[go: up one dir, main page]

WO2019217822A1 - Composés et procédés d'utilisation de composés pour la prévention ou le traitement d'états inflammatoires - Google Patents

Composés et procédés d'utilisation de composés pour la prévention ou le traitement d'états inflammatoires Download PDF

Info

Publication number
WO2019217822A1
WO2019217822A1 PCT/US2019/031729 US2019031729W WO2019217822A1 WO 2019217822 A1 WO2019217822 A1 WO 2019217822A1 US 2019031729 W US2019031729 W US 2019031729W WO 2019217822 A1 WO2019217822 A1 WO 2019217822A1
Authority
WO
WIPO (PCT)
Prior art keywords
chloro
sulfamoyl
propyl
thiazol
phenoxy
Prior art date
Application number
PCT/US2019/031729
Other languages
English (en)
Inventor
Olga BABICH
Tina Garyantes
Yanlin WANG-FISCHER
Original Assignee
Chromocell Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chromocell Corporation filed Critical Chromocell Corporation
Publication of WO2019217822A1 publication Critical patent/WO2019217822A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • compositions and methods for preventing or treating inflammatory conditions are provided herein.
  • NSAIDs Nonsteroidal anti-inflammatory drugs
  • NSAIDs are the most commonly prescribed drugs to treat for example post-traumatic inflammation and pain.
  • NSAIDs carry significant risk of adverse side effect, such as bleeding in the gastrointestinal tract
  • the present disclosure provides methods for preventing or treating inflammatory conditions comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to Formula (G) or a pharmaceutically acceptable salt, or tautomeric form thereof, or any combination of the foregoing compounds.
  • the present disclosure provides methods for preventing or treating inflammatory conditions induced by, or associated with autoimmune, metabolic, or cardiovascular disease.
  • the present disclosure provides methods for preventing or treating inflammatory conditions induced, or associated with surgery, or trauma.
  • the at least one symptom induced by or associated with inflammatory conditions is one chosen from edema, swelling, warmth, redness, change in level of a molecular inflammatory marker (e.g., increase in the level of at least one of pro- inflammatory marker, decrease in the level of at least one anti-inflammatory marker, or both), presence of inflammatory disease, and pain.
  • the symptom induced or associated with inflammatory conditions include, but are not limited to any one of the clinical signs of inflammatory disease listed in Table 4.
  • the at least one symptom induced by or associated with inflammatory conditions are a change in at least one molecular inflammatory marker.
  • the change in molecular marker is an increase in at least one pro-inflammatory marker, a decrease in at least one anti-inflammatory marker, or both.
  • the at least one symptom induced by or associated with inflammatory conditions is one chosen from edema, swelling, redness, warmth.
  • the at least one symptom induced by or associated with inflammatory conditions is one chosen from edema, swelling, redness, warmth, and pain. [0009] In one embodiment, the at least one symptom induced by or associated with inflammatory conditions is not pain.
  • a compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof wherein the compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof, or any combination of the foregoing compounds is administered for the duration of the inflammatory condition.
  • a compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof wherein the compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof, or any combination of the foregoing compounds is administered for at least as along as the duration of the inflammatory condition.
  • a compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof wherein the compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof, or any combination of the foregoing compounds is administered prior to surgery.
  • a compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof wherein the compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof, or any combination of the foregoing compounds is administered following detection of the inflammatory condition.
  • Z is -O- or -S-;
  • X is (C 6 -Cio)aryl or 5- or 6-membered heteroaryl
  • Ri is a partially unsaturated or aromatic 5- or 6-membered heterocycle
  • R 2 is independently at each occurrence -F, -Cl, -Br, -CH 3 or -CN;
  • R 3 is independently at each occurrence -H, -F, -Cl, -Br, -CF 3 , -OCF 3, -CN, (Ci-Ci 2 )alkyl, or (Ci-Ci 2 )alkoxy;
  • R 4 and Rs are each independently H, (Ci-C9)alkyl, (C 4 -Ci 2 )cycloalkyl, or R 4 and R 5 together form a 5- to 7-membered heterocycloalkyl ring; with the proviso that:
  • R 4 and Rs are not both H
  • R 4 and Rs independently or said heterocycloalkyl ring formed by R 4 and R 5 together is substituted with 1 or 2 substituents selected from the group consisting of -C0 2 H, -C0 2 R 6 , -CN, -OH, -CONR 7 Rs, and -NR 7 Rs; wherein:
  • R 6 is (Ci-Ci 2 ) alkyl
  • R 7 and Rs are each independently H, (Ci-Ci 2 )alkyl, or R 7 and Rs together form a 4- to 7-membered heterocycloalkyl ring;
  • R 9 is (Ci-C 6 )alkyl, (C 3 -Cs)cycloalkyl, pyrazolyl or pyridinyl; wherein R 9 is optionally further substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COORn, -CONR11R12, -SO2R11, -SO2NR11R12, -OH, -CN, -OR11, and -NR 11 R 12 ; wherein Rn and R 12 may form a 6 membered heterocycloalkyl ring Rio is R 11 , (C 3 -C 6 )alkynyl, (C 3 -C 6 )alkenyl, -COR 11 , -COOR 11 , -SO 2 R 11 ,
  • R9 and Rio together form a piperazinone or a 4-to 8- membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 substituents selected from the group consisting of - COOH, -COORn, -CH 2 -COOR 11 , -OH, -NH 2 , -CN, and (Ci-C 8 )alkoxy; or R 9 and Rio together form a unsubstituted 4- to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is fused with a 5-membered heteroaryl; and R 11 and R 12 are independently H or (Ci-C 6 )alkyl, optionally substituted with 4- to 8- membered heterocycloalkyl ring; and
  • n are each independently 1, 2, 3, or 4.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein Y is -(CH 2 ) 3 -NR 9 R IO .
  • the compounds of Formula (G) for use in the methods disclosed are those wherein Ri is an aromatic 5- or 6-membered heterocycle, with 1-3 heteroatoms independently selected from the group consisting of N, O, and S.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein Ri is pyridyl or pyrimidinyl.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein Ri is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein Ri is thiazolyl. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein Ri is l,2,4-thiadiazol-5-yl.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein R 2 is independently at each occurrence -F or -Cl.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein n is 1, 2, or 3. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein n is 2.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein Z is -O .
  • the compounds of Formula (G) for use in the methods disclosed are those wherein R 3 is independently at each occurrence -H, -F, -Cl, or -Br. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein R 3 is -H or -Cl. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein R 3 is -Cl.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein m is 1, 2, or 3. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein m is 1.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein R 9 is (Ci-C 6 )alkyl; wherein R 9 is optionally further substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOMe, -CONH 2 , and -NH 2 .
  • the compounds of Formula (G) for use in the methods disclosed are those wherein R 9 is methyl or ethyl. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein R 9 is further substituted with -COOH. [0023] In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein Rio is -H, -COMe, -COOEt. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein Rio is -H or -COMe. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein Rio is -H.
  • the compounds of Formula (G) for use in the methods disclosed are those Rio is H and R 9 is (Ci-C 6 )alkyl, wherein R 9 is further substituted with - COR 11 R 12 , and wherein Rn and R 12 are independently H or (Ci-C 6 )alkyl.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein the R 9 is methyl.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein the R 9 is further substituted with -CONH 2 .
  • the compounds of Formula (G) for use in the methods disclosed are those wherein R 9 and Rio together form a 4 to 8 membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 groups selected from the group consisting of -COOH, -COOMe, -COOEt, -CH 2 -COOH, and -NH 2.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein R 9 and Rio together form a 4 to 8 membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 groups selected from the group consisting of -COOH, -CH 2 -COOH, and -NFb .
  • the compounds of Formula (G) for use in the methods disclosed are those wherein R 9 and Rio together form a piperidine substituted with 1 or 2 groups selected from the group consisting of -COOH, -COOMe, - COOEt, -CH 2 -COOH, -CH 2 -COOMe, -CH 2 -COOEt, and -NH 2.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein R 9 and Rio together form a piperidine substituted with 1 or 2 groups selected from the group consisting of - COOH, -CH 2 -COOH, and -NH 2.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein X is 5- or 6-membered heteroaryl. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein X is pyridyl or pyrimidinyl. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein X is pyridyl.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein R 4 is H and Rs is (Ci-C9)alkyl.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein Rs is methyl or ethyl, substituted with 1 or 2 substituents selected from the group consisting of -C0 2 H, -CO2R6, and -CONR 7 R S .
  • the compounds of Formula (G) for use in the methods disclosed are those wherein R 6 is (Ci-C 6 )alkyl.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein R 5 is methyl or ethyl, substituted with -CO2H.
  • the compounds of Formula (G) for use in the methods disclosed are those wherein Y is 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-(2-yl or 3-yl). In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein Y is 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-3-yl.
  • the compound for use in the methods disclosed is N-(0032]
  • the compound for use in the methods disclosed is N-(0033]
  • the compounds for use in the methods disclosed herein are ary loxy sulfonamides, sulfonated amines, aryloxysulfonylated amides, acylsulfonyl ureas, arylindazole sulfonylated amides, bicyclic core sulfonamides, substituted piperazine or piperazine methylenoxy arylsulfonamides, benzo-oxazolone core sulfonamides,
  • the method comprises
  • the compound for use in the methods disclosed herein is a
  • the NaVl.7 inhibitor for use in the methods disclosed herein is selective for the inactivated state of the NaVl.7 channel.
  • the methods disclosed herein wherein the inflammatory condition is associated with an increase in at least one anti-inflammatory marker, a decrease in at least one pro-inflammatory marker, or both.
  • the methods disclosed herein wherein the administration of the compound(s) disclosed herein to a subject in need thereof, results in a decrease of at least one pro-inflammatory marker or an increase in at least one anti-inflammatory marker, or both.
  • the methods disclosed herein wherein administration of the compound(s) disclosed herein to a subject in need thereof, results in an improvement of one or more symptoms of inflammation.
  • the one or more symptoms of inflammation is chosen from: swelling, edema, redness, warmth, and pain.
  • the methods disclosed herein wherein administration of the compound(s) disclosed herein to a subject in need thereof results in a reduction in immune cell infiltration into tissue.
  • the inflammatory condition is chosen from: atherosclerosis,
  • autoimmune hepatitis primary biliary cirrhosis (PBC), asthma, alopecia areata, autoimmune urticarial, bullous pemphigoid, dermatitis herpetiformis, discoid lupus erythematosus, epidermolysis bullosa acquisita, linear IgA disease, pemphigus vulgaris, Mucha-Habermann disease, psoriasis, vitiligo, Addison's disease, autoimmune polyendocrine syndrome (APS) type 1, autoimmune polyendocrine syndrome (APS) type 2, autoimmune polyendocrine syndrome
  • APS autoimmune pancreatitis
  • diabetes mellitus type 1 autoimmune thyroiditis, Ord's thyroiditis
  • Graves' disease Sjogren's syndrome, coeliac disease, inflammatory diseases, autoimmune neutropenia, idiopathic thrombocytopenic purpura, pernicious anemia, ankylosing spondylitis, enthesitis-related arthritis, juvenile arthritis, mixed connective tissue disease, psoriatic arthritis, relapsing polychondritis, rheumatic fever, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, fibromyalgia, myasthenia gravis, Guillain-Barre syndrome, autoimmune uveitis, autoimmune inner ear disease, Meniere's disease, granulomatosis with polyangiitis, vasculitis, post-surgical or post-traumatic inflammation.
  • the methods as disclosed herein wherein the inflammatory condition is not associated with pain.
  • a disease selected from: Alzheimer’s, Atheros
  • Pernicious anemia Primary biliary cirrhosis (PBC), Psoriasis, Rheumatic fever, Sjogren’s syndrome, Autoimmune myocarditis, Autoimmune cardiomyopathy, Coxsackie myocarditis, and Vitiligo.
  • PBC Primary biliary cirrhosis
  • Psoriasis Psoriasis
  • Rheumatic fever Psoriasis
  • Sjogren’s syndrome Autoimmune myocarditis
  • Autoimmune cardiomyopathy Autoimmune cardiomyopathy
  • Coxsackie myocarditis Coxsackie myocarditis
  • Vitiligo Vitiligo.
  • the methods as disclosed herein wherein the inflammatory condition is associated with pain.
  • the methods as disclosed herein wherein the inflammatory condition is associated with pain and wherein the inflammatory condition is induced by or
  • a disease selected from: Addison’s disease, Ankylosing Spondylitis,
  • Autoimmune pancreatitis Autoimmune pancreatitis (AIP), Autoimmune uveitis, Dermatomyositis, Diabetes mellitus type I, Enthesitis-related arthritis, Diverticulitis, Fibromyalgia, Granulomatosis with polyangiitis, Inflammatory Bowel diseases, Juvenile Arthritis, Mixed connective tissue disease, Mucha- Habermann disease, Pemphigus vulgaris, Post-surgical inflammation, Post-traumatic
  • the methods as disclosed herein further comprise the step of selecting a subject in need of prevention or treatment of an inflammatory condition.
  • the subject is a mammal. In one embodiment, the subject is a human.
  • a method for treating or preventing at least one inflammatory condition in a subject in need thereof comprising detecting at least one symptom induced by or associated with an inflammatory condition and administering an effective amount of a compound according to Formula (G).
  • the symptom is swelling, edema, redness, warmth, or pain.
  • a method for treating or preventing at least one inflammatory condition in a subject in need thereof comprising measuring an increase in at least one pro-inflammatory marker or a decrease in at least one anti-inflammatory marker, or both, determining an decrease in at least one anti-inflammatory marker, an increase in at least one pro- inflammatory, or both and administering an effective amount of a compound according to Formula (G).
  • the methods as disclosed herein wherein the pro- inflammatory marker is infiltration of inflammatory cells into the site of inflammation, proinflammatory cytokines, tumor necrosis factor (TNF), interferon gamma (IFN-gamma), MCP-1, MCP-2, MCP-3, GROa, NGF beta, RANTES, ENA-78, MIP-Ia, PDGF-BB, FGF-2, EGF, M-CSF, PLGF, IL-9, GM-CSF, IL-la, CD40L, IL-15, IL-18, IL-2, IL-31, IL-7, TRAIL,
  • TNF tumor necrosis factor
  • IFN-gamma interferon gamma
  • TSLP TWEAK
  • VEGF-A IL-Ib
  • IL-8 TNF-a
  • APRIL IFN-a
  • IL-16 IL-23
  • IL-27 BAFF
  • IFNy IL-3
  • IP-10 IP-10
  • TNF-R2 MIR-Ib
  • IL-l2p70 IL-17A
  • IL-la IL-2R
  • IL-21 MDC
  • MIPla MIP3a
  • Eotaxin Eotaxin-2
  • Eotaxin-3 G-CSF
  • MIF SCF
  • SDF-la TNF-b
  • NMP-l BLC
  • CD30 CD30
  • IL-22 1-TAC
  • MIG VEGF-D
  • LIF IL-6
  • Fractalkine granulocyte-macrophage colony stimulating factor
  • chemokine granulocyte-macrophage colony stimulating factor
  • inflammatory marker is an anti-inflammatory cytokine, IL-10, IL-13, IL-20, IL-4, IL-5, IL-1RA, BDNF, FGF-basic, NGF-b, HGF, and IFN-alpha or transforming growth factor-beta (TGF-b).
  • the methods as disclosed herein comprise administering a therapeutically effective amount to alleviate an inflammatory condition in a subject, wherein a compound according to Formula (G), or a pharmaceutically acceptable salt, or tautomeric form thereof, shows reduction the inflammatory condition at a dose between 0.01 mg/kg and 10,000 mg/kg, at a dose between 0.1 mg/kg and 1,000 mg/kg, at a dose between 0.5 mg/kg and 100 mg/kg, or at a dose between 1 mg/kg to 50mg/kg.
  • a compound according to Formula (G), or a pharmaceutically acceptable salt, or tautomeric form thereof shows reduction the inflammatory condition at a dose between 0.01 mg/kg and 10,000 mg/kg, at a dose between 0.1 mg/kg and 1,000 mg/kg, at a dose between 0.5 mg/kg and 100 mg/kg, or at a dose between 1 mg/kg to 50mg/kg.
  • the methods as disclosed herein, wherein the compound(s) is administered orally, intravenously, topically, transdermally, patch, buccal, intramuscular, interperitoneally, or subcutaneously.
  • composition comprising a compound according to Formula
  • inflammatory condition is induced by, or associated with autoimmune, metabolic, and cardiovascular diseases.
  • the inflammatory condition is induced by or associated with surgery or trauma.
  • an article of manufacture comprising packaging material and a pharmaceutical agent contained within said packaging material, wherein said packaging material comprises a label which indicates said pharmaceutical may be administered, for a sufficient term at an effective dose, for preventing and/or treating inflammatory conditions together with a pharmaceutically acceptable carrier, wherein the pharmaceutical agent comprises a compound according to Formula (G), or a pharmaceutically acceptable salt, or a tautomeric form thereof.
  • kits for preventing or treating inflammatory conditions comprising administering to a subject in need thereof a therapeutically effective amount of a compound inhibiting NaVl.7.
  • the compound inhibiting NaVl.7 is at least one compound according to Formula (G).
  • A“Compound” or“Compounds” as used herein comprise a compound that is known to inhibit the signaling of NaVl .7, a compound of Formula (I), a compound of Formula (G), a compound of Formula (la), a compound of Formula (I’a), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, a compound listed in Table 2, or a compound listed in Table 3, or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof .
  • A“pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts of the
  • Compounds include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N’- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.
  • Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and
  • A“stereoisomer” or“stereoisomeric form” refers to one stereoisomer of a
  • stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • the Compounds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.
  • mixtures comprising equal or unequal amounts of the enantiomers of a particular Compound may be used in methods and compositions disclosed herein. These isomers may be
  • Tautomers refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
  • An“aryl” group is an aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring ( e.g ., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl).
  • aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms in the ring portions of the groups.
  • Particular aryls include, but are not limited to, phenyl, naphthyl and the like.
  • A“heteroaryl” group is an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms.
  • heteroaryl groups contain 5 to 6 ring atoms, and in others from 6 to 9 or even 6 to 10 atoms in the ring portions of the groups. Suitable heteroatoms include oxygen, sulfur and nitrogen.
  • the heteroaryl ring system is monocyclic or bicyclic.
  • Examples include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., l,2,4-thiadiazolyl), pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (for example, pyrrolopyridyl or 1H- pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (for example, lH-benzo[d] imidazolyl), imidazopyridyl, pyrazolopyridyl, triazolop
  • A“partially unsaturated or aromatic heterocycle” is a partially unsaturated or aromatic ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms. If the“partially unsaturated or aromatic heterocycle” is an aromatic heterocycle, then the aromatic heterocycle is a“heteroaryl” as defined above. In one embodiment, the partially unsaturated or aromatic heterocycle is a partially unsaturated or aromatic 5- or 6-membered heterocycle.
  • partially unsaturated heterocycles include, but are not limited to, groups such as 2,5-dihydro-lH-pyrrolyl, 2,5-dihydrofuranyl, 2,5-dihydrothiophenyl, 4,5-dihydrooxazolyl, 4,5-dihydrothiazolyl, 4,5- dihydro-lH-imidazolyl, 4,5-dihydro-lH-l,2,3-triazolyl, l,2,5,6-tetrahydropyridinyl, and 1, 4,5,6- tetrahydropyrimidinyl groups.
  • A“heterocycloalkyl” group is a non-aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S and N.
  • Examples of a heterocycloalkyl group include, but are not limited to, morpholinyl, pyrrolidinyl, piperazinyl, (l,4)-dioxanyl, and (l,3)-dioxolanyl.
  • Heterocycloalkyls can also be bonded at any ring atom ( i.e ., at any carbon atom or heteroatom of the heterocyclic ring).
  • the heterocycloalkyl is a 5- or 6-membered or 4- to 8-membered heterocycloalkyl.
  • An“alkyl” group is a saturated straight chain or branched non-cyclic hydrocarbon having, for example, from 1 to 12 carbon atoms, 1 to 9 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 2 to 6 carbon atoms.
  • Representative alkyl groups include -methyl, -ethyl, - «- propyl, - «-butyl, - «-pentyl and - «-hexyl; while branched alkyls include -isopropyl, -sec- butyl, -zso-butyl, -ieri-butyl, - /.so- pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3- dimethylbutyl and the like
  • An“alkenyl” group is a partially unsaturated straight chain or branched non- cyclic hydrocarbon having, for example, from 3 to 6 carbon atoms, 3 to 4 carbon atoms, or 3 carbon atoms.
  • Representative alkenyl groups include allyl, propenyl and the like.
  • An“alkynyl” group is a partially unsaturated straight chain or branched non- cyclic hydrocarbon having, for example, from 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 3 carbon atoms. Representative alkynyl groups include propynyl, butynyl and the like.
  • A“cycloalkyl” group is a saturated cyclic alkyl group of from 3 to 12 carbon atoms having a single cyclic ring or multiple condensed or bridged rings. In some embodiments, the cycloalkyl group has 4 to 12 ring members, whereas in other embodiments the number of ring carbon atoms ranges, for example, from 3 to 5, 3 to 6, or 3 to 7.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, or multiple or bridged ring structures such as adamantyl and the like.
  • A“subject in need thereof’ refers to a mammal (e.g ., human, dog, horse, or cat) in need of treatment with any method provided herein.
  • the subject is a patient.
  • anti-inflammatory refers to serving to reduce one or more symptoms of inflammation, such as, but not limited to, swelling, edema, redness, warmth, and pain.
  • anti-inflammatory agent refers to an agent or drug that acts to prevent or reduce one or more symptoms of inflammation, such as, but not limited to, swelling, edema, redness, warmth, and pain.
  • pro -inflammatory refers to capable of promoting inflammation.
  • anti-inflammatory refers to capable of preventing or treating inflammation.
  • the term“change in molecular inflammatory marker” or“change in molecular marker”, or“change in inflammatory marker” as used herein, refers to a change (increase or decrease) in the level of at least one molecular inflammatory marker.
  • Figures 1A &1B show the effect of Compound 49 treatment on cytokines plasma levels in the rat STZ-induced model of diabetes.
  • Figure 2A shows the effect of Compound 49 on the number of inflammatory cells that infiltrated into the islets of the pancreas in a rat STZ diabetes model.
  • the diabetic challenge induced inflammatory cells infiltrating into the pancreas islets in the vehicle group.
  • Treatment with Compound 49 significantly reduced the inflammatory cell infiltration into islets after 8 weeks of treatment (week 20) and at 5 weeks after treatment cessation (week 25).
  • Figure 2B shows the effect of Compound 49 on the density of b-cells in islets of the pancreas after diabetic induction via STZ injection.
  • week 20 After 7-8 weeks of treatment (day 9 to week 8 for early treatment (“early”) group and weeks 12 to 20 for late treatment (“late”) group, although the total area of pancreas islets was reduced (data not shown) after a STZ injection compared to non-diabetic, sham animals, both early and late treatments with Compound 49 significantly increased b-cell density per unit of islet (Fig. 2B).
  • Figures 3A-D show the effect of early treatment of Compound 49 on levels of beta cells secreted metabolic hormones, insulin and amylin, in the blood plasma of STZ-induced
  • FIGS 3C-D show the effect of early treatment of Compound 49 on levels of metabolic hormones in the blood plasma secreted from other cells (pancreas PP cells and intestinal L-cells). Plasma samples for hormone tests were collected at week 20, 12 weeks after the cessation of 7 weeks of treatment (early treatment group). STZ induced diabetes
  • Fig.3A significantly reduced insulin levels in diabetic rats compared to sham
  • Fig.3B Early treatment with Compound 49 improved insulin and amylin levels
  • Fig.3C-D both hormones are secreted from beta-cells
  • Fig.3C-D synergistic partner hormones
  • Polypeptide (PP) is secreted from pancreas PP cells (Fig.3C) and Glucagon-Like Peptide (GLP- 1), an incretin, secreted by intestinal enteroendocrine L-cells (Fig.3D).
  • GLP1 receptor is known to be expressed in pancreatic beta cells.
  • the vagus nerve is the major regulator to the secretion on these metabolic hormones (Williams JA. The Pancreapedia 2014, and Rocca AS, Role of the Vagus Nerve in Mediating Proximal Nutrient- Induced Glucagon-Like Peptide- 1 Secretion. Endocrinology, Vol. 140, No. 4, 1999).
  • Inflammatory and diabetic damage to the vagus nerve may disturb the function of the nerve and interfere with the secretion of these metabolic hormones.
  • Treatment with Compound 49 significantly increased PP (Fig.3C) and GLP-l levels (Fig.3D) compared to sham or vehicle treated animals.
  • Figures 4A-D show the effect of the treatment with Compounds as disclosed herein on animal health beyond pain in the STZ-induced diabetic model. Additional scores were implemented to assess animals’ overall well-being. Fecal consistency (Fig.4A), fur-cleaning scores (Fig. 4B), and“animals selected” for supplemental care as judged by the facilities’ veterinarian, expressed as % (Fig. 4C) are signs of overall animal health. Fecal consistency is also a sign of metabolic disorders and vagus nerve damage from inflammation and diabetes (Fig. 4A). Figure 4D shows the effect of compounds on animal coordination as measured in the foot fault test.
  • Compound 49 was dosed in the animal’s drinking water ad libitum for 7-8 weeks. Early treatment was started on day 9 after a STZ injection and stopped at week-8 (light grey shaded area). Late- treatment was started at week- 12 after STZ injection and stopped at week-20 (dark grey shaded area). Both Early- and Late- treatment with Compound 49 improved animal overall well-being as measured by improved fecal consistency (Fig.4 A), cleanliness of fur (Fig. 4B) and significantly reduced number of animals selected for supplemental care by the facility’s veterinarian (Fig.
  • Figure 5 shows the effect of Compound 49 on inflammatory paw edema induced by CFA injection.
  • Compound 49 at 25mg/kg or at 50mg/kg or vehicle (20% PEG600 / 0.5% Methocellulose / 0.2% Tween 80 / water) at 4ml/kg was given by oral (p.o.) gavage twice a day (b.i.d) for 7 days starting on day 1 after a CFA injection. Paw thickness was measured on day 5. The thickness was significantly increased in vehicle treated group in comparison with sham group.
  • Compound 49 at both 25mg/kg and 50 mg/kg bid significantly reduced the swelling as compared to vehicle.
  • Figures 6A, 6B, and 6C show the effect of Compound 11 dosed at 30mg/kg /day by intraperitoneal (ip) (Fig. 6A), Compound 49 dosed at 1,10, 30, or lOOmg/kg by ip (Fig. 6B), and Compound 54 dosed at 30mg/kg by po (Fig. 6C) on post-surgical paw edema.
  • Ibuprofen Sigma-Aldrich, Cat#: I7905-5G
  • Fig. 7C vehicle (2% PEG600 / water)
  • the present disclosure provides methods for preventing or treating inflammatory conditions comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to Formula (G) or a pharmaceutically acceptable salt, or tautomeric form thereof, or any combination of the foregoing compounds. In one embodiment, the present disclosure provides methods for preventing or treating
  • the present disclosure provides methods for preventing or treating inflammatory conditions induced, or associated with surgery, or trauma.
  • the at least one symptom induced by or associated with inflammatory conditions is one chosen from edema, swelling, warmth, redness, and pain.
  • the at least one symptom induced by or associated with inflammatory conditions is a change in at least one molecular inflammatory marker.
  • the change in molecular inflammatory marker is an increase in at least one pro-inflammatory marker, a decrease in at least one anti-inflammatory marker, or both.
  • the symptom induced or associated with inflammatory conditions include, but are not limited to any one of the clinical signs of inflammatory disease listed in Table 4.
  • the at least one symptom induced by or associated with inflammatory conditions is one chosen from edema, swelling, redness, and warmth.
  • the at least one symptom induced by or associated with inflammatory conditions is not pain.
  • a compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof wherein the compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof, or any combination of the foregoing compounds is administered for the duration of the inflammatory condition.
  • a compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof wherein the compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof, or any combination of the foregoing compounds is administered for at least as along as the duration of the inflammatory condition.
  • a compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof wherein the compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof, or any combination of the foregoing compounds is administered prior to surgery.
  • a compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof wherein the compound according to Formula (G) or a pharmaceutically acceptable salt, or a tautomeric form thereof, or any combination of the foregoing compounds is administered following detection of the inflammatory condition.
  • Z is -O- or -S-;
  • X is (C 6 -Cio)aryl or 5- or 6-membered heteroaryl
  • Ri is a partially unsaturated or aromatic 5- or 6-membered heterocycle
  • R 2 is independently at each occurrence -F, -Cl, -Br, -CH 3 or -CN;
  • R 3 is independently at each occurrence -H, -F, -Cl, -Br, -CF 3 , -OCF 3, -CN, (Ci-Ci 2 )alkyl, or (Ci-Ci 2 )alkoxy;
  • R 4 and Rs are each independently H, (Ci-C9)alkyl, (C 4 -Ci 2 )cycloalkyl, or R 4 and R 5 together form a 5- to 7-membered heterocycloalkyl ring; with the proviso that:
  • R 4 and Rs are not both H
  • R 4 and Rs independently or said heterocycloalkyl ring formed by R 4 and R 5 together is substituted with 1 or 2 substituents selected from the group consisting of -C0 2 H, -C0 2 R 6 , -CN, -OH, -CONR 7 Rs, and -NR 7 Rs; wherein:
  • R 6 is (Ci-Ci 2 ) alkyl
  • R 7 and Rs are each independently H, (Ci-Ci 2 )alkyl, or R 7 and Rs together form a 4- to 7-membered heterocycloalkyl ring;
  • R 9 is (Ci-C 6 )alkyl, (C 3 -Cs)cycloalkyl, pyrazolyl or pyridinyl; wherein R 9 is optionally further substituted with 1 or 2 substituents selected from the group consisting
  • Rn and RI 2 may form a 6 membered heterocycloalkyl ring
  • Rio is Rn, -COR 11 , -COOR 11 , -SO 2 R 11 , 5-methyl-2-oxo-l,3-dioxol-4-yl,
  • R 9 and Rio together form a piperazinone or a 4-to 8- membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOR 11 , -CH 2 - COORn, -OH, -NH 2 , -CN, and (Ci-C 8 )alkoxy;
  • R 11 and R 12 are independently H or (Ci-C 6 )alkyl, optionally substituted with 4- to 8- membered heterocycloalkyl ring;
  • n are each independently 1, 2, 3, or 4.
  • Rio is R 11 , (C 3 -C 6 )alkynyl, (C 3 -C 6 )alkenyl, -COR 11 , -COOR 11 , -SO 2 R 11 ,
  • R 9 and Rio together form a piperazinone or a 4-to 8- membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOR 11 , -CH 2 - COOR 11 , -OH, -NH 2 , -CN, and (Ci-Cs)alkoxy; or R 9 and Rio together form a unsubstituted 4- to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is fused with a 5-membered heteroaryl; and
  • the compounds of Formula (I) or Formula (G) are those wherein Y is -(CH 2 )3-NR9RIO.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is an aromatic 5- or 6-membered heterocycle, with 1-3 heteroatoms independently selected from the group consisting of N, O, and S.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is pyridyl or pyrimidinyl.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is thiazolyl.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is l,2,4-thiadiazol-5-yl.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is thiadiazol-4-yl.
  • the compounds of Formula (I) or Formula (G) are those wherein R 2 is independently at each occurrence -F or -Cl.
  • the compounds of Formula (I) or Formula (G) are those wherein n is 1, 2, or 3. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein n is 2. [00102] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Z is -0-.
  • the compounds of Formula (I) or Formula (G) are those wherein R 3 is independently at each occurrence -H, -F, -Cl, or -Br. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R 3 is -H or -Cl.
  • the compounds of Formula (I) or Formula (G) are those wherein R 3 is -Cl.
  • the compounds of Formula (I) or Formula (G) are those wherein m is 1, 2, or 3. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein m is 1.
  • the compounds of Formula (I) or Formula (G) are those wherein R 9 is (Ci-C 6 )alkyl; wherein R 9 is optionally further substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOMe, -CONH 2 , and -NH 2 .
  • the compounds of Formula (I) or Formula (G) are those wherein R 9 is methyl or ethyl.
  • the compounds of Formula (I) or Formula (G) are those wherein R 9 is further substituted with -COOH.
  • the compounds of Formula (I) or Formula (G) are those wherein Rio is H and R 9 is (Ci-C 6 )alkyl; wherein R 9 is further substituted
  • the compounds of Formula (I) or Formula (G) are those wherein R 9 is further substituted with -CONH 2 .
  • the compounds of Formula (I) or Formula (G) are those wherein R 9 is methyl and wherein R 9 is further substituted with -CONH 2 .
  • the compounds of Formula (I) or Formula (G) are those wherein Rio is -H, -COMe, -COOEt. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Rio is -H or -COMe. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Rio is -H.
  • the compounds of Formula (I) or Formula (G) are those wherein R9 and Rio together form a 4 to 8 membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 groups selected from the group consisting of -COOH, -COOMe, -COOEt, -CH2-COOH, and -NFh .
  • the compounds of Formula (I) are those wherein R9 and Rio together form a 4 to 8 membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 groups selected from the group consisting of -COOH, -CH2-COOH, and -NH2 .
  • the compounds of Formula (I) or Formula (G) are those wherein R9 and Rio together form a piperidine substituted with 1 or 2 groups selected from the group consisting of -COOH, -COOMe, -COOEt, -CH2-COOH, -CH 2 -COOMe, -CH 2 - COOEt, and -NH2 .
  • the compounds of Formula (I) or Formula (G) are those wherein R9 and Rio together form a piperidine substituted with 1 or 2 groups selected from the group consisting of -COOH, -CH2-COOH, and -NH2 .
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is an aromatic 5- or 6-membered heterocycle, with 1-3 heteroatoms independently selected from the group consisting of N, O, and S.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is pyridyl or pyrimidinyl.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.
  • Formula (G) are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is thiazolyl.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is l,2,4-thiadiazol-5-yl.
  • the compounds of Formula (I) or Formula (G) are those wherein R 2 is independently at each occurrence -F or -Cl.
  • the compounds of Formula (I) or Formula (G) are those wherein n is 1, 2, or 3. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein n is 2.
  • the compounds of Formula (I) or Formula (G) are those wherein Z is -0-.
  • the compounds of Formula (I) or Formula (G) are those wherein R 3 is independently at each occurrence -H, -F, -Cl, or -Br. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R 3 is -H or -Cl.
  • the compounds of Formula (I) or Formula (G) are those wherein R 3 is -Cl.
  • the compounds of Formula (I) or Formula (G) are those wherein m is 1, 2, or 3. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein m is 1.
  • the compounds of Formula (I) or Formula (G) are those wherein X is 5- or 6-membered heteroaryl.
  • the compounds of Formula (I) or Formula (G) are those wherein X is pyridyl or pyrimidinyl.
  • the compounds of Formula (I) or Formula (G) are those wherein X is pyridyl.
  • the compounds of Formula (I) or Formula (G) are those wherein R 4 is H and Rs is (Ci-C9)alkyl.
  • the compounds of Formula (I) or Formula (G) are those wherein Rs is methyl or ethyl, substituted with 1 or 2 substituents selected from the group consisting of -C0 2 H, -CO2R6, and -CONR 7 Rs.
  • the compounds of Formula (I) or Formula (G) are those wherein R 6 is (Ci-C 6 )alkyl.
  • the compounds of Formula (I) or Formula (G) are those wherein R 5 is methyl or ethyl, substituted with -CO2H.
  • the compounds of Formula (I) or Formula (G) are those wherein Y is 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-(2-yl or 3-yl). In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Y is 4, 5,6,7- tetrahydropyrazolo[ 1 ,5-a]pyrimidine-3-yl.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is an aromatic 5- or 6-membered heterocycle, with 1-3 heteroatoms independently selected from the group consisting of N, O, and S.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is pyridyl or pyrimidinyl.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is thiazolyl.
  • the compounds of Formula (I) or Formula (G) are those wherein Ri is l,2,4-thiadiazol-5-yl.
  • the compounds of Formula (I) or Formula (G) are those wherein R 2 is independently at each occurrence -F or -Cl.
  • the compounds of Formula (I) or Formula (G) are those wherein n is 1, 2, or 3. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein n is 2.
  • the compounds of Formula (I) or Formula (G) are those wherein Z is -0-.
  • the compounds of Formula (I) or Formula (G) are those wherein R 3 is independently at each occurrence -H, -F, -Cl, or -Br. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R 3 is -H or -Cl. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R 3 is -Cl.
  • the compounds of Formula (I) or Formula (G) are those wherein m is 1, 2, or 3. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein m is 1.
  • the compounds of Formula (I) or Formula (G) are those wherein the compound is selected from the group consisting of the compounds in Table 1 or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.
  • the compounds of Formula (I) or Formula (G) are those wherein the compound is selected from the group consisting of the compounds in Table 2 or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof. [00136] Table 2
  • the compounds of Formula (I) or Formula (G) are those wherein the compound is selected from the group consisting of the compounds in Table 3 or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.
  • Table 1, Table 2, and Table 3 serve to define that a particular structure is associated with a particular name. Whenever a particular name is recited in this disclosure or the claims, the chemical structure associated with that particular name shall be the structure identified in Table 1, Table 2, or Table 3.
  • the compounds of Formula (I) or Formula (G) are those wherein the compound is
  • the compounds of Formula (I) or Formula (G) are those wherein the compound is
  • the compounds of Formula (I) or Formula (G) are those wherein the compound is
  • the compound according to Formula (I) or Formula (G) is 2- ((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop- 2-yn-l-yl)amino)acetic acid (Compound 54).
  • the compound according to Formula (I) or Formula (G) is2- ((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-)
  • Ri is a partially unsaturated or aromatic 5- or 6-membered heterocycle
  • R 2 is independently at each occurrence -F, -Cl, -Br, -CH 3 or -CN;
  • R 3 is independently at each occurrence -H, -F, -Cl, -Br, -CF 3 , -OCF 3, -CN, (Ci-Ci 2 )alkyl, or (Ci-Ci 2 )alkoxy;
  • R 9 is (Ci-C 6 )alkyl, (C;i-Cx)cycloalkyl, pyrazolyl or pyridinyl; wherein R 9 is optionally further substituted with 1 or 2 substituents selected from the group consisting
  • Rn and R 12 may form a 6 membered heterocycloalkyl ring
  • Rio is R 11 , -COR 11 , -COOR 11 , -SO 2 R 11 , 5-methyl-2-oxo-l,3-dioxol-4-yl,
  • R 9 and Rio together form a piperazinone or a 4-to 8- membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOR 11 , -CH 2 -
  • R 11 and R 12 are independently H or (Ci-C 6 )alkyl, optionally substituted with 4- to 8-membered heterocycloalkyl ring;
  • n are each independently 1, 2, 3, or 4.
  • Rio is Rn, (C3-C 6 )alkynyl, (C 3 -C6)alkenyl, -COR11, -COOR11, -SO2R11,
  • R9 and Rio together form a piperazinone or a 4-to 8- membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOR11, -CH2- COOR11, -OH, -NH2, -CN, and (Ci-Cs)alkoxy; or R9 and Rio together form a
  • the compounds of Formula (la) or Formula (I’a) are those wherein Ri is an aromatic 5- or 6-membered heterocycle, with 1-3 heteroatoms independently selected from the group consisting of N, O, and S.
  • the compounds of Formula (la) or Formula (I’a) are those wherein Ri is pyridyl or pyrimidinyl.
  • the compounds of Formula (la) or Formula (F a) are those wherein Ri is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.
  • the compounds of Formula (la) or Formula (Fa) are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl.
  • the compounds of Formula (la) or Formula (Fa) are those wherein Ri is thiazolyl.
  • the compounds of Formula (la) or Formula (Fa) are those wherein Ri is l,2,4-thiadiazol-5-yl.
  • the compounds of Formula (la) or Formula (Fa) are those wherein Ri is thiadiazol-4-yl.
  • the compounds of Formula (la) or Formula (I’a) are those wherein R 2 is independently at each occurrence -F or -Cl.
  • the compounds of Formula (la) or Formula (I’a) are those wherein n is 1, 2, or 3.
  • the compounds of Formula (la) or Formula (Fa) are those wherein n is 2.
  • the compounds of Formula (la) or Formula (Fa) are those wherein Z is -0-.
  • the compounds of Formula (la) or Formula (Fa) are those wherein R 3 is independently at each occurrence -H, -F, -Cl, or -Br. In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein R 3 is -H or -Cl. In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein R is -Cl.
  • the compounds of Formula (la) or Formula (Fa) are those wherein m is 1, 2, or 3. In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein m is 1.
  • the compounds of Formula (la) or Formula (Fa) are those wherein R 9 is (Ci-C 6 )alkyl; wherein R 9 is optionally further substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOMe, -CONH2, and -NH 2 .
  • the compounds of Formula (la) or Formula (Fa) are those wherein R 9 is methyl or ethyl.
  • the compounds of Formula (la) or Formula (Fa) are those wherein R 9 is further substituted with -COOH.
  • the compounds of Formula (la) or Formula (Fa) are those wherein Rio is H and R 9 is (Ci-C 6 )alkyl; wherein R 9 is further substituted
  • the compounds of Formula (la) or Formula (I’a) are those wherein R9 is methyl and wherein R9 is further substituted with -CONH 2 .
  • the compounds of Formula (la) or Formula (I’a) are those wherein Rio is -H, -COMe, -COOEt.
  • the compounds of Formula (la) or Formula (Fa) are those wherein Rio is -H or -COMe.
  • the compounds of Formula (la) or Formula (Fa) are those wherein Rio is -H or -COMe.
  • the compounds of Formula (la) or Formula (Fa) are those wherein Rio is -H.
  • the compounds of Formula (la) or Formula (Fa) are those wherein R9 and Rio together form a 4 to 8 membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 groups selected from the group consisting of -COOH, -COOMe, -COOEt, -CH2-COOH, and -NFb .
  • the compounds of Formula (I) are those wherein R9 and Rio together form a 4 to 8 membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 groups selected from the group consisting of -COOH, -CH2-COOH, and -NH2 .
  • the compounds of Formula (la) or Formula (Fa) are those wherein R9 and Rio together form a piperidine substituted with 1 or 2 groups selected from the group consisting of -COOH, -COOMe, -COOEt, -CH2-COOH, -CH 2 -COOMe, -CH 2 - COOEt, and -NH2 .
  • the compounds of Formula (la) or Formula (Fa) are those wherein R9 and Rio together form a piperidine substituted with 1 or 2 groups selected from the group consisting of -COOH, -CH2-COOH, and -NH2 .
  • the compounds of Formula (la) or Formula (Fa) are selected from the group consisting of
  • the compounds of Formula (la) or Formula (I’a) are selected from the group comprising
  • the compounds of Formula (la) or Formula (I’a) are selected from the group comprising
  • X is (C 6 -Cio)aryl or 5- or 6-membered heteroaryl
  • Ri is a partially unsaturated or aromatic 5- or 6-membered heterocycle
  • R 2 is independently at each occurrence -F, -Cl, -Br, -CH 3 or -CN;
  • R 3 is independently at each occurrence -H, -F, -Cl, -Br, -CF 3 , -OCF 3, -CN, (Ci-Ci 2 )alkyl, or (Ci-Ci 2 )alkoxy;
  • R 4 and R5 are each independently H, (Ci-C9)alkyl, (C4-Ci 2 )cycloalkyl, or R 4 and R5 together form a 5- to 7-membered heterocycloalkyl ring; with the proviso that:
  • R 4 and R5 are not both H
  • R 4 and R5 independently or said heterocycloalkyl ring formed by R 4 and R5 together is substituted with 1 or 2 substituents selected from the group consisting of -C0 2 H, -C0 2 R 6 , -CN, -OH, -CONR 7 Rs, and -NR 7 Rs; wherein:
  • R 6 is (Ci -Ci 2) alkyl
  • R 7 and Rs are each independently H, (Ci-Ci 2 )alkyl, or R 7 and Rs together form a 4- to 7-membered heterocycloalkyl ring; and m and n are each independently 1, 2, 3, or 4.
  • the compounds of Formula (lb) are those wherein Ri is an aromatic 5- or 6-membered heterocycle, with 1-3 heteroatoms independently selected from the group consisting of N, O, and S.
  • the compounds of Formula (lb) are those wherein Ri is pyridyl or pyrimidinyl.
  • the compounds of Formula (lb) are those wherein Ri is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.
  • the compounds of Formula (lb) are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl.
  • the compounds of Formula (lb) are those wherein Ri is thiazolyl.
  • the compounds of Formula (lb) are those wherein Ri is l,2,4-thiadiazol-5-yl.
  • the compounds of Formula (lb) are those wherein R 2 is independently at each occurrence -F or -Cl.
  • the compounds of Formula (lb) are those wherein n is
  • the compounds of Formula (lb) are those wherein n is 2.
  • the compounds of Formula (lb) are those wherein Z is -O- .
  • the compounds of Formula (lb) are those wherein R 3 is independently at each occurrence -H, -F, -Cl, or -Br. In a particular embodiment, the compounds of Formula (lb) are those wherein R 3 is -H or -Cl. In a particular embodiment, the compounds of Formula (lb) are those wherein R 3 is -Cl.
  • the compounds of Formula (lb) are those wherein m is 1, 2, or 3. In a particular embodiment, the compounds of Formula (lb) are those wherein m is 1. [00172] In a particular embodiment, the compounds of Formula (lb) are those wherein X is 5- or 6-membered heteroaryl. In a particular embodiment, the compounds of Formula (lb) are those wherein X is pyridyl or pyrimidinyl. In a particular embodiment, the compounds of Formula (lb) are those wherein X is pyridyl.
  • the compounds of Formula (lb) are those wherein R 4 is H and R 5 is (Ci-C9)alkyl.
  • the compounds of Formula (lb) are those wherein Rs is methyl or ethyl, substituted with 1 or 2 substituents selected from the group consisting of -C0 2 H, -CO2R6, and -CONR 7 R 8 .
  • the compounds of Formula (lb) are those wherein R 6 is (Ci-C 6 )alkyl.
  • the compounds of Formula (lb) are those wherein R 5 is methyl or ethyl, substituted with -C0 2 H.
  • Ri is a partially unsaturated or aromatic 5- or 6-membered heterocycle
  • R 2 is independently at each occurrence -F, -Cl, -Br, -CH 3 or -CN;
  • R 3 is independently at each occurrence -H, -F, -Cl, -Br, -CF 3 , -OCF 3, -CN, (Ci-Ci 2 )alkyl, or (Ci-Ci 2 )alkoxy;
  • R 4 and Rs are each independently H, (Ci-C9)alkyl, (C 4 -Ci 2 )cycloalkyl, or R 4 and Rs together form a 5- to 7-membered heterocycloalkyl ring; with the proviso that:
  • R 4 and Rs are not both H
  • R 4 and Rs independently or said heterocycloalkyl ring formed by R 4 and R 5 together is substituted with 1 or 2 substituents selected from the group consisting of -C0 2 H, -C0 2 R 6 , -CN, -OH, -CONR 7 Rs, and -NR 7 Rs; wherein:
  • R 6 is (Ci-Ci 2 ) alkyl
  • R 7 and Rs are each independently H, (Ci-Ci 2 )alkyl, or R 7 and Rs together form a 4- to 7-membered heterocycloalkyl ring; and m and n are each independently 1, 2, 3, or 4.
  • the compounds of Formula (Ic) are those wherein Ri is an aromatic 5- or 6-membered heterocycle, with 1-3 heteroatoms independently selected from the group consisting of N, O, and S.
  • the compounds of Formula (Ic) are those wherein Ri is pyridyl or pyrimidinyl.
  • the compounds of Formula (Ic) are those wherein Ri is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.
  • the compounds of Formula (Ic) are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl.
  • the compounds of Formula (Ic) are those wherein Ri is thiazolyl.
  • the compounds of Formula (Ic) are those wherein Ri is l,2,4-thiadiazol-5-yl.
  • the compounds of Formula (Ic) are those wherein R 2 is independently at each occurrence -F or -Cl.
  • the compounds of Formula (Ic) are those wherein n is
  • the compounds of Formula (Ic) are those wherein n is 2.
  • the compounds of Formula (Ic) are those wherein Z is 0
  • the compounds of Formula (Ic) are those wherein R 3 is independently at each occurrence -H, -F, -Cl, or -Br. In a particular embodiment, the compounds of Formula (I) are those wherein R 3 is -H or -Cl. In a particular embodiment, the compounds of Formula (Ic) are those wherein R 3 is -Cl.
  • the compounds of Formula (Ic) are those wherein m is 1, 2, or 3. In a particular embodiment, the compounds of Formula (Ic) are those wherein m is 1.
  • the compounds of Formula (Ic) are those wherein X is 5- or 6-membered heteroaryl. In a particular embodiment, the compounds of Formula (Ic) are those wherein X is pyridyl or pyrimidinyl. In a particular embodiment, the compounds of Formula (Ic) are those wherein X is pyridyl.
  • the compounds of Formula (Ic) are those wherein R 4 is H and R 5 is (Ci-C9)alkyl.
  • the compounds of Formula (Ic) are those wherein Rs is methyl or ethyl, substituted with 1 or 2 substituents selected from the group consisting of -COiH, -C0 2 R 6 , and -CONR 7 R 8 .
  • the compounds of Formula (Ic) are those wherein R 6 is (Ci-C 6 )alkyl.
  • the compounds of Formula (Ic) are those wherein Rs is methyl or ethyl, substituted with -C0 2 H.
  • the compounds of Formula (Ic) are selected from the group consisting of
  • Y is 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-(2-yl or 3-yl);
  • Z is -O- or -S-;
  • Ri is a partially unsaturated or aromatic 5- or 6-membered heterocycle
  • R 2 is independently at each occurrence -F, -Cl, -Br, -CH 3 or -CN;
  • R 3 is independently at each occurrence -H, -F, -Cl, -Br, -CF 3 , -OCF 3, -CN, (Ci-Ci 2 )alkyl, or (Ci-Ci 2 )alkoxy;
  • n are each independently 1, 2, 3, or 4.
  • the compounds of Formula (Id) are those wherein Y is 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-(2-yl or 3-yl). In a particular embodiment, the compounds of Formula (Id) are those wherein Y is 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-
  • the compounds of Formula (Id) are those wherein Ri is an aromatic 5- or 6-membered heterocycle, with 1-3 heteroatoms independently selected from the group consisting of N, O, and S.
  • the compounds of Formula (Id) are those wherein Ri is pyridyl or pyrimidinyl.
  • the compounds of Formula (Id) are those wherein Ri is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.
  • the compounds of Formula (Id) are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl.
  • the compounds of Formula (Id) are those wherein Ri is thiazolyl.
  • the compounds of Formula (Id) are those wherein Ri is l,2,4-thiadiazol-5-yl.
  • the compounds of Formula (Id) are those wherein R 2 is independently at each occurrence -F or -Cl.
  • the compounds of Formula (Id) are those wherein n is 1, 2, or 3. In a particular embodiment, the compounds of Formula (Id) are those wherein n is 2.
  • the compounds of Formula (Id) are those wherein Z is 0
  • the compounds of Formula (Id) are those wherein R 3 is independently at each occurrence -H, -F, -Cl, or -Br. In a particular embodiment, the compounds of Formula (Id) are those wherein R 3 is -H or -Cl. In a particular embodiment, the compounds of Formula (Id) are those wherein R 3 is -Cl.
  • the compounds of Formula (Id) are those wherein m is 1, 2, or 3. In a particular embodiment, the compounds of Formula (Id) are those wherein m is
  • the Compounds provided herein can contain unnatural proportions of atomic isotopes at one or more of the atoms.
  • the Compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine- 125 ( 125 I), sulfur-35 ( 35 S), or carbon- 14 ( 14 C), or may be isotopically enriched, such as with deuterium (3 ⁇ 4), carbon-l3 ( 13 C), or nitrogen-l5 ( 15 N).
  • an“isotopologue” is an isotopically enriched Compound.
  • isotopically enriched refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a Compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term“isotopic composition” refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched Compounds are useful as therapeutic agents, e.g., cancer and inflammation therapeutic agents; research reagents, e.g., binding assay reagents; and diagnostic agents, e.g., in vivo imaging agents.
  • therapeutic agents e.g., cancer and inflammation therapeutic agents
  • research reagents e.g., binding assay reagents
  • diagnostic agents e.g., in vivo imaging agents.
  • isotopologues of the Compounds are deuterium, carbon- 13, or nitrogen- 15 enriched Compounds.
  • the compounds provided herein are inhibitors of NaVl.7. [00206] In one embodiment, the compounds provided herein are inhibitors of NaV 1.7. In a specific embodiment, the compound provided herein has an IC50 for NaVl.l, NaVl.2,
  • NaVl.3, NaVl.4, NaVl.5, NaVl.6, NaVl.8, and NaVl.9 that is each independently at least 10 fold, 20 fold, 50 fold, 100 fold, 200 fold, 500 fold, 1000 fold, 2000 fold, 5000 fold, or 10000 fold higher than the NaVl.7 IC50 for said compound.
  • the IC50 at a given sodium channel is measured using an FDSS membrane potential assay or the patch-clamp method or any other method known in the art, such as the methods described in W02007/109324 to Fraser et al.
  • a Compound provided herein inhibits the activity of a sodium ion channel, such as a voltage-gated sodium ion channel.
  • a voltage-gated sodium ion channel is NaVl.7 (whose alpha subunit is encoded by the human gene SCN9A).
  • a Compound provided herein reduces the sodium ion flux through NaVl.7 by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 100%, or by ranges between any of the recited percentages ( e.g ., 10-20%, 10-30%, 10-40%, 20-30%, or 20-40%) relative to the activated channel in the absence of the Compound.
  • a Compound provided herein desensitizes the response of NaVl.7 to the change in membrane potential such that the channel requires at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or ranges between any of the recited percentages (e.g., 10-20%, 10-30%, 10-40%, 20-30%, or 20-40%) higher change in membrane potential to be activated relative to the channel in the absence of the Compound.
  • a Compound provided herein affects a voltage-gated sodium ion channel, e.g., NaVl.7, in one or more of the following states: resting (closed), activated (open), or inactivated (closed). In certain embodiments, a Compound provided herein, affects activation, inactivation, or deinactivation of a voltage-gated sodium ion channel, e.g., NaVl.7.
  • a Compound provided herein inhibits NaVl.7 specifically, i.e., the compound inhibits NaVl.7 to at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000% higher degree than another voltage-gated sodium ion channel (such as NaVl.l, NaVl.2, NaVl.3, NaVl.4, NaVl.5, NaVl.6, NaVl.8, and/or NaVl.9), or to a higher degree between any of the recited percentages (e.g., 10-20%, 10- 30%, 10-40%, 20-30%, or 20-40%) than another voltage-gated sodium channel.
  • another voltage-gated sodium ion channel such as NaVl.l, NaVl.2, NaVl.3, NaVl.4, NaVl.5, NaVl.6, NaVl.8, and/or NaVl.9
  • a Compound provided herein inhibits NaVl.7 specifically, i.e., the compound inhibits NaVl.7 to at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000% higher degree than one or more voltage-gated sodium ion channel selected from NaVl.l, NaVl.2, NaVl.3, NaVl.4, NaVl.5, NaVl.6, NaVl.8, and NaVl.9, or to a higher degree between any of the recited percentages (e.g., 10-20%, 10-30%, 10-40%, 20-30%, or 20-40%) than one or more of NaVl. l, NaVl.2, NaVl.3, NaVl.4, NaVl.5, NaVl.6, NaVl.8, and NaVl.9.
  • the compound inhibits NaVl.7 to at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%,
  • a Compound provided herein binds to NaVl.7 with at least 5-fold, lO-fold, 50-fold, lOO-fold, 500-fold, or lOOO-fold higher affinity than it binds to either one of or all of NaVl. l, NaVl.2, NaVl.3, NaVl.4, NaVl.5, NaVl.6, NaVl.8, and NaVl .9.
  • a Compound provided herein binds to NaVl .7 with at least 5- fold, lO-fold, 50-fold, lOO-fold, 500-fold, or lOOO-fold higher affinity than it binds to one or more sodium channels selected from NaVl. l, NaVl.2, NaVl.3, NaVl.4, NaVl.5, NaVl.6, NaVl.8, and NaVl.9.
  • a Compound provided herein binds to the inactivated (closed) state of NaVl.7 with at least 5-fold, lO-fold, 50-fold, lOO-fold, 500-fold, or lOOO-fold higher affinity than to any other state of NaVl.7, i.e., deactivated (closed) and activated (open).
  • a Compound provided herein binds to NaVl.7 with at least 5-fold, lO-fold, 50-fold, lOO-fold, 500-fold, or lOOO-fold higher affinity than it binds to one or more sodium channels selected from NaVl. l, NaVl.2, NaVl.3, NaVl.4, NaVl.5, NaVl.6, NaVl.8, and NaVl.9.
  • Compound provided herein has an IC50 for NaVl.l, NaVl.2, NaVl.3, NaV 1.4, NaVl.5, NaVl.6, NaVl.8, and NaVl.9, that is each independently at least 10 fold, 20 fold, 50 fold, 100 fold, 200 fold, 500 fold, 1000 fold, 2000 fold, 5000 fold, or 10000 fold higher than the NaV 1.7 IC50 for said Compound.
  • a Compound provided herein has an IC50 for one or more of NaVl.l, NaVl.2, NaVl.3, NaV 1.4, NaVl.5, NaVl.6, NaVl.8, and NaVl.9, that is each independently at least 10 fold, 20 fold, 50 fold, 100 fold, 200 fold, 500 fold, 1000 fold, 2000 fold, 5000 fold, or 10000 fold higher than the NaVl.7 IC50 for said Compound.
  • the compound has a NaVl.3 IC50 of at least at least 10 fold, 20 fold, 50 fold, 100 fold, 200 fold, 500 fold, 1000 fold, 2000 fold, 5000 fold, or 10000 fold higher than the NaVl.7 IC50 for said compound.
  • the IC50 is measured using an FDSS membrane potential assay or the patch-clamp method.
  • any assay known to the skilled artisan can be used to test the effect of a compound provided herein on a voltage-gated sodium ion channel.
  • a wide variety of assay methods are known in the art to profile Compounds provided herein against human sodium channels stably expressed in human embryonic kidney (HEK293) cells.
  • Such assays are disclosed, for example, in W02007/109324 to Fraser et al, which is incorporated herewith in its entirety.
  • such assays are disclosed in Example 3, pages 94-99 of W02007/109324, which is herewith incorportated in its entirety.
  • a cell culture assay is used, wherein the voltage-gated sodium ion channel is recombinantly expressed in the cultured cells.
  • the alpha subunit of the voltage-gated sodium ion channel is expressed but no accessory proteins are recombinantly expressed in the same cell.
  • SCN9A and SCN9B1 and SCN9B2 are co-expressed in the same cell.
  • the alpha subunit of the voltage-gated sodium ion channel is expressed and at least one accessory protein (e.g ., a beta-subunit) is co-expressed in the same cell.
  • an FDSS membrane potential assay can be used to test the activity of the voltage-gated sodium ion channel (see the Section entitled“FDSS Membrane Potential In-Vitro Assay” below).
  • the current through a voltage-gated sodium ion channel is tested using the patch clamp method (see the Section entitled“Patchliner Electrophysiological In-Vitro Assay” below).
  • the compounds provided herein are any compounds that inhibit NaVl.7.
  • the compounds provided herein are any of the compounds disclosed or discussed in Zuliani et al., 2014,“Sodium channel blockers: a patent review (2010- 2014)” Expert. Opin. Ther. Patents 25(3), Pages 1-12.
  • the compounds provided herein are, for example, any of the sodium channel blockers, such as tetrodoxotin or saxitoxin disclosed in US2017/0000797 to Buschmann et al.
  • the compounds provided herein are, for example, any of the fluorinated aromatic ethers disclosed in WO 2017035271 Al to Hemeon et al.
  • the compounds provided herein are, for example, any of the heterocyclyl benzenesulfonamide compounds disclosed in WO 2017058821 Al to Bergeron et al.
  • the compounds provided herein are, for example, any of the benzenesulfonamide compounds disclosed in WO 20170082688 Al to Lee et al.
  • the compounds provided herein are, for example, any of the indazolecarboxamide compounds disclosed in WO 2017091592 Al to Chen et al.
  • the compounds provided herein are, for example, any of the
  • the compounds provided herein are any of the compounds disclosed or discussed in Bagal et al, 2014,“Recent progress in sodium channel modulators for pain,” Bioorganic & Medicinal Chemistry Letters 24(16), Pages 3690-3699.
  • the compounds provided herein are aryloxysulfonamides, sulfonated amines, aryloxysulfonylated amides, acylsulfonyl ureas, arylindazole sulfonylated amides, bicyclic core sulfonamides, substituted piperazine or piperazine methylenoxy
  • arylsulfonamides benzo-oxazolone core sulfonamides, cycloalkyloxyaryl-sulfonamides, aryloxybiaryls, biaryls, cyclopropyl-spiro-piperidines, pyridinyl morpholinones, or
  • oxazolotriazoles heteroarylamides, or pyrrolopyridinones, biaryl spiro-pyrrolidine-lactams, or spiro-piperidines.
  • the compounds provided herein are aryloxysulfonamides or sulfonated amines.
  • the compounds provided herein are, for example, those disclosed in US2013/0005706 to Corkey et al, WO2013/114250 to Bagal et al, and W02012/007868 to Brown et al.
  • the compounds provided herein are aryloxysulfonylated amides, acylsulfonyl ureas, or arylindazole sulfonylated amides.
  • the compounds provided herein are, for example, those disclosed in WO2013/093688 to Storer et al, WO2013/088315 to Rawson et al, WO2012/095781 to Bell et al, W02014008458 to Dehnhardt et al, WO2013177224 to Andrez et al.
  • the compounds provided herein are bicyclic core
  • the compounds provided herein are, for example, those disclosed in WO2013/025883 to Dineen et al. , WO2013/086229 to Boezio et al. ,
  • the compounds provided herein are substituted piperazine or piperazine methylenoxy arylsulfonamides or ary loxy sulfonamides.
  • the compounds provided herein are, for example, those disclosed in WO2013/064983 to Sun et al. and WO2013/064984 to Liu et al.
  • the compounds provided herein are benzo-oxazolone core sulfonamides.
  • the compounds provided herein are, for example, those disclosed in WO2013/063459 to Layton et al.
  • the compounds provided herein are cycloalkyloxyaryl- sulfonamides.
  • the compounds provided herein are, for example, those disclosed in WO2013/118854 to Shinozuka et al.
  • the compounds provided herein are aryloxybiaryls.
  • the compounds provided herein are, for example, those disclosed in W02013/136170 to Tafesse et al, WO2013/072758 to Shao, WO2013064884 to Engel et al, WO2013/064884 to Yao, WO2013/064883 to Yao, W02013030665 to Ni et al, and
  • the compounds provided herein are biaryls, cycloprop yl- spiro-piperidines, pyridinyl morpholinones, or oxazolotriazoles.
  • the compounds provided herein are, for example, those disclosed in W02013/131018 to Pajouhesh et al, WO2012/047703 to Ho et al, WO2013/161929 to Hattori et al, and WO2013/161928 to Hattori et al.
  • the compounds provided herein are heteroarylamides or pyrrolopyridinones.
  • the compounds provided herein are, for example, those disclosed in WO2012/053186 to Yamagishi et al, WO2013/161312 to Kawamura et al, and W02013/161308 to Yamagishi et al.
  • the compounds provided herein are biaryl spiro-pyrrolidine- lactams.
  • the compounds provided herein are, for example, those disclosed in WO2013179049 to Giblin et al, WO2013175206 to Giblin et al, WO2013175205 to Giblin et al. , WO2013093496 to Witty et al. , and WO2013093497 to Witty et al.
  • the compounds provided herein are spiro-piperidines.
  • the compounds provided herein are, for example, those disclosed in US20120196869 to Hadida-Ruah et al, WO2014022639 to Littler et al, WO2012125613 to Hadida-Ruah et al, WO2013109521 to Hadida-Ruah et al.
  • the compounds provided herein are AZD3161, PF-04856264, CNV1014802, DSP-2230, PF-05089771, XEN402, and XEN403.
  • Symptoms induced by or associated with inflammatory conditions can include, but are not limited to edema, swelling, redness, warmth, change in level of molecular
  • inflammatory marker e.g. increase in at least one pro-inflammatory marker, decrease in at least one anti-inflammatory marker, or both
  • presence of inflammatory disease e.g. increase in at least one pro-inflammatory marker, decrease in at least one anti-inflammatory marker, or both
  • pain is not a symptom induced by or associated with an inflammatory condition.
  • the symptom induced or associated with inflammatory conditions include, but are not limited to any one of the clinical signs of inflammatory disease listed in Table 4.
  • provided herein are methods of preventing or treating inflammatory conditions by administering to a subject in need thereof at least one Compound provided herein (i.e ., a compound of Formula (I), a compound of Formula (G), a compound of Formula (la), a compound of Formula (I’a), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof.
  • a compound of Formula (I) i.e ., a compound of Formula (I), a compound of Formula (G), a compound of Formula (la), a compound of Formula (I’a), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof.
  • kits for preventing or treating inflammatory conditions comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to Formula (G).
  • kits for preventing or treating inflammatory conditions induced by or associated with autoimmune diseases, metabolic diseases, cardiovascular diseases, surgery, or trauma comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to Formula (G).
  • provided herein are methods preventing or treating one or more symptoms induced by or associated with inflammatory conditions comprising
  • the one or more symptom is selected from edema, swelling, redness, warmth, and pain. In one embodiment the one or more symptom is selected from edema, swelling, redness, and warmth, but not pain.
  • kits for preventing or treating inflammatory conditions comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to Formula (G), wherein the administration of said compound is not followed by or associated with undesirable side effects.
  • provided herein are methods of treating symptoms associated with inflammatory conditions by administering to a subject in need thereof at least one Compound provided herein (i.e ., a compound of Formula (I), a compound of Formula (G), a compound of Formula (la), a compound of Formula (I’a), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof.
  • a compound of Formula (I) i.e ., a compound of Formula (I), a compound of Formula (G), a compound of Formula (la), a compound of Formula (I’a), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof.
  • the compound used in the methods disclosed is a Compound provided herein ⁇ i.e., a compound of Formula (I), a compound of Formula (G), a compound of Formula (la), a compound of Formula (I’a), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof.
  • the compound used in the methods disclosed is a Compound provided herein ⁇ i.e., a compound of Formula (I), a compound of Formula (F), a compound of Formula (la), a compound of Formula (Fa), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof used in the methods disclosed herein is compound 54.
  • a Compound provided herein ⁇ i.e., a compound of Formula (I), a compound of Formula (F), a compound of Formula (la), a compound of Formula (Fa), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof used in the methods disclosed herein is compound 54.
  • the compound used in the methods disclosed is a Compound provided herein ⁇ i.e., a compound of Formula (I), a compound of Formula (F), a compound of Formula (la), a compound of Formula (Fa), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof used in the methods disclosed herein is compound 49.
  • a Compound provided herein ⁇ i.e., a compound of Formula (I), a compound of Formula (F), a compound of Formula (la), a compound of Formula (Fa), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof used in the methods disclosed herein is compound 49.
  • the compound used in the methods disclosed is a Compound provided herein (i.e ., a compound of Formula (I), a compound of Formula (G), a compound of Formula (la), a compound of Formula (I’a), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof used in the methods disclosed herein is compound 11.
  • a Compound provided herein i.e ., a compound of Formula (I), a compound of Formula (G), a compound of Formula (la), a compound of Formula (I’a), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof used in the methods disclosed herein is compound 11.
  • the compound used in the methods disclosed is not a compound of Formula (I), a compound of Formula (G), a compound of Formula (la), a compound of Formula (I’a), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), or a compound listed in Table 1, Table 2, or Table 3.
  • the compound according to Formula (I), a compound of Formula (F), a compound of Formula (la), a compound of Formula (Fa), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof used in the methods disclosed is not compound 49.
  • the compound used in the methods disclosed is not a compound of Formula (I), a compound of Formula (F), a compound of Formula (la), a compound of Formula (Fa), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), or a compound listed in Table 1, Table 2, or Table 3.
  • the compound according to Formula (I), a compound of Formula (F), a compound of Formula (la), a compound of Formula (Fa), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof used in the methods disclosed is not compound 54.
  • the compound used in the methods disclosed is not a compound of Formula (I), a compound of Formula (G), a compound of Formula (la), a compound of Formula (I’a), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), or a compound listed in Table 1, Table 2, or Table 3.
  • the compound according to Formula (I), a compound of Formula (G), a compound of Formula (la), a compound of Formula (I’a), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof used in the methods disclosed is not compound 11.
  • the present disclosure is directed to a method for the prevention inflammatory conditions comprising the step of administering to a patient a Compound provided herein (i.e ., a compound of Formula (I), a compound of Formula (F), a compound of Formula (la), a compound of Formula (Fa), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a
  • the method comprises administering to the subject in need of such prevention or treatment a therapeutically effective amount of a Compound or pharmaceutically acceptable salt, solvate or tautomeric form thereof.
  • the methods are those, wherein the therapeutically effective amount of a Compound or a
  • the pharmaceutically acceptable salt, solvate or tautomeric form thereof is effective to prevent or alleviate an inflammatory condition in a subject, wherein the Compound shows prevention or reduction in the inflammatory condition at a dose between O.lmg/kg and 1,000 mg/kg, at a dose between 0.5mg/kg and 100 mg/kg, at a dose between 1 mg/kg to 50 mg/kg, or at a dose of 30 mg/kg, or at a dose of 5 mg/kg.
  • the methods are those, wherein the therapeutically effective amount of a Compound or a pharmaceutically acceptable salt, solvate or tautomeric form thereof, is effective to alleviate the inflammatory condition in a subject ,
  • the Compound provides prevention or reduction in the inflammatory conditions response by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 100%, or by ranges between any of the recited percentages (e.g., 10-20%, 10-30%, 10-40%, 20- 30%, or 20-40%) relative to a vehicle control.
  • the symptoms of an inflammatory condition include, but are not limited to, swelling, edema, redness, warmth, and pain.
  • the inflammatory condition is associated with a change (increase or decrease) in at least one pro- and/or anti-inflammatory marker.
  • the inflammatory condition is associated with an increase in at least one pro-inflammatory marker or a decrease in at least one anti-inflammatory marker, or both.
  • administration of a Compound provided herein i.e ., a compound of Formula (I), a compound of Formula (G), a compound of Formula (la), a compound of Formula (I’a), a compound of Formula (lb), a compound of Formula (Ic), a compound of Formula (Id), a compound listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof, results in a decrease of at least one pro-inflammatory marker, or an increase in at least one anti-inflammatory marker, or both.
  • compositions required by the present disclosure comprises a compound useful in the methods of the disclosure and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption.
  • the methods of treating or preventing inflammatory conditions in a subject in need thereof results in a reduction by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% or any range resulting from a combination of any two of the foregoing percentages, for example, at least about 5% to about 10% or at least about 15% to about 50%, relative to the inflammatory condition prior to the administration of a Compound provided herein.
  • the methods of treating or preventing at least one symptom induced by or associated with inflammatory conditions is reduced by at least about 5%, 10%, 15%, 20%, 25%,
  • the at least one symptom is one selected from: edema, swelling, redness, warmth, and pain. In one embodiment, the at least one symptom is not pain.
  • Table 4 provides a non-limiting list of inflammatory diseases, including their clinical symptoms.
  • Inflammatory conditions can be induced by or associated with autoimmune, metabolic, and cardiovascular diseases. Additionally, inflammatory conditions can be induced by or associated with surgery as indicated by, but not limited to, for example post-surgical edema, swelling, redness, warmth, or pain, and to non-surgical trauma as indicated by, but not limited to, for example post-trauma edema, swelling, redness, warmth, or pain. Additionally, changes (increase or decrease) in pro- and anti-inflammatory markers, such as the markers disclosed herein are symptoms of inflammatory conditions. Accordingly, inflammatory conditions can be
  • autoimmune, metabolic, or cardiovascular disease assessed by diagnosis of an autoimmune, metabolic, or cardiovascular disease in a subject.
  • One or more symptoms described by a patient such as for example edema, swelling, redness, warmth, or pain.
  • Diagnosis of one or more symptom such as edema, swelling, redness, warmth, or pain in a patient.
  • testing for changes (increase or decrease) in pro- and anti inflammatory markers can be used to assess inflammatory conditions.
  • presence of any one of the clinical signs as for example listed in Table 4 can serve to assess inflammatory disease and/or condition.
  • the subject in need for prevention or treatment of an inflammatory condition has not been previously treated for the inflammatory condition.
  • the subject in need for prevention or treatment of an inflammatory condition is female. In one embodiment, the subject in need for prevention or treatment of an inflammatory condition is pregnant. In one embodiment, prevention or treatment of an inflammatory condition is male. In one embodiment, the subject in need for Pharmaceutical Compositions and Routes of Administration is a human.
  • compositions comprising a Compound provided herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions are those, wherein the composition is suitable for topical, oral, subcutaneous, or intravenous administration.
  • compositions comprising an effective amount of a Compound and compositions comprising an effective amount of a Compound and a pharmaceutically acceptable carrier or vehicle.
  • the pharmaceutical composition described herein are suitable for oral, parenteral, mucosal, transdermal or topical administration.
  • the Compounds can be administered to a patient orally or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions and syrups.
  • Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient (e.g ., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose,
  • hydroxymethylcellulose polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch
  • a disintegrator e.g., starch, carboxymethylcellulose, hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate
  • a lubricant e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate
  • a flavoring agent e.g., citric acid, menthol, glycine or orange powder
  • a preservative e.g., sodium benzoate, sodium bisulfite, methylparaben or
  • propylparaben e.g., citric acid, sodium citrate or acetic acid
  • a suspending agent e.g., methylcellulose, polyvinyl pyrroliclone or aluminum stearate
  • a dispersing agent e.g., sodium citrate or acetic acid
  • the effective amount of the Compound in the pharmaceutical composition may be at a level that will exercise the desired effect; for example, about 0.1 mg/kg to about 1000 mg/kg or about 0.5mg/kg to about lOOmg/kg of a patient’s body weight in unit dosage for both oral and parenteral administration.
  • the dose of a Compound to be administered to a patient is rather widely variable and can be the judgment of a health-care practitioner.
  • the Compounds can be administered one to four times a day in a dose of about 0.1 mg/kg of a patient’s body weight to about 1000 mg/kg of a patient’s body weight in a patient, but the above dosage may be properly varied depending on the age, body weight and medical condition of the patient and the type of administration.
  • the dose is about 0.05 mg/kg of a patient’s body weight to about 500 mg/kg of a patient’s body weight, 0.05 mg/kg of a patient’s body weight to about 100 mg/kg of a patient’s body weight, about 0.5 mg/kg of a patient’s body weight to about 100 mg/kg of a patient’s body weight, about 0.1 mg/kg of a patient’s body weight to about 50 mg/kg
  • the amount of the Compound administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.
  • kits for the prevention or treatment one or more inflammatory conditions comprising the administration of about 7.5 mg/day to about 75 g/day, about 3.75 mg/day to about 37.5 g/day, about 3.75 mg/day to about 7.5 g/day, about 37.5 mg/day to about 7.5 g/day, about 7.5 mg/day to about 3.75 g/day, about 3.75 mg/day to about 1.875 g/day, about 3.75 mg/day to about 1,000 mg/day, about 3.75 mg/day to about 800 mg/day, about 3.75 mg/day to about 500 mg/day, about 3.75 mg/day to about 300 mg/day, or about 3.75 mg/day to about 150 mg/day of a Compound to a patient in need thereof.
  • the methods disclosed herein comprise the administration of 1 mg/day, 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 45 mg/day,
  • the inflammatory conditions is induced by or associated with an autoimmune, metabolic, or cardiovascular disease. In one embodiment, the inflammatory conditions is induced by or associated with surgery, or trauma.
  • unit dosage formulations that comprise between about 7.5 mg to about 75 g, about 3.75 mg to about 37.5 g, about 3.75 mg to about 7.5 g, about 37.5 mg to about 7.5 g, about 7.5 mg to about 3.75 g, about 3.75 mg to about 1.875 g, about 3.75 mg to about 1,000 mg, about 3.75 mg to about 800 mg, about 3.75 mg to about 500 mg, about 3.75 mg to about 300 mg, or about 3.75 mg to about 150 mg of a
  • unit dosage formulation comprising about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg, 800 mg 1,000 mg, 1,500 mg,
  • unit dosage formulations that comprise a Compound dosage that achieves a target plasma concentration of the Compound in a patient or an animal model.
  • unit dosage formulations that achieves a plasma concentration of the Compound ranging from approximately 0.001 pg/mL to approximately 100 mg/mL, approximately 0.01 pg/mL to approximately 100 mg/mL, approximately 0.01 pg/mL to approximately 10 mg/mL, approximately 0.1 pg/mL to approximately 10 mg/mL, approximately 0.1 pg/mL to approximately 500 pg/mL, approximately 0.1 pg/mL to approximately 500 pg/mL, approximately 0.1 pg/mL to approximately 100 pg/mL, or approximately 0.5 pg/mL to approximately 10 pg/mL in a patient or an animal model.
  • a Compound or a pharmaceutical composition thereof may be administered at doses that vary from 0.001 pg to 100,000 mg, depending upon the route of administration.
  • subsequent doses of a Compound may be adjusted accordingly based on the plasma concentrations of the Compound achieved with initial doses of the Compound or pharmaceutical composition thereof administered to the subject.
  • a Compound can be administered once, twice, three, four or more times daily.
  • a Compound can be administered orally for reasons of convenience.
  • a Compound when administered orally, a Compound is administered with a meal and water.
  • the Compound is dispersed in water or juice (e.g ., apple juice or orange juice) and administered orally as a suspension.
  • a Compound when administered orally, a Compound is administered in a fasted state.
  • the Compound can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally,
  • the mode of administration is left to the discretion of the health-care practitioner, and can depend in-part upon the site of the medical condition.
  • capsules containing a Compound without an additional carrier, excipient or vehicle are provided herein.
  • compositions comprising an effective amount of a Compound and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.
  • a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.
  • the composition is a pharmaceutical composition.
  • compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like.
  • compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid.
  • the solutions are prepared from water-soluble salts.
  • all of the compositions are prepared according to known methods in pharmaceutical chemistry.
  • Capsules can be prepared by mixing a Compound with a suitable carrier or diluent and filling the proper amount of the mixture in capsules.
  • the usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
  • the pharmaceutical composition is lactose-free.
  • Typical tablet binders are
  • Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
  • a lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the die.
  • the lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
  • Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, com and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet.
  • the compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation
  • Cocoa butter is a traditional suppository base, which can be modified by addition of waxes to raise its melting point slightly.
  • Water- miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use.
  • a slowly soluble pellet of the Compound can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device.
  • the technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets.
  • Tablets, capsules, or pellets can be coated with a film that resists dissolution for a predictable period of time (the coating may comprise, for example, polymethylacrylates or ethyl cellulose).
  • parenteral preparations can be made long-acting, by dissolving or suspending the
  • the Surgical Incision (SI) Model is a model of post-surgical wound infection associated with inflammation and pain on soft tissue damage from surgery or other trauma. Edema or swelling is macroscopic evidence of inflammation. Edema is a significant
  • inflammation may extend the post-surgical pain. Reductions in the edema or pain around the surgical wounded tissue are important indications of anti-inflammation effects.
  • Paw swelling was assessed by measuring the paw thickness before and after surgery with plastic calipers in millimeter (mm).
  • test Compounds 49, 11 and 54 were dosed daily starting day 1 after surgery and the surgically incised and contralateral paw thicknesses were measured daily starting 24 hours after surgery.
  • CFA model was induced with Complete Freund’s adjuvant (CFA) (Sigma- Aldrich, Cat# F5881-10ML). CFA lOOul was injected in a hind-paw plantar surface to induce multiple small joints and soft tissue inflammatory pain.
  • CFA Complete Freund’s adjuvant
  • Compound 49 (also called CC7423) was given orally (p.o.) twice daily (bid) for 7 days starting on day 1 after a CFA injection. Paw thickness was measured on day 5.
  • Type I diabetes was induced by a single injection (intraperitoneally, or intravenously) of 65 mg/kg of streptozotocin (STZ, Sigma Chemicals, St. Louis, MO or VWR) freshly dissolved in sodium citrate (0.01 M, pH 4.5). Sham animals were injected with saline or the STZ vehicle. After two to three days, diabetes was confirmed in STZ-injected rats by measuring the plasma
  • glucose concentrations in blood samples from the tail vein under non-fast condition were assayed using a mini glucose monitor (kit for AlphaTRAK 2 meter, available from Abbott Laboratories). Only STZ-injected animals with a final blood glucose level above 400- mg/dl were selected for the study. Glucose levels in the sham animals remained normal.
  • Plasma samples were collected to assess drug exposure and to measure cytokines (such as TNF-a, IL-4) and the pancreas was collected for histological assessment at various timepoints during and following drug dosing.
  • cytokines such as TNF-a, IL-4
  • the STZ model of diabetes and the surgical incision models were studied: as described above in Examples 1-2.
  • the STZ model b-cells in the pancreas are damaged, resulting in inflammation of the pancreas.
  • test Compound 49 was dosed starting 9 days after STZ injection through week 8 (early group) or from week 12 through week 20 after STZ injection (late group). Plasma samples were taken for the measurement of IL-4 and TNF-a at week 2, 4 and 9 after induction of diabetes by STZ injection in the early treatment groups. Rats were sacrificed and their pancreas were examined by histology on weeks 20 (end of late treatment) and 25 (5 weeks after late treatment). Plasma samples for hormone tests were collected at week 20, 12 weeks after the Early treatment withdrawal. Compound 49 or vehicle (0.2% PEG600), or Pregabalin (positive control, purchased from eNovation Chemicals, Cat#: D320170) were dosed in the animal’s drinking water ad libitum. All results were compared between compound dosed, vehicle dosed and sham animals. Plantar and von Frey tests were measured weekly as well.
  • test compound was expressed as a percent recovery (% Recovery) relative to the sham group in each model and calculated according to the formula:
  • %Recovery 1 00 %- ⁇ [(sham mean-test compound mean)/ (sham mean- vehicle mean)] x 100% ⁇
  • sham mean refers to average score in the sham group
  • test compound mean refers to average score in the surgically treated group in the surgical incision model and the STZ injected group in the STZ model treated with a test compound
  • vehicle mean refers to average score in the group that underwent surgery or were dosed with STZ injected and dosed with vehicle. The above formula was used to obtain data for the following in vivo behavioral tests.
  • the plantar test quantitatively assesses the thermal threshold of the hind paw.
  • Rats were placed on the glass surface of a thermal testing apparatus (Model 226, IITC/Life Science Instruments, Woodland Hills (CA)) and were allowed to acclimate for 10 min before testing on the glass surface at room temperature.
  • the animals were placed in chambers with the temperature of the glass surface maintained constant at 30-32°C.
  • a mobile radiant heat source located under the glass is focused to the hind paw of each rat.
  • the device was set at 55% (heating rate 3 °C per sec) heating intensity with a cut-off at 10 sec.
  • the paw withdrawal latency was recorded by a digital timer.
  • the thermal threshold was determined as the mean withdrawal latency from two to three consecutive trial of both hind paws.
  • the cutoff of 10 sec was used to prevent tissue damage.
  • Tactile Allodynia (Von Frey Test) [00297] The von Frey test quantifies mechanical sensitivity of the hind paw. The test utilizes a non-noxious stimulus and is therefore considered a measure of tactile allodynia.
  • the next smaller von Frey probe was applied. Whenever a withdrawal response to a given probe occurred, the next smaller von Frey probe was applied. Whenever a negative response occurred, the next smaller von Frey probe was applied. The test continued until (1) the responses of four or more stimuli (total 3-5 trials) after the first change in response was obtained or (2) the upper/lower end of the von Frey hair was reached (bending). If the animal showed no response to any of the von Frey hairs, a value of 26 g, corresponding to the next log increment in potential von Frey filament, was assigned as the threshold. The testing was continued until the hair with the lowest force to induce a rapid flicking of paw was determined or when the cut off force of approximately 26 g was reached.
  • the foot fault test was performed essentially as described Wang-Fischer YL. Manual of Surgical Stroke Models in Rats. I st Edit. CRC. FL 2008.8.1 a book with 24 chapters, Page 202.
  • the foot fault test also called as wire screen test/grid walking task/foot fault task, is a measure of the test rodent’s grip strength and motor coordination skills. Foot fault tests are routinely employed to pre-clinically assess neuromuscular effects of drug treatments in rodent stroke and/or ischemia models.
  • Diabetic animals tend to have soft or pasty stool, therefore fecal consistency was hypothesized to potentially be a good indicator of well-being.
  • Treatment with Compound 49 also showed significant effects on inflammatory cell infiltration and b-cell density in the pancreas.
  • CC8464 treatment showed significant effects on levels of plasma metabolic hormones.
  • Compound 49 treatment showed significant reduction on inflammatory paw edema on an arthritic model induced with CFA (Fig.5).
  • Paw thickness in millimeters (mm) of the dorsal-plantar axis at the metatarsal level was measured on day 5 after the beginning of treatment. The thickness was significantly increased in the vehicle treated group in comparison with the sham group. Oral gavage administration of Compound 49 at 25 or 50 mg/kg bid. (twice a day) induced a statistically significant reduction of paw thickness.
  • the thickness of the surgically treated hind paw was significantly increased in vehicle-treated group in comparison with sham group by one-day post-surgery.
  • Compound 11 treatment also significantly inhibited post-surgical incision pain (data not shown).
  • pancreas islet and anti-diabetic hormones levels (insulin and its synergetic hormones amylin, pancreatic polypeptide (PP) and glucagon like peptide (GLP-l), along with indications of improved overall health, such as cleaner fur, firmer feces and reduced mortality and number of animals being selected for supplemental care by the facility’s veterinarian, without side-effects.
  • Treatments with Compound 49 also reduced edema in the CFA-induced arthritic model and the post-surgical pain model.
  • Compound 11, Compound 49 and Compound 54 also significantly reduced tissue edema and tissue recovery from surgical incision wound model.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés et méthodes d'utilisation de composés pour prévenir ou traiter des maladies inflammatoires chez un sujet qui a besoin d'une telle prévention ou d'un tel traitement. En particulier, l'invention concerne des composés et des procédés d'utilisation de composés pour le traitement d'états inflammatoires provoqués par des maladies auto-immunes, métaboliques ou cardiovasculaires ou associés à ces dernières et d'états inflammatoires provoqués par une chirurgie et un traumatisme ou associés à ces derniers. Plus particulièrement, l'invention concerne des composés destinés à être utilisés en tant qu'agents anti-inflammatoires, tels que les composés de Formule I ou les composés de Formule I'.
PCT/US2019/031729 2018-05-11 2019-05-10 Composés et procédés d'utilisation de composés pour la prévention ou le traitement d'états inflammatoires WO2019217822A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862670072P 2018-05-11 2018-05-11
US62/670,072 2018-05-11

Publications (1)

Publication Number Publication Date
WO2019217822A1 true WO2019217822A1 (fr) 2019-11-14

Family

ID=68467578

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/031729 WO2019217822A1 (fr) 2018-05-11 2019-05-10 Composés et procédés d'utilisation de composés pour la prévention ou le traitement d'états inflammatoires

Country Status (1)

Country Link
WO (1) WO2019217822A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130109696A1 (en) * 2010-07-09 2013-05-02 Pfizer Limited Chemical Compounds
US20130109667A1 (en) * 2010-07-09 2013-05-02 Pfizer Limited Chemical Compounds
US20140256736A1 (en) * 2011-10-31 2014-09-11 Xenon Pharmaceuticals Inc. Biaryl ether sulfonamides and their use as therapeutic agents
US20160046617A1 (en) * 2013-03-15 2016-02-18 Chromocell Corporation Sodium channel modulators for the treatment of pain
US20160221974A1 (en) * 2013-09-10 2016-08-04 Chromocell Corporation Sodium channel modulators for the treatment of pain and diabetes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130109696A1 (en) * 2010-07-09 2013-05-02 Pfizer Limited Chemical Compounds
US20130109667A1 (en) * 2010-07-09 2013-05-02 Pfizer Limited Chemical Compounds
US20140256736A1 (en) * 2011-10-31 2014-09-11 Xenon Pharmaceuticals Inc. Biaryl ether sulfonamides and their use as therapeutic agents
US20160046617A1 (en) * 2013-03-15 2016-02-18 Chromocell Corporation Sodium channel modulators for the treatment of pain
US20160221974A1 (en) * 2013-09-10 2016-08-04 Chromocell Corporation Sodium channel modulators for the treatment of pain and diabetes

Similar Documents

Publication Publication Date Title
CN113227071B (zh) 治疗与IL-12、IL-23和/或IFN-α的调节相关的病症的酰胺取代的杂环化合物
JP6552117B2 (ja) 敗血症の予防治療剤
ES2603129T3 (es) Métodos de tratamiento utilizando inhibidores selectivos de Bcl-2
JP7496838B2 (ja) 置換１－オキソ－イソインドリン－５－カルボキサミド化合物、その組成物、およびそれによる治療方法
CN115154470B (zh) 使用食欲素-2受体拮抗剂治疗抑郁症的方法
ES2687598T3 (es) Moduladores del canal de sodio para el tratamiento del dolor y la diabetes
CA2705294C (fr) Methodes de traitement de l'arthrite par l'administration de benzenesulfonamides substitues
AU2018250214B2 (en) Methods and compositions for treating aging-associated impairments using CCR3-inhibitors
TW201118095A (en) 8-ethyl-6-(aryl)pyrido[2,3-d]pyrimidin-7(8h)-ones for the treatment of CNS disorders
KR20010014279A (ko) 뮤 오피오이드 화합물의 호흡 저하 및 수반되는 부작용을감소시키기 위한 조성물 및 그 방법
EP1945243B1 (fr) Utilisation de calcitonine pour traiter la pr
KR20180088373A (ko) 섬유증의 치료를 위한 세니크리비록 병용 요법
EP3464266A1 (fr) Indazoles substitués utiles pour le traitement et la prévention de maladies allergiques et/ou inflammatoires chez des animaux
US20240025891A1 (en) Heterocyclic compounds and their use for treatment of helminthic infections and diseases
CN114728001A (zh) 使用bcn057和bcn512的治疗方法
WO2019217822A1 (fr) Composés et procédés d'utilisation de composés pour la prévention ou le traitement d'états inflammatoires
JP5364168B2 (ja) ジペプチジルペプチダーゼ−ｉｖの活性を阻害する化合物及び異なる抗糖尿または抗肥満薬物を有効成分として含む糖尿または肥満の予防及び治療用薬学的組成物
JP6483272B2 (ja) 白色脂肪組織の褐色化を誘導するための化合物および方法
CN117693340A (zh) Nlrp3抑制剂治疗骨关节炎的给药方案
WO2022189636A1 (fr) Dérivés de carboxamide anti-inflammatoires
JP7528065B2 (ja) Ｃｃｒ３阻害剤を用いて、加齢性機能障害を治療するための方法および組成物
CN117279906A (zh) 经取代的杂环化合物
JP2020520366A (ja) 鎮痛剤化合物
JP4503942B2 (ja) 止痒剤
WO2019200369A1 (fr) Composés et méthodes d'utilisation de composés pour la prévention ou le traitement de lésions des nerfs périphériques

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19800114

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19800114

Country of ref document: EP

Kind code of ref document: A1