# US 2018/0022746 A1 · Indazole and azaindazole substituted compounds as mglur4 allosteric potentiators, compositions, and methods of treating neurological dysfunction

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- Number: US 2018/0022746 A1
- Document ID: US20180022746A1
- Status: Published application
- Kind: A1
- Application number: 15/547,781
- Filed: 2016-02-01
- Published: 2018-01-25
- Earliest claimed: 2015-01-30
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: P. Jeffrey Conn; Corey R. Hopkins; Craig W. Lindsley; Colleen M. Niswender; Darren W. Engers; Joe Panarese; Joanne Bronson; Yong-Jin Wu; Jason Guernon
- Web page: https://patentgrep.com/patent/US20180022746A1

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/416: condensed with carbocyclic ring systems, e.g. indazole
- A61K 31/4162: condensed with heterocyclic ring 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 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- 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
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- 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)

## Abstract

Compounds which are useful as allosteric potentiators/positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4); synthetic methods for making the compounds; 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 represented by the formula:
wherein the variables are substituted or unsubstituted and:
X is N, alkyl, alkoxy, or CH, CD, and optionally together with Y forms a six membered ring optionally substituted with one or more R;
Y is N, alkyl, alkoxy, or CH and optionally together with X forms a six membered ring optionally substituted with one or more R;
Z is N, CH, CD, or C-halogen, C—Me, C—O—Me, C—CN;
R is independently chosen from H, Cl, F, CN, alkyl, cycloalkyl, Me, OMe, alkoxy;
X1 is N, NH, CH, CD, CR1;
X2 is N, NR1, or NR2;
X3 is N, NH, CH, CD, CR1;
provided that one of X1 or X3 is CH or CR1;
R1 is independently H, alkyl, cycloalkyl, phenyl, cycloheteroalkyl, halogen, CF3, Cl, CD3, CD2R, CDRR2, aryl, heteroaryl, SO2R3. O—R, O-aryl, O-heteroaryl, NHR, NR2R2, perfluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH2heteroaryl), alkene, alkyl-cycloalkyl, O-alkyl-cycloalkyl, CH2-cycloalkyl, CH2—CF3, hydroxyalkyl, alkyl-alkoxy, alkyl-cycloheteroalkyl, alkyl-heteroaryl, alkyl-carboxylic acid, CO—CF3, alkyl-CO—O-alkyl, CO-alkyl-sulfonyl-alkyl, CO-cycloheteroalkyl, CO—NH-cycloalkyl, CN, alkoxy-cycloalkyl, alkoxy-cycloheteroalkyl, O-alkoxy, O-phenyl, O-alkoxyphenyl-O-dioxothian, hydroxyl, alkoxy, O-alkyl-heteroaryl, O-alkyl-cycloheteroalkyl, alkoxy-heteroalkyl, methylsulfonyl, O-cycloheteroalkyl, O-alkoxy-cycloheteroalkyl, O-alkoxyaryl, alkoxy-heteroaryl, alkoxy, alkyl-phenyl, cycloheteroalkyl, O—CD3, O—CD2R, hydroxyl, amino, CO-alkyl, CO-cycloalkyl, CO-alkyl-cycloalkyl, CO-amino-alkyl-sulfonylmethyl, CO-amino-cycloalkyl;
R2 is independently H, heteroaryl, alkyl, phenyl, aryl, O-cycloheteroalkyl, alkoxy-cycloheteroalkyl, O-alkoxy-cycloheteroalkyl, O-alkoxyaryl, O-heteroaryl, alkoxy-heteroaryl, alkoxy, alkoxycycloheteroalkyl, alkyl-phenyl, cycloheteroalkyl, O—CD3, O—CD2R, hydroxyl, amino, cycloalkyl, CH2-cycloalkyl, CO-alkyl; cycloheteroalkyl, H, CF3, halogen, CD3, CD2R, CDRR2, aryl, SO2R3, OR, Oaryl, NHR, NR1R1, perfluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH2heteroaryl), alkene, alkyl-cycloalkyl, CH2-cycloalkyl, CH2—CF3, hydroxyalkyl, alkyl-alkoxy, alkyl-cycloheteroalkyl, alkyl-heteroaryl, O-alkyl-heteroaryl, alkyl-carboxylic acid, CO—CF3, alkyl-CO—O-alkyl, CO-alkyl-sulfonyl-alkyl, CO-cycloheteroalkyl, CO—NH-cycloalkyl, CN, alkoxy-cycloalkyl, O-dioxothian, hydroxyl, methylsulfonyl;
R3 is H, alkyl, alkoxyphenyl, pyridine, nitrilepyridine, chloropyridine;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X and Y together form:

### Claim 3 (depends on 1)

The compound of claim 1, wherein R, when present, is F.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Z is N, CH, CD, or C—Cl.

### Claim 5 (depends on 1)

The compound of claim 1, of the following formula:

### Claim 6 (depends on 1)

The compound of claim 1, of the following formula:

### Claim 7 (depends on 6)

The compound of claim 6, wherein R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; and R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

### Claim 8 (depends on 1)

A compound of claim 1, of the following formula:

### Claim 9 (depends on 1)

A compound of claim 1, of the following formula:
wherein R1 is H, alkyl, cycloalkyl, heterocycloalkyl, alkyl-cycloalkyl, trifluoroalkyl, hydroxyalkyl, alkyl-alkoxy; and R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

### Claim 10 (depends on 1)

A compound of claim 1, of the following formula:
wherein R1 is H, alkyl, cycloalkyl, heterocycloalkyl, CO—CF3, CD2-alkyl, alkyl-heteroaryl, alkyl-cycloalkyl, cycloalkyl, and R2 is H, alkyl, cycloalkyl, heterocycloalkyl, alkyl-phenyl, cycloalkyl.

### Claim 11 (depends on 1)

A compound of claim 1, of the following formula:
wherein R1 is H, alkyl, cycloalkyl, heterocycloalkyl, and R2is H, alkyl, cycloalkyl, heterocycloalkyl.

### Claim 12 (depends on 1)

A compound of claim 1, of the following formula:
wherein R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, and R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

### Claim 13 (depends on 1)

A compound of claim 1, of the following formula:
wherein R1 is H, alkyl, alkene, alkyl-heteroalkyl, alkyl-heterocycloalkyl alkyl, heterocycloalkyl, trifluoroalkyl, alkyl-cycloalkyl, cycloalkyl, alkyl-heteroaryl, heteroaryl, alkyl-acetic acid, CD3, alkoxy, CD2-alkyl, alkyl-CO-alkoxy, CF3, phenyl; fluorophenyl, alkylcarbontrichloride, alkyltricluorocarbon, and R2 is H, alkyl, Cl, CF3, heteroaryl, cyclopentene, alkyl-phenyl, trifluoroalkyl, cycloheteroalkyl, amino-alkyl-carboxylate ester; hydoxy, alkyl-cycloalkyl, amino, amino-CO—CF3, cycloalkyl.

### Claim 14 (depends on 1)

A compound of claim 1, of the following formula:
wherein R1 is H, alkyl, cycloalkyl; and R2 is H, alkyl, alkyl-cycloalkyl, alkyl-heteroaryl, CD3.

### Claim 15 (depends on 1)

A compound of claim 1, of the following formula:
wherein R may be optionally present and when present is O—Me; R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkyl-heteroalkyl; and R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

### Claim 16 (depends on 1)

A compound of claim 1, of the following formula:
wherein Z is N, C—H, C—Me, C—O—Me; R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, CN, methylsulfonyl, O-alkoxy, O-cycloheteroalkyl, cycloheteroalkyl, alkoxycycloheteroalkyl, halogen, and R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkyl-heteroaryl, alkyl-acetic acid, heterocycloalkyl, CD3.

### Claim 17 (depends on 1)

A compound of claim 1, of the following formula:
wherein R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; and R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkene.

### Claim 18 (depends on 1)

A compound of claim 1, of the following formula:
wherein R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkoxy, alkyl-cycloalkyl, R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, cycloheteroalkyl.

### Claim 19 (depends on 1)

A compound of claim 1, of the following formula:
wherein R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; and R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

### Claim 20 (depends on 1)

A compound of claim 1, of the following formula:
wherein Z is N, CH, CD, C, halogen, C—O—Me; R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, methylsulfonyl; and R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkyl-heteroaryl, CD3.

### Claim 21 (depends on 1)

A compound of claim 1, of the following formula:
wherein R1A is H, alkyl, cycloalkyl, alkyl-cycloalkyl, amino-alkyl-sulfonylmethyl, cycloheteroalkyl, amino-cycloalkyl; and R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

### Claim 22 (depends on 1)

A compound of claim 1, of the following formula:
wherein R1B is H, alkyl, cycloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, alkoxy, alkyl-cycloheteroalkyl, alkoxyphenyl, heteroaryl, nitrilepyridine, chloropyridine; and R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

### Claim 23 (depends on 1)

A compound of claim 1, of the following formula:
wherein R may be optionally present and when present is F; R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkoxy, hydroxyl, cycloalkyl, methysulfonyl; R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkyl-heteroaryl.

### Claim 24 (depends on 1)

A compound of claim 1, of the following formula:
wherein R may be optionally present and when present is; R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

### Claim 25 (depends on 1)

A compound of claim 1, of the following formula:
wherein R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkyl-heteroaryl; or
a compound of claim 1, of the following formula:
wherein R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; R2 is alkyl, alkyl-cycloalkyl, alkylheteroaryl.

### Claim 26 (depends on 1)

A compound of claim 1, of the following formula:
wherein R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, heterocycloalkyl, alkoxyphenyl, alkoxyfluorophenyl, heteroaryl, alkylheteroaryl, triflouroalkyl, alkoxyheteroaryl, alkoxy.

### Claim 27 (depends on 1)

A compound of claim 1, of the following formula:
wherein Z is C or C—Cl; R1B is H, alkyl, cycloalkyl, alkyl-cycloalkyl, heteroaryl, alkylheteroaryl, alkoxy, CD3, CD2alkyl, alkylcycloalkyl, alkylphenyl, alkoxy, alkyl-heterocycloalkyl; R2 is heterocycloalkyl, H, alkyl, cycloalkyl, alkyl-cycloalkyl.

### Claim 28 (depends on 1)

A compound of claim 1, of the following formula:
wherein R is F; R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, CD3.

### Claim 29 (depends on 1)

A compound of claim 1, of the following formula:
wherein R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

### Claim 30 (depends on 1)

A compound of claim 1, of the following formula:
wherein Y is N or CH; Z is CH, CD, C—Cl, N; R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkene, CD3, alkyl, alkyl-heteroaryl; and R3 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

### Claim 31 (depends on 1)

A compound of claim 1, of the following formula:
wherein Y is N or CH, CD, Z is C or N; Z is CH, CD, C—Cl, N; R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkene, CD3, alkyl, alkyl-heteroaryl; and R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

### Claim 32 (depends on 1)

A compound of claim 1, of the following formula:
Z is CH, CD, C—Cl, N; R is optionally and independently present, and when present is H, alkyl, F; R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; and R3 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, CD3.

### Claim 33 (depends on 1)

A compound of claim 1, of the following formula:
R1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; R2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; and R3 is alkoxy phenyl, pyridine, nitrilepyridine, chloropyridine.

### Claim 34 (depends on 1)

A compound of claim 1, where X1 is N and R1 is alkyl, alkene, CH2-cycloalkyl, cycloalkyl, CH2—CF3, hydroxyalkyl, cycloheteroalkyl, alkyl-alkoxy, heteroaryl, alkyl-cycloheteroalkyl, alkyl-heteroaryl, alkyl-carboxylic acid, CD3, CO—CF3, alkyl-CO—O-alkyl.

### Claim 35 (depends on 1)

A compound of claim 1, where X1 is CH and R1 is CO-alkyl-sulfonyl-alkyl, CO-cycloheteroalkyl, CO—NH-cycloalkyl, CN, alkoxy-cycloalkyl, alkoxy-cycloheteroalkyl, O-alkoxy, O-dioxothian, hydroxyl, alkoxy, cycloalkyl, O-heteroalkyl, alkoxy-heteroalkyl, methylsulfonyl.

### Claim 36 (depends on 9)

A compound of claim 9, where R1 is cyclopentylmethyl, cyclobutylmethyl, cyclobutyl, cyclopropyl, cyclohexyl, tetrahydropyran, methoxyethyl.

### Claim 37 (depends on 10)

A compound of claim 10, wherein R1 is pyridine.

### Claim 38 (depends on 12)

A compound of claim 12, wherein R1 is pyridinepyrazole.

### Claim 39 (depends on 13)

A compound of claim 13, wherein R1 is benzisoxizole, fluoropyridine-substituted isoxazole, cyclopropyl-substituted isozazole, tetrahydropyran, methylquinolone, alkyl, piperidine, alkyl-piperadine, trifluoroethyl, cyclobutyl, methylisoxazole, methylcyclopropyl, methylcyclobutyl, methyldifluorocyclobutyl, alkylmorpholine, methyl oxadiazole, alkyl-methyl benzixoxazole.

### Claim 40 (depends on 14)

A compound of claim 14, wherein R1 is methylbenzisoxizole.

### Claim 41 (depends on 15)

A compound of claim 15, wherein R1 is methylbenzisoxizole.

### Claim 42 (depends on 16)

A compound of claim 16, wherein R2 is piperazine.

### Claim 43 (depends on 18)

A compound of claim 18, wherein R1 is methylcyclobutyl.

### Claim 44 (depends on 21)

A compound of claim 21, wherein R1A is difluoropiperidine, piperidine, piperidine-carboxamide, fluoropiperidine, thiazine, dioxothiazine, piperizine, methyl piperizine, morpholino, pyrolidine, methylsulfonylpyrrolidine, fluoropyrrolidine, difluoropyrrolidine, N-cyclobutyl, N-difluorocyclobutyl.

### Claim 45 (depends on 22)

A compound of claim 22, wherein R1B is cyclopropyl, difluorocyclopropyl, piperidine, methylpiperidine, oxetane, methyloxetame, thiane, dioxothiane, tetrahydrofuran, pyridine, carbonitrilepyridine, tetrahydropyran, morpholine, morpholinoethoxy.

### Claim 46 (depends on 1)

A compound of claim 1, of the following formula:

### Claim 47

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

### Claim 48 (depends on 1)

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

### Claim 49 (depends on 1)

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

### Claim 50 (depends on 1)

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

### Claim 51 (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 at position 52

52-62. (canceled)

### Claim 63 (depends on 1)

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

### Claim at position 54

64-89. (canceled)

### Claim 90 (depends on 1)

A compound of claim 1, wherein heteroaryl is substituted or unsubstituted and chosen from isoxazole, methyl-isoxazole, alkyl-isoxazole, benzoisoxazole, quinnoline, pyridine, nitrilepyridine, or chloropyridine.

### Claim 91 (depends on 1)

A compound of claim 1, wherein cycloheteroaryl is substituted or unsubstituted and chosen from pyrolidin-one, methyl-pyrolidin-one, alkyl-pyrolidin-one, piperidine, fluoro-piperidine, di-fluoro-piperidine, tetrahydropyran, piperazine, methyl-piperazine, thiomorpholine-dioxide, morpholine, pyrolidine, or oxetane.

### Claim 92 (depends on 21)

A compound of claim 21, of the following formula:
and pharmaceutically acceptable salts thereof.

### Claim 93 (depends on 22)

A compound of claim 22, of the following formula:
and pharmaceutically acceptable salts thereof.

### Claim 94 (depends on 1)

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

### Claim at position 60

95-98. (canceled)

### Claim 99 (depends on 1)

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

### Claim at position 62

100-102. (canceled)