# US 11,077,100 B2 · Tetrahydroquinoline derivatives as P2X7 receptor antagonists

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- Number: US 11,077,100 B2
- Document ID: US11077100B2
- Status: Granted
- Kind: B2
- Application number: 16/491,119
- Filed: 2018-03-13
- Published: 2020-12-31
- Granted: 2021-08-03
- Earliest claimed: 2017-03-13
- Assignees: RaQualia Pharma Inc.; Asahi Kasei Pharma Corporation
- Applicants: RaQualia Pharma Inc.; Asahi Kasei Pharma Corporation
- Inventors: Hirohide Noguchi; Yoshimasa Arano; Kazuo Ando; Kazuki Toyoshima; Toshihiko Sone
- Web page: https://patentgrep.com/patent/US11077100B2

## CPC

- A61K 31/47: Quinolines; Isoquinolines
- A61P 13/12: of the kidneys
- A61P 9/06: Antiarrhythmics
- A61P 19/00: Drugs for skeletal disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 215/06: having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
- C07D 215/20: Oxygen atoms
- C07D 215/48: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 221/04: Ortho- or peri-condensed ring systems
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 471/10: Spiro-condensed systems
- C07D 491/08: Bridged systems
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D 498/10: Spiro-condensed systems
- C07F 7/1804: {Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896)}
- 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)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

The present invention relates to tetrahydroquinoline derivatives of the present invention or a pharmaceutically acceptable salt thereof or a prodrug thereof, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders which are mediated via the P2X7 receptor.

## Claims

### Claim 1

A compound selected from the group consisting of (5S,8S)—N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide; (5S,8S)—N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide; (5 S,8 S)—N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide; (5S,8S)—N—((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide; (5S,8S)—N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide; (5S,8S)—N—((R)-1-(2,4-dichlorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide; (5 S,8 S)—N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide; (5S,8S)—N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide; (5S,8S)—N-(2,4-dichloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide; (5S,8S)—N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide; (5S,8S)—N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide; and (2R,5′S)—N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide; and a pharmaceutically acceptable salt of any of the aforementioned compounds.

### Claim 2 (depends on 1)

The compound of claim 1, which is (5S,8S)—N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, which is (5S,8S)—N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1, which is (5S,8S)—N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1, which is (5S,8S)—N—((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1, which is (5S,8S)—N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound of claim 1, which is (5S,8S)—N—((R)-1-(2,4-di chlorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound of claim 1, which is (5S,8S)—N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound of claim 1, which is (5S,8S)—N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The compound of claim 1, which is (5S,8S)—N-(2,4-dichloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound of claim 1, which is (5S,8S)—N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1, which is (5S,8S)—N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The compound of claim 1, which is (2R,5′S)—N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 2)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 2, and a pharmaceutically acceptable carrier.

### Claim 15 (depends on 3)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 3, and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 4)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 4, and a pharmaceutically acceptable carrier.

### Claim 17 (depends on 5)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 5, and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 6)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 6, and a pharmaceutically acceptable carrier.

### Claim 19 (depends on 7)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 7, and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 8)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 8, and a pharmaceutically acceptable carrier.

### Claim 21 (depends on 9)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 9, and a pharmaceutically acceptable carrier.

### Claim 22 (depends on 10)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 10, and a pharmaceutically acceptable carrier.

### Claim 23 (depends on 11)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 11, and a pharmaceutically acceptable carrier.

### Claim 24 (depends on 12)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 12, and a pharmaceutically acceptable carrier.

### Claim 25 (depends on 13)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 13, and a pharmaceutically acceptable carrier.

### Claim 26 (depends on 2)

The compound according to claim 2, which is: (5S,8S)—N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide.

### Claim 27 (depends on 3)

The compound according to claim 3, which is: (5S,8S)—N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide.

### Claim 28 (depends on 4)

The compound according to claim 4, which is: (5S,8S)—N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide.

### Claim 29 (depends on 5)

The compound according to claim 5, which is: (5S,8S)—N—((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide.

### Claim 30 (depends on 6)

The compound according to claim 6, which is: (5S,8S)—N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide.

### Claim 31 (depends on 7)

The compound according to claim 7, which is: (5S,8S)—N—((R)-1-(2,4-di chlorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide.

### Claim 32 (depends on 8)

The compound according to claim 8, which is: (5S,8S)—N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide.

### Claim 33 (depends on 9)

The compound according to claim 9, which is: (5S,8S)—N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide.

### Claim 34 (depends on 10)

The compound according to claim 10, which is: (5S,8S)—N-(2,4-dichloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide.

### Claim 35 (depends on 11)

The compound according to claim 11, which is: (5S,8S)—N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide.

### Claim 36 (depends on 12)

The compound according to claim 12, which is: (5S,8S)—N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide.

### Claim 37 (depends on 13)

The compound according to claim 13, which is: (2R,5′S)—N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide.

### Claim 38

A compound which is (5S,8R)—N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide; or a pharmaceutically acceptable salt thereof.

### Claim 39

A compound which is (5S,8R)—N—((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide, or a pharmaceutically acceptable salt thereof.

### Claim 40

A compound which is (5S,8R)—N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide, or a pharmaceutically acceptable salt thereof.

### Claim 41

A compound which is (5S,8R)—N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide, or a pharmaceutically acceptable salt thereof.