[go: up one dir, main page]

WO2024211969A1 - Modulateurs de pparg - Google Patents

Modulateurs de pparg Download PDF

Info

Publication number
WO2024211969A1
WO2024211969A1 PCT/AU2024/050351 AU2024050351W WO2024211969A1 WO 2024211969 A1 WO2024211969 A1 WO 2024211969A1 AU 2024050351 W AU2024050351 W AU 2024050351W WO 2024211969 A1 WO2024211969 A1 WO 2024211969A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
alkyl
mmol
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/AU2024/050351
Other languages
English (en)
Inventor
Jasmine L. KING
Adrian Scaffidi
Craig D. STEWART
W. Joost LESTERHUIS
Matthew J. PIGGOTT
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Setonix Pharmaceuticals Pty Ltd
Original Assignee
Setonix Pharmaceuticals Pty Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2023901076A external-priority patent/AU2023901076A0/en
Application filed by Setonix Pharmaceuticals Pty Ltd filed Critical Setonix Pharmaceuticals Pty Ltd
Publication of WO2024211969A1 publication Critical patent/WO2024211969A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/66—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/74—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/76—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/40—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • 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
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • 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
    • C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/22—Nitrogen and oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • 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

Definitions

  • PPARG modulators Cross reference This application claims priority to both Australian provisional patent application no. 2023901074 and 2023901076 (both filed 12 April 2023), the entire contents of both of which are incorporated herein by reference.
  • Field of the invention relates to compounds possessing activity at peroxisome proliferator- activated receptor gamma (PPAR ⁇ or PPARG).
  • the invention also relates to pharmaceutical compositions comprising the compounds and to the use of the compounds in the treatment of diseases, conditions and/or disorders associated with PPAR ⁇ .
  • PPAR ⁇ Peroxisome proliferator-activated receptor gamma
  • PPAR ⁇ belongs to the nuclear receptor subfamily, and is a ligand-regulated transcription factor.
  • PPAR ⁇ receptors mainly reside in the nucleus, bound to corepressor peptides that restrict activity to basal levels.
  • RXR ⁇ retinoid X receptor alpha
  • the heterodimer recognises and binds specific repeats of DNA, termed peroxisome proliferator response elements (PPREs), which initiate recruitment of gene transcription machinery, chromatin relaxation and upregulation of certain genes.
  • PPREs peroxisome proliferator response elements
  • the ⁇ 2 isoform has an additional 30 N-terminal amino acids and is primarily located in adipose tissue, while the ⁇ 1 isoform is expressed more ubiquitously.
  • the ligand- binding domain (LBD) of PPAR ⁇ comprises four ⁇ -sheets and 12 ⁇ -helices that fold into three layers and form a large ( ⁇ 1400 ⁇ 3 ), flexible ligand binding pocket (LBP).
  • Apo (ligand-free) PPAR ⁇ has a dynamic structure in which helix-12 (h12) is constantly switching between transcriptionally active and repressive conformations. Upon binding of a ligand, h12 may be stabilised in a closed conformation critical for the activation or repression of PPAR ⁇ activity.
  • PPAR ⁇ is mainly found in adipose and vascular tissue and is involved in regulating insulin sensitivity, glucose and lipid metabolism, inflammation, and cell proliferation. Pharmacological intervention at PPAR ⁇ , may therefore be useful in the treatment of diabetes, and other conditions including obesity and cancer.
  • Small-molecule modulators of PPAR ⁇ have been described. These modulators possess agonist (eg rosiglitazone), partial agonist, inverse agonist (eg T0070907) or antagonist (eg GW9662) activity.
  • a 1 is selected from N, N(O) and CR 1
  • a 2 is selected from N
  • a 3 is selected from N, N(O) and CR 3
  • R is selected from optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted aryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted -C 1-6 alkyl-C 3-8 cycloalkyl, optionally substituted -C 1-6 alkyl-aryl, optionally substituted - C 1-6 alkyl-3-12-membered heterocyclyl;
  • R 1 , R 3 and R 4 are each independently selected from: H, deutero-, halo, optionally substituted
  • the inventors have surprisingly discovered that compounds of formula (I) are able to modulate the activity of PPAR ⁇ . Without wishing to be bound by theory, it is believed that the compounds covalently bind PPAR ⁇ through an SNAr reaction and once bound can change PPAR ⁇ activity.
  • the compounds of formula (I) may therefore be useful in treating PPAR ⁇ associated diseases, conditions and/or disorders.
  • the compound is not In some embodiments, all of conditions (a) to (g) apply.
  • at least one of R 1 , R 3 and R 4 is other than H; and A 2 is N or N(O).
  • X is Cl or F.
  • a 2 is C–CN.
  • a 2 is selected from N and N(O); conditions (a) to (d) apply: (a) no more than one of A 1 , A 2 and A 3 is N(O); (b) A 1 and A 3 are not both N; (c) X is F when A 2 is N(O), R 1 is H and R 3 is H; (d) R is not 4-pyridyl when A 2 is N, R 1 and R 3 are each H and X is chloro; and R is not phenyl when A 2 is N, R 1 and R 3 are each methyl and X is chloro.
  • a 2 is selected from N and N(O); conditions (a) to (d) apply: (a) no more than one of A 1 , A 2 and A 3 is N(O); (b) A 1 and A 3 are not both N; (c) when A 2 is N(O), R 1 is H and R 3 is H, X is F or X is Cl and the compound is selected from Group Q; (d) R is not 4-pyridyl when A 2 is N, R 1 and R 3 are each H and X is chloro; and R is not phenyl when A 2 is N, R 1 and R 3 are each methyl and X is chloro; wherein Group Q is as otherwise defined herein.
  • a 2 is selected from N and N(O); conditions (a) to (d) apply: (a) no more than one of A 1 , A 2 and A 3 is N(O); (b) A 1 and A 3 are not both N; (c) X is F or Cl when A 2 is N(O), R 1 is H and R 3 is H; (d) R is not 4-pyridyl when A 2 is N, R 1 and R 3 are each H and X is chloro and R is not phenyl when A 2 is N, R 1 and R 3 are each methyl and X is chloro. In some embodiments, when A 2 is N then at least one of R 1 , R 3 and R 4 are not H.
  • the compound of formula (I) is provided as a compound of any one of formulas (IIai), (IIaii), (IIaiii) and (IIaiv): wherein R, R 1 , R 3 , R 4 , R a , R b and X are as defined for formula (I).
  • the compound of formula (I) is provided as a compound of formula (Ib): (Ib) wherein one or more of provisos i), ii), iii) and iv) are satisfied; i) at least one of R 1 , R 3 and R 4 is other than H; ii) when A 1 is N and R 3 and R 4 are H, then the compound is not selected from the group B; iii) when A 3 is N and R 1 and R 4 are H, then the compound is not selected from the group C; iv) A 1 and A 3 are not both N; wherein group B and group C are as otherwise defined herein; and wherein A 1 , A 3 , R, R 1 , R 3 , R 4 , R a , R b and X are as otherwise defined for formula (I).
  • provisos i), ii) and iii) are satisfied.
  • provisos i), ii), iii) and iv) are satisfied.
  • provisos i), ii) and iii) are satisfied.
  • the compound of formula (I) is provided as a compound of formula (IIb) wherein R, R 1 , R 3 , R 4 , R a , R b and X are as defined for formula (Ib).
  • the compound of formula (I) is provided as a compound of formula (IIIb) (IIIb) wherein R, R 3 , R 4 , R a , R b and X are as defined for formula (Ib).
  • the compound of formula (I) is provided as a compound of formula (IVb) wherein R, R 1 , R 4 , R a , R b and X are as defined for formula (Ib).
  • a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, solvate, tautomer, N- oxide, stereoisomer and/or prodrug thereof; and optionally a pharmaceutically acceptable excipient.
  • a method of treating a disease, condition or disorder associated with PPAR ⁇ activity comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof; or a pharmaceutical composition of the invention.
  • a method of modulating PPAR ⁇ activity comprising contacting a cell expressing PPAR ⁇ with a compound of the invention or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof.
  • a method of treating a disease, condition or disorder selected from: a disorder of lipid and/or glucose metabolism; inflammation obesity, a metabolic syndrome, a viral infection; and a proliferative disorder comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof; or a pharmaceutical composition of the invention.
  • the method comprises forming a covalent bond between the compound of formula (I) and PPAR ⁇ .
  • a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof in the preparation of a medicament for one or more of: i. treating a disease, condition or disorder associated with PPAR ⁇ activity; and/or ii. modulating PPAR ⁇ activity; and/or iii. treating a disease, condition or disorder selected from: a disorder of lipid and/or glucose metabolism; inflammation; obesity, a metabolic syndrome, a viral infection; and a proliferative disorder; and/or iv. covalently modifying PPAR ⁇ .
  • kit of parts comprising a compound of formula (I) of the invention, or a pharmaceutically acceptable salt, solvate, tautomer, N- oxide, stereoisomer and/or prodrug thereof; and instructions for its use in a method of the invention.
  • Any embodiment herein shall be taken to apply mutatis mutandis to any other embodiment unless specifically stated otherwise.
  • the present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally- equivalent products, compositions and methods are clearly within the scope of the invention, as described herein.
  • C 1-6 alkyl refers to optionally substituted straight chain or branched chain hydrocarbon groups having from 1 to 6 carbon atoms.
  • C 1-6 alkyl also encompasses alkyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent.
  • C 2-6 alkenyl refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one double bond of either E or Z stereochemistry where applicable and 2 to 6 carbon atoms. Examples include vinyl, 1-propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
  • C 2-6 alkenyl also encompasses alkenyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. “C 2-4 alkenyl” and “C 2-3 alkenyl” including ethenyl, propenyl and butenyl are preferred with ethenyl being particularly preferred.
  • C 2-6 alkynyl refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one triple bond and 2 to 6 carbon atoms.
  • C 2-6 alkynyl also encompasses alkynyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent.C 2-3 alkynyl is preferred.
  • C 3-10 cycloalkyl refers to non-aromatic cyclic groups having from 3 to 10 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. It will be understood that cycloalkyl groups may be saturated such as cyclohexyl or unsaturated such as cyclohexenyl. C 3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are preferred.
  • Cycloalkyl groups also include polycyclic carbocycles and include fused, bridged and spirocyclic systems.
  • heteroalkyl refers to an alkyl group wherein one or more chain carbon atoms is replaced with a heteroatom, preferably a heteroatom selected from O, N, Si and S (including in various oxidation states, such as N-oxides, sulphoxides, SO 2 , silanes and so on), provided that not all carbon atoms are replaced.
  • a heteroatom in a heteroalkyl group may occupy any position, including a terminal position.
  • the alkyl group may be any alkyl group described herein including straight chain and branched chain groups.
  • a C 1-6 heteroalkyl refers to an alkyl group having from 1-6 carbon atoms wherein at least one of these carbon atoms is replaced by a heteroatom.
  • a heteroalkyl group possess 1, 2 or 3 heteroatoms, preferably 1 to 2.
  • C 1-6 alkoxy refers to an alkyl group as defined above containing 1 to 6 carbon atoms covalently bound via an O linkage, such as methoxy, ethoxy, propoxy, isoproxy, butoxy, tert-butoxy and pentoxy.
  • C 1-4 alkoxy and “C 1-3 alkoxy” including methoxy, ethoxy, propoxy and butoxy are preferred with methoxy being particularly preferred.
  • haloC 1-4 alkyl and “C 1-4 alkylhalo” refer to a C 1-4 alkyl which is substituted with one or more halogens.
  • HaloC 1-3 alkyl groups are preferred, such as for example, -CH 2 CF 3 , and -CF 3 .
  • the terms “haloC 1-6 alkoxy” and “C 1-6 alkoxyhalo” refer to a C 1-6 alkoxy which is substituted with one or more halogens. C 1-3 alkoxyhalo groups are preferred, such as for example, - OCF 3 .
  • the term “carboxylate” or “carboxyl” refers to the group -COO- or -COOH.
  • esters refers to a carboxyl group having the hydrogen replaced with, for example a C 1-6 alkyl group (“carboxylC 1-6 alkyl” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on.
  • CO 2 C 1-3 alkyl groups are preferred, such as for example, methylester (CO 2 Me), ethylester (CO 2 Et) and propylester (CO 2 Pr) and includes reverse esters thereof (e.g. -OC(O)Me, -OC(O)Et and -OC(O)Pr).
  • hydroxy and “hydroxyl” refer to the group -OH.
  • cyano and “nitrile” refer to the group -CN.
  • nitro refers to the group -NO 2 .
  • amino refers to the group -NH 2 .
  • substituted amino refers to an amino group having at least one hydrogen replaced with, for example a C 1-6 alkyl group (“C 1-6 alkylamino”), an aryl or aralkyl group (“arylamino”, “aralkylamino”) and so on.
  • Substituted amino groups include “monosubstituted amino” (or “secondary amino”) groups, which refer to an amino group having a single hydrogen replaced with, for example a C 1-6 alkyl group, an aryl or aralkyl group and so on.
  • Preferred secondary amino groups include C 1-3 alkylamino groups, such as for example, methylamino (NHMe), ethylamino (NHEt) and propylamino (NHPr).
  • Substituted amino groups also include “disubstituted amino” (or “tertiary amino”) groups, which refer to amino groups having both hydrogens replaced with, for example C 1-6 alkyl groups, which may be the same or different (“dialkylamino”), aryl and alkyl groups (“aryl(alkyl)amino”) and so on.
  • Preferred tertiary amino groups include di(C 1-3 alkyl)amino groups, such as for example, dimethylamino (NMe 2 ), diethylamino (NEt 2 ), dipropylamino (NPr 2 ) and variations thereof (e.g. N(Me)(Et) and so on).
  • acyl and “acetyl” refers to the group –C(O)CH 3 .
  • ketone refers to a carbonyl group which may be represented by –C(O)-.
  • substituted ketone refers to a ketone group covalently linked to at least one further group, for example, a C 1-6 alkyl group (“C 1-6 alkylacyl” or “alkylketone” or “ketoalkyl”), an aryl group (“arylketone”), an aralkyl group (“aralkylketone) and so on.
  • C 1- 3alkylacyl groups are preferred.
  • the term “amido” or “amide” refers to the group -C(O)NH 2 .
  • the term “substituted amido” or “substituted amide” refers to an amido group having a hydrogen replaced with, for example a C 1-6 alkyl group (“C 1-6 alkylamido” or “C 1-6 alkylamide”), an aryl (“arylamido”), aralkyl group (“aralkylamido”) and so on.
  • C 1-3 alkylamide groups are preferred, such as for example, methylamide (-C(O)NHMe), ethylamide (-C(O)NHEt) and propylamide (-C(O)NHPr) and includes reverse amides thereof (e.g. -NHMeC(O)-, -NHEtC(O)- and –NHPrC(O)-).
  • disubstituted amido or “disubstituted amide” refers to an amido group having the two hydrogens replaced with, for example a C 1-6 alkyl group (“di(C 1-6 alkyl)amido” or “di(C 1-6 alkyl)amide”), an aralkyl and alkyl group (“alkyl(aralkyl)amido”) and so on.
  • Di(C 1-3 alkyl)amide groups are preferred, such as for example, dimethylamide (- C(O)NMe 2 ), diethylamide (-C(O)NEt 2 ) and dipropylamide ((-C(O)NPr 2 ) and variations thereof (e.g.
  • thiol refers to the group -SH.
  • C 1-6 alkylthio refers to a thiol group having the hydrogen replaced with a C 1-6 alkyl group.
  • C 1-3 alkylthio groups are preferred, such as for example, thiolmethyl, thiolethyl and thiolpropyl.
  • substituted sulfinyl or “sulfoxide” refers to a sulfinyl group having the hydrogen replaced with, for example a C 1-6 alkyl group (“C 1-6 alkylsulfinyl” or “C 1-6 alkylsulfoxide”), an aryl (“arylsulfinyl”), an aralkyl (“aralkyl sulfinyl”) and so on.
  • C 1-3 alkylsulfinyl groups are preferred, such as for example, -SOmethyl, -SOethyl and -SOpropyl.
  • sulfonyl refers to the group -SO 2 H.
  • substituted sulfonyl refers to a sulfonyl group having the hydrogen replaced with, for example a C 1-6 alkyl group (“sulfonylC 1-6 alkyl”), an aryl (“arylsulfonyl”), an aralkyl (“aralkylsulfonyl”) and so on.
  • SulfonylC 1-3 alkyl groups are preferred, such as for example, -SO 2 Me, -SO 2 Et and -SO 2 Pr.
  • sulfonylamido refers to the group -SO 2 NH 2 .
  • substituted sulfonamido refers to an sulfonylamido group having a hydrogen replaced with, for example a C 1-6 alkyl group (e.g.
  • sulfonylamidoC 1-6 alkyl an aryl (“arylsulfonamide”), aralkyl (“aralkylsulfonamide”) and so on.
  • SulfonylamidoC 1-3 alkyl groups are preferred, such as for example, -SO 2 NHMe, -SO 2 NHEt and -SO 2 NHPr and includes reverse sulfonamides thereof (e.g. -NHSO 2 Me, -NHSO 2 Et and -NHSO 2 Pr).
  • the alkylsulfonamides may be optionally substituted, for example with a halo group.
  • disubstituted sulfonamido refers to an sulfonylamido group having the two hydrogens replaced with, for example a C 1-6 alkyl group, which may be the same or different (“sulfonylamidodi(C 1-6 alkyl)”), an aralkyl and alkyl group (“sulfonamido(aralkyl)alkyl”) and so on.
  • Sulfonylamidodi(C 1-3 alkyl) groups are preferred, such as for example, -SO 2 NMe 2 , -SO 2 NEt 2 and -SO 2 NPr 2 and variations thereof (e.g. -SO 2 N(Me)Et and so on) and includes reserve sulfonamides thereof (e.g. – N(Me)SO 2 Me and so on).
  • sulfate refers to the group OS(O) 2 OH and includes groups having the hydrogen replaced with, for example a C 1-6 alkyl group (“alkylsulfates”), an aryl (“arylsulfate”), an aralkyl (“aralkylsulfate”) and so on.
  • C 1-3 sulfates are preferred, such as for example, OS(O) 2 OMe, OS(O) 2 OEt and OS(O) 2 OPr.
  • the term “sulfonate” refers to the group SO 3 H and includes groups having the hydrogen replaced with, for example a C 1-6 alkyl group (“alkylsulfonate”), an aryl (“arylsulfonate”), an aralkyl (“aralkylsulfonate”) and so on.
  • alkylsulfonate an aryl
  • aralkyl aralkyl
  • C 1-3 sulfonates are preferred, such as for example, SO 3 Me, SO 3 Et and SO 3 Pr.
  • aryl refers to a carbocyclic (non-heterocyclic) aromatic ring or mono-, bi- or tri- cyclic ring system.
  • Poly-cyclic ring systems may be referred to as “aryl” provided at least 1 of the rings within the system is aromatic.
  • the aromatic ring or ring system is generally composed of 6 to 10 carbon atoms.
  • Examples of aryl groups include but are not limited to phenyl, biphenyl, naphthyl and tetrahydronaphthyl.6-membered aryls such as phenyl are preferred.
  • alkylaryl refers to C 1-6 alkylaryl such as benzyl.
  • alkoxyaryl refers to C 1-6 alkyloxyaryl such as benzyloxy.
  • heterocyclyl refers to a moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound which moiety has from 3 to 10 ring atoms (unless otherwise specified), of which 1, 2, 3 or 4 are ring heteroatoms with each heteroatom being independently selected from O, S and N.
  • Heterocyclyl groups include monocyclic and polycyclic (such as bicyclic) ring systems, such as fused, bridged and spirocyclic systems, provided at least one of the rings of the ring system contains at least one heteroatom.
  • the prefixes 3-, 4-, 5-, 6-, 7-, 8-, 9- and 10- membered denote the number of ring atoms, or range of ring atoms, whether carbon atoms or heteroatoms.
  • the term “3-10 membered heterocylyl”, as used herein, pertains to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms.
  • heterocylyl groups include 5-6-membered monocyclic heterocyclyls and 9-10 membered fused bicyclic heterocyclyls.
  • Examples of monocyclic heterocyclyl groups include, but are not limited to, those containing one nitrogen atom such as aziridine (3-membered ring), azetidine (4- membered ring), pyrrolidine (tetrahydropyrrole), pyrroline (e.g., 3-pyrroline, 2,5- dihydropyrrole), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) or pyrrolidinone (5- membered rings) , piperidine, dihydropyridine, tetrahydropyridine (6-membered rings), and azepine (7-membered ring); those containing two nitrogen atoms such as imidazoline, pyrazolidine (diazolidine), imidazoline, pyrazoline (dihydropyrazole) (5- membered rings), piperazine (6-membered ring); those containing one oxygen atom such as oxirane (3-membered ring),
  • Heterocyclyls encompass aromatic heterocyclyls and non-aromatic heterocyclyls. Such groups may be substituted or unsubstituted.
  • aromatic heterocyclyl may be used interchangeably with the term “heteroaromatic” or the term “heteroaryl” or “hetaryl”.
  • the heteroatoms in the aromatic heterocyclyl group may be independently selected from N, S and O.
  • the aromatic heterocyclyl groups may comprise 1, 2, 3, 4 or more ring heteroatoms. In the case of fused aromatic heterocyclyl groups, only one of the rings must contain a heteroatom and not all rings must be aromatic.
  • Heteroaryl is used herein to denote a heterocyclic group having aromatic character and embraces aromatic monocyclic ring systems and polycyclic (e.g. bicyclic) ring systems containing one or more aromatic rings.
  • aromatic heterocyclyl also encompasses pseudoaromatic heterocyclyls.
  • pseudoaromatic heterocyclyl refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings.
  • aromatic heterocyclyl therefore covers polycyclic ring systems in which all of the fused rings are aromatic as well as ring systems where one or more rings are non-aromatic, provided that at least one ring is aromatic.
  • heteroaryl groups are monocyclic and bicyclic groups containing from five to ten ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or two fused five membered rings.
  • Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Aromatic heterocyclyl groups may be 5-membered or 6-membered mono-cyclic aromatic ring systems.
  • 5-membered monocyclic heteroaryl groups include but are not limited to furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including 1,2,3 and 1,2,4 oxadiazolyls and furazanyl i.e. 1,2,5-oxadiazolyl), thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (including 1,2,3, 1,2,4 and 1,3,4 triazolyls), oxatriazolyl, tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls) and the like.
  • 6-membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, oxazinyl, dioxinyl, thiazinyl, thiadiazinyl and the like.
  • 6-membered aromatic heterocyclyls containing nitrogen include pyridyl (1 nitrogen), pyrazinyl, pyrimidinyl and pyridazinyl (2 nitrogens).
  • Aromatic heterocyclyl groups may also be bicyclic or polycyclic heteroaromatic ring systems such as fused ring systems (including purine, pteridinyl, napthyridinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl and the like) or linked ring systems (such as oligothiophene, polypyrrole and the like).
  • fused ring systems including purine, pteridinyl, napthyridinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl and the like
  • linked ring systems such as oligothiophene, polypyrrole and the like.
  • Fused ring systems may also include aromatic 5-membered or 6-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, naphtyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like, such as 5- membered aromatic heterocyclyls containing nitrogen fused to phenyl rings, 5-membered aromatic heterocyclyls containing 1 or 2 nitrogens fused to phenyl ring.
  • aromatic 5-membered or 6-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, naphtyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like, such as 5- membered aromatic heterocyclyls containing nitrogen fused to phenyl rings, 5-membered aromatic heterocyclyls containing 1 or 2 nitrogens fused to phenyl ring.
  • a bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; f) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; g) an oxazole ring fused to a 5- or 6-membered
  • bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) and imidazoimidazole (e.g. imidazo[1,2-a]imidazole).
  • imidazothiazole e.g. imidazo[2,1-b]thiazole
  • imidazoimidazole e.g. imidazo[1,2-a]imidazole
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g.
  • pyrazolo[1 ,5-a]pyrimidine benzodioxole and pyrazolopyridine (e.g. pyrazolo[1,5-a]pyridine) groups.
  • pyrazolopyridine groups e.g. pyrazolo[1,5-a]pyridine
  • a further example of a six membered ring fused to a five membered ring is a pyrrolopyridine group such as a pyrrolo[2,3-b]pyridine group.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
  • heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro- benzo[1,4]dioxine, benzo[1,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, indoline, isoindoline and indane groups.
  • aromatic heterocyclyls fused to carbocyclic aromatic rings may therefore include but are not limited to benzothiophenyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, isobenzoxazoyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazinyl, phthalazinyl, carbolinyl and the like.
  • non-aromatic heterocyclyl encompasses optionally substituted saturated and unsaturated rings which contain at least one heteroatom selected from the group consisting of N, S and O.
  • the ring may contain 1, 2 or 3 heteroatoms.
  • the ring may be a monocyclic ring or part of a polycyclic ring system.
  • Polycyclic ring systems include fused rings and spirocycles. Not every ring in a non-aromatic heterocyclic polycyclic ring system must contain a heteroatom, provided at least one ring contains one or more heteroatoms.
  • Non-aromatic heterocyclyls may be 3-7 membered mono-cyclic rings.
  • Examples of 5-membered non-aromatic heterocyclyl rings include 2H-pyrrolyl, 1- pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, imidazolidinyl, 3-dioxalanyl, thiazolidinyl, isoxazolidinyl, 2-imidazolinyl and the like.
  • 6-membered non-aromatic heterocyclyls include piperidinyl, piperidinonyl, pyranyl, dihyrdopyranyl, tetrahydropyranyl, 2H pyranyl, 4H pyranyl, thianyl, thianyl oxide, thianyl dioxide, piperazinyl, diozanyl, 1,4-dioxinyl, 1,4-dithianyl, 1,3,5-triozalanyl, 1,3,5- trithianyl, 1,4-morpholinyl, thiomorpholinyl, 1,4-oxathianyl, triazinyl, 1,4-thiazinyl and the like.
  • Non-aromatic heterocyclyls examples include azepanyl, oxepanyl, thiepanyl and the like.
  • Non-aromatic heterocyclyl rings may also be bicyclic heterocyclyl rings such as linked ring systems (for example uridinyl and the like) or fused ring systems.
  • Fused ring systems include non-aromatic 5-membered, 6-membered or 7-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like.
  • non-aromatic 5-membered, 6-membered or 7-membered heterocyclyls fused to carbocyclic aromatic rings include indolinyl, benzodiazepinyl, benzazepinyl, dihydrobenzofuranyl and the like.
  • halo refers to fluoro, chloro, bromo or iodo. In some embodiments, fluoro, chloro and bromo are preferred.
  • the term “optionally substituted” or “optional substituent” as used herein refers to a group which may or may not be further substituted with 1, 2, 3, 4 or more groups, preferably 1, 2 or 3, more preferably 1 or 2 groups selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, hydroxyl, oxo, C 1-6 alkoxy, aryloxy, C 1-6 alkoxyaryl, halo, C 1-6 alkylhalo (such as CF 3 ), C 1-6 alkoxyhalo (such as OCF 3 ), carboxyl, esters, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketones, substituted ketones, amides, aminoacyl, substituted amides, disubstituted amides, thiol, alkylthio, thioxo, sulfates,
  • Optional substituents in the case of heterocycles containing N may also include but are not limited to C 1-6 alkyl i.e. N-C 1-3 alkyl, more preferably methyl particularly N-methyl.
  • C 1-6 alkyl i.e. N-C 1-3 alkyl, more preferably methyl particularly N-methyl.
  • the optional substituent or substituents are preferably selected from halo, aryl, heterocyclyl, C 3-8 cycloalkyl, C 1-6 alkoxy, hydroxyl, oxo, aryloxy, haloC 1-6 alkyl, haloC 1-6 alkoxyl and carboxyl.
  • Each of these optional substituents may also be optionally substituted with any of the optional substituents referred to above, where nitro, amino, substituted amino, cyano, heterocyclyl (including non-aromatic heterocyclyl and heteroaryl), C 1-6 alkyl, C 2- 6 akenyl, C 2-6 alkynyl, C 1-6 alkoxyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, halo, hydroxyl and carboxyl are preferred.
  • heteroatom is intended to include oxygen, nitrogen, sulfur, silicon or phosphorus. In some embodiments, the heteroatom is selected from the group consisting of oxygen, nitrogen, and sulfur.
  • any unoccupied valencies for a heteroatom included in a heteroalkyl or heterocyclyl group as defined herein may be filled with any suitable optional substituent, preferably an optionally substituted C 1-4 alkyl group.
  • suitable derivatives of aromatic heterocyclyls containing nitrogen include N-oxides thereof.
  • substituent radicals describing two moieties that may both form a bond attaching the radical to the rest of the compound, such as alkylamino and alkylaryl no direction in the order of groups is intended, so the point of attachment may be to any of the moieties included in the hybrid radical.
  • alkylaryl and arylalkyl are intended to refer to the same group and the point of attachment may be via the alkyl or the aryl moiety (or both in the case of diradical species).
  • the direction of attachment of such a hybrid radical may be denoted by inclusion of a bond, for example, “-alkylaryl” or “arylalkyl-” denotes that the point of attachment of the radical to the rest of the compound is via the alkyl moiety, and “alkylaryl-“ or “-arylalkyl” denotes that the point of attachment is via the aryl moiety.
  • the compound is or is not selected from: , , , , , or a salt thereof. In some embodiments, the compound is not In some embodiments, the compound is not In some embodiments, the compound i In some embodiments, all of conditions (a) to (g) apply. In some embodiments, at least one of R 1 , R 3 and R 4 is other than H; and A 2 is N or N(O).
  • X is F when A 2 is N(O), R 1 is H and R 3 is H; or the compound is selected from Group Q (put another way, when A 2 is N(O), R 1 is H and R 3 is H, X is F or X is Cl and the compound is selected from Group Q); wherein Group Q consists of: A 2 is selected from N and N(O) In some embodiments, wherein A 2 is selected from N and N(O); the following conditions (a) to (d) apply: (a) no more than one of A 1 , A 2 and A 3 is N(O); (b) A 1 and A 3 are not both N; (c) X is F when A 2 is N(O), R 1 is H and R 3 is H (d) R is not 4-pyridyl when A 2 is N, R 1 and R 3 are each H and X is chloro and R is not phenyl when A 2 is N, R 1 and R 3 are each methyl and X is chloro.
  • a 2 is selected from N and N(O)
  • the following conditions (a) to (d) apply: (e) no more than one of A 1 , A 2 and A 3 is N(O); (f) A 1 and A 3 are not both N; (g) X is F when A 2 is N(O), R 1 is H and R 3 is H; or the compound is selected from Group Q; (h) R is not 4-pyridyl when A 2 is N, R 1 and R 3 are each H and X is chloro and R is not phenyl when A 2 is N, R 1 and R 3 are each methyl and X is chloro; wherein Group Q is as otherwise defined herein.
  • a 2 is selected from N and N(O); conditions (a) to (d) apply: (a) no more than one of A 1 , A 2 and A 3 is N(O); (b) A 1 and A 3 are not both N; (c) X is F or Cl when A 2 is N(O), R 1 is H and R 3 is H; (d) R is not 4-pyridyl when A 2 is N, R 1 and R 3 are each H and X is chloro and R is not phenyl when A 2 is N, R 1 and R 3 are each methyl and X is chloro. In some embodiments, when A 2 is N then at least one of R 1 , R 3 and R 4 are not H.
  • the compound of formula (I) is provided as a compound of formula (Ib): wherein one or more of provisos i), ii), iii) and iv) are satisfied; i) at least one of R 1 , R 3 and R 4 is other than H; ii) when A 1 is N and R 3 and R 4 are H, then the compound is not selected from the group B; iii) when A 3 is N and R 1 and R 4 are H, then the compound is not selected from the group C; iv) A 1 and A 3 are not both N; wherein group B and group C are as otherwise defined herein; and wherein A 1 , A 3 , R, R 1 , R 3 , R 4 , R a , R b and X are as otherwise defined for formula (I).
  • provisos i), ii) and iii) are satisfied. In some embodiments of formula (Ib), provisos i), ii), iii) and iv) are satisfied. In some embodiments of formula (Ib), provisos i), ii) and iii) are satisfied.
  • X, R a and R b In some embodiments, X is Cl, F, or -SO 2 R a . In some embodiments, X is F, Cl or SO 2 Me. In some embodiments, X is F. In some embodiments, X is Cl. In some embodiments, X is F or Cl. In some embodiments, X is SO 2 Me.
  • R a and R b are independently selected from optionally substituted C 1-4 alkyl, optionally substituted haloC 1-4 alkyl. In some embodiments, R a and R b are independently selected optionally substituted C 1-4 alkyl.
  • a 1 , A 2 and A 3 In some embodiments, A 1 is selected from N and CR 1 . In some embodiments, A 1 is selected from N(O) and CR 1 . In some embodiments, A 1 is selected from N and N(O). In some embodiments, A 1 is N. In some embodiments, A 1 is N(O). In some embodiments, A 1 is CR 1 . In some embodiments, A 2 is N. In some embodiments, A 2 is N(O).
  • a 2 is C-CN. In some embodiments A 2 is selected from N and N(O). In some embodiments, A 2 is selected from N and C-CN. In some embodiments, A 2 is selected from N(O) and C-CN. In some embodiments, A 3 is selected from N and CR 3 . In some embodiments, A 3 is selected from N(O) and CR 3 . In some embodiments, A 3 is selected from N and N(O). In some embodiments, A 3 is N. In some embodiments, A 3 is N(O). In some embodiments, A 3 is CR 3 . In some embodiments, A 1 is CR 1 and A 3 is CR 3 . In some embodiments, A 1 is N and A 3 is CR 3 .
  • a 1 is CR 1 and A 3 is N. In some embodiments, A 1 , A 2 and A 3 are according to any one of the following embodiments: In some embodiments, A 1 , A 2 and A 3 are according to any one of embodiments 1 to 12. In some embodiments, A 1 , A 2 and A 3 are according to any one of embodiments 13 to 17. R 1 , R 3 and R 4 In some embodiments wherein when A 2 is N, then R 1 is not H. In some embodiments wherein when A 2 is N, then R 3 is not H. In some embodiments wherein when A 2 is N, then R 4 is not H. In some embodiments wherein when A 2 is N, then at least two of R 1 , R 3 and R 4 are not H.
  • R 1 , R 3 and R 4 are not H. In some embodiments wherein when A 2 is N(O), then R 1 is not H. In some embodiments wherein when A 2 is N(O), then R 3 is not H. In some embodiments wherein when A 2 is N(O), then R 4 is not H. In some embodiments wherein when A 2 is N(O), then at least one of R 1 , R 3 and R 4 is not H. In some embodiments wherein when A 2 is N(O), then at least two of R 1 , R 3 and R 4 are not H. In some embodiments wherein when A 2 is N(O), then all of R 1 , R 3 and R 4 are not H.
  • R 1 , R 3 and R 4 are independently selected from H, deutero-, halo, C 1-4 alkyl, haloC 1-4 alkyl, C 3-8 cycloalkyl, haloC 3-8 cycloalkyl, -CN. In some embodiments, R 1 , R 3 and R 4 are independently selected from H, deutero-, halo, optionally substitutedC 1-2 alkyl, optionally substituted haloC 1-2 alkyl, optionally substituted C 3-5 cycloalkyl, optionally substituted haloC 3-5 cycloalkyl, -CN.
  • R 1 , R 3 and R 4 are independently selected from H, deutero-, halo, -CN. In some embodiments, R 1 , R 3 and R 4 are independently selected from H, optionally substituted C 1-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3- 8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl. In some embodiments, R 1 , R 3 and R 4 are independently selected from H, deutero-, halo; preferably H and halo. In some embodiments, the halo at one or more of R 1 , R 3 and R 4 is independently selected from F and Cl.
  • the halo at one or more of R 1 , R 3 and R 4 is F. In some embodiments, the halo at one or more of R 1 , R 3 and R 4 is Cl. In some embodiments, R 1 , R 3 and R 4 are independently selected from H, F, Cl and trifluoromethyl. In some embodiments, R 1 is selected from H, halo, C 1-4 alkyl, and haloC 1-4 alkyl. In some embodiments, R 3 is selected from H, halo, C 1-4 alkyl, and haloC 1-4 alkyl. In some embodiments, R 4 is selected from H and halo. In some embodiments, R 1 is selected from H, F, Cl and trifluoromethyl.
  • R 1 is selected from H, F, and Cl.
  • R 3 is selected from H, F, Cl and trifluoromethyl. In some embodiments, R 3 is selected from H, F, and Cl.
  • R 4 is selected from H, F, Cl and trifluoromethyl. In some embodiments, R 4 is selected from H, F, and Cl. In some embodiments, R 4 is selected from H and F. In some embodiments, R 4 is selected from H and Cl.
  • R 1 is H and R 3 and R 4 are independently selected from H, deutero- , halo, optionally substituted C 1-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 3 is H and R 1 and R 4 are independently selected from H, deutero- , halo, optionally substituted C 1-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 4 is H and R 1 and R 3 are independently selected from H, deutero- , halo, optionally substituted C 1-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 1 and R 3 are H and R 4 is selected from H, deutero-, halo, optionally substituted C 1-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 1 and R 4 are H and R 3 is selected from H, deutero-, halo, optionally substituted C 1-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3- 8 cycloalkyl, optionally substituted haloC 3- 8 cycloalkyl, -CN.
  • R 4 and R 3 are H and R 1 is selected from H, deutero-, halo, optionally substituted C 1-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • At least one of R 1 , R 3 and R 4 is selected from halo, optionally substituted C 1-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3- 8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, and –CN, preferably halo.
  • at least one of R 3 and R 4 is selected from halo, optionally substituted C 1- 4alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, and –CN, preferably halo.
  • one of R 3 and R 4 is selected from halo, optionally substituted C 1-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3- 8 cycloalkyl, and –CN, preferably halo.
  • one of R 1 , R 3 and R 4 is halo; and the remainder of R 1 , R 3 and R 4 are H.
  • R 4 is halo and R 1 and R 3 are H.
  • R 4 is halo, R 1 and R 3 are H, and A 2 is C-CN.
  • R 3 is halo and R 1 and R 4 are H, and X is SO 2 Me. In some embodiments, R 3 is halo and R 1 and R 4 are H, and A 2 is C–CN, and X is SO 2 Me. In some embodiments, R 3 is trifluoromethyl and A 2 is N. In some embodiments, R 3 is trifluoromethyl, A 2 is N, and X is halo, preferably chloro. In some embodiments, R 3 is halo (preferably chloro) and A 2 is N. In some embodiments, R 3 is halo (preferably chloro), A 2 is N, and X is halo, preferably chloro. In some embodiments, R 3 and R 4 are halo.
  • R 3 and R 4 are halo and A 2 is N. In some embodiments, A 2 is NO. In some embodiments, when A 2 is NO then one or more of R 1 , R 3 and R 4 are H. In some embodiments, when A 2 is NO then all of R 1 , R 3 and R 4 are H. In some embodiments, when R 3 is trifluoromethyl and A 2 is N, then X is not SO 2 Me. In some embodiments, when R 3 is trifluoromethyl and A 2 is N, then R is not optionally substituted 3-12 membered heterocyclyl. In some embodiments, when A 2 is N then X is not SO 2 Me. In some embodiments, when A 2 is N and R3 is Cl then X is not SO 2 Me.
  • R 3 when A 2 is N and R3 is SO 2 Me then X is not SO 2 Me. In some embodiments, when R 3 is halo, A 2 is N, and X is halo, then R is not optionally substituted C 1-6 alkyl or optionally substituted C 3-8 cycloalkyl. In some embodiments, when A 2 is N then R 1 is not halo. In some embodiments, when A 2 is N and X is halo, then R 1 is not halo. In some embodiments, when A 2 is N and X is halo, then R 1 is not chloro. In some embodiments, R 3 is not methyl. In some embodiments, when A 2 is N then R 3 is not methyl.
  • R 3 when A 2 is N and X is halo, then R 3 is not methyl. In some embodiments, R 1 is not methyl. In some embodiments, when A 2 is N then R 1 is not methyl. In some embodiments, when A 2 is N and R 3 is halo, then R 1 is not methyl. In some embodiments, when A 2 is N and R 3 is methyl, then R 1 is not methyl. In some embodiments, when R 3 is trifluoromethyl and A 2 is N, then X is Cl or F.
  • R 3 when R 3 is trifluoromethyl and A 2 is N, then R is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted aryl, optionally substituted -C 1-6 alkyl-C 3-8 cycloalkyl, optionally substituted -C 1-6 alkyl-aryl, optionally substituted -C 1-6 alkyl-3-12-membered heterocyclyl.
  • X when A 2 is N then X is Cl or F.
  • a 2 when A 2 is N and R3 is Cl then X is Cl or F.
  • R 3 when R 3 is halo, A 2 is N, and X is halo, then R is selected from the group consisting of optionally substituted 3-12 membered heterocyclyl, optionally substituted aryl, optionally substituted -C 1-6 alkyl-C 3-8 cycloalkyl, optionally substituted -C 1-6 alkyl-aryl, optionally substituted -C 1-6 alkyl-3-12-membered heterocyclyl.
  • R 1 is selected from: H, deutero-, optionally substituted C 1-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 1 is selected from: H, deutero-, fluoro, optionally substituted C 1-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 1 is selected from: H, deutero-, fluoro, optionally substituted C 1-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3- 8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 1 is selected from: H, deutero-, optionally substituted C 1-4 alkyl, optionally substituted haloC 1- 4alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 3 is selected from: H, deutero-, halo, optionally substituted C 2- 4alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN. In some embodiments, R 3 is selected from: H, deutero-, halo, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 3 is selected from: H, deutero-, halo, optionally substituted C 2-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN. In some embodiments, when A 2 is N then R 3 is selected from: H, deutero-, halo, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 3 is selected from: H, deutero-, halo, optionally substituted C 2-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 3 is selected from: H, deutero-, halo, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 1 is selected from: H, deutero-, halo, optionally substituted C 2-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN. In some embodiments, R 1 is selected from: H, deutero-, halo, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 1 is selected from: H, deutero-, halo, optionally substituted C 2-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 1 is selected from: H, deutero-, halo, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 1 when A 2 is N and R 3 is halo, then R 1 is selected from: H, deutero-, halo, optionally substituted C 2-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN. In some embodiments, when A 2 is N and R 3 is halo, then R 1 is selected from: H, deutero-, halo, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R 1 when A 2 is N and R 3 is methyl, then R 1 is selected from: H, deutero-, halo, optionally substituted C 2-4 alkyl, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN. In some embodiments, when A 2 is N and R 3 is methyl, then R 1 is selected from: H, deutero-, halo, optionally substituted haloC 1-4 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted haloC 3-8 cycloalkyl, -CN.
  • R is selected from C 1-6 alkyl, C 3-8 cycloalkyl, aryl, 3-12 membered heterocyclyl, -C 1-6 alkyl-C 3-8 cycloalkyl, -C 1-6 alkyl-aryl, -C 1-6 alkyl-3-12-membered heterocyclyl.
  • R is selected from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 3-9 membered heterocyclyl, optionally substituted -C 1-4 alkyl-C 3-6 cycloalkyl, optionally substituted -C 1-4 alkyl-phenyl, optionally substituted -C 1-4 alkyl-3-9-membered heterocyclyl.
  • R is selected from optionally substituted C 3-8 cycloalkyl, optionally substituted aryl, optionally substituted 3-12 membered heterocyclyl.
  • R is selected from optionally substituted C 1-6 alkyl, optionally substituted -C 1-6 alkyl-C 3-8 cycloalkyl, optionally substituted -C 1-6 alkyl-aryl, optionally substituted -C 1-6 alkyl-3-12-membered heterocyclyl.
  • R is selected from optionally substituted aryl, optionally substituted 3-12 membered heterocyclyl.
  • the optionally substituted aryl at R is optionally substituted phenyl.
  • the optionally substituted heterocyclyl at R is optionally substituted heteroaryl, preferably optionally substituted pyridyl.
  • the optionally substituted heterocyclyl at R is not heteroaromatic, and is preferably saturated, more preferably optionally substituted tetrahydropyranyl. In some embodiments, the optionally substituted heterocyclyl at R is fused.
  • the group at R is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 8 cycloalkyl, hydroxyl, oxo, C 1-6 alkoxy, aryloxy, C 1-6 alkoxyaryl, halo, C 1-6 alkylhalo (such as CF 3 ), C 1-6 alkoxyhalo (such as OCF 3 ), carboxyl, esters, cyano, nitro, amino, substituted amino, disubstituted amino, amides, aminoacyl, substituted amides, disubstituted amides, thiol, alkylthio, thioxo, sulfates, sulfonates, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonylamides
  • the group at R is optionally substituted with one or two substituents. In some embodiments, the group at R is optionally substituted with one substituent. In some embodiments, the group at R is unsubstituted. The group at R is preferably optionally substituted with one or more substituent(s) selected from halo, haloC 1-4 alkyl and haloC 1-4 alkoxy. In some embodiments, R is provided by partial formula (IIIa): wherein T is N or CH. In some embodiments, T is N. In some embodiments, T is CH.
  • R is selected from the group consisting of: In some embodiments, R is selected from the group consisting of: In some embodiments, R is selected from the group consisting of: . In some embodiments, R is selected from the group consisting of: In some embodiments, R is selected from the group consisting of:
  • the compound of formula (I) is not selected from one or more of formula (IIa), formula (IIai), formula (IIaii), formula (IIaiii), formula (IIaiv), formula (Ib), formula (IIb), formula (IIIb) and formula (IVb); wherein Group A consists of one or more of:
  • the compound of formula (I) is not selected from one or more of formula (IIa), formula (IIai), formula (IIaii), formula (IIaiii), formula (IIaiv), formula (Ib), formula (IIb), formula (IIIb) and formula (IVb); wherein Group A consists of one or more of:
  • the compound of formula (I) is not selected from one or more of formula (IIa), formula (IIai), formula (IIaii), formula (IIaiii) and formula (IIaiv). In some embodiments wherein R is selected from Group A, then the compound of formula (I) is not selected from one or more of formula (Ib), formula (IIb), formula (IIIb) and formula (IVb).
  • R is selected from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted -C 1-4 alkyl-C 3-6 cycloalkyl, optionally substituted -C 1-4 alkyl-phenyl, optionally substituted - C 1-4 alkyl-3-9-membered heterocyclyl.
  • R does not include partial formula (IV): wherein G 1 and G 2 independently represent a group selected from N and CR 9 , wherein G 1 and G 2 are not simultaneously CR 9 , R 9 is independently selected from the group consisting of: a) a five or six-membered heteroaryl ring optionally substituted by one or more substituents selected from the group consisting of halogen atom, cyano group, -COOH group, linear or branched C 1- C 3 alkyl group, linear or branched C 1- C 3 alkoxy, linear or branched C 1- C 3 haloalkyl group, C 3- C 4 cycloalkyl, and C 3- C 4 cycloalkoxy; b) phenyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom, cyano group, -COOH group, linear or branched C 1- C 3 alkyl group, linear or branched C 1- C 3 alkoxy, linear or
  • the compound of formula (I) is provided as a compound of any one of formulas (IIai), (IIaii), (IIaiii) and (IIaiv): wherein R, R 1 , R 3 , R 4 , R a , R b and X are as defined for formula (I).
  • the compound of formula (I) is provided as a compound of formula (IIai) and formula (IIaii).
  • the compound of formula (I) is provided as a compound of formula (IIai) and formula (IIaiii).
  • the compound of formula (I) is provided as a compound of formula (IIaii) and formula (IIaiii). In some embodiments, the compound of formula (I) is provided as a compound of formula (IIai). In some embodiments, the compound of formula (I) is provided as a compound of formula (IIaii). In some embodiments, the compound of formula (I) is provided as a compound of formula (IIaiii). In some embodiments, the compound of formula (I) is provided as a compound of formula (IIaiv).
  • the compound of formula (I) is provided as a compound of formula (IIa): wherein T is CH or N; and A 1 , A 2 , A 3 , R 1 , R 3 , R 4 , R a , R b and X are as defined for formula (I).
  • the compound of formula (I) is provided as a compound of formula (IIb) wherein R, R 1 , R 3 , R 4 , R a , R b and X are as defined for formula (Ib).
  • the compound of formula (I) is provided as a compound of formula (IIIb) wherein R, R 3 , R 4 and X are as defined for formula (Ib).
  • the compound of formula (I) is provided as a compound of formula (IVb)
  • R, R 1 , R 4 and X are as defined for formula (Ib).
  • the compound of formula (I) is provided as a compound of formula (IIb) or formula (IIIb).
  • the compound of formula (I) is provided as a compound of formula (IIb) or formula (IVb).
  • the compound of formula (I) is provided as a compound of formula (IIIb) or formula (IVb).
  • Compounds In some embodiments, the compound of formula (I) is not selected from one or more of the group consisting of: ,
  • the compound of formula (I) (preferably formula (Ib)) is not selected from one or more of the group consisting of: pharmaceutically acceptable salt thereof.
  • the compound of formula (I) is selected from the compounds of Table 1. Table 1: Compounds of formula (I)
  • the compound of formula (I) does not include one or more of compound 2, 3 and 109. In some embodiments, the compound of formula (I) does not include one or more of compound 2, 3 and 109, or a salt thereof. In some embodiments, the compound of formula (I) is selected from any one of compounds 1, 4 to 108 and 110 to 113. In some embodiments, the compound of formula (I) is selected from any one of compounds 1 to 113. In some embodiments, the compound of formula (I) is selected from any one of compounds 1 to 113 and 121 to 125. In some embodiments, the compound of formula (I) is selected from any one of compounds 1 to 35 and 121 to 125.
  • the compound of formula (I) is selected from any one of compounds 1 and 4 to 35. In some embodiments, the compound of formula (I) is selected from any one of compounds 1 to 7 and 10. In some embodiments, the compound of formula (I) is selected from any one of compounds 1, 4, 5 and 6. In some embodiments, the compound of formula (I) is selected from any one of compounds 6, 7 and 10. In some embodiments, the compound of formula (I) is selected from any one of compounds 36 to 113. In some embodiments, the compound the compound of formula (I) is selected from any one of compounds 36 to 97, 99 to 105 and 111 to 113.
  • the compound of formula (I) is selected from any one of compounds 38, 42, 50 to 53, 72, 80, 92 and 98 to 110. In some embodiments, the compound of formula (I) is selected from any one of compounds 38, 42, 50 to 53, 72, 80, 92 and 99 to 105. In some embodiments, the compound of formula (I) is selected from any one of compounds 50 to 52, 72, 92 and 98 to 112. In some embodiments, the compound of formula (I) is selected from any one of compounds 50 to 52, 72, 92 and 98 to 110. In some embodiments, the compound of formula (I) is selected from any one of compounds 50, 51, 72, 92, 98 to 104, 107, 108, 110, 112 and 113.
  • the compound of formula (I) is selected from any one of compounds 50, 51, 92, 98, 99, 102, 103, 107, 108, 110, 112 and 113. In some embodiments, the compound of formula (I) is selected from any one of compounds 50, 51, 92, 99, 102, 103, 105 and 111 to 113.
  • Methods of preparation Typically, the compounds of the invention may be prepared by techniques known in the art. Suitable syntheses of compounds of formula (I) – and its various subformulas – are outlined in the Examples below. The specific reagents and conditions for effecting any synthetic steps will depend on the specific substituents selected for the relevant reagents/reactants.
  • a compound of the invention or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof, for use in the treatment of a disease, condition and/or disorder associated with PPAR ⁇ .
  • a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, solvate, tautomer, N- oxide, stereoisomer and/or prodrug thereof, and optionally a pharmaceutically acceptable excipient.
  • a method of treating a disease, condition or disorder associated with PPAR ⁇ activity comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof; or a pharmaceutical composition of the invention.
  • a method of modulating PPAR ⁇ activity comprising contacting a cell expressing PPAR ⁇ with a compound of the invention, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof.
  • a method of treating a disease, condition or disorder selected from: a disorder of lipid and/or glucose metabolism; inflammation; obesity, a metabolic syndrome, a viral infection; and a proliferative disorder comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof ; or a pharmaceutical composition of the invention.
  • the method comprises forming a covalent bond between the compound of formula (I) and PPAR ⁇ .
  • a compound of the invention or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof, in the preparation of a medicament for one or more of: i. treating a disease, condition or disorder associated with PPAR ⁇ activity; and/or ii. modulating PPAR ⁇ activity; and/or iii. treating a disease, condition or disorder selected from: a disorder of lipid and/or glucose metabolism; inflammation; obesity, a metabolic syndrome, a viral infection; and a proliferative disorder.
  • Covalent modification of PPAR ⁇ may be advantageous in one or more of: i. treating a disease, condition or disorder associated with PPAR ⁇ activity; and/or ii. modulating PPAR ⁇ activity; and/or iii. treating a disease, condition or disorder selected from: a disorder of lipid and/or glucose metabolism; inflammation; obesity, a metabolic syndrome, a viral infection; and a proliferative disorder.
  • a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof for use as a medicament.
  • medicaments comprising a compound of formula (I), or or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • the term "therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • the salts of the compounds of Formula (I) are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure, for example, as these may be useful as intermediates in the preparation of pharmaceutically acceptable salts or in methods not requiring administration to a subject.
  • pharmaceutically acceptable may be used to describe any salt, solvate, tautomer, N-oxide, stereoisomer and/or prodrug thereof, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of Formula (I) or an active metabolite or residue thereof and typically that is not deleterious to the subject.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, n
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
  • pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
  • inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
  • the invention includes all crystalline forms of a compound of Formula (I) including anhydrous crystalline forms, hydrates, solvates and mixed solvates. If any of these crystalline forms demonstrates polymorphism, all polymorphs are within the scope of this invention.
  • Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds.
  • Formula (I) includes compounds having the indicated structures, including the hydrated or solvated forms, as well as the non-hydrated and non- solvated forms.
  • the compounds of Formula (I) or salts, tautomers, N-oxides, polymorphs or prodrugs thereof may be provided in the form of solvates.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, alcohols such as methanol, ethanol or isopropyl alcohol, DMSO, acetonitrile, dimethyl formamide (DMF), acetic acid, and the like with the solvate forming part of the crystal lattice by either non-covalent binding or by occupying a hole in the crystal lattice. Hydrates are formed when the solvent is water, alcoholates are formed when the solvent is alcohol.
  • Solvates of the compounds of the present invention can be conveniently prepared or formed during the processes described herein. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the invention.
  • Basic nitrogen-containing groups may be quarternised with such agents as C 1-6 alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others. Nitrogen containing groups may also be oxidised to form an N-oxide.
  • the compound of Formula (I) or salts, tautomers, N-oxides, solvates and/or prodrugs thereof that form crystalline solids may demonstrate polymorphism.
  • the compound of Formula (I) may demonstrate tautomerism. Tautomers are two interchangeable forms of a molecule that typically exist within an equilibrium. Any tautomers of the compounds of Formula (I) are to be understood as being within the scope of the invention.
  • the compound of Formula (I) may contain one or more stereocentres. All stereoisomers of the compounds of formula (I) are within the scope of the invention. Stereoisomers include enantiomers, diastereomers, geometric isomers (E and Z olephinic forms and cis and trans substitution patterns) and atropisomers.
  • the compound is a stereoisomerically enriched form of the compound of formula (I) at any stereocentre.
  • the compound may be enriched in one stereoisomer over another by at least about 60, 70, 80, 90, 95, 98 or 99%.
  • the compound of Formula (I) or its salts, tautomers, solvates, N-oxides, and/or stereoisomers may be isotopically enriched with one or more of the isotopes of the atoms present in the compound.
  • the compound may be enriched with one or more of the following minor isotopes: 2 H, 3 H, 13 C, 14 C, 15 N and/or 17 O.
  • An isotope may be considered enriched when its abundance is greater than its natural abundance.
  • a "prodrug” is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce a compound of formula (I) provided herein.
  • a prodrug may be an acylated derivative of a compound as provided herein.
  • Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively.
  • prodrugs examples include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
  • Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined to free amino, and amido groups of compounds of Formula (I).
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3- methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of Formula (I) through the carbonyl carbon prodrug sidechain.
  • compositions may be formulated from compounds according to Formula (I) for any appropriate route of administration including, for example, oral, rectal, nasal, vaginal, topical (including transdermal, buccal, ocular and sublingual), parenteral (including subcutaneous, intraperitoneal, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, intracisternal injection as well as any other similar injection or infusion techniques), inhalation, insufflation, infusion or implantation techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).
  • parenteral including subcutaneous, intraperitoneal, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, intracister
  • compositions in a form suitable for oral use or parenteral use are preferred.
  • suitable oral forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • aqueous or oily suspensions dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
  • Such formulations may be prepared by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride or glycine, and having a buffered pH compatible with physiological conditions to produce an aqueous solution, and rendering said solution sterile.
  • physiologically compatible substances such as sodium chloride or glycine
  • the formulations may be present in unit or multi-dose containers such as sealed ampoules or vials. Examples of components are described in Martindale – The Extra Pharmacopoeia (Pharmaceutical Press, London 1993), and Remington: The Science and Practice of Pharmacy, 21st Ed., 2005, Lippincott Williams & Wilkins.
  • All methods include the step of bringing the active ingredient, for example a compound defined by Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, N-oxide and/or prodrug thereof, into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient, for example a compound defined by Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, N-oxide and/or prodrug thereof, into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect.
  • the method of the invention comprises administering a pharmaceutical comprising a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, N-oxide and/or prodrug thereof and a pharmaceutically acceptable carrier, diluent and/or excipient.
  • a pharmaceutical comprising a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, N-oxide and/or prodrug thereof and a pharmaceutically acceptable carrier, diluent and/or excipient.
  • administering and variations of that term including “administer” and “administration”, includes contacting, applying, delivering or providing a compound or composition of the invention to an organism, or a surface by any appropriate means.
  • the dose of the biologically active compound according to the invention may vary within wide limits and may be adjusted to individual requirements. Active compounds according to the present invention are generally administered in a therapeutically effective amount.
  • the daily dose may be administered as a single dose or in a plurality of doses.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the subject, time of administration, route of administration, and rate of excretion, drug combination (i.e. other drugs being used to treat the subject), and the severity of the particular disorder undergoing therapy. Such treatments may be administered as often as necessary and for the period of time judged necessary by the treating physician.
  • the dosage regime or therapeutically effective amount of the compound of formula (I) to be administered may need to be optimized for each individual. It will also be appreciated that different dosages may be required for treating different disorders.
  • An effective amount of an agent is that amount which causes a statistically significant decrease in PPARG activity.
  • the terms “treating”, “treatment” and “therapy” are used herein to refer to curative therapy, prophylactic therapy and preventative therapy. Thus, in the context of the present disclosure the term “treating” encompasses curing, ameliorating or tempering the severity of disease, condition and/or disorder, and/or associated symptom(s).
  • Preventing means preventing the occurrence of the disease, condition and/or disorder or tempering the severity of the disease, condition and/or disorder if it develops subsequent to the administration of the compounds or pharmaceutical compositions of the present invention.
  • Subject includes any human or non-human animal.
  • the compounds of the present invention may also be useful for veterinary treatment of mammals, including companion animals and farm animals, such as, but not limited to dogs, cats, horses, cows, sheep, and pigs.
  • the compounds of the present invention may be administered along with a pharmaceutical carrier, diluent and/or excipient as described above.
  • the methods of the present disclosure can be used to prevent or treat the following disease(s), condition(s) and/or disorder(s) in a subject: a disorder of lipid and/or glucose metabolism, including Types I and II diabetes mellitus (preferably type II diabetes mellitus (T2DM)); inflammation; obesity; a metabolic syndrome; a viral infection; and proliferative disorders including cancer, such as cancers of a tissue expressing PPARG, for example skin, liver, oesophageal, breast, bladder, pancreatic and prostate cancers.
  • compounds of the invention may be used to treat type II diabetes mellitus.
  • T2DM thiazolidinediones
  • T2DM thiazolidinediones
  • the TZDs work by preventing the phosphorylation of Ser273 on PPAR ⁇ by cyclin- dependent kinase 5 (Cdk5) which is overactivated in the obese state, rather than through activation of the receptor as initially believed.
  • Ligands lacking classical transcriptional agonism may also inhibit Cdk5-mediated Ser273 phosphorylation, and exhibit antidiabetic effects, without the side effects resulting from over-activation of PPAR ⁇ .
  • the compounds of the invention may be used to treat a proliferative disease. Inhibiting PPAR ⁇ may be useful in the treatment of cancer.
  • PPAR ⁇ antagonists and inverse agonists have been found to exhibit anticancer effects by affecting cell shape, adhesion and survival, and invasiveness of in vitro and in vivo cancer models, including for skin, liver, oesophageal, breast, bladder, pancreatic and prostate cancers.
  • PPAR ⁇ has also been identified as a key negative regulator of immune activation, and genetic deletion of PPAR ⁇ in mice immune cells, including T cells, B cells, monocytes, macrophages, and dendritic cells has resulted in enhanced immune activation.
  • the compounds of the invention may be useful in treating any of these cancers and may be useful in combination with immune checkpoint antibodies, including PD-1/PD-L1 inhibitors.
  • the compound of the invention may be administered in combination with a further active pharmaceutical ingredient (API).
  • the API may be any that is suitable for treating any of the diseases, conditions and/or disorders associated with PPARG, such as those described herein.
  • the compound of the invention may be co- formulated with the further API in any of the pharmaceutical compositions described herein, or the compound of the invention may be administered in a concurrent, sequential or separate manner.
  • Concurrent administration includes administering the compound of the invention at the same time as the other API, whether coformulated or in separate dosage forms administered through the same or different route.
  • Sequential administration includes administering, by the same or different route, the compound of the invention and the other API according to a resolved dosage regimen, such as within about 0.5, 1, 2, 3, 4, 5, or 6 hours of the other.
  • the compound of the invention may be administered before or after administration of the other API.
  • Separate administration includes administering the compound of the invention and the other API according to regimens that are independent of each other and by any route suitable for either active, which may be the same or different.
  • the methods may comprise administering the compound of Formula (I) in any pharmaceutically acceptable form.
  • the compound of Formula (I) is provided in the form of a pharmaceutically acceptable salt, solvate, N-oxide, polymorph, tautomer or prodrug thereof, or a combination of these forms in any ratio.
  • the methods may also comprise administering a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt, solvate, N-oxide, polymorph, tautomer or prodrug thereof to the subject in need thereof.
  • the pharmaceutical composition may comprise any pharmaceutically acceptable carrier, diluent and/or excipient described herein.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt or prodrug thereof, as defined herein, may be administered by any suitable means, for example, orally, rectally, nasally, vaginally, topically (including buccal and sub-lingual), parenterally, such as by subcutaneous, intraperitoneal, intravenous, intramuscular, or intracisternal injection, inhalation, insufflation, infusion or implantation techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).
  • the compounds of the invention may be provided as pharmaceutical compositions including those for oral, rectal, nasal, topical (including buccal and sub-lingual), parenteral administration (including intramuscular, intraperitoneal, sub-cutaneous and intravenous), or in a form suitable for administration by inhalation or insufflation.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt or prodrug thereof, together with a conventional adjuvant, carrier or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids as solutions, suspensions, emulsions, elixirs or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Kits Also provided is a kit of parts, comprising in separate parts: ⁇ a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, N- oxide, polymorph, tautomer or prodrug thereof; and ⁇ instructions for its use in any of the methods of the invention.
  • a kit of parts comprising in separate parts: ⁇ a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, N- oxide, polymorph, tautomer or prodrug thereof; and ⁇ instructions for its use in any of the methods of the invention.
  • Examples The compounds, compositions, kits and methods described herein are described by the following illustrative and non-limiting examples.
  • CHEMISTRY Synthesis Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. The reactions for preparing compounds of the invention can be carried out in suitable solvents, which can be readily selected by one of skill in the art of organic synthesis.
  • Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M.
  • reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high-performance liquid chromatography (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry
  • HPLC high-performance liquid chromatography
  • ambient temperature e.g. a reaction temperature
  • room temperature e.g. a temperature from about 20 oC to about 30 oC.
  • Compounds of the invention can be prepared according to numerous preparatory routes known in the literature. Experimental General details All amide coupling reactions were performed stoppered and, unless otherwise stated, all other reactions were performed under an atmosphere of N 2 at rt. Air sensitive reactions were conducted in flame-dried glassware with the use of syringe and septum-cap techniques.
  • reaction temperatures refer to the temperature of the heating or cooling bath unless under heating reflux, in which case the temperature is the boiling point of the solution.
  • All organic extracts were dried using anhydrous MgSO 4 then filtered. Solvents were evaporated under reduced pressure at 35–50 °C, and then trace solvents were removed under a flow of N 2 . Solvents Dry solvents refer to those stored over activated 3 ⁇ sieves for at least 24 h. EtOAc and hexanes were distilled prior to use. Anhydrous THF was obtained from a Pure Solv 5-Mid Solvent Purification System (Innovative Technology, Inc.). 'Hexanes' refers to the hydrocarbon fraction distilling from 64–67 °C.
  • Target compounds Purity of target compounds was assessed by high performance liquid chromatography (HPLC) using an Agilent Technologies 1260 Infinity II system, equipped with a variable wavelength detector and an Apollo 5 ⁇ m C 18 250 ⁇ 4.60 mm column. Gradient elution with a mobile phase composed of MeCN and 0.1 % aqueous trifluoroacetic acid (TFA) solution with a flow rate of 1 mL./min was used. The gradient increased from 1:99 MeCN/TFA (v/v) to 100 % MeCN over 30 min. All target compounds submitted for biological testing were assessed as ⁇ 95 % pure by HPLC at 254 nm.
  • HPLC high performance liquid chromatography
  • Compounds of the invention may be prepared according to general amide coupling of Scheme 1 below.
  • the relevant benzoic acid may be converted to a benzoyl halide, using a dehydrative halogenating agent, such as SOCl 2 , and then treated with the relevant amine, and a base, such as an amine (NEt 3 etc).
  • the relevant benzoic acid may be directly coupled to the relevant amine using an amide coupling reagent, such as TCTU or EDC hydrochloride.
  • Scheme 1 Amide coupling general procedures of the invention are further detailed in General procedures A-C below.
  • Precursor 1 5 ⁇ Cyano ⁇ 2,3 ⁇ difluorobenzoic acid.
  • a mixture of 3,4-difluoro-5-methylbenzene (153 mg, 1.00 mmol), Br 2 (336 mg, 2.10 mmol), H 2 O (1.2 mL) and (trifluoromethyl)benzene (6 mL) was vigorously stirred and irradiated with blue LED light ( ⁇ 460 nm) for 2 d.
  • the attached reflux condenser was open to air.
  • the reaction mixture was diluted with EtOAc (60 mL) and extracted with half- saturated Na 2 CO 3 (3 ⁇ 20 mL). The aqueous extract was acidified to pH 2 with conc.
  • Precursor 5 4-(Methylsulfonyl)nicotinic acid. Sodium methanesulfinate (153 mg, 1.50 mmol) was added to 4-chloronicotinic acid (158 mg, 1.00 mmol) in NMP (1 mL) and heated in a sealed vial at 50 °C for 3 h. The reaction mixture was cooled, diluted with EtOAc (60 mL) and washed with 1 M HCl (2 ⁇ 20 mL), then dried and evaporated. The crude product was recrystallised (DCM/hexanes) to afford the title compound as a white powder (147 mg, 73 %).
  • Trifluoroacetic acid (0.1 mL) was added to tert ⁇ butyl N ⁇ [4 ⁇ (4 ⁇ chloro ⁇ 5 ⁇ cyano ⁇ 2 ⁇ methanesulfonylbenzamido)phenyl]methyl ⁇ carbamate (Compound 21) (16 mg, 0.034 mmol) in DCM (0.9 mL) and the resulting solution was stirred at rt for 1 h. The volatiles were evaporated, the residue was redissolved in 1:1 MeOH/DCM and evaporated (3 ⁇ 1 mL) to afford the title compound as an off-white powder (16 mg, quant.).
  • Compound 85 4-(2-(4,6-Dichloronicotinamido)ethyl)benzoic acid. Lithium hydroxide monohydrate (150 mg, 3.57 mmol) was added to methyl 4-(2-(4,6- dichloronicotinamido)ethyl)benzoate (Compound 84) (50 mg, 0.15 mmol) in 1:1 THF/H 2 O (4 mL) and the mixture stirred overnight at rt. The reaction was partitioned between Et 2 O (25 mL) and H 2 O (25 mL). The aqueous phase was acidified with citric acid and extracted with EtOAc (25 mL).
  • Lithium hydroxide monohydrate 150 mg, 3.57 mmol was added to methyl 4-(4,6- dichloronicotinamido)benzoate (Compound 86) (50 mg, 0.16 mmol) in 1:1 THF/H 2 O (4 mL) and the mixture stirred overnight at rt.
  • the reaction was partitioned between Et 2 O (25 mL) and H 2 O (25 mL).
  • the aqueous phase was acidified with citric acid and extracted with EtOAc (25 mL).
  • the organic phase was washed with brine (2 ⁇ 25 mL), dried and concentrated.
  • the crude product was subjected to flash chromatography.
  • Test compounds were dissolved in DMSO to give 20 mM stock solutions and then diluted with DMSO as required to obtain final well concentrations of 1 ⁇ 10 -5 , 1 ⁇ 10 -4 , 1 ⁇ 10 -3 , 1 ⁇ 10 -2 , 0.1, 1, 10 and 100 ⁇ M.
  • Solutions of PPAR ⁇ ligand binding domain (GST-PPAR ⁇ -LBD), terbium-labelled anti-GST antibody, and FluormoneTM Pan-PPAR Green were prepared with proprietary TR-FRET PPAR assay buffer containing 5 mM dithiothreitol (DTT) to well concentrations of 0.5 nM, 5 nM, and 5 nM, respectively. The final well volume was 10 ⁇ L.
  • Example 3 Stability assay Test compounds (200 ⁇ M) are assessed for stability in buffer containing either N-acetylcysteine or glutathione (10 mM) as follows. An aliquot of 20 mM stock solution of test compound in DMSO (10 ⁇ L) is added to 100 mM pH 7.2 Sorensen buffer (990 ⁇ L) containing a large excess of N-acetylcysteine or glutathione (10 mM final concentration), followed by incubation at 37 °C. Consumption of test compound is monitored every 2 h for 24 h by HPLC.
  • HPLC is performed on an Agilent Technologies 1200 system, equipped with a multiple wavelength detector and an Alltima 5 ⁇ m C18150 ⁇ 2.1 mm column.
  • the mobile phase consists of 1:99 MeCN/0.1 % aqueous trifluoroacetic acid (TFA) solution (v/v), increased in a gradient to 100 % MeCN over 24 min, with a flow rate of 0.3 mL/min and a final hold of 5 min.
  • TFA trifluoroacetic acid
  • Example 4 Cellular transcriptional reporter assay Test compounds with significant binding affinity (i.e., reactivity after 2 h) are assessed for PPAR ⁇ functional activity and selectivity over PPAR ⁇ and PPAR ⁇ selectivity in a reporter assays using a HG5LN GAL4-PPAR cells, as described in Seimandi, M. et al. Anal. Biochem.2005, 344(1), 8-15. It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Virology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I) et des sels, solvates, tautomères, stéréoisomères, polymorphes et/ou promédicaments de ceux-ci. L'invention concerne également l'utilisation des composés de formule (I) pour moduler PPARγ.
PCT/AU2024/050351 2023-04-12 2024-04-12 Modulateurs de pparg Pending WO2024211969A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
AU2023901076A AU2023901076A0 (en) 2023-04-12 PPARG modulators
AU2023901074 2023-04-12
AU2023901076 2023-04-12
AU2023901074A AU2023901074A0 (en) 2023-04-12 Modulators of PPARγ

Publications (1)

Publication Number Publication Date
WO2024211969A1 true WO2024211969A1 (fr) 2024-10-17

Family

ID=93058538

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2024/050351 Pending WO2024211969A1 (fr) 2023-04-12 2024-04-12 Modulateurs de pparg

Country Status (1)

Country Link
WO (1) WO2024211969A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107243A1 (fr) * 2010-03-01 2011-09-09 Qualimed Innovative Medizinprodukte Gmbh Endoprothèse vasculaire radialement expansible
WO2018019676A1 (fr) * 2016-07-29 2018-02-01 Bayer Cropscience Aktiengesellschaft Combinaisons de composés actifs et procédés pour protéger le matériau de propagation des plantes
WO2019115498A1 (fr) * 2017-12-12 2019-06-20 Medibiofarma, S.L. Nouveaux dérivés benzamides utilisés en tant que modulateurs de ppar-gamma
WO2021170046A1 (fr) * 2020-02-26 2021-09-02 Beigene, Ltd. Inhibiteur de tyk-2
WO2022187203A1 (fr) * 2021-03-02 2022-09-09 Flare Therapeutics, Inc. Agonistes inverses de pparg et leurs utilisations
WO2023014861A1 (fr) * 2021-08-05 2023-02-09 Flare Therapeutics Inc. Agonistes inverses de pparg et leurs utilisations
WO2023172846A1 (fr) * 2022-03-08 2023-09-14 Flare Therapeutics Inc. Agonistes inverses de pparg et leurs utilisations

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107243A1 (fr) * 2010-03-01 2011-09-09 Qualimed Innovative Medizinprodukte Gmbh Endoprothèse vasculaire radialement expansible
WO2018019676A1 (fr) * 2016-07-29 2018-02-01 Bayer Cropscience Aktiengesellschaft Combinaisons de composés actifs et procédés pour protéger le matériau de propagation des plantes
WO2019115498A1 (fr) * 2017-12-12 2019-06-20 Medibiofarma, S.L. Nouveaux dérivés benzamides utilisés en tant que modulateurs de ppar-gamma
WO2021170046A1 (fr) * 2020-02-26 2021-09-02 Beigene, Ltd. Inhibiteur de tyk-2
WO2022187203A1 (fr) * 2021-03-02 2022-09-09 Flare Therapeutics, Inc. Agonistes inverses de pparg et leurs utilisations
WO2023014861A1 (fr) * 2021-08-05 2023-02-09 Flare Therapeutics Inc. Agonistes inverses de pparg et leurs utilisations
WO2023172846A1 (fr) * 2022-03-08 2023-09-14 Flare Therapeutics Inc. Agonistes inverses de pparg et leurs utilisations

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 31 March 2023 (2023-03-31), ANONYMOUS: "3-Pyridinecarboxamide, 2-chlor o-4-fluoro-N-methyl- (CA IN DEX NAME)", XP093224372, Database accession no. 2918967-75-4 *
DATABASE REGISTRY 31 March 2023 (2023-03-31), ANONYMOUS: "3-Pyridinecarboxamide, 4,6-dic hloro-N-(1-methylethyl)- (C A INDEX NAME)", XP093224373, Database accession no. 2918832-72-9 *
DATABASE REGISTRY 4 December 2011 (2011-12-04), ANONYMOUS: "4-Pyridazinecarboxamide, N-[2- [(1H-benzimidazol-2-ylmeth yl)(5,6,7,8- tetrahydro-8-quinolinyl)ami no]ethyl]-3,5-dichloro- (CA I NDEX NAME)", XP093224376, Database accession no. 1348682-74-5 *

Similar Documents

Publication Publication Date Title
JP5916700B2 (ja) アミド化合物、組成物およびそれらの使用
JP5931752B2 (ja) 縮環複素環誘導体
RU2684641C1 (ru) Производные пиразолопиридина в качестве модуляторов активности tnf
RU2390522C2 (ru) Гетероциклические соединения
JP5608655B2 (ja) Ｐ２ｘ３受容体活性のモジュレーター
DE69209576T4 (de) Pyridinderivate, deren Herstellung und Anwendung
RU2719422C2 (ru) Необязательно конденсированные гетероциклил-замещенные производные пиримидина, пригодные для лечения воспалительных, метаболических, онкологических и аутоиммунных заболеваний
RU2684635C1 (ru) Производные тетрагидроимидазопиридина в качестве модуляторов активновти tnf
JP2010518026A (ja) ナトリウムチャネルが介在する疾患または状態の治療に有用なピリドピリミジノン化合物
AU2023233066A1 (en) Quinazolinones as PARP14 inhibitors
CA2633760A1 (fr) Composes antiviraux
EP2794569B1 (fr) Composés hétérocycliques d'urée
AU2014367283B2 (en) Maleimide derivatives as modulators of WNT pathway
AU2011290126A1 (en) Heterocyclic compound and use thereof
CN104271577A (zh) 作为mek抑制剂的杂环基化合物
BR112014004741B1 (pt) Entidade química, seu uso e composição farmacêutica compreendendo a mesma
JP2022521536A (ja) イミダゾピリジニル化合物及び神経変性障害の処置のためのその使用
JP2010506829A (ja) 新規な抗不安薬化合物
JP2011525924A (ja) プロリルヒドロキシラーゼ阻害剤
TW200924758A (en) Therapeutic agents
US20230080486A1 (en) Cftr modulator compounds, compositions, and uses thereof
WO2024211969A1 (fr) Modulateurs de pparg
CN113666853A (zh) 可用作RORγ调节剂的联芳基类化合物
US20240067654A1 (en) Oxytocin receptor modulators
JP2020193209A (ja) チアゾール誘導体の製造方法

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE