WO2023028536A1 - Dérivés de 1, 2, 4-triazine utiles en tant qu'inhibiteurs de nlrp3 - Google Patents

Dérivés de 1, 2, 4-triazine utiles en tant qu'inhibiteurs de nlrp3 Download PDF

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Publication number
WO2023028536A1
WO2023028536A1 PCT/US2022/075423 US2022075423W WO2023028536A1 WO 2023028536 A1 WO2023028536 A1 WO 2023028536A1 US 2022075423 W US2022075423 W US 2022075423W WO 2023028536 A1 WO2023028536 A1 WO 2023028536A1
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compound
amino
methyl
4alkyl
triazin
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PCT/US2022/075423
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English (en)
Inventor
Nadiya Sydorenko
Rauful Alam
Scott J. BARRAZA
Lauren BEJCEK
Bradley B. GILBERT
Hua Gong
Seyedmorteza HOSSEYNI
Eduardo HUARTE
Jing Li
Meenu PILLAI
Anthony Turpoff
Matthew G. WOLL
Nanjing Zhang
Xiaoyan Zhang
Yan Zhang
Tianyi ZHENG
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Ptc Therapeutics, Inc.
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Publication of WO2023028536A1 publication Critical patent/WO2023028536A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines 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

Definitions

  • the present invention relates to compounds that are useful as inhibitors of NOD-like receptor protein 3 (NLRP3) inflammasome pathway.
  • the present invention also relates to processes for the preparation of said compounds, pharmaceutical compositions comprising said compounds, methods of using said compounds in the treatment of various diseases and disorders, and medicaments containing them, and their use in diseases and disorders mediated by NLRP3.
  • NLRP3 NOD-like receptor protein 3
  • inflammasome was coined by Martinon et al. to describe the molecular platform triggering activation of inflammatory caspases and processing of interleukin 1 (IL-1) family cytokines (Fabio Martinon et al., Mol Cell 10(2):417-26, 2002).
  • Inflammasomes are part of the innate immune system. Inflammasome activation is initiated by assembling of a multiprotein complex, including nucleotide binding oligomerization domain (NOD)-like receptor (NLR), the adapter apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and the effector protease caspase- 1.
  • NOD nucleotide binding oligomerization domain
  • NLR nucleotide binding oligomerization domain
  • ASC caspase recruitment domain
  • the assemble of the complex results in the activation of caspase- 1 and the release of the mature proinflammatory cytokines, such as IL-
  • NLR family NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome has been studied extensively and was found to be activated by a wide spectrum of stimuli.
  • the regulatory mechanisms of NLRP3 activation are summarized in a recent review paper (Seungwha Paik et al., Cell Mol Immunol 18(5): 1141-1160, 2021).
  • NLRP3 activation is triggered by various infectious, non- infectious molecules, including molecular byproducts of aging, physical inactivity and overnutrition. Once activated, it boosts the downstream production of the inflammatory cytokines IL-ip and IL-18. Gain-of function mutations of NLRP3 are associated with several genetic disorders including cryopyrin-associated periodic syndromes (CAPS). Additionally, NLRP3 is implicated in numerous common I) autoimmune, II) autoinfl ammatory, III) neurodegenerative, IV) cardiovascular and V) neuromuscular and muscular degenerative diseases e.g.
  • RPE retinal pigment epithelium
  • NLRP3 activation is associated with severe COVID-19 cases and cytokine release syndrome (CRS) caused by cell-based therapeutics and biologic treatments (Tracey L Freeman and Talia H Swartz Front Immunol 11 : 1518, 2020; Lin et al., PLoS Pathog 6;15(6):el007795, 2019).
  • CRS cytokine release syndrome
  • an NLRP3 inflammasome inhibitor could be used as a single or combination of agents clinically as novel therapies for these diseases.
  • NLRP3 inflammasome pathway to provide new and/or alternative treatments for these inflammasome-related diseases, disorders , such as autoinflammatory fever syndrome cryopyrin- associated periodic syndrome (CAPS), sickle cell disease, chronic liver disease, nonalcoholic steatohepatitis (NASH), gout, hyperoxaluria, pseudogout (chondrocalcinosis), Type EType II diabetes and related complications (e.g.
  • CAPS autoinflammatory fever syndrome cryopyrin- associated periodic syndrome
  • NASH nonalcoholic steatohepatitis
  • gout hyperoxaluria
  • pseudogout chondrocalcinosis
  • Type EType II diabetes and related complications e.g.
  • nephropathy, retinopathy fibrosis, rheumatoid arthritis, inflammatory bowel diseases, asthma and allergic airway inflammation, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease), neuromuscular and muscular degenerative diseases, atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis).
  • CvRR cardiovascular risk reduction
  • cancer e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis.
  • the inflammasome a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta Mol Cell 10(2):417-26, 2002.
  • Ri is selected from hydrogen, Ci.4alkyl, deutero-Ci-4alkyl, Ci-4alkyl-amino, (Ci- 4alkyl)2amino, Ci.4alkoxy, phenyl and Ci-4alkyl-thio;
  • R2 is selected from hydrogen, halogen, Ci.4alkyl, deutero-Ci-4alkyl and Ci.4alkoxy;
  • R3 is selected from hydrogen, halogen, -CF3, -OCHF2, -OCF3, Ci.4alkyl, deutero-Ci- 4alkyl, halo-Ci-4alkyl, deutero-Ci.4alkyl, Ci- 4 alkoxy, halo-Ci.4alkoxy, C3-i4cycloalkyl, heteroaryl, and C2-salkenyl, wherein heteroaryl is a 5-6 membered monocyclic ring system;
  • Y is selected from NR’; wherein R’ is selected from hydrogen, halogen, Ci-4alkyl, deutero-Ci.4alkyl, halo-Ci- 4alkyl, hydroxy-Ci- 4 alkyl, halo-Ci- 4 alkylamino and C3-i4cyclocycloalkyl; and
  • Z is selected from heterocyclyl, heterocyclyl-Ci- 4 alkyl, Ci- 4 alkyl and C3-i4cycloalkyl, wherein each Z is optionally substituted with Ci- 4 alkyl, hydroxy, halo-Ci- 4 alkyl, hydroxy-Ci- 4 alkyl, -CH2CH2OCF2, CF3, or CHF2, and wherein heterocyclyl is a saturated or partially unsaturated membered monocyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S; wherein a form of the compound may be selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer, and isotope enriched form thereof.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the definition of the compound of Formula I as disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is useful in the treatment of diseases and/or disorders related to the NLRP3 activity.
  • the invention provides a combination, in particular a pharmaceutical combination, as disclosed herein, for use as a medicament.
  • the invention provides a compound of Formula I as disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder in which the NLRP3 signaling contributes to the pathology, and/or symptoms, and/or progression, of said disease or disorder.
  • the invention provides a method of treating a disease or disorder in which the NLRP3 signaling contributes to the pathology, and/or symptoms, and/or progression, of said disease or disorder, comprising administering a therapeutically effective amount of a compound of Formula I, or subformulae thereof, as disclosed herein, or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of inhibiting the NLRP3 inflammasome activity in a subject in need thereof, the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of Formula I as disclosed herein, or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention relates to the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, as a medicament.
  • Another aspect of the invention relates to a compound of Formula I a pharmaceutically acceptable salt thereof, for use as a medicament.
  • Another aspect of the invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from inflammasome-related disease/disorders, immune diseases, inflammatory diseases, autoimmune diseases, or auto-inflammatory diseases.
  • a disease or disorder selected from inflammasome-related disease/disorders, immune diseases, inflammatory diseases, autoimmune diseases, or auto-inflammatory diseases.
  • Ri is selected from hydrogen, Ci.4alkyl, deutero-Ci-4alkyl, Ci-4alkyl-amino, (Ci- 4alkyl)2amino, Ci.4alkoxy, phenyl and Ci-4alkyl-thio;
  • R2 is selected from hydrogen, halogen, Ci.4alkyl, deutero-Ci-4alkyl and Ci.4alkoxy;
  • R3 is selected from hydrogen, halogen, -CF3, -OCHF2, -OCF3, Ci.4alkyl, halo-Ci-4alkyl, deutero-Ci-4alkyl, Ci- 4 alkoxy, halo-Ci.4alkoxy, C3-i4cycloalkyl, heteroaryl, and C2-salkenyl, wherein heteroaryl is a 5-6 membered monocyclic ring system;
  • Y is selected from NR’, wherein R’ is selected from hydrogen, halogen, Ci-4alkyl, deutero-Ci.4alkyl, halo-Ci- 4alkyl, hydroxy-Ci- 4 alkyl, halo-Ci- 4 alkylamino and C3-i4cyclocycloalkyl; and
  • Z is selected from heterocyclyl, heterocyclyl-Ci- 4 alkyl, Ci- 4 alkyl and C3-i4cycloalkyl, wherein each Z is optionally substituted with Ci- 4 alkyl, hydroxy, halo-Ci- 4 alkyl, hydroxy-Ci- 4 alkyl, -CH2CH2OCF2, CF3, or CHF2, and wherein heterocyclyl is a saturated or partially unsaturated membered monocyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S; wherein a form of the compound may be selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer, and isotope enriched form thereof.
  • Another aspect includes a compound of Formula I, wherein Ri is Ci- 4 alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • Another aspect includes a compound of Formula I, wherein Ri is Ci- 4 alkyl selected from methyl and ethyl.
  • Another aspect includes a compound of Formula I, wherein Ri is deutero-Ci- 4 alkyl wherein Ci- 4 alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl partially or completely substituted with one or more deuterium atoms where allowed by available valences.
  • Another aspect includes a compound of Formula I, wherein Ri is Ci- 4 alkyl-amino wherein Ci- 4 alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • Another aspect includes a compound of Formula I, wherein Ri is Ci-4alkyl-amino wherein Ci-4alkyl is methyl.
  • Another aspect includes a compound of Formula I, wherein Ri is methylamino.
  • Another aspect includes a compound of Formula I, wherein Ri is (Ci-4alkyl)2amino, wherein Ci-4alkyl is each independently selected from methyl, ethyl, isopropyl, tert-butyl, 2- m ethylbutyl, and 3 -methylpentyl.
  • Another aspect includes a compound of Formula I, wherein Ri is (Ci-4alkyl)2amino, wherein Ci-4alkyl is methyl or ethyl.
  • Another aspect includes a compound of Formula I, wherein Ri is dimethylamino or diethylamino.
  • Another aspect includes a compound of Formula I, wherein Ri is dimethylamino.
  • Another aspect includes a compound of Formula I, wherein Ri is C alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.
  • Another aspect includes a compound of Formula I, wherein Ri methoxy.
  • Another aspect includes a compound of Formula I, wherein Ri ethoxy.
  • Another aspect includes a compound of Formula I, wherein Ri is Ci-4alkyl-thio selected from methylthio, ethylthio, propylthio, isopropylthio, butylthio, and tert-butylthio.
  • Another aspect includes a compound of Formula I, wherein Ri methylthio.
  • Another aspect includes a compound of Formula I, wherein R2 is hydrogen.
  • Another aspect includes a compound of Formula I, wherein R2 is halogen selected from bromo, chloro, fluoro, and iodo.
  • Another aspect includes a compound of Formula I, wherein R2 is fluoro.
  • Another aspect includes a compound of Formula I, wherein R2 is Ci-4alkyl selected from methyl, ethyl, isopropyl, tert-butyl, 2-methylbutyl, and 3 -methylpentyl.
  • Another aspect includes a compound of Formula I, wherein R2 is C alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.
  • Another aspect includes a compound of Formula I, wherein R2 methoxy.
  • Another aspect includes a compound of Formula I, wherein Rj is hydrogen.
  • Another aspect includes a compound of Formula I, wherein Rj is Ci-4alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • Another aspect includes a compound of Formula I, wherein Rj is Ci-4alkyl selected from methyl or ethyl.
  • Another aspect includes a compound of Formula I, wherein Rj is methyl.
  • Another aspect includes a compound of Formula I, wherein Rj is ethyl.
  • Another aspect includes a compound of Formula I, wherein Rj is isopropyl.
  • Another aspect includes a compound of Formula I, wherein Rj is deutero-Ci.4alkyl wherein Ci-4alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl partially or completely substituted with one or more deuterium atoms where allowed by available valences.
  • Another aspect includes a compound of Formula I, wherein Rj is C alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.
  • Another aspect includes a compound of Formula I, wherein Rj methoxy.
  • Another aspect includes a compound of Formula I, wherein Rj ethoxy.
  • Another aspect includes a compound of Formula I, wherein Rj is Cs-ucycloalkyl selected from cyclopropyl, cylcob utyl, cyclopentyl or cyclohexyl.
  • Another aspect includes a compound of Formula I, wherein Rj is cyclopropyl.
  • Another aspect includes a compound of Formula I, wherein Rj is heteroaryl is pyridinyl, pyrimidinyl, pyridazinyl, l,2,4triazinyl, 1,3,5-triazinyl or 1,2,3-triazinyl.
  • Another aspect includes a compound of Formula I, wherein Rj is 1,2,3-triazinyl.
  • Another aspect includes a compound of Formula I, wherein Rj is C2-salkenyl selected from ethenyl, allyl or propenyl.
  • Another aspect includes a compound of Formula I, wherein Rj is propenyl.
  • Another aspect includes a compound of Formula I, wherein Rj is halogen selected from bromo, chloro, fluoro, and iodo.
  • R3 is chloro or bromo.
  • Another aspect includes a compound of Formula I, wherein R3 is halo-Ci.4alkyl selected from CF3 or CHF2.
  • Another aspect includes a compound of Formula I, wherein R3 is halo-Ci.4alkoxy selected from OCF3 or OCHF2.
  • Another aspect includes a compound of Formula I, wherein Z is C3-i4cycloalkyl selected from cyclopropyl, cylcob utyl, cyclopentyl and cyclohexyl.
  • Another aspect includes a compound of Formula I, wherein Z is cyclobutyl.
  • Another aspect includes a compound of Formula I, wherein Z is heterocyclyl wherein heterocyclyl is a saturated or partially unsaturated membered monocyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N and O,
  • Another aspect includes a compound of Formula I, wherein Z is piperidinyl, tetrahydro- 2//-pyran or pyrrolidinyl.
  • Another aspect includes a compound of Formula I, wherein Z is piperidinyl.
  • Another aspect includes a compound of Formula I, wherein Z is optionally substituted by Ci-4alkyl, hydroxy, halo-Ci-4alkyl, hydroxy-Ci- 4 alkyl, -CH2CH2OCF2, CF3 or CHF2.
  • Another aspect includes a compound of Formula I, wherein Z is optionally substituted by Ci-4alkyl, wherein Ci.4alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, and tert-butyl.
  • Another aspect includes a compound of Formula I, wherein Z is optionally substituted by Ci-4alkyl selected from methyl and ethyl.
  • Another aspect includes a compound of Formula I, wherein Y is NR’.
  • Another aspect includes a compound of Formula I, wherein R’ is hydrogen.
  • Another aspect includes a compound of Formula I, wherein R’ is halogen selected from bromo, chloro, fluoro, and iodo.
  • Another aspect includes a compound of Formula I, wherein R’ is chloro or bromo.
  • Another aspect includes a compound of Formula I, wherein R’ is bromo.
  • Another aspect includes a compound of Formula I, wherein R’ is fluoro.
  • Another aspect includes a compound of Formula I, wherein R’ is Ci.4alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • Another aspect includes a compound of Formula I, wherein R’ is Ci.4alkyl selected from methyl and ethyl.
  • Another aspect includes a compound of Formula I, wherein R’ is deutero-Ci-4alkyl wherein Ci-4alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl, partially or completely substituted with one or more deuterium atoms where allowed by available valences.
  • Another aspect includes a compound of Formula I, wherein R’ is halo-Ci-4alkyl, wherein Ci-4alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, and isobutyl partially or completely substituted with one or more halogen atoms where allowed by available valences.
  • Another aspect includes a compound of Formula I, wherein R’ is hydroxy-Ci- 4 alkyl wherein Ci.4alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, and isobutyl partially or completely substituted with one or more hydroxy groups where allowed by available valences.
  • Another aspect includes a compound of Formula I, wherein R’ is halo-Ci-4alkylamino, wherein Ci-4alkyl is selected from isopropyl and tert-butyl, partially or completely substituted with one or more halogen atoms where allowed by available valences.
  • Another aspect includes a compound of Formula I, wherein R’ is Cs-ucycloalkyl selected from cyclopropyl, cylcob utyl, cyclopentyl and cyclohexyl.
  • Another aspect includes a compound of Formula I, wherein Y and Z when taken together is selected from: wherein R is selected from hydrogen, optionally substituted Ci-4alkyl, halo-Ci-4alkyl, and hydroxy-Ci-4alkyl; R” is selected from halogen, hydroxyl, Ci.4alkyl, halo-Ci-4alkyl and Ci.4alkoxy;
  • Q is selected from absent and (CHR x ) n , wherein R x is independently selected from hydrogen, halogen and Ci-4alkyl, and wherein n is 0, 1,2, 3 or 4; and
  • R z is selected from hydrogen and Ci.4alkyl; wherein a form of the compound may be selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer, and isotope enriched form thereof.
  • Another aspect includes a compound of Formula I, wherein R is hydrogen.
  • Another aspect includes a compound of Formula I, wherein R is Ci-4alkyl selected from methyl, ethyl and isopropyl.
  • Another aspect includes a compound of Formula I, wherein R is methyl.
  • Another aspect includes a compound of Formula I, wherein R is ethyl.
  • Another aspect includes a compound of Formula I, wherein R is isopropyl.
  • Another aspect includes a compound of Formula I, wherein R is Ci- 4 alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.
  • Another aspect includes a compound of Formula I, wherein R is ethoxy.
  • Another aspect includes a compound of Formula I, wherein R is hydroxy-Ci- 4 alkyl wherein Ci- 4 alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, and isobutyl partially or completely substituted with one or more hydroxy groups where allowed by available valences.
  • Another aspect includes a compound of Formula I, wherein R is methyl, ethyl, -CH2CHOH, -CH 2 CH 2 C(Me) 2 OH, -CH 2 C(Me) 2 OH, -CH 2 CH 2 OCF 2 , -CF 3 , CHF 2 , or -CH 2 CHF 2
  • Another aspect includes a compound of Formula I, wherein R” is hydrogen.
  • Another aspect includes a compound of Formula I, wherein Q is CH 2 .
  • Another aspect includes a compound of Formula I, wherein R z is selected from hydrogen and Ci- 4 alkyl.
  • Another aspect includes a compound of Formula I, wherein R z is Ci- 4 alkyl, wherein Ci- 4 alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.
  • Another aspect includes a compound of Formula I, wherein R z is methyl.
  • An aspect of the compound of Formula I or a form thereof includes a compound selected from the group consisting of the following: wherein a form of the compound may be selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer, and isotope enriched form thereof.
  • Another aspect includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
  • Another aspect includes a method for treating or ameliorating a disease modulated by NLRP3 in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula I.
  • Another aspect includes a method of treating or ameliorating a disease modulated by NLRP3 with an effective amount of a compound of Formula I, wherein the disease is selected from Alzheimer disease, Frontotemporal dementia (FTD), Huntington's disease, Parkinson's disease, Perioperative neurocognitive disorders, Post-cardiac arrest cognitive impairment, Poststroke cognitive impairment, Sepsis, Sepsis associated encephalopathy, Subarachnoid hemorrhage, Macular Degeneration, Retinal neovascularization, Uveitis, Colitis, Endothelial dysfunction, Gout, Pseudogout, Graft-versus-host-disease (GvHD), Systemic lupus erythematosus-lupus nephritis, Cryopyrin-associated periodic syndromes (CAPS), Cystic fibrosis, Sickle-cell disease, VCP-associated disease, Liver fibrosis, Nonalcoholic fatty liver disease (NASH), muscle atrophy, inherited and acquired myopathies,
  • Duchenne Muscular Dystrophy (DMD), Hyperalgesia, Multiple sclerosis-associated neuropathic pain, Acute Kidney Injury, Chronic crystal nephropathy, Chronic Kidney Disease, asthma and allergic airway inflammation Diabetes-associated atherosclerosis, Diabetic encephalopathy, Diabetic kidney disease, Islet transplantation rejection, Obesity-associated renal disease, Oxalate-induced nephropathy, Renal fibrosis, Renal hypertension, Type I diabetes, Type II diabetes, Psoriasis, Hidradenitis suppurativa, Atherosclerosis and Cytokine Release Syndrome (CRS).
  • DMD Duchenne Muscular Dystrophy
  • Hyperalgesia Multiple sclerosis-associated neuropathic pain
  • Acute Kidney Injury Chronic crystal nephropathy, Chronic Kidney Disease, asthma and allergic airway inflammation
  • Diabetes-associated atherosclerosis Diabetic encephalopathy
  • Diabetic kidney disease Islet transplantation rejection
  • Obesity-associated renal disease Ox
  • Another aspect includes a method of treating or ameliorating a disease modulated by NLRP3 with an effective amount of a compound of Formula I, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.
  • Another aspect includes a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in treating or ameliorating a disease modulated by NLRP3 selected from Alzheimer disease, Frontotemporal dementia (FTD), Huntington's disease, Parkinson's disease, Perioperative neurocognitive disorders, Post-cardiac arrest cognitive impairment, Poststroke cognitive impairment, Sepsis, Sepsis associated encephalopathy, Subarachnoid hemorrhage, Macular Degeneration, Retinal neovascularization, Uveitis, Colitis, Endothelial dysfunction, Gout, Pseudogout, Graft-versus-host-disease (GvHD), Systemic lupus erythematosus-lupus nephritis, Cryopyrin-associated periodic syndromes (CAPS), Cystic fibrosis, Sickle-cell disease, VCP-associated disease, Liver fibrosis, Nonalcoholic fatty liver disease (NASH), muscle atrophy, inherited and acquired myopathies, Hyperalgesi
  • Another aspect includes use of a compound of Formula I in treating or ameliorating a disease modulated by NLRP3, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.
  • Another aspect includes use of a compound according to a compound of Formula I in the preparation of a pharmaceutical composition for treating or ameliorating a disease modulated by NLRP3 in a subject in need thereof comprising, administering to the subject an effective amount of the compound or a form thereof in admixture with one or more of the pharmaceutically acceptable excipients.
  • NLRP3 -induced IL-ip and IL-18 have been found to be responsible for a set of rare autoinflammatory diseases known as CAPS (Ozaki et al, J. Inflammation Research, 2015, 8, 15- 27; Schroder et al, Cell, 2010, 140:821-832; Menu et al, Clinical and Experimental Immunology, 2011, 166, 1-15).
  • CAPS are heritable diseases characterized by recurrent fever and inflammation and are comprised of three autoinflammatory disorders that form a clinical continuum. These diseases, in order of increasing severity, are familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile cutaneous neurological articular syndrome (CINCA; also called neonatal-onset multisystem inflammatory disease, NOMID), and all have been shown to result from gain-of-function mutations in the NLRP3 gene, which leads to increased secretion of IL-I beta.
  • FCAS familial cold autoinflammatory syndrome
  • MFS Muckle-Wells syndrome
  • CINCA chronic infantile cutaneous neurological articular syndrome
  • NOMID neonatal-onset multisystem inflammatory disease
  • NLRP3 has also been implicated in a number of autoinflammatory diseases, including pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), Sweet’s syndrome, chronic nonbacterial osteomyelitis (CNO), and acne vulgaris (Cook et al, Eur J. Immunol., 2010, 40, 595-653).
  • a number of autoimmune diseases have been shown to involve NLRP3 including, in particular, multiple sclerosis, type-1 diabetes (T1D), psoriasis, rheumatoid arthritis (RA), Behcet’s disease, Schnitzler syndrome, macrophage activation syndrome (Braddock et al. Nat. Rev. Drug Disc.
  • 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, 2014, 184: 42-54; Kim et al. Am. J. Respir Crit Care Med, 2017, 196(3), 283-97).
  • NLRP3 has also been suggested to have a role in a number of central nervous system conditions, including Multiple Sclerosis (MS), Parkinson’s disease (PD), Alzheimer’s disease (AD), dementia,
  • MS Multiple Sclerosis
  • PD Parkinson’s disease
  • AD Alzheimer’s disease
  • NRLP3 activity has also been shown to be involved in various metabolic diseases including type 2 diabetes (T2D) and its organ-specific complications, atherosclerosis, obesity, gout, pseudogout, metabolic syndrome (Wen et al, Nature Immunology, 2012, 13, 352-357; Duewell et al, Nature, 2010, 464, 1357-1361; Strowig et al, Nature, 2014, 481, 278-286), and non-alcoholic steatohepatitis (Mridha et al. J. Hepatol. 2017, 66(5), 1037-46).
  • T2D type 2 diabetes
  • atherosclerosis obesity
  • gout pseudogout
  • metabolic syndrome Wang et al, Nature Immunology, 2012, 13, 352-357
  • Duewell et al Nature, 2010, 464, 1357-1361
  • Strowig et al Nature, 2014, 481, 278-286
  • non-alcoholic steatohepatitis Mridha et al. J. Hepatol. 2017,
  • NLRP3 NLRP3-related macular degeneration
  • ocular diseases such as both wet and dry age-related macular degeneration (Doyle et al. Nature Medicine, 2012, 18, 791-798; Tarallo et al. Cell 2012, 149(4), 847-59), diabetic retinopathy (Loukovaara et al. Acta Ophthalmol., 2017, 95(8), 803-8), non- infectious uveitis and optic nerve damage (Puyang et al. Sci. Rep.
  • liver diseases including non-alcoholic steatohepatitis (NASH) and acute alcoholic hepatitis (Henao-Meija et al, Nature, 2012, 482, 179-185); inflammatory reactions in the lung and skin (Primiano et al. J. Immunol. 2016, 197(6), 2421-33) including contact hypersensitivity (such as bullous pemphigoid (Fang et al. J Dermatol Sci. 2016, 83(2), 116-23)), atopic dermatitis (Niebuhr et al. Allergy, 2014, 69(8), 1058-67), Hidradenitis suppurativa (Alikhan et al. J. Am. Acad.
  • isolated means the physical state of a compound of Formula I or a form thereof after being isolated and/or separated and/or purified from a synthetic process (e.g., from a reaction mixture) or natural source or combination thereof according to an isolation, separation or purification process or processes described herein or which are well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • protected means that a functional group on a compound of Formula I or a form thereof is in a form modified to preclude undesired side reactions of the functional group when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (2007), Wiley, New York.
  • prodrug means that a functional group on a compound of Formula I is in a form (e.g., acting as an active or inactive drug precursor) that is transformed in vivo to yield an active or more active compound of Formula I or a form thereof.
  • the transformation may occur by various mechanisms (e.g., by metabolic and/or non-metabolic chemical processes), such as, for example, by hydrolysis and/or metabolism in blood, liver and/or other organs and tissues.
  • a discussion of the use of prodrugs is provided by V. J. Stella, et. al., “Biotechnology: Pharmaceutical Aspects, Prodrugs: Challenges and Rewards,” American Association of Pharmaceutical Principles and Springer Press, 2007.
  • a prodrug when a compound of Formula I or a form thereof contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a functional group such as alkyl and the like.
  • a prodrug when a compound of Formula I or a form thereof contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a functional group such as alkyl or carbonyloxy and the like.
  • a prodrug when a compound of Formula I or a form thereof contains an amine functional group, a prodrug can be formed by the replacement of one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl.
  • prodrugs of compounds of Formula I or a form thereof include those compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonate esters, amino acid esters, phosphonate esters (e.g., a phosphoramidic acid used to derive a phosphoramidic acid) and mono-, di- or triphosphate esters further substituted with alkyl, where appropriate. As described herein, it is understood by a person of ordinary skill in the art that one or more of such substituents may be used to provide a compound of Formula I or a form thereof as a prodrug.
  • the compounds of Formula I or a form thereof can form salts, which are intended to be included within the scope of this description.
  • Reference to a compound of Formula I or a form thereof herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • a compound of Formula I or a form thereof contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term “salt(s)" as used herein.
  • salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in compounds of Formula I or a form thereof described herein.
  • Embodiments of acid addition salts include, and are not limited to, acetate, acid phosphate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, hydrobromide, hydrochloride, dihydrochloride, hydroiodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate
  • acid addition salts include chloride, hydrochloride, dihydrochloride, trihydrochloride, hydrobromide, acetate, diacetate, methanesulfonate, sulfate, trifluoroacetate, trifluoroacetic acid salt and the like. More particular embodiments include a chloride, hydrochloride, dihydrochloride, hydrobromide, methanesulfonate, sulfate, trifluoroacetate, trifluoroacetic acid salt and the like.
  • the compound is isolated as a salt form, wherein the compound is conjugated with the salt in a ratio represented as, in a non-limiting example, “compound: salt (A:B),” wherein “A” and “B” represent the equivalents of compound to salt in the isolated form.
  • Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.
  • Certain compounds of Formula I or a form thereof described herein can also form pharmaceutically acceptable salts with organic bases (for example, organic amines) such as, but not limited to, dicyclohexylamines, tert-butyl amines and the like, and with various amino acids such as, but not limited to, arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g., methyl, ethyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g., decyl, lauryl, and
  • the compounds of Formula I or a form thereof may contain asymmetric or chiral centers, and, therefore, may exist in different stereoisomeric forms.
  • the present description is intended to include all stereoisomeric forms of the compounds of Formula I as well as mixtures thereof, including racemic mixtures.
  • the compounds of Formula I or a form thereof described herein may include one or more chiral centers, and as such may exist as racemic mixtures (R'S) or as substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or S enantiomers (when one chiral center is present).
  • the compounds of Formula I or a form thereof described herein are (5) isomers and may exist as enantiomerically pure compositions substantially comprising only the (5) isomer.
  • the compounds of Formula I or a form thereof described herein are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer.
  • the compounds of Formula I or a form thereof described herein may also exist as a (R,R), (RS), (S,R) or (S,S) isomer, as defined by IUPAC Nomenclature Recommendations.
  • substantially pure refers to compounds of Formula I or a form thereof consisting substantially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of the single isomer.
  • a compound of Formula I or a form thereof is a substantially pure (5) enantiomer present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
  • a compound of Formula I or a form thereof is a substantially pure (R) enantiomer present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
  • racemate refers to any mixture of isometric forms that are not “enantiomerically pure”, including mixtures such as, without limitation, in a ratio of about 50/50, about 60/40, about 70/30, or about 80/20, about 85/15 or about 90/10.
  • the compounds of Formula I or a form thereof described herein embrace all geometric and positional isomers.
  • a compound of Formula I or a form thereof incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures thereof, are embraced within the scope of the compounds of Formula I or a form thereof described herein.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by use of a chiral HPLC column or other chromatographic methods known to those skilled in the art.
  • Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • the present compounds of Formula I or a form thereof including salts, solvates, esters and prodrugs and transformed prodrugs thereof
  • which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, diastereomeric and regioisomeric forms, are contemplated within the scope of the description herein.
  • Individual stereoisomers of the compounds of Formula I or a form thereof described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture, as described supra.
  • salt is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, isotope enriched or prodrugs of the instant compounds.
  • One or more compounds of Formula I or a form thereof described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to embrace both solvated and unsolvated forms.
  • solvate means a physical association of a compound of Formula I or a form thereof described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. As used herein, “solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • One or more compounds of Formula I or a form thereof described herein may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • a typical, non-limiting process involves dissolving a compound of Formula I or a form thereof in a desired amount of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example infrared spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • the term “hydrate” means a solvate wherein the solvent molecule is water.
  • Polymorphic crystalline and amorphous forms of the compounds of Formula I or a form thereof, and of the salts, solvates, esters and prodrugs of the compounds of Formula I or a form thereof, are further intended to be included in the scope of the compounds of Formula I or a form thereof described herein.
  • isotope enriched means a compounds of Formula I or a form thereof which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of Formula I or a form thereof described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as H 2 , H 3 , C 13 , C 14 , N 15 , O 18 , O 17 , P 31 , P 32 , S 35 , F 18 , Cl 35 and Cl 36 , respectively, each of which is also within the scope of this description.
  • Ci-4alkyl refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration, including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertbutyl and the like.
  • a Ci-4alkyl radical may be optionally substituted where allowed by available valences.
  • C2-salkenyl refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including, without limitation, ethenyl, allyl, propenyl and the like.
  • C2-salkenyl includes C2-ealkenyl, C2-4alkenyl and the like.
  • a C2-salkenyl radical may be optionally substituted where allowed by available valences.
  • Ci-4alkoxy refers to saturated hydrocarbon radicals of from one to four carbon atoms having a straight or branched chain configuration of the formula: OCi- 4alkyl, including, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
  • Ci.4alkoxy includes Ci- salkoxy, Ci.2alkoxy and the like.
  • a Ci.4alkoxy radical may be optionally substituted where allowed by available valences.
  • Ci-4alkoxy-C2-4alkyl refers to a radical of the formula - C2- 4alkyl- Ci-4alkoxy.
  • C3-i4cycloalkyl refers to a saturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, IH-indanyl, indenyl, 2,3-dihydro-lH-indenyl, tetrahydronaphthalenyl and the like.
  • C3-i4cycloalkyl includes C3- scycloalkyl, Cs-scycloalkyl, C3-iocycloalkyl and the like.
  • a C3-i4cycloalkyl radical may be optionally substituted where allowed by available valences.
  • aryl refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical, including phenyl.
  • An aryl radical may be optionally substituted where allowed by available valences.
  • heteroaryl refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms, such as an O, S or N atom, including, without limitation, pyridinyl, pyrimidinyl, pyridazinyl, l,2,4triazinyl, 1,3,5-triazinyl or 1,2,3-triazinyl
  • a heteroaryl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with a heteroatom, such as an O, S or N atom, including without limitation, piperidinyl, tetrahydro-2//- pyran or pyrrolidinyl.
  • a heterocyclyl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences.
  • halo or “halogen” generally refers to a halogen atom radical, including fluoro, chloro, bromo and iodo.
  • Ci-4alkylamino refers to a radical of the formula: NHCi.4alkyl.
  • (Ci-4alkyl)2amino refers to a radical of the formula: N(Ci- 4alkyl)2.
  • Ci-4alkyl-thio refers to a radical of the formula: -S-Ci-4alkyl.
  • deutero-Ci.4alkyl refers to a radical of the formula: Ci- 4alkyldeutero, wherein Ci-4alkyl is partially or completely substituted with one or more deuterium atoms where allowed by available valences.
  • halo-Ci.4alkyl refers to a radical of the formula: Ci.4alkylhalo, wherein Ci-4alkyl is partially or completely substituted with one or more halogen atoms where allowed by available valences.
  • halo-Ci.4alkoxy refers to a radical of the formula: OCi- 4alkylhalo, wherein Ci.4alkyl is partially or completely substituted with one or more halogen atoms where allowed by available valences.
  • halo-Ci.4alkylamino refers to a radical of the formula: NHCi- 4alkylhalo.
  • halo-C-i-4alkyl)2amino refers to a radical of the formula: N(Ci-4alkylhalo)2.
  • heterocyclyl-Ci.4alkyl refers to a radical of the formula: Ci- 4alkylheterocy clyl .
  • hydroxy refers to a radical of the formula: -OH.
  • hydroxy-C-i.4alkyl refers to a radical of the formula: Ci- 4alkylOH, wherein Ci-4alkyl is partially or completely substituted with one or more hydroxy radicals where allowed by available valences.
  • substituted means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown.
  • substituents having a double bond may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure of Formula I).
  • substituents having a double bond may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure of Formula I).
  • a person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended for those substituents.
  • the term “and the like,” with reference to the definitions of chemical terms provided herein, means that variations in chemical structures that could be expected by one skilled in the art include, without limitation, isomers (including chain, branching or positional structural isomers), hydration of ring systems (including saturation or partial unsaturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations where allowed by available valences which result in a stable compound.
  • substituted means positional variables on the atoms of a core molecule that are attached at a designated atom position, replacing one or more hydrogen atoms on the designated atom, provided that the atom of attachment does not exceed the available valence or shared valences, such that the substitution results in a stable compound. Accordingly, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. It should also be noted that any carbon as well as heteroatom with a valence level that appears to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown.
  • each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently and/or optionally substituted.
  • the terms “independently selected,” or “each selected” refer to functional variables in a substituent list that may be attached more than once on the structure of a core molecule, where the pattern of substitution at each occurrence is independent of the pattern at any other occurrence.
  • a generic substituent on a core structure for a compound provided herein is understood to include the replacement of the generic substituent with specie substituents that are included within the particular genus, e.g., aryl may be independently replaced with phenyl or naphthalenyl (also referred to as naphthyl) and the like, such that the resulting compound is intended to be included within the scope of the compounds described herein.
  • the term “optionally substituted” means that the specified substituent variables, groups, radicals or moieties represent the scope of the genus and may be independently chosen as needed to replace one or more hydrogen atoms on the designated atom of attachment of a core molecule.
  • stable compound or “stable structure” means a compound that is sufficiently robust to be isolated to a useful degree of purity from a reaction mixture and formulations thereof into an efficacious therapeutic agent.
  • the terms “subject” and “patient” are used interchangeably to refer to an animal or any living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food.
  • Nonlimiting examples include members of the human, equine, porcine, bovine, rattus, murine, canine and feline species.
  • the subject is a mammal or a warm-blooded vertebrate animal.
  • the subject is a non-human animal.
  • the subject is a human.
  • the compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers.
  • Oral administration can be in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions, syrups, or suspensions.
  • Compounds of the present invention are efficacious when administered by other routes of administration including continuous (intravenous drip) topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal, nasal, inhalation and suppository administration, among other routes of administration.
  • the preferred manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the degree of affliction and the patient's response to the active ingredient.
  • a compound or compounds of the present invention, as well as their pharmaceutically useable salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
  • the pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use.
  • a typical preparation will contain from about 5% to about 95% active compound or compounds (w/w).
  • preparation or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the target organ or tissue and on the desired dose and pharmacokinetic parameters.
  • excipient refers to a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
  • the compounds of this invention can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • a "pharmaceutically acceptable salt” form of an active ingredient may also initially confer a desirable pharmacokinetic property on the active ingredient which were absent in the non-salt form, and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body.
  • pharmaceutically acceptable salt of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid,
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • the compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • the compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the compounds of the present invention may be formulated for administration as suppositories.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
  • the compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds of the present invention may be formulated for nasal administration.
  • the solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray.
  • the formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • the compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
  • the compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, tri chlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by a metered valve.
  • the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial.
  • Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support.
  • the compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylaza- cycloheptan-2-one).
  • Sustained release delivery systems are inserted subcutaneously into to the subdermal layer by surgery or injection.
  • the subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polyactic acid.
  • Suitable formulations along with pharmaceutical carriers, diluents and expcipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania.
  • a skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.
  • the modification of the present compounds to render them more soluble in water or other vehicle may be easily accomplished by minor modifications (salt formulation, esterification, etc.), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.
  • terapéuticaally effective amount means an amount required to reduce symptoms of the disease in an individual.
  • the dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved.
  • a daily dosage of between about 0.01 and about 1000 mg/kg body weight per day should be appropriate in monotherapy and/or in combination therapy.
  • a preferred daily dosage is between about 0.1 and about 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg body weight and most preferred 1.0 and about 10 mg/kg body weight per day.
  • the dosage range would be about 7 mg to 0.7 g per day.
  • the daily dosage can be administered as a single dosage or in divided dosages, typically between 1 and 5 dosages per day. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect for the individual patient is reached.
  • One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • reagents and solvents were used as purchased (from a variety of vendors), except where noted.
  • the term “Celite” is used as shown in the following examples to represent the tradename CELITE® (brand of diatomaceous earth).
  • chromatographic separations were performed using techniques and equipment commonly available such as, for example, by using an ISCO CombiFlash® Rf system.
  • NMR spectra were obtained using techniques and equipment commonly available such as, for example, by using a Bruker Avance III 500 spectrometer with deuterated solvents such as, for example, DMSO-tL or residual solvent as standard.
  • melting points were determined using techniques and equipment commonly available such as, for example, by using a SRS OptiMelt® MPA100 (values as obtained without correction/calibration).
  • TLC analysis was performed using techniques and equipment commonly available such as, for example, by using Aldrich 254 nm glass-backed plates (60 A, 250 pm), visualized using UV and L stains.
  • ESI mass spectra were obtained using techniques and equipment commonly available such as, for example, by using an ACQUITY UPLC® System, with values shown as [M+H] + or [M-H]', unless otherwise indicated.
  • the structure of the product was obtained via a 2D NOESY (Nuclear Overhauser SpectroscopY) experiment.
  • the final compounds or their precursors may be further elaborated using the standard, well- known synthetic methods such as SN2 displacement reaction, metal catalyzed coupling reactions like Suzuki coupling, Negishi coupling and Buchwald coupling, reductive amination, etc. to afford the compounds of the general Formula I.
  • Compound Al (where Xi and X2 are independently bromine, chlorine and the like) is converted to Compound A2 by a nucleophilic substitution with either an appropriate amine in the presence of a suitable base (such as DIPEA and the like) in a suitable solvent (such as NMP and the like) or with an appropriate alcohol in the presence of a suitable base (such as NaH and the like) in a suitable solvent (such as anhydrous THF and the like).
  • a suitable base such as DIPEA and the like
  • a suitable solvent such as NMP and the like
  • an appropriate alcohol such as NaH and the like
  • a suitable solvent such as anhydrous THF and the like
  • Compound A2 is converted to Compound A3 by a Suzuki coupling with an aryl- or heteroaryl-boronic acid (or pinacol boronic ester) in the presence of a catalyst (such as Pd(dppf)C12 and the like) and base (such as aqueous K2CO3 and the like) in a suitable solvent (such as 1,4-di oxane and the like).
  • a catalyst such as Pd(dppf)C12 and the like
  • base such as aqueous K2CO3 and the like
  • a suitable solvent such as 1,4-di oxane and the like.
  • Any protecting groups are removed upon treatment with appropriate conditions (such as HC1 for a MOM protecting group or BBr, for OMe protecting group).
  • Compound Bl (where Xi and X2 are independently bromine, chlorine and the like) is converted to Compound B2 by a Suzuki coupling with an aryl- or heteroaryl-boronic acid (or pinacol boronic ester) in the presence of a catalyst (such as Pd(dppf)C12 and the like) and base (such as aqueous K2CO3 and the like) in a suitable solvent (such as 1,4-di oxane and the like).
  • a catalyst such as Pd(dppf)C12 and the like
  • base such as aqueous K2CO3 and the like
  • suitable solvent such as 1,4-di oxane and the like
  • Compound B2 is converted to Compound B3 by a Buchwald-Hartwig coupling with an appropriate amine in the present of a catalyst (such as Pd2(dba)3 and the like), a ligand (such as RuPhos and the like) and a base (such as NaO’Bu and the like) in a suitable solvent (such as PhMe and the like).
  • a catalyst such as Pd2(dba)3 and the like
  • a ligand such as RuPhos and the like
  • a base such as NaO’Bu and the like
  • PhMe PhMe and the like
  • Compound B2 is converted to Compound B3 by a nucleophilic substitution with either an appropriate amine in the presence of a suitable base (such as DIPEA and the like) in a suitable solvent (such as NMP and the like) or with an appropriate alcohol in the presence of a suitable base (such as NaH and the like) in a suitable solvent (such as anhydrous THF and the like).
  • a suitable base such as DIPEA and the like
  • a suitable solvent such as NMP and the like
  • an appropriate alcohol such as NaH and the like
  • a suitable solvent such as anhydrous THF and the like.
  • Any protecting groups are removed upon treatment with appropriate conditions (such as HC1 for a MOM protecting group or BBr, for OMe protecting group).
  • Compound C2 is prepared from compound Cl (where Xi is chlorine, bromine and the like) by a Suzuki coupling with an aryl- or heteroaryl-boronic acid (or pinacol boronic ester) in the presence of a catalyst (such as Pd(dppf)C12 and the like) and base (such as aqueous K2CO3 and the like) in a suitable solvent (such as 1,4-di oxane and the like).
  • a catalyst such as Pd(dppf)C12 and the like
  • base such as aqueous K2CO3 and the like
  • a suitable solvent such as 1,4-di oxane and the like.
  • Compound C2 is converted to Compound C3 (where X is chlorine, bromine and the like) by treatment with a dehydrative halogenating agent POX3 (such as POCI3 and the like).
  • Compound C3 is converted to Compound C4 (where R” is alkyl, cycloalkyl, aryl, heterocyclic, alkoxy, hydroxy, thioalxoxy, amino, mono- or bis-substituted amino) by a reaction with an appropriate reagent.
  • R is alkyl, cycloalkyl, aryl, heterocyclic, alkoxy, hydroxy, thioalxoxy, amino, mono- or bis-substituted amino
  • Compound C3 is converted to Compound C4 by a Suzuki coupling with a boronic acid (or pinacol boronic ester) in the presence of a catalyst (such as Pd(dppf)C12 and the like) and base (such as aqueous K2CO3 and the like) in a suitable solvent (such as 1,4-di oxane and the like).
  • a catalyst such as Pd(dppf)C12 and the like
  • base such as aqueous K2CO3 and the like
  • suitable solvent such as 1,4-di oxane and the like
  • R is alkoxy or hydroxy or thioalkoxy or amino or mono- or bis-substituted amino
  • Compound C3 is converted to Compound C4 by SNAr reaction with an appropriate nucleophile in a suitable solvent (such as DMSO and the like).
  • SNAr reaction of C4 with a nucleophile Y-Z in a suitable solvent (such as DMSO and the like) at an elevated temperature (such as 130°C and the like) provides compound C5.
  • Any protecting groups are removed upon treatment with appropriate conditions (such as HC1 for a MOM protecting group or BBr, for OMe protecting group).
  • Compound D2 is prepared from compound DI (where Xi is chlorine, bromine and the like) by a Suzuki coupling with an aryl- or heteroaryl-boronic acid (or pinacol boronic ester) in the presence of a catalyst (such as Pd(dppf)C12 and the like) and base (such as aqueous K2CO3 and the like) in a suitable solvent (such as 1,4-di oxane and the like).
  • a catalyst such as Pd(dppf)C12 and the like
  • base such as aqueous K2CO3 and the like
  • a suitable solvent such as 1,4-di oxane and the like
  • Compound D2 is converted to Compound D3 by an addition of organometal halide (such as MeMgCl and the like) in a suitable solvent (such as THF and the like).
  • Compound D4 is formed upon treatment of compound D3 with an appropriate oxidant (such as DDQ and the like) in a suitable solvent (such as DCE and the like). SNAr reaction of D4 with a nucleophile Y-Z in a suitable solvent (such as DMSO and the like) at an elevated temperature (such as 130°C and the like) provides Compound D5. Any protecting groups are removed upon treatment with appropriate conditions (such as HC1 for a MOM protecting group or BBr, for OMe protecting group).
  • PC1 5 phosphorus perchloride or phosphorus pentachloride
  • Pd2(dba) 3 or Pd2dba 3 tris(dibenzylideneacetone)dipalladium(0)
  • Step 1 To a dry screw cap vial were added: 6-bromo-3-methylsulfanyl-l,2,4-triazine (100 mg, 0.49 mmol), [l,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.049mmol), (2-methoxy-4,6-dimethyl-phenyl)boronic acid (131 mg, 0.73 mmol) and aq. K2CO3 (2.0 M, 0.24 mL). The resulted mixture was degassed with argon for 10 min, then dioxane (2 mL) was added and the reaction was heated at 90 °C for 5 h.
  • Step 2 To a solution of 6-(2-methoxy-4,6-dimethyl-phenyl)-3-methylsulfanyl-l,2,4- triazine (50 mg, 0.19 mmol) in dichloromethane (3.0 mL) was added 3 -chloroperoxybenzoic acid (66 mg, 0.38 mmol) and the mixture was stirred for Ih at ambient temperature.
  • Step 3 To a solution 6-(2-methoxy-4,6-dimethyl-phenyl)-3-methylsulfonyl-l,2,4-triazine (40 mg, 0.14 mmol) in DMSO (1.0 mL) was added N,N-diisopropylethylamine (0.72 mL, 0.41 mmol) and (3R)-l-methylpiperi din-3 -amine (24 mg, 0.21 mmol).
  • Step 4 A solution of 6-(2 -methoxy -4, 6-dimethyl-phenyl)-N-[(3R)-l -methyl-3-piperidyl]- l,2,4-triazin-3-amine (28 mg, 0.086 mmol) in dichloromethane (2 mL) was cooled to 0°C. A solution of BBr 3 (1.0 M in CH2Q2, 1.0 mL) was added dropwise at 0°C. The resulting pale orange solution was allowed to warm to rt and stirred for 4h at rt. The reaction mixture was quenched with ice-water and the pH was adjusted to 10 by addition of 2.0 M NaOH.
  • Step 1 A solution of 3,5,6-trichloro-l,2,4-triazine (2.0 g, 10.8 mmol) in dry THF (22 mL) was cooled to -78 °C and methylmagnesium bromide (1 mol/L in THF) (11 mL,l 1.4 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 5h and then was allowed to warm to rt slowly. Upon completion, the reaction was quenched with water and partitioned between water and ethyl acetate.
  • Step 2 A suspension of 3,6-dichloro-5-methyl-l,2,4-triazine (40 mg, 0.24 mmol), (37?)-l- methylpiperi din-3 -amine (29 mg, 0.26 mmol, 1.05 eq.), and sodium bicarbonate (41 mg, 0.49 mmol) in 1,4-dioxane (1.0 mL) was stirred for 4h at 90 °C. The reaction was cooled to rt and concentrated.
  • Step 3 To a dry screw cap vial were added: 6-chloro-5-methyl-A-[rac-(3A)-l-methyl-3- piperidyl]-l,2,4-triazin-3-amine (39.7 mg, 0.16 mmol), 2-hydroxy-4- (trifluoromethyl)phenylboronic acid (44 mg, 0.21 mmol), XPhos Pd G4 (16 mg, 0.016 mmol). The resulted mixture was degassed with argon for 10 min, then dioxane (1.0 mL) and aq. K2CO3 (2.0 M, 0.22 mL 0.44 mmol) were added and the reaction was heated at 90 °C for 5 h.
  • Step 1 To a dry round bottom flask were added: (2-methoxy-4- (trifluoromethyl)phenyl)boronic acid (15 g, 68.2 mmol), 6-bromo-l,2,4-triazine-3,5-diol (18.3 g, 95.5 mmol), Pd(dppf)C12 (4.99 g, 6.82 mmol), K2CO3 (18.8 g, 136.4 mmol). The resulting mixture was degassed with argon for 10 min, then dioxane (160 mL) and water (40 mL) were added and the reaction was heated at 90 °C for 2 h.
  • (2-methoxy-4- (trifluoromethyl)phenyl)boronic acid 15 g, 68.2 mmol
  • 6-bromo-l,2,4-triazine-3,5-diol 18.3 g, 95.5 mmol
  • Pd(dppf)C12 (4.99 g
  • Step 2 To a solution of 6-(2-methoxy-4-(trifluoromethyl)phenyl)-l,2,4-triazine-3,5-diol (10.0 g, 34.8 mmol) in POCI3 (70 mL) was added PCI5 (14.5 g, 69.6 mmol) and N,N- dimethylaniline (10.5 g, 87 mmol). The mixture was stirred at 110°C for 2 hours. The reaction mixture was cooled to rt and solvent was removed under reduced pressure. The residue was dissolved in DCM, and then triethylamine was added to adjust the pH to 6.
  • Step 3 A solution of 3,5-dichloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-l,2,4-triazine (500 mg, 1.54 mmol) and Fe(acac)3 (55 mg, 0.155 mmol) in THF (10 mL) and NMP (1 mL) was cooled to -78°C. EtMgBr (2.33 mL, 2.33 mmol) was added then dropwise. The mixture was stirred at -78°C for 0.5 h.
  • Step 4 To a solution of 3-chloro-5-ethyl-6-(2-methoxy-4-(trifluoromethyl)phenyl)-l,2,4- triazine (100 mg, 0.315 mmol) in DMSO (1 mL) was added DIPEA (0.335 mL, 1.89 mmol) and (R)- 1-methylpiperi din-3 -amine (133 mg, 0.945 mmol). The mixture was stirred at 50°C for 2 h.
  • Step 5 To a solution of (R)-5-ethyl-6-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(l- methylpiperi din-3 -yl)-l, 2, 4-triazin-3 -amine (35 mg, 0.089 mmol) in CH2Q2 (2 mL) was added BBn (0.2 mL). The mixture was stirred at room temperature for 3 h, then quenched with MeOH (15 mL) and stirred for Ih at rt.
  • Example 4 Step 1 To a solution of 3,5-dichloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-l,2,4- triazine (300 mg, 0.93mmol) in dioxane (1.5 mL) were added dimethyl amine (2.0 M in THF, 0.46 mL, 0.93 mmol) and DIPEA (179 mg, 1.39 mmol). The mixture was stirred at 25°C for 1 h, then concentrated to give crude-chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-N,N-dimethyl- l,2,4-triazin-5-amine (160 mg, 52% yield) which was used in the next step without further purification. MS m/z 332.9, 334.9 [M+H] + .
  • Step 2 In a microwave tube were mixed 3-chloro-6-(2-methoxy-4- (trifluoromethyl)phenyl)-N,N-dimethyl-l,2,4-triazin-5-amine (160 mg, 0.48 mmol), DMSO (1 mL), DIPEA (717 mg, 5.56 mmol), and (R)- 1-methylpiperi din-3 -amine (520 mg, 2.78 mmol). The mixture was heated in a microwave at 120°C for 2 h.
  • Step 3 To a solution of (R)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-N5,N5-dimethyl- N3-(l-methylpiperidin-3-yl)-l,2,4-triazine-3,5-diamine (60 mg, 0.146 mmol) in CH2CI2 (2 mL) was added BBr, (0.2 mL). The mixture was stirred at rt for 3 h, then quenched with MeOH (15 mL) and stirred for Ih at rt.
  • Example 5 Using the procedure described for Example 4, above, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Example 5
  • Step 1 To a dry round bottom flask were added: (4-chloro-2-methoxyphenyl)boronic acid (23.3 g, 125 mmol), 6-bromo-l,2,4-triazine-3,5-diol (20 g, 104 mmol), Pd(dppf)C12 (7.55 g, 10.4 mmol) and K2CC>3(43 g, 312 mmol). The resulted mixture was degassed with argon for 10 min, then dioxane (300 mL) and water (100 mL) were added and the reaction was heated at 90 °C for 16 h.
  • Step 2 To a solution of 6-(4-chloro-2-methoxyphenyl)-l,2,4-triazine-3,5-diol (11.0 g, 43.3 mmol) in POCL (100 mL) were added PCI5 (22 g, 107 mmol) and N,N-dimethylaniline (16.3 g, 134.5 mmol). The mixture was stirred at 110°C for 10 h then cooled to rt, concentrated.
  • Step 3 A solution of 3, 5-dichloro-6-(4-chloro-2-methoxyphenyl)-l, 2, 4-triazine (500 mg, 1.72 mmol) and Fe(acac)3 (61 mg, 0.173 mmol) in THF (5 mL) and NMP (0.5 mL) was cooled to -78°C. Solution of MeMgBr (1.0M, 2.6 mL, 2.6 mmol) was added then dropwise. The mixture was stirred at -78°C for 6h.
  • Step 4 In a microwave vial were mixed 3-chloro-6-(4-chloro-2-methoxyphenyl)-5- m ethyl- 1,2, 4-triazine (110 mg, 0.41 mmol), ACN (3 mL), DIPEA (0.36 mL, 2.03 mmol) and (A)-l-methylpiperidin-3-amine (137 mg, 1.2 mmol). The mixture was heated in a microwave at 70°C for 3 h.
  • Step 5 To a dry microwave vial were added: (R)-6-(4-chloro-2-methoxyphenyl)-5- methyl-N-(l-methylpiperi din-3 -yl)-l, 2, 4-triazin-3 -amine (200 mg, 0.57 mmol), 4, 4,5,5- tetramethyl-2-vinyl-l,3,2-dioxaborolane (177 mg, 1.15 mmol), XPhos Pd G3 (48 mg, 0.057 mmol) and K2CO3 (236.3 mg, 1.71 mmol).
  • Step 6 To a solution of (R)-6-(2-methoxy-4-vinylphenyl)-5-methyl-N-(l- methylpiperi din-3 -yl)-l, 2, 4-triazin-3 -amine (90 mg, 0.27 mmol) in EtOAc (3 mL) was added Pd/C (9 mg, 5% Pd). The mixture was subjected to 15 psi H2 and stirred for 2 h. The mixture was filtered, solids were washed with MeOH.
  • Step 7 To a solution of (R)-6-(4-ethyl-2-methoxyphenyl)-5-methyl-N-(l- methylpiperi din-3 -yl)-l, 2, 4-triazin-3 -amine (40 mg, 0.12 mmol) in CH2Q2 (2 mL) was added solution of BBr 3 (1.0 M in CH2Q2, 0.4 mL, 0.4 mmol). The mixture was stirred at room temperature for 30 min, then quenched with MeOH (15 mL) and stirred for Ih at rt.
  • Step 1 To a dry screw cap vial were added: 6-bromo-3-(methylthio)-l,2,4-triazine (700 mg, 3.4 mmol), Pd XPhos G3 (170 mg, 0.2 mmol), 2-(2-fluoro-6-(methoxymethoxy)-4- methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.3 g, 4.42 mmol) and aq. K2CO3 (2.0 M, 3.5 mL). The resulted mixture was degassed with argon for 10 min, then dioxane (6 mL) was added and the reaction was heated at 90 °C for 1 hour.
  • Step 2 A solution of 6-(2-fluoro-6-(methoxymethoxy)-4-methylphenyl)-3-(methylthio)- 1,2,4-triazine (800 mg, 2.70 mmol) in THF (2.0 mL) was cooled to 0°C. Solution of MeMgBr (1.0 M in THF, 6.0 mL, 6.0 mmol) was added then dropwise under Nitrogen. The mixture was then stirred at 0°C for Ih then quenched with aqueous ammonium chloride solution while stirred at 0°C.
  • MeMgBr 1.0 M in THF, 6.0 mL, 6.0 mmol
  • Step 3 To a solution of 6-(2-fluoro-6-(methoxymethoxy)-4-methylphenyl)-3- (methylthio)-l,2,4-triazine (316 mg, l.Olmmol) in CH2CI2 (4.0 mL) was added 2,3-dichloro-5,6- di cyano- 1,4-benzoquinone (340 mg, 1.50 mmol). The mixture was stirred at rt for Ih. The reaction was then partitioned between CH2Q2 and water. Washed with aqueous 2M K2CO3 solution and water.
  • Step 4 To a solution of 6-(2-fluoro-6-(methoxymethoxy)-4-methylphenyl)-5-methyl-3- (methylthio)-l,2,4-triazine (200.0 mg, 0.65 mmol) in CH2Q2 (2.0 mL) at 0°C was added mCPBA (200 mg, 0.81 mmol). The mixture was stirred at 0°C for 30.0 min. Upon completion, the reaction was concentrated and 6-(2-fluoro-6-(methoxymethoxy)-4-methylphenyl)-5-methyl- 3-(methylsulfinyl)-l,2,4-triazine used for following step without further purification. MS m/z: 326.1 [M+H] +
  • Step 5 To a solution of crude 6-(2-fluoro-6-(methoxymethoxy)-4-methylphenyl)-5- methyl-3-(methylsulfinyl)-l,2,4-triazine (60 mg, 0.18 mmol) in MeCN (0.50 mL) were added DIPEA (0.40 mg, 0.30 mmol) and (R)- 1-methylpiperi din-3 -amine (100 mg, 0.90 mmol). The mixture was heated at 70°C for 3 h.
  • Monocytic THP-1 cells (ATCC: TIB-202) were maintained in growth media consisting of RPMI 1640 medium (ThermoFisher, Cat# 11875-085), 10% FBS (ThermoFisher) and 0.05mM P -mercaptoethanol (ThermoFisher, Cat# 21985-023), according to the provider’s instructions.
  • the cell concentration was adjusted to 7.5xl0 5 cells/mL, and plated in complete growth media with a final concentration of lOOng/mL phorbol 12-myristate 13-acetate (PMA, Sigma #P8139).
  • PMA lOOng/mL phorbol 12-myristate 13-acetate
  • ⁇ InM is listed as *****; data 1-10 nM is listed as ****; data 10-100 nM is listed as ***; data 100-300 nM is listed as **; and data 300-1000nM is listed as *.

Abstract

La présente invention concerne de nouveaux composés de formule I, dans laquelle chaque élément parmi R1, R2, R3, Y et Z sont tels que définis dans la description, qui inhibent l'activité inflammasome de la protéine 3 du récepteur de type NOD (NLRP3). L'invention concerne en outre les procédés pour leur préparation, des compositions pharmaceutiques et des médicaments les contenant, et leur utilisation dans le traitement de maladies et de troubles médiés par NLRP3.
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