Novel substituted sulfonylurea derivatives

Patent metadata

Field	Value
Publication number	US-2022169605-A1
Application number	US-202017422500-A
Country	US
Kind code	A1
Filing date	Jan 13, 2020
Priority date	Jan 14, 2019
Publication date	Jun 2, 2022
Grant date	—

Abstract

The present invention relates to novel heterocyclic compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers and polymorphs. The invention also relates to processes for the preparation of the compounds of invention, pharmaceutical compositions containing the compounds and their use as the compounds of the invention belong to the family of NOD-like receptor family (NLR) protein NLRP3 modulators. The present invention thus relates to novel NLRP3 modulators as well as to the use of the novel inhibitor compounds in the treatment of diseases or conditions in which interleukin 1β activity is implicated.

First claim

1 . A compound having the structure of general formula (I)

or a tautomeric form, a stereoisomer, an enantiomer, or a pharmaceutically acceptable salt, thereof,
wherein,
R 1 at each occurrence is independently selected from hydrogen, halogen, haloalkyl, cyano, and optionally substituted groups selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, NH 2 , NH(C 1 -C 6 )alkyl, N(C 3 -C 7 )cycloalkyl, N(C 1 -C 6 alkyl) 2 , aryl, heteroaryl, heterocyclyl, benzyl, thiol, mercapto alkyl, SO 2 (C 1 -C 6 )alkyl, (C 1 -C 6 )thio-alkoxy, and amide;
X is N—R 5 , O, S, or SO 2 ;
R 5 at each occurrence is independently selected from hydrogen, halogen, haloalkyl, cyano, and optionally substituted groups selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkylSO 2 (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylN(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylN(C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, tert-butyloxycarbonyl, thiol, mercapto alkyl, SO 2 (C 1 -C 6 )alkyl, SO 2 (C 3 -C 7 )cycloalkyl, SO 2 -aryl, SO 2 -heterocyclyl, (C 1 -C 6 )thioalkyl, (C 1 -C 6 )thioalkoxy, (C 1 -C 6 )alkylSO 2 NH 2 , —CONH 2 , —CO(C 1 -C 6 )alkyl, —CO(C 1 -C 6 )haloalkyl, —CO-aryl, —CO-heteroaryl, —CO-heterocyclyl, 4- to 7-membered heterocyclic ring, 7- to 14-membered bicyclic heterocyclic ring system, and bridged or spiro ring system having optionally one or more than one heteroatoms;
m and n is independently selected from integer 0-3;
q and r is independently selected from integer 1-4;
R 2 at each occurrence is independently selected from hydrogen, halogen, cyano, and optionally substituted groups selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, benzyl, aryl, heteroaryl, heterocyclyl, thiol, thioalkyl, thio-alkoxy, SO 2 (C 1 -C 6 )alkyl, SO(C 1 -C 6 )alkyl, and bridged or spiro ring system having optionally one or more than one heteroatoms;
each of R 3 and R 4 at each occurrence is independently selected from hydrogen, halogen, haloalkyl, cyano, nitro, amide, sulphonamide, acyl, hydroxyl, and optionally substituted groups selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, SO 2 (C 1 -C 6 )alkyl, thiol, mercapto alkyl, benzyl, aryl, heteroaryl, and heterocyclyl; alternatively R 3 and R 4 forms a bond;
‘B’ is selected from the following ring systems

wherein X, Y, Z at each occurrence are independently selected from C, N, S, SO 2 and O, which may, wherever possible be optionally substituted;
each of R 6 , R 7 , R 8 , R 9 , R 10 and R 11 at each occurrence are independently selected from hydrogen, halogen, cyano, amide, sulphonamide, acyl, hydroxyl, and optionally substituted groups selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, benzyl, aryl, heteroaryl, and heterocyclyl; alternatively each of R 7 and R 8 , R 8 and R 9 , R 9 and R 10 or R 10 and R 11 wherever possible, together may form a 4 to 7 membered saturated or partially saturated ring containing from 0-2 additional heteroatoms selected from the group consisting of N, O, and S(O) p ; and
p is 1 or 2.

2 . The compound of claim 1 , wherein R 1 at each occurrence is selected from hydrogen, halogen, haloalkyl, and optionally substituted (C 1 -C 6 )alkyl.

3 . The compound of claim 1 , wherein R 2 at each occurrence is selected from hydrogen, halogen, haloalkyl, and optionally substituted (C 1 -C 6 )alkyl.

4 . The compound of claim 1 , wherein R 3 and R 4 at each occurrence are independently selected from hydrogen, halogen, haloalkyl, and optionally substituted (C 1 -C 6 )alkyl.

5 . The compound of claim 1 , wherein each of R 6 , R 7 , R 8 , R 9 , R 10 and R 11 at each occurrence are independently selected from hydrogen, halogen, and optionally substituted groups selected from (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl.

6 . The compound of claim 1 , wherein when any of the optionally substituted groups is substituted, the substituents are selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkyloxy, alkylthio (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkoxy, aryl, heterocyclyl, heteroaryl, —COR 12 , —CSR 12 , C(O)OR 12 , C(O)—R 12 , —C(O)—NR 12 R 13 , —C(S)—NR 12 R 13 , and —SO 2 R 12 , wherein each of R 12 and R 13 is independently selected from hydrogen and an optionally substituted group selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )cycloalkyl, aryl, heteroaryl, and heterocyclyl.

7 . The compound of claim 1 selected from the group consisting of:
(R,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide;
(S,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-propylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(1-(cyclopropylmethyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)-pyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(1-acetylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethene-1-sulfonamide;
(E)-2-(1-benzylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide;
tert-butyl(R,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)-vinyl)pyrrolidine-1-carboxylate;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-methoxyethyl)pyrrolidin-2-yl)ethenesulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(isopropylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide;
(R,E)-2-(1-((3-fluorophenyl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(pyrazine-2-carbonyl)pyrrolidin-2-yl)ethenesulfonamide;
(R,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1-carboxamide;
(R,E)-2-(1-(cyclopropanecarbonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-(methylthio)ethyl)pyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isobutylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(1-(ethylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(3-(methylsulfonyl)propyl)pyrrolidin-2-yl)ethenesulfonamide;
(R,E)-2-(1-benzoylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

Assignees

• Cadila Healthcare Ltd

Inventors

• Sharma Rajiv
• Agarwal Sameer

Classifications

• A61P25/28

  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 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P29/00

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

• C07D309/04

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title