WO2023066825A1 - Fused bicyclic heteroaryl compounds useful as nlrp3 inhibitors - Google Patents

Fused bicyclic heteroaryl compounds useful as nlrp3 inhibitors Download PDF

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Publication number
WO2023066825A1
WO2023066825A1 PCT/EP2022/078755 EP2022078755W WO2023066825A1 WO 2023066825 A1 WO2023066825 A1 WO 2023066825A1 EP 2022078755 W EP2022078755 W EP 2022078755W WO 2023066825 A1 WO2023066825 A1 WO 2023066825A1
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Prior art keywords
methyl
oxazolo
pyridin
amino
phenol
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PCT/EP2022/078755
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English (en)
French (fr)
Inventor
Lewis Scott AITKEN
Lea Aurelie BOUCHE
Wolfgang Guba
Georg Jaeschke
Heather Jennifer JOHNSTON
Stefanie Katharina MESCH
Angélique PATINY-ADAM
Jonathan Martin SHANNON
Christian Schnider
Sandra Steiner
Andreas Michael TOSSTORFF
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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Priority to IL310442A priority Critical patent/IL310442A/en
Priority to EP22803219.9A priority patent/EP4419532A1/en
Priority to KR1020247012834A priority patent/KR20240088922A/ko
Priority to JP2024523187A priority patent/JP2024539068A/ja
Priority to CA3228369A priority patent/CA3228369A1/en
Priority to AU2022369332A priority patent/AU2022369332A1/en
Priority to CR20240158A priority patent/CR20240158A/es
Priority to CN202280070404.0A priority patent/CN118119626A/zh
Application filed by F Hoffmann La Roche AG, Hoffmann La Roche Inc filed Critical F Hoffmann La Roche AG
Priority to MX2024004503A priority patent/MX2024004503A/es
Priority to PE2024000806A priority patent/PE20241176A1/es
Publication of WO2023066825A1 publication Critical patent/WO2023066825A1/en
Priority to CONC2024/0004552A priority patent/CO2024004552A2/es
Priority to US18/637,966 priority patent/US20240279237A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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Definitions

  • the present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to compounds that modulate NLRP3 inhibition.
  • the present invention provides novel compounds of formula Ic wherein
  • a 1 is -N- or-CR 10 -;
  • a 2 is -O-, -NH-, -NCH3-, or -S-;
  • R 1 is H, halo, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl or alkylsulfonyl;
  • R 9 is H, alkyl, halo or cyano; or R 1 and R 9 form a 4-to-6-membered cycloalkyl or heterocycle comprising a single O heteroatom;
  • R 2 is H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxyalkyl, or hydroxyalkyl
  • R 3 is H, halo, or alkyl, wherein at least one of R 2 and R 3 is not H;
  • R 8 is H or halo
  • R 10 is selected from H, alkyl, acetyl, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkylalkyl, cyano, halo, haloalkyl, alkoxy, haloalkoxy, and NR’R”, wherein R’ and R’ ’ are independently selected from H and alkyl, or R’ and R” and the N atom to which they are attached form either a 4-to-6 membered N-containing heterocycle optionally substituted with -OH, or a 5-membered lactam ring; n can be 0 or 1;
  • R x is H, alkyl, alkoxyalkyl, or hydroxyalkyl
  • W is selected from a 4-to- 10-membered heterocycle comprising up to 3 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, optionally substituted by 1 or 2 substituents selected from oxo, -OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkyl, hydroxyalkyl, cyano, haloalkyl, alkylester, alkylsulfon, cycloalkyl, heterocycle comprising a single O heteroatom, cycloalkyl substituted with -OH, cycloalkyl-CH2- substituted with -OH, a 6-membered heteroaryl substituted with alkoxy, and a 5-membered heteroaryl with 2 N heteroatoms, a 4-to-6-membered heterocycle-CH2- comprising up to 2 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, optionally substituted by alkyl,
  • the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.
  • NLR NOD-like receptor
  • NLRP3 pyrin domain-containing protein 3
  • NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC then polymerises to form a large aggregate known as an ASC speck. Polymerised ASC in turn interacts with the cysteine protease caspase-1 to form a complex termed the inflammasome. This results in the activation of caspase- 1, which cleaves the precursor forms of the proinflammatory cytokines IL-ip and IL- 18 (termed pro-IL-ip and pro-IL-18 respectively) to thereby activate these cytokines.
  • ASC caspase activation and recruitment domain
  • Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis.
  • the ASC speck can also recruit and activate caspase-8, which can process pro-IL-ip and pro-IL- 18 and trigger apoptotic cell death.
  • Caspase- 1 cleaves pro-IL-ip and pro-IL-18 to their active forms, which are secreted from the cell. Active caspase- 1 also cleaves gasdermin-D to trigger pyroptosis. Through its control of the pyroptotic cell death pathway, caspase- 1 also mediates the release of alarmin molecules such as IL-33 and high mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2 resulting in its degradation and allowing the release of IL-la. In human cells caspase-1 may also control the processing and secretion of IL-37. A number of other caspase-1 substrates such as components of the cytoskeleton and glycolysis pathway may contribute to caspase- 1- dependent inflammation.
  • NLRP3 -dependent ASC specks are released into the extracellular environment where they can activate caspase-1, induce processing of caspase-1 substrates and propagate inflammation.
  • cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury.
  • IL-ip signalling induces the secretion of the pro-inflammatory cytokines IL-6 and TNF.
  • IL-ip and IL- 18 synergise with IL-23 to induce IL- 17 production by memory CD4 Th 17 cells and by ⁇ T cells in the absence of T cell receptor engagement.
  • IL- 18 and IL-12 also synergise to induce IFN-y production from memory T cells and NK cells driving a Thl response.
  • NLRP3 The inherited CAPS diseases Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal -onset multisystem inflammatory disease (NOMID) are caused by gain-of-function mutations in NLRP3, thus defining NLRP3 as a critical component of the inflammatory process.
  • NLRP3 has also been implicated in the pathogenesis of a number of complex diseases, notably including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout.
  • NLRP3 has also been suggested to have a role in a number of central nervous system conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis (Walsh et al., Nature Reviews, 15: 84-97, 2014, and Dempsey et al. Brain. Behav. Immun. 201761 : 306-316).
  • Parkinson's disease PD
  • AD Alzheimer's disease
  • dementia Huntington's disease
  • cerebral malaria brain injury from pneumococcal meningitis
  • NLRP3 has also been shown to play a role in a number of lung diseases including chronic obstructive pulmonary disorder (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al., Am. J. Pathol., 184: 42-54, 2014 and Kim et al. Am J Respir Crit Care Med. 2017 196(3): 283-97). Furthermore, NLRP3 has a role in the development of liver disease, kidney disease and aging. Many of these associations were defined using Nlrp3 ⁇ 7 ⁇ mice, but there have also been insights into the specific activation of NLRP3 in these diseases. In type 2 diabetes mellitus (T2D), the deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-ip signalling, resulting in cell death and inflammation.
  • COPD chronic obstructive pulmonary disorder
  • asthma including steroid-resistant asthma
  • asbestosis asbestosis
  • Glyburide inhibits IL-ip production at micromolar concentrations in response to the activation of NLRP3 but not NLRC4 or NLRP1.
  • Other previously characterised weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-P-nitrostyrene and dimethyl sulfoxide (DMSO), although these agents have limited potency and are nonspecific.
  • NLRP3-related diseases include biologic agents that target IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-ip antibody canakinumab and the soluble decoy IL-1 receptor rilonacept. These approaches have proven successful in the treatment of CAPS, and these biologic agents have been used in clinical trials for other IL-ip-associated diseases.
  • the present invention provides novel compounds of formula Ic wherein
  • a 1 is -N- or-CR 10 -;
  • a 2 is -O-, -NH-, -NCH3-, or -S-;
  • R 1 is H, halo, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl or alkylsulfonyl;
  • R 9 is H, alkyl, halo or cyano; or R 1 and R 9 form a 4-to-6-membered cycloalkyl or heterocycle comprising a single O heteroatom;
  • R 2 is H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxyalkyl, or hydroxyalkyl, and
  • R 3 is H, halo, or alkyl, wherein at least one of R 2 and R 3 is not H;
  • R 8 is H or halo
  • R 10 is selected from H, alkyl, acetyl, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkylalkyl, cyano, halo, haloalkyl, alkoxy, haloalkoxy, and NR’R”, wherein R’ and R’ ’ are independently selected from H and alkyl, or R’ and R” and the N atom to which they are attached form either a 4-to-6 membered N-containing heterocycle optionally substituted with -OH, or a 5-membered lactam ring; n can be 0 or 1;
  • R x is H, alkyl, alkoxyalkyl, or hydroxyalkyl
  • W is selected from a 4-to- 10-membered heterocycle comprising up to 3 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, optionally substituted by 1 or 2 substituents selected from oxo, -OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkyl, hydroxyalkyl, cyano, haloalkyl, alkylester, alkylsulfon, cycloalkyl, heterocycle comprising a single O heteroatom, cycloalkyl substituted with -OH, cycloalkyl-CH2- substituted with -OH, a 6-membered heteroaryl substituted with alkoxy, and a 5-membered heteroaryl with 2 N heteroatoms, a 4-to-6-membered heterocycle-CH2- comprising up to 2 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, optionally substituted by alkyl,
  • alkyl denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms. In some embodiments, if not otherwise described, alkyl comprises 1 to 6 carbon atoms (Ci-6-alkyl), or 1 to 4 carbon atoms (Ci-4-alkyl).
  • Ci-6-alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl.
  • Particular alkyl groups include methyl and ethyl.
  • alkoxy denotes a group of the formula -O-R’, wherein R’ is a Ci-6-alkyl group.
  • Ci-6-alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.
  • Particular alkoxy groups include methoxy and ethoxy.
  • alkoxyalkyl denotes an alkyl group wherein one of the hydrogen atoms of the alkyl group have been replaced by an alkoxy group. Particular examples of alkoxyalkyl are methoxymethyl and meth oxy ethyl.
  • amino denotes an -NH2 group.
  • alkylamino denotes an amino group wherein one of the hydrogen atoms of the amino group have been replaced by an alkyl group. Particular example is methylamino.
  • alkylaminoalkyl denotes an aminoalkyl group wherein one of the hydrogen atoms of the amino group has been replaced by an alkyl group.
  • alkylaminoalkyl groups include methyl aminomethyl and methylaminoethyl.
  • dialkylamino denotes an amino group wherein two of the hydrogen atoms of the amino group have been replaced by two alkyl groups. Particular example is dimethylamino.
  • dialkylaminoalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a dialkylamino group.
  • dialkylaminoalkyl examples include (dimethylamino)methyl and (dimethyl amino)ethyl. Particular example is (dimethylamino)methyl.
  • aminoalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an amino group.
  • aminoalkyl include aminomethyl and aminoethyl.
  • esters denotes a carboxyl group bridging two moieties linked at carbon atoms. Examples include methoxycarbonyl.
  • alkylester denotes an ester group wherein one of the hydrogen atoms of the ester group have been replaced by an alkyl group. Particular examples are 2-methoxy-2-oxo- ethyl and 3 -methoxy-3 -oxo-propyl.
  • sulfonyl denotes an -S(O)2- group.
  • alkyl sulfonyl denotes a group of the formula -S(O)2-R’, wherein R’ is an alkyl group.
  • alkylsulfonyl groups include groups of the formula -S(O)2-R’, wherein R’ is methyl.
  • cycloalkyl denotes monocyclic or polycyclic saturated or partially unsaturated, non-aromatic hydrocarbon. In some embodiments, unless otherwise described, cycloalkyl comprises 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, spiro[3.3]heptanyl, and the like. Particular examples include cyclobutyl, cyclopentyl, and cyclohexyl. Other particular examples include cyclopropyl and cyclohexyl.
  • halogen halide and halo are used interchangeably herein and denote fluoro, chloro, bromo or iodo. Particular halogens are fluoro and chloro.
  • haloalkyl denotes a Ci-6-alkyl group wherein at least one of the hydrogen atoms of the Ci-6-alkyl group has been replaced by the same or different halogen atoms.
  • Example of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl. Particular examples are difluorom ethyl, difluoropropyl and trifluoromethyl.
  • haloalkoxy denotes a Ci-6-alkoxy group wherein at least one of the hydrogen atoms of the Ci-6-alkoxy group has been replaced by the same or different halogen atoms. Examples of haloalkoxy are difluoromethoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy. Paricular examples are difluoromethoxy and trifluoromethoxy.
  • heteroaryl denotes a monovalent aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
  • heteroaryl group examples include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinoliny
  • heterocycle ring or “heterocycle” denotes a monovalent saturated or partly unsaturated mono- or bicycle ring system of 4 to 10 ring atoms, or 4 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
  • Examples for monocyclic saturated heterocycle rings are azetidinyl, diazepanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and piperazinyl.
  • polycyclic saturated heterocycle rings are azaspiroheptanyl, diazaspiroheptanyl, azaspirooctanyl, diazospirooctanyl, diazaspirononanyl, oxaazaspirooctanyl, and oxadiazaspirononanyl.
  • Particular examples of 4-member heterocycle rings are azetidinyl and oxetanyl.
  • 5-member heterocycle rings are pyrrolidinyl, tetrahydrofuranyl, and pyrrolidinyl.
  • 6-member heterocycle rings are piperidyl, morpholinyl, tetrahydropyranyl, and piperazinyl.
  • a particular example of a 7-member heterocycle ring is azepanyl.
  • Particular examples of 8-member heterocycle rings are azabicyclo[2.2.2]octan-4-yl and Hexahydrofuro[3,4-c]pyrrol-5-yl.
  • Particular examples of 9-member heterocycle rings are octahydroindolizinyl, octahydropyrrolo[2,3-c]pyridin-l-yl, diazaspirononan7-yl, and hexahydro- 2H-pyrrolo[3,4-b][l,4]oxazin-4-yl.
  • 10-member heterocycle rings are octahydro-1, 7-naphthyridin-l-yl and hexahydro-2H-pyrido[4,3-b][l,4]oxazin-4-yl.
  • hydroxy denotes a -OH group.
  • hydroxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group.
  • examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylethyl, hydroxymethylpropyl and dihydroxypropyl. Particular examples are hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxymethyl ethyl.
  • lactam ring denotes a cyclic amide. Particular example is 2-oxopyrrolidin-l-yl.
  • pyrrolidinylalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a pyrrolidinyl group.
  • Example of pyrrolidinylalkyl is pyrrolidinylmethyl.
  • salts refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
  • the salts are formed with inorganic acids such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein.
  • salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts.
  • Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins.
  • the compound of formula I can also be present in the form of zwitterions.
  • Particularly preferred pharmaceutically acceptable salts of compounds of formula I are the salts formed with formic acid and the salts formed with hydrochloric acid yielding a hydrochloride, dihydrochloride or trihydrochloride salt.
  • uM means microMolar and is equivalent to the symbol pM.
  • the abbreviation uL means microliter and is equivalent to the symbol ⁇ L.
  • the abbreviation ug means microgram and is equivalent to the symbol pg.
  • the compounds of formula Ic can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the asymmetric carbon atom can be of the "R” or "S” configuration.
  • an embodiment of the present invention provides compounds according to formula Ic as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula Ic as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula Ic as described herein.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein A 2 is -O- or -NH-.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein A 2 is -O-.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein
  • R 1 is H, halo, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl or alkylsulfonyl;
  • R 9 is H, alkyl, halo or cyano; or R 1 and R 9 form a 5-membered heterocycle comprising a single O heteroatom.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein
  • R 1 is halo, alkyl, haloalkyl, or cyano
  • R 9 is H; or R 1 and R 9 form a 5-membered heterocycle comprising a single O heteroatom.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein R 1 is halo or cyano and R 9 is H.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein R 2 is alkyl or alkoxyalkyl and R 3 is H.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein R 8 is H.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein R 10 is selected from H, alkyl, acetyl, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkylalkyl, cyano, alkoxy, and NR’R”, wherein R’ and R” and the N atom to which they are attached form either a 4-to-5-membered N-containing heterocycle optionally substituted with -OH, or a 5-membered lactam ring.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein R 10 is selected from H, cyano, and alkoxy.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein R 10 is H.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein R x is H, alkoxyalkyl, or hydroxyalkyl.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein R x is H.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein W is selected from a 4-to- 10-membered heterocycle comprising up to 3 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, optionally substituted by 1 or 2 substituents selected from oxo, -OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkyl, hydroxyalkyl, haloalkyl, a 4- membered cycloalkyl, a 4-membered heterocycle comprising 1 O heteroatom, a 4- membered cycloalkyl substituted with -OH, and a 4-membered cycloalkyl-CH2- substituted with -OH, a 4-to-6-membered heterocycle-CH2- comprising up to 2 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, optionally substituted by alkyl, a 3-to-6-member
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein W is selected from a 6-to-9-membered heterocycle comprising up to 3 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, optionally substituted by 1 or 2 substituents selected from oxo, -OH, halo, alkyl and hydroxyalkyl, a 6-membered heterocycle-CH2- comprising a single N heteroatom, substituted by alkyl, and a 5-membered cycloalkyl substituted with dialkylamino.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein W is a 6-membered heterocycle comprising a single N heteroatom, optionally substituted by either alkyl or oxo, or both alkyl and -OH;
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein
  • a 1 is -N- or-CR 10 -;
  • a 2 is -O- or -NH-;
  • R 1 is H, halo, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl or alkyl sulfonyl, •
  • R 9 is H, alkyl, halo or cyano; or R 1 and R 9 form a 5-membered heterocycle comprising a single O heteroatom;
  • R 2 is H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxyalkyl, or hydroxyalkyl
  • R 3 is H, halo, or alkyl, wherein at least one of R 2 and R 3 is not H;
  • R 8 is H or halo
  • R 10 is selected from H, alkyl, acetylalkylamino, dialkylamino, hydroxyalkyl, hydroxyalkylalkyl, cyano, alkoxy, and NR’R”, wherein R’ and R” and the N atom to which they are attached form either a 4-to-5-membered N-containing heterocycle optionally substituted with -OH, or a 5-membered lactam ring; n can be 0 or 1;
  • R x is H, alkoxyalkyl, or hydroxyalkyl
  • W is selected from a 4-to- 10-membered heterocycle comprising up to 3 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, optionally substituted by 1 or 2 substituents selected from oxo, -OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkyl, hydroxyalkyl, haloalkyl, a 4-membered cycloalkyl, a 4-membered heterocycle comprising a single O heteroatom, a 4-membered cycloalkyl substituted with -OH, and a 4-membered cycloalkyl-CH2- substituted with -OH, a 4-to-6-membered heterocycle-CH2- comprising up to 2 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, optionally substituted by alkyl, a 3-to-6-membered cycloalkyl optionally substituted with -OH, al
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein
  • a 1 is -N- or-CR 10 -;
  • a 2 is -O-
  • R 1 is halo, alkyl, haloalkyl, or cyano
  • R 9 is H; or R 1 and R 9 form a 5-membered heterocycle comprising a single O heteroatom;
  • R 2 is alkyl or alkoxyalkyl and R 3 is H;
  • R 8 is H
  • R 10 is selected from H, cyano and alkoxy; n can be 0 or 1;
  • R x is H
  • W is selected from a 6-to-9-membered heterocycle comprising up to 3 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, optionally substituted by 1 or 2 substituents selected from oxo, -OH, halo, alkyl and hydroxyalkyl, a 6-membered heterocycle-CH2- comprising a single N heteroatom, substituted by alkyl, and a 5-membered cycloalkyl substituted with dialkylamino; and pharmaceutically acceptable salts.
  • An embodiment of the present invention provides compounds according to formula Ic as described herein, wherein
  • a 1 is -N- or-CR 10 -;
  • a 2 is -O-
  • R 1 is halo or cyano
  • R 9 is H
  • R 2 is alkyl or alkoxyalkyl and R 3 is H;
  • R 8 is H
  • R 10 is H; n can be 0 or 1;
  • R x is H
  • W is a 6-membered heterocycle comprising a single N heteroatom, optionally substituted by either alkyl or oxo, or both alkyl and -OH; and pharmaceutically acceptable salts.
  • An embodiment of the present invention provides compounds according to formula lb, wherein the compound of formula lb is a compound of formula Ic lb.
  • the compounds of formula lb can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • an embodiment of the present invention provides compounds according to formula lb as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula lb as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula lb as described herein.
  • An embodiment of the present invention provides compounds according to formula lb as described herein, wherein
  • a 1 is -N- or-CR 10 -;
  • a 2 is -O-, -NH-, -NCH3-, or -S-;
  • R 1 is H, halogen, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, or cycloalkyl;
  • R 9 is H or halogen; or R 1 and R 9 form a 4 to 6 membered cycloalkyl or heterocycloalkyl ring comprising a single O heteroatom;
  • R 2 is H, halogen, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, or alkoxyalkyl
  • R 3 is H, halogen, or alkyl, wherein at least one of R 2 and R 3 is not H;
  • R 8 is H or halo
  • R 10 is selected from i. H, ii. alkyl, iii. hydroxyalkyl, iv. cyano, v. halogen v. haloalkyl, vi. alkoxy, vii. haloalkoxy, viii. a 5-6 membered heterocycle comprising 1 or 2 N atoms optionally substituted with either halo or methyl, or ix.
  • NR’R wherein R’ and R” are independently selected from H or alkyl, or R’ and R’ ’ and the N atom to which they are attached form either a 4-6 membered N-containing heterocycle ring or a 5-membered lactam ring; n can be 0 or 1;
  • W is a heterocycloalkyl optionally substituted with 1 to 2 substituents independently selected from: oxo, -OH, alkyl, alkylamino, alkylaminoalkyl, amino, aminoalkyl, cyano, cycloalkyl, or cycloalkyl substituted with amino, halogen, dialkylamino, dialkylaminoalkyl, ester, haloalkyl, hydroxyalkyl, sulfonyl or pyrrolidinylalkyl, or
  • W is a 3-to-6-membered cycloalkyl optionally substituted with 1 to 2 substituents independently selected from -OH, alkyl, alkylamino, amino, dialkylamino, halogen, haloalkyl and tert-Butyl N-methylcarbamate; and pharmaceutically acceptable salts.
  • An embodiment of the present invention provides compounds according to formula lb as described herein, wherein
  • a 1 is -N- or -CR 10 -;
  • a 2 is -O-, or -NH
  • R 1 is halogen, haloalkyl, cyano, alkoxy or cycloalkyl
  • R 9 is H or halogen; or R 1 and R 9 form a 5-membered heterocycle ring comprising a single O heteroatom;
  • R 2 is H, alkyl, cyano, haloalkyl, alkoxy, or alkoxyalkyl
  • R 3 is H, or alkyl, wherein at least one of R 2 and R 3 is not H;
  • R 8 is H
  • R 10 is selected from H or methyl; n can be 0 or 1;
  • W is selected from ring systems:
  • B 2 is -CHR 4 - or -NCH 3 ;
  • B 3 is -CHR 5 -, -O-, or -NR 6 -
  • B 5 is -CH-;
  • B 6 is -NH-;
  • B 7 is -CH 2 -;
  • B 8 is -N-
  • B 9 is -CH 2 -;
  • B 10 is -CHR 7 -;
  • R 4 is H or dialkylaminoalkyl
  • R 5 is H, -OH, alkylamino, or hydroxyalkyl
  • R 6 is H or alkyl
  • R 7 is -OH; wherein W can only have a maximum of 2 heteroatoms and 2 non-hydrogen substituents; wherein if W is ring system (C), ring system (E), or B 1 is -N-, then n is 0; and pharmaceutical acceptable salts.
  • An embodiment of the present invention provides compounds according to formula lb as described herein, wherein
  • a 1 is -N- or -CR 10 -;
  • a 2 is -O-, or -NH
  • R 1 is halogen, haloalkyl, cyano, or alkoxy
  • R 9 is H or halogen; or R 1 and R 9 form a 5-membered heterocycle ring comprising a single O heteroatom;
  • R 2 is H, alkyl, cyano, haloalkyl, or alkoxyalkyl, and R 3 is H, or alkyl, wherein at least one of R 2 and R 3 is not H; R 8 is H;
  • R 10 is selected from H or methyl; n can be 0 or 1;
  • W is selected from ring systems: wherein,
  • B 1 is -CH-
  • B 2 is -CHR 4 -;
  • B 3 is-NR 6 -
  • R 4 is H
  • R 6 is H or alkyl; wherein W can only have a maximum of 2 heteroatoms and 2 non-hydrogen substituents; wherein if W is ring system (E) then n is 0; and pharmaceutical acceptable salts.
  • An embodiment of the present invention provides compounds according to formula lb as described herein, wherein
  • a 1 is -N- or -CR 10 -;
  • a 2 is -O-
  • R 1 is halogen, haloalkyl, cyano, or alkoxy
  • R 9 is H or halogen
  • R 2 is alkyl, cyano, or alkoxyalkyl, and R 3 is H;
  • R 8 is H
  • R 10 is H; n can be 0 or 1;
  • W is selected from ring systems: wherein,
  • B 1 is -CH-
  • B 2 is -CHR 4 -;
  • B 3 is-NR 6 -
  • R 4 is H;
  • R 6 is H or alkyl; wherein W can only have a maximum of 2 heteroatoms and 2 non-hydrogen substituents; wherein if W is ring system (E) then n is 0; and pharmaceutical acceptable salts.
  • An embodiment of the present invention provides compounds according to formula lb as described herein, wherein
  • a 1 is -N- or -CR 10 -;
  • a 2 is -O-
  • R 1 is halogen, haloalkyl, or cyano
  • R 9 is H
  • R 2 is alkyl and R 3 is H;
  • R 8 is H
  • R 10 is H; n can be 0 or 1;
  • W is selected from ring systems: wherein, B 1 is -CH-;
  • B 2 is -CHR 4 -;
  • B 3 is-NR 6 -
  • B 4 is -CH 2 -;
  • R 4 is H
  • R 6 is alkyl; wherein W can only have a maximum of 2 heteroatoms and 2 non-hydrogen substituents; wherein if W is ring system (E) then n is 0; and pharmaceutical acceptable salts.
  • An embodiment of the present invention provides compounds according to formula lb as described herein, wherein
  • a 1 is -CR 10 -;
  • a 2 is -O-
  • R 1 is halogen or cyano
  • R 9 is H
  • R 2 is alkyl and R 3 is H;
  • R 8 is H
  • R 10 is H; n can be 0 or 1;
  • W is selected from ring systems: wherein,
  • B 2 is -CHR 4 -;
  • B 3 is-NR 6 -
  • B 4 is -CH 2 -;
  • R 4 is H
  • R 6 is alkyl; wherein W can only have a maximum of 2 heteroatoms and 1 non-hydrogen substituents; wherein if W is ring system (E) then n is 0; and pharmaceutical acceptable salts.
  • An embodiment of the present invention provides compounds according to formula I, wherein the compound of formula l is a compound of formula lb
  • the compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • an embodiment of the present invention provides compounds according to formula I as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula I as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula I as described herein.
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein
  • a 1 is -N- or -CH-;
  • a 2 is -O-, -NH-, -NCH3-, or -S-;
  • R 1 is halogen, alkyl, haloalkyl, or haloalkoxy
  • R 2 is H, halogen, or alkyl and R 3 is H, halogen, or alkyl, wherein at least one of R 2 and R 3 is not H; n can be 0 or 1;
  • W is a heterocycle ring optionally substituted with 1 to 2 substituents independently selected from: oxo, -OH, alkyl, alkylamino, alkylaminoalkyl, amino, aminoalkyl, cycloalkyl, cycloalkyl substituted with halogen, dialkylamino, dialkylaminoalkyl, haloalkyl, hydroxyalkyl, and pyrrolidinylalkyl, or
  • W is a 4-to-6-membered cycloalkyl optionally substituted with 1 to 2 substituents independently selected from -OH, alkyl, alkylamino, amino, dialkylamino, halogen, haloalkyl and tert-Butyl N-methylcarbamate; and pharmaceutically acceptable salts.
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein A 1 is -N- or -CH-;
  • a 2 is -O-, -NH-, -NCH3-, or -S-;
  • R 1 is halogen, alkyl, haloalkyl, or haloalkoxy
  • R 2 is H, halogen, or alkyl and R 3 is H, halogen, or alkyl, wherein at least one of R 2 and R 3 is not H; n can be 0 or 1;
  • B 2 is -CHR 4 - or -NCH 3 ;
  • B 3 is -CHR 5 -, -O-, or -NR 6 -
  • B 5 is -CH-
  • B 6 is -NH-
  • B 7 is -CH2-
  • B 8 is -N-
  • B 9 is -CH2-
  • B 10 is -CHR 7 -;
  • R 4 is H, dialkylaminoalkyl or hydroxyalkyl
  • R 5 is H, -OH, alkylamino, dialkylaminoalkyl or hydroxyalkyl;
  • R 6 is H or alkyl;
  • R 7 is -OH; wherein W can only have a maximum of 2 heteroatoms and 2 non-hydrogen substituents; wherein if W is ring system C or B 1 is -N-, then n is 0; and pharmaceutical acceptable salts.
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein
  • a 1 is -CH-
  • a 2 is -O-, or -NH-;
  • R 1 is haloalkyl or halogen
  • R 2 is alkyl and R 3 is H; n can be 0 or 1;
  • B 2 is -CHR 4 - or -NCH 3 ;
  • B 3 is -CHR 5 -, -O-, or -NR 6 -
  • B 5 is -CH-;
  • B 6 is -NH-
  • B 7 is -CH 2 -;
  • B 8 is -N-
  • B 9 is -CH 2 -;
  • B 10 is -CHR 7 -;
  • R 4 is H, or dialkylaminoalkyl
  • R 5 is H, -OH, alkylamino, or hydroxyalkyl
  • R 6 is H or alkyl
  • R 7 is -OH; wherein W can only have a maximum of 2 heteroatoms and 2 non-hydrogen substituents; wherein if W is ring system C or B 1 is -N-, then n is 0; and pharmaceutical acceptable salts.
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein
  • a 1 is -CH-
  • a 2 is -O-, or -NH-;
  • R 1 is haloalkyl or halogen
  • R 2 is alkyl and R 3 is H; n can be 0 or 1; W is ring system , or
  • B 2 is -CHR 4 -;
  • B 3 is -CHR 5 -, or -NR 6 -
  • B 5 is -CH-
  • B 6 is -NH-
  • B 7 is -CH2-
  • B 8 is -N-
  • B 9 is -CH2-
  • B 10 is -CHR 7 -;
  • R 4 is H, or dialkylaminoalkyl
  • R 5 is H, -OH, alkylamino, or hydroxyalkyl
  • R 6 is H or alkyl
  • R 7 is -OH; wherein W can only have a maximum of 2 heteroatoms and 1 non-hydrogen substituents; wherein if W is ring system C or B 1 is -N-, then n is 0; and pharmaceutical acceptable salts.
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein
  • a 1 is -CH-
  • a 2 is -O-, or -NH-;
  • R 1 is haloalkyl
  • R 2 is alkyl and R 3 is H; n can be 0 or 1;
  • B 2 is -CHR 4 -;
  • B 3 is -CHR 5 -, or -NR 6 -
  • B 5 is -CH-
  • B 6 is -NH-
  • B 7 is -CH 2 -;
  • B 8 is -N-
  • B 9 is -CH 2 -;
  • B 10 is -CHR 7 -;
  • R 4 is H, or dialkylaminoalkyl;
  • R 5 is H, -OH, alkylamino, or hydroxyalkyl
  • R 6 is H or alkyl
  • R 7 is -OH; wherein W can only have a maximum of 2 heteroatoms and 1 non-hydrogen substituents; wherein if W is ring system C or B 1 is -N-, then n is 0; and pharmaceutical acceptable salts.
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein
  • a 1 is -CH-
  • a 2 is -O-, or -NH-;
  • R 1 is haloalkyl
  • R 2 is alkyl and R 3 is H; n can be 0 or 1;
  • W is ring system (A) , or (B)
  • B 2 is -CHR 4 -;
  • B 3 is -CHR 5 -, or -NR 6 -
  • B 5 is -CH-;
  • B 6 is -NH-;
  • B 7 is -CH2-
  • R 4 is H, or dialkylaminoalkyl
  • R 5 is H, -OH, alkylamino, or hydroxyalkyl
  • R 6 is H or alkyl; wherein W can only have a maximum of 2 heteroatoms and 1 non-hydrogen substituents; wherein if B 1 is -N-, then n is 0; and pharmaceutical acceptable salts.
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein
  • a 1 is -CH-
  • a 2 is -O-, or -NH-;
  • R 1 is haloalkyl
  • R 2 is alkyl and R 3 is H; n can be 0 or 1;
  • B 2 is -CHR 4 -;
  • B 3 is -CHR 5 -, or -NR 6
  • B 4 is -O-, or -CH2-;
  • R 4 is H, or dialkylaminoalkyl;
  • R 5 is H
  • R 6 is alkyl; wherein W can only have a maximum of 2 heteroatoms and 1 non-hydrogen substituents; wherein if B 1 is -N-, then n is 0; and pharmaceutical acceptable salts.
  • An embodiment of the present invention provides compounds according to formula I as described herein, wherein
  • a 1 is -CH-
  • a 2 is -O-
  • R 1 is haloalkyl
  • R 2 is alkyl and R 3 is H; n is 1;
  • B 1 is-CH-
  • B 2 is -CHR 4 -;
  • B 3 is -NR 6 -
  • B 4 is -CH2-
  • R 4 is H; R 6 is alkyl; and pharmaceutical acceptable salts.
  • Preferred examples of compounds of formula Ic as described herein are selected from 2-[2-[[(8R,8aS)-l,2,3,5,6,7,8,8a-Octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5- yl]-5-chloro-3-methyl -phenol or 2-[2-[[(8S,8aR)-l,2,3,5,6,7,8,8a-Octahydroindolizin-8- yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol;
  • More preferred examples of compounds of formula Ic as described herein are selected from 5-Chloro-2-[2-[[(3R)-l-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl- phenol;
  • More preferred examples of compounds of formula I as described herein are selected from 2-[2-[(3S or 3R)-3-[(Dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]- 3-methyl-5-(trifluoromethyl)phenol;
  • the compounds of formula Ic of the present invention may be prepared in accordance with the process variants described below and with the following schemes 1, la, lb, 2, 3, 3a, 3b and 4.
  • the order of transformations as described can be modified in various orders. These transformations can include e.g. the protect! on/cleavage of protecting groups, Pd-catalyzed couplings, reductive aminations and/or nucleophilic substitutions.
  • the starting materials are commercially available or may be prepared in accordance with methods known in the public domain.
  • the commercially available building blocks of formula II wherein X is a halogen atom such as bromine, chlorine or iodine more preferably chlorine or bromine can be submitted to a cyclisation commonly using l,l'-Carbonyldiimidazole(CDI) or similar reagents as l,l'-thiocarbonyl diimidazole or carbon disulfide followed by the addition of methyl iodide in the presence of an conventional inorganic base (such as potassium carbonate) or via reaction with a chlorinating agent such as POCI3 to prepare compounds of general formula III or IV, respectively. These then can be subjected to a nucleophilic aromatic substitution in order to prepare compounds of formula V.
  • CDI l,l'-Carbonyldiimidazole
  • similar reagents as l,l'-thiocarbonyl diimidazole or carbon disulfide
  • methyl iodide in the presence of an conventional inorganic base (such as potassium
  • the nucleophilic aromatic substitution are carried out with a suitable amine, e.g NR X -W, but not limited to, wherein W and R x have the meaning given in the claims of this current invention, with n being either 1 or 0, in the presence of organic bases as N, V-dii sopropyl ethylamine (DIEA) or trimethylamine which are common and known to the skilled person and/or commercially available.
  • a suitable amine e.g NR X -W, but not limited to, wherein W and R x have the meaning given in the claims of this current invention, with n being either 1 or 0, in the presence of organic bases as N, V-dii sopropyl ethylamine (DIEA) or trimethylamine which are common and known to the skilled person and/or commercially available.
  • DIEA V-dii sopropyl ethylamine
  • NMP A-methyl-2-pyrrolidine
  • the reaction can be also done under microwave irradiation.
  • the left-hand side is added to the compound of general formula V to form the compound of formula VI using palladium catalyzed type reactions such as Suzuki cross coupling in the presence of a palladium catalyst and a boronic acid or boronic pinacol ester according to standard conditions well known to the skilled person, leading to final compounds of general formula Ic (depending of the substitution of the boronic acid or ester).
  • a methyl ether-protecting group in a final step, this is usually cleaved with boron tribromide (BBn) in di chloromethane delivering the compounds of general formula Ic.
  • BBn boron tribromide
  • R’ can be OH or -C(CH3)2-and R is a protecting group known to the skilled person such as Me, SEM, benzyl or any other suitable protecting group for phenols (for examples, see in Protective Groups in organic Synthesis, T.W. Greene and P.GM)
  • the isocyanates as describe can be prepared by reacting a primary amine of general formula as depicted in scheme 3b with thiophosgene under ice cooling.
  • Suitable solvents for the reaction are e g. DCM or DCE.
  • nitration was conducted in the presence of strong acids as eg. fuming nitric acid, known to the person skilled of the art, with X being iodine or bromine, preferably iodine.
  • strong acids as eg. fuming nitric acid, known to the person skilled of the art, with X being iodine or bromine, preferably iodine.
  • Reduction using tin(II)chloride or iron(III)chloride in e.g methanol afforded aniline XX.
  • Subsequent cyclisation was achieved by addition of TCDI and heating.
  • Key intermediate XXII was obtained after reaction with a chlorinating agent such as oxalyl chloride or POC13 in, e.g. DMF at elevated temperatures.
  • the compound was subjected to nucleophilic aromatic substitution, using a suitable amine NH-W or W containing a secondary amine or NR X - W, wherein W and R x have the meaning given for general formula Ic in the presence of organic bases as N, V-di isopropyl ethylamine (DIEA) or trimethylamine which are common and known to the skilled person and/or commercially available.
  • DIEA V-di isopropyl ethylamine
  • 1,4-di oxane as solvent was used, but solvents such as dimethyl sulfoxide (DMSO) or A-methyl-2 -pyrrolidine (NMP) are also suitable.
  • the compound of formula lb may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8.
  • a compound of formula I is formulated in an acetate buffer, at pH 5.
  • the compound of formula lb is sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
  • compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing
  • the compounds of formula Ic and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical formulations Lactose, com starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.
  • the compounds of formula lb and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical formulations Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.
  • the compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical formulations Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.
  • Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
  • Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
  • Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
  • Suitable adjuvants for topical ocular formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.
  • the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • the formulation can contain 0.001% to 15% by weight of medicament and the required dose, which can be between 0.1 and 25 mg in can be administered either by single dose per day or per week, or by multiple doses (2 to 4) per day, or by multiple doses per week It will, however, be clear that the upper or lower limit given herein can be exceeded when this is shown to be indicated.
  • An embodiment of the present invention is a compound according to formula Ic as described herein for use as a therapeutically active substance.
  • An embodiment of the present invention is a compound according to formula Ic as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.
  • An embodiment of the present invention is a compound according to formula Ic as described herein for the treatment or prophylaxis of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.
  • An embodiment of the present invention is a compound according to formula lb as described herein for use as a therapeutically active substance.
  • An embodiment of the present invention is a compound according to formula lb as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.
  • An embodiment of the present invention is a compound according to formula lb as described herein for the treatment or prophylaxis of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.
  • An embodiment of the present invention is a compound according to formula I as described herein for use as a therapeutically active substance.
  • An embodiment of the present invention is a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.
  • An embodiment of the present invention is a compound according to formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.
  • NLRP3 inhibition refers to the complete or partial reduction in the level of activity of NLRP3 and includes, for example, the inhibition of active NLRP3 and/or the inhibition of activation of NLRP3.
  • NLRP3 -induced IL-1 and IL- 18 There is evidence for a role of NLRP3 -induced IL-1 and IL- 18 in the inflammatory responses occurring in connection with, or as a result of, a multitude of different disorders (Menu et al., Clinical and Experimental Immunology, 166: 1-15, 2011; Strowig et al., Nature, 481 : 278- 286, 2012).
  • the disease, disorder or condition is selected from:
  • the disease, disorder or condition is selected from:
  • the disease, disorder or condition is inflammation.
  • inflammation examples include inflammatory responses occurring in connection with, or as a result of:
  • a skin condition such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopical dermatitis, contact dermatitis, allergic contact dermatitis, seborrhoetic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythemas, or alopecia;
  • a joint condition such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still’s disease, relapsing polychondritis, rheumatoid arthritisjuvenile chronic arthritis, gout, or a seronegative spondyloarthropathy (e.g. ankylosing spondylitis, psoriatic arthritis or Reiter’s disease);
  • a muscular condition such as polymyositis or myasthenia gravis
  • a gastrointestinal tract condition such as inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), colitis, gastric ulcer, Coeliac disease, proctitis, pancreatitis, eosinopilic gastro-enteritis, mastocytosis, antiphospholipid syndrome, or a food-related allergy which may have effects remote from the gut (e.g., migraine, rhinitis or eczema);
  • a respiratory system condition such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust asthma, and particularly chronic or inveterate asthma, such as late asthma and airways hyper-responsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, rhinitis caseosa, hypertrophic rhinitis, rhinitis pumlenta, rhinitis sicca, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis e.g.
  • COPD chronic obstructive pulmonary disease
  • asthma including eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust asthma, and particularly chronic or inveterate asthma, such as late asthma and airways hyper-responsiveness
  • bronchitis
  • hay fever, and vasomotor rhinitis sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer’s lung, silicosis, asbestosis, volcanic ash induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia;
  • IPF idiopathic pulmonary fibrosis
  • sarcoidosis farmer’s lung, silicosis, asbestosis, volcanic ash induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia
  • vascular condition such as atherosclerosis, Behcet’s disease, vasculitides, or Wegener’s granulomatosis;
  • an autoimmune condition such as systemic lupus erythematosus, Sjogren’s syndrome, systemic sclerosis, Hashimoto’s thyroiditis, type I diabetes, idiopathic thrombocytopenia purpura, or Graves disease;
  • an ocular condition such as uveitis, allergic conjunctivitis, or vernal conjunctivitis;
  • a nervous condition such as multiple sclerosis or encephalomyelitis
  • x an infection or infection-related condition, such as Acquired Immunodeficiency Syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, mycobacterium tuberculosis (including mycobacterium tuberculosis and HIV co-infection), mycobacterium avium intracellulare, pneumocystis carinii pneumonia, orchitis/epidydimitis, legionella, Lyme disease, influenza A, Epstein-Barr virus infection, viral encephalitis/aseptic meningitis, or pelvic inflammatory disease;
  • AIDS Acquired Immunodeficiency Syndrome
  • acute or chronic bacterial infection such as acute or
  • a renal condition such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerular nephritis, obesity related glomerulopathy, acute renal failure, acute kidney injury, uremia, nephritic syndrome, kidney fibrosis including chronic crystal nephropathy, or renal hypertension;
  • xiii a condition of, or involving, the immune system, such as hyper IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft versus host disease;
  • a hepatic condition such as chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, liver fibrosis, or liver failure;
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • AFLD alcoholic fatty liver disease
  • ASH alcoholic steatohepatitis
  • primary biliary cirrhosis fulminant hepatitis
  • liver fibrosis or liver failure
  • a metabolic disease such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudo-gout; and/or
  • (xix) pain such as inflammatory hyperalgesia, pelvic pain, allodynia, neuropathic pain, or cancer-induced bone pain.
  • An embodiment of the present invention is a compound according to formula Ic as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from:
  • An embodiment of the present invention is the use of a compound according to formula Ic as described herein in the treatment or prophylaxis of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.
  • An embodiment of the present invention is the use of a compound according to formula Ic as described herein in the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.
  • An embodiment of the present invention is the use a compound according to formula Ic as described herein for use in the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  • An embodiment of the present invention is the use a compound according to formula Ic as described herein for use in the treatment or prophylaxis of a disease, disorder or condition selected from inflammatory bowel disease (including Crohn’s disease and ulcerative colitis).
  • An embodiment of the present invention is a compound according to formula Ic as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.
  • An embodiment of the present invention is a compound according to formula Ic as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  • An embodiment of the present invention is a compound according to formula Ic as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from inflammatory bowel disease (including Crohn’s disease and ulcerative colitis).
  • An embodiment of the present invention is the use of a compound according to formula Ic as described herein for preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.
  • An embodiment of the present invention is the use of a compound according to formula Ic as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  • An embodiment of the present invention is the use of a compound according to formula Ic as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from inflammatory bowel disease (including Crohn’s disease and ulcerative colitis).
  • An embodiment of the present invention is a method of treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease, which method comprises administering an effective amount of a compound according to formula Ic as described herein.
  • An embodiment of the present invention is a method of treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD, which method comprises administering an effective amount of a compound according to formula Ic as described herein.
  • An embodiment of the present invention is a method of treatment or prophylaxis of a disease, disorder or condition selected from inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), which method comprises administering an effective amount of a compound according to formula Ic as described herein.
  • An embodiment of the present invention relates to a method of inhibiting NLRP3, which method comprises administering an effective amount of a compound according to formula Ic as described herein.
  • An embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to formula Ic as described herein and a therapeutically inert carrier.
  • An embodiment of the present invention is the use of a compound according to formula lb as described herein in the treatment or prophylaxis of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.
  • An embodiment of the present invention is the use of a compound according to formula lb as described herein in the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.
  • An embodiment of the present invention is the use a compound according to formula lb as described herein for use in the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  • An embodiment of the present invention is the use a compound according to formula lb as described herein for use in the treatment or prophylaxis of a disease, disorder or condition selected from inflammatory bowel disease (including Crohn’s disease and ulcerative colitis).
  • An embodiment of the present invention is a compound according to formula lb as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.
  • An embodiment of the present invention is a compound according to formula lb as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  • An embodiment of the present invention is a compound according to formula lb as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from inflammatory bowel disease (including Crohn’s disease and ulcerative colitis).
  • An embodiment of the present invention is the use of a compound according to formula lb as described herein for preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.
  • An embodiment of the present invention is the use of a compound according to formula lb as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  • An embodiment of the present invention is the use of a compound according to formula lb as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from inflammatory bowel disease (including Crohn’s disease and ulcerative colitis).
  • An embodiment of the present invention is a method of treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease, which method comprises administering an effective amount of a compound according to formula lb as described herein.
  • An embodiment of the present invention is a method of treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD, which method comprises administering an effective amount of a compound according to formula lb as described herein.
  • An embodiment of the present invention is a method of treatment or prophylaxis of a disease, disorder or condition selected from inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), which method comprises administering an effective amount of a compound according to formula lb as described herein.
  • An embodiment of the present invention relates to a method of inhibiting NLRP3, which method comprises administering an effective amount of a compound according to formula lb as described herein.
  • an embodiment of the present invention are compounds of formula lb as described herein, when manufactured according to any one of the described processes.
  • An embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to formula lb as described herein and a therapeutically inert carrier.
  • An embodiment of the present invention is the use of a compound according to formula I as described herein in the treatment or prophylaxis of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.
  • An embodiment of the present invention is the use of a compound according to formula I as described herein in the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.
  • An embodiment of the present invention is the use a compound according to formula I as described herein for use in the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  • An embodiment of the present invention is the use a compound according to formula I as described herein for use in the treatment or prophylaxis of a disease, disorder or condition selected from inflammatory bowel disease (including Crohn’s disease and ulcerative colitis).
  • An embodiment of the present invention is a compound according to formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.
  • An embodiment of the present invention is a compound according to formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  • An embodiment of the present invention is a compound according to formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from inflammatory bowel disease (including Crohn’s disease and ulcerative colitis).
  • An embodiment of the present invention is the use of a compound according to formula I as described herein for preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.
  • An embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.
  • An embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from inflammatory bowel disease (including Crohn’s disease and ulcerative colitis).
  • An embodiment of the present invention is a method of treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease, which method comprises administering an effective amount of a compound according to formula I as described herein.
  • An embodiment of the present invention is a method of treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD, which method comprises administering an effective amount of a compound according to formula I as described herein.
  • An embodiment of the present invention is a method of treatment or prophylaxis of a disease, disorder or condition selected from inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), which method comprises administering an effective amount of a compound according to formula I as described herein.
  • An embodiment of the present invention relates to a method of inhibiting NLRP3, which method comprises administering an effective amount of a compound according to formula I as described herein.
  • An embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to formula I as described herein and a therapeutically inert carrier.
  • THP-1 cells (ATCC # TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835) supplemented with ImM sodium pyruvate (Sigma # S8636) and penicillin (lOOunits/ml) / streptomycin (O.lmg/ml) (Sigma # P4333) in 10% Fetal Bovine Serum (FBS) (Sigma # F0804). The cells were routinely passaged and grown to confluency ( ⁇ 10 6 cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended into RPMI medium (without FBS). The cells were then counted and viability (>90%) checked by Trypan blue (Sigma # T8154).
  • IC50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)
  • IL-ip was measured according to the manufacturer protocol (Perkin Elmer- AlphaLisa IL-1 Kit AL220F-5000)
  • the pure enantiomers or diastereomers can be obtained by methods described herein or by methods known to those skilled in the art, such as e.g. chiral chromatography or crystallization.
  • the absolute stereoconfiguration was not determined but attributed based on biological activity (determined e.g. in the THP-assay).
  • NMR spectra were run on Bruker 400 MHz spectrometers using ICON-NMR, under Top Spin program control. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance.
  • Detection wavelength 220 and 254 nm. Before each new run, the cartridge was cleaned using the conditioning method.
  • the mixture was extracted with a suitable organic solvent such as ethyl acetate and the organic phase washed with e.g. half-saturated aq. NH4Cl-solution.
  • a suitable organic solvent such as ethyl acetate
  • the combined organic layers were dried e.g. over sodium sulfate, filtered and concentrated in vacuo and finally purified either via column chromatography or HPLC.
  • Step 1 (mc)-5-Chloro-A-(l -ethyl-3 -piperidyl )oxazolol4,5-Z>1Pyridin-2-amine
  • Step 2 l-Ethyl-3-piperidyl)amino1oxazolor4,5-Z>1Pyridin-5-yl1-3-methyl-5- (trifluoromethyl)phenol
  • Step 1 (rac)-l -[4-(5-Chlorooxazolo[4,5-61pyridin-2-yl )morpholin-3-yl1-A, A-dim ethyl - methanamine
  • Step 2 (rac)-2-12-13-l(Dimethylamino)methyl]morDholin-4-yl]oxazolol4,5-Z>lDyridin-5-yl]-3- methyl-5-(trifluoromethyl)phenol
  • Step 3 2-12-1 or 35)-3-l(Dimethylamino)methyl1morpholin-4-yl1oxazolol4,5-Z>1pyridin-5-yl1-
  • LCMS mlz 437.3 [M+H]+, ESI pos.
  • Step 1 (rac)-l-(5-Chlorooxazolor4,5-Z>1Pyridin-2-yl)piperidin-3-ol
  • Step 2 -Methoxy-6-methyl-4-('trifluoromethyl )phenyl1oxazolol4.5-#1pyridin-2- yllpiperi din-3 -ol
  • Step 3 (rac)-l-15-12-E[ydroxy-6-methyl-4-(trifluoromethyl)phenyl1oxazolor4,5-Z>1pyri din-2- yllpiperi din-3 -ol
  • Step 4 (3R or 3M-l-r5-r2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl1oxazolor4,5-Z>1pyridin-2- yllpiperi din-3 -ol and (3S o l-15-r2-hvdroxy-6-methyl-4- (trifluoromethyl)Dhenyl1oxazolor4,5-blDyridin-2-yllDiDeridin-3-ol
  • Step 1 5-Chloro-2-morpholino-oxazolc>r4,5-Z>1pyridine
  • Step 3 3-Methyl-2-(2-morpholinooxazolor4,5-Z>1Pyridin-5-yl)-5-(trifluoromethyl)phenol
  • Example 4 step 2
  • boron tribromide (1 M solution in dichloromethane) (2.28 g, 0.860 mL, 0.860 mmol, 3.55 eq) dropwise at 0 °C.
  • the reaction mixture was extracted with ethyl acetate and water.
  • the aqueous layer was backextracted with ethyl acetate.
  • the organic layers were washed with water and brine.
  • the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo.
  • the crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 5% methanol in dichloromethane). All fractions containing product were combined and concentrated in vacuo.
  • Step 1 5-r2-Methoxy-6-methyl-4-(trifluoromethyl)phenyl]-2-piperazin-l-yl-oxazolol4,5- Z>]pyridine
  • Step 2 3-Methyl-2-(2-piperazin-l-yloxazolor4,5-Z>1pyridin-5-yl)-5-(trifluoromethyl)phenol; formic acid salt
  • Step 1 tert-butyl 7V-[3-[(5-chlorooxazolo[4,5-61pyridin-2-yl)amino1cvclohexyl1-7V-methyl- carbamate
  • 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine CAS # 1783370-92-2, 88 mg, 0.439 mmol, 1.0 eq
  • 1,4-dioxane (0.90 mL) was added tert-butyl 7V-(3-aminocyclohexyl)-7V- methyl-carbamate (CAS # 1783996-31-5, 100 mg, 0.438 mmol, 0.99 eq) followed by triethylamine (67.3 qL, 0.438 mmol, 1.1 eq).
  • Step 2 tert-Butyl /f- methoxy-b-methyM-ltrifluoromethyl )phenyl]oxazolol4.5- Z>1pyridin-2-yl1amino1cvclohexyl1-A-methyl-carbamate
  • Step 3 3-Methyl-2- (methylamino)cvclohexyl]amino]oxazolor4,5-Z>1Pyridin-5-yl]-5- (trifluoromethyl)phenol
  • Step 3 tert-butyl 4-(5-bromo-lJ/-imidazor4,5-Z>]pyridin-2-yl)piperazine-l-carboxylate
  • Step 4 tert-butyl 4-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-lJ/-imidazo 14,5- Z>]pyridin-2-yl)piperazine- 1 -carboxylate
  • Step 5 3-Methyl-2-(2-piperazin-l-yl-lJ/-imidazor4,5-Z>]pyridin-5-yl)-5 (trifluoromethyl)phenol;2,2,2-trifluoroacetic acid
  • Step 1 /rac)-5-(5-Bromooxazolor4,5-Z>]pyridin-2-yl)piperidin-2-one
  • Step 1 l-(5-Chlorooxazolol4,5-Z>1Pyridin-2-yl)azetidin-3-ol
  • 5-chloro-2-(methylthio)oxazolo[4,5-Z>]pyridine CAS # 1783370-92-2, 0.100 g, 0.473 mmol, 1.0 eq
  • 1,4-dioxane azetidin-3-ol
  • azetidin-3-ol CAS # 45347-82-838.3 mg, 0.524 mmol, 1.11 eq
  • triethylamine 53.7 mg, 74 ⁇ L, 0.531 mmol, 1.12 eq).
  • the brown solution was stirred at 90 °C overnight.
  • the reaction mixture was cooled to room temperature and extracted with ⁇ 20 mL ethyl acetate, 20 mL di chloromethane (solubility problems) and ⁇ 5 mL saturated NaHCCh-solution.
  • the aqueous layer was backextracted with ⁇ 40 mL di chloromethane.
  • the organic layers were washed with ⁇ 5 mL water and ⁇ 5 mL brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo.
  • Step 2 l-[5-[2-EIvdroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolor4,5-6]pyridin-2- yl]azetidin-3-ol
  • Step 1 3-r(5-Chlorooxazolor4,5-Z>lDyridin-2-yl)amino1cvclohexanol
  • 3 -aminocyclohexanol (23.9 mg, 0.208 mmol, 0.550 eq) was added to the reaction mixture and stirred for five hrs. LC-MS showed a small educt peak. 3 -aminocyclohexanol (23.9 mg, 0.208 mmol, 0.550 eq) was added to the reaction mixture and it was stirred at 90°C overnight. After reaction completion, the mixture was cooled to room temperature and extracted with ⁇ 40 mL ethyl acetate and ⁇ 5 mL saturated NaHCCh-solution. The aqueous layer was back extracted with ⁇ 40mL ethyl acetate.
  • Step 2 2-12-1(3-14 vdroxycvclohexyl)amino1oxazolol4,5-Z>1Pyridin-5-yl1-3-methyl-5- (trifluoromethyl) phenol
  • the reaction mixture was flushed with argon and stirred at 100 °C for one hr.
  • the reaction mixture was cooled to room temperature and extracted with ⁇ 5 mL ethyl acetate and ⁇ 5 mL water.
  • the aqueous layer was backextracted with ⁇ 5 mL ethyl acetate.
  • the organic layers were washed with ⁇ 5 mL water and ⁇ 5 mL brine.
  • the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo.
  • Step 1 5-Chloro-A-r(37?)-l-ethyl-3-piperidyl1oxazolor4,5-61pyridin-2-amine
  • the reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was backextracted with ethyl acetate. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo.
  • the crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 100% (dichloromethane:methanol:NH4OH 9: 1 :0.05) in di chloromethane). All fractions containing product were combined and concentrated in vacuo.
  • Step 1 5-Chloro-A-[(3A)-l -methyl-3-piperidyl1oxazolo[4,5-61pyridin-2-amine
  • Step 2 3-Methyl-2-r2-rr(3A)-l-methyl-3-piperidyl1amino1oxazolol4,5-61pyridin-5-yl1-5- (trifluoromethyl)phenol
  • Step 1 (rac)-A-(2-amino-6-brom opyri din-3 -yl )-l -methylpiperidine-2-carboxamide
  • Step 2 -5-Bromo-2-(l-methylpiperidin-2-yl)-377-imidazor4,5-Z>]pyridine
  • the reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (100 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, filtrated and the filtrate was concentrated under reduced pressure.
  • the residue was purified by prep-HPLC (Method: Column Phenomenex luna Cis 150*40 mm* 15 p m; Condition: water (0.1% TFA)-acetonitrile: Begin B 23 End B 53; Gradient Time (min): 11; 100% B Hold Time (min): 2; FlowRate (mL/min): 60) and following up lyophilization to afford the title compound (100 mg, 48% yield) as a yellow solid.
  • Step 3 -5-(2-Methoxy-6-methyl-4-(trifluoromethyl)phenyl)-2-(l-methylpiperidin-2-yl) - 377-imidazor4,5-Z>1pyridine
  • Step 4 (rac)-3-Methyl-2-(2-(l -methylpiperidin-2-yl )-3//-imidazor4.5-/?1pyridin-5-yl )-5- (trifluoromethyl)phenol
  • Step 1 (rac)-terLButyl 2-((2-amino-6-bromopyridin-3-yl)carbamoyl)pyrrolidine-l-carboxylate
  • DIPEA 1.22 g, 9.29 mmol, 2 eq
  • 6-bromopyridine-2, 3 -diamine 874 mg, 4.65 mmol, 1.0 eq
  • T3P 3.25 g, 5.11 mmol, 1.1 eq, 50% purity in ethyl acetate
  • Step 2 (mc)-tert-Butyl 2-(5-bromo-lJ/-imidazor4,5-Z>]pyridin-2-yl)pyrrolidine-l-carboxylate
  • (rac)-/c/7-butyl 2-((2-amino-6-brom opyri din-3 -yl)carbamoyl)pyrrolidine- 1- carboxylate 500.0 mg, 1.3 mmol, 1.0 eq
  • ethanol a solution of NaOH (779 mg, 19.5 mmol, 15 eq) in water (1 mL).
  • the reaction was stirred at 100 °C for 4 hrs.
  • Step 3 Butyl 2-(5-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-17/-imidazo 14.5- Z>1pyridin-2-yl)pyrrolidine- 1 -carboxylate

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US12441728B2 (en) 2021-04-07 2025-10-14 Ventus Therapeutics U.S., Inc. Pyridazine compounds for inhibiting NLRP3
US12312350B2 (en) 2021-04-07 2025-05-27 Ventus Therapeutics U.S., Inc. Compounds for inhibiting NLRP3 and uses thereof
US12410167B2 (en) 2021-04-07 2025-09-09 Ventus Therapeutics U.S., Inc. Pyridazine compounds for inhibiting NLRP3
US12168657B2 (en) 2022-03-25 2024-12-17 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
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WO2024023266A1 (en) * 2022-07-28 2024-02-01 Ac Immune Sa Novel compounds
US12398136B2 (en) 2022-10-31 2025-08-26 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US12312351B2 (en) 2022-10-31 2025-05-27 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US12331048B2 (en) 2022-10-31 2025-06-17 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
WO2024169895A1 (zh) * 2023-02-14 2024-08-22 深圳众格生物科技有限公司 一种抑制nlrp3的化合物及制备方法和应用
WO2024218100A1 (en) 2023-04-19 2024-10-24 F. Hoffmann-La Roche Ag Oxazolo[4,5-b]pyrazine and oxazolo[4,5-b]pyridine derivatives as nlrp3 inhibitors for the treatment of e.g. inflammatory diseases
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WO2025146160A1 (zh) * 2024-01-05 2025-07-10 北京普祺医药科技股份有限公司 杂环化合物及其药物组合物
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WO2025172521A1 (en) * 2024-02-15 2025-08-21 Evotec International Gmbh Nlrp3 modulators

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