# US 2014/0194471 A1 · Substituted 1-benzylindolin-2-one analogs as positive allosteric modulators of muscarinic acetylcholine m1 receptors

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- Number: US 2014/0194471 A1
- Document ID: US20140194471A1
- Status: Published application
- Kind: A1
- Application number: 13/735,017
- Filed: 2013-01-06
- Published: 2014-07-10
- Earliest claimed: 2013-01-06
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: Craig W. Lindlsley; P. Jeffrey Conn; Michael R. Wood; Bruce J. Melancon; Michael S. Poslusney
- Web page: https://patentgrep.com/patent/US20140194471A1

## CPC

- C07D 403/10: linked by a carbon chain containing aromatic rings
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/416: condensed with carbocyclic ring systems, e.g. indazole
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 401/14: containing three or more hetero rings
- 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)

## Abstract

In one aspect, the invention relates to substituted 1-benzylindolin-2-one analog compounds, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M1 (mAChR M1); synthesis 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 having a structure represented by a formula:
wherein n is 0 or 1;
wherein L is selected from O, (C═O), and NR3;
wherein Q1 is selected from N and CR1a; wherein Q2 is selected from N and CR1b; wherein Q3 is selected from N and CR1c; wherein Q4 is selected from N and CR1d; and wherein 0, 1, or 2 of Q1, Q2, Q3, and Q4 are N;
wherein each of R1a, R1b, R1c, and R1d, when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkylamino, C1-C6 haloalkyl-oxy-C1-C6 alkyl, C1-C6 polyhaloalkyl-oxy-C1-C6 alkyl, and C1-C6 dialkylamino;
wherein R2 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein R3 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl;
wherein R4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl;
wherein each of R5a and R5b is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein Q5 is selected from N and CR6a; wherein Q6 is selected from N and CR6b; wherein Q7 is selected from N and CR6c; wherein Q8 is selected from N and CR6d; and wherein 0, 1, or 2 of Q5, Q6, Q7, and Q8 are N;
wherein each of R6a, R6b, R6c, and R6d, when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein R7 is a heterocyclyl substituted with 0-3 groups selected from halogen, hydroxyl, cyano, —NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino;
or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein each of Q1, Q2, Q3, and Q4 is not N.

### Claim 3 (depends on 1)

The compound of claim 1, wherein each of Q5, Q6, Q3, and Q8 is not N.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R2 is —CF3.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R4 is selected from hydrogen and —CH3.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R4 is hydrogen.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R7 is selected from 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl; and wherein R7 is monosubstituted with a group selected from methyl, ethyl, propyl, and isopropyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein n is 1; L is O; wherein R2 is selected from hydrogen, —CH3, —CH2CH3, —CH2F, —CHF2, —CF3, —CH2Cl, —CHCl2, —CCl3, —CH2CH2F, —CH2CHF2, —CH2CF3, —CH2CH2Cl, —CH2CHCl2, and —CH2CCl3; R4 is hydrogen; wherein each of R5a and R5b is hydrogen; wherein R7 is selected from 1-methyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-4-yl, and 1-propyl-1H-pyrazol-4-yl; wherein each of Q1, Q2, Q3, and Q4 is not N; and wherein each of Q5, Q6, Q7, and Q8 is not N.

### Claim 9 (depends on 1)

The compound of claim 1, having a structure represented by a formula:
wherein each of R1a, R1b, R1c, and R1d is independently selected from hydrogen, —F, and —Cl; wherein each of R6a, R6b, R6c, and R6d is independently selected from hydrogen, —F, and —Cl; wherein each of R8a and R8b is independently selected from hydrogen, halogen, hydroxyl, cyano, —NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; and wherein R9 is selected from hydrogen and C1-C6 alkyl.

### Claim 10

A method for the treatment of a neurological and/or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal comprising the step of administering to the mammal an effective amount of least one compound having a structure represented by a formula:
wherein n is 0 or 1;
wherein L is selected from O, (C═O), and NR3;
wherein Q1 is selected from N and CR1a; wherein Q2 is selected from N and CR1b; wherein Q3 is selected from N and CR1c; wherein Q4 is selected from N and CR1d; and wherein 0, 1, or 2 of Q1, Q2, Q3, and Q4 are N;
wherein each of R1a, R1b, R1c, and R1d, when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkylamino, C1-C6 haloalkyl-oxy-C1-C6 alkyl, C1-C6 polyhaloalkyl-oxy-C1-C6 alkyl, and C1-C6 dialkylamino;
wherein R2 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein R3 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl;
wherein R4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl;
wherein each of R5a and R5b is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein Q5 is selected from N and CR6a; wherein Q6 is selected from N and CR6b; wherein Q7 is selected from N and CR6c; wherein Q8 is selected from N and CR6d; and wherein 0, 1, or 2 of Q5, Q6, Q7, and Q8 are N;
wherein each of R6a, R6b, R6c, and R6d, when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein R7 is a heterocyclyl substituted with 0-3 groups selected from halogen, hydroxyl, cyano, —NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino;
or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

### Claim 11 (depends on 10)

The method of claim 10, wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.

### Claim 12 (depends on 10)

The method of claim 10, further comprising the step of identifying a mammal in need of treatment of the disorder.

### Claim 13 (depends on 12)

The method of claim 12, wherein the disorder is associated with a mAChR M1 dysfunction.

### Claim 14 (depends on 10)

The method of claim 10, wherein the disorder is a neurological and/or psychiatric disorder associated with mAChR M1 dysfunction.

### Claim 15 (depends on 10)

The method of claim 10, wherein the disorder is selected from Alzheimer's disease, schizophrenia, a sleep disorder, a pain disorder and a cognitive disorder.

### Claim 16 (depends on 15)

The method of claim 15, wherein the disorder is Alzheimer's disease.

### Claim 17 (depends on 10)

The method of claim 10, wherein the disorder is selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder, autistic disorder; movement disorders, Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, and memory disorders.

### Claim 18

A kit comprising at least one compound having a structure represented by a formula:
wherein n is 0 or 1;
wherein L is selected from O, (C═O), and NR3;
wherein Q1 is selected from N and CR1a; wherein Q2 is selected from N and CR1b; wherein Q3 is selected from N and CR1c; wherein Q4 is selected from N and CR1d; and wherein 0, 1, or 2 of Q1, Q2, Q3, and Q4 are N;
wherein each of R1a, R1b, R1c, and R1d, when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkylamino, C1-C6 haloalkyl-oxy-C1-C6 alkyl, C1-C6 polyhaloalkyl-oxy-C1-C6 alkyl, and C1-C6 dialkylamino;
wherein R2 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein R3 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl;
wherein R4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl;
wherein each of R5a and R5b is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein Q5 is selected from N and CR6a; wherein Q6 is selected from N and CR6b; wherein Q7 is selected from N and CR6C; wherein Q8 is selected from N and CR6d; and wherein 0, 1, or 2 of Q5, Q6, Q7, and Q8 are N;
wherein each of R6a, R6b, R6c, and R6d, when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein R7 is a heterocyclyl substituted with 0-3 groups selected from halogen, hydroxyl, cyano, —NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino;
or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof;
and one or more of:
(a) at least one agent known to increase mAChR M1 activity;
(b) at least one agent known to decrease mAChR M1 activity;
(c) at least one agent known to treat a disorder associated with cholinergic activity;
(d) instructions for treating a disorder associated with cholinergic activity;
(e) instructions for treating a disorder associated with mAChR M1 receptor activity; or
(f) instructions for administering the compound in connection with cognitive or behavioral therapy.

### Claim 19 (depends on 18)

The kit of claim 18, wherein the at least one compound and the at least one agent are co-formulated.

### Claim 20 (depends on 18)

The kit of claim 18, wherein the at least one compound and the at least one agent are co-packaged.