WO2019217822A1

WO2019217822A1 - Compounds and methods of using compounds for the prevention or treatment of inflammatory conditions

Info

Publication number: WO2019217822A1
Application number: PCT/US2019/031729
Authority: WO
Inventors: Olga BABICH; Tina Garyantes; Yanlin WANG-FISCHER
Original assignee: Chromocell Corporation
Priority date: 2018-05-11
Filing date: 2019-05-10
Publication date: 2019-11-14

Abstract

Provided herein are compounds and methods of using compounds for preventing or treating inflammatory diseases in a subject in need of such prevention or treatment. In particular, provided herein are compounds and methods of using compounds for the treatment of inflammatory conditions induced by or associated with autoimmune, metabolic, or cardiovascular diseases and with inflammatory conditions induced by or associated with surgery and trauma. More particularly, provided herein are compounds for use as anti-inflammatory agents, such as the compounds of Formula I or compounds of Formula I':

Description

COMPOUNDS AND METHODS OF USING COMPOUNDS FOR THE PREVENTION

OR TREATMENT OF INFUAMMATORY CONDITIONS

This application claims the benefit of U.S. provisional application 62/670,072 filed May 11, 2018 which is incorporated by reference herein in its entirety.

FIEUD

Provided herein are compounds, compositions and methods for preventing or treating inflammatory conditions. In particular, provided herein are compounds, compositions, and methods of preventing or treating inflammatory conditions related to autoimmune, metabolic, and cardiovascular diseases, surgery and trauma.

BACKGROUND

[0001] Epidemiological data provide evidence that although having successfully reduced the burden of infectious diseases, developed societies provide an environment where inflammatory conditions associated with metabolic, cardiovascular, and autoimmune diseases thrive. Thus, there remains a need in the field for prevention or treatment of inflammatory conditions induced by or associated with autoimmune, metabolic, and cardiovascular diseases. Additionally, prevention or treatment of inflammatory conditions related to surgery and non- surgical trauma continue to be important targets for drug development.

Animal models of inflammation are used to assess the production of inflammatory mediators systemically and at sites of inflammation. Also, edema (swelling), hypersensitivity to a noxious stimulus (hyperalgesia), or sensitivity to a nonnoxious stimulus (allodynia) can be used to macroscopically assess inflammation in an animal model, thus providing multiple methods to monitor inflammatory responses and the reversal or prevention of these responses with anti inflammatory agents. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed drugs to treat for example post-traumatic inflammation and pain. However, NSAIDs carry significant risk of adverse side effect, such as bleeding in the gastrointestinal tract

(Scanzello, C.R. et. ah, 2008, Curr. Rheumatol. Rep. 10: 49-56). Corticosteroids, an alternative class of anti-inflammatory drugs, have been shown to have adverse effects on wound healing and their lack of specificity can lead to many other potentially serious side effects (Wang, A.S. et al, 2013 , Am.J.Surg. 206: 410-417; Buchman, A.L., 2001, J. Immunol. 187: 1222-1234). Thus, there remains a great medical need for novel, safe anti-inflammatory compounds with or without analgesic properties.

SUMMARY

[0002] In one embodiment, 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.

[0003] In one embodiment, the present disclosure provides methods for preventing or treating inflammatory conditions induced by, or associated with autoimmune, metabolic, or cardiovascular disease.

[0004] In one embodiment, the present disclosure provides methods for preventing or treating inflammatory conditions induced, or associated with surgery, or trauma.

[0005] In one embodiment, 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. In one embodiment, 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.

[0006] In one embodiment the at least one symptom induced by or associated with inflammatory conditions are a change in at least one molecular inflammatory marker. In one embodiment 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.

[0007] In one embodiment, the at least one symptom induced by or associated with inflammatory conditions is one chosen from edema, swelling, redness, warmth.

[0008] In one embodiment, 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.

[0010] In one embodiment, 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.

[0011] In one embodiment, 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.

[0012] In one embodiment, 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.

[0013] In one embodiment, 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.

[0014] In one embodiment, provided herein are compounds of Formula (G) for use in the methods disclosed:

Formula (I’)

or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof, wherein:

Z is -O- or -S-;

Y is -X-C(=0)NR₄R5, -(CH₂)3-NR₉RIO, or 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine- (2-yl or 3-yl);

X is (C₆-Cio)aryl or 5- or 6-membered heteroaryl;

Ri is a partially unsaturated or aromatic 5- or 6-membered heterocycle;

R₂ is independently at each occurrence -F, -Cl, -Br, -CH₃ or -CN;

R₃ is independently at each occurrence -H, -F, -Cl, -Br, -CF₃, -OCF_3, -CN, (Ci-Ci₂)alkyl, or (Ci-Ci₂)alkoxy;

R₄ and Rs are each independently H, (Ci-C9)alkyl, (C₄-Ci₂)cycloalkyl, or R₄ and R₅ together form a 5- to 7-membered heterocycloalkyl ring; with the proviso that:

R₄ and Rs are not both H; and

at least one of R₄ and Rs independently or said heterocycloalkyl ring formed by R₄ and R₅ together is substituted with 1 or 2 substituents selected from the group consisting of -C0₂H, -C0₂R₆, -CN, -OH, -CONR₇Rs, and -NR₇Rs; wherein:

R₆ is (Ci-Ci₂) alkyl;

R₇ and Rs are each independently H, (Ci-Ci₂)alkyl, or R₇ and Rs together form a 4- to 7-membered heterocycloalkyl ring;

R₉ is (Ci-C₆)alkyl, (C₃-Cs)cycloalkyl, pyrazolyl or pyridinyl; wherein R₉ is optionally further substituted with 1 or 2 substituents selected from the group consisting

of -COOH, -COORn, -CONR11R12, -SO2R11, -SO2NR11R12, -OH, -CN, -OR11, and -NR₁₁R₁₂; wherein Rn and R₁₂ may form a 6 membered heterocycloalkyl ring Rio is R₁₁, (C₃-C₆)alkynyl, (C₃-C₆)alkenyl, -COR₁₁, -COOR₁₁, -SO₂R₁₁,

5-methyl-2-oxo- 1 ,3-dioxol-4-yl,

, -COO-CH(CH3)OCOCH(CH₃)2; or 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, -CH₂-COOR₁₁, -OH, -NH₂, -CN, and (Ci-C₈)alkoxy; or R₉ and Rio together form a unsubstituted 4- to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is fused with a 5-membered heteroaryl; and R₁₁ and R₁₂ are independently H or (Ci-C₆)alkyl, optionally substituted with 4- to 8- membered heterocycloalkyl ring; and

m and n are each independently 1, 2, 3, or 4.

[0015] In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein Y is -(CH₂)₃-NR₉R_IO.

[0016] In one embodiment, 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. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein Ri is pyridyl or pyrimidinyl. In one embodiment, 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. In one embodiment, 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.

[0017] In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein R₂ is independently at each occurrence -F or -Cl.

[0018] In one embodiment, 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.

[0019] In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein Z is -O .

[0020] In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein R₃ 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 R₃ is -H or -Cl. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein R₃ is -Cl.

[0021] In one embodiment, 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.

[0022] In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein R₉ is (Ci-C₆)alkyl; wherein R₉ is optionally further substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOMe, -CONH₂, and -NH₂.

In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein R₉ is methyl or ethyl. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein R₉ 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.

[0024] In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those Rio is H and R₉ is (Ci-C₆)alkyl, wherein R₉ is further substituted with - COR₁₁R₁₂, and wherein Rn and R₁₂ are independently H or (Ci-C₆)alkyl. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein the R₉ is methyl. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein the R₉ is further substituted with -CONH₂.

[0025] In one embodiment, the compounds of Formula (G) for use in the methods disclosed 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 -NH_2.

[0026] In one embodiment, the compounds of Formula (G) for use in the methods disclosed 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 -NFb_. In one embodiment, the compounds of Formula (G) for use in the methods disclosed 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, -CH₂-COOMe, -CH₂-COOEt, and -NH_2. In one embodiment, the compounds of Formula (G) for use in the methods disclosed 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 -NH_2.

[0027] In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein Y is -X-C(=0)NR₄R₅.

[0028] In one embodiment, 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.

[0029] In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein R₄ is H and Rs is (Ci-C9)alkyl. In one embodiment, 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 -C0₂H, -CO2R6, and -CONR₇R_S. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein R₆ is (Ci-C₆)alkyl. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein R₅ is methyl or ethyl, substituted with -CO2H.

[0030] 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-(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.

[0031] In one embodiment, the compound for use in the methods disclosed is

3-(4-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5- chlorophenyl)picolinamido)propanoic acid,

2-(4-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5- chlorophenyl)picolinamido)acetic acid,

5-(4-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5- chlorophenyl)picolinamido)pentanoic acid,

4-(4-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5- chlorophenyl)picolinamido)butanoic acid,

2-(4-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5- chlorophenyl)picolinamido)propanoic acid,

(R)-2-(4-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5- chlorophenyl)picolinamido)propanoic acid,

2-(6-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5- chlorophenyl)picolinamido)acetic acid,

(S)-2-(4-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5- chlorophenyl)picolinamido)propanoic acid,

3-(4-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-cyanophenoxy)-5- chlorophenyl)picolinamido)propanoic acid,

3-(4-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)-5- chlorophenyl)picolinamido)propanoic acid,

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetic acid,

3-((3-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5- chlorophenyl)propyl)amino)propanoic acid,

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetic acid,

1-(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)piperidine-4-carboxylic acid,

3 -((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanoic acid,

4-amino- l-(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)piperidine-4-carboxylic acid,

2-amino-4-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl) sulfamoyl)phenoxy)phenyl)propyl)amino)butanoic acid,

2-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetic acid,

1-(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)piperidine-3-carboxylic acid,

2-((3-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5- fluorophenoxy)phenyl)propyl)amino)acetic acid,

2-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetic acid,

3-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanoic acid,

3-((3-(5-chloro-2-(2-cyano-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanoic acid,

methyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetate,

3-((3-(2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)-5- fluorophenyl)propyl)amino)propanoic acid,

3 -((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanamide,

2-(N-(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)acetamido)acetic acid,

2-(l-(3-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5- chlorophenyl)propyl)piperidin-4-yl)acetic acid,

3 -((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanoic acid,

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)-N-methylacetamide,

5-chloro-4-(4-chloro-2-(3-((2-(methylsulfonyl)ethyl)amino)propyl)phenoxy)-2-fluoro-N- (thiazol-4-yl)benzenesulfonamide,

1-(3-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5- chlorophenyl)propyl)piperidine-4-carboxylic acid,

5-chloro-4-(4-chloro-2-(4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidin-3-yl)phenoxy)-2-fluoro-N-

(thiazol-4-yl)benzenesulfonamide,

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)(ethoxycarbonyl)amino)acetic acid,

ethyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetate,

4-(2-(3-((lH-pyrazol-4-yl)amino)propyl)-4-chlorophenoxy)-5-chloro-2-fluoro-N-(thiazol-2- yl)benzenesulfonamide,

3-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanoic acid,

4-(2-(3-((lH-pyrazol-3-yl)amino)propyl)-4-chlorophenoxy)-5-chloro-2-fluoro-N-(thiazol-4- yl)benzenesulfonamide,

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)(methyl)amino)acetic acid,

5-chloro-4-(4-chloro-2-(3-(6, 7-dihydro- lH-pyrazolo[4, 3-c]pyridin-5(4H)-yl)propyl)phenoxy)-2- fluoro-N-(thiazol-4-yl)benzenesulfonamide,

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetamide,

isopentyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetate,

isopropyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetate,

methyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)(methyl)amino)acetate,

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)((pentyloxy)carbonyl)amino)acetic acid,

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn- 1 -yl)amino)acetic acid,

5-chloro-4-(4-chloro-2-(3-(5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)propyl)phenoxy)-2- fluoro-N-(thiazol-4-yl)benzenesulfonamide,

5-chloro-2-fluoro-4-(2-(4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidin-3-yl)phenoxy)-N-(thiazol-2- yl)benzenesulfonamide,

(thiazol-2-yl)benzenesulfonamide,

5-chloro-2-fluoro-4-(2-(4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidin-3-yl)phenoxy)-N-(thiazol-4- yl)benzenesulfonamide,

5-chloro-4-(4-chloro-2-(3-((2-(methylsulfonyl)ethyl)amino)propyl)phenoxy)-2-fluoro-N-

(thiazol-2-yl)benzenesulfonamide,

2-((3-(2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetamide,

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn- 1 -yl)amino)acetic acid,

2-(allyl(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetic acid,

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetamide,

2-(but-2-yn-l-yl(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetic acid,

2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)(propyl)amino)acetic acid,

3 -((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn- 1 -yl)amino)propanoic acid,

2-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2- yn-l-yl)amino)acetic acid,

ethyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)(methyl)amino)acetate, or

2-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetamide;

or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.

[0032] In one embodiment, the compound for use in the methods disclosed is

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)((pentyloxy)carbonyl)amino)acetic acid, or

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn- 1 -yl)amino)acetic acid;

[0033] In one embodiment, the compound for use in the methods disclosed is

3 -((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-

yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanoic acid,

2-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2- yn-l-yl)amino)acetic acid, or

[0034] In one embodiment, 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,

eye loalkyloxyaryl- sulfonamides, aryloxybiaryls, biaryls, cyclopropyl- spiro-piperidines, pyridinyl morpholinones, or oxazolotriazoles, heteroarylamides, or pyrrolopyridinones, biaryl spiro- pyrrolidine-lactams, or spiro-piperidines. In one embodiment, the method comprises

administering the at least one compound according to Formula (G).

[0035] In one embodiment, the compound for use in the methods disclosed herein is a

NaVl.7 inhibitor.

[0036] In one embodiment, the NaVl.7 inhibitor for use in the methods disclosed herein is selective for the inactivated state of the NaVl.7 channel.

[0037] In one embodiment, 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.

[0038] In one embodiment, 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.

[0039] In one embodiment, 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.

[0040] In one embodiment, the one or more symptoms of inflammation is chosen from: swelling, edema, redness, warmth, and pain.

[0041] In one embodiment, 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.

[0042] In one embodiment, the inflammatory condition is chosen from: atherosclerosis,

Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematous (SLE), nephritis, Parkinson's disease, ulcerative colitis, myocarditis, anti- Glomerular Basement Membrane nephritis, lupus nephritis,

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) type 3, autoimmune pancreatitis (AIP), 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.

[0043] In one embodiment, the methods as disclosed herein wherein the inflammatory condition is not associated with pain.

[0044] In one embodiment, the methods as disclosed herein wherein the inflammatory condition is not associated with pain and wherein the inflammatory condition is induced by or associated with a disease selected from: Alzheimer’s, Atherosclerosis, Alopecia Areata, Anti- Glomerular Basement Membrane nephritis, Asthma, Autoimmune hepatitis, Autoimmune inner ear disease, Autoimmune neutropenia, Autoimmune polyendocrine syndrome (APS) type 1, Autoimmune polyendocrine syndrome (APS) type 2, Autoimmune polyendocrine syndrome (APS) type 3, Autoimmune thyroiditis, Autoimmune urticaria, Coeliac disease, Grave’s disease, Guillain-Barre syndrome, Idiopathic thrombocytopenic purpura, Linear IgA disease, Lupus nephritis, Meniere’s disease, Myasthenia gravis, Ord’s thyroiditis, Parkinson’s disease,

Pernicious anemia, Primary biliary cirrhosis (PBC), Psoriasis, Rheumatic fever, Sjogren’s syndrome, Autoimmune myocarditis, Autoimmune cardiomyopathy, Coxsackie myocarditis, and Vitiligo.

[0045] In one embodiment, the methods as disclosed herein wherein the inflammatory condition is associated with pain.

[0046] In one embodiment, the methods as disclosed herein wherein the inflammatory condition is associated with pain and wherein the inflammatory condition is induced by or

associated with a disease selected from: Addison’s disease, Ankylosing Spondylitis,

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

inflammation, Psoriatic arthritis, Relapsing polychondritis, Rheumatoid arthritis, Systemic Lupus Erythematosus, and Vasculitis.

[0047] In one embodiment, the methods as disclosed herein further comprise the step of selecting a subject in need of prevention or treatment of an inflammatory condition. In one embodiment the subject is a mammal. In one embodiment, the subject is a human.

[0048] In one embodiment, 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). In one embodiment the symptom is swelling, edema, redness, warmth, or pain.

[0049] In one embodiment, a method for treating or preventing at least one inflammatory condition in a subject in need thereof, the method 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).

[0050] In one embodiment, 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,

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, 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, IL-22, 1-TAC, MIG, VEGF-D, LIF, IL-6, Fractalkine, granulocyte-macrophage colony stimulating factor, or a chemokine.

[0051] In one embodiment, the methods as disclosed herein wherein the anti

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).

[0052] In one embodiment, 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.

[0053] In one embodiment, the methods as disclosed herein, wherein the compound(s) is administered orally, intravenously, topically, transdermally, patch, buccal, intramuscular, interperitoneally, or subcutaneously.

[0054] In one embodiment, the use of a compound according to Formula (G) as an anti inflammatory agent.

[0055] In one embodiment, the use of a compound according to Formula (G) for the manufacture of a medicament for the prevention or treatment of an inflammatory condition.

[0056] In one embodiment, a composition comprising a compound according to Formula

(G) when used for prevention or treatment of an inflammatory condition, wherein the

inflammatory condition is induced by, or associated with autoimmune, metabolic, and

cardiovascular diseases. In one embodiment, the inflammatory condition is induced by or associated with surgery or trauma.

[0057] In one embodiment, 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.

[0058] In one embodiment, provided herein are methods for preventing or treating inflammatory conditions comprising administering to a subject in need thereof a therapeutically effective amount of a compound inhibiting NaVl.7. In some embodiments the compound inhibiting NaVl.7 is at least one compound according to Formula (G).

DETAILED DESCRIPTION

[0059] 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 .

[0060] 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

methanesulfonic acids. Others are well known in the art, see for example, Remington’s

Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, l9th eds., Mack Publishing, Easton PA (1995).

[0061] A“stereoisomer” or“stereoisomeric form” refers to one stereoisomer of a

Compound that is substantially free of other stereoisomers of that Compound. For example, 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. The use of stereomerically pure forms of such Compounds, as well as the use of mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, 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

asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel,

E. L., Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0062] “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:

[0063] As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism and all tautomers of the Compounds provided herein are within the scope of the present disclosure.

[0064] 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). In some embodiments, 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.

[0065] 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. In some embodiments, 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. In certain embodiments, 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, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0066] 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. Examples of 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.

[0067] 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). In one embodiment, the heterocycloalkyl is a 5- or 6-membered or 4- to 8-membered heterocycloalkyl.

[0068] 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

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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. In one embodiment the subject is a patient.

[0073] The term“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.

[0074] The term“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.

[0075] The term“pro -inflammatory” refers to capable of promoting inflammation.

[0076] The term“anti-inflammatory” refers to capable of preventing or treating inflammation.

[0077] 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.

Brief Description of the Drawings

[0078] Figures 1A &1B show the effect of Compound 49 treatment on cytokines plasma levels in the rat STZ-induced model of diabetes.

Plasma samples were collected at week 2, 4 and 9 after induction of diabetes by STZ injection. Bars represent the average cytokine level from 2, 4 and 9 weeks.

While diabetic challenge significantly increased both the anti-inflammatory marker IL-4 (Fig.

1A) and the pro -inflammatory marker TNF-a (Fig. 1B) levels in the diabetic vehicle-treated group (sham vs. vehicle), treatment with Compound 49 increased anti-inflammatory cytokine IL- 4 (Fig. 1A) to even higher levels and concomitantly reduced pro-inflammatory cytokine TNF-a (Fig.lB) (vehicle vs. Compound 49) in diabetic animals.

Mean ± se, n= 9-10/ group, *p<0.05, **p<0.01, a=2 in comparison to vehicle.

[0079] 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). n=5-6/ group, *p<0.05, **p<0.01, a=2 in comparison to vehicle.

[0080] 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. At 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). n=5-6/ group, *p<0.05, **p<0.01, ***p<0.001, a=2 in comparison to vehicle.

[0081] 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

diabetic animals. Figures 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

significantly reduced insulin levels in diabetic rats compared to sham (Fig.3A), but Early treatment with Compound 49 improved insulin and amylin levels (Fig. 3A-B, both hormones are secreted from beta-cells) and its synergistic partner hormones (Fig.3C-D). Pancreatic

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. Mean ± se, n=5-6/ group, *p<0.05, **r<0.01, ***r<0.001, a=2 in comparison compared to vehicle.

[0082] 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, vehicle (0.2% PEG600), or Pregabalin (eNovation Chemicals, Cat#: D320170) 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.

4C). The improvements were sustained for 4-5 weeks after the treatment with Compound 49 had stopped. Pregabalin treatment did not significantly improve clinical scores of fecal consistency (Fig 4 A) or fur cleaning (Fig 4B) and increased the number of animals selected for supplemental care (Fig 4C). Pregabalin treatment also reduced coordination as measured in the foot fault test unlike Compound 49 (Fig 4D). N=10-15, a=2, *p<0.05, **r<0.01, ***p<0.00l in comparison to vehicle.

[0083] 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. N=l0, a=2, *p<0.05, ***p<0.00l in comparison to vehicle.

[0084] 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) at 50mg/kg by ip (Fig. 7C), and vehicle (2% PEG600 / water) (Fig. 6 A, 6B, and 6C) at 4ml/kg were given by ip once daily for 8 days starting on day 1 after a surgical incision on right hind-paw plantar. Paw thickness was measured periodically. The thickness was significantly increased in the vehicle treated group in comparison with the sham group. All three compounds (11, 49 and 54) were associated with a significant reduction on post- surgical tissue edema with continuous tissue recovery after drug withdrawal. Ibuprofen also was

associated with a reduction on edema, but the effect stopped after drug withdrawal. N=10, a=2, *p<0.05, **p<0.01 in comparison to vehicle.

[0085] In one embodiment, 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

inflammatory conditions induced by, or associated with autoimmune, metabolic, or

cardiovascular disease.

[0086] In one embodiment, the present disclosure provides methods for preventing or treating inflammatory conditions induced, or associated with surgery, or trauma.

[0087] In one embodiment, the at least one symptom induced by or associated with inflammatory conditions is one chosen from edema, swelling, warmth, redness, and pain. In one embodiment the at least one symptom induced by or associated with inflammatory conditions is a change in at least one molecular inflammatory marker. In one embodiment 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. In one embodiment, 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.

[0088] In one embodiment, the at least one symptom induced by or associated with inflammatory conditions is one chosen from edema, swelling, redness, and warmth.

[0089] In one embodiment, the at least one symptom induced by or associated with inflammatory conditions is not pain.

[0090] Provided herein, is 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.

[0091] Provided herein, is 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.

[0092] Provided herein, is 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.

[0093] Provided herein, is 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.

[0094] Provided herein are compounds of Formula (I),

Formula (I)

Z is -O- or -S-;

Y is -X-C(=0)NR₄R_{5, -}(CH₂)3-NR₉R_IO, or 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-(2-yl or 3-yl);

X is (C₆-Cio)aryl or 5- or 6-membered heteroaryl;

Ri is a partially unsaturated or aromatic 5- or 6-membered heterocycle;

R₂ is independently at each occurrence -F, -Cl, -Br, -CH₃ or -CN;

R₄ and Rs are not both H; and

R₆ is (Ci-Ci₂) alkyl;

of -COOH, -COORn, -CONRHRI₂, -S0₂RH , -S0₂NRHRI₂, -OH, -CN, -ORn, and -NRHRI₂; wherein Rn and RI₂ may form a 6 membered heterocycloalkyl ring

Rio is Rn, -COR₁₁, -COOR₁₁, -SO₂R₁₁, 5-methyl-2-oxo-l,3-dioxol-4-yl,

, -COO-CH(CH₃)OCOCH(CH₃)₂; or 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- COORn, -OH, -NH₂, -CN, and (Ci-C₈)alkoxy;

R₁₁ and R₁₂ are independently H or (Ci-C₆)alkyl, optionally substituted with 4- to 8- membered heterocycloalkyl ring; and

m and n are each independently 1, 2, 3, or 4.

[0095] In a certain embodiment, the compounds of Formula (G)

Formula (G)

are those wherein

Rio is R₁₁, (C₃-C₆)alkynyl, (C₃-C₆)alkenyl, -COR₁₁, -COOR₁₁, -SO₂R₁₁,

5-methyl-2-oxo- 1 ,3-dioxol-4-yl,

, -COO-CH(CH₃)OCOCH(CH₃)₂; or 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

unsubstituted 4- to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is fused with a 5-membered heteroaryl; and

wherein all other substituents are defined as in paragraph [0094] above.

[0096] In a certain embodiment, the compounds of Formula (I) or Formula (G) are those wherein Y is -(CH₂)3-NR9RIO.

[0097] In a particular embodiment, 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.

[0098] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is pyridyl or pyrimidinyl.

[0099] In a particular embodiment, 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. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is thiazolyl. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is l,2,4-thiadiazol-5-yl. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is thiadiazol-4-yl.

[00100] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₂ is independently at each occurrence -F or -Cl.

[00101] In a particular embodiment, 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-.

[00103] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₃ 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 R₃ is -H or -Cl.

In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₃ is -Cl.

[00104] In a particular embodiment, 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.

[00105] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₉ is (Ci-C₆)alkyl; wherein R₉ is optionally further substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOMe, -CONH₂, and -NH₂. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₉ is methyl or ethyl. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₉ is further substituted with -COOH.

[00106] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Rio is H and R₉ is (Ci-C₆)alkyl; wherein R₉ is further substituted

with -CONR₁₁R₁₂, and wherein Rn and R₁₂ are independently H or (Ci-C₆)alkyl. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₉ is further substituted with -CONH₂. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₉ is methyl and wherein R₉ is further substituted with -CONH₂.

[00107] In a particular embodiment, 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.

[00108] In a particular embodiment, 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_. In a particular embodiment, 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_.

[00109] In a particular embodiment, 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, -CH₂-COOMe, -CH₂- COOEt, and -NH2_. In a particular embodiment, 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_.

[00110] In a certain embodiment, the compounds of Formula (I) or Formula (G) are those wherein Y is -X-C(=0)NR₄R₅.

[00111] In a particular embodiment, 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.

[00112] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is pyridyl or pyrimidinyl.

[00113] In a particular embodiment, 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. In a particular embodiment, the compounds of Formula (I) or

Formula (G) are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is thiazolyl. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is l,2,4-thiadiazol-5-yl.

[00114] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₂ is independently at each occurrence -F or -Cl.

[00115] In a particular embodiment, 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.

[00116] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Z is -0-.

[00117] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₃ 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 R₃ is -H or -Cl.

[00118] In a particular embodiment, 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.

[00119] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein X is 5- or 6-membered heteroaryl. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein X is pyridyl or pyrimidinyl. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein X is pyridyl.

[00120] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₄ is H and Rs is (Ci-C9)alkyl.

[00121] In a particular embodiment, 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 -C0₂H, -CO2R6, and -CONR₇Rs.

[00122] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₆ is (Ci-C₆)alkyl.

[00123] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₅ is methyl or ethyl, substituted with -CO2H.

[00124] In a certain embodiment, 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.

[00125] In a particular embodiment, 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.

[00126] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is pyridyl or pyrimidinyl.

[00127] In a particular embodiment, 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. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is thiazolyl. In

a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is l,2,4-thiadiazol-5-yl.

[00128] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₂ is independently at each occurrence -F or -Cl.

[00129] In a particular embodiment, 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.

[00130] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Z is -0-.

[00131] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₃ 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 R₃ is -H or -Cl. In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₃ is -Cl.

[00132] In a particular embodiment, 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.

[00133] In a certain embodiment, 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.

[00134] Table 1

* Chemical Names automatically generated with ChemDraw Ultra, Version 12.0.

[00135] In a certain embodiment, 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

* Chemical Names automatically generated with ChemDraw Ultra, Version 12.0.

[00137] In a certain embodiment, 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.

[00138] Table 3

* Chemical Names automatically generated with ChemDraw Ultra, Version 12.0.

[00139] For the proposes of this disclosure, 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.

[00140] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein the compound is

2-(4-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5- chlorophenyl)picolinamido)propanoic acid, or

3-((3-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5- chlorophenyl)propyl)amino)propanoic acid;

[00141] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein the compound is

[00142] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein the compound is

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl) sulfamoyl)phenoxy)phenyl)propyl)(propyl)amino)acetic acid,

[00143] In one embodiment, 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).

[00144] In one embodiment, the compound according to Formula (I) or Formula (G) is2- ((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-

4yl) sulfamoyl)phenoxy)phenyl)propyl)amino)acetamide (Compound 49) .

[00145] Further provided herein are compounds of Formula (la),

Formula (la)

or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof, wherein: Z is -O- or -S-;

Ri is a partially unsaturated or aromatic 5- or 6-membered heterocycle;

R₂ is independently at each occurrence -F, -Cl, -Br, -CH₃ or -CN;

R₉ is (Ci-C₆)alkyl, (C;i-Cx)cycloalkyl, pyrazolyl or pyridinyl; wherein R₉ is optionally further substituted with 1 or 2 substituents selected from the group consisting

of -COOH, -COORn, -CONR11R12, -SO2R11, -SO2NR11R12, -OH, -CN, -OR11, and -NR₁₁R₁₂; wherein Rn and R₁₂ may form a 6 membered heterocycloalkyl ring

Rio is R₁₁, -COR₁₁, -COOR₁₁, -SO₂R₁₁, 5-methyl-2-oxo-l,3-dioxol-4-yl,

, -COO-CH(CH₃)OCOCH(CH₃)₂; or 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-

COORn, -OH, -NH₂, -CN, and (Ci-C₈)alkoxy;

R₁₁ and R₁₂ are independently H or (Ci-C₆)alkyl, optionally substituted with 4- to 8-membered heterocycloalkyl ring; and

m and n are each independently 1, 2, 3, or 4.

[00146] In a certain embodiment, the compounds of Formula (I’a)

are those wherein

Rio is Rn, (C3-C₆)alkynyl, (C₃-C6)alkenyl, -COR11, -COOR11, -SO2R11,

5-methyl-2-oxo- 1 ,3-dioxol-4-yl,

, -COO-CH(CH₃)OCOCH(CH₃)2; or 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

wherein all other substituents are defined as in paragraph [00145] above.

[00147] In a particular embodiment, 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.

[00148] In a particular embodiment, the compounds of Formula (la) or Formula (I’a) are those wherein Ri is pyridyl or pyrimidinyl.

[00149] In a particular embodiment, 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. In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein Ri is thiazolyl. In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein Ri is l,2,4-thiadiazol-5-yl. In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein Ri is thiadiazol-4-yl.

[00150] In a particular embodiment, the compounds of Formula (la) or Formula (I’a) are those wherein R₂ is independently at each occurrence -F or -Cl.

[00151] In a particular embodiment, the compounds of Formula (la) or Formula (I’a) are those wherein n is 1, 2, or 3. In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein n is 2.

[00152] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein Z is -0-.

[00153] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein R₃ 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 R₃ is -H or -Cl. In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein R is -Cl.

[00154] In a particular embodiment, 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.

[00155] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein R₉ is (Ci-C₆)alkyl; wherein R₉ is optionally further substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOMe, -CONH2, and -NH₂. In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein R₉ is methyl or ethyl. In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein R₉ is further substituted with -COOH.

[00156] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein Rio is H and R₉ is (Ci-C₆)alkyl; wherein R₉ is further substituted

with -CONRi ₁ R _12, and wherein Rn and RI₂ are independently H or (Ci-C₆)alkyl. In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein R₉ is further

substituted with -CONH₂. In a particular embodiment, the compounds of Formula (la) or Formula (I’a) are those wherein R9 is methyl and wherein R9 is further substituted with -CONH₂.

[00157] In a particular embodiment, the compounds of Formula (la) or Formula (I’a) are those wherein Rio is -H, -COMe, -COOEt. In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein Rio is -H or -COMe. In a particular

embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein Rio is -H.

[00158] In a particular embodiment, 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_. In a particular embodiment, 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_.

[00159] In a particular embodiment, 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, -CH₂-COOMe, -CH₂- COOEt, and -NH2_. In a particular embodiment, 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_.

[00160] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are selected from the group consisting of

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-

yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetic acid,

3 -((3 -(5-chloro-2-(2,5 -difluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanoic acid,

3-((3-(5-chloro-2-(2-cyano-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanoic acid, methyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetate,

2-(N-(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-

yl)sulfamoyl)phenoxy)phenyl)propyl)acetamido)acetic acid,

ethyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetate, and

4-(2-(3-((lH-pyrazol-4-yl)amino)propyl)-4-chlorophenoxy)-5-chloro-2-fluoro-N-(thiazol-2- yl)benzenesulfonamide;

[00161] In a particular embodiment, the compounds of Formula (la) or Formula (I’a) are selected from the group comprising

ethyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)(methyl)amino)acetate,

2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)((5- methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl)amino)acetic acid,

2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)((l- (isobutyryloxy)ethoxy)carbonyl)amino)acetic acid,

2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(((5- methyl-2-oxo- 1 ,3-dioxol-4-yl)methoxy)carbonyl)amino)acetic acid,

5-chloro-4-(4-chloro-2-(3-(3-oxopiperazin-l-yl)propyl)phenoxy)-2-fluoro-N-(thiazol-2- yl)benzenesulfonamide, and

5-chloro-4-(4-chloro-2-(3-((3-morpholino-3-oxopropyl)amino)propyl)phenoxy)-2-fluoro-N-

(thiazol-2-yl)benzenesulfonamide;

[00162] In a particular embodiment, the compounds of Formula (la) or Formula (I’a) are selected from the group comprising

(thiazol-4-yl)benzenesulfonamide,

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-

yl)sulfamoyl)phenoxy)phenyl)propyl)((pentyloxy)carbonyl)amino)acetic acid,

(thiazol-2-yl)benzenesulfonamide,

ethyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)(methyl)amino)acetate, and

[00163] Provided herein are compounds of Formula (lb),

Formula (lb)

X is (C₆-Cio)aryl or 5- or 6-membered heteroaryl;

Ri is a partially unsaturated or aromatic 5- or 6-membered heterocycle;

R₂ is independently at each occurrence -F, -Cl, -Br, -CH₃ or -CN;

R₄ and R5 are each independently H, (Ci-C9)alkyl, (C4-Ci₂)cycloalkyl, or R₄ and R5 together form a 5- to 7-membered heterocycloalkyl ring; with the proviso that:

R₄ and R5 are not both H; and

at least one of R₄ and R5 independently or said heterocycloalkyl ring formed by R₄ and R5 together is substituted with 1 or 2 substituents selected from the group consisting of -C0₂H, -C0₂R₆, -CN, -OH, -CONR₇Rs, and -NR₇Rs; wherein:

R₆ is (Ci -Ci 2) alkyl;

R₇ and Rs are each independently H, (Ci-Ci₂)alkyl, or R₇ and Rs together form a 4- to 7-membered heterocycloalkyl ring; and m and n are each independently 1, 2, 3, or 4.

[00164] In a particular embodiment, 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.

[00165] In a particular embodiment, the compounds of Formula (lb) are those wherein Ri is pyridyl or pyrimidinyl.

[00166] In a particular embodiment, 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. In a particular embodiment, the compounds of Formula (lb) are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compounds of Formula (lb) are those wherein Ri is thiazolyl. In a particular embodiment, the compounds of Formula (lb) are those wherein Ri is l,2,4-thiadiazol-5-yl.

[00167] In a particular embodiment, the compounds of Formula (lb) are those wherein R₂ is independently at each occurrence -F or -Cl.

[00168] In a particular embodiment, the compounds of Formula (lb) are those wherein n is

1, 2, or 3. In a particular embodiment, the compounds of Formula (lb) are those wherein n is 2.

[00169] In a particular embodiment, the compounds of Formula (lb) are those wherein Z is -O- .

[00170] In a particular embodiment, the compounds of Formula (lb) are those wherein R₃ is independently at each occurrence -H, -F, -Cl, or -Br. In a particular embodiment, the compounds of Formula (lb) are those wherein R₃ is -H or -Cl. In a particular embodiment, the compounds of Formula (lb) are those wherein R₃ is -Cl.

[00171] In a particular embodiment, 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.

[00173] In a particular embodiment, the compounds of Formula (lb) are those wherein R₄ is H and R₅ is (Ci-C9)alkyl.

[00174] In a particular embodiment, 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 -C0₂H, -CO2R6, and -CONR₇R₈.

[00175] In a particular embodiment, the compounds of Formula (lb) are those wherein R₆ is (Ci-C₆)alkyl.

[00176] In a particular embodiment, the compounds of Formula (lb) are those wherein R₅ is methyl or ethyl, substituted with -C0₂H.

[00177] Provided herein are compounds of Formula (Ic),

Formula (Ic)

Ri is a partially unsaturated or aromatic 5- or 6-membered heterocycle;

R₂ is independently at each occurrence -F, -Cl, -Br, -CH₃ or -CN;

R₄ and Rs are each independently H, (Ci-C9)alkyl, (C₄-Ci₂)cycloalkyl, or R₄ and Rs together form a 5- to 7-membered heterocycloalkyl ring; with the proviso that:

R₄ and Rs are not both H; and

R₆ is (Ci-Ci₂) alkyl;

[00178] In a particular embodiment, 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.

[00179] In a particular embodiment, the compounds of Formula (Ic) are those wherein Ri is pyridyl or pyrimidinyl.

[00180] In a particular embodiment, 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. In a particular embodiment, the compounds of Formula (Ic) are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compounds of Formula (Ic) are those wherein Ri is thiazolyl. In a particular embodiment, the compounds of Formula (Ic) are those wherein Ri is l,2,4-thiadiazol-5-yl.

[00181] In a particular embodiment, the compounds of Formula (Ic) are those wherein R₂ is independently at each occurrence -F or -Cl.

[00182] In a particular embodiment, the compounds of Formula (Ic) are those wherein n is

1, 2, or 3. In a particular embodiment, the compounds of Formula (Ic) are those wherein n is 2.

[00183] In a particular embodiment, the compounds of Formula (Ic) are those wherein Z is 0

[00184] In a particular embodiment, the compounds of Formula (Ic) are those wherein R₃ is independently at each occurrence -H, -F, -Cl, or -Br. In a particular embodiment, the compounds of Formula (I) are those wherein R₃ is -H or -Cl. In a particular embodiment, the compounds of Formula (Ic) are those wherein R₃ is -Cl.

[00185] In a particular embodiment, 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.

[00186] In a particular embodiment, 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.

[00187] In a particular embodiment, the compounds of Formula (Ic) are those wherein R₄ is H and R₅ is (Ci-C9)alkyl.

[00188] In a particular embodiment, 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, -C0₂R₆, and -CONR₇R₈.

[00189] In a particular embodiment, the compounds of Formula (Ic) are those wherein R₆ is (Ci-C₆)alkyl.

[00190] In a particular embodiment, the compounds of Formula (Ic) are those wherein Rs is methyl or ethyl, substituted with -C0₂H.

[00191] In a particular embodiment, the compounds of Formula (Ic) are selected from the group consisting of

3-(4-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-cyanophenoxy)-5- chlorophenyl)picolinamido)propanoic acid, and

3-(4-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)-5- chlorophenyl)picolinamido)propanoic acid; or

a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.

[00192] Provided herein are compounds of Formula (Id),

Formula (Id)

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;

R₂ is independently at each occurrence -F, -Cl, -Br, -CH₃ or -CN;

R₃ is independently at each occurrence -H, -F, -Cl, -Br, -CF₃, -OCF_3, -CN, (Ci-Ci₂)alkyl, or (Ci-Ci₂)alkoxy; and

m and n are each independently 1, 2, 3, or 4.

[00193] In a certain embodiment, 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-

3-yl.

[00194] In a particular embodiment, 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.

[00195] In a particular embodiment, the compounds of Formula (Id) are those wherein Ri is pyridyl or pyrimidinyl.

[00196] In a particular embodiment, 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. In a particular embodiment, the compounds of Formula (Id) are those wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compounds of Formula (Id) are those wherein Ri is thiazolyl. In a particular embodiment, the compounds of Formula (Id) are those wherein Ri is l,2,4-thiadiazol-5-yl.

[00197] In a particular embodiment, the compounds of Formula (Id) are those wherein R₂ is independently at each occurrence -F or -Cl.

[00198] In a particular embodiment, 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.

[00199] In a particular embodiment, the compounds of Formula (Id) are those wherein Z is 0

[00200] In a particular embodiment, the compounds of Formula (Id) are those wherein R₃ is independently at each occurrence -H, -F, -Cl, or -Br. In a particular embodiment, the compounds of Formula (Id) are those wherein R₃ is -H or -Cl. In a particular embodiment, the compounds of Formula (Id) are those wherein R₃ is -Cl.

[00201] In a particular embodiment, 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

1.

[00202] In a particular embodiment, the compound of Formula (Id) is

(thiazol-4-yl)benzenesulfonamide, or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.

[00203] In a particular embodiment, the compound of Formula (Id) is

5-chloro-4-(4-chloro-2-(4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidin-3-yl)phenoxy)-2-fluoro-N- (thiazol-2-yl)benzenesulfonamide, or

5-chloro-2-fluoro-4-(2-(4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidin-3-yl)phenoxy)-N-(thiazol-4- yl)benzenesulfonamide;

[00204] It should also be noted the Compounds provided herein can contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the Compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine- 125 (¹²⁵I), sulfur-35 (³⁵S), or carbon- 14 (¹⁴C), or may be isotopically enriched, such as with deuterium (¾), carbon-l3 (¹³C), or nitrogen-l5 (¹⁵N). As used herein, an“isotopologue” is an isotopically enriched Compound. The term“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. All isotopic variations of the Compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, there are provided isotopologues of the Compounds, for example, the isotopologues are deuterium, carbon- 13, or nitrogen- 15 enriched Compounds.

[00205] In one embodiment, 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. In a particular embodiment, 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.

[00207] In certain embodiments, a Compound provided herein inhibits the activity of a sodium ion channel, such as a voltage-gated sodium ion channel. In more specific embodiments, such a voltage-gated sodium ion channel is NaVl.7 (whose alpha subunit is encoded by the human gene SCN9A).

[00208] In certain embodiments, 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.

[00209] In certain embodiments, 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.

[00210] In certain embodiments, 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.

[00211] In certain embodiments, 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. In certain embodiments, 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.

[00212] In certain embodiments, 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. In certain embodiments, 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.

[00213] In certain embodiments, 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).

[00214] In certain embodiments, 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.

[00215] In one embodiment, 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. In one embodiment, 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. In one embodiment, 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.

[00216] In one embodiment, the IC50 is measured using an FDSS membrane potential assay or the patch-clamp method.

[00217] 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. In particular, such assays are disclosed in Example 3, pages 94-99 of W02007/109324, which is herewith incorportated in its entirety.

[00218] In certain embodiments, a cell culture assay is used, wherein the voltage-gated sodium ion channel is recombinantly expressed in the cultured cells. In certain more specific embodiments, the alpha subunit of the voltage-gated sodium ion channel is expressed but no accessory proteins are recombinantly expressed in the same cell. In a specific embodiment, SCN9A and SCN9B1 and SCN9B2 are co-expressed in the same cell. In other embodiments, 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.

[00219] In certain embodiments, 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). In other embodiments, 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). In one embodiment, the compounds provided herein are any compounds that inhibit NaVl.7.

[00220] In one embodiment, 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.

[00221] In one embodiment, 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.

[00222] In one embodiment, the compounds provided herein are, for example, any of the fluorinated aromatic ethers disclosed in WO 2017035271 Al to Hemeon et al.

[00223] In one embodiment, the compounds provided herein are, for example, any of the heterocyclyl benzenesulfonamide compounds disclosed in WO 2017058821 Al to Bergeron et al.

[00224] In one embodiment, the compounds provided herein are, for example, any of the benzenesulfonamide compounds disclosed in WO 20170082688 Al to Lee et al.

[00225] In one embodiment, the compounds provided herein are, for example, any of the indazolecarboxamide compounds disclosed in WO 2017091592 Al to Chen et al.

[00226] In one embodiment, the compounds provided herein are, for example, any of the

Nl-phenylpropane-l, 2-diamine compounds disclosed in WO 2017165204 Al to Roecker et al.

[00227] In one embodiment, 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.

[00228] In one embodiment, 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.

[00229] In one embodiment, the compounds provided herein are aryloxysulfonamides or sulfonated amines. In a specific embodiment, 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.

[00230] In one embodiment, the compounds provided herein are aryloxysulfonylated amides, acylsulfonyl ureas, or arylindazole sulfonylated amides. In a specific embodiment, 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.

[00231] In one embodiment, the compounds provided herein are bicyclic core

sulfonamides. In a specific embodiment, the compounds provided herein are, for example, those disclosed in WO2013/025883 to Dineen et al. , WO2013/086229 to Boezio et al. ,

WO2013/122897 to Boezio et al, WO2013/134518 to Dineen et al, W02014/066490 to Pero et al. , WO2014066491 to Pero et al. , and W02014/061970 to Kim et al.

[00232] In one embodiment, the compounds provided herein are substituted piperazine or piperazine methylenoxy arylsulfonamides or ary loxy sulfonamides. In a specific embodiment, the compounds provided herein are, for example, those disclosed in WO2013/064983 to Sun et al. and WO2013/064984 to Liu et al.

[00233] In one embodiment, the compounds provided herein are benzo-oxazolone core sulfonamides. In a specific embodiment, the compounds provided herein are, for example, those disclosed in WO2013/063459 to Layton et al.

[00234] In one embodiment, the compounds provided herein are cycloalkyloxyaryl- sulfonamides. In a specific embodiment, the compounds provided herein are, for example, those disclosed in WO2013/118854 to Shinozuka et al.

[00235] In one embodiment, the compounds provided herein are aryloxybiaryls. In a specific embodiment, 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

W02012085650 to Ni et al.

[00236] In one embodiment, the compounds provided herein are biaryls, cycloprop yl- spiro-piperidines, pyridinyl morpholinones, or oxazolotriazoles. In a specific embodiment, 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.

[00237] In one embodiment, the compounds provided herein are heteroarylamides or pyrrolopyridinones. In a specific embodiment, 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.

[00238] In one embodiment, the compounds provided herein are biaryl spiro-pyrrolidine- lactams. In a specific embodiment, 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.

[00239] In one embodiment, the compounds provided herein are spiro-piperidines. In a specific embodiment, 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.

[00240] In one embodiment the compounds provided herein are AZD3161, PF-04856264, CNV1014802, DSP-2230, PF-05089771, XEN402, and XEN403.

[00241]

Methods for Making Compounds

[00242] The synthesis and preparation of a compound of Formula (la), (I’a), (lb), (Ic),(Id), Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof, has been described previously in PCT/US 15/48927, published October 26, 2017, the contents of which are incorporated herewith by reference.

Methods of Use

[00243] In one embodiment, provided herein are methods of preventing or treating inflammatory conditions induced or associated with autoimmune diseases, metabolic diseases, cardiovascular diseases, surgery, or trauma.

[00244] 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, and pain. In some embodiments, pain is not a symptom induced by or associated with an inflammatory condition.

In one embodiment, 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.

[00245] In one embodiment, 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.

[00246] In one embodiment, provided herein are methods 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).

[00247] In one embodiment, provided herein are methods 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).

[00248] In one embodiment, provided herein are methods preventing or treating one or more symptoms induced by or associated with inflammatory conditions comprising

administering to a subject in need thereof a therapeutically effective amount of at least one compound according to Formula (G). In one embodiment 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.

[00249] In one embodiment, provided herein are methods 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.

[00250] In one embodiment, 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.

[00251] In one embodiment, 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.

[00252] In one embodiment, 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.

[00253] In one embodiment, 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.

[00254] In one embodiment, 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.

[00255] In one embodiment, 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. In one embodiment, 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.

[00256] In one embodiment, 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. In one embodiment, 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.

[00257] In one embodiment, 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. In one embodiment, 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.

[00258] 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

pharmaceutically acceptable salt, solvate or tautomeric form thereof.

[00259] Provided herein are methods for prevention or treatment of one or more inflammatory condition in a subject, wherein 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. In one embodiment, 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 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. In one embodiment, 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 ,

wherein 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. In one embodiment, the symptoms of an inflammatory condition include, but are not limited to, swelling, edema, redness, warmth, and pain. In one embodiment, the inflammatory condition is associated with a change (increase or decrease) in at least one pro- and/or anti-inflammatory marker. In one embodiment, 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. In one embodiment, 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.

[00260] The pharmaceutical compositions required by the present disclosure comprises a compound useful in the methods of the disclosure and a pharmaceutically acceptable carrier. As used herein“pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption.

[00261] In one embodiment, 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. I one embodiment, 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%,

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 at least one symptom prior to the administration of a Compound provided herein. In one embodiment, 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.

[00262] In one embodiment, use of a compound as disclosed herein as an anti

inflammatory agent or drug.

[00263] Table 4 provides a non-limiting list of inflammatory diseases, including their clinical symptoms.

Table 4¹

¹ Referenced form e.wikipedia.org/wiki/List of autoimmune diseases.

Assessment of Inflammatory Conditions

[00264] 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

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. Furthermore, testing for changes (increase or decrease) in pro- and anti inflammatory markers, such as the markers disclosed herein, can be used to assess inflammatory conditions. Additionally, presence of any one of the clinical signs as for example listed in Table 4 can serve to assess inflammatory disease and/or condition.

Patient Populations

[00265] In one embodiment, the subject in need for prevention or treatment of an inflammatory condition has not been previously treated for the inflammatory condition.

[00266] In one embodiment, 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.

[00267] Provided herein are pharmaceutical compositions comprising a Compound provided herein and a pharmaceutically acceptable carrier. In a particular embodiment, the pharmaceutical compositions are those, wherein the composition is suitable for topical, oral, subcutaneous, or intravenous administration.

[00268] Provided herein are compositions comprising an effective amount of a Compound and compositions comprising an effective amount of a Compound and a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutical composition described herein are suitable for oral, parenteral, mucosal, transdermal or topical administration.

[00269] 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), a stabilizer (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., hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol). 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.

[00270] 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. In general, 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. In one embodiment, 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

of a patient’s body weight or about 0.1 mg/kg of a patient’s body weight to about 25 mg/kg of a patient’s body weight. In one embodiment, one dose is given per day. In another embodiment, two doses are given per day. In any given case, 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.

[00271] In another embodiment, provided herein are methods 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. In a particular embodiment, 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,

50 mg/day, 60 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 200 mg/day,

250 mg/day, 300 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1,000 mg/day, 1,500 mg/day, 2,000 mg/day, 2,500 mg/day, 5,000 mg/day, or 7,500 mg/day of a Compound to a in need thereof. In one embodiment, 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.

[00272] In another embodiment, provided herein are 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

Compound.

[00273] In one embodiment, provided herein are 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,

2,000 mg, 2,500 mg, 5,000 mg, or 7,500 mg of a Compound.

[00274] In another embodiment, provided herein are unit dosage formulations that comprise a Compound dosage that achieves a target plasma concentration of the Compound in a patient or an animal model. In a particular embodiment, provided herein are 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. To achieve such plasma concentrations, 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. In certain embodiments, 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.

[00275] A Compound can be administered once, twice, three, four or more times daily.

[00276] A Compound can be administered orally for reasons of convenience. In one embodiment, when administered orally, a Compound is administered with a meal and water. In another embodiment, the Compound is dispersed in water or juice ( e.g ., apple juice or orange juice) and administered orally as a suspension. In another embodiment, when administered orally, a Compound is administered in a fasted state.

[00277] The Compound can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally,

sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin. 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.

[00278] In one embodiment, provided herein are capsules containing a Compound without an additional carrier, excipient or vehicle.

[00279] In another embodiment, provided herein are 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. In one embodiment, the composition is a pharmaceutical composition.

[00280] The 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. In one embodiment, the solutions are prepared from water-soluble salts. In general, 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.

[00281] Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and

disintegrators as well as the compound. 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. In one

embodiment, the pharmaceutical composition is lactose-free. Typical tablet binders are

substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. 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.

[00282] 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.

[00283] When it is desired to administer a Compound as a suppository, typical bases can be used. 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.

[00284] The effect of the Compound can be delayed or prolonged by proper formulation.

For example, 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).

Even the parenteral preparations can be made long-acting, by dissolving or suspending the

Compound in oily or emulsified vehicles that allow it to disperse slowly in the serum.

EXAMPLES

[00285] In order that this invention be more fully understood, the following examples are set forth. These examples are only for the purpose of illustration and are not to be construed as limiting the scope of the invention in any way.

EXAMPLE 1

[00286] Model and Method of Surgical Incision

[00287] 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

complication that follows surgery, particularly where soft tissue is damaged. Wound

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.

[00288] 250-400g male Sprague-Dawley rats from appropriate animal resources were used. The surgical incision on a hind paw was performed under aseptic conditions on day 1 on all animals except those in the sham group. Animals in the sham group underwent anesthesia and surgical prep without surgery. Baseline testing for mechanical allodynia using the von Frey test was assessed before surgery. The von Frey test and the plantar test were assessed every day or every other day during the first 2 weeks, then once or twice weekly during the last 2 weeks. Any animals that exhibited extensive motor deficiency (such as paw dragging) after recovery from surgery or failed to exhibit subsequent tactile allodynia were excluded from further testing. Animals thus chosen for the study were administered the vehicle or drug at the appropriate time points post-surgery in accordance with the treatment regimens that are detailed below. Paw

swelling (edema) was assessed by measuring the paw thickness before and after surgery with plastic calipers in millimeter (mm).

In the surgical incision model, 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.

EXAMPLE 2

[00289] Method of CFA model

[00290] 250-400g male Sprague-Dawley rats from appropriate animal resources were used. 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.

[00291] In the CFA model, 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.

EXAMPLE 3

[00292] Model and Method of Streptozotocin (STZ) Induced Diabetes

[00293] 250-400g male Sprague-Dawley rats from appropriate animal resources were used. 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. The glucose level was 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.

Other parameters (water intake, food intake, and bodyweight) were monitored before, during and after treatment. 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.

To evaluate the ability of the test compounds to reduce inflammation, the STZ model of diabetes and the surgical incision models were studied: as described above in Examples 1-2. In the STZ model b-cells in the pancreas are damaged, resulting in inflammation of the pancreas.

In the STZ model, 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.

EXAMPLE 4

[00294] Data analysis

The analgesic effect of 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% }

wherein "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.

All results were compared between compound dosed, the positive controls (such as Ibuprofen), vehicle dosed and sham animals. Plantar and von Frey tests were measured daily shortly before the paw thickness measurements (in SI and CFA models).

EXAMPLE 5

Description of Measurement Tests used to assess the Effect of Test Compounds on

Experimental Animals

[00295] Thermal Hyperalgesia (Plantar Test):

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.

[00296] 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.

[00298] Animals were placed under clear plastic boxes above a wire mesh floor, which allowed full access to the paws. Behavioral acclimation was allowed for at least 5 min.

Mechanical paw withdrawal thresholds (PWTs) were measured with the up-down testing paradigm. Von Frey filaments in log increments of force (2.0, 4.0, 6.0, 8.0, 10.0, 15.0, 26 g or size 4.31, 4.56, 4.74, 4.93, 5.07, 5.18, 5.46) were applied for a duration of 2-3 s to the mid- plantar paw in neuropathic pain ( e.g ., PSNL or diabetic) animals. Application was to the central region of the plantar surface avoiding the foot pads. The 4.0-g stimulus was applied first.

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. This cut off force was used, because it represented approximately 10% of the animals‘body weight and served to prevent rising of the entire limb due to the use of stiffer hairs, which would have changed the nature of the stimulus. The value of each hair was confirmed weekly by measuring the magnitude in grams exerted by the hair when applied to an electronic balance.

[00299] The hair was applied only when the rat was stationary and standing on all four paws. A withdrawal response was considered valid only if the hind paw was completely removed from the platform. Although infrequent if a rat walked immediately after application of a hair instead of simply lifting the paw, the hair was reapplied. On rare occasions, the hind paw only flinched after a single application; as the hind paw was not lifted from the platform, this was not considered a withdrawal response. A trial consisted of the application of a von Frey

hair to the hind paw five times at 5 s intervals or as soon as the hind paw was placed appropriately on the platform. If withdrawal did not occur during five applications of a particular hair, the next larger hair in the series was applied in a similar manner. When the hind paw was withdrawn from a particular hair either four or five times out of the five applications, the value of that hair in grams was considered to be the withdrawal threshold. Once the threshold was determined for the left hind paw, the same testing procedure was repeated on the right hind paw after 5 min.

[00300] Foot fault test for CNS or muscular deficiency for side effects

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. In this test, the animals (healthy, diseased or treated) were placed on a steel wire (diameter = 0.5 mm) mesh screen floor with dimensions of 3 cm x 3cm and housed in a box with dimensions of 38 cm x 36 cm x 17.5 cm (W x L x D). Healthy animals or those without neurological deficits exhibit precise placement of their feet and walk along the grid gripping the metal wires while diseased animals exhibiting neurological deficits misplace their steps and display paw slips through the metal grid. The number of paw slips/mis-placements are recorded manually or aided by video cameras over a two-minute period. In this study, the foot fault test was conducted on animals soon after completion of behavioral pain measurements.

[00301] Animal well-being measurements

[00302] To help quantitate the rats’ well-being, three novel measures were developed and utilized in the STZ model; a measure of fur cleanliness, a measure of fecal consistency and a holistic measure of animal distress (animals selected for intensive supplemental care).

[00303] Normal small rodents routinely groom to keep their fur clean. When animals feel fatigue or sick, they look unkempt appearance. To quantitate the rodent’s ability to groom, a scoring system was created for fur cleanliness. Scoring criteria were as follows: 0 = normal clean fur, 1 = dirty tail but otherwise clean fur, 2 = a dirty tail and some brown color on the rodent’s back fur, 3 = a dirty tail, some brown color on the rodent’s back fur and a wet dirty belly, and 4 = a dirty tail, a wet dirty belly and some feces on the rodent’s back fur.

[00304] Diabetic animals tend to have soft or pasty stool, therefore fecal consistency was hypothesized to potentially be a good indicator of well-being. The following score was used to quantitate fecal consistency: 0 = full solid feces, 1 = loose feces, 2 = pasty diarrhea, and 3 = watery diarrhea.

[00305] The animals in our study were routinely assessed for signs of dehydration, sleepiness, unkempt appearance, excessive weight loss (daily body weight loss of >10%), anemia (pale eyes, ears and paws), decreased food or water intake, skin or eye infection and mortality by a fully blinded veterinarian that worked for Rutgers University as the supervising veterinarian of the vivarium. Animals deemed by this veterinarian as unhealthy were given supplemental medical care or treatments such as soft gel food, subcutaneous saline injections at 5mL/kg/day, topical antibiotics or early sacrifice. These determinations by the veterinarian that extra care was needed were recorded as“selected for intensive supplemental care” and used as a surrogate endpoint for well-being and recorded weekly.

EXAMPLE 6

Results of the various Test Models

[00306] In STZ- induced diabetic rat model, treatment with Compound 49 showed effects on plasma levels of inflammatory cytokines.

[00307] Specifically, in the STZ-induced diabetic animals treated with Compound 49 at 30 mg/kg/day significantly increased anti-inflammatory cytokine (IL-4) levels and decreased proinflammatory cytokine (TNF-a) levels toward the TNF- a levels seen in the non-diabetic sham animals (Figs. 1A and 1B, respectively).

[00308] Treatment with Compound 49 also showed significant effects on inflammatory cell infiltration and b-cell density in the pancreas.

[00309] Specifically, treatment with Compound 49 at 30 mg/kg/day for 8 weeks starting from week 12 to week 20 after STZ induction significantly reduced the inflammatory cell infiltration measured at week 20 (just after treatment) and at week 25 (5 weeks after treatment cessation) (Fig.2A), as indications of decreased insulitis.

[00310] Treatment with CC8464 significantly increased b-cell density per unit of islet in pancreas tissue stain (Fig.2B).

CC8464 treatment showed significant effects on levels of plasma metabolic hormones.

Specifically, treatment with Compound 49 at 30 mg/kg/day orally (p.o.) increased insulin, amylin, PP and GLP-l levels compared to vehicle-treated STZ induced diabetic rats (Fig. 3A-D).

[00311] Treatment with Compound 49 also showed significant improvement on rat’s general well-being.

[00312] Specifically both early and late treatments of Compound 49 at 30 mg/kg/day orally (p.o.) improved overall well-being of the STZ-induced diabetic animals compared to both vehicle- and Pregab alin-treated groups. The improvements included 1) firmer feces, 2) better fur cleanliness, 3) a reduction in the number of animals selected for supplemental care by a blinded veterinarian at Rutgers University animal laboratory, the rats were periodically assessed for signs of dehydration, sleepiness, and unkempt appearance, daily body weight loss >10%, anemia (pale look), 24h-food and water-intake and mortality (Fig. 4A-C). There were no adverse findings in the foot fault test (Fig. 4D).

[00313] As a result of treatment with Compound 49, the increase in anti-hyperglycemia hormone levels and reduced blood glucose and HbAlC levels, are indications of reduced insulitis (data not shown). Treatment with Compound 49 also significantly inhibited diabetic neuropathic pain (data not shown).

[00314] CFA- induced inflammatory rat model:

[00315] 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.

[00316] Surgical incision model of pain:

[00317] 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. Administration of Compound 11, Compound 49 and Compound 54, by intraperitoneal injection (i.p) for 8 days at 30 mg/kg/day statistically significantly reduced paw thickness, (Fig.6A-C). Compound 11 treatment also significantly inhibited post-surgical incision pain (data not shown).

[00318] Summary of Results:

[00319] In an STZ- induced diabetic model, treatment with Compound 49, a NaVl.7 inhibitor, significantly improved inflammatory markers indicated by a reduction of inflammatory cells infiltrating into pancreas islets and lowering of the proinflammatory cytokine, TNF-a, levels, as well as increasing the anti-inflammatory cytokine, interleukin 4 (IL-4), levels. The apparent reduction in inflammation ameliorated insulitis with increased b-cell density per unit of 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.

[00320] The embodiments described herein are intended to be merely exemplary, and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. All such equivalents are considered to be within the scope of the present invention and are covered by the following embodiments.

[00321] All references (including patent applications, patents, and publications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[00322] The embodiments described herein are intended to be merely exemplary, and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. All such equivalents are considered to be within the scope of the present invention and are covered by the following embodiments.

[00323] All references (including patent applications, patents, and publications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A method of treating or preventing one or more inflammatory conditions the method comprising administering to a subject in need of such prevention or treatment a therapeutically effective amount of a compound Formula (I’):

Formula (I’)

Z is -O- or -S-;

X is (C₆-Cio)aryl or 5- or 6-membered heteroaryl;

Ri is a partially unsaturated or aromatic 5- or 6-membered heterocycle;

R₂ is independently at each occurrence -F, -Cl, -Br, -CH₃ or -CN;

R₄ and Rs are not both H; and

R₆ is (Ci-Ci₂)alkyl;

R₉ is (Ci-C₆)alkyl, (C₃-C₈₎cycloalkyl, pyrazolyl or pyridinyl; wherein R₉ is optionally further substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOR11, -CONR11R12, -SO2R11, -SO2NR11R12, -OH, -CN, -OR11, and -NR₁₁R₁₂; wherein Rn and R₁₂ may form a 6 membered heterocycloalkyl ring Rio is R₁₁, (C₃-C₆)alkynyl, (C₃-C₆)alkenyl, -COR₁₁, -COOR₁₁, -SO₂R₁₁,

5-methyl-2-oxo- 1 ,3-dioxol-4-yl,

, -COO-CH(CH3)OCOCH(CH₃)2; or 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-C₈)alkoxy; or R₉ and Rio together form a unsubstituted 4- to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is fused with a 5-membered heteroaryl; and R₁₁ and R₁₂ are independently H or (Ci-C₆)alkyl, optionally substituted with 4- to 8- membered heterocycloalkyl ring; and m and n are each independently 1, 2, 3, or 4.

2. The method of claim 1, wherein Y is -(CH₂)₃-NR₉R_IO.

3. The method of claim 1 or 2, 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.

4. The method of any one of claims 1 -3, wherein Ri is pyridyl or pyrimidinyl.

5. The method of any one of claims 1 -4, wherein Ri is an aromatic 5-membered

heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.

6. The method of any one of claims 1-5 wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl.

7. The method of any one of claims 1-6, wherein Ri is thiazolyl.

8. The method of any one of claims 1-7, wherein Ri is thiazol-4-yl.

9. The method of any one of claims 1-8 wherein Ri is l,2,4-thiadiazol-5-yl.

10. The method of any one of claims 1-9, wherein R₂ is independently at each occurrence -F or -Cl.

11. The method of any one of claims 1-10, wherein n is 1, 2, or 3.

12. The method of any one of claims 1-11, wherein n is 2.

13. The method of any one of claims 1-12, wherein Z is -0-.

14. The method of any one of claims 1-13, wherein R₃ is independently at each

occurrence -H, -F, -Cl, or -Br.

15. The method of any one of claims 1-14, wherein R₃ is -H or -Cl.

16. The method of any one of claims 1-15, wherein R₃ is -Cl.

17. The method of any one of claims 1-16, wherein m is 1, 2, or 3.

18. The method of any one of claims 1-17, wherein m is 1.

19. The method of any one of claims 1-18, wherein R9 is (Ci-C₆)alkyl; wherein R9 is optionally further substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOMe, -CONH₂, and -NH₂.

20. The method of any one of claims 1-19, wherein R9 is methyl or ethyl.

21. The method of any one of claims 1-20, wherein R9 is further substituted with -COOH.

22. The method of any one of claims 1-21, wherein Rio is -H, -COMe, -COOEt.

23. The method of any one of claims 1-22, wherein Rio is -H or -COMe.

24. The method of any one of claims 1-23, wherein Rio is -H.

25. The method of any one of claims 1-25, wherein Rio is H and R9 is (Ci-C₆)alkyl, wherein

R9 is further substituted with -COR11R12, and wherein Rn and R12 are independently H or (Ci-Ce)alkyl.

26. The method of claim 25 wherein the R9 is methyl.

27. The method of claim 26, wherein the R9 is further substituted with -CONH2.

28. The method of any one of claims 1-27, 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 -NH_2.

29. The method of any one of claims 1-27, 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_.

30. The method of any one of claims 1-27, 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, -CH₂-COOMe, -CH₂-COOEt, and -NH_2.

31. The method of any one of claims 1-27, wherein R9 and Rio together form a piperidine substituted with 1 or 2 groups selected from the group consisting of -COOH, -CH2-COOH, and -NH_2.

32. The method of claim 1, wherein Y is -X-C(=0)NR₄R5.

33. The method of claim 32, 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.

34. The method of any one of claims 32 or 33, wherein Ri is pyridyl or pyrimidinyl.

35. The method of any one of claims 32-34, wherein Ri is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.

36. The method of any one of claims 32-35, or 38 wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl.

37. The method of any one of claims 32-36, or 39, wherein Ri is thiazolyl.

38. The method of any one of claims 32-37, wherein Ri is l,2,4-thiadiazol-5-yl.

39. The method of any one of claims 32-38, wherein R₂ is independently at each occurrence -F or -Cl.

40. The method of any one of claims 32-39, wherein n is 1, 2, or 3.

41. The method of any one of claims 32-40, wherein n is 2.

42. The method of any one of claims 32-41, wherein Z is -0-.

43. The method of any one of claims 32-42, wherein R₃ is independently at each occurrence -H, -F, -Cl, or -Br.

44. The method of any one of claims 32-43, wherein R₃ is -H or -Cl.

45. The method of any one of claims 32-44, wherein R₃ is -Cl.

46. The method of any one of claims 32-45, wherein m is 1, 2, or 3.

47. The method of any one of claims 32-46, wherein m is 1.

48. The method of any one of claims 32-47, wherein X is 5- or 6-membered heteroaryl.

49. The method of any one of claims 32-48, wherein X is pyridyl or pyrimidinyl.

50. The method of any one of claims 32-49, wherein X is pyridyl.

51. The method of any one of claims 32-50, wherein R₄ is H and Rs is (Ci-C9)alkyl.

52. The method of any one of claims 32-51, wherein Rs is methyl or ethyl, substituted with 1 or 2 substituents selected from the group consisting of -C0₂H, -CO2R6, and -CONR₇Rs.

53. The method of any one of claims 32-52, wherein R₆ is (Ci-C₆)alkyl.

54. The method of any one of claims 32-53, wherein R₅ is methyl or ethyl, substituted with -CO2H.

55. The method of claim 1, wherein Y is 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-(2-yl or 3-yl).

56. The method of claim 55, wherein Y is 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-3-yl.

57. The method of any one of claims 55 or 56, 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.

58. The method of any one of claims 55-57, wherein Ri is pyridyl or pyrimidinyl.

59. The method of any one of claims 55-58, wherein Ri is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.

60. The method any one of claims 55-59, wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl.

61. The method any one of claims 55-60, wherein Ri is thiazolyl.

62. The method any one of claims 55-61, 62, or 63, wherein Ri is l,2,4-thiadiazol-5-yl.

63. The method any one of claims 55-62, wherein R₂ is independently at each occurrence -F or -Cl.

64. The method of any one of claims 55-63, wherein n is 1, 2, or 3.

65. The method of any one of claims 55-64, wherein n is 2.

66. The method of any one of claims 55-65, wherein Z is -0-.

67. The method of any one of claims 55-66, wherein R₃ is independently at each occurrence

-H, -F, -Cl, or -Br.

68. The method of any one of claims 55-67, wherein R₃ is -H or -Cl.

69. The method of any one of claims 55-68, wherein R₃ is -Cl.

70. The method of any one of claims 55-69, wherein m is 1, 2, or 3.

71. The method of any one of claims 55-70, wherein m is 1.

72. The method of claim 1, wherein the compound is

(R)-2-(4-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-

chlorophenyl)picolinamido)propanoic acid,

2-((3-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-

fluorophenoxy)phenyl)propyl)amino)acetic acid,

(thiazol-4-yl)benzenesulfonamide,

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-

yl)sulfamoyl)phenoxy)phenyl)propyl)(ethoxycarbonyl)amino)acetic acid,

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-

yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn- 1 -yl)amino)acetic acid,

(thiazol-2-yl)benzenesulfonamide,

ethyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-

yl)sulfamoyl)phenoxy)phenyl)propyl)(methyl)amino)acetate, or

73. The method of claim 1, wherein the compound is

2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)((pentyloxy)carbonyl)amino)acetic acid, or 2-((3 -(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn- 1 -yl)amino)acetic acid;

74. The method of of claim 1, wherein the compound is

75. The method of any one of claims 1-74, wherein said compound is an aryloxysulfonamide, sulfonated amine, aryloxysulfonylated amide, acylsulfonyl urea, arylindazole sulfonylated amide, bicyclic core sulfonamide, substituted piperazine or piperazine methylenoxy

arylsulfonamide, benzo-oxazolone core sulfonamide, cycloalky loxyaryl- sulfonamide, aryloxybiaryl, biaryl, cyclopropyl-spiro-piperidine, pyridinyl morpholinone, or oxazolotriazole, heteroarylamide, or pyrrolopyridinone, biaryl spiro-pyrrolidine-lactam, or spiro-piperidine.

76. The method of any one of claims 1-75, wherein said compound is a Nav 1.7 inhibitor.

77. The method of claim 76, wherein the NaVl.7 inhibitor is selective for the inactivated state of the NaVl.7 channel.

78. The method of any one of claims 1- 77, wherein said 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.

79. The method of any one of claim 1- 78, wherein said inflammatory condition is associated with at least one symptom of inflammation chosen from: edema, swelling, warmth, redness and pain.

80. The method of any one of claims 1-79, wherein the administration of said compound 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.

81. The method of any one of claims 1-80, wherein administration of an effective amount of said compound to a subject in need thereof results in an improvement of one or more symptoms of inflammation chosen from: swelling, edema, redness, warmth, and pain.

82. The method of any one of claims 1-81, wherein administration of a therapeutically effective amount of the compound to a subject in need thereof results in a reduction in immune cell infiltration into the tissue.

83. The method of claim 1-82, wherein said inflammatory condition is chosen from:

atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematous (SLE), nephritis, Parkinson's disease, ulcerative colitis, myocarditis, anti- Glomerular Basement Membrane nephritis, lupus nephritis, 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) type 3, autoimmune pancreatitis (AIP), 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.

84. The method of any one of claims 1-83, wherein said inflammatory condition is not associated with pain.

85. The method of any one of claim 1-83, wherein said inflammatory conditions is associated with pain.

86. The method of claim 85, wherein the pain precedes, accompanies, or follows at least one inflammatory condition.

87. The method of claim 84, wherein said inflammatory condition is induced by or associated with a disease selected from: Alzheimer’s, Atherosclerosis, Alopecia Areata, Anti- Glomerular Basement Membrane nephritis, Asthma, Autoimmune hepatitis, Autoimmune inner ear disease, Autoimmune neutropenia, Autoimmune polyendocrine syndrome (APS) type 1, Autoimmune polyendocrine syndrome (APS) type 2, Autoimmune polyendocrine syndrome (APS) type 3, Autoimmune thyroiditis, Autoimmune urticaria, Coeliac disease, Grave’s disease, Guillain-Barre syndrome, Idiopathic thrombocytopenic purpura, Linear IgA disease, Lupus nephritis, Meniere’s disease, Myasthenia gravis, Ord’s thyroiditis, Parkinson’s disease, Pernicious anemia, Primary biliary cirrhosis (PBC), Psoriasis, Rheumatic fever, Sjogren’s syndrome, Autoimmune myocarditis, Autoimmune cardiomyopathy, Coxsackie myocarditis, and Vitiligo.

88. The method of claim 85 or 86, wherein said inflammatory condition is induced by or associated with a disease selected from: Addison’s disease, Ankylosing Spondylitis,

Autoimmune pancreatitis (AIP), Autoimmune uveitis, Dermatomyositis, Diabetes mellitus type I, Enthesitis-related arthritis, Dermatitis herpetiformis, Diverticulitis, Epidermolysis bullosa acquisita, Fibromyalgia, Granulomatosis with polyangiitis, Inflammatory Bowel diseases, Juvenile Arthritis, Mixed connective tissue disease, Mucha-Habermann disease, Pemphigus vulgaris, Post surgical inflammation, Post traumatic inflammation, Psoriatic arthritis, Relapsing polychondritis, Rheumatoid arthritis, Systemic Lupus Erythematosus, and Vasculitis.

89. A method for treating or preventing at least one inflammatory condition in a subject in need thereof, the method comprising:

(a) detecting at least one symptom induced by or associated with an inflammatory condition; and

(b) administering an effective amount of a compound according to Formula (I).

90. The method of claim 89, wherein said symptom in (a) is one selected from swelling, edema, redness, warmth, and pain.

91. A method for treating or preventing at least one inflammatory condition in a subject in need thereof, the method comprising:

(a) measuring an increase in at least one pro -inflammatory marker or a decrease in at least one anti-inflammatory marker, or both;

(b) determining an increase in at least one anti-inflammatory marker, a decrease, in at least one pro-inflammatory marker; and

(c) administering an effective amount of a compound according to Formula (I).

92. The method of any of claims 78-91, wherein said pro-inflammatory marker is selected from: infiltration of inflammatory cells into the site of inflammation, proinflammatory cytokines, proinflammatory cytokines, tumor necrosis factor (TNF), interferon gamma (IFN- gamma), MCP-l, MCP-2, MCP-3, GROa, NGF beta, RANTES, ENA-78, MIP-la, 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, TSLP, TWEAK, VEGF-A, IL- I b, IL-8. TNF-a, APRIL, IFN-a, IL-16, IL-23, IL-27, BAFF, IENg, IL-3, 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, IL-22, 1-TAC, MIG, VEGF-D, LIF, IL-6, Fractalkine, granulocyte-macrophage colony stimulating factor, or a chemokine.

93. The method of any of claims 78-92, wherein said anti-inflammatory marker is selected from: anti-inflammatory cytokines, IL-10, IL-13, IL-20, IL-4, IL-5, IL-1RA, BDNF, FGF-basic, NGF-b, HGF, and IFN-alpha and transforming growth factor-beta (TGF-b).

94. The method of any one of claims 1-93, wherein the therapeutically effective amount is effective to alleviate at least one symptom associated with said inflammatory condition in a subject, wherein a compound according to Formula (G), or a pharmaceutically acceptable salt, or a tautomeric form thereof, shows a reduction in at least one symptom associated with said 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 50 mg/kg.

95. The method of any one of claims 1-94, wherein the compound is administered orally, intravenously, topically, transdermally, patch, buccal, intramuscular, interperitoneally, or subcutaneously

96. Use of a compound according to Formula (G) for the manufacture of a medicament for the treatment or prevention of inflammatory conditions.

97. A composition comprising a compound according to Formula (G) used for treatment or prevention of inflammatory conditions.

98. 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 treating and/or preventing 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.