# US 11,026,958 B2 · Substituted 6-membered aryl or heteroaryl allosteric modulators of nicotinic acetylcholine receptors

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- Number: US 11,026,958 B2
- Document ID: US11026958B2
- Status: Granted
- Kind: B2
- Application number: 16/345,997
- Filed: 2017-10-30
- Published: 2021-03-18
- Granted: 2021-06-08
- 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; Brian T. Campbell; Thomas J. Greshock; Vanessa L. Rada
- Web page: https://patentgrep.com/patent/US11026958B2

## CPC

- A61K 31/695: Silicon compounds
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/4164: 1,3-Diazoles
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/4245: Oxadiazoles
- A61K 31/4418: having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/50: Pyridazines; Hydrogenated pyridazines
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- 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
- C07D 213/34: to which a second hetero atom is attached
- C07D 233/60: with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- C07D 237/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 241/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 249/08: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D 271/06: 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07F 7/0812: {comprising a heterocyclic ring}
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## 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 6-membered heteroaryl ring which is substituted with 1 to 4 R groups each independently selected from OH, oxo, amino, amido, carboxyl, keto, cyano, 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 halogen, 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, Si(CH3)3 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 and R8 are independently selected from H, (C1-C6)alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from halogen, OH, CF3, (C1-C4)alkyl, O(C1-C4)alkyl, cycloalkyl, CN, aryl, heteroaryl, and heterocyclyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from halogen, OH, CF3, (C1-C4)alkyl, O(C1-C4)alkyl, CN;
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 of claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is H.

### Claim 4 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein A is selected from pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyridinone, pyrimidinone, pyrazinone, and pyridazinone each 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 optionally substituted with one or more substituents independently selected from halogen, CN, (C1-C4)alkyl, (C═O)O(C1-C4)alkyl and phenyl, wherein said alkyl is optionally substituted with one or more halogen.

### Claim 5 (depends on 4)

The compound of 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 of claim 5, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are independently H, F, Si(CH3)3 or methyl.

### Claim 7 (depends on 6)

The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R7 and R8 are independently selected from H, (C1-C6)alkyl, cyclopentyl and phenyl wherein said alkyl and phenyl are optionally substituted with halogen or phenyl.

### Claim 8 (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 pyridine, pyrimidine, pyridazine and pyrazine each substituted with 1 R group selected from (C1-C6)alkyl, O(C1-C6)alkyl, NR7R8, (C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each are optionally substituted with one or more substituents independently selected from halogen, CF3, CN, (C1-C4)alkyl, (C═O)O(C1-C4)alkyl and phenyl;
R3 is H or Si(CH3)3;
R4 is H; and
R7 and R8 are independently selected from H, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from halogen and phenyl.

### Claim 9 (depends on 8)

The compound of claim 8 having the formula Ia, or a pharmaceutically acceptable salt thereof, wherein;
A is selected from pyridine, pyrimidine, pyridazine and pyrazine each substituted with 1 R group selected from (C1-C6)alkyl, O(C1-C6)alkyl, NR7R8, cyclobutyl, cyclopentyl, phenyl, pyridinyl, morpholinyl, imidazolyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, triazolyl and tetrahydropyranyl wherein each are optionally substituted with one or more substituents independently selected from halogen, CF3, CN, (C1-C4)alkyl, (C═O)O(C1-C4)alkyl and phenyl;
R3 is H or Si(CH3)3;
R4 is H; and
R7 and R8 are independently selected from H, (C1-C6)alkyl, cyclopentyl and phenyl, wherein each alkyl, cyclopentyl, and phenyl are optionally substituted with one or more substituents independently selected from halogen and phenyl.

### Claim 10 (depends on 1)

The compound of claim 1 which is selected from the group consisting of
4-{trans-2-[6-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[2-(Morpholin-4-yl)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;
4-[trans-2-(6-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;
4-[trans-2-(5-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;
4-{trans-2-[4-(Propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[6-(Pyrrolidin-1-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[2-(Propan-2-yl)pyridin-4-yl]cyclopropyl}benzenesulfonamide;
4-[(1R,3R)-2,2-Dimethyl-3-{4-[5-(trifluoromethyl)pyridin-3-yl]pyrimidin-2-yl}cyclopropyl]benzenesulfonamide;
4-{trans-2-[4-(3-Fluorophenyl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;
4-(trans-2-{4-[5-(Trifluoromethyl)pyridin-3-yl]pyrimidin-2-yl}cyclopropyl)benzenesulfonamide;
4-{trans-2-[6-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[4-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[5-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-[trans-2-(6-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;
4-{trans-2-[5-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[5-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[3-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[6-(1H-Pyrazol-1-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[6-(Tetrahydro-2H-pyran-4-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[6-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[4-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-[trans-2-(6-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;
4-[trans-2-(5-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;
4-{2-[6-(Propan-2-yl)pyridin-3-yl]-3-(trimethylsilyl)cyclopropyl}benzenesulfonamide;
4-{trans-2-[6-(Propan-2-yl)pyridazin-3-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[6-(Propan-2-yl)pyrazin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[5-(Propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[5-(Propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[4-(Propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;
4-{(1R,3R)-2,2-Difluoro-3-[4-(3-fluorophenyl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[2-(Dimethylamino)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[2-(Cyclopentylamino)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[2-(Benzylamino)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;
tert-Butyl 4-{4-[trans-2-(4-sulfamoylphenyl)cyclopropyl]pyrimidin-2-yl}piperazine-1-carboxylate;
4-(trans-2-{2-[(2,2-Dimethylpropyl)amino]pyrimidin-4-yl}cyclopropyl)benzenesulfonamide;
4-(trans-2-{2-[Methyl(phenyl)amino]pyrimidin-4-yl}cyclopropyl)benzenesulfonamide;
4-{trans-2-[2-(Pyrrolidin-1-yl)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;
4-(trans-2-[2-[(4-Fluorophenyl)amino]pyrimidin-4-yl}cyclopropyl)benzenesulfonamide;
4-[trans-2-(2-Phenylpyrimidin-4-yl)cyclopropyl]benzenesulfonamide;
4-(trans-2-{2-[(2-Phenylethyl)amino]pyrimidin-4-yl}cyclopropyl)benzenesulfonamide;
4-{trans-2-[2-(Phenylamino)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[2-(Propan-2-yl)pyridin-4-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[2-(Propan-2-yl)pyridin-4-yl]cyclopropyl}benzenesulfonamide;
4-[trans-2-(2-Cyclobutylpyridin-4-yl)cyclopropyl]benzenesulfonamide;
4-{trans-2-[6-(Propan-2-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[5-(Pyrrolidin-1-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[6-(1H-Pyrazol-1-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[6-(Propan-2-yloxy)pyridin-3-yl]cyclopropyl}benzenesulfonamide; and
4-{trans-2-[6-(2-Cyanopropan-2-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide;
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 11)

The pharmaceutical composition of claim 11, further comprising a second therapeutic agent selected from the group consisting of acetylcholinesterase inhibitors; NMDA receptor antagonists; antipsychotics; MAO-B inhibitors; and levodopa.

### Claim 13 (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 of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the patient.

### Claim 14 (depends on 1)

A method for modulating α7 nAChR activity in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.