# US 12,006,323 B2 · Ethynyl derivatives

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 12,006,323 B2
- Document ID: US12006323B2
- Status: Granted
- Kind: B2
- Application number: 17/315,349
- Filed: 2021-05-09
- Published: 2021-09-02
- Granted: 2024-06-11
- Earliest claimed: 2015-07-15
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Barbara Biemans; Wolfgang Guba; Georg Jaeschke; Lothar Lindemann; Fionn O'Hara; Antonio Ricci; Daniel Rueher; Eric Vieira
- Web page: https://patentgrep.com/patent/US12006323B2

## CPC

- C07D 487/10: Spiro-condensed systems
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 35/00: Antineoplastic agents
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 471/10: Spiro-condensed systems
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D 491/20: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) that may be used for the treatment of conditions such as Parkinson's disease, anxiety, emesis, obsessive compulsive disorder, autism, neuroprotection, cancer, depression and diabetes type 2.

## Claims

### Claim 1

A method for the treatment of anxiety, the method comprising administering to a mammal in need thereof an effective amount of a compound of formula I:
wherein:
R1 is lower alkyl;
R2 is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;
n is 0, 1 or 2;
V/U are independently from each other O or CH2, wherein V and U cannot be simultaneously O;
L is a five or six membered heteroaryl group, selected from:
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound of formula I is a compound of formula IA:
wherein:
R1 is lower alkyl;
R2 is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;
L is a five or six membered heteroaryl group, selected from:
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound of formula I is selected from the group consisting of:
(8S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[6,7-dihydro-5H-isoquinoline-8,6′-hexahydropyrimidine]-2′,4′-dione;
(6S)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1-methyl-spiro[hexahydropyrimidine-6,1′-tetralin]-2,4-dione;
(5S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[7,8-dihydro-6H-quinoline-5,6′-hexahydropyrimidine]-2′,4′-dione;
(5S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[7,8-dihydro-6H-isoquinoline-5,6′-hexahydropyrimidine]-2′,4′-dione;
(5S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[7,8-dihydro-6H-quinazoline-5,6′-hexahydropyrimidine]-2′,4′-dione;
(8S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-ethyl-spiro[6,7-dihydro-5H-isoquinoline-8,6′-hexahydropyrimidine]-2′,4′-dione;
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[1,5,6,7-tetrahydroindazole-4,6′-hexahydropyrimidine]-2′,4′-dione;
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′,2-dimethyl-spiro[6,7-dihydro-5H-indazole-4,6′-hexahydropyrimidine]-2′,4′-dione; and
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1,1′-dimethyl-spiro[6,7-dihydro-5H-indazole-4,6′-hexahydropyrimidine]-2′,4′-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound of formula I is a compound of formula IB:
wherein:
R1 is lower alkyl;
R2 is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;
L is a five or six membered heteroaryl group, selected from:
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound of formula I is:
(6S)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1-methyl-spiro[hexahydropyrimidine-6,1′-indane]-2,4-dione; or
(5S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[6,7-dihydrocyclopenta[b]pyridine-5,6′-hexahydropyrimidine]-2′,4′-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound of formula I is a compound of formula IC:
wherein:
R1 is lower alkyl;
R2 is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;
L is a five or six membered heteroaryl group, selected from:
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound of formula I is:
(4S)-3′-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1′-methyl-spiro[chromane-4,6′-hexahydropyrimidine]-2′,4′-dione; or
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[2,3-dihydropyrano[2,3-b]pyridine-4,6′-hexahydropyrimidine]-2′,4′-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound of formula I is a compound of formula ID:
wherein:
R1 is lower alkyl;
R2 is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;
L is a five or six membered heteroaryl group, selected from:
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound of formula I is:
(6S)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1-methyl-spiro[hexahydropyrimidine-6,4′-isochromane]-2,4-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound of formula I is a compound of formula IE:
wherein:
R1 is lower alkyl;
R2 is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;
L is a five or six membered heteroaryl group, selected from:
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound of formula I is selected from the group consisting of:
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[5,6,7,8-tetrahydro-1H-cyclohepta[c]pyrazole-4,6′-hexahydropyrimidine]-2′,4′-dione;
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1,1′-dimethyl-spiro[5,6,7,8-tetrahydrocyclohepta[c]pyrazole-4,6′-hexahydropyrimidine]-2′,4′-dione; and
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′,2-dimethyl-spiro[5,6,7,8-tetrahydrocyclohepta[c]pyrazole-4,6′-hexahydropyrimidine]-2′,4′-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 12

A method for the treatment of anxiety, the method comprising administering to a mammal in need thereof an effective amount of a compound, wherein the compound is:
(6S)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1-methyl-spiro[hexahydropyrimidine-6,1′-tetralin]-2,4-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 13

A method for the treatment of anxiety, the method comprising administering to a mammal in need thereof an effective amount of a compound, wherein the compound is:
(6S)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1-methyl-spiro[hexahydropyrimidine-6,1′-indane]-2,4-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 14

A method for the treatment of anxiety, the method comprising administering to a mammal in need thereof an effective amount of a compound, wherein the compound is:
((5S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[7,8-dihydro-6H-quinoline-5,6′-hexahydropyrimidine]-2′,4′-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 15

A method for the treatment of anxiety, the method comprising administering to a mammal in need thereof an effective amount of a compound, wherein the compound is:
(5S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[7,8-dihydro-6H-quinazoline-5,6′-hexahydropyrimidine]-2′,4′-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

### Claim 16

A method for the treatment of anxiety, the method comprising administering to a mammal in need thereof an effective amount of a compound, wherein the compound is:
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[2,3-dihydropyrano[2,3-b]pyridine-4,6′-hexahydropyrimidine]-2′,4′-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.