# US 2018/0022745 A1 · Isoquiniline and napthalene-substituted compounds as mglur4 allosteric potentiators, compositions, and methods of treating neurological dysfunction

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- Number: US 2018/0022745 A1
- Document ID: US20180022745A1
- Status: Published application
- Kind: A1
- Application number: 15/547,775
- Filed: 2016-02-01
- Published: 2018-01-25
- Earliest claimed: 2015-01-30
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: P. Jeffrey Conn; Craig W. Lindsley; Colleen M. Niswender; Corey R. Hopkins; Joanne Bronson; Yong-Jin Wu; Kyle Emmitte; Joe Panarese; Darren W. Engers; Julie Engers
- Web page: https://patentgrep.com/patent/US20180022745A1

## CPC

- C07D 471/04: Ortho-condensed systems
- 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 31/4725: containing further heterocyclic rings
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/502: ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- A61K 31/554: having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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 401/12: linked by a chain containing hetero atoms as chain links
- C07D 487/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- 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

## Abstract

Compounds which are useful as allosteric potentiators/positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4); pharmaceutical compositions comprising the compounds; and methods of using the compounds, for example, in treating neurological and psychiatric disorders or other disease state associated with glutamate dysfunction.

## Claims

### Claim 1

A compound having a structure of the following formula:
wherein the variables are substituted or unsubstituted and:
W is CH, CD, N, C-alkyl, C-halogen;
X is N, CH, CD, C-alkyl, or may form a 6-membered ring with Y optionally substituted with at least one R;
X1 is CH, CD, C—R2, N, or is N and together with R1 forms a 5 or 6 membered ring;
X2 is CH, CD, C—R2, or N, or together with R3 forms a 5 or 6 membered ring;
Y is N, CH, CD, C-alkyl, or may form a 6-membered ring with X optionally substituted with at least one R;
Z1 is CH, CD, C-alkyl, N, C-halogen, C-alkoxy;
Z2 is CH, CD, C-alkyl, N, C-halogen, C-alkoxy;
R is halogen, CN, Me, alkyl, OMe, alkoxy;
R1 H, alkyl, aklene, cycloalkyl, NR4R5, aryl, halogen, CF3, cycloheteroalkyl, alkoxy, OH, CN, Oalkyl, Oaryl, Oheteroaryl, NHalkyl, NHaryl, NHheteroaryl, heteroaryl, CH2F, CHF2, NR4R5, CO-heteroaryl, CO—NH-alkyl, CO—NH-methoxyalkyl, CO-amino, CO-aryl, CO-heteroaryl, CO-aminocycloalkyl, CO-amino-alkoxy, CO-alkyl, Nalkylalkyl, NH-alkoxy, or together with X1 forms a 5 or 6 membered ring;
R2 is H, halogen, alkyl, alkoxy, OMe, CONH2, CN, O;
R3 is H, alkyl, alkene, cycloalkyl, aryl, heteroaryl, alkoxy, hydroxyl, amino, aminoalkoxy, halogen, or together with X2 forms a 5 or 6 membered ring;
R4 is H, alkyl, cycloalkyl, aryl, heteroaryl, alkyl-aryl, methoxyalkyl;
R5 is H, alkyl, cycloalkyl, aryl, heteroaryl;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 2 (depends on 1)

A compound of claim 1, of the following formula:
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 3 (depends on 1)

A compound of claim 1, of the following formula:
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 4 (depends on 1)

A compound of claim 1, of the following formula:
wherein:
R1A is amino, piperazine, piperazine-ethanone, NH-methylsulfonylalkyl, pyrrolidine, fluoropyrrolidine, NH-cyclobutyl, NH-fluorocyclobutyl, NH-difluorocyclobutyl, piperazine, sulfonylpiperazine, methylsulfonylpiperazine, thiazepan, dioxothiazepan, pyrrolidine, sulfonylpyrrolidine, oxazepan, methylsulfonylpyrrolidine, difluoropyrrolidin, piperidine, piperidine-carboxamide, fluoropiperidine, alkylpiperidine, difluoropiperidine, CO-amino, amino-alkyl, dihydrothiazone, morpholine, thiomorpholino, dioxothiomorpholino, amino-alkoxy, amino-cycloalkyl, methoxyalkyl, pyrazolo, azaspiroheptane, difluoroazaspiroheptaneaklyl; and
R1B is alkyl-tetrahydropyran, alkyl, alkyl-dimethylamino, phenyl, trifluoromethylphenyl, amino-alkyl, pyrazole, alkoxyphenyl;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 5 (depends on 1)

A compound of claim 1, wherein R1 is piperidine, methyl-piperidine, piperazine, pyrimidine, piperazine-pyrimidine, pyrimidine, pyrazole, triazole, pyrazole-alkyl, amino-triflouroalkyl, morpholine, thiophene, aminobenzyl, aminocycloalkyl, triflouromethylpyrrolidine, pyrrolidine, pyrimidine-carbonyl, trifluoromethylpyrrolidinecarbonyl, pyrrolo-pyridine, carbonyl-morpholine, benzopyrazole, benzotrimethylpyrazole, azetidine, difluoroazetidine, amino-pyrrolidine, amino-alkoxy.

### Claim 6 (depends on 1)

A compound of claim 1, wherein R2 is H, alkyl, CN, CO—NH2, halogen, amino-alkyl, alkoxy.

### Claim 7 (depends on 1)

A compound of claim 1, wherein R3 is trifluoroalkyl, pyrazole, methylpyrazole, pyridine, fluoropyridine, furan, fluoroalkyl, cyclopropyl, cyclopentyl, piperidine, pyrrolidine, morpholine, amino, amino-alkyl-cycloalkyl, fluoro-pyrrolidine, dialkylamino.

### Claim 8 (depends on 1)

A compound of claim 1, wherein:
cycloalkyl is cyclobutyl, cyclopropyl, cyclopentyl; and
cycloheteroaryl is piperazine, pyrrolidin, thiazepin, piperazin-ethanone, azaspiroheptane, oxazepan, tetrahydropyran, morpholino, thiomorpholino, dioxothiomorpholino.

### Claim 9 (depends on 1)

A compound of claim 1, wherein:
heteroaryl is pyrazole, triazol, isoxazol, azetidin, thiophen, pyrozolopyrimidine, imidazole, indazole, indazole, pyrazolo-pyridin, and tetramethyl-furopyrazole.

### Claim 10 (depends on 1)

A compound of claim 1, of the following formula:
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 11 (depends on 1)

A compound of claim 1, of the following formula:
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 12 (depends on 1)

A compound of claim 1, of the following formula:
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 13 (depends on 1)

A compound of claim 1, of the following formula:
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 14

A compound having a structure of the following formula:
wherein the variables are substituted or unsubstituted, and:
X1 is CH, CD, C—R2, N, or is N and together with R1 forms a 5 or 6 membered ring;
X2 is CH, CD, C—R2, or N;
Y is N, CH, CD, C-alkyl, or may form a 6-membered ring with Y optionally substituted with at least one R;
R is halogen, CN, Me, alkyl, OMe, alkoxy;
R1 is H, alkyl, aklene, cycloalkyl, NR4R5, aryl, halogen, CF3, cycloheteroalkyl, alkoxy, OH, CN, Oalkyl, Oaryl, Oheteroaryl, NHalkyl, NHaryl, NHheteroaryl, heteroaryl, CH2F, CHF2, NR4R5, CO-heteroaryl, CO—NH-alkyl, CO—NH-methoxyalkyl, CO-amino, CO-aryl, CO-heteroaryl, CO-aminocycloalkyl, CO-amino-alkoxy, CO-alkyl, Nalkylalkyl, NH-alkoxy, or together with X1 forms a 5 or 6 membered ring;
R2 is H, halogen, alkyl, alkoxy, OMe;
R3 is H, alkyl, cycloalkyl, aryl, heteroaryl;
R4 is H, alkyl, cycloalkyl, aryl, heteroaryl, alkyl-aryl, methoxyalkyl;
R5 is H, alkyl, cycloalkyl, aryl, heteroaryl;
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 14)

A compound of claim 14, of the following formula:

### Claim 16 (depends on 1)

A method for the treatment of a neurotransmission dysfunction and other disease states associated with mGluR4 activity in a mammal comprising the step of administering to the mammal at least one compound of claim 1 in a dosage and amount effective to treat the dysfunction in the mammal.

### Claim 17 (depends on 16)

The method of claim 16, wherein the mammal is a human.

### Claim 18 (depends on 16)

The method of claim 16, wherein the dysfunction is Parkinson's disease.

### Claim at position 19

19-27. (canceled)

### Claim 28 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim at position 21

29-51. (canceled)

### Claim 52 (depends on 1)

A method for the treatment of a neurotransmission dysfunction or other disease state associated with mGluR4 activity in a mammal comprising the step of co-administering to the mammal at least one compound of claim 1 in a dosage and amount effective to treat the dysfunction in the mammal, with (i) a drug having a known side-effect of increasing metabotropic glutamate receptor activity, (ii) a drug known to treat a disorder associated with increasing metabotropic glutamate receptor activity, and/or (iii) a drug known to treat the neurotransmission dysfunction or other disease state associated with potentiation of mGluR4.

### Claim 53

(canceled)

### Claim 54 (depends on 52)

The method of claim 52, wherein the mammal is a human and the dysfunction is Parkinson's disease.

### Claim at position 25

55-56. (canceled)

### Claim 57 (depends on 1)

A compound of claim 1, of the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 58 (depends on 1)

A compound of claim 1, of the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 59 (depends on 1)

A compound of claim 1, of the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 60 (depends on 1)

A compound of claim 1, the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 61

A compound of the following formula:
wherein the variables are substituted or unsubstituted, and:
R is substituted or unsubstituted, and chosen from halogen, CN, Me, alkyl, OMe, alkoxy;
R2 is substituted or unsubstituted, and chosen from R2 is H, halogen, alkyl, alkoxy, OMe, CONH2, CN, O;
R3 is substituted or unsubstituted, and chosen from H, alkyl, alkene, cycloalkyl, aryl, heteroaryl, alkoxy, hydroxyl, amino, aminoalkoxy, halogen, or together with X2 forms a 5 or 6 membered ring containing C or N as the ring members;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 62 (depends on 61)

A compound of claim 61, of the following formula:

### Claim 63 (depends on 61)

A compound of claim 61, of the following formula:

### Claim 64

A pharmaceutical composition comprising a compound having a structure represented by a formula:
wherein the variables are substituted or unsubstituted, and:
R is halogen, CN, Me, alkyl, OMe, alkoxy;
R1 is H, alkyl, aklene, cycloalkyl, NR4R5, aryl, halogen, CF3, cycloheteroalkyl, alkoxy, OH, CN, Oalkyl, Oaryl, Oheteroaryl, NHalkyl, NHaryl, NHheteroaryl, heteroaryl, CH2F, CHF2, NR4R5, CO-heteroaryl, CO—NH-alkyl, CO—NH-methoxyalkyl, CO-amino, CO-aryl, CO-heteroaryl, CO-aminocycloalkyl, CO-amino-alkoxy, CO-alkyl, Nalkylalkyl, NH-alkoxy, or together with X1 forms a 5 or 6 membered ring;
R2 is H, halogen, alkyl, alkoxy, OMe, CONH2, CN, O;
R3 is H, alkyl, alkene, cycloalkyl, aryl, heteroaryl, alkoxy, hydroxyl, amino, aminoalkoxy, halogen, or together with X2 forms a 5 or 6 membered ring;
R4 is H, alkyl, cycloalkyl, aryl, heteroaryl, alkyl-aryl, methoxyalkyl;
R5 is H, alkyl, cycloalkyl, aryl, heteroaryl;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.

### Claim 65 (depends on 64)

The composition of claim 64, wherein the compound is of the following formula:

### Claim 66 (depends on 65)

The composition of claim 65, wherein the compound is of the following formula: