# US 2019/0167688 A1 · Positive allosteric modulators of the muscarinic acetylcholine receptor m4

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- Number: US 2019/0167688 A1
- Document ID: US20190167688A1
- Status: Published application
- Kind: A1
- Application number: 16/210,495
- Filed: 2018-12-05
- Published: 2019-06-06
- Earliest claimed: 2017-12-05
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: Craig W. Lindsley; P. Jeffrey Conn; Darren W. Engers; Julie L. Engers
- Web page: https://patentgrep.com/patent/US20190167688A1

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 25/00: Drugs for disorders of the nervous system
- 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
- C07D 495/14: Ortho-condensed systems
- 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)

## Abstract

Disclosed herein are tricyclic compounds, including thieno[2,3-d:4,5-d′]dipyrimidin-4-amine and pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-8-amine compounds, which may be useful as positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4). Also disclosed herein are methods of 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.

## Claims

### Claim 1

A compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein:
X is N or CR5;
R5 is selected from hydrogen, halo, and cyano;
R1 is selected from C1-C4-alkyl, C3-C6-cycloalkyl, hydrogen, halo, —ORa, and —NRbRc;
R2 and R3 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, heterocycle, and —(CReRf)n—Y;
or R2 and R3 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring;
Y is selected from halo, —OR, —SR, —C(O)R, —C(O)OR, —S(O)R, —SO2R, —NR2, —C(O)NR2, —S(O)2NR2, aryl, heteroaryl, cycloalkyl, and heterocycle;
n is 1, 2, 3, 4, 5, 6, 7, or 8;
each Ra, Rb, and Rc is independently selected from hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycle;
each Re and Rf is independently selected from hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, and halo; and
each R is independently selected from hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, and heteroalkyl;
wherein each aryl, cycloalkyl, heterocycle, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
X is CR5.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula (Ia):
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula (Ib):
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula (Ie):
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of C1-C4 alkyl and C3-C6-cycloalkyl.

### Claim 8 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from the group consisting of methyl, ethyl, cyclopropyl and isobutyl.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R2 is hydrogen or C1-C4 alkyl; and
R3 is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, heterocycle, and —(CReRf)n—Y.

### Claim 10 (depends on 9)

The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein
R2 is hydrogen;
R3 is selected from C3-C6 cycloalkyl and —(CReRf)n—Y;
n is 1;
Re and Rf are each hydrogen; and
Y is aryl;
wherein each cycloalkyl and aryl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, halo, hydroxy, C3-C6 cycloalkyl, and —(CRgRh)—Z;
Rg is selected from hydrogen and hydroxy;
Rh is selected from hydrogen and C1-C4 alkyl; and
Z is C3-C6 cycloalkyl.

### Claim 11 (depends on 10)

The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein
R2 is hydrogen;
R3 is —(CReRf)n—Y;
n is 1;
Re and Rf are each hydrogen; and
Y is phenyl, which is unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4 hydroxyalkyl, C1-C4 alkoxy, halo, C3-C6 cycloalkyl, and —(CRgRh)—Z.

### Claim 12 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R2 and R3 are taken together with the nitrogen atom to which they are attached to form a 4-, 5-, 6-, or 7-membered heterocyclic ring which is unsubstituted or substituted with 1, 2 or 3 substituents.

### Claim 13 (depends on 12)

The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein
R2 and R3 are taken together with the nitrogen atom to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, or 3-azabicyclo[3.1.0]hexanyl group, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4 alkyl and halogen.

### Claim 14 (depends on 1)

A compound of claim 1, selected from:
2-(4-(((7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidin-4-yl)amino)methyl)phenyl)propan-2-ol;
7,9-dimethyl-4-(pyrrolidin-1-yl)thieno[2,3-d:4,5-d′]dipyrimidine;
N-(3-fluoro-4-methoxybenzyl)-7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidin-4-amine;
N-cyclopentyl-7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidin-4-amine;
2-(4-(((7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidin-4-yl)amino)methyl-d2)phenyl)propan-2-ol;
1-(4-(((7,9-dimethylthieno[2,3-d :4, 5-d′]dipyrimidin-4-yl)amino)methyl)phenyl)cyclobutan-1-ol;
1-cyclopropyl-1-(4-(((7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidin-4-yl)amino)methyl)phenyl)ethan-1-ol;
4-(3-azabicyclo[3.1.0]hexan-3-yl)-7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidine;
4-(7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidin-4-yl)morpholine;
6-(7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane;
2,4-dimethyl-8-(pyrrolidin-1-yl)pyrido[4′,3′:4, 5]thieno[2,3-d]pyrimidine;
2,4-dimethyl-8-(1-piperidyl)pyrido[4′,3′:4, 5]thieno[2,3-d]pyrimidine;
N-(3-fluoro-4-methoxybenzyl)-2,4-dimethylpyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-8-amine;
2-(4-(((2,4-dimethylpyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-8-yl)amino)methyl)phenyl)propan-2-ol;
N-cyclopentyl-2,4-dimethylpyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-8-amine;
4-(azetidin-1-yl)-7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidine;
4-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidine;
4-(3,3-difluoropyrrolidin-1-yl)-7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidine;
(S)-4-(3-fluoropyrrolidin-1-yl)-7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidine;
(R)-4-(3-fluoropyrrolidin-1-yl)-7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidine;
4-(4,4-difluoropiperidin-1-yl)-7,9-dimethylthieno[2,3-d:4,5-d′]dipyrimidine;
2-[4-[[(2,4-dimethylpyrido[4,5]thieno[1,2-b]pyrimidin-8-yl)amino]methyl]-3-fluoro-phenyl]propan-2-ol;
4-[[(2,4-dimethylpyrido[4,5]thieno[1,2-b]pyrimidin-8-yl)amino]methyl]-N,N-diethyl-benzamide;
N,N-diethyl-2,4-dimethyl-pyrido[4,5]thieno[1,2-b]pyrimidin-8-amine;
8-(3,3-difluoropyrrolidin-1-yl)-2,4-dimethyl-pyrido[4,5]thieno[1,2-b]pyrimidine;
N-cyclobutyl-2,4-dimethyl-pyrido[4,5]thieno[1,2-b]pyrimidin-8-amine;
2-[4-[[(2-cyclopropyl-4-methyl-pyrido[4,5]thieno[1,2-d]pyrimidin-8-yl)amino]methyl]-2-fluoro-phenyl]propan-2-ol;
2-[4-[[(2-cyclopropyl-4-methyl-pyrido[4,5]thieno[1,2-d]pyrimidin-8-yl)amino]methyl]phenyl]propan-2-ol;
2-cyclopropyl-N-[(3,4-difluorophenyl)methyl]-4-methyl-pyrido[4,5]thieno[1,2-d]pyrimidin-8-amine;
4-(2-cyclopropyl-4-methyl-pyrido[4,5]thieno[1,2-d]pyrimidin-8-yl)morpholine;
2-[4-[[(2,4-dimethylpyrido[4,5]thieno[1,2-b]pyrimidin-8-yl)amino]methyl]-2-fluoro-phenyl]propan-2-ol;
N,2-dicyclopropyl-4-methyl-pyrido[4,5]thieno[1,2-d]pyrimidin-8-amine;
2-ethyl-N-[(3-fluoro-4-methoxy-phenyl)methyl]-4-methyl-pyrido[4,5]thieno[1,2-b]pyrimidin-8-amine;
2-[4-[[(2-ethyl-4-methyl-pyrido[4,5]thieno[1,2-b]pyrimidin-8-yl)amino]methyl]phenyl]propan-2-ol;
8-(3,3-difluoropyrrolidin-1-yl)-2-ethyl-4-methyl-pyrido[4,5]thieno[1,2-b]pyrimidine;
2-[4-[[(2-isobutyl-4-methyl-pyrido[4,5]thieno[1,2-b]pyrimidin-8-yl)amino]methyl]phenyl]propan-2-ol;
2-cyclopropyl-4-methyl-8-(1-piperidyl)pyrido[4,5]thieno[1,2-d]pyrimidine;
2-cyclopropyl-4-methyl-8-pyrrolidin-1-yl-pyrido[4,5]thieno[1,2-d]pyrimidine;
N-cyclopentyl-2-cyclopropyl-4-methyl-pyrido[4,5]thieno[1,2-d]pyrimidin-8-amine;
2-cyclopropyl-8-(4-fluoro-1-piperidyl)-4-methyl-pyrido[4,5]thieno[1,2-d]pyrimidine;
2-(4-(((5-chloro-2,4-dimethylpyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-8-yl)amino)methyl)phenyl)propan-2-ol;
5-chloro-N-[(3-fluoro-4-methoxy-phenyl)methyl]-2,4-dimethyl-pyrido[4,5]thieno[1,2-b]pyrimidin-8-amine;
5-chloro-N-[(3,4-difluorophenyl)methyl]-2,4-dimethyl-pyrido[4,5]thieno[1,2-b]pyrimidin-8-amine;
5-chloro-N-cyclobutyl-2,4-dimethyl-pyrido[4,5]thieno[1,2-b]pyrimidin-8-amine;
5-chloro-2,4-dimethyl-8-pyrrolidin-1-yl-pyrido[4,5]thieno[1,2-b]pyrimidine; and
8-((4-(2-hydroxypropan-2-yl)benzyl)amino)-2,4-dimethylpyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-5-carbonitrile, or
a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is isotopically labeled.

### Claim 16 (depends on 15)

The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein
R2 is hydrogen;
R3 is —(CReRf)n—Y;
each Re is deuterium; and
each Rf is deuterium.

### Claim 17 (depends on 16)

The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein
n is 1;
Y is phenyl that is substituted with a C1-C4-hydroxyalkyl group.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 19 (depends on 1)

A method for treating a neurological and/or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal, comprising a step of administering to the mammal a therapeutically effective amount of a compound of claim 1, or pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 19)

The method of claim 19, wherein the disorder is associated with a mAChR M4 dysfunction.

### Claim 21 (depends on 19)

The method of claim 19, wherein the disorder is a neurological and/or psychiatric disorder associated with mAChR M4 dysfunction.

### Claim 22 (depends on 19)

The method of claim 19, wherein the disorder is selected from Alzheimer's disease, schizophrenia, a sleep disorder, a pain disorder, and a cognitive disorder.

### Claim 23 (depends on 22)

The method of claim 22, wherein the disorder is Alzheimer's disease.

### Claim 24 (depends on 19)

The method of claim 19, 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, 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 25

(canceled)

### Claim 26

(canceled)

### Claim 27

(canceled)

### Claim 28

(canceled)

### Claim 29

(canceled)

### Claim 30 (depends on 1)

A kit comprising a compound of claim 1, or pharmaceutically acceptable salt thereof, and one or more of: (a) at least one agent known to increase mAChR M4 activity; (b) at least one agent known to decrease mAChR M4 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 M4 receptor activity; and (f) instructions for administering the compound in connection with cognitive or behavioral therapy.