WO2019043610A1 - Novel substituted sulfonylurea derivatives - Google Patents
Novel substituted sulfonylurea derivatives Download PDFInfo
- Publication number
- WO2019043610A1 WO2019043610A1 PCT/IB2018/056619 IB2018056619W WO2019043610A1 WO 2019043610 A1 WO2019043610 A1 WO 2019043610A1 IB 2018056619 W IB2018056619 W IB 2018056619W WO 2019043610 A1 WO2019043610 A1 WO 2019043610A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carbamoyl
- hexahydro
- indacen
- ethenesulfonamide
- alkyl
- Prior art date
Links
- LBCOQBCYKWPCHF-MDZDMXLPSA-N CC[n]1c(/C=C/S(NC(Nc2c(CCC3)c3cc3c2CCC3)=O)(=O)=O)cnc1 Chemical compound CC[n]1c(/C=C/S(NC(Nc2c(CCC3)c3cc3c2CCC3)=O)(=O)=O)cnc1 LBCOQBCYKWPCHF-MDZDMXLPSA-N 0.000 description 1
- WSJMPFSWSGYREF-RMKNXTFCSA-N COc1cccc(OC)c1NC(NS(/C=C/c1ncc[s]1)(=O)=O)=O Chemical compound COc1cccc(OC)c1NC(NS(/C=C/c1ncc[s]1)(=O)=O)=O WSJMPFSWSGYREF-RMKNXTFCSA-N 0.000 description 1
- YIEJORXCBUSMRX-NTEUORMPSA-N CS(CCC[n]1c(/C=C/S(NC(Nc2c(CCC3)c3cc3c2CCC3)=O)(=O)=O)ncc1)(=O)=O Chemical compound CS(CCC[n]1c(/C=C/S(NC(Nc2c(CCC3)c3cc3c2CCC3)=O)(=O)=O)ncc1)(=O)=O YIEJORXCBUSMRX-NTEUORMPSA-N 0.000 description 1
- POGOPQMAZNZPDV-VMPITWQZSA-N Cc1c(C)c([N+]([O-])=O)c(C)c(C)c1NC(NS(/C=C/c1ncc[s]1)(=O)=O)=O Chemical compound Cc1c(C)c([N+]([O-])=O)c(C)c(C)c1NC(NS(/C=C/c1ncc[s]1)(=O)=O)=O POGOPQMAZNZPDV-VMPITWQZSA-N 0.000 description 1
- BXSRFKGTQKWHGO-VMPITWQZSA-N O=C(Nc1c(C(F)(F)F)cccc1)NS(/C=C/c1ncc[s]1)(=O)=O Chemical compound O=C(Nc1c(C(F)(F)F)cccc1)NS(/C=C/c1ncc[s]1)(=O)=O BXSRFKGTQKWHGO-VMPITWQZSA-N 0.000 description 1
- YVDLEXGAYUJORS-CSKARUKUSA-N O=C(Nc1c(CCC2)c2cc2c1CCC2)NS(/C=C/c1c[s]cc1)(=O)=O Chemical compound O=C(Nc1c(CCC2)c2cc2c1CCC2)NS(/C=C/c1c[s]cc1)(=O)=O YVDLEXGAYUJORS-CSKARUKUSA-N 0.000 description 1
- OWFPZRKKHCDMDD-WYMLVPIESA-N O=C(Nc1c(CCC2)c2cc2c1CCC2)NS(/C=C/c1cccc(-c2cccnc2)c1)(=O)=O Chemical compound O=C(Nc1c(CCC2)c2cc2c1CCC2)NS(/C=C/c1cccc(-c2cccnc2)c1)(=O)=O OWFPZRKKHCDMDD-WYMLVPIESA-N 0.000 description 1
- OVBGJVJWJCVTKP-FMIVXFBMSA-N O=C(Nc1c(CCC2)c2cc2c1CCC2)NS(/C=C/c1ccncc1)(=O)=O Chemical compound O=C(Nc1c(CCC2)c2cc2c1CCC2)NS(/C=C/c1ccncc1)(=O)=O OVBGJVJWJCVTKP-FMIVXFBMSA-N 0.000 description 1
- GCTLFNRWVYLUQW-PKNBQFBNSA-N O=C(Nc1c(CCC2)c2cc2c1CCC2)NS(/C=C/c1cnccc1)(=O)=O Chemical compound O=C(Nc1c(CCC2)c2cc2c1CCC2)NS(/C=C/c1cnccc1)(=O)=O GCTLFNRWVYLUQW-PKNBQFBNSA-N 0.000 description 1
- TZQFBQIDYFVIMY-SDNWHVSQSA-N O=C(Nc1c(CCC2)c2cc2c1CCC2)NS(/C=C/c1ncc[n]1-c(cc1)ccc1F)(=O)=O Chemical compound O=C(Nc1c(CCC2)c2cc2c1CCC2)NS(/C=C/c1ncc[n]1-c(cc1)ccc1F)(=O)=O TZQFBQIDYFVIMY-SDNWHVSQSA-N 0.000 description 1
- GWFNORFHKYFCSR-UHFFFAOYSA-N O=C(Nc1c(CCC2)c2cc2c1CCC2)NS(C#Cc1ccccc1)(=O)=O Chemical compound O=C(Nc1c(CCC2)c2cc2c1CCC2)NS(C#Cc1ccccc1)(=O)=O GWFNORFHKYFCSR-UHFFFAOYSA-N 0.000 description 1
- ONWRSBMOCIQLRK-VOTSOKGWSA-N O=S(/C=C/c1ccccc1)(Cl)=O Chemical compound O=S(/C=C/c1ccccc1)(Cl)=O ONWRSBMOCIQLRK-VOTSOKGWSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/32—Sulfur atoms
- C07D213/34—Sulfur atoms to which a second hetero atom is attached
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/52—Y being a hetero atom
- C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
- C07C311/55—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
Definitions
- 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.
- NLR NOD- like receptor family
- 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 as well as treatment of disease states mediated by NLRP3 as well as treatment of diseases or conditions in which interleukin 1 ⁇ activity and interleukin-18 (IL-18) is implicated.
- NLR protein NLRP3 is an intracellular signaling molecule that senses many pathogens, environmental and host-derived factors. (Wen., et. al., Immunity. 2013; 39:432–441). Activation of NLRP3 leads to binding with apoptosis associated speck-like protein containing a CARD (ASC). ASC in turn interacts with the cysteine protease caspase-1, forming a complex termed the inflammasome. This results in the activation of caspase-1, which cleaves the pro-inflammatory cytokines IL-1 ⁇ and IL-18 to their active forms and mediates a type of inflammatory cell death known as pyroptosis. (Latz, et. al., Nat Rev Immunol.2013; 13:397–411).
- the NLRP3 inflammasome acts as a key mediator of inflammatory responses through the activation of caspase- 1 leading to processing and release of the pro- inflammatory cytokines interleukin-1 ⁇ (IL-1 ⁇ ) and interleukin-18 (IL-18).
- the NLRP3 inflammasome is a component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as the rare periodic fever syndrome, cryopyrin associated periodic syndromes (CAPS), Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, atherosclerosis, asthma, gouty arthritis, Juvenile arthritis, and inflammatory central nervous system (CNS) diseases.
- CAPS cryopyrin associated periodic syndromes
- TRAPS Tumor necrosis factor receptor-associated periodic syndrome
- CNS central nervous system
- Inflammation is an essential host response to infection and injury.
- IL-1 ⁇ cytokine interleukin-1 ⁇
- NLRP3 inflammasome activation plays a key role in each of the components including induction of pro-inflammatory signaling, hepatocellular injury and cell death, and activation of the hepatic stellate cells (HSC) that are responsible for collagen deposition and liver fibrosis.
- HSC hepatic stellate cells
- NLRP3 related diseases include biologic agents that target IL-1. These are the recombinant IL-1 receptor antagonist Anakinra, the neutralizing IL-1 ⁇ antibody Canakinumab and the soluble decoy IL-1 receptor Rilonacept.
- novel heterocyclic compounds of general formula (I) which are NLRP3 modulators for the prevention and treatment of disease states mediated by NLRP3 or conditions in which interleukin 1 ⁇ activity and interleukin-18 (IL-18) are implicated including inflammation, gouty arthritis, type 2 diabetes, atherosclerosis, and liver fibrosis. More particularly, embodiments of the present invention are useful as therapeutics in the treatment of a variety of pathological conditions including (but not limited to) lymphoma, auto-immune diseases, heteroimmune diseases, inflammatory diseases, type 1 diabetes, chronic inflammation, cancer, and neurodegenerative diseases or conditions.
- pathological conditions including (but not limited to) lymphoma, auto-immune diseases, heteroimmune diseases, inflammatory diseases, type 1 diabetes, chronic inflammation, cancer, and neurodegenerative diseases or conditions.
- the present invention discloses heterocyclic compounds as defined by the general formula (I) that are NLRP3 modulators for the prevention and treatment of disease states mediated by NLRP3 as well as treatment of diseases or conditions in which interleukin 1 ⁇ activity and interleukin-18 (IL-18) are implicated.
- the compounds of the present invention are useful in the treatment of human or animal body, by inhibition of NLRP3.
- the compounds of this invention are therefore suitable for the prevention and treatment of disease states mediated by NLRP3.
- An embodiment of the present invention provides novel heterocyclic compounds represented by the general formula (I), their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts and pharmaceutical compositions containing them or their mixtures thereof.
- compositions containing compounds of the general formula (I), their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
- heterocyclic compounds of the present invention as NLRP3 modulators, by administering a therapeutically effective and non-toxic amount of compounds of general formula (I) or their pharmaceutically acceptable compositions to the mammals.
- the present invention relates to the compounds of the general formula (I)
- ‘A’ is selected from unsubstituted or substituted (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 3 - C 7 )cycloalkyl, aryl, heteroaryl, 4-7 membered heterocyclic ring system, 7- to 14-membered bicyclic heterocyclic ring system, bridged bicyclic heterocyclic or spiro cyclic system, having optionally one or more than one heteroatoms;
- R 1 which represents one or more substituents on‘A’, at each occurrence independently represents hydrogen, halogen, haloalkyl, cyano, 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, aryl, heteroaryl, heterocyclyl, benzyl, thiol, mercapto alkyl (sulfur and its oxidized forms, like S, SO 2 ), (C 1 - C 6 )thio-alkoxy groups;
- R 1 at each occurrence may represent one or more substituents selected from hydrogen, halogen, haloalkyl, cyano, 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, sulfur and its oxidized forms, (C 1 -C 6 )thio-alkoxy, bridged or spiro ring system having optionally one or more than one heteroatoms; ‘B’ is selected from optionally one or more than one heteroatoms; ‘
- ‘B’ is selected from the following ring system
- X, Y, Z at each occurrence is independently selected from C, N, S, SO 2 , and O, which may, wherever possible be optionally substituted;
- R 2 at each occurrence independently represents hydrogen, halogen, cyano, 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, sulfur and its oxidized forms, thio-alkoxy, bridged or spiro ring system having optionally one or more than one heteroatoms;
- Each of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 at each occurrence are independently selected from hydrogen, halogen, haloalkyl, cyano, nitro, amide, sulphonamide, acyl, hydroxyl, optionally substituted groups selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )
- ‘A’ is selected from aryl, heteroaryl, 4-7 membered heterocyclic ring system, 7- to 14-membered bicyclic heterocyclic ring system having optionally one or more than one heteroatoms;
- R 1 at each occourence is independently selected from hydrogen, halogen, haloalkyl, cyano, 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, sulfur and its oxidized forms, (C 1 -C 6 )thio-alkoxy having optionally one or more than one heteroatoms;
- R 2 is independently selected from hydrogen, halogen, cyano, optionally substituted groups selected from (C 1 - C 6
- R 5 , R 6 , R 7 , R 8 , R 9 and R 10 at each occurrence are independently selected from hydrogen, halogen, haloalkyl, cyano, nitro, optionally substituted group selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy;
- X, Y, Z at each occurrence is independently selected from C;
- substitutions on them may be selected from those described above or may additionally be 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, -COR 11, -CSR 11, C(O)OR 11, C(O)-R 11, - C(O)-NR 11 R 12, -C(S)-NR 11 R 12, -SO 2 R 11 group, wherein each of R 11 and R 12 is independently selected from hydrogen, optionally substituted group selected from (C 1 -C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 1 -C 6 )alkyl,
- alkyl group examples include but not are limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert. - butyl, pentyl, hexyl etc.
- alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, C (1-6) is intended.
- Alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise.
- alkenyl examples include but not limited to vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, l -propenyl, 2-butenyl, 2-methyl -2- butenyl etc. Where the specified number of carbon atoms permits, e. g., from C (5-10) , the term alkenyl also includes cycloalkenyl groups and combinations of linear, branched and cyclic structures. When no number of carbon atoms is specified, C (2-6) is intended.
- Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof.
- alkynyl examples include ethynyl, propargyl, 3-methyl- l -pentynyl etc.
- carbocycle or “carbocyclic residue” is intended to mean any stable monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic.
- carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
- carbocycle is intended to include, wherever applicable, the groups representing cycloalkyl, phenyl and other saturated, partially saturated or aromatic residues;
- Cycloalkyl is the subset of alkyl and means saturated carbocyclic ring having a specified number of carbon atoms, preferably 3-6 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.
- a cycloalkyl group generally is monocyclic unless otherwise stated. In a preferred embodiment, cycloalkyl groups are saturated unless and otherwise stated.
- alkoxy refers to the straight or branched chain alkoxides of the number of carbon atoms specified.
- Aryl means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
- heterocycle or “heterocyclic system” is intended to mean a stable 4- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms & also contains from 1 to 4 hetero atoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above- defined heterocyclic rings is fused to a benzene ring.
- heterocycle as used in the specification includes both aromatic and non-aromatic single or fused cyclic system containing at least one heteroatom selected from N, O and S.
- the nitrogen and sulfur hetero atoms may optionally be oxidized.
- the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
- a skilled person is well aware of the terms "heterocycle” or “heterocyclic system” and the present invention encompasses all such variations, alterations of definitions which are within the scope of such a skilled person.
- the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
- nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these hetero atoms are not adjacent to one another.
- the total number of S and O atoms in the heterocycle is not more than 1.
- aromatic heterocyclic system is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Also included are fused ring, bridged bicyclic heterocycles, spiro compounds containing, for example, the above heterocycles.
- the term“fused rings” is intended to mean, one ring is a 4-7- membered monocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic) and comprises a 4-membered heterocycle, 5-membered heterocycle, 6- membered heterocycle, 7-membered heterocycle, or a carbocycle, each fused to a second ring.
- the second ring is a 5- 7-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic), and comprises a 4-membered heterocycle, 5- membered heterocycle, 6-membered heterocycle, 7-membered heterocycle or a carbocycle.
- the term“spiro compound” is intended to mean 7-14 membered bicyclic heterocyclic ring system in which both rings are connected through just one atom.
- the term “bridged bicyclic heterocycle” is intended to mean a stable 6-12 membered saturated N,O, S containing heterocyclic ring system fused to another ring system on non adjacent atoms by one or more bridges, where at least one ring system is heterocyclic ring.
- Heteroaryl means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus include heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic.
- heteroaryl groups include; pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolin
- haloalkyl means an alkyl structure in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another.
- The“haloalkoxy” group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxyz, fluoroethoxy, chloroethoxy and the like;
- halogen atoms are not all the same as one another.
- Aryloxyalkyl means an alkyl radical substituted with aryloxy group as defined herein.
- Aryloxyaryl means an aryl radical substituted with aryloxy group as defined herein.
- Aryloxyheteroaryl means a heteroaryl radical substituted with aryloxy group as defined herein.
- Halo/ Halogen refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred. Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
- substituted means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
- substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
- “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the basic residues.
- Optional' or‘optionally' means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not.
- Optionally substituted alkyl' means either 'alkyl' or 'substituted alkyl'.
- an optionally substituted group includes an unsubstituted group.
- structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. Particularly useful compounds may be selected from but not limited to the following:
- Phorbol 12-myristate 13-acetate IL1 ⁇ Interleukin 1 beta
- TNF ⁇ Tumor necrosis factor alpha
- DAMP damage ⁇ associated molecular pattern
- PAMP pathogen ⁇ associated molecular pattern
- TLR Toll ⁇ like receptor.
- the novel compounds of the present invention can be prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art.
- the reactions can be performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being affected. Preferred methods include, but not limited to those described below, where all symbols are as defined earlier unless and otherwise defined below.
- the compounds of the general formula (I) can be prepared as described in schemes below along with suitable modifications/variations which are well within the scope of a person skilled in the art. Scheme 1 Wherein each of A, B, R 1 , R 2 , R 3
- Compound 2 can be prepared by variety of methods familiar to those skilled in art using reagent like sulfuryl dichloride from commercially available styrene (1).
- Compound (2) on treatment with ammonia under suitable conditions and appropriate solvents afforded compound 3.
- Compound 3 on treatment with isocyanato derivative (4) under suitable conditions, base like sodium hydride and appropriate solvent afforded compound of formula (I).
- Specific reaction conditions, solvents and other parameters necessary for carrying out the process steps as described above are well within the capabilities of a person skilled in the art.
- Compound (6) can be prepared by variety of methods familiar to those skilled in art using a reagent like Boc anhydride from commercially available methane sulfonamide (5).
- Compound (6) on treatment with diphenylphosphinic chloride under suitable conditions and appropriate solvents provided compound 7 (ref. Synthesis 2003, 15, 2321-24).
- Compound 7 on treatment with aldehyde or ketone derivative (8) under suitable conditions in presence of base like sodium hydride and appropriate solvent provided compound (9), which can be deprotected under suitable conditions to afford compound (3).
- THP1 monocytes were differentiated with PMA (100ng/ml) and incubated at 37 ° C for 20hrs in presence of 5% CO 2 .
- 2X10 5 differentiated cells were plated per well of 96 well tissue culture plates. The cells were primed using 500ng/ml Lipopolysaccharide and incubating for 4hrs under the same condition. The cells were then treated with various concentrations of the compounds for 30 min followed by treatment with 5mM ATP for 1hr. The supernatants were collected and analysed by IL-1b (Mabtech Cat # 3415-1H-20) or TNF-a (Mabtech; Cat # 3510-1H-20) detection kit.
- In-vivo LPS and ATP induced IL-1 ⁇ assay Female C57 mice (6-8 weeks) received intraperitoneal injection of 50 ⁇ g/mouse of lipopolysaccharide (LPS) in PBS. Animals were treated immediately with the test compounds or the vehicle. After 2h of LPS injection, animals were administered with ATP at 12.5 mg/mouse dissolved in PBS via intraperitoneal route. After 30 minutes of ATP injection, serum was collected for IL-1 ⁇ estimation by ELISA. Representative data of some of the test compounds are listed in Table-2. Table 2
- novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
- the compounds of formula (I) or pharmaceutical compositions containing them are useful as a medicament for the inhibition of NLRP3 activity and suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
- a pharmaceutical composition comprising the compounds of the present invention may comprise a suitable binder, suitable bulking agent &/or diluent and any other suitable agents as may be necessary.
- the pharmaceutical composition may be suitably coated with suitable coating agents.
- the compounds of the present invention (I) are NLRP3 inhibitors and are useful in the treatment of disease states mediated by NLRP3, preferably diseases or conditions in which interleukin 1 ⁇ activity is implicated and related disorders.
- the quantity of active component that is, the compounds of Formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
- the compounds of the present invention, formula (I) may be used alone or in any combination with one or more other therapeutic agents which a skilled medical practitioner can easily identify.
- Such other therapeutic agent may be selected depending on the type of disease being treated, the severity, other medications being taken by the patients etc.
- one or more DMARDs may be used in combination with the compounds of the present invention.
- compound of formula (I) of the present invention may be used in combination with one or more suitable pharmaceutically active agents selected from following therapeutic agents in any combination.
- Inhibitors of interleukin-1 ⁇ e.g.
- immune-suppressants e.g., Methotrexate, Cyclosporine, mercaptopurine, cyclophosphamide
- metabolic disorders drugs e.g., glucocorticoids (e.g., dexamethasone, methylprednisolone, prednisone), non-steroidal anti- inflammatory drugs, Cox-2 specific inhibitors, Janus kinase (JAK) inhibitors (e.g., Tofacitinib, Filgotinib), anti-inflammatory drugs (e.g., mesalamine, Sulfasalazine, Balsalazide), TNF- ⁇ binding proteins (eg.
- Infliximab, etanercept interferon- 13, interferon, interleukin-2, antihistamines, beta-agonist, BTK inhibitors, anticolinergics, anti- cancer agents or their suitable pharmaceutically acceptable salts.
- NASH Non-Alcoholic Steato- Hepatitis
- fibrosis drugs anticancer antibiotics, hormones, Aromatase inhibitors, antibodies, cytokines, vaccines, drug conjugates, inhibitors of mitogen-activated protein kinase signaling (ex: BAY 43- 9006), Caspase Inhibitors, Syk inhibitors, mTOR inhibitors, antibodies (Rituxan), and BCR/ABL antagonist While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
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 as well as treatment of disease states mediated by NLRP3 as well as treatment of diseases or conditions in which interleukin 1β activity and interleukin-18 (IL-18) is implicated.
Description
NOVEL SUBSTITUTED SULFONYLUREA DERIVATIVES FIELD OF THE INVENTION
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 as well as treatment of disease states mediated by NLRP3 as well as treatment of diseases or conditions in which interleukin 1β activity and interleukin-18 (IL-18) is implicated.
BACKGROUND OF THE INVENTION
The NOD-like receptor family (NLR) protein NLRP3 is an intracellular signaling molecule that senses many pathogens, environmental and host-derived factors. (Wen., et. al., Immunity. 2013; 39:432–441). Activation of NLRP3 leads to binding with apoptosis associated speck-like protein containing a CARD (ASC). ASC in turn interacts with the cysteine protease caspase-1, forming a complex termed the inflammasome. This results in the activation of caspase-1, which cleaves the pro-inflammatory cytokines IL-1β and IL-18 to their active forms and mediates a type of inflammatory cell death known as pyroptosis. (Latz, et. al., Nat Rev Immunol.2013; 13:397–411).
The NLRP3 inflammasome acts as a key mediator of inflammatory responses through the activation of caspase- 1 leading to processing and release of the pro- inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). The NLRP3 inflammasome is a component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as the rare periodic fever syndrome, cryopyrin associated periodic syndromes (CAPS), Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, atherosclerosis, asthma, gouty arthritis, Juvenile arthritis, and inflammatory central nervous system (CNS) diseases. (Masters, et. al., Annu Rev Immunol. 2009; 27:621–668; Strowig, et. al., Nature 2012, 481, 278−286; Guo, et. al., Nat. Med.2015, 21, 677.)
Inflammation is an essential host response to infection and injury. The regulation of the pro-inflammatory cytokine interleukin-1β (IL-1β), which is central to host responses to infection, also causes tissue injury when activated inappropriately. (Dinarello, et. al., Nat. Rev. Drug Discovery 2012, 11, 633−652.) NLRP3 inflammasome activation plays a key role in each of the components including induction of pro-inflammatory signaling, hepatocellular injury and cell death, and activation of the hepatic stellate cells (HSC) that are responsible for collagen deposition and liver fibrosis. (Mridha, et. al., Journal of Hepatology, 2017, 66 (5), 1037-1046)
Current treatments for NLRP3 related diseases include biologic agents that target IL-1. These are the recombinant IL-1 receptor antagonist Anakinra, the neutralizing IL-1β antibody Canakinumab and the soluble decoy IL-1 receptor Rilonacept.
Published patent applications WO98/32733, WO2001/019390, WO2014/190015, WO2016/123229 discloses certain compounds which are modulators of NLRP3. WO/2016/131098 filed by The University of Queensland disclosed sulfonylureas derivatives and related compounds as NLRP3 inflammasome inhibitors. WO2017/017469 filed by The University of Manchester, disclosed certain cyclic diarylboron derivatives as NLRP3 inflammasome inhibitors for the treatment of diseases or conditions in which interleukin 1 β activity is implicated. Some of the recent patent applications such as WO2017031161, WO2017079352, WO2017129897, WO2017184604, WO2017184623, WO2017184624 and WO2018015445 also disclose certain classes of compounds as NLRP3 inhibitors.
We herein disclose novel heterocyclic compounds of general formula (I) which are NLRP3 modulators for the prevention and treatment of disease states mediated by NLRP3 or conditions in which interleukin 1β activity and interleukin-18 (IL-18) are implicated including inflammation, gouty arthritis, type 2 diabetes, atherosclerosis, and liver fibrosis. More particularly, embodiments of the present invention are useful as therapeutics in the treatment of a variety of pathological conditions including (but not limited to) lymphoma, auto-immune diseases, heteroimmune diseases, inflammatory diseases, type 1 diabetes, chronic inflammation, cancer, and neurodegenerative diseases or conditions. SUMMARY OF THE INVENTION The present invention discloses heterocyclic compounds as defined by the general formula (I) that are NLRP3 modulators for the prevention and treatment of disease states
mediated by NLRP3 as well as treatment of diseases or conditions in which interleukin 1β activity and interleukin-18 (IL-18) are implicated. The compounds of the present invention are useful in the treatment of human or animal body, by inhibition of NLRP3. The compounds of this invention are therefore suitable for the prevention and treatment of disease states mediated by NLRP3. EMBODIMENT(S) OF THE INVENTION An embodiment of the present invention provides novel heterocyclic compounds represented by the general formula (I), their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts and pharmaceutical compositions containing them or their mixtures thereof.
In a further embodiment of the present invention is provided pharmaceutical compositions containing compounds of the general formula (I), their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
In a still further embodiment is provided the use of heterocyclic compounds of the present invention as NLRP3 modulators, by administering a therapeutically effective and non-toxic amount of compounds of general formula (I) or their pharmaceutically acceptable compositions to the mammals.
In a still further embodiment is provided a process for preparing the novel compounds of the present invention. DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to the compounds of the general formula (I)
‘A’ is selected from unsubstituted or substituted (C1-C6)alkyl, (C2-C6)alkenyl, (C3- C7)cycloalkyl, aryl, heteroaryl, 4-7 membered heterocyclic ring system, 7- to 14-membered bicyclic heterocyclic ring system, bridged bicyclic heterocyclic or spiro cyclic system, having optionally one or more than one heteroatoms;
R1, which represents one or more substituents on‘A’, at each occurrence independently represents hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, thiol, mercapto alkyl (sulfur and its oxidized forms, like S, SO2), (C1- C6)thio-alkoxy groups;
In an embodiment when‘A’ represents ring, R1 at each occurrence, may represent one or more substituents selected from hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C1- C6)alkoxy, (C3-C7)cycloalkyl, NH2, NH(C1-C6)alkyl, N(C3-C7)cycloalkyl; N(C1-C6 alkyl)2, aryl, heteroaryl, heterocyclyl, benzyl, thiol, mercapto alkyl, sulfur and its oxidized forms, (C1-C6)thio-alkoxy, bridged or spiro ring system having optionally one or more than one heteroatoms; ‘B’ is selected from optionally substituted (C3-C7)cycloalkyl, aryl, heteroaryl and heterocyclyl groups;
In a preferred embodiment,‘B’ is selected from the following ring system
R2 at each occurrence independently represents hydrogen, halogen, cyano, optionally substituted groups selected from (C1-C6)alkyl, (C2-C6) alkenyl, (C1-C6)alkoxy (C3-C7)cycloalkyl, benzyl, aryl, heteroaryl, heterocyclyl, thiol, thioalkyl, sulfur and its
oxidized forms, thio-alkoxy, bridged or spiro ring system having optionally one or more than one heteroatoms; Each of R3, R4, R5, R6, R7, R8, R9 and R10 at each occurrence are independently selected from hydrogen, halogen, haloalkyl, cyano, nitro, amide, sulphonamide, acyl, hydroxyl, optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C3- C7)cycloalkyl, (C1-C6)alkoxy, thiol, mercapto alkyl, sulfur and its oxidized forms, benzyl, aryl, heteroaryl, heterocyclyl; Alternatively, R3 and R4 may form a bond; Alternatively, R3 and‘A’ together with the atom to which they are attached may form an optionally substituted 5 to 7 membered heterocyclic ring system having optionally one or more than one heteroatoms; Alternatively each of R5 and R6
, R7 and R8 or R8 and R9 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; p = 1-2. In a preferred embodiment‘A’ is selected from aryl, heteroaryl, 4-7 membered heterocyclic ring system, 7- to 14-membered bicyclic heterocyclic ring system having optionally one or more than one heteroatoms;
In a preferred embodiment R1 at each occourence is independently selected from hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1- C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, NH2, NH(C1- C6)alkyl, N(C3-C7)cycloalkyl; N(C1-C6 alkyl)2, aryl, heteroaryl, heterocyclyl, benzyl, thiol, mercapto alkyl, sulfur and its oxidized forms, (C1-C6)thio-alkoxy having optionally one or more than one heteroatoms; In a preferred embodiment R2 is independently selected from hydrogen, halogen, cyano, optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)alkoxy; In a preferred embodiment R3 and R4 is hydrogen; Alternatively, R3 and R4 may form a bond;
In a preferred embodiment R5, R6, R7, R8, R9 and R10 at each occurrence are independently selected from hydrogen, halogen, haloalkyl, cyano, nitro, optionally substituted group selected from (C1-C6)alkyl, (C1-C6)alkoxy;
In a preferred embodiment X, Y, Z at each occurrence is independently selected from C;
When any of above defined group is substituted the substitutions on them may be selected from those described above or may additionally be selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkyloxy, alkylthio (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C7)cycloalkyl, (C1-C6)alkoxy, -COR11, -CSR11, C(O)OR11, C(O)-R11, - C(O)-NR11R12, -C(S)-NR11R12, -SO2R11 group, wherein each of R11 and R12 is independently selected from hydrogen, optionally substituted group selected from (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl groups; In a preferred embodiment, the groups, radicals described above may be selected from: "Alkyl", as well as other groups having the prefix "alk", such as alkoxy and alkanoyl means a carbon chain which may further be substituted with an oxygen atom as is well understood by a skilled artisan, which may further be either linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl group include but not are limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert. - butyl, pentyl, hexyl etc. Where the specified number of carbon atoms permits e.g. from C(3- 10), the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, C(1-6) is intended. "Alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkenyl include but not limited to vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, l -propenyl, 2-butenyl, 2-methyl -2- butenyl etc. Where the specified number of carbon atoms permits, e. g., from C(5-10), the term alkenyl also includes cycloalkenyl groups and combinations of linear, branched and cyclic structures. When no number of carbon atoms is specified, C(2-6) is intended. "Alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl- l -pentynyl etc. The“thioalkyl” group used either alone or in combination with other radicals, denotes an alkyl group, as defined above, attached to a group of formula–SR’, where R’
represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be optionally substituted.
As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). In a broader perspective, the term carbocycle is intended to include, wherever applicable, the groups representing cycloalkyl, phenyl and other saturated, partially saturated or aromatic residues; "Cycloalkyl" is the subset of alkyl and means saturated carbocyclic ring having a specified number of carbon atoms, preferably 3-6 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. A cycloalkyl group generally is monocyclic unless otherwise stated. In a preferred embodiment, cycloalkyl groups are saturated unless and otherwise stated. The term "alkoxy" refers to the straight or branched chain alkoxides of the number of carbon atoms specified. "Aryl" means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 4- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms & also contains from 1 to 4 hetero atoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above- defined heterocyclic rings is fused to a benzene ring. The term heterocycle as used in the specification includes both aromatic and non-aromatic single or fused cyclic system containing at least one heteroatom selected from N, O and S. The nitrogen and sulfur hetero atoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. A skilled person
is well aware of the terms "heterocycle" or "heterocyclic system" and the present invention encompasses all such variations, alterations of definitions which are within the scope of such a skilled person. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. In a further optional embodiment, nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these hetero atoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Also included are fused ring, bridged bicyclic heterocycles, spiro compounds containing, for example, the above heterocycles. As used herein, the term“fused rings” is intended to mean, one ring is a 4-7- membered monocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic) and comprises a 4-membered heterocycle, 5-membered heterocycle, 6- membered heterocycle, 7-membered heterocycle, or a carbocycle, each fused to a second ring. The second ring is a 5- 7-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic), and comprises a 4-membered heterocycle, 5- membered heterocycle, 6-membered heterocycle, 7-membered heterocycle or a carbocycle. As used herein, the term“spiro compound” is intended to mean 7-14 membered bicyclic heterocyclic ring system in which both rings are connected through just one atom. As used herein, the term "bridged bicyclic heterocycle" is intended to mean a stable 6-12 membered saturated N,O, S containing heterocyclic ring system fused to another ring system on non adjacent atoms by one or more bridges, where at least one ring system is heterocyclic ring.
"Heteroaryl" means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus include heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic. Examples of heteroaryl groups include; pyrrolyl, isoxazolyl, isothiazolyl,
pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyt, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl etc. For heterocyclyl; and heteroaryl groups, rings and ring systems containing from 3-15 carbon atoms are included, forming 1-3 rings. The term "haloalkyl "means an alkyl structure in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another. The“haloalkoxy” group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxyz, fluoroethoxy, chloroethoxy and the like;
In certain other embodiment in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another. "Aryloxyalkyl" means an alkyl radical substituted with aryloxy group as defined herein. "Aryloxyaryl" means an aryl radical substituted with aryloxy group as defined herein. "Aryloxyheteroaryl" means a heteroaryl radical substituted with aryloxy group as defined herein. "Halo/ Halogen" refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred. Suitable groups and substituents on the groups may be selected from those described anywhere in the specification. The term "substituted," as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the
designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the basic residues. Such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1 , 2-ethanedisulfonic, 2- acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromie, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, -lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic. The term 'optional' or‘optionally' means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not. For example, Optionally substituted alkyl' means either 'alkyl' or 'substituted alkyl'. Further an optionally substituted group includes an unsubstituted group. Unless otherwise stated in the specification, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. Particularly useful compounds may be selected from but not limited to the following:
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-phenylethene-1-sulfonamide; (E)-2-(4-fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(p-tolyl)ethenesulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4- (trifluoromethyl)phenyl)ethenesulfonamide;
(E)-2-(3-fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyridin-3- yl)ethenesulfonamide;
sodium(E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((4- methoxystyryl)sulfonyl)amide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(3-methoxyphenyl)ethene sulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(2-hydroxypropan-2- yl)phenyl)ethenesulfonamide;
(E)-2-(4-cyanophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-phenylethynesulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiophen-2- yl)ethenesulfonamide;
(E)-ethyl 5-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamoyl)vinyl)furan-3-carboxylate;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(2-hydroxypropan-2- yl)furan-2-yl)ethenesulfonamide;
(E)-2-cyclohexyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiophen-3- yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyridin-4- yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(hydroxymethyl)furan-2- yl)ethenesulfonamide;
(E)-2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-N-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4- (trifluoromethoxy)phenyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide;
(E)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyridin-2- yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(pyridin-3- yl)phenyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(3-(pyridin-3- yl)phenyl)ethenesulfonamide;
(E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-phenylethenesulfonamide;
(E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(3-(2-hydroxypropan-2- yl)phenyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropyl-1H-imidazol-2- yl)ethenesulfonamide;
(E)-2-(benzo[d]thiazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-phenylprop-1-ene-1- sulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-methylthiazol-2- yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropyl-4-methyl-1H- imidazol-2-yl)ethenesulfonamide;
(E)-ethyl2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamoyl)vinyl)thiazole-4-carboxylate;
(E)-N-((8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2- phenylethenesulfonamide;
(E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)thiazole-4- carboxylic acid;
(E)-N-((2-fluoro-6-(trifluoromethyl)phenyl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide; (E)-N-((2-fluoro-6-(trifluoromethyl)phenyl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide; (E)-N-((8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2- phenylethenesulfonamide;
(E)-N-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2- phenylethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(2-hydroxypropan-2- yl)thiazol-2-yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(3- (methylsulfonyl)propoxy)phenyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(quinolin-2- yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrazin-2- yl)ethenesulfonamide;
(E)-2-(1-ethyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((2,5-bis(trifluoromethyl)phenyl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(hydroxymethyl)thiazol-2- yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-4- yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-5- yl)ethenesulfonamide;
(E)-2-(1-ethyl-4-methyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
4-((E)-2-(4-(1H-pyrazol-1-yl)phenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2,2,2-trifluoroethyl)-1H- imidazol-2-yl)ethenesulfonamide;
(E)-N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide; (E)-N-((8-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide;
(E)-N-((8-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2,2,2- trifluoroethyl)-1H-imidazol-2-yl)ethenesulfonamide;
(E)-4-(2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-1H- imidazol-1-yl)butanoic acid;
(E)-2-(3,4-difluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene- sulfonamide;
(E)-2-(3-((dimethylamino)methyl)phenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-sulfonamide;
(E)-2-(4-((dimethylamino)methyl)phenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-((methylsulfonyl)methyl)- 1H-imidazol-2-yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-(methylthio)ethyl)-1H- imidazol-2-yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(5-methylthiazol-2-yl)ethene- sulfonamide;
or pharmaceutically acceptable salts of any of the compounds above.
Following is a list of abbreviations used in the description of the preparation of the compounds of the present invention:
bs: broad singlet CDC13: Deuterated chloroform
CHC13: Chloroform
d: doublet
dd: doublet of doublet
dt: doublet of triplet
DCM: Dichloromethane
DMAC: N,N-(Dimethylacetamide)
DMAP: 4-(Dimethylamino) pyridine
DMF: N,N-Dimethyl formamide
DMSO: Dimethyl sulfoxide EDTA: Ethylenediaminetertraacetic acid EtOAc: Ethyl acetate
EtOH: Ethanol
HCl(g): Hydrogen chloride (gas)
K2CO3: Potassium carbonate
MeOH: Methanol
m: multiplet
mmol: millimoles
µg : microgram
MS: Mass spectrum
Na2CO3: Sodium carbonate
ng : nanogram
NIS: N-iodosuccinimide
1H NMR : Proton nuclear magnetic resonance POCI3: Phosphorylchloride
s: singlet
t: Triplet
td: triplet of doublet
THF: Tetrahydrofuran
TLC: Thin layer chromatography
RT: room temperature
N2: Nitrogen
PMA: Phorbol 12-myristate 13-acetate IL1β: Interleukin 1 beta
TNF α: Tumor necrosis factor alpha
DAMP: damage‐associated molecular pattern;
PAMP: pathogen‐associated molecular pattern;
TLR: Toll‐like receptor. General Process for Preparation The novel compounds of the present invention can be prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art. The reactions can be performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being affected. Preferred methods include, but not limited to those described below, where all symbols are as defined earlier unless and otherwise defined below. The compounds of the general formula (I) can be prepared as described in schemes below along with suitable modifications/variations which are well within the scope of a person skilled in the art. Scheme 1
Wherein each of A, B, R1, R2, R3
, and R4, are as defined earlier. Compound 2 can be prepared by variety of methods familiar to those skilled in art using reagent like sulfuryl dichloride from commercially available styrene (1). Compound (2) on treatment with ammonia under suitable conditions and appropriate solvents afforded compound 3. Compound 3 on treatment with isocyanato derivative (4) under suitable conditions, base like sodium hydride and appropriate solvent afforded compound of formula (I). Specific
reaction conditions, solvents and other parameters necessary for carrying out the process steps as described above are well within the capabilities of a person skilled in the art. Scheme 2
, and R4, are as defined earlier. Compound (6) can be prepared by variety of methods familiar to those skilled in art using a reagent like Boc anhydride from commercially available methane sulfonamide (5). Compound (6) on treatment with diphenylphosphinic chloride under suitable conditions and appropriate solvents provided compound 7 (ref. Synthesis 2003, 15, 2321-24). Compound 7 on treatment with aldehyde or ketone derivative (8) under suitable conditions in presence of base like sodium hydride and appropriate solvent provided compound (9), which can be deprotected under suitable conditions to afford compound (3). Compound (3) on treatment with isocyanato derivative (4) under suitable conditions in presence of base like sodium hydride and appropriate solvent to afford compound of formula (I). Specific reaction conditions, solvents and other parameters necessary for carrying out the process steps as described above are well within the capabilities of a person skilled in the art. The invention is further illustrated by the following non-limiting examples which describe the preferred way of carrying out the present invention. These are provided without limiting the scope of the present invention in any way.
1H NMR spectral data given in the examples (vide infra) are recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and reported in δ scale. Until and otherwise mentioned the solvent used for NMR is CDCl3 using TMS as the internal standard. Example-1: Preparation of (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 2-phenylethenesulfonamide
Intermediate-1: Preparation (E)-2-phenylethene-1-sulfonyl chloride
Styrene (5.56 ml, 48.0 mmol) was added to a solution of Sulfuryl Chloride (7.81 ml, 96 mmol) in DMF (50.0 ml) at room temperature in three portions under Nitrogen atmosphere conditions & heated at 90°C for 3h. The reaction was cooled & then poured into cold water (100 ml), extract with Et2O (50 mL x2), organic layers were collected, dried over sodium sulfate and distilled under vacuum to give crude product. The crude product was used for next reaction.
1H NMR (400 MHz, DMSO-d6): δ = 7.75 (d, J = 15.6 Hz, 1H), 7.58– 7.52 (m, 3H), 7.52– 7.47 (m, 2H), 7.25 (d, J = 15.6 Hz, 1H) Intermediate 2: Preparation of (E)-2-phenylethene-1-sulfonamide
(E)-2-phenylethenesulfonyl chloride (1.0 g, 4.93 mmol) was dissolved in Acetonitrile (20 ml) to give a colorless solution. Ammonia gas was introduced to the reaction mixture at 0-5°C for 30 min. Acetonitrile was distilled & chilled water (50 ml) was added , stirred and solid material formed was filtered through Buchner funnel to give product.
1H NMR (400 MHz, DMSO-d6): δ = 7.68– 7.65 (m, 2H), 7.44– 7.40 (m, 3H), 7.30 (d, J = 15.6 Hz, 1H), 7.22 (d, J = 15.6 Hz, 1H), 7.10 (s, 2H); MS (ESI): m/z (%) = 183.15 (100%) (M+H)+, 181.35 (100%) (M-1) (100%)
Example-1:
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-phenylethene-1- sulfonamide
To a solution of (E)-2-phenylethenesulfonamide (0.2 g, 1.092 mmol) in THF (4 mL) under Nitrogen atmosphere conditions was added sodium methanolate (0.059 g, 1.092 mmol) in one portion. The resulted suspension was stirred further for 3 h at RT. A solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (0.239 g, 1.201 mmol) in THF (2.0 ml) was added drop wise to above suspension and reaction mixture (RM) was heated to reflux for 4 h. The R.M was concentrated under reduced pressure. Then it was acidified with dil. HCl and it was diluted with EA (15 mL), layers were separated, aq. layer was back extracted with EA (15 mLX2), all org. layer was combined and washed with water (15 mL), brine (15 mL), dried it over Na2SO4 and conc. under reduced pressure. Crude product was purified by preparative HPLC. 1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 10.48 (br, s, 1H), 8.09 (s, 1H), 7.74 (m, 2H), 7.58 (d, J = 15.6 Hz, 1H), 7.49– 7.43 (m, 4H), 6.93 (s, 1H), 2.79 (d, J = 7.2 Hz, 4H), 2.66 (d, J = 7.2 Hz, 4H), 1.96– 1.89 (m, 4H); MS (ESI): m/z (%) = 383.1 (100%) (M+H)+, 400.0 (60%) (M+NH4)+, 381.15 (M-1) (100%). Using appropriate starting materials and suitable modifications of the process described in example 1, including suitable addition and/or deletion of steps as may be necessary which are well within the scope of a person skilled in the art, the following compounds were prepared in an analogues manner.
Example 2
(E)-2-(4-fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide
Example 3
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(p-tolyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 10.50 (br, s, 1H), 8.09 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 15.6 Hz, 1H), 7.38 (d, J = 15.6 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 6.49 (s, 1H), 2.49 (s, 3H), 2.79 (t, J = 7.2 Hz, 4H), 2.65 (d, J = 6.2 Hz, 4H), 2.08– 1.91 (m, 4H); MS (ESI): m/z (%) = 397.20 (100%) (M+H)+, 414.25 (30%) (M+NH4)+. Example 4
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4- (trifluoromethyl)phenyl)
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 10.63 (br, s, 1H), 8.13 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.66 (s, 2H), 6.95 (s, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 8.0 Hz, 4H), 1.97– 1.91 (m, 4H); MS (ESI): m/z (%) = 451.30 (100%) (M+H)+, 468.35 (M+NH +
4 ), 449.35 (M-1).
Example 5
(E)-2-(3-fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 10.61 (br, s, 1H), 8.10 (s, 1H), 7.72– 7.69 (m, 1H), 7.60– 7.57 (m, 3H), 7.52– 7.46 (m, 1H), 7.33– 7.28 (m, 1H), 6.95 (s, 1H),
2.79 (t, J = 7.6 Hz, 4H), 2.65 (t, J = 7.6 Hz, 4H), 1.97– 1.90 (m, 4H); MS (ESI): m/z (%) = 401.10 (100%) (M+H)+, 418.25 (30%) (M+NH +
4 ), 399.25 (100%) (M-1).
Example 6
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyridin-3- yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 8.71 (s, 1H), 8.52 (dd, J = 1.6, J = 4.8 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.44– 7.39 (m, 2H), 7.16 (d, J = 16.0 Hz, 1H), 6.79 (s, 1H), 2.75 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 1.92– 1.88 (m, 4H); MS (ESI): m/z (%) = 384.10 (100%) (M+H)+, 406.20 (30%) (M+NH +
4 ), 382.15 (100%) (M-1).
Example 7
Sodium (E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((4- methoxystyryl)sulfonyl)amide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 10.41 (brs, 1H), 8.06 (s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 15.2 Hz, 1H), 7.28 (d, J = 15.6 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 3.80 (s, 1H), 278 (t, J = 7.6 Hz, 4H), 2.65 (t, J = 7.2 Hz, 4H), 1.97– 1.90 (m, 4H); MS (ESI): m/z (%) = 413.15 (100%) (M+H)+, 435.25 (100%) (M+NH +
4 ), 411.15 (100%) (M-1). Example 8
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(3-methoxyphenyl)ethene sulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 7.39 (s, 1H), 7.29– 7.25 (m, 2H), 7.07 – 6.99 (m, 3H), 6.88– 6.92 (m, 1H), 6.76 (s, 1H), 2.77– 2.70 (m, 4H), 2.69– 2.67 (m, 4H), 1.92– 1.88 (m, 4H); MS (ESI): m/z (%) = 413.10 (100%) (M+H)+, 411.15 (100%) (M-1).
Example 9
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(2-hydroxypropan-2- yl)phenyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 7.47– 7.40 (m, 5H), 7.21 (d, J = 15.6 Hz, 1H), 7.03 (d, J = 16.0 Hz, 1H), 6.77 (s, 1H), 5.05 (s, 1H), 2.77– 2.69 (m, 8H), 1.92– 1.88 (m, 4H), 1.41 (s, 6H); MS (ESI): m/z (%) = 441.27 (100%) (M+H)+, 439.16 (100%) (M-1).
Example 10
(E)-2-(4-cyanophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 8.01 (s, 1H), 7.91– 7.59 (m, 4H), 7.65 (d, J = 15.6 Hz, 1H), 7.53 (d, J = 15.2 Hz, 1H), 6.91 (s, 1H), 2.78 (t, J = 7.2 Hz, 4H), 7.66 (t, J = 6.4 Hz, 4H), 1.96– 1.89 (m, 4H); MS (ESI): m/z (%) = 408.10 (100%) (M+H)+, 406.10 (100%) (M-1).
Example 11
N-((1,2,3,5,6,7-hexahydro-s-in n-4- l r m l -2- henylethynesulfonamide
Example 12
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiophen-2- yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 7.54 (d, J = 4.8 Hz, 1H), 7.38 (s, 1H), 7.28 (d, J = 3.6 Hz, 1H), 7.20 (d, J = 15.6 Hz, 1H), 7.07 (d, J = 3.6 Hz, 1H), 7.08– 7.06 (m, 1H), 6.77 (s, 1H), 2.75 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.6 Hz, 4H), 1.94– 1.87 (m, 4H); MS (ESI): m/z (%) = 389.05 (100%) (M+H)+, 387.00 (100%) (M-1).
Example 13
(E)-ethyl 5-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamoyl)vinyl)furan-3-carboxylate
Example 14
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(2-hydroxypropan-2- yl)furan-2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 10.5 (br, s, 1H), 8.11 (s, 1H), 7.67 (s, 1H), 7.34 (d, J = 15.2 Hz, 1H), 7.04 (s, 1H), 6.94 (d, J = 15.2 Hz, 1H), 6.95 (s, 1H), 5.03 (s, 1H), 2.79 (t, J = 7.6 Hz, 4H), 2.66 (t, J = 7.2 Hz, 4H), 1.97– 1.91 (m, 4H), 1.37 (s, 6H); MS (ESI): m/z (%) = 430.12 (10%) (M+H)+, 429.10 (100%) (M-1).
Example 15
(E)-2-cyclohexyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 7.86 (s, 1H), 6.89 (s, 1H), 6.56– 6.51 (m, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.17– 2.19 (m, 1H), 1.99– 1.91 (m, 4H), 1.70– 1.68 (m, 4H), 1.63– 1.60 (m, 1H), 1.31– 1.22 (m, 3H), 1.18– 1.05 (m, 3H); MS (ESI): m/z (%) = 441.27 (100%) (M+H)+, 439.16 (100%) (M-1).
Example 16
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiophen-3- yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 10.48 (br, s, 1H), 8.08 - 805 (m, 2H), 7.66– 7.64 (m, 1H), 7.59– 7.54 (m, 2H), 7.27 (d, J = 15.2 Hz, 1H), 6.94 (s, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 7.2 Hz, 4H), 1.97– 1.90 (m, 4H); MS (ESI): m/z (%) = 389.06 (100%) (M+H)+, 411.04 (30%) (M+Na).
Example 17
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyridin-4- yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 8.60 (d, J = 6.0 Hz, 2H), 7.77 (s, 1H), 7.63 (d, J = 15.6 Hz, 1H), 7.60 (d, J = 6.0 Hz, 1H), 7.27 (d, J = 15.6 Hz, 1H), 6.87 (s, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 1.95– 1.88 (m, 4H); MS (ESI): m/z (%) = 384.10 (100%) (M+H)+, 406.05 (30%) (M+NH +
4 ), 382.05 (100%) (M-1). Example 18
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(hydroxymethyl)furan- 2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 7.94 (s, 1H), 7.70 (s, 1H), 7.25 (d, J = 14.8 Hz, 1H), 6.97 (d, J = 15.6 Hz, 1H), 6.92 (s, 1H), 6.91 (s, 1H), 5.17– 4.98 (m, 1H), 4.33– 4.32 (m, 2H), 2.88– 2.78 (m, 4H), 2.79– 2.63 (m, 4H), 1.86– 2.08 (m, 4H); MS (ESI): m/z (%) = 402.98 (100%) (M+H)+, 424.96 (40%) (M+Na+).
Example 19 (E)-2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-N-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 10.6 (br, s, 1H), 8.90 (s, 1H), 8.12 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 15.6 Hz, 1H), 7.55 (d, J = 15.2 Hz, 1H), 6.94 (s, 1H), 2.78 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 7.2 Hz, 4H), 1.96– 1.89 (m, 4H); MS (ESI): m/z (%) = 548.96 (100%) (M+H)+, 570.9410%) (M+NH +
4 ).
Example 20 (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4- (trifluoromethoxy)phenyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 10.55 (br, s, 1H), 8.11 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 15.2 Hz, 1H), 7.52 (d, J = 15.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 1.98– 1.88 (m, 4H); MS (ESI): m/z (%) = 466.97 (100%) (M+H)+, 488.95(10%) (M+Na+).
Example 21
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 10.7 (br, s, 1H), 8.23 (s, 1H), 8.05 (d, J = 2.8 Hz, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 15.2 Hz, 1H), 7.58 (d, J = 15.2 Hz, 1H), 6.96 (s, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 6.8 Hz, 4H), 1.98– 1.91 (m, 4H); MS (ESI): m/z (%) = 389.92 (100%) (M+H)+, 411.90 (20%) (M+Na+).
Example 22
(E)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.4 (br, s, 1H), 8.05 (s, 1H), 7.43 (d, J = 15.6 Hz, 1H) 7.31 (d, J = 2.0 Hz, 2H), 7.28 (d, J = 15.2 Hz, 1H), 7.22 (dd, J = 15.6 Hz, J = 2.0 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.28 (d, J = 5.2 Hz, 2H), 4.26 (d, J = 5.2 Hz, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 1.97– 1.94 (m, 4H); MS (ESI): m/z (%) = 440.94 (100%) (M+H)+, 462.92 (10%) (M+Na+).
Example 23
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyridin-2- yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.6 (br, s, 1H), 8.66 (d, J = 3.6 Hz, 1H), 8.20 (s, 1H), 7.93– 7.89 (m, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 15.2 Hz, 1H), 8.52 (d, J = 15.2 Hz, 1H), 7.48– 7.44 (m, 1H), 6.95 (s, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 7.2 Hz, 4H), 1.97– 1.92 (m, 4H); MS (ESI): m/z (%) = 383.95 (100%) (M+H)+, 405.92 (20%) (M+Na+).
Example 24 (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(pyridin-3- yl)phenyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.54 (s, 1H), 8.97 (S, 1H), 8.60 (d, J = 3.2 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 7.90– 7.83 (m, 4H), 7.64– 7.49 (m, 3H), 6.94 (s, 1H), 2.79 (t, J = 7.6 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 1.97– 1.92 (m, 4H); MS (ESI): m/z (%) = 459.88 (100%) (M+H)+.
Example 25
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(3-(pyridin-3- yl)phenyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.55 (s, 1H), 8.99 (d, J = 2.0 Hz, 1H), 8.60 (dd, J = 1.6 Hz, J = 4.8 Hz, 1H), 8.19– 8.17 (m, 2H), 8.07 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.69– 7.49 (m, 4H), 6.93 (s, 1H), 2.78 (t, J = 7.6 Hz, 4H), 2.67 (t, J = 6.8 Hz, 4H), 1.95– 1.88 (m, 4H); MS (ESI): m/z (%) = 459.88 (100%) (M+H)+, 457.95 (100%) (M-1)
Example 26
(E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-phenylethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.67 (s, 1H), 7.92 (s, 1H), 7.73 (m, 2H), 7.59 (d, J = 15.6 Hz, 1H), 7.47– 7.43 (m, 4H), 7.26– 7.22 (m, 1H), 7.11 (d, J = 8.0 Hz, 2H), 3.04– 2.97 (m, 2H), 1.04 (s, 12H); MS (ESI): m/z (%) = 386.94 (100%) (M+H)+, 408.91 (100%) (M+Na).
Example 27
(E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.88 (s, 1H), 8.06– 8.05 (m, 3H), 8.01 (d, J = 3.2 Hz, 1H), 7.76 (d, J = 15.2 Hz, 1H), 7.56 (d, J = 15.2 Hz, 1H), 7.27– 7.23 (m, 1H), 7.13 (d, J = 8.0 Hz, 2H), 3.05– 2.98 (m, 2H), 1.05 (s, 12H); MS (ESI): m/z (%) = 393.89 (100%) (M+H)+, 415.87 (20%) (M+Na).
Example 28 (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(3-(2-hydroxypropan-2- yl)phenyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.5 (s, 1H), 8.01 (s, 1H), 7.77 (s, 1H), 7.58 (m, 3H), 7.45 (d, J = 15.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 5.11 (s, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.64 (t, J = 7.2 Hz, 4H), 1.97– 1.90 (m, 4H), 1.43 (s, 6H); MS (ESI): m/z (%) = 440.92 (70%) (M+H)+, 462.92 (40%) (M+Na), 438.98 (M-1).
Example 29 (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropyl-1H-imidazol- 2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.59 (s, 1H), 8.19 (s, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.49 (d, J = 14.8 Hz, 1H), 7.31 (d, J = 14.8 Hz, 1H), 7.15 (s, 1H), 6.95 (s, 1H), 4.75– 4.68 (m, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 7.6 Hz, 4H), 1.98– 1.90 (m, 4H), 1.38 (d, J = 6.8 Hz, 6H); MS (ESI): m/z (%) = 415.19 (100%) (M+H)+.
Example 30
(E)-2-(benzo[d]thiazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 8.20 (d, J = 7.6 Hz, 1H), 8.15 (brs, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 15.6 Hz, 1H), 7.71 (d, J = 15.6 Hz, 1H), 7.59 (td, J = 7.2 Hz, J = 1.2 Hz, 1H), 7.54 (td, J = 8.4 Hz, J = 1.6 Hz, 1H), 6.92 (s, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 1.97– 1.90 (m, 4H); MS (ESI): m/z (%) = 440.12 (50%) (M+H)+. Example 31
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-phenylprop-1-ene-1- sulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.63 (s, 1H), 8.09 (s, 1H), 7.59– 7.54 (m, 2H), 7.46– 7.43 (m, 3H), 6.95 (s, 1H), 6.81 (s, 1H), 2.79 (t, J = 7.6 Hz, 4H), 2.66 (t, J = 7.2 Hz, 4H), 2.50 (s, 3H), 1.99– 1.90 (m, 4H); MS (ESI): m/z (%) = 397.17 (100%) (M+H)+, 419.15 (20%) (M+Na)+.
Example 32 (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-methylthiazol-2- yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.68 (s, 1H), 8.21 (s, 1H), 7.65 (d, J = 15.2 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J = 15.6 Hz, 1H), 6.96 (s, 1H), 2.78 (t, J = 7.6 Hz, 4H), 2.65
(d, J = 7.6 Hz, 4H), 2.42 (s, 3H), 1.99– 1.93 (m, 4H); MS (ESI): m/z (%) = 444.10 (100%) (M+H)+, 401.99 (100%) (M-1).
Example 33 (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropyl-4-methyl-1H- imidazol-2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.55 (s, 1H), 8.17 (s, 1H), 7.42 (d, J = 14.8 Hz, 1H), 7.28– 7.18 (m, 2H), 6.95 (s, 1H), 4.66- 4.63 (m, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 6.8 Hz, 4H), 2.12 (s, 3H), 1.96– 1.93 (m, 4H), 1.35 (d, J = 6.4 Hz, 6H); MS (ESI): m/z (%) = 429.18 (100%) (M+H)+.
Example 34 (E)-ethyl2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamoyl)vinyl)thiazole-4-carboxylate
1H NMR (400 MHz, DMSO-d6): δ = 10.80 (s, 1H), 8.71 (s, 1H), 7.76 (d, J = 15.2 Hz, 1H), 7.68 (d, J = 15.2 Hz, 1H), 6.95 (s, 1H), 7.33 (t, J = 7.2 Hz, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 1.98– 1.91 (m, 4H), 1.31 (t, J = 7.2 Hz, 3H); MS (ESI): m/z (%) = 462.30 (90%) (M+H)+.
Example 35 (E)-N-((8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2- phenylethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.59 (s, 1H), 8.18 (s, 1H), 7.75– 7.73 (m, 2H), 7.56 (d, J = 15.6 Hz, 1H), 7.47– 7.44 (m, 4H), 2.83– 2.77 (m, 8H), 2.01– 1.94 (m, 4H); MS (ESI): m/z (%) = 461.04 (100%) (M)+, 463.05 (100%) (M+2).
Example 36
(E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamoyl)vinyl)thiazole-4-carboxylic acid
1H NMR (400 MHz, DMSO-d6): δ = 8.11 (s, 1H), 7.52– 7.48 (m, 2H), 7.26 (d, J = 16.4 Hz, 1H), 6.78 (s, 1H), 2.77– 2.67 (m, 8H), 1.94– 1.89 (m, 4H); MS (ESI): m/z (%) = 434.10 (100%) (M+H)+, 451.10 (100%) (M+NH4)+.
Example 37 (E)-N-((2-fluoro-6-(trifluoromethyl)phenyl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 8.01– 7.87 (m, 3H), 7.57– 7.30 (m, 5H); MS (ESI): m/z (%) = 395.98 (80%) (M+H)+, 417.96 (100%) (M+Na).
Example 38
(E)-2-(thiazol-2-yl)-N-((2-(trifluoromethyl)phenyl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 8.14 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 3.2 Hz, 1H), 7.87 (d, J = 3.2 Hz, 1H), 7.60– 7.52 (m, 2H), 7.48– 7.37 (m, 3H), 7.14 (t, J = 5.4 Hz, 1H); MS (ESI): m/z (%) = 377.95 (80%) (M+H)+, 399.95 (100%) (M+Na), 375.95 (100%) (M-1).
Example 39
(E)-N-((8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2- phenylethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.58 (s, 1H), 8.19 (s, 1H), 7.75– 7.73 (m, 2H), 7.56 (d, J = 15.6 Hz, 1H), 7.48– 7.44 (m, 4H), 2.83 (d, J = 7.6 Hz, 4H), 2.75 (d, J = 7.2 Hz, 4H), 2.02– 1.95 (m, 4H); MS (ESI): m/z (%) = 417.10 (100%) (M)+, 415.05 (100%) (M-1).
Example 40
(E)-N-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2- phenylethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.66 (s, 1H), 8.47 (s, 1H), 7.75– 7.73 (m, 2H), 7.56 (d, J = 15.6 Hz, 1H), 7.46– 7.42 (m, 4H), 2.95 (d, J = 7.2 Hz, 4H), 2.74 (d, J = 7.2 Hz, 4H), 2.06– 1.99 (m, 4H); MS (ESI): m/z (%) = 408.15 (100%) (M)+, 406.05 (100%) (M-1).
Example 41
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(2-hydroxypropan-2- yl)thiazol-2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 8.01 (s, 1H), 7.95 (s, 1H), 7.56– 7.42 (m, 3H), 6.89 (s, 1H), 5.27 (s, 1H), 2.87– 2.76 (m, 4H), 2.68 (d, J = 7.6 Hz, 4H), 1.96– 1.89 (m, 4H), 1.45 (s, 6H); MS (ESI): m/z (%) = 447.1 (80%) (M+H)+, 470.10 (100%) (M+Na)+, 446.15 (50%) (M-1).
Example 42
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(3- (methylsulfonyl)propoxy)phenyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.42 (s, 1H), 8.06 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 15.6 Hz, 1H), 7.29 (d, J = 15.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.94 (s, 1H), 4.15 (t, J = 6.0 Hz, 2H), 3.27 (d, J = 7.2 Hz, 2H), 3.02 (s, 1H), 2.79 (d, J = 7.2 Hz, 4H), 2.65 (d, J = 7.8 Hz, 4H), 2.18– 2.08 (m, 2H), 1.97– 1.90 (m, 4H); MS (ESI): m/z (%) = 519.13 (100%) (M+H)+, 541.12 (50%) (M+Na)+.
Example 43
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(quinolin-2- yl)ethenesulfonamide;
1H NMR (400 MHz, DMSO-d6): δ = 10.73 (s, 1H), 8.50 (d, J = 8.4 Hz, 1H), 8.21 (S, 1H), 8.06– 8.00 (m, 3H), 7.91 (d, J = 15.2 Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.74 (d, J = 15.2 Hz, 1H), 7.69 (t, J = 6.8 Hz, 1H), 6.94 (s, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 1.96 (quin, J = 7.2 Hz, 4H); MS (ESI): m/z (%) = 435.34 (100%) (M+H)+. Example 44
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrazin-2- yl)ethenesulfonamide;
1H NMR (400 MHz, DMSO-d6): δ = 8.94 (s, 1H), 8.71 (s, 1H), 8.68 (s, 1H), 7.94 (bs, 1H), 7.78 (d, J = 15.2 Hz, 1H), 7.50 (d, J = 15.6 Hz, 1H), 6.88 (s, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 1.96 (quin, J = 7.2 Hz, 4H); MS (ESI): m/z (%) = 385.15 (100%) (M+H)+, 383.10 (100%) (M-H)+.
Example 45
(E)-2-(1-ethyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO): δ = 10.55 (bs, 1H), 8.20 (s, 1H), 7.46-7.42 (m, 2H), 7.29 (d, J=14.8Hz, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 4.16 (q, J=7.2Hz, 2H), 2.82-2.78 (m, 4H), 2.67-2.64 (m, 4H), 1.98-1.91 (m, 4H), 4.16 (t, J=7.2Hz, 3H); MS (ESI): m/z (%) = 401.15 (100%) (M+H)+; 423.15 (50%) (M+Na)+.
Example 46
(E)-N-((2,5-bis(trifluoromethyl)phenyl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 8.73 (s, 1H), 7.93 (d, J = 3.2 Hz, 1H), 7.85 (d, J = 3.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.49– 7.39 (m, 3H), 7.32 (d, J = 15.6 Hz, 1H); MS (ESI): m/z (%) = 446.01 (100%) (M+H)+, 467.99 (20%) (M+Na).
Example 47
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(hydroxymethyl)thiazol- 2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 8.22 (s, 1H), 7.71 (s, 1H), 7.67 (d, J = 15.2 Hz, 1H), 7.53 (d, J = 15.6 Hz, 1H), 6.96 (s, 1H), 5.45 (t, J = 5.6 Hz, 1H), 4.60 (d, J = 4.4 Hz, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 7.2 Hz, 4H), 1.99– 1.91 (m, 4H); MS (ESI): m/z (%) = 420.06 (100%) (M+H)+, 442.04 (20%) (M+Na)+.
Example 48
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-4- yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.66 (brs, 1H), 9.21 (d, J = 1.6 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.15 (s, 1H), 7.62 (d, J = 15.2 Hz, 1H), 7.37 (d, J = 14.8 Hz, 1H), 6.94 (s, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.66 (d, J = 7.2 Hz, 4H), 2.00– 1.90 (m, 4H); MS (ESI): m/z (%) = 390.07 (100%) (M+1)+, 412.05 (50%) (M-1).
Example 49
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-5- yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.59 (s, 1H), 9.24 (s,1H), 8.38 (s, 1H), 8.13 (s, 1H), 7.85 (d, J = 15.2 Hz, 1H), 7.27 (d, J = 15.6 Hz, 1H), 6.95 (s, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 7.2 Hz, 4H), 1.98– 1.91 (m, 4H); MS (ESI): m/z (%) = 390.09 (100%) (M+H)+, 412.07 (30%) (M+Na)+.
Example 50
(E)-2-(1-ethyl-4-methyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.55 (s, 1H), 8.16 (s, 1H), 7.36 (d, J = 14.8 Hz, 1H), 7.21 (d, J = 14.8 Hz, 1H), 7.17 (s, 1H), 6.95 (s, 1H), 4.08 (q, J = 7.2 Hz, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 7.2 Hz, 4H), 2.12 (s, 3H), 1.98– 1.91 (m, 4H), 1.27 (d, J = 7.2 Hz, 3H); MS (ESI): m/z (%) = 415.18 (100%) (M+H)+.
Example 51
4-((E)-2-(4-(1H-pyrazol-1-yl)phenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.52 (s, 1H), 8.62 (s, 1H), 8.10 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 15.6 Hz, 1H), 7.49 (d, J = 15.6 Hz, 1H), 6.94 (s, 1H), 6.59 (s, 1H), 6.58 (d, J = 2.4 Hz, 1H) 2.79 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 7.2 Hz, 4H), 1.97 (t, J = 7.2 Hz, 4H); MS (ESI): m/z (%) = 449 (100%) (M+1).
Example 52
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2,2,2-trifluoroethyl)- 1H-imidazol-2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.63 (s, 1H), 8.19 (s, 1H), 7.59 (d, J = 14.8 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J = 14.8 Hz, 1H), 7.21 (d, J = 1.2 Hz, 1H), 6.96 (s, 1H), 5.35 (q, J = 9.2 Hz, 2H), 2.78 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 7.2 Hz, 4H), 1.99– 1.91 (m, 4H); MS (ESI): m/z (%) = 455.13 (100%) (M+H)+, 477.11 (10%) (M+Na)+.
Example 53
(E)-N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.98 (s, 1H), 8.01 (d, J = 2.8Hz, 2H), 7.64 (s, 1H), 7.53 (d, J = 15.2 Hz, 1H), 7.13 (s, 2H), 3.03 (m, 2H), 1.05 (d, J = 6.0 Hz, 12H); MS (ESI): m/z (%) = 428 (100%) (M+1).
Example 54
(E)-N-((8-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.64 (s, 1H), 8.15 (s, 1H), 8.05 (d, J = 3.2 Hz, 1H), 8.02 (d, J = 3.2 Hz, 1H), 7.73 (d, J = 15.2 Hz, 1H), 7.57 (d, J = 15.2 Hz, 1H), 2.74 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.08 (s, 3H), 1.99– 1.91 (m, 4H); MS (ESI): m/z (%) = 404.10 (100%) (M+H)+.
Example 55
(E)-N-((8-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2,2,2- trifluoroethyl)-1H-imidazol-2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.58 (s, 1H), 8.09 (s, 1H), 7.58 (d, J = 14.8 Hz, 1H), 7.49 (s, 1H), 7.42 (d, J = 14.8 Hz, 1H), 7.21 (s, 1H), 5.43 (q, J = 8.4 Hz, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.09 (s, 3H), 1.97– 1.94 (m, 4H); MS (ESI): m/z (%) = 469.14 (100%) (M+H)+, 491.13 (10%) (M+Na)+.
Example 56
(E)-4-(2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-1H- imidazol-1-yl)butanoic acid
1H NMR (400 MHz, DMSO-d6): δ = 12.25 (bs, 1H), 10.58 (bs, 1H), 8.14 (s, 1H), 7.43 (d, J = 14.8 Hz, 1H), 7.24 (s, 1H), 7.32 (d, J = 14.8 Hz, 1H), 7.12 (s, 1H), 6.94 (s, 1H), 4.14 (t, J = 7.2 Hz, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 7.6 Hz, 4H), 2.19 (t, J = 7.2 Hz, 2H), 1.97– 1.90 (m, 4H), 1.88– 1.82 (m, 2H); MS (ESI): m/z (%) = 459.16 (100%) (M+H)+, 481.15 (5%) (M+Na)+.
Example 57
(E)-2-(3,4-difluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-sulfonami
1H NMR (400 MHz, DMSO-d6): δ = 10.56 (s, 1H), 8.08 (s, 1H), 8.03– 7.97 (m, 1H), 7.66– 7.49 (m, 1H), 7.56– 7.49 (m, 3H), 6.95 (s, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.6 Hz, 4H), 1.97 (quin, J = 7.6 Hz, 4H); MS (ESI): m/z (%) = 419.10 (80%) (M+H)+, 441.08 (28%) (M+Na)+.
Example 58
(E)-2-(3-((dimethylamino)methyl)phenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-sulfonamide;
1H NMR (400 MHz, DMSO-d6): δ = 10.40 (bs, 1H), 8.13 (s, 1H), 7.74 (s, 1H), 7.71 – 7.69 (m, 1H), 7.51– 7.42 (m, 4H), 6.92 (s, 1H), 3.87 (s, 2H), 2.80 (t, J = 7.6 Hz, 4H), 2.68 (t, J = 6.8 Hz, 4H), 2.45 (s, 6H), 1.96 (quin, J = 7.2 Hz, 4H); MS (ESI): m/z (%) = 440.18 (100%) (M+H)+.
Example 59
(E)-2-(4-((dimethylamino)methyl)phenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-ethenesulfonamide;
1H NMR (400 MHz, DMSO-d6): δ = 7.92 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.41 (s, 2H), 7.39 (d, J = 8.0 Hz, 4H), 6.90 (s, 1H), 3.62 (s, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 6.8 Hz, 4H), 2.28 (s, 6H), 1.99 (quin, J = 8.0 Hz, 4H); MS (ESI): m/z (%) = 440.19 (100%) (M+H)+.
Example 60 (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1- ((methylsulfonyl)methyl)-1H-imidazol-2-yl)ethenesulfonamide;
Example 61
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-(methylthio)ethyl)- 1H-imidazol-2-yl)ethenesulfonamide;
1H NMR (400 MHz, DMSO-d6): δ = 10.52 (s, 1H), 8.18 (s, 1H), 7.50 (d, J = 14.8 Hz, 1H), 7.47 (s, 1H), 7.30 (d, J = 14.8 Hz, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 4.36 (s, 2H), 2.81 (t, J = 6.4 Hz, 6H), 2.67 (t, J = 7.6 Hz, 4H), 1.98 (s, 3H), 1.96 (quin, J = 7.2 Hz, 4H); MS (ESI): m/z (%) = 447.14 (100%) (M+H)+.
Example 62
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(5-methylthiazol-2- yl)ethene-sulfonamide;
1H NMR (400 MHz, DMSO-d6): δ = 10.77 (s, 1H), 8.21 (s, 1H), 7.75 (bs, 1H), 7.66 (d, J = 12.8 Hz, 1H), 7.48 (d, J = 15.2 Hz, 1H), 6.95 (s, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 1.96 (quin, J = 7.2 Hz, 4H), 1.24 (s, 1H); MS (ESI): m/z (%) = 404.10 (100%) (M+H)+, 402.10 (100%) (M-H)+.
Example 63
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(4-hydroxybutyl)-1H- imidazol-2-yl)ethenesulfonamide
(E)-ethyl 4-(2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamoyl)vinyl)-1H-imidazol-1-yl)butanoate
1H NMR (400 MHz, DMSO-d6): δ = 10.65 (bs, 1H), 8.15 (s, 1H), 7.44– 7.40 (m, 2H), 7.31 (d, J = 14.8 Hz, 1H), 7.12 (s, 1H), 6.94 (s, 1H), 4.15 (t, J = 6.8 Hz, 2H), 4.02 (q, J = 7.2 Hz, 2H), 2.79 (t, J = 7.6 Hz, 4H), 2.66 (t, J = 7.6 Hz, 4H), 2.27 (t, J = 7.2 Hz, 2H), 1.98– 1.87 (m, 6H), 1.15 (t, J = 7.2 Hz, 3H); MS (ESI): m/z (%) = 487.18 (100%) (M+H)+. Example 65
(E)-2-cyclopentyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.32 (s, 1H), 8.07 (s, 1H), 6.96 (s, 1H), 6.78 (dd, J = 15.2 Hz, J = 8.0 Hz, 1H), 6.67 (d, J = 15.6 Hz, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.72– 2.65 (m, 5H), 2.01– 1.93 (m, 4H), 1.81– 1.76 (m, 2H), 1.66– 1.60 (m, 4H), 1.46– 1.31 (m, 2H); MS (ESI): m/z (%) = 375.16 (100%) (M+H)+, 397.14 (50%) (M+Na)+. Example 66 (E)-2-(1-ethyl-4,5-dimethyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.48 (brs, 1H), 8.14 (s, 1H), 7.34 (d, J = 14.8 Hz, 1H), 7.14 (d, J = 14.8 Hz, 1H), 6.95 (s, 1H), 4.03 (q, J = 7.2 Hz, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 7.2 Hz, 4H), 2.17 (s, 3H), 2.08 (s, 3H), 1.98– 1.91 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H); MS (ESI): m/z (%) = 429.19 (100%) (M+H)+, 427.13 (100%) (M-1). Example 67 (E)-2-(1-(4-fluorophenyl)-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.57 (brs, 1H), 8.19 (s, 1H), 7.68 (d, J = 0.8 Hz, 1H), 7.57– 7.53 (m, 2H), 7.47– 7.43 (m, 2H), 7.35– 7.31 (m, 2H), 7.02 (d, J = 14.8 Hz, 1H), 6.95 (s, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.63 (t, J = 7.2 Hz, 4H), 1.98– 1.91 (m, 4H); MS (ESI): m/z (%) = 467.10 (100%) (M+H)+, 489.15(15%) (M+Na)+, 465.05 (100%) (M-1). Example 68 (1E,1'E)-N,N'-(((2,3,5,6-tetramethyl-1,4-phenylene)bis(azanediyl))bis(carbonyl))bis(2- (thiazol-2-yl)ethenesulfonamide)
1H NMR (400 MHz, DMSO-d6): δ = 7.91 (s, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.80 (s, 1H), 7.43 (s, 1H), 2.01 (s, 6H); MS (ESI): m/z (%) = 597 (100%) (M+1).
Example 69 (E)-N-((2,3,5,6-tetramethyl-4-nitrophenyl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 8.13 (s, 1H), 7.97 (d, J= 2.8 Hz, 1H), 7.90 (s, 1H), 7.49 (s, 1H), 2.04 (s, 12H); MS (ESI): m/z (%) = 411 (100%) (M+1). Example 70 (E)-2-(1-(cyclopropylmethyl)-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.55 (bs, 1H), 8.19 (s, 1H), 7.49-7.45 (m, 2H), 7.29 (d, J=14.8Hz, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 4.02 (d, J=7.2Hz, 2H), 2.79 (t, J=7.6Hz, 4H), 2.65 (t, J=7.2Hz, 4H), 1.98-1.90 (m, 4H), 1.20-1.05 (m, 1H), 0.52-0.47 (m, 2H), 0.38-0.35 (m, 2H); MS (ESI): m/z (%) = 427.17 (100%) (M+H)+. Example 71 (E)-2-(1-ethyl-1H-imidazol-5-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- ethene-sulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.35 (s, 1H), 8.08 (s, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.41 (d, J = 15.2 Hz, 1H), 7.00 (d, J = 15.2 Hz, 1H), 6.95 (s, 1H), 4.03 (q, J = 7.2 Hz, 2H), 2.81 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 7.2 Hz, 4H), 1.98 (quin, J = 7.2 Hz, 4H), 1.35 (t, J = 7.2 Hz, 3H); MS (ESI): m/z (%) = 401.15 (100%) (M+H)+, 487.10 (30%) (M+Na)+
, 399.15 (100%) (M-H)+.
Example 72 ((E)-2-(5-chloro-1-ethyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide
1H NMR (400 MHz, DMSO-d6): δ =8.01 (s, 1H), 7.39 (s, 1H), 7.36 (s, 1H), 7.20 (s, 1H), 6.89 (s, 1H), 4.14 (q, J = 7.2 Hz, 2H), 2.78 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.6 Hz, 4H), 1.92 (m,4H), 1.23 (t, J = 3.2 Hz, 3H); MS (ESI): m/z (%) = 435 (100%) (M+1). Example 73
(E)-N-((2,3,5,6-tetramethylphenyl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 7.96 (d, J=2.8 Hz, 1H), 7.88 (s, 1H), 7.73 (s, 1H), 7.53 (d, J=12 Hz, 1H), 7.44 (s, 1H), 6.82 (s, 1H), 2.14 (s, 6H), 1.99 (s, 6H); MS (ESI): m/z (%) = 366 (100%) (M+1). Example 74 (E)-N-((2,6-dimethoxyphenyl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO): δ = 10.7 (bs, 1H), 8.06-8.01 (m, 2H), 7.72 (d, J=15.2Hz, 1H), 7.59-7.55 (m, 2H), 7.23-7.18 (m, 1H), 6.67 (d, J=8.8Hz, 2H), 3.71 (s, 6H); MS (ESI): m/z (%) = 370.04 (15%) (M+H)+; 392.03 (100%) (M+Na)+. Example 75 (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(3- (methylsulfonyl)propyl)-1H-imidazol-2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.83 (br s, 1H), 8.39 (s, 1H), 7.65 (s, 1H), 7.53 (s, 2H), 7.42 (s, 1H), 6.96 (s, 1H), 4.33 (t, J = 6.8 Hz, 2H), 3.11 (t, J = 7.6 Hz, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.16– 2.09 (m, 2H), 1.99– 1.92 (m, 4H); MS (ESI): m/z (%) = 493.15 (100%) (M+H)+, 515.43 (10%) (M+Na)+.
Example 76 (E)-2-(1-ethyl-1H-imidazol-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.46 (s, 1H), 8.10 (s, 1H), 7.89 (s, 1H), 7.66 (s, 1H), 7.41 (d, J = 15.2 Hz, 1H), 7.17 (d, J = 15.2 Hz, 1H), 6.95 (s, 1H), 4.12 (q, J = 7.2 Hz, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 7.2 Hz, 4H), 1.95 (quin, J = 7.2 Hz, 4H), 1.30 (t, J = 7.2 Hz, 3H); MS (ESI): m/z (%) = 401.15 (100%) (M+H)+, 399.10 (100%) (M-H)+; Example 77 (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(3-(pyrrolidin-1- ylmethyl)phenyl)ethene
1H NMR (400 MHz, DMSO-d6): δ = 10.28 (s, 1H), 7.82 (bs, 1H), 7.66 (bs, 1H), 7.59– 7.58 (m, 1H), 7.44 (d, J = 15.6 Hz, 1H), 7.42– 7.41 (m, 2H), 7.34 (d, J = 15.6 Hz, 1H), 6.87 (s, 1H), 3.91 (s, 2H), 2.79– 2.75 (m, 8H), 2.69 (t, J = 7.2 Hz, 4H), 1.91 (quin, J = 7.2 Hz, 4H), 1.7.9 (bs, 4H); MS (ESI): m/z (%) = 466.25 (100%) (M+H)+.
Example 78 (E)-2-(4,5-dichloro-1-ethyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ =8.17 (s, 1H), 7.39 (s, 2H), 6.94 (s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.71 (t, J = 11.2 Hz, 4H), 1.95 (m,4H), 1.24 (t, J = 7.2 Hz, 3H); MS (ESI): m/z (%) = 469 (100%) (M+1). Example 79 (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(pyrrolidin-1-ylmethyl)- thiazol-2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.33 (br s, 1H), 7.87 (s, 1H), 7.72 (s, 1H), 7.61 (d, J = 15.2 Hz, 1H), 7.34 (d, J = 15.6 Hz, 1H), 6.84 (s, 1H), 4.32 (m, 2H), 3.10 (s, 4H), 2.77 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 1.95– 1.87 (m, 8H); MS (ESI): m/z (%) = 471.20 (100%) (M+H)+, 473.16 (100%) (M-1). Example 80 (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(3-(pyrrolidin-1-yl)- propyl)-1H-imidazol-2-yl)ethenesulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.26 (s, 1H), 8.03 (s, 1H), 7.71 (s, 1H), 7.26 (d, J = 15.2 Hz, 1H), 6.95 (s, 1H), 6.76 (d, J = 15.2 Hz, 1H), 4.44 (t, J = 5.6 Hz, 2H), 4.08 (t, J = 6.0 Hz, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 7.2 Hz, 4H), 2.23– 2.19 (m, 2H), 1.95 (quin, J = 7.2 Hz, 4H); MS (ESI): m/z (%) = 429.15 (100%) (M+H)+. Example 82 (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-phenylbut-1-ene-1- sulfonamide
1H NMR (400 MHz, DMSO-d6): δ = 10.35 (brs, 1H), 8.05 (s, 1H), 7.40– 7.17 (m, 6H), 6.96 (s, 1H), 6.74 (d, J = 15.2 Hz, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.74 (t, J = 7.6 Hz, 2H), 2.67 (t, J = 7.6 Hz, 4H), 2.56 (t, J = 7.6 Hz, 2H), 2.01– 1.91 (m, 4H); MS (ESI): m/z (%) = 411.17 (100%) (M+H)+.
The following compounds can be synthesized following the same procedure as described for example 1 and are considered to be encompassed within the scope of the present invention. (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrimidin-2-yl)ethene-1- sulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrimidin-5-yl)ethene-1- sulfonamide; (E)-2-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (E)-2-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (E)-2-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (E)-2-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (E)-2-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (E)-2-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(5,6,7,8- tetrahydropyrazolo[5,1-b][1,3]oxazepin-3-yl)ethene-1-sulfonamide; (E)-2-(2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(3- (morpholinomethyl)phenyl)ethene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(3-(piperidin-1- ylmethyl)phenyl)ethene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(3-((4-methylpiperazin-1- yl)methyl)phenyl)ethene-1-sulfonamide; (E)-2-(4-((dimethylamino)methyl)thiazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(piperidin-1- ylmethyl)thiazol-2-yl)ethene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(morpholinomethyl)thiazol- 2-yl)ethene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-((4-methylpiperazin-1- yl)methyl)thiazol-2-yl)ethene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4- ((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)thiazol-2-yl)ethene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(thiazol-2-yl)-1H-imidazol- 2-yl)ethene-1-sulfonamide; (E)-2-(1-(2-(dimethylamino)ethyl)-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl)carbamoyl)ethene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-(pyrrolidin-1-yl)ethyl)- 1H-imidazol-2-yl)ethene-1-sulfonamide; (E)-2-(1-(3-(dimethylamino)propyl)-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(3-morpholinopropyl)-1H- imidazol-2-yl)ethene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-isopropylthiazol-2- yl)ethene-1-sulfonamide; (E)-2-(4-cyclopropylthiazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide; (E)-2-(1-ethyl-4-isopropyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide; (E)-2-(4-cyclopropyl-1-ethyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide;
(E)-2-(1-ethyl-5-isopropyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide; (E)-2-(4-((dimethylamino)methyl)cyclohexyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(5-methyl-4,5,6,7- tetrahydrothiazolo[4,5-c]pyridin-2-yl)ethene-1-sulfonamide; (E)-2-(4-((ethylthio)methyl)thiazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide;
(E)-2-(4-((ethylsulfonyl)methyl)thiazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide;
Biological Activity:
In-vitro assays: THP1 monocytes were differentiated with PMA (100ng/ml) and incubated at 37 °C for 20hrs in presence of 5% CO2. 2X105 differentiated cells were plated per well of 96 well tissue culture plates. The cells were primed using 500ng/ml Lipopolysaccharide and incubating for 4hrs under the same condition. The cells were then treated with various concentrations of the compounds for 30 min followed by treatment with 5mM ATP for 1hr. The supernatants were collected and analysed by IL-1b (Mabtech Cat # 3415-1H-20) or TNF-a (Mabtech; Cat # 3510-1H-20) detection kit. The data were analyzed using GraphPad Prism V7.0. Dose Response Curve (DRC) was constructed to determine the IC50 value by fitting percentage cell survival data to the GraphPad Prism using nonlinear regression analysis. The invitro IL-1β inhibitory activity (IC50) for representative compounds are listed in Table 1. Table 1
In vivo efficacy studies: Demonstration of in vivo efficacy of test compounds in rats mice, oral routes of administration. Animals All the animal experiments were carried out in female rats and mice, bred in-house. Animals were housed in groups of 6 animals per cage, for a week, in order to habituate them to vivarium conditions (25 ± 4 °C, 60-65 % relative humidity, 12: 12 h light: dark cycle, with lights on at 7.30 am). All the animal experiments were carried out according to the internationally valid guidelines following approval by the 'Zydus Research Center animal ethical committee'. In-vivo LPS and ATP induced IL-1β assay: Female C57 mice (6-8 weeks) received intraperitoneal injection of 50 µg/mouse of lipopolysaccharide (LPS) in PBS. Animals were treated immediately with the test compounds or the vehicle. After 2h of LPS injection, animals were administered with ATP at 12.5 mg/mouse dissolved in PBS via intraperitoneal route. After 30 minutes of ATP injection, serum was collected for IL-1β estimation by ELISA. Representative data of some of the test compounds are listed in Table-2.
Table 2
Claims
1. Compound having the structure of general formula (I)
‘A’ is selected from unsubstituted or substituted (C1-C6)alkyl, (C2-C6)alkenyl, (C3- C7)cycloalkyl, aryl, heteroaryl, 4-7 membered heterocyclic ring system, 7- to 14- membered bicyclic heterocyclic ring system, bridged bicyclic heterocyclic or spiro cyclic system, having optionally one or more than one heteroatoms;
R1, which represents one or more substituents on ‘A’, at each occurrence independently represents hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, thiol, mercapto alkyl (sulfur and its oxidized forms, like S, SO2), (C1-C6)thio-alkoxy groups;
In an embodiment when‘A’ represents ring, R1 at each occurrence, may represent one or more substituents selected from hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C2- C6)alkenyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, NH2, NH(C1-C6)alkyl, N(C3- C7)cycloalkyl; N(C1-C6 alkyl)2, aryl, heteroaryl, heterocyclyl, benzyl, thiol, mercapto alkyl, sulfur and its oxidized forms, (C1-C6)thio-alkoxy, bridged or spiro ring system having optionally one or more than one heteroatoms; ‘B’ is selected from optionally substituted (C3-C7)cycloalkyl, aryl, heteroaryl and heterocyclyl groups;
R2 at each occurrence independently represents hydrogen, halogen, cyano, optionally substituted groups selected from (C1-C6)alkyl, (C2-C6) alkenyl, (C1-C6)alkoxy (C3- C7)cycloalkyl, benzyl, aryl, heteroaryl, heterocyclyl, thiol, thioalkyl, sulfur and its
oxidized forms, thio-alkoxy, bridged or spiro ring system having optionally one or more than one heteroatoms; Each of R3, R4, R5, R6, R7, R8, R9 and R10 at each occurrence are independently selected from hydrogen, halogen, haloalkyl, cyano, nitro, amide, sulphonamide, acyl, hydroxyl, optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, (C1-C6)alkoxy, thiol, mercapto alkyl, sulfur and its oxidized forms, benzyl, aryl, heteroaryl, heterocyclyl; Alternatively, R3 and R4 may form a bond; Alternatively, R3 and‘A’ together with the atom to which they are attached may form an optionally substituted 5 to 7 membered heterocyclic ring system having optionally one or more than one heteroatoms; Alternatively each of R5 and R6
, R7 and R8 or R8 and R9 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; p = 1-2.
2. The compound as claimed in claim 1, wherein‘A’ is selected from aryl, heteroaryl, 4- 7 membered heterocyclic ring system, 7- to 14-membered bicyclic heterocyclic ring system having optionally one or more than one heteroatoms selected from O, N or S.
3. The compound as claimed in claim 1, wherein‘B’ is selected from the following ring system
4. The compound as claimed in claim 3, wherein R5, R6, R7, R8, R9 and R10 at each occurrence are independently selected from hydrogen, halogen, haloalkyl, cyano, nitro, optionally substituted group selected from (C1-C6)alkyl, (C1-C6)alkoxy.
5. The compound as claimed in claim 1, wherein R1 at each occurrence is selected from hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1- C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, NH2, NH(C1-C6)alkyl, N(C3-C7)cycloalkyl; N(C1-C6 alkyl)2, aryl, heteroaryl, heterocyclyl, benzyl, thiol, mercapto alkyl, sulfur and its oxidized forms, (C1-C6)thio-alkoxy having optionally one or more than one heteroatoms selected from O, N or S.
6. The compound as claimed in claim 1, wherein R2 is selected from hydrogen, halogen, cyano, optionally substituted groups selected from (C1-C6)alkyl, (C1- C6)alkoxy.
7. The compound as claimed in claim 1, wherein R3 and R4 is hydrogen; Alternatively, R3 and R4 may form a bond.
8. The compound as claimed in claim 1 wherein heterocyclyl is selected from single or fused mono, bi or tricyclic aromatic or non-aromatic groups containing one or more hetero atoms selected from O, N or S.
9. The compound as claimed in claim 7, wherein the heterocyclic group is selected from tetrahydrofuran (THF), dihydrofuran, 1, 4-dioxane, morpholine, 1 ,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1, 3-dioxane, 1, 3- dithiane, oxathiane, thiomorpholine, cyclohexyl, cyclopentyl.
10. The compound as claimed in claim 1, wherein heteroaryl group is selected from pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyt, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl.
11. The compound as claimed in any preceding claim, wherein when any of the above group is substituted, the substitutions are selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkyloxy, alkylthio (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, C1-C6 alkoxy, -COR11, -CSR11, C(O)OR11, C(O)-R11, -C(O)- NR11R12, -C(S)-NR11R12, -SO2R11 group, wherein each of R10, R11 and R12 is independently selected from hydrogen, optionally substituted group selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl groups.
12. A compound as claimed in claim 1 selected from the group comprising of: (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-phenylethene-1- sulfonamide;
(E)-2-(4-fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(p- tolyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4- (trifluoromethyl)phenyl)ethenesulfonamide;
(E)-2-(3-fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyridin-3- yl)ethenesulfonamide;
sodium(E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((4- methoxystyryl)sulfonyl)amide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(3- methoxyphenyl)ethene sulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(2-hydroxypropan-2- yl)phenyl)ethenesulfonamide;
(E)-2-(4-cyanophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2- phenylethynesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiophen-2- yl)ethenesulfonamide;
(E)-ethyl 5-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamoyl)vinyl)furan-3-carboxylate;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(2-hydroxypropan-2- yl)furan-2-yl)ethenesulfonamide;
(E)-2-cyclohexyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiophen-3- yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyridin-4- yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4- (hydroxymethyl)furan-2-yl)ethenesulfonamide;
(E)-2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-N-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4- (trifluoromethoxy)phenyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide;
(E)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyridin-2- yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(pyridin-3- yl)phenyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(3-(pyridin-3- yl)phenyl)ethenesulfonamide;
(E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-phenylethenesulfonamide;
(E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(3-(2-hydroxypropan-2- yl)phenyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropyl-1H- imidazol-2-yl)ethenesulfonamide;
(E)-2-(benzo[d]thiazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-phenylprop-1-ene-1- sulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-methylthiazol-2- yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropyl-4-methyl- 1H-imidazol-2-yl)ethenesulfonamide;
(E)-ethyl2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamoyl)vinyl)thiazole-4-carboxylate;
(E)-N-((8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2- phenylethenesulfonamide;
(E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamoyl)vinyl)thiazole-4-carboxylic acid;
(E)-N-((2-fluoro-6-(trifluoromethyl)phenyl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide;
(E)-N-((2-fluoro-6-(trifluoromethyl)phenyl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide;
(E)-N-((8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2- phenylethenesulfonamide;
(E)-N-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2- phenylethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(2-hydroxypropan-2- yl)thiazol-2-yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4-(3- (methylsulfonyl)propoxy)phenyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(quinolin-2- yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrazin-2- yl)ethenesulfonamide;
(E)-2-(1-ethyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((2,5-bis(trifluoromethyl)phenyl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(4- (hydroxymethyl)thiazol-2-yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-4- yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-5- yl)ethenesulfonamide;
(E)-2-(1-ethyl-4-methyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
4-((E)-2-(4-(1H-pyrazol-1-yl)phenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2,2,2-trifluoroethyl)- 1H-imidazol-2-yl)ethenesulfonamide;
(E)-N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide;
(E)-N-((8-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide;
(E)-N-((8-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2,2,2- trifluoroethyl)-1H-imidazol-2-yl)ethenesulfonamide;
(E)-4-(2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)- 1H-imidazol-1-yl)butanoic acid;
(E)-2-(3,4-difluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-sulfonamide;
(E)-2-(3-((dimethylamino)methyl)phenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-sulfonamide;
(E)-2-(4-((dimethylamino)methyl)phenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1- ((methylsulfonyl)methyl)-1H-imidazol-2-yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-(methylthio)ethyl)- 1H-imidazol-2-yl)ethenesulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(5-methylthiazol-2- yl)ethene-sulfonamide.
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as claimed in any of the preceding claims and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.
14. A method of treating diseases medicated by the NLRP3 modulators as well as treatment of diseases or conditions in which interleukin 1β activity and interleukin-18 (IL-18) are implicated which comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) as claimed in any of the preceding claims or its suitable pharmaceutical composition.
15. The use of compounds of formula (I) or its pharmaceutical compositions as claimed in any of the preceding claim suitable for treatment of diseases wherein the NLRP3 modulator has a pathophysiological function.
16. The pharmaceutical composition as claimed in claims 1 and 6 in combination with one or more suitable pharmaceutically active agents selected from Inhibitors of interleukin-1β; immune-suppressants; metabolic disorders drugs, glucocorticoids, non-steroidal anti-inflammatory drugs, COX-2 specific inhibitors, anti-inflammatory drugs, TNF-α binding proteins, interferon-13, interferon, interleukin-2, antihistamines, beta-agonist, BTK inhibitors, anticolinergics, anti-cancer agents or their suitable pharmaceutically acceptable salts, Non-Alcoholic Steato- Hepatitis (NASH) and fibrosis drugs, anticancer drugs, antibiotics, hormones, aromatase inhibitors, inhibitors of mitogen-activated protein kinase signaling, Syk inhibitors, mTOR inhibitors, and BCR/ABL antagonists.
17. A process for the preparation of compound of formula (I) as claimed in claim 1, comprising the following steps:
(i) reacting compound of formula (3) with isocyanato derivative of compound of formula (4) to obtain compound of formula (I)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN201721030899 | 2017-08-31 | ||
| IN201721030899 | 2017-08-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2019043610A1 true WO2019043610A1 (en) | 2019-03-07 |
Family
ID=63683248
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2018/056619 WO2019043610A1 (en) | 2017-08-31 | 2018-08-30 | Novel substituted sulfonylurea derivatives |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2019043610A1 (en) |
Cited By (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020035466A1 (en) | 2018-08-15 | 2020-02-20 | Inflazome Limited | Novel sulfoneurea compounds |
| JP2020505381A (en) * | 2017-01-23 | 2020-02-20 | ジェネンテック， インコーポレイテッド | Chemical compounds as inhibitors of interleukin-1 activity |
| WO2020035465A1 (en) | 2017-08-15 | 2020-02-20 | Inflazome Limited | Novel sulfoneurea compounds |
| WO2020035464A1 (en) | 2018-08-15 | 2020-02-20 | Inflazome Limited | Novel sulfonamideurea compounds |
| WO2020104657A1 (en) | 2018-11-23 | 2020-05-28 | Inflazome Limited | Nlrp3 inhibitors |
| WO2020148619A1 (en) | 2019-01-14 | 2020-07-23 | Cadila Healthcare Limited | Novel substituted sulfonylurea derivatives |
| WO2020208249A1 (en) | 2019-04-12 | 2020-10-15 | Inflazome Limited | Nlrp3 inflammasome inhibition |
| WO2020254697A1 (en) | 2019-06-21 | 2020-12-24 | Ac Immune Sa | Fused 1,2 thiazoles and 1,2 thiazines which act as nl3p3 modulators |
| WO2021002887A1 (en) | 2019-07-02 | 2021-01-07 | Novartis Inflammasome Research, Inc. | Gut-targeted nlrp3 antagonists and their use in therapy |
| WO2021032591A1 (en) | 2019-08-16 | 2021-02-25 | Inflazome Limited | Macrocyclic sulfonylurea derivatives useful as nlrp3 inhibitors |
| WO2021043966A1 (en) | 2019-09-06 | 2021-03-11 | Inflazome Limited | Nlrp3 inhibitors |
| WO2021165245A1 (en) | 2020-02-18 | 2021-08-26 | Inflazome Limited | Compounds |
| WO2021171230A1 (en) * | 2020-02-28 | 2021-09-02 | Cadila Healthcare Limited | Novel substituted sulfonylurea and sulfoximineurea derivatives |
| WO2021255279A1 (en) | 2020-06-19 | 2021-12-23 | Ac Immune Sa | D i h yd rooxazo le and thiourea derivatives modulating the nlrp3 inflammasome pathway |
| WO2022023907A1 (en) | 2020-07-31 | 2022-02-03 | Novartis Ag | Methods of selecting and treating patients at elevated risk of major adverse cardiac events |
| CN114746087A (en) * | 2019-09-12 | 2022-07-12 | 载度思生命科学有限公司 | Novel substituted sulfoximine derivatives |
| WO2022171185A1 (en) * | 2021-02-10 | 2022-08-18 | 杭州英创医药科技有限公司 | Compound serving as nlrp3 inhibitor |
| US11518739B2 (en) | 2017-08-15 | 2022-12-06 | Inflazome Limited | Sulfonamide carboxamide compounds |
| US11560391B2 (en) | 2018-07-20 | 2023-01-24 | Genentech, Inc. | Sulfonylurea compounds as inhibitors of interleukin-1 activity |
| WO2023118521A1 (en) | 2021-12-22 | 2023-06-29 | Ac Immune Sa | Dihydro-oxazol derivative compounds |
| US11773058B2 (en) | 2017-08-15 | 2023-10-03 | Inflazome Limited | Sulfonamide carboxamide compounds |
| WO2024013395A1 (en) | 2022-07-14 | 2024-01-18 | Ac Immune Sa | Pyrrolotriazine and imidazotriazine derivatives as modulators of the nlrp3 inflammasome pathway |
| WO2024023266A1 (en) | 2022-07-28 | 2024-02-01 | Ac Immune Sa | Novel compounds |
Citations (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2979437A (en) * | 1958-09-02 | 1961-04-11 | Pfizer & Co C | Substituted styryl, and thienylethenyl, pyridylethenyl sulfonylureas and method of treating diabetes |
| GB1473200A (en) * | 1973-12-05 | 1977-05-11 | Pfizer | Hypolipidemic alkenesulphonamides |
| GB2110691A (en) * | 1981-12-07 | 1983-06-22 | Du Pont | Herbicidal sulfonamides |
| US4440565A (en) * | 1981-03-24 | 1984-04-03 | Hoechst Aktiengesellschaft | Heterocyclically substituted (halogeno)alkyl- and (halogeno)alkoxysulfonylureas, and their use in agriculture |
| US4725679A (en) * | 1983-08-25 | 1988-02-16 | Hoechst Aktiengesellschaft | Process for producing 2-amino-alkenylsulfonylurea derivatives |
| WO1998032733A1 (en) | 1997-01-29 | 1998-07-30 | Pfizer Inc. | Sulfonyl urea derivatives and their use in the control of interleukin-1 activity |
| US6147115A (en) * | 1990-07-17 | 2000-11-14 | Eli Lilly And Company | Antitumor compositions and methods of treatment |
| WO2001019390A1 (en) | 1999-09-14 | 2001-03-22 | Pfizer Products Inc. | Combination treatment with il-1ra and diaryl sulphonyl urea compounds |
| WO2014190015A1 (en) | 2013-05-21 | 2014-11-27 | Virginia Commonwealth University | Cryopyrin inhibitors for preventing and treating inflammation |
| WO2016123229A1 (en) | 2015-01-29 | 2016-08-04 | Yale University | Compositions and methods for treating nlrp3 inflammasome-related diseases and disorders |
| WO2016131098A1 (en) | 2015-02-16 | 2016-08-25 | The University Of Queensland | Sulfonylureas and related compounds and use of same |
| WO2017017469A1 (en) | 2015-07-30 | 2017-02-02 | The University Of Manchester | Cyclic diarylboron derivatives as nlrp3 inflammasome inhibitors |
| WO2017031161A1 (en) | 2015-08-17 | 2017-02-23 | Twi Biotechnology, Inc. | Diacerein or its analogs for inhibiting expression of asc, nlrp3, and/or formation of nlrp3 inflammasome complex |
| WO2017079352A2 (en) | 2015-11-04 | 2017-05-11 | Idera Pharmaceuticals, Inc. | Compositions for inhibiting nlrp3 gene expression and uses thereof |
| WO2017129897A1 (en) | 2016-01-25 | 2017-08-03 | Galderma Research & Development | Nlrp3 inhibitors for the treatment of inflammatory skin disorders |
| WO2017184623A1 (en) | 2016-04-18 | 2017-10-26 | Ifm Therapeutics, Inc | Compounds and compositions for treating conditions associated with nlrp activity |
| WO2017184604A1 (en) | 2016-04-18 | 2017-10-26 | Ifm Therapeutics, Inc | Compounds and compositions for treating conditions associated with nlrp activity |
| WO2018015445A1 (en) | 2016-07-20 | 2018-01-25 | NodThera Limited | Sulfonyl urea derivatives and their use in the control of interleukin-1 activity |
-
2018
- 2018-08-30 WO PCT/IB2018/056619 patent/WO2019043610A1/en active Application Filing
Patent Citations (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2979437A (en) * | 1958-09-02 | 1961-04-11 | Pfizer & Co C | Substituted styryl, and thienylethenyl, pyridylethenyl sulfonylureas and method of treating diabetes |
| GB1473200A (en) * | 1973-12-05 | 1977-05-11 | Pfizer | Hypolipidemic alkenesulphonamides |
| US4440565A (en) * | 1981-03-24 | 1984-04-03 | Hoechst Aktiengesellschaft | Heterocyclically substituted (halogeno)alkyl- and (halogeno)alkoxysulfonylureas, and their use in agriculture |
| GB2110691A (en) * | 1981-12-07 | 1983-06-22 | Du Pont | Herbicidal sulfonamides |
| US4725679A (en) * | 1983-08-25 | 1988-02-16 | Hoechst Aktiengesellschaft | Process for producing 2-amino-alkenylsulfonylurea derivatives |
| US6147115A (en) * | 1990-07-17 | 2000-11-14 | Eli Lilly And Company | Antitumor compositions and methods of treatment |
| WO1998032733A1 (en) | 1997-01-29 | 1998-07-30 | Pfizer Inc. | Sulfonyl urea derivatives and their use in the control of interleukin-1 activity |
| WO2001019390A1 (en) | 1999-09-14 | 2001-03-22 | Pfizer Products Inc. | Combination treatment with il-1ra and diaryl sulphonyl urea compounds |
| WO2014190015A1 (en) | 2013-05-21 | 2014-11-27 | Virginia Commonwealth University | Cryopyrin inhibitors for preventing and treating inflammation |
| WO2016123229A1 (en) | 2015-01-29 | 2016-08-04 | Yale University | Compositions and methods for treating nlrp3 inflammasome-related diseases and disorders |
| WO2016131098A1 (en) | 2015-02-16 | 2016-08-25 | The University Of Queensland | Sulfonylureas and related compounds and use of same |
| WO2017017469A1 (en) | 2015-07-30 | 2017-02-02 | The University Of Manchester | Cyclic diarylboron derivatives as nlrp3 inflammasome inhibitors |
| WO2017031161A1 (en) | 2015-08-17 | 2017-02-23 | Twi Biotechnology, Inc. | Diacerein or its analogs for inhibiting expression of asc, nlrp3, and/or formation of nlrp3 inflammasome complex |
| WO2017079352A2 (en) | 2015-11-04 | 2017-05-11 | Idera Pharmaceuticals, Inc. | Compositions for inhibiting nlrp3 gene expression and uses thereof |
| WO2017129897A1 (en) | 2016-01-25 | 2017-08-03 | Galderma Research & Development | Nlrp3 inhibitors for the treatment of inflammatory skin disorders |
| WO2017184623A1 (en) | 2016-04-18 | 2017-10-26 | Ifm Therapeutics, Inc | Compounds and compositions for treating conditions associated with nlrp activity |
| WO2017184624A1 (en) | 2016-04-18 | 2017-10-26 | Ifm Therapeutics, Inc | Compounds and compositions for treating conditions associated with nlrp activity |
| WO2017184604A1 (en) | 2016-04-18 | 2017-10-26 | Ifm Therapeutics, Inc | Compounds and compositions for treating conditions associated with nlrp activity |
| WO2018015445A1 (en) | 2016-07-20 | 2018-01-25 | NodThera Limited | Sulfonyl urea derivatives and their use in the control of interleukin-1 activity |
Non-Patent Citations (10)
| Title |
|---|
| DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 29 June 2001 (2001-06-29), XP002785942, retrieved from STN Database accession no. 343974-11-8 * |
| DINARELLO, NAT. REV. DRUG DISCOVERY, vol. 11, 2012, pages 633 - 652 |
| GUO, NAT. MED., vol. 21, 2015, pages 677 |
| KIYOSHI HASEGAWA ET AL: "The Reactions of 2-Arylacetylene-1-sulfonamides with Heterocumulenes", BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, vol. 51, no. 6, 1 June 1978 (1978-06-01), JP, pages 1805 - 1810, XP055517229, ISSN: 0009-2673, DOI: 10.1246/bcsj.51.1805 * |
| LATZ, NAT REV IMMUNOL., vol. 13, 2013, pages 397 - 411 |
| MASTERS, ANNU REV IMMUNOL, vol. 27, 2009, pages 621 - 668 |
| MRIDHA, JOURNAL OF HEPATOLOGY, vol. 66, no. 5, 2017, pages 1037 - 1046 |
| STROWIG, NATURE, vol. 481, 2012, pages 278 - 286 |
| SYNTHESIS, vol. 15, 2003, pages 2321 - 24 |
| WEN, IMMUNITY, vol. 39, 2013, pages 432 - 441 |
Cited By (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP7163293B2 (en) | 2017-01-23 | 2022-10-31 | ジェネンテック， インコーポレイテッド | Chemical compounds as inhibitors of interleukin-1 activity |
| JP2020505381A (en) * | 2017-01-23 | 2020-02-20 | ジェネンテック， インコーポレイテッド | Chemical compounds as inhibitors of interleukin-1 activity |
| US11702428B2 (en) | 2017-01-23 | 2023-07-18 | Genentech, Inc. | Chemical compounds as inhibitors of interleukin-1 activity |
| WO2020035465A1 (en) | 2017-08-15 | 2020-02-20 | Inflazome Limited | Novel sulfoneurea compounds |
| US11773058B2 (en) | 2017-08-15 | 2023-10-03 | Inflazome Limited | Sulfonamide carboxamide compounds |
| US11518739B2 (en) | 2017-08-15 | 2022-12-06 | Inflazome Limited | Sulfonamide carboxamide compounds |
| US11560391B2 (en) | 2018-07-20 | 2023-01-24 | Genentech, Inc. | Sulfonylurea compounds as inhibitors of interleukin-1 activity |
| WO2020035464A1 (en) | 2018-08-15 | 2020-02-20 | Inflazome Limited | Novel sulfonamideurea compounds |
| WO2020035466A1 (en) | 2018-08-15 | 2020-02-20 | Inflazome Limited | Novel sulfoneurea compounds |
| WO2020104657A1 (en) | 2018-11-23 | 2020-05-28 | Inflazome Limited | Nlrp3 inhibitors |
| WO2020148619A1 (en) | 2019-01-14 | 2020-07-23 | Cadila Healthcare Limited | Novel substituted sulfonylurea derivatives |
| WO2020208249A1 (en) | 2019-04-12 | 2020-10-15 | Inflazome Limited | Nlrp3 inflammasome inhibition |
| WO2020254697A1 (en) | 2019-06-21 | 2020-12-24 | Ac Immune Sa | Fused 1,2 thiazoles and 1,2 thiazines which act as nl3p3 modulators |
| WO2021002887A1 (en) | 2019-07-02 | 2021-01-07 | Novartis Inflammasome Research, Inc. | Gut-targeted nlrp3 antagonists and their use in therapy |
| WO2021032591A1 (en) | 2019-08-16 | 2021-02-25 | Inflazome Limited | Macrocyclic sulfonylurea derivatives useful as nlrp3 inhibitors |
| WO2021043966A1 (en) | 2019-09-06 | 2021-03-11 | Inflazome Limited | Nlrp3 inhibitors |
| EP4027986A4 (en) * | 2019-09-12 | 2023-10-04 | Zydus Lifesciences Limited | Novel substituted sulfoximine derivatives |
| CN114746087A (en) * | 2019-09-12 | 2022-07-12 | 载度思生命科学有限公司 | Novel substituted sulfoximine derivatives |
| WO2021165245A1 (en) | 2020-02-18 | 2021-08-26 | Inflazome Limited | Compounds |
| WO2021171230A1 (en) * | 2020-02-28 | 2021-09-02 | Cadila Healthcare Limited | Novel substituted sulfonylurea and sulfoximineurea derivatives |
| CN115190762A (en) * | 2020-02-28 | 2022-10-14 | 兹杜斯生命科学有限公司 | Novel substituted sulfonylurea and sulfonimidurea derivatives |
| WO2021255279A1 (en) | 2020-06-19 | 2021-12-23 | Ac Immune Sa | D i h yd rooxazo le and thiourea derivatives modulating the nlrp3 inflammasome pathway |
| WO2022023907A1 (en) | 2020-07-31 | 2022-02-03 | Novartis Ag | Methods of selecting and treating patients at elevated risk of major adverse cardiac events |
| WO2022171185A1 (en) * | 2021-02-10 | 2022-08-18 | 杭州英创医药科技有限公司 | Compound serving as nlrp3 inhibitor |
| WO2023118521A1 (en) | 2021-12-22 | 2023-06-29 | Ac Immune Sa | Dihydro-oxazol derivative compounds |
| WO2024013395A1 (en) | 2022-07-14 | 2024-01-18 | Ac Immune Sa | Pyrrolotriazine and imidazotriazine derivatives as modulators of the nlrp3 inflammasome pathway |
| WO2024023266A1 (en) | 2022-07-28 | 2024-02-01 | Ac Immune Sa | Novel compounds |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2019043610A1 (en) | Novel substituted sulfonylurea derivatives | |
| US11236045B2 (en) | Substituted sulfoximine compounds | |
| EP3102579B1 (en) | Heterocyclic compounds | |
| AU747920B2 (en) | Bicyclic pyridine and pyrimidine derivatives as neuropeptide Y receptor antagonists | |
| KR20080080395A (en) | Anti-viral compounds | |
| KR20070045227A (en) | Condensed pyridines as kinase inhibitors | |
| JP2000510870A (en) | Amides as NPY5 receptor antagonists | |
| TW201141857A (en) | Analogues for the treatment or prevention of flavivirus infections | |
| KR20090101281A (en) | Purine derivatives | |
| TW201629012A (en) | Heterocyclic derivatives and use thereof | |
| JP2008501768A (en) | Novel compounds and use of tetrahydropyridothiophene | |
| JP2010540424A (en) | Thienopyrimidine compounds and compositions | |
| CA3126467A1 (en) | Novel substituted sulfonylurea derivatives | |
| CN117510468A (en) | Dual MAGL and FAAH inhibitors | |
| WO2021111351A1 (en) | Novel substituted sulfonylurea and sulfoximineurea derivatives | |
| SK2622001A3 (en) | Tan-1057 derivatives | |
| EP4110058A1 (en) | Novel substituted sulfonylurea and sulfoximineurea derivatives | |
| EA030636B1 (en) | PIPERIDINE SUBSTITUTED TRICYCLIC PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES WITH INHIBITORY ACTIVITY ON THE REPLICATION OF THE RESPIRATORY SYNCYTIAL VIRUS (RSV) | |
| SI9720045A (en) | Azolo triazines and pyrimidines | |
| WO2021048809A9 (en) | Novel substituted sulfoximine derivatives | |
| CA3226058A1 (en) | Treatment for cryopyrin associated periodic syndromes (caps) | |
| OA20271A (en) | Novel substituted sulfonylurea derivatives. | |
| CN117940126A (en) | Treatment for cold-related periodic syndromes (CAPS) | |
| WO2023280290A1 (en) | Pyrrole sulfonyl derivative, and preparation method therefor and use thereof | |
| KR20240052009A (en) | Treatment of Neuroinflammatory Disorders |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18774127 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 18774127 Country of ref document: EP Kind code of ref document: A1 |