)-2,2-Dimethyl-3-([1,3]oxazolo[5,4-b]pyridin-2-yl)cyclopropyl]benzenesulfonamide;
4-[trans-2-(Quinoxalin-2-yl)cyclopropyl]benzenesulfonamide;
4-((1R,3R)-3-(Imidazo[1,2-b]pyridazin-2-yl)-2,2-dimethylcyclopropyl)benzenesulfonamide;
4-((1S,3S)-3-(Benzo[d]thiazol-2-yl)-2,2-dimethylcyclopropyl)benzenesulfonamide;
4-((1S,3S)-3-(6-Fluorobenzo[d]thiazol-2-yl)-2,2-dimethylcyclopropyl)benzenesulfonamide;
4-[(1R,3R)-3-(5,6-Dihydro-4H-cyclopenta[d][1,3]oxazol-2-yl)-2,2-dimethylcyclopropyl] benzenesulfonamide;
4-[(1R,3R)-2,2-Dimethyl-3-(5,6,7,8-tetrahydroquinazolin-2-yl)cyclopropyl]benzenesulfonamide;
4-[(1R,3R)-3-(4,4-Dimethyl-4H-3,1-benzoxazin-2-yl)-2,2-difluorocyclopropyl]benzenesulfonamide;
4-[(1S,3S)-3-(4-Methoxy-1,3-benzoxazol-2-yl)-2,2-dimethyl-cyclopropyl]benzenesulfonamide;
4-[(1R,2R)-2-(6-Fluoro-1,3-benzoxazol-2-yl)cyclopropyl]benzenesulfonamide;
4-[(1S,3S)-3-(4,6-Difluoro-1,3-benzothiazol-2-yl)-2,2-dimethyl-cyclopropyl] benzenesulfonamide;
4-[(1S,3S)-3-(1,3-Benzoxazol-2-yl)-2,2-dimethyl-cyclopropyl]benzenesulfonamide;
4-[(1S,3S)-3-(6-Chloro-1,3-benzoxazol-2-yl)-2,2-dimethyl-cyclopropyl]benzenesulfonamide;
4-[(1S,3S)-3-(5-Chloro-1,3-benzoxazol-2-yl)-2,2-dimethyl-cyclopropyl]benzenesulfonamide;
4-[(1R,3R)-3-(1,3-Benzoxazol-2-yl)-2,2-difluoro-cyclopropyl]benzenesulfonamide;
4-[(1R,3S)-3-(1,3-Benzothiazol-2-yl)-2,2-difluoro-cyclopropyl]benzenesulfonamide;
4-[(1R,3R)-3-(1H-Benzimidazol-2-yl)-2,2-difluorocyclopropyl]benzenesulfonamide;
4-[(1R,3R)-3-(4,6-Difluoro-1,3-benzoxazol-2-yl)-2,2-dimethyl-cyclopropyl]benzenesulfonamide;
4-[(1R,3R)-3-(6-Fluoro-1,3-benzoxazol-2-yl)-2,2-dimethyl-cyclopropyl]benzenesulfonamide;
4-[(1R,3R)-3-(1,3-Benzothiazol-2-yl)-2,2-dimethyl-cyclopropyl]benzenesulfonamide;
4-[(1S,2S)-2-(1,3-Benzoxazol-2-yl)cyclopropyl]benzenesulfonamide;
4-[(1R,3R)-3-(6-Chloro-1,3-benzoxazol-2-yl)-2,2-dimethyl-cyclopropyl]benzenesulfonamide;
4-[(1R,3R)-3-(5-Chloro-1,3-benzoxazol-2-yl)-2,2-dimethyl-cyclopropyl]benzenesulfonamide;
4-[(1S,2S)-2-(6-Fluoro-1,3-benzoxazol-2-yl)cyclopropyl]benzenesulfonamide;
4-[(1R,3R)-3-(4,6-Difluoro-1,3-benzothiazol-2-yl)-2,2-dimethyl-cyclopropyl] benzenesulfonamide;
4-[(1R,3R)-3-(6-Fluoro-1,3-benzothiazol-2-yl)-2,2-dimethyl-cyclopropyl]benzenesulfonamide;
4-[(1R,3R)-3-(5-Methoxy-1,3-benzoxazol-2-yl)-2,2-dimethyl-cyclopropyl]benzenesulfonamide;
4-[(1S,3S)-3-(1,3-Benzoxazol-2-yl)-2,2-difluoro-cyclopropyl]benzenesulfonamide;
4-[(1S,3R)-3-(1,3-Benzothiazol-2-yl)-2,2-difluoro-cyclopropyl]benzenesulfonamide;
4-[(1S,3S)-2,2-Dimethyl-3-quinazolin-2-yl-cyclopropyl]benzenesulfonamide;
4-[(1S,3S)-3-(5-Fluoroquinazolin-2-yl)-2,2-dimethyl-cyclopropyl]benzenesulfonamide;
4-[(1S,3S)-2,2-Dimethyl-3-(4,5,6,7-tetrahydro-1,3-benzoxazol-2-yl)cyclopropyl] benzenesulfonamide;
4-[(1R,3R)-2,2-Difluoro-3-(4,5,6,7-tetrahydro-1,3-benzoxazol-2-yl)cyclopropyl] benzenesulfonamide;
4-[(1R,3R)-2,2-Dimethyl-3-quinazolin-2-yl-cyclopropyl]benzenesulfonamide;
4-[(1R,3R)-2,2-Dimethyl-3-oxazolo[5,4-c]pyridin-2-yl-cyclopropyl]benzenesulfonamide;
4-[(1R,3R)-2,2-Dimethyl-3-(4,5,6,7-tetrahydro-1,3-benzoxazol-2-yl)cyclopropyl] benzenesulfonamide;
4-[(1R,3R)-3-(5,7-Difluoro-1-methyl-benzimidazol-2-yl)-2,2-dimethyl-cyclopropyl] benzenesulfonamide;
4-[(1S,3S)-3-(4,4-Dimethyl-4H-3,1-benzoxazin-2-yl)-2,2-difluorocyclopropyl]benzenesulfonamide;
4-[2-(2-Methyl-1,3-benzothiazol-4-yl)cyclopropyl]benzenesulfonamide;
4-[2-(7-Chloro-1,5-naphthyridin-3-yl)cyclopropyl]benzenesulfonamide;
4-(2-Pyrazolo[1,5-a]pyridin-3-ylcyclopropyl)benzenesulfonamide;
4-(2-Quinoxalin-6-ylcyclopropyl)benzenesulfonamide;
4-[2-[3-(Trifluoromethyl)cinnolin-7-yl] cyclopropyl]benzenesulfonamide;
4-[2-(3-Chloro-7-isoquinolyl)cyclopropyl]benzenesulfonamide;
4-(2-Thieno[2,3-c]pyridin-2-ylcyclopropyl)benzenesulfonamide;
4-[2-(1,7-Naphthyridin-2-yl)cyclopropyl]benzenesulfonamide;
4-[2-(1-Methylindazol-5-yl)cyclopropyl]benzenesulfonamide;
4-[2-(4,5,6,7-Tetrahydropyrazolo[1,5-a]pyridin-2-yl)cyclopropyl]benzenesulfonamide;
4-(2-Furo[2,3-b]pyridin-5-ylcyclopropyl)benzenesulfonamide;
4-[2-(2-Methylindazol-6-yl)cyclopropyl]benzenesulfonamide;
4-[2-(4-Methyl-2,3-dihydropyrido[3,2-b][1,4]oxazin-7-yl)cyclopropyl]benzenesulfonamide; and
4-[2-(5,6,7,8-Tetrahydroquinolin-3-yl)cyclopropyl]benzenesulfonamide;
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9, further comprising a second therapeutic agent selected from the group consisting of acetylcholinesterase inhibitors; NMDA receptor antagonists; antipsychotics; MAO-B inhibitors; and levodopa.

### Claim 11 (depends on 1)

A method of treating a patient with cognitive impairments associated with Alzheimer's disease, Parkinson's disease, and schizophrenia, the method comprising administering to the patient the compound according to claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the patient.

### Claim 12 (depends on 1)

A method of modulating α7 nAChR activity in a mammal comprising administering to the mammal an effective amount of compound according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

A method of treating a patient with mild to moderate dementia of the Alzheimer's type, the method comprising administering to the patient the compound according to claim 1 or a pharmaceutically acceptable salt thereof, in an amount effective to treat the patient.