# US 8,772,509 B2 · Indole compounds as positive allosteric modulators of the muscarinic receptor

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- Number: US 8,772,509 B2
- Document ID: US8772509B2
- Status: Granted
- Kind: B2
- Application number: 13/702,800
- Filed: 2011-06-21
- Published: 2013-08-15
- Granted: 2014-07-08
- Earliest claimed: 2010-06-21
- Assignees: Vanderbilt University
- Applicants: Craig W. Lindsley; P. Jeffrey Conn; Michael R. Wood; James C. Tarr; Thomas M. Bridges
- Inventors: Craig W. Lindsley; P. Jeffrey Conn; Michael R. Wood; James C. Tarr; Thomas M. Bridges
- Web page: https://patentgrep.com/patent/US8772509B2

## CPC

- C07D 413/14: containing three or more hetero rings
- C07D 209/30: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D 213/12: from unsaturated compounds
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

In one aspect, the invention relates to indole compounds, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M1 (mAChR M1); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

## Claims

### Claim 1

A compound represented by a formula:
wherein each R1a-R1d is independently selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; provided that at least one of R1a or R1c is F;
wherein n is 0, 1, or 2;
wherein R2 is selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
wherein R3 comprises two substituents independently selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
wherein R4 is selected from hydrogen, a hydrolysable residue, and optionally substituted alkyl;
wherein A1 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and
wherein A2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein each of R1a and R1c is F.

### Claim 3 (depends on 1)

The compound of claim 1, wherein each of R1b and R1d is hydrogen.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R2 is hydrogen.

### Claim 5 (depends on 1)

The compound of claim 1, wherein n is 2.

### Claim 6 (depends on 1)

The compound of claim 1, wherein A1 is selected from optionally substituted pyridine, optionally substituted pyrimidine, optionally substituted furan, optionally substituted thiophene, optionally substituted pyrrole, optionally substituted isoxazole, optionally substituted isothiazole, optionally substituted pyrazole, optionally substituted oxazole, optionally substituted thiazole, and optionally substituted imidazole.

### Claim 7 (depends on 1)

The compound of claim 1, wherein A1 is optionally substituted oxazole.

### Claim 8 (depends on 1)

The compound of claim 1, wherein A2 is selected from optionally substituted aryl and optionally substituted heteroaryl.

### Claim 9 (depends on 1)

The compound of claim 1, represented by a formula:
wherein R5a, R5c, and R5e are independently selected from H, Cl, Br, F, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and
wherein R5b and R5d are independently selected from H, Cl, Br, azido, amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; provided that at least one of R5b and R5d is not hydrogen.

### Claim 10 (depends on 9)

The compound of claim 9, wherein each of R1a and R1c is F.

### Claim 11 (depends on 9)

The compound of claim 9, wherein each of R1b and R1d is hydrogen.

### Claim 12

A compound represented by a formula:
wherein each R1a-R1d is independently selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
wherein n is 1 or 2;
wherein R2 is selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
wherein R3 comprises two substituents independently selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
wherein R4 is selected from hydrogen, a hydrolysable residue, and optionally substituted alkyl;
wherein A1 is selected from pyridinyl, pyridinylmethyl, pyridazinyl, pyrimidinyl, 5-methylisoxazol-3-yl, benzoxazolyl, benzoisoxazolyl, oxetanyl, and thiazolyl, and A1 is substituted with 0-2 groups selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxyl, and C1-C4 haloalkyl;
wherein each R5a-R5e is independently selected from hydrogen, fluoro, chloro, bromo, iodo, azido, amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; provided that at least one of R5a-R5e is selected from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or at least two of R5a-R5e are independently selected from fluoro, chloro, bromo, iodo, azido, amino, alkyl, and alkoxy.

### Claim 13 (depends on 12)

The compound of claim 12, wherein n is 2.

### Claim 14 (depends on 12)

The compound of claim 12, wherein at least one of R5a-R5e is selected from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

### Claim 15 (depends on 12)

The compound of claim 12, wherein each R1a-R1d is hydrogen.

### Claim 16 (depends on 12)

The compound of claim 12, wherein at least one of R1a or R1c is F.