Pyrazolo-pyrrolo-pyrimidine-dione derivatives as P2X3 inhibitors

Patent metadata

Field	Value
Publication number	US-11319324-B2
Application number	US-201816759262-A
Country	US
Kind code	B2
Filing date	Oct 18, 2018
Priority date	Oct 27, 2017
Publication date	May 3, 2022
Grant date	May 3, 2022

Abstract

The present invention covers substituted. Pyrazolo-pyrrolo-pyrimidine-dione (PPPD) compounds of general formula (I): in which R1, R2 and R3 are as defined herein, methods of preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of neurogenic diseases, as a sole agent or in combination with other active ingredients.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein
R 1 is H, C 1 -C 6 -alkyl, C 3 -C 5 -cycloalkyl, —(C 1 -C 3 -alkyl)-(C 3 -C 5 -cycloalkyl) or halogen, wherein said C 1 -C 6 -alkyl, C 3 -C 5 -cycloalkyl and —(C 1 -C 3 -alkyl)-(C 3 -C 5 -cycloalkyl) are optionally substituted with one or more fluorine atoms;
R 2 is
H,
—OH,
halogen,
—CN,
—CO 2 H,
—C(O)R 5 ,
—C(O)OR 5 ,
—C(O)NH 2 ,
—C(O)N(R 4 )(R 5 ),
NH 2 ,
—N(R 4 )(R 5 ),
—N(R 4 )C(O)R 5 ,
—N(R 4 )—C(O)OR 5 ,
—N(R 4 )C(O)N(R 4 )(R 5 ),
—N(R 4 )SO 2 R 5 ,
—SO 2 R 8 ,
—SO 2 NH 2 ,
—SO 2 N(R 8 )(R 9 ),
C 1 -C 6 -alkyl, optionally substituted with 1 to 3 substituents R 2a which are the same or different,
C 2 -C 6 -alkenyl, optionally substituted with 1 to 3 substituents R 2a which are the same or different,
C 2 -C 6 -alkynyl, optionally substituted with 1 to 3 substituents R 2a which are the same or different,
C 3 -C 7 -cycloalkyl, optionally substituted with one or more substituents R 2b which are the same or different,
—OC 1 -C 6 -alkyl, optionally substituted with 1 to 3 substituents R 2a which are the same or different,
—OC 3 -C 7 -cycloalkyl, optionally substituted with one or more substituents R 2b which are the same or different,
4- to 6-membered heterocycloalkyl, wherein said 4- to 6-membered heterocycloalkyl contains 1 or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of N, NH, N(R 2c ), O, S, SO and SO 2 , and wherein said 4- to 6-membered heterocycloalkyl is optionally substituted at one or more carbon atoms with 1 to 4 substituents R 2d which are the same or different, and wherein optionally in said 4- to 6-membered heterocycloalkyl one —CH 2 — group adjacent to a nitrogen atom, if present, is replaced by a —C(═O)— group,
5- to 6-membered heterocycloalkenyl, wherein said 5- to 6-membered heterocycloalkenyl contains 1 or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of N, NH, N(R 2c ), O, S, SO and SO 2 , and wherein said 5- to 6-membered heterocycloalkenyl is optionally substituted at one or more carbon atoms with 1 to 4 substituents R 2d which are the same or different, and wherein optionally in said 5- to 6-membered heterocycloalkenyl one —CH 2 — group adjacent to a nitrogen atom, if present, is replaced by a —C(═O)— group,
6- to 9-membered heterobicycloalkyl, wherein said 6- to 9-membered heterobicycloalkyl contains 1 or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of N, NH, N(R 2c ), O, S, SO and SO 2 , and wherein said 6- to 9-membered heterobicycloalkyl is optionally substituted at one or more carbon atoms with 1 to 4 substituents R 2d which are the same or different, and wherein optionally in said 6- to 9-membered heterobicycloalkyl one —CH 2 — group adjacent to a nitrogen atom, if present, is replaced by a
—C(═O)— group,

phenyl, optionally substituted with 1 to 3 substituents R 2d which are the same or different, or
5- or 6-membered heteroaryl, wherein said 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, N(R 2c ) and O, and wherein said 6-membered heteroaryl contains 1 or 2 N, and wherein said 5- or 6-membered heteroaryl is optionally substituted at one or more carbon atoms with 1 to 3 substituents R 2d which are the same or different;

R 2a is
C 3 -C 5 -cycloalkyl, optionally substituted with 1 to 3 substituents R 10 which are the same or different,
F,
Cl,
OH,
O(R 6 ),
—CN,
—C(O)NH 2 ,
—C(O)N(R 4 )(R 5 ),
—N(R 4 )(R 5 ),
—N(R 4 )C(O)R 5 ,
4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of N, NH, N(R 7 ), O, S, SO and SO 2 , and wherein said 4- to 6-membered heterocycloalkyl is optionally substituted at one or more carbon atoms with 1 to 4 substituents R 10 which are the same or different, and wherein optionally in said 4- to 6-membered heterocycloalkyl one —CH 2 — group adjacent to a nitrogen atom, if present, is replaced by a —C(═O)— group,
5- to 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of N, NH, N(R 7 ), O, S, SO and SO 2 , and wherein said 5- to 6-membered heterocycloalkenyl is optionally substituted at one or more carbon atoms with 1 to 4 substituents R 10 which are the same or different, and wherein optionally in said 5- to 6-membered heterocycloalkenyl one —CH 2 — group adjacent to a nitrogen atom, if present, is replaced by a —C(═O)— group,
6- to 9-membered heterobicycloalkyl containing 1 or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of N, NH, N(R 7 ), O, S, SO and SO 2 , and wherein said 6- to 9-membered heterobicycloalkyl is optionally substituted at one or more carbon atoms with 1 to 4 substituents R 10 which are the same or different, and wherein optionally in said 6- to 9-membered heterobicycloalkyl one —CH 2 — group adjacent to a nitrogen atom, if present, is replaced by a —C(═O)— group, or
5- or 6-membered heteroaryl wherein said 5-membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of S, N, NH, N(R 7 ) and O, and wherein said 6-membered heteroaryl contains 1 or 2 N, and wherein said 5- or 6-membered heteroaryl is optionally substituted at one or more carbon atoms with 1 to 3 substituents R 10 which are the same or different;

R 2b is C 1 -C 4 -alkyl, Cl, F, OH, —C(O)N(R 4 )(R 5 ), N(R 4 )(R 5 ), —N(R 4 )C(O)R 5 or 4-to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, N(R 7 ), O and SO 2 , and wherein said C 1 -C 4 -alkyl and 4- to 6-membered heterocycloalkyl are optionally substituted at one or more carbon atoms with 1 to 4 substituents R 10 which are the same or different;
R 2c is C 1 -C 4 -alkyl, C 3 -C 5 -cycloalkyl, —(C 1 -C 3 -alkyl)-(C 3 -C 5 -cycloalkyl), —C(O)R 5 , —C(O)OR 5 , —SO 2 R 8 , or 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of N, NH, N(R 7 ), O and SO 2 ; and
wherein said C 1 -C 4 -alkyl, C 3 -C 5 -cycloalkyl, (C 1 -C 3 -alkyl)-(C 3 -C 5 -cycloalkyl) and 4-to 6-membered heterocycloalkyl are optionally substituted at one or more carbon atoms with 1 to 4 substituents R 10 which are the same or different;

R 2d is F, Cl, OH, CN, —C(O)N(R 4 )(R 5 ), N(R 4 )(R 5 ), —N(R 4 )C(O)R 5 , C 1 -C 4 -alkyl, C 3 -C 5 -cycloalkyl, —OC 1 -C 4 -alkyl, —OC 3 -C 5 -cycloalkyl or 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms or heteroatom-containing groups selected from the group consisting of N, NH, N(R 7 ), O and SO 2 ; and
wherein said C 1 -C 4 -alkyl, C 3 -C 5 -cycloalkyl, —OC 1 -C 4 -alkyl, —OC 3 -C 5 -cycloalkyl and 4- to 6-membered heterocycloalkyl are optionally substituted at one or more carbon atoms with 1 to 4 substituents R 10 which are the same or different;

R 3 is
C 1 -C 6 -alkyl, optionally substituted with 1 to 3 substituents R 3a which are the same or different,
C 3 -C 7 -cycloalkyl, optionally substituted with one or more substituents R 3b which are the same or different,
4- to 6-membered heterocycloalkyl, wherein said 4- to 6-membered heterocycloalkyl is linked through a carbon atom and contains 1 or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of N, NH, N(R 3c ), O, S, SO and SO 2 , and wherein

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

• Koppitz Marcus
• Siebeneicher Holger
• Bräuer Nico
• Pook Elisabeth
• Rotgeri Andrea
• Neuhaus Roland
• Fischer Oliver Martin
• Nagel Jens
• Davenport Adam James
• Carr James Lindsay
• Townsend Robert James
• Connelly Ursinyova Nina
• Parrott Shelley Anne

Classifications

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P13/00

  Drugs for disorders of the urinary system · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title