WO2019200369A1

WO2019200369A1 - Compounds and methods of using compounds for the prevention or treatment of peripheral nerve damage

Info

Publication number: WO2019200369A1
Application number: PCT/US2019/027424
Authority: WO
Inventors: Olga BABICH; Tina Garyantes; Srinivasan VENKATACHALAN; Yanlin WANG-FISCHER
Original assignee: Chromocell Corporation
Priority date: 2018-04-13
Filing date: 2019-04-15
Publication date: 2019-10-17

Abstract

Provided herein are compounds and methods of using compounds for preventing or treating peripheral nerve damage in a subject in need of such prevention or treatment. In particular, provided herein are compounds and methods of using compounds for the prevention of peripheral nerve damage from chemotherapy, metabolic dysfunction, surgery/trauma, and other causes (PND). More particularly, provided herein are compounds and methods of using compounds as neuroprotective agents which are compounds that inhibit sodium channels that allow peripheral nociceptive neurons to signal to the central nervous system, 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 PERIPHERAL NERVE DAMAGE

This application claims the benefit of U.S. provisional application 62/657,097 filed April 13, 2018 which is incorporated by reference herein in its entirety.

FIELD

[0001] Provided herein are compounds and methods of using compounds for preventing or treating peripheral nerve damage. In particular, provided herein are methods of preventing peripheral nerve damage induced or associated with chemotherapy, metabolic dysregulation and trauma. Also, provided herein are compounds for use in preventing or treating peripheral nerve damage or peripheral neuropathy (PND) induced or associated with chemotherapy, metabolic disorders, surgery /trauma or other insults. More particularly, provided herein are compounds and methods of using compounds for the prevention PND.

BACKGROUND

[0002] Peripheral neuropathy is a condition of the peripheral nervous system in which damage to peripheral nerves can cause pain, numbness, tingling sensations, burning sensations, paresthesia and muscle weakness in various parts of the body. Pain is more easily measured non-clinically than the other signs of peripheral neuropathy and therefore the prevention of nerve injury induced pain is a good surrogate of nerve damage.

The methods for diagnosis of nerve damage may involve both symptomatic clinical signs and pathohistological examination on tissues (such as skin or nerve biopsies) Hovaguimian A. et al., Curr Pain Headache Rep. 2011 June; 15(3): 193-200. The sensitivity and specificity of skin biopsy for diagnosing sensory nerve damage are 78%-92% and 65%-90%, respectively. Since biopsy is an invasive procedure that is difficult to perform and may itself cause neuropathic side effects, thorough neurological and physical examinations are very commonly used to evaluate nerve damage in patients by identifying the person’s ability to sense vibration, light touch (such as von Frey test used for both human and animal pain models), body position (such as body weight bearing test in animal study), and temperature (such as plantar test was adapted for animal pain study). [0003] Peripheral neuropathy can be caused by a range of factors including as a result of infectious agents (such as viruses), inflammatory conditions, metabolic imbalances (such as diabetes), trauma or exposure to neurotoxic compounds. Peripheral neuropathy can also result as a side effect of drug treatment regimens, for example, anti-HIV drugs and chemotherapeutic agents. In fact, many commonly-employed chemotherapeutic agents are limited in their effectiveness due to side-effects such as peripheral neuropathy (Hue Jung Park, Korean J Anaesthesiol 2014 July 67(1): 4-7). For example, platinum drugs for use as chemotherapeutic agents are known to induce neuropathic pain in patients. This impacts compliance with prescription and administration, or dosing of chemotherapeutic drugs and effectively limits the amount and frequency of administration of chemotherapeutic drugs of the platinum family.

[0004] Accordingly, there is a clear need for effective strategies to prevent peripheral neuropathy from infection, trauma, xenobiotics, metabolic imbalances, surgery/trauma and other harmful natural compounds or other sources.

SUMMARY

[0005] In one embodiment, the present disclosure provides methods for preventing or treating peripheral nerve damage comprising administering to a subject in need thereof a therapeutically effective amount of a compound that is known to inhibit the signaling of peripheral nociceptive neurons.

[0006] In one embodiment, the present disclosure provides methods for preventing or treating peripheral nerve damage comprising administering to a subject in need thereof a therapeutically effective amount of a compound that is known to inhibit voltage-gated sodium channels.

[0007] In one embodiment, the methods are those, wherein the voltage-gated sodium channel is

NaVl.7.

[0008] In one embodiment, the present disclosure provides methods for preventing or treating peripheral nerve damage comprising administering to a subject in need thereof a therapeutically effective amount of a compound that is known to inhibit the signaling of NaVl.7 and is peripherally restricted.

[0009] In one embodiment, the present disclosure provides methods for preventing peripheral nerve damage 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 a tautomeric form thereof, or any combination of the foregoing compounds.

[0010] In one embodiment, the present disclosure provides methods for treating peripheral nerve damage 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 a tautomeric form thereof.

[0011] In one embodiment, the present disclosure provides methods for preventing or treating peripheral nerve damage wherein the peripheral nerve damage is induced, or associated with treatment of a subject in need of such a treatment with at least one chemotherapeutic agent.

[0012] In one embodiment, the present disclosure provides methods for preventing or treating peripheral nerve damage wherein the peripheral nerve damage is induced, or associated with nerve injury, surgery, viral infection, bacterial infection, parasitic infection or neuron damaging disease.

[0013] In one embodiment, the present disclosure provides methods for preventing or treating at least one symptom induced by or associated with peripheral nerve damage.

[0014] In one embodiment, the at least one symptom induced by or associated with peripheral nerve damage is one chosen from burning, tingling (“pins and needles” feeling), loss of feeling

(numbness or just less ability to sense pressure, touch, heat, or cold), trouble using fingers to pick up or jolt things, dropping things, balance problems, trouble with tripping or stumbling while walking, pressure or temperature hurt more than usual (mostly cold; this is called cold sensitivity), shrinking muscles, muscle weakness, trouble swallowing, constipation, trouble passing urine, blood pressure changes and altered nerve conduction velocity with decrease or no reflexes, headache, and general pain.

[0015] In one embodiment, the present disclosure provides methods for preventing or treating pain induced by or associated with peripheral nerve damage.

[0016] In one embodiment, the present disclosure provides methods for preventing or treating chemotherapy-induced peripheral neuropathy (CINP).

[0017] 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 administration of the nerve damage inducing agent.

[0018] 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 administration of the nerve damage inducing agent.

[0019] 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 administration of the nerve damage inducing agent.

[0020] 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 administration of the nerve damage inducing agent.

[0021] 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 simultaneously or in conjunction with the nerve damage inducing agent.

[0022] In one embodiment, the nerve damage inducing agent is at least one chemotherapeutic agent. In one embodiment, the at least one chemotherapeutic agent is selected from Amiodarone, Bortezobid, Carboplatin, Chloramphenicol, Chloroquine, Cisplatin, Colchicine, Cytarabine, Dapsone, Didanosine, Disulfiram, Docetaxel, Etanercept, Ethambutol, Fluoroquinolones, Gold, Hydralazine, Hydeoxychloroquine, Infliximab, Isoniazid (antibiotic), Leflunomide, Lenalidomide, Metronidazole, Misonidazole, Nitrofurantoin, Oxaliplatin, Paclitaxel, Phenytoin, Procainamide, Procarbazine, Pyridoxine (vitamin B6), Atorvastatin, Pitavastatin, Lovastatin, Simvastatin, Pravastatin, fluvastatin, rosuvastatin, Stavudine, Suramin, Thalidomide, Vinblastine, Vincristine, Zalcitabine, and Perhexiline or an analogue or derivative of the foregoing.

[0023] In one embodiment, the chemotherapeutic agent is oxaliplatin or an analogue or derivative thereof.

[0024] In one embodiment, the compound is administered orally, intravenously, topically, transdermally, patch, buccal, intramuscular, interperitoneally, or subcutaneously.

[0025] In one embodiment, provided herein are compounds of Formula (F) for use in the methods disclosed:

Formula (G)

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

Z is -O- or -S-;

Y is -X-C(=0)NR₄R^ -(CH₂)₃-NR₉R_IO, or 4,5,6, 7-tetrahydropyrazolo[l,5-o]pyrimidine-(2-yl or

3-yl);

X is (Cg-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, -CFF or -CN;

R₃ is independently at each occurrence -H, -F, -Cl, -Br, -CF₃, -OCF₃ -CN, (Ci-Ci₂)alkyl, or (Ci-Ci₂)alkoxy;

R_t and Rs are each independently H, (Ci-C9)alkyl, (C4-Ci₂)cycloalkyl, or Ri and Rs 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 R_t and R5 together is substituted with 1 or 2 substituents selected from the group consisting of- C0₂H, -C0₂R₆, -CN, -OH, -CONRvRs, and -NR₇R«: wherein:

R_¾ is (Ci-Ci₂)alkyl;

R7 and Rx are each independently H, (Ci-Ci2)alkyl, or R7 and Rx together form a

4- to 7-membered heterocycloalkyl ring;

R₉ is (Ci-Cg)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, -ORn, and -NR₁₁R₁₂; wherein Rn and R₁₂ may form a 6 membered heterocycloalkyl ring Rio is Rn, (C3-Cg)alkynyl, (C3-Cg)alkenyl, -CORn, -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-Cx)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

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

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

[0026] In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein Y is -(Grh^-NRgRio.

[0027] 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.

[0028] 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.

[0029] In one embodiment, the compounds of Formula (F) 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.

[0030] In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein Z is -O .

[0031] In one embodiment, the compounds of Formula (F) 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 (F) for use in the methods disclosed are those wherein R3 is -H or -Cl. In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein R3 is -Cl.

[0032] In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein m is 1, 2, or 3. In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein m is 1.

[0033] In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein R9 is (Ci-Cg)alkyl; wherein R9 is optionally further substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOMe, -CONH2, and -NFb. In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein R9 is methyl or ethyl. In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein R9 is further substituted with -COOH.

[0034] In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein Rio is -H, -COMe, -COOEt. In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein Rio is -H or -COMe. In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein Rio is -H.

[0035] In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those Rio is H and R₉ is (Ci-Cg)alkyl, wherein R₉ is further substituted with -COR₁₁R₁₂, and wherein Rn and R₁₂ are independently H or (Ci-Cg)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 (F) for use in the methods disclosed are those wherein the R₉ is further substituted with - CONH₂.

[0036] In one embodiment, the compounds of Formula (F) 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 -NH₂

[0037] In one embodiment, the compounds of Formula (F) 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 -NH_2. In one embodiment, the compounds of Formula (F) 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, -GE-COOMe, -GE- 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 -NH₂

[0038] In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein Y is -X-C(=0)NRIR5.

[0039] In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein X is 5- or 6-membered heteroaryl. In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein X is pyridyl or pyrimidinyl. In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein X is pyridyl.

[0040] In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein R₄ is H and R₅ is (Ci-C₉)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 1 or 2 substituents selected from the group consisting of -CO₂H, -CO₂R₅, and -CONRvRs. In one embodiment, the compounds of Formula (G) for use in the methods disclosed are those wherein Rg is (Ci-Cg)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.

[0041] In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein Y is 4,5,6,7-tetrahydropyrazolo[l,5-o]pyrimidine-(2-yl or 3-yl). In one embodiment, the compounds of Formula (F) for use in the methods disclosed are those wherein Y is 4, 5,6,7- tetrahydropyrazolo [ 1 ,5 -o]pyrimidine-3 -yl .

[0042] 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-( 1 ,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-l- 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,

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,

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-l- 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- 1 -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-l- 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.

[0043] In one embodiment, the compound for use in the methods disclosed is

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)((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-l- yl)amino)acetic acid;

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

[0044] In one embodiment, the compound for use in the methods disclosed is

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

[0045] In one embodiment, the method comprises administering the at least one compound according to Formula (G) and the at least one chemotherapeutic agent via the same route.

[0046] In one embodiment, the method comprises administering the at least one compound according to Formula (G) and the at least one chemotherapeutic agent via different routes.

[0047] In one embodiment, the method comprises administering the at least one compound according to Formula (G) to a subject in need thereof in a pharmaceutically acceptable formulation.

[0048] In one embodiment, the peripheral nerve damage is the result of damage selected from damage to the neuronal cell body, axonal transport system, the myelin sheet, glial support structures, or any combination of the forgoing.

[0049] In one embodiment, the peripheral nerve damage is the result of activation of the immune system.

[0050] In one embodiment, the methods as disclosed herein further comprise the step of selecting a subject in need of prevention or treatment of peripheral nerve damage. In one embodiment the subject is a mammal. In one embodiment, the subject is a human.

[0051] In one embodiment, the methods as disclosed herein comprise administering a therapeutically effective amount to alleviate pain in a subject, wherein a compound according to Formula (G), or a pharmaceutically acceptable salt, or tautomeric form thereof, shows reduction in pain 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.

[0052] In one embodiment, the use of a compound according to Formula (G) as a

neuroprotective agent.

[0053] In one embodiment, the use of a compound according to Formula (G) for the manufacture of a medicament for the prevention or treatment of peripheral nerve damage.

[0054] In one embodiment, a composition comprising a compound according to Formula (G) when used for prevention or treatment of peripheral nerve damage, wherein said peripheral nerve damage is induced by, or associated with treatment by at least one chemotherapeutic agent.

[0055] 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 peripheral nerve damage 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.

[0056] In one embodiment, provided herein are methods for preventing or treating peripheral nerve damage 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 (F).

DETAILED DESCRIPTION

[0057] A“Compound” or“Compounds” as used herein comprise a compound that is known to inhibit the signaling of peripheral nociceptors, or 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 .

[0058] 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, benzene sulfonic, 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).

[0059] 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).

[0060] “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:

[0061] 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.

[0062] 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.

[0063] 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 lH-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.

[0064] 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, 1, 2,5,6- tetrahydropyridinyl, and l,4,5,6-tetrahydropyrimidinyl groups.

[0065] 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.

[0066] 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, - .so -butyl -tert- butyl, -iso- pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] The term“neuroprotective” refers to serving to protect nerve cells from damage or degeneration.

[0072] The term“neuroprotective agent” refers to an agent or drug that protects the peripheral nervous system from damage or degeneration.

Brief Description of the Drawings

[0073] Figures 1A &1B show the preventive effect of the test compound(s) as disclosed herein on neuropathic pain induced by or associated with treatment by a chemotherapeutic agent measured via the von Frey test for tactile allodynia (Fig.1 A) and via the Plantar test for thermal hyperalgesia (Fig.1B).

Oxaliplatin at a dose of 4mg/kg per day was injected intraperitoneally (4 mg/kg ip q.d) on days 1, 2, 3, 4 and 8 for a total of 5 doses into male Sprague-Dawley (CD) rats with a body weight of 400 ±50 grams.

Pain as measured via the von Frey test or the Plantar test fully developed in the vehicle treated animals on

day 11 after the I^st Oxaliplatin dose (dashed line). Test Rats (light grey line) received 30mg/kg of test Compound (Compound 54) at a dose of 30mg/kg oral gavage (po) 30 min before Oxaliplatin

administration or at that same time on days 1-5, and on day 8-11 for a total of 9 doses. In the vehicle group, the test compound was replaced with 2%PEG600 in O.lMTris at 2mL/kg po. Rats in the test group remained pain-free after cessation of oxaliplatin administration. Rats in the vehicle group continued to experience pain even after cessation of oxaliplatin administration. Sham rats, not dosed with Oxaliplatin are shown in the black line. To facilitate visualization of the days of drug dosing, some data point areas have been shaded or framed. *** indicate 99.9% confidence level.

[0074] Figures 2A &2B show the effect of treatment of Oxaliplatin induced neuropathy by the test compound(s) as disclosed herein on pain inhibition and neuropathic pain recovery measured via the von Frey test for tactile Allodynia (Fig.2A) and via the Plantar test for thermal hyperalgesia (Fig.2B). Oxaliplatin at a dose of 4mg/kg per day was injected intraperitoneally (4 mg/kg ip q.d) on days 1, 2, 3, 4 and 8 for a total of 5 doses into male CD rats with a body weight of 400 ±50 grams. Pain as measured via the von Frey test or the Plantar test fully developed on day 11 after the I^st Oxaliplatin dose (dashed line). Test Rats (dotted line) received lOmg/kg of Compound 54 once daily via po gavage starting on day 36 through day 40 for a total of 5 doses (see shaded area extending from day 36 to day 40), and 30mg/kg from day 43 to day 45 for a total of 3 doses (see shaded area from day 43 to 46). Morphine (grey line) at a dose of 3mg/kg po gavage was started on day 23 through day 29 for a total of 7 doses as a positive control (see light shaded area extending from day 23 to 29). Oral administration of the test compound (Compound 54) reversed both hyperalgesia and mechanical allodynia. In the vehicle group, the test compound was replaced with 2%PEG600 in 0. lMTris at 2mL/kg po and morphine was replaced with 0.9% NaCL at 2mg/kg po. *** indicate 99.9% confidence level.

[0075] Figure 3 shows the effect of preventive and therapeutic treatment of the test

compound(s) (Compound 49) as disclosed herein on neuroprotection (early) and the treatment associated with diabetes induced nerve damage (late) in the STZ-induced model of diabetes measured via the Plantar test as described in Examples 3-5. The box from weeks 1-8 with a dashed frame show the duration of dosing in the preventive protocol. The light box with a dotted frame from weeks 12-20 shows the duration of dosing in the treatment protocol. To facilitate visualization, some data point areas have been shaded and framed. The upper shaded and framed area for example indicates that no nerve damage (as evidenced by lack of development of pain) has occurred in the drug treated rats when treatment started

before the establishment of nerve damage, whereas, when the animals already had developed nerve damage and are subsequently dosed with compound (late treatment weeks 12-20) the pain caused by the nerve damage is reversed during treatment but the nerve damage is not reversed as evidenced by the immediate re-establishment of pain as soon as the test compound is cleared from the animal’s plasma (see lower shaded area). *** indicate 99.9% confidence level.

[0076] Figures 4A, 4B, and 4C show the effect of early and late treatment with a test compound

(Compound 49) as disclosed herein on sciatic nerve ligation in the PSNL model measured via the Paw Pressure Test (Fig. 4A), the Plantar Test (Fig. 4B) and the Body Bearing Test (Fig. 4C) and as described in Example 2, 4, and 5. The upper shade box with dashed outline shows the duration of dosing for the preventive dosing group. The lighter square box with a dotted outline show the duration of treatment for the therapeutic dosing group. Neuroprotection (as evidenced by absence of pain development after the cessation of dosing) was observed when the compound was administered before nerve damage had occurred (early/preventive treatment, see also upper shaded box). Administration of the test compound (Compound 49) after (late/therapeutic treatment, lower shaded box) nerve damage developed led to an initial alleviation from pain, followed by re-development of pain after cessation of administration and clearance of test compound from animal’s plasma (see framed blank box). ** indicate 99% confidence level.

[0077] Figure 5 shows the effect of various concentrations of Oxaliplatin on cell viability as measured spectrophotometrically in the absence of test compound (black bars), in the presence of ImM test compound (Compound 54, dark grey bars) and in the presence of 10 mM test compound (Compound 54, light grey bars). Whereas cell viability decreases with increasing concentrations of oxaliplatin, cell viability increases with administration of increasing concentrations of test compound at a given

Oxaliplatin concentrations. * indicate 95% confidence level

[0078] In one embodiment, the compounds provided herein are any compounds that inhibit

NaVl.7.

[0079] 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.

[0080] 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.

[0081] In one embodiment, the compounds provided herein are, for example, any of the fluorinated aromatic ethers disclosed in WO 2017035271 Al to Hemeon el al.

[0082] 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.

[0083] In one embodiment, the compounds provided herein are, for example, any of the benzenesulfonamide compounds disclosed in WO 20170082688 Al to Lee et al.

[0084] In one embodiment, the compounds provided herein are, for example, any of the indazolecarboxamide compounds disclosed in WO 2017091592 Al to Chen el al.

[0085] 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 el al.

[0086] 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.

[0087] 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.

[0088] 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 WO2012/007868 to Brown et al.

[0089] 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.

[0090] 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, WO2014/066490 to Pero et al, WO2014066491 to Pero et al, and WO2014/061970 to Kim et al.

[0091] In one embodiment, the compounds provided herein are substituted piperazine or piperazine methylenoxy arylsulfonamides or aryloxysulfonamides. 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] In one embodiment, the compounds provided herein are biaryls, cyclopropyl-spiro- piperidines, pyridinyl morpholinones, or oxazolotriazoles. In a specific embodiment, the compounds provided herein are, for example, those disclosed in WO2013/131018 to Pajouhesh et al,

WO2012/047703 to Ho et al, WO2013/161929 to Hattori et al, and WO2013/161928 to Hattori et al.

[0096] 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.

[0097] In one embodiment, the compounds provided herein are biaryl spiro-pyrrolidine-lactams.

WO2013179049 to Giblin et al, WO2013175206 to Giblin et al, WO2013175205 to Giblin et al,

WO2013093496 to Witty e Witty et al.

[0098] 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 ei al.. WO2012125613 to Hadida-Ruah ei al..

WO2013109521 to Hadida-Ruah et al.

[0099] In one embodiment the compounds provided herein are AZD3161, PF-04856264,

CNV1014802, DSP-2230, PF-05089771, XEN402, and XEN403.

[00100] 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-o]pyrimidine-(2-yl or 3-yl);

X is (Cg-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, -CFF or -CN;

R3 is independently at each occurrence -H, -F, -Cl, -Br, -CF3, -OCF3_, -CN, (Ci-Ci₂)alkyl, or

(Ci-Ci₂)alkoxy;

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, -CONRvRx. and -NR₇Rx: wherein:

R<5 is (Ci-Ci₂)alkyl;

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

R₉ is (Ci-Cg)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, -ORn, and -NR₁₁R₁₂; wherein Rn and R₁₂ 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;

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

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

[00101] In a certain embodiment, the compounds of Formula (G)

Formula (F)

are those wherein

Rio is Rn, (C₃-Cg)alkynyl, (C₃-Cg)alkenyl, -CORn, -COOR₁₁, -SO₂R₁₁, 5-methyl-2-oxo-l,3-dioxol-4-yl,

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 (CVCx)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 [0079] above.

[00102] In a certain embodiment, the compounds of Formula (I) or Formula (G) are those wherein

Y is -(CH₂)3-NR₉RIO.

[00103] 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.

[00104] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is pyridyl or pyrimidinyl.

[00105] 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.

[00106] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R2 is independently at each occurrence -F or -Cl.

[00107] 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 (F) are those wherein n is 2.

[00108] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Z is -O-.

[00109] 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 (F) are those wherein R₃ is -H or -Cl. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein R₃ is -Cl.

[00110] In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein m is 1, 2, or 3. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein m is 1.

[00111] In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein R₉ is (Ci-Cg)alkyl; wherein R₉ is optionally further substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOMe, -CONH₂, and -NFb. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein R₉ is methyl or ethyl. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein R₉ is further substituted with -COOH.

[00112] In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein Rio is H and R₉ is (Ci-Cg)alkyl; wherein R₉ is further substituted with -CONR₁₁R₁₂, and wherein R₁₁ and R₁₂ are independently H or (Ci-Cg)alkyl. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein R₉ is further substituted with -CONH₂. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein R₉ is methyl and wherein R₉ is further substituted with -CONH₂.

[00113] In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein Rio is -H, -COMe, -COOEt. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein Rio is -H or -COMe. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein Rio is -H.

[00114] In a particular embodiment, the compounds of Formula (I) or Formula (F) 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. 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_.

[00115] 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 (F) 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

[00116] In a certain embodiment, the compounds of Formula (I) or Formula (F) are those wherein

Y is -X-C(=0)NR4R₅.

[00117] 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.

[00118] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is pyridyl or pyrimidinyl.

[00119] 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 (F) are those wherein Ri is thiazolyl. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein Ri is l,2,4-thiadiazol-5-yl.

[00120] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R2 is independently at each occurrence -F or -Cl.

[00121] 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 (F) are those wherein n is 2.

[00122] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Z is -0-.

[00123] 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 (F) are those wherein R3 is -H or -Cl. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein R3 is -Cl.

[00124] In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein m is 1, 2, or 3. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein m is 1.

[00125] In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein X is 5- or 6-membered heteroaryl. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein X is pyridyl or pyrimidinyl. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein X is pyridyl.

[00126] In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein R4 is H and R5 is (Ci-C9)alkyl.

[00127] In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein R5 is methyl or ethyl, substituted with 1 or 2 substituents selected from the group consisting of -CO2H, -CC Re, and -CONRvRs.

[00128] In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein Rg is (Ci-Cg)alkyl.

[00129] In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein R5 is methyl or ethyl, substituted with -CO2H.

[00130] In a certain embodiment, the compounds of Formula (I) or Formula (F) are those wherein

Y is 4,5,6,7-tetrahydropyrazolo[l,5-o]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[l,5- o]pyrimidine-3-yl.

[00131] 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.

[00132] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Ri is pyridyl or pyrimidinyl.

[00133] 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 (F) are those wherein Ri is thiazolyl. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein Ri is l,2,4-thiadiazol-5-yl.

[00134] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein R₂ is independently at each occurrence -F or -Cl.

[00135] 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 (F) are those wherein n is 2.

[00136] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein Z is -O-.

[00137] 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 (F) are those wherein R₃ is -H or -Cl. In a particular embodiment, the compounds of Formula (I) or Formula (F) are those wherein R₃ is -Cl.

[00138] 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.

[00139] 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.

[00140] Table 1

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

[00141] 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.

[00142] Table 2

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

[00143] 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.

[00144] Table 3

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

[00145] 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.

[00146] 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-( 1 ,2,4-thiadiazol-5 -yl)sulfamoyl)-2-chloro-5 -fluorophenoxy)-5 - chlorophenyl)propyl)amino)propanoic acid;

[00147] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein the compound is

[00148] In a particular embodiment, the compounds of Formula (I) or Formula (G) are those wherein the compound is

[00149] 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).

[00150] 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).

[00151] Further provided herein are compounds of Formula (la),

Formula (la)

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;

Rio is Rn, -CORn, -COORn, -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, -COORn, -CH₂- COORn, -OH, -NH₂, -CN, and (Ci-C₈)alkoxy;

Rn and R₁₂ are independently H or (Ci-Co)alkyl. optionally substituted with 4- to 8-membered

heterocycloalkyl ring; and

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

[00152] In a certain embodiment, the compounds of Formula (I’a)

Formula (Fa)

are those wherein

Rio is Rn, (C₃-Cg)alkynyl, (CVGdalkenyl. -CORn, -COORn, -SO₂R₁₁, 5-methyl-2-oxo-l,3-dioxol-4-yl,

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 (CVCx)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 [00151] above.

[00153] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) 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.

[00154] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein Ri is pyridyl or pyrimidinyl.

[00155] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) 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.

[00156] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein R₂ is independently at each occurrence -F or -Cl.

[00157] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) 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.

[00158] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein Z is -O-.

[00159] 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 R₃ is -Cl.

[00160] 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.

[00161] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein R₉ is (Ci-Cg)alkyl; wherein R₉ is optionally further substituted with 1 or 2 substituents selected from the group consisting of -COOH, -COOMe, -CONH₂, and -NFh. 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.

[00162] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are those wherein Rio is H and R₉ is (Ci-Cg)alkyl; wherein R₉ is further substituted with -CONR₁₁R₁₂, and wherein R₁₁ and R₁₂ are independently H or (Ci-Cg)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 (Fa) are those wherein R₉ is methyl and wherein R₉ is further substituted with -CONH₂.

[00163] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) 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.

[00164] 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 -NH_2. 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 -NH_2.

[00165] 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

[00166] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are selected from the group consisting of

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

[00167] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) 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-l,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-l,3-dioxol-4-yl)methoxy)carbonyl)amino)acetic acid,

5 -chloro-4-(4-chloro-2-(3 -(3 -oxopiperazin- 1 -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;

[00168] In a particular embodiment, the compounds of Formula (la) or Formula (Fa) are selected from the group comprising

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

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

(thiazol-4-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

[00169] Provided herein are compounds of Formula (lb),

Formula (lb)

Z is -O- or -S-;

X is (Cg-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, -OCF3_, -CN, (Ci-Ci2)alkyl, or

(Ci-Ci2)alkoxy;

R_t 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 R_t and R5 together is substituted with 1 or 2 substituents selected from the group consisting of- C0₂H, -C0₂R, -CN, -OH, -CONRvRs. and -NR₇R_X: wherein:

R, is (Ci-Ci₂)alkyl;

R7 and ¾ are each independently H, (Ci-Ci2)alkyl, or R7 and ¾ together form a 4- to 7-membered heterocycloalkyl ring; and

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

[00170] 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.

[00171] In a particular embodiment, the compounds of Formula (lb) are those wherein Ri is pyridyl or pyrimidinyl.

[00172] 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 1,2,4- thiadiazol-5-yl.

[00173] In a particular embodiment, the compounds of Formula (lb) are those wherein R₂ is independently at each occurrence -F or -Cl.

[00174] 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.

[00175] In a particular embodiment, the compounds of Formula (lb) are those wherein Z is -0-.

[00176] 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.

[00177] 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.

[00178] 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.

[00179] In a particular embodiment, the compounds of Formula (lb) are those wherein R₄ is H and R5 is (Ci-C₉)alkyl.

[00180] In a particular embodiment, the compounds of Formula (lb) are those wherein R5 is methyl or ethyl, substituted with 1 or 2 substituents selected from the group consisting of -CO₂H, -CO₂ Rian d -CONR₇R₈.

[00181] In a particular embodiment, the compounds of Formula (lb) are those wherein 5 is

(Ci-C₆)alkyl.

[00182] In a particular embodiment, the compounds of Formula (lb) are those wherein R5 is methyl or ethyl, substituted with -CO2H.

[00183] Provided herein are compounds of Formula (Ic),

Formula (Ic)

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, -CFR or -CN;

(Ci-Ci2)alkoxy;

R_t 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, -CO₂R₆, -CN, -OH, -CONRvRs. and -NR₇Rx: wherein:

5 is (Ci-Ci2)alkyl;

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

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

[00184] 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.

[00185] In a particular embodiment, the compounds of Formula (Ic) are those wherein Ri is pyridyl or pyrimidinyl.

[00186] 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 1,2,4- thiadiazol-5-yl.

[00187] In a particular embodiment, the compounds of Formula (Ic) are those wherein R2 is independently at each occurrence -F or -Cl.

[00188] 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.

[00189] In a particular embodiment, the compounds of Formula (Ic) are those wherein Z is -O-.

[00190] 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.

[00191] 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.

[00192] 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.

[00193] In a particular embodiment, the compounds of Formula (Ic) are those wherein R4 is H and

R₅ is (Ci-C₉)alkyl.

[00194] In a particular embodiment, the compounds of Formula (Ic) are those wherein R5 is methyl or ethyl, substituted with 1 or 2 substituents selected from the group consisting of -CO₂H, -CO₂R₅, and -CONR7R8.

[00195] In a particular embodiment, the compounds of Formula (Ic) are those wherein 5 is

(Ci-C₆)alkyl.

[00196] In a particular embodiment, the compounds of Formula (Ic) are those wherein R5 is methyl or ethyl, substituted with -CO2H.

[00197] In a particular embodiment, the compounds of Formula (Ic) are selected from the group consisting of

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

chlorophenyl)picolinamido)butanoic acid,

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.

[00198] Provided herein are compounds of Formula (Id),

Formula (Id)

or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof, wherein: Y is 4,5,6,7-tetrahydropyrazolo[l,5-o]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, -OCF3_, -CN, (Ci-Ci₂)alkyl, or (Ci-Ci₂)alkoxy; and

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

[00199] In a certain embodiment, the compounds of Formula (Id) are those wherein Y is 4,5,6,7- tetrahydropyrazolo[l,5-o]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-o]pyrimidine-3-yl.

[00200] 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.

[00201] In a particular embodiment, the compounds of Formula (Id) are those wherein Ri is pyridyl or pyrimidinyl.

[00202] 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 1,2,4- thiadiazol-5-yl.

[00203] In a particular embodiment, the compounds of Formula (Id) are those wherein R₂ is independently at each occurrence -F or -Cl.

[00204] 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.

[00205] In a particular embodiment, the compounds of Formula (Id) are those wherein Z is -O-.

[00206] 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.

[00207] 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.

[00208] 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-4- yl)benzenesulfonamide, or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.

[00209] 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;

[00210] 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 (¾), iodine-l25 (¹²⁵I), sulfur-35 (³⁵S), or carbon-l4 (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.

[00211] In one embodiment, the compounds provided herein are inhibitors of NaV 1.7.

[00212] 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, NaV 1.4, NaVl.5, NaV 1.6, NaV 1.8, 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 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.

[00213] 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 NaV 1.7 (whose alpha subunit is encoded by the human gene SCN9A).

[00214] 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.

[00215] 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.

[00216] 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.. NaV l .7.

[00217] 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 NaV 1.9), 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.

[00218] In certain embodiments, a Compound provided herein binds to NaVl.7 with at least 5- fold, 10-fold, 50-fold, lOO-fold, 500-fold, or 1000-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 1000-fold higher affinity than it binds to one or more sodium channels selected from NaV 1.1, NaV 1.2, NaVl.3, NaVl.4, NaVl.5, NaVl.6, NaVl.8, and NaVl.9.

[00219] 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 NaV 1.7, i.e., deactivated (closed) and activated (open).

[00220] 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.

[00221] In one embodiment, Compound provided herein has an IC50 for NaVl.l, NaVl.2,

NaVl.3, NaV 1.4, NaVl.5, NaV 1.6, NaV 1.8, 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 .1, NaVl .2, NaVl .3, NaV 1.4, NaVl .5, NaV 1.6, NaV 1.8, 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, 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 NaV 1.7 IC50 for said compound.

[00222] In one embodiment, the IC50 is measured using an FDSS membrane potential assay or the patch-clamp method.

[00223] 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.

[00224] 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.

[00225] 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)

Methods for Making Compounds

[00226] The synthesis and preparation of a compound of Formula (la), (Fa), (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/US15/48927, published October 26, 2017, the contents of which are incorporated herewith by reference.

Methods of Use

[00227] Symptoms of chemotherapy induced neuropathy or peripheral neuropathy or peripheral nerve damage include, but are not limited to, burning, tingling (“pins and needles” feeling), loss of feeling (numbness or just less ability to sense pressure, touch, heat, or cold), trouble using fingers to pick up or jolt things, dropping things, balance problems, trouble with tripping or stumbling while walking, pressure or temperature hurt more than usual (mostly cold; this is called cold sensitivity), shrinking muscles, muscle weakness, trouble swallowing, constipation, trouble passing urine, blood pressure changes and altered nerve conduction velocity with decrease or no reflexes, headache, and general pain. In one embodiment, provided herein are methods of preventing or treating neuropathy or peripheral neuropathy or peripheral nerve damage.

[00228] In one embodiment, provided herein are methods of preventing or treating peripheral nerve damage induced or associated with chemotherapy.

[00229] In one embodiment, provided herein are methods of preventing or treating peripheral nerve damage induced or associated with metabolic dysfunction.

[00230] In one embodiment, provided herein are methods of preventing or treating peripheral nerve damage induced or associated with trauma or surgery.

[00231] In one embodiment, provided herein are methods of preventing or treating pain induced by or associated with peripheral nerve damage.

[00232] In one embodiment, the peripheral nerve damage is induced by or associated with treatment of a chemotherapeutic agent.

[00233] In one embodiment, provided herein are methods of preventing or treating

chemotherapy-induced peripheral nerve damage 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.

[00234] In one embodiment, provided herein are methods for preventing or treating peripheral nerve damage comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to Formula (F).

[00235] In one embodiment, provided herein are methods for preventing or treating peripheral neuropathy induced by or associated with chemotherapy-induced peripheral nerve damage comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to Formula (F).

[00236] In one embodiment, provided herein are methods preventing or treating pain induced by or associated with chemotherapy-induced peripheral nerve damage comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to Formula (F).

[00237] In one embodiment, provided herein are methods for preventing peripheral nerve damage comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to Formula (F).

[00238] In one embodiment, provided herein are methods for preventing pain induced by or associated with chemotherapy-induced peripheral nerve damage comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to Formula (F).

[00239] In one embodiment, provided herein are methods for preventing chemotherapy-induced peripheral nerve damage comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to Formula (F).

[00240] In one embodiment, provided herein are methods for preventing or treating peripheral nerve damage comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to Formula (F), wherein the administration of said compound is not followed by or associated with undesirable side effects.

[00241] In one embodiment, provided herein are methods of preventing pain associated with chemotherapy-induced peripheral nerve damage 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.

[00242] 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.

[00243] 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 54.

[00244] 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.

[00245] 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 49.

[00246] 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 54.

[00247] The present disclosure is directed to a method for the prevention of chemotherapy induced peripheral nerve damage comprising the step of administering to a patient 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.

[00248] Provided herein are methods for prevention or treatment of pain 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 pain in a subject, wherein the Compound shows prevention or reduction I pain response at a dose between 0. 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 pain in a subject , wherein the Compound provides prevention or reduction in pain 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 pain is induced or associated with treatment with a chemotherapeutic agent.

[00249] In one embodiment, the methods are those, wherein pain is induced by or associated with peripheral nerve damage. In one embodiment, the methods are those wherein pain is induced by or associated with chemotherapy -induced peripheral nerve damage. In another embodiment, the methods are those wherein chemotherapy-induced neuropathic pain is induced by or associated with peripheral nerve damage.

[00250] 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.

In one embodiment, the methods of treating or preventing chemotherapy-induced neuropathic pain in a subject in need thereof 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 chemotherapy-induced neuropathic pain prior to the administration of a Compound provided herein.

In one embodiment, use of a compound as disclosed herein as a neuroprotective agent.

In one embodiement, use of a compound as disclosed herein as a neuroprotective agent of the peripheral nervous system.

In one embodiment, use of a compound as disclosed herein as neuroprotective agent of the central nervous system. In some embodiments, the blood-brain barrier is compromised by for example, but not limited to Multiple Sclerosis (MS) or spinal chord injury.

In one embodiment, provided herein are methods of preventing or treating peripheral nerve damage induced or associated with chemotherapy.

In one embodiment, provided herein are methods for preventing or treating peripheral nerve damage comprising use of a Compound as disclosed herein, as a voltage-gated sodium channel inhibitor. In one embodiment, the methods are those, wherein the peripheral nerve damage is induced by or associated with administration of a xenobiotic, metabolic dysregulation, or trauma. In one embodiment, the xenbiotic is a chemotherapeutic agent. In one embodiment, the chemotherapeutic agent is oxaliplatin.

In one embodiment, the metabolic dysregulation is diabetes. In one embodiment, the trauma is surgery. In one embodiment, the methods are those, wherein the methods result in inhibiton of the voltage gated sodium channel. In one embodiment, the methods are those, wherein the voltage-gated sodium channel is one or more selected from NaVl.3, NaVl.6, NaV1.7, NaV1.8 and NaVl.9. In one

embodiment, the methods are those, wherein the voltage-gated sodium channel is NaV1.7. In one embodiment, the methods are those, wherein the voltage-gated sodium channel is NaV1.8.

Assessment of peripheral nerve damage (PND)

Peripheral nerve damage or PND is a significant complication of metabolic dysregulation (e.g. diabetes), trauma (e.g. surgery), or treatment with xenobiotics (e.g. chemotherapy). For example, PND is a noteworthy obstacle in the successful treatment of many cancers, the prevalence of sensory neuropathies induced by or associated with chemotherapy varies from 33-90% of patients under chemotherapy. The methods for assessment of Chemotherapy-induced peripheral nerve damage or CIPN in patients is described in Clin J Oncol Nurs. 2013 April. 17(2): 138-144 and include the following:

1. Symptoms described by a patient, which may present as exaggerated sensation (neuropathic pain), loss of sensation (numbness, muscle weakness, loss of balance) or both, symptoms usually present bilaterally and occur in a distal to proximal pattern, beginning in the tips of the fingertips and toes and involving more of the upper and/or lower extremities as it progresses.

2. Neurologic exams include vibratory testing (like von Frey test) and reflexes (for neuro-muscular response).

3. Questionaria (ask patients about feeling of Numbness and/or tingling in the distal extremities). 4. Methods for the assessment of peripheral nerve damage induced by or associated with metabolic dysregulation (e.g. diabetes), trauma (e.g. surgery), auto-immune or infectious diseases are substantially similar to the methods described above for the assessment of peripheral nerve damage induced by or associated with chemotherapy.

Patient Populations

[00251] In one embodiment, the subject in need for prevention or treatment of peripheral nerve damage has not been previously treated for peripheral nerve damage. In one embodiment, the subject in need for prevention or treatment of chemotherapy-induced neuropathic pain has not been previously treated for peripheral nerve damage.

[00252] In one embodiment, the subject in need for prevention or treatment of peripheral nerve damage is an adult female. In one embodiment, the subject in need for prevention or treatment of peripheral nerve damage is pregnant. In one embodiment, prevention or treatment of peripheral nerve damage is male. In one embodiment, the subject in need for prevention or treatment of chemotherapy- induced neuropathic pain is female. In one embodiment, the subject in need for prevention or treatment of chemotherapy -induced neuropathic pain is pregnant. In one embodiment, the subject in need for prevention or treatment of chemotherapy-induced neuropathic pain is male.

Pharmaceutical Compositions and Routes of Administration

[00253] 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.

[00254] 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.

[00255] 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.

[00256] 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.

[00257] In another embodiment, provided herein are methods for the prevention or treatment peripheral nerve damage; 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, nerve damage is induced by or associated with administration of a chemotherapeutic agent.

[00258] 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.

[00259] 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.

[00260] 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.

[00261] A Compound can be administered once, twice, three, four or more times daily.

[00262] 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.

[00263] 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.

[00264] In one embodiment, provided herein are capsules containing a Compound without an additional carrier, excipient or vehicle.

[00265] 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.

[00266] 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 fdling 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.

[00267] 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.

[00268] 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.

[00269] 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.

[00270] 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-re lease 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

[00271] 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

Chemotherapy Induced Nerve Damage Model with Oxaliplatin

[00272] The Chemotherapy Induced Nerve Damage Model is a model of nerve damage induced by or associated with a common cancer chemotherapeutic. Chemotherapy-induced peripheral neurotoxicity is a significant complication in the successful treatment of many cancers. In the peripheral nervous system, the major brunt of the toxic attack is directed against the peripheral nerve, targeting the neuronal cell body, the axonal transport system, the myelin sheath, and glial support structures, resulting in chemotherapy-induced peripheral neuropathy. The nerve damage from Oxaliplatin in animal models mimics human nerve damage.

[00273] Method of Chemotherapy Induced Neuronal Damage Model (CIND) using

Oxaliplatin

[00274] 250-400g male Sprague-Dawley rats from appropriate animal resources were used.

Nerve damage was caused by 5 once daily injections, (intraperitoneally, or intravenously) of 4 mg/kg of Oxaliplatin (cat# PHR1528-200MG, Sigma Chemicals, St. Louis, MO) freshly dissolved in 0.9% saline 2ml/kg. Sham animals were injected with 0.9% saline without Oxaliplatin. Neuronal damage was assessed through measurement of pain, (plantar test for thermal hyperalgesia and von Frey test for allodynia). No pain was observed in sham animals. Other parameters (water intake, food intake, and body weight) were monitored before, during and after the treatment with a test compound.

EXAMPLE 2 [00275] Partial Sciatic Nerve Ligation (PSNL)

[00276] The Partial Sciatic Nerve Ligation Model is a nerve damage model caused by the partial ligation of the sciatic nerve.

[00277] Partial Sciatic Nerve Ligation (PSNL) Model Method

[00278] 250-400g male Sprague -Dawley rats from appropriate animal resources were anesthetized with 2.5% isoflurane. A hind leg was shaved, and the skin was sterilized with 0.5% iodine and 75% alcohol. All surgical instruments were sterilized before surgery and between animals. An incision (1 cm) was made at the middle of the thigh in parallel with the muscle and sciatic nerve distribution. The muscle was exposed and dissected at the joint of two muscles (biceps femoris) indicated by the light colored (whitez) fascia line. The sciatic nerve was just beneath the muscle and was hooked out using an 18-20G feeding needle (90 degree curved); the sciatic nerve was flat on the feeding needle and approximately one-half the diameter of the nerve is tightly ligated with 7-0 silk suture. A response of the injured leg twitch indicates the success of ligation. After checking hemostasis, bupivacaine 0.1-0.2 mL (0.125%) was given at the incision area, the muscle and the adjacent fascia are closed with 5-0 absorbable sutures. The skin was sutures with absorbable suture and tissue glue. The control group underwent the same surgical procedure but with no nerve ligation. Animals were returned to their home cage after recovery from anesthesia.

EXAMPLE 3

Streptozotocin Induced Model of Diabetes (STZ)

[00279] The Streptozotocin (STZ)-Induced Model of Diabetic Neuropathy

[00280] The STZ Model is a chemotherapy induced model of type-I diabetes, where nerves are damaged by high blood glucose levels, similar to what is seen in diabetic patients.

[00281] The Streptozotocin (STZ)-Induced Model of Diabetic Neuropathy Method

[00282] 250-400g male Sprague-Dawley rats from appropriate animal resources were used. Type

I diabetes was induced by one or two injections, (intraperitoneally, intravenously or intramuscularly) of

50-100 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 about two days, diabetes was confirmed in STZ-injected rats by measuring the plasma glucose concentrations in blood samples from the tail vein after a fast of 6 hours. 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 200 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.

EXAMPLE 4

[00283] 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 l 00%} wherein "sham mean" refers to average score in the sham group; "test compound mean" refers to average score in the Oxaliplatin treated group in the Chemotherapy Induced Neuronal Damage CIND model, sciatic nerve ligation group in the PSNL model and the STZ injected group in the STZ model treated with a test compound; "vehicle mean" refers to average score in the Oxaliplatin treated group in the CIND model, the sciatic nerve ligation group in the PSNL model and the STZ injected group in the STZ model treated with vehicle only. The above formula was used to obtain data for the following in vivo behavioral tests.

[00284] To evaluate the ability of the test articles to prevent nerve damage as measured by pain or treat nerve damage induced pain, three different nerve injury models were studied: CIND, STZ and PSNL models as described above in Examples 1-3. In the CIND model the insult causing nerve damage was only for the 5 days of Oxaliplatin dosing. In the STZ and PSNL models, the ligation and high glucose insults that cause nerve damage continued throughout the study.

[00285] In the CIND model, the test compound was dosed either at the initiation of Oxaliplatin induction (30 minutes before Oxaliplatin injection) or starting 36 days after the initiation of Oxaliplatin dosing, when nerve damage had totally developed. Compound 54 was tested in the early and late treatment groups (Figs. 1A, 1B, 2A and 2B). Compound 49 was tested in the late treatment group. Test article was dosed for 8 days in either case. Behavioral tests were the plantar and von Frey tests.

[00286] In the PSNL model, the test compound was administered either 4 hours after the partial sciatic nerve ligation surgery, before the neuropathic pain developed, or starting 8 days after surgery, when neuropathy had totally developed. The test article was dosed for 15 days when started four hours after surgery and 8 days when started 8 days after surgery. Behavioral tests were plantar, body bearing, and paw pressure.

[00287] In the diabetic model (STZ), the compound was given 9 days (before neuropathy) or 12 weeks (neuropathy had totally formed) after STZ injection. The test article was dosed for 49 days (7 weeks) for the early group and 56 days (8 weeks) for the late group. Behavioral tests were the plantar and von Frey tests.

EXAMPLE 5

Description of tests used to assess the effect of test compounds on experimental animals

[00288] Thermal Hyperalgesia (Plantar Test):

[00289] 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 lOs was used to prevent potential tissue damage.

[00290] Mechanical Hyperalgesia (Paw pressure test)

[00291] The paw pressure test assesses nociceptive mechanical thresholds, is expressed in grams, and is measured with a Ugo Basile Analgesiometer (Varese, Italy).

[00292] The test was performed by applying a noxious (painful) pressure to the hind paw.

By pressing a pedal that activates a motor the force was increased (32 g/s) on a linear scale. When the animal displayed pain withdrawal of the paw or vocalization, the pedal was immediately released and the nociceptive pain threshold was read on a scale (a cutoff of 150 g was used to avoid tissue injury)

(Courteix et al. Study of the sensitivity of the diabetes-induced pain model in rats to a range of analgesics. Pain 1994, May; 57(2): 153-160). Both hind paws were used for assessment of mechanical hyperalgesia. At least two trials, separated by 10 min, were performed in each rat, and the mean value was used. A testing session for a rat began after 5 min of habituation or a soon as the rat stopped exploring and appeared acclimatized to the testing environment.

[00293] Tactile Allodynia (Von Frey Test)

[00294] 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.

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, 60 g or size 4.31, 4.56, 4.74, 4.93, 5.07, 5.18, 5.46, 5.88) 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.

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.

[00295] Body Bearing (Spontaneous Pain)

The body bearing test was conducted in the partial sciatic nerve ligation model described herein. Rats were tested for hypersensitivity and spontaneous pain in the weight- bearing test, using an

Incapacitance tester (Linton Instruments, Norfolk, UK). The rat was placed into the plastic box of the device. The integrated paw pressure during this period (1-2 seconds) was displayed separately for the right and left leg. The ratio between the pressure of the right and left leg was calculated as left/right hind leg weight distribution ratio. The weight bearing assay was repeated 3 times in 5 minutes. The mean distribution ratio of 3 assays was calculated.

EXAMPLE 6

[00296] Results of the various test models

Neuropathy refers to nerve disease or dysfunction of one or more peripheral nerves, typically associated with burning pain (especially at night), allodynia pain (from stimuli that are normally painless such as a light touch), numbness, tingling sensations.

The methods for diagnosis of nerve damage may involve both symptomatic clinical signs and pathohistological examination on tissues (such as skin or nerve biopsies) Hovaguimian A. et al, Curr Pain Headache Rep. 2011 June; 15(3): 193-200. The sensitivity and specificity of skin biopsy for diagnosing sensory nerve damage are 78%-92% and 65%-90%, respectively. Since biopsy is an invasive

procedure that is difficult to perform and may itself cause neuropathic side effects, thorough neurological and physical examinations are very commonly used to evaluate nerve damage in patients by identifying the person’s ability to sense vibration, light touch (such as von Frey test used for both human and animal pain models), body position (such as body weight bearing test in animal study), and temperature (such as plantar test was adapted for animal pain study).

[00297] In the CIND model, Compound 54 dosed at 30 mg/kg prevented the development of all pain (Plantar and von Frey tests) when compound dosing began with the administration of Oxaliplatin. The test compounds (Compounds 54 (30mg/kg), and Compound 49 (30mg/kg)) also showed dose- responsive pain inhibition after the pain had totally development. No pain developed after the cessation of compound administration in the group where dosing overlapped the Oxaliplatin treatment, confirming a lack of nerve damage. In contrast, pain rapidly came back after the cessation of treatment in the group where dosing started after pain had totally developed. As has been seen in earlier work, pain as measured by the plantar test returned faster than pain measured by the von Frey test. See also Figs. 1A, 1B, 2A, and 2B.

[00298] In the STZ model test compound (Compound 49) dosed at 30 mg/kg prevented the development of 89% of pain (plantar and von Frey tests) when compound dosing began 9 days after a single STZ injection on day 1 and pain (as measured by the plantar test) developed only over 30 days (4.5 weeks) after the cessation of compound administration suggesting that the nerve damage caused by STZ- induced hyperglycemia was prevented. This delay in nerve damage/pain was in stark contrast to the rapid return of pain (within one day after the cessation of test article administration) seen in animals were the nerve damage was allowed to develop for 12 weeks after STZ-injection and prior to the administration of test article. The rapid onset of pain (as measured by the Plantar test) in this therapeutically dosed group followed the kinetics of the drug levels in the plasma. The reversal of the von Frey test, does not follow the plasma exposure of molecules in this class. See also Figure 3.

[00299] In the PSNL model test compounds (Compound 49) dosed at 50 mg/kg prevented the development of 75% of pain (plantar, paw pressure, body bearing and von Frey tests) when compound dosing began 4 hours after surgical nerve ligation and pain (as measured by the plantar, paw pressure and body bearing, von Frey tests) only developed over 9 days after the cessation of compound administration, suggesting that the nerve damage caused by ligation did not start until after compound dosing stopped.

This delay in nerve damage/pain was in stark contrast to the rapid return of pain (within one day after the cessation of test article administration) seen in animals were the nerve damage from ligation was allowed to develop prior to the administration of test article. The rapid onset of pain (as measured by the plantar, paw pressure and body bearing tests) in this therapeutically dosed group followed the kinetics of the drug levels in the plasma. See also Figures 4A-4C.

EXAMPLE 7

[00300] Side effects of drug treatment as measured via the Foot Fault Test

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.

Effect of the test compound(s) as disclosed herein in the CIND model was measured via the foot fault test. Compound 54 at 30 mg/kg was administered early and late as described as described in Figs.1A and 2A. Morphine was administered orally at 3 mg/kg for 7 days in Oxaliplatin induced neuropathic pain male CD rats 20-30 min before behavior tests. The foot fault test was conducted just after the plantar test. Sham animals received no Oxaliplatin and served as a normal control. Administration of Compound 54 had now effect on the foot fault test. In contrast, administration of Morphine at 3mg/kg showed side effects as measured by the foot fault test.

EXAMPLE 8

[00301] In vitro neuroprotective effects of sodium channel inhibition: The effect of the compounds as disclosed herein on chemotherapy-induced cytotoxicity was tested as follows. HEK293 cells stably expressing NaVl.7 were incubated with Oxaliplatin at increasing concentrations ranging from 0.05mM to 100 mM and cell viability was measured spectrophotometrically. Specifically, Resazurin dye from Promega’s Cell Titer Blue® assay kit was used as the viability marker. The assay is based on conversion, by viable cells, of the dye to a fluorescent molecule (Resorufm) which can be monitored via a plate reader that measures emission fluorescence at 590nm wavelength.

[00302] As shown in Fig. 5, increasing concentrations of Oxaliplatin led to reduced cell viability.

In contrast, co-incubation of HEK293 cells with Compound 54 at ImM and 10 mM led to increased cell viability at all Oxaliplatin concentrations measured and increased concentrations of Compound 54 led to increased cell viability at the tested Oxaliplatin concentrations

[00303] 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.

[00304] 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 for preventing or treating peripheral nerve damage in a subject in need of such

treatment, the method comprising administering to the subject a therapeutically effective amount of a compound that inhibits the signaling of peripheral nociceptive neurons.

2. A method for preventing or treating peripheral nerve damage in a subject in need of such

treatment, the method comprising administering to the subject a therapeutically effective amount of a compound that inhibits the signaling of peripheral nociceptive neurons, wherein the compound inhibits NaVl.3, NaVl.6, NaVl.7, NaVl.8 and/or NaVl.9.

3. A method for preventing or treating peripheral nerve damage in a subject in need of such

treatment, the method comprising administering to the subject a therapeutically effective amount of a compound that inhibits the signaling of peripheral nociceptive neurons, wherein the compound inhibits NaVl.7.

4. A method for preventing peripheral nerve damage in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound wherein the compound inhibits NaVl.7.

5. A method for preventing peripheral or treating nerve damage in a subject in need of such

treatment, the method comprising administering to the subject a therapeutically effective amount of at least one compound according to Formula (G)

Formula (I’)

Z is -O- or -S-;

Y is -X-C(=0)NR₄FL -(CH₂)₃-NR₉R_IO, or 4,5,6, 7-tetrahydropyrazolo[l,5-o]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, -OCF3, -CN, (Ci-Ci2)alkyl, or (Ci-Ci2)alkoxy;

R₄ and R5 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 R5 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 -CCkH, -CO2R6, -CN, -OH, -CONR7R8, and -NR7R8; wherein:

R.6 is (Ci-Ci2)alkyl;

R7 and R8 are each independently H, (Ci-Ci2)alkyl, or R7 and Rx together form a 4- to 7-membered heterocycloalkyl ring;

R9 is (Ci-Ce)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 R11 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-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- COOR₁₁, -OH, -NH₂, -CN, and (Ci-Cx)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 (C_|-G,)alkyl. optionally substituted with 4- to 8-membered heterocycloalkyl ring; and

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

6. The method of claim 5, wherein Y is -(CFb^-NRgRio.

7. The method of claim 5 or 6, 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.

8. The method of any one of claims 5-7, wherein Ri is pyridyl or pyrimidinyl.

9. The method of any one of claims 5-8, wherein Ri is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.

10. The method of any one of claims 5-9 wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl.

11. The method of any one of claims 10, wherein Ri is thiazolyl.

12. The method of any one of claims 10, wherein Ri is thiazol-4-yl.

13. The method of any one of claim 10, wherein Ri is l,2,4-thiadiazol-5-yl.

14. The method of any one of claims 5-13, wherein R₂ is independently at each occurrence -F or -Cl.

15. The method of any one of claims 5-14, wherein n is 1, 2, or 3.

16. The method of any one of claims 15, wherein n is 2.

17. The method of any one of claims 5-16, wherein Z is -O-.

18. The method of any one of claims 5-17, wherein R₃ is independently at each occurrence -H, - F, -Cl, or -Br.

19. The method of any one of claims 5-18, wherein R₃ is -H or -Cl.

20. The method of any one of claims 5-18, wherein R3 is -Cl.

21. The method of any one of claims 5-20, wherein m is 1, 2, or 3.

22. The method of any one of claims 5-21, wherein m is 1.

23. The method of any one of claims 5-22, wherein R9 is (Ci-Cg)alkyl; wherein R9 is optionally

further substituted with 1 or 2 substituents selected from the group consisting

of -COOH, -COOMe, -CONH₂, and -Nth.

24. The method of any one of claims 5-23, wherein R9 is methyl or ethyl.

25. The method of any one of claims 5-24, wherein R9 is further substituted with -COOH.

26. The method of any one of claims 5-25, wherein Rio is -H, -COMe, -COOEt.

27. The method of any one of claims 5-26, wherein Rio is -H or -COMe.

28. The method of any one of claims 5-27, wherein Rio is -H.

29. The method of any one of claims 5-23, wherein Rio is H and R9 is (Ci-Cg)alkyl. wherein R9 is further substituted with -COR11R12, and wherein Rn and R12 are independently H or (Ci-Cg)alkyl.

30. The method of claim 29 wherein the R9 is methyl.

31. The method of claim 30, wherein the R9 is further substituted with -CONH2.

32. The method of any one of claims 5-23, 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 -NH2_.

33. The method of any one of claims 5-23, 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_.

34. The method of any one of claims 5-23, 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, -OT-COOMe, -CH₂-COOEt, and -NH₂

35. The method of any one of claims 5-23, wherein R9 and Rio together form a piperidine substituted with 1 or 2 groups selected from the group consisting of-COOH, -CH2-COOH, and -Nth_.

36. The method of 5, wherein Y is -X-C(=0)NR_IR₅.

37. The method of claim 36, 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.

38. The method of any one of claims 36 or 37, wherein Ri is pyridyl or pyrimidinyl.

39. The method of any one of claims 36-38, wherein Ri is an aromatic 5-membered heterocycle with

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

40. The method of any one of claims 36-39 wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl.

41. The method of any one of claims 36-40, wherein Ri is thiazolyl.

42. The method of any one of claims 36-40, wherein Ri is l,2,4-thiadiazol-5-yl.

43. The method of any one of claims 36-40, wherein R2 is independently at each occurrence -F or -Cl.

45. The method of any one of claims 36-40, wherein n is 1, 2, or 3.

46. The method of any one of claims 45, wherein n is 2.

47. The method of any one of claims 36-46, wherein Z is -O-.

48. The method of any one of claims 36-47, wherein R3 is independently at each occurrence -H, -F, -Cl, or -Br.

49. The method of any one of claims 36-48, wherein R3 is -H or -Cl.

50. The method of any one of claims 36-48, wherein R3 is -Cl.

51. The method of any one of claims 36-50, wherein m is 1, 2, or 3.

52. The method of any one of claims 36-50, wherein m is 1.

53. The method of any one of claims 36-52, wherein X is 5- or 6-membered heteroaryl.

54. The method of any one of claims 36-53, wherein X is pyridyl or pyrimidinyl.

55. The method of any one of claims 36-54, wherein X is pyridyl.

56. The method of any one of claims 36-55, wherein R4 is H and R5 is (Ci-C9)alkyl.

57. The method of any one of claims 36-56, wherein R5 is methyl or ethyl, substituted with 1 or 2 substituents selected from the group consisting of -CO₂H, -CO₂R₅, and -CONR₇R_X.

58. The method of any one of claims 36-57, wherein 5 is (CrG,)alkyl.

59. The method of any one of claims 36-58, wherein R5 is methyl or ethyl, substituted with -CO2H.

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

61. The method of claim 60, wherein Y is 4,5,6,7-tetrahydropyrazolo[l,5-o]pyrimidine-3-yl.

62. The method of any one of claims 60 or 61, 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.

63. The method of any one of claims 60-62, wherein Ri is pyridyl or pyrimidinyl.

64. The method of any one of claims 60-63 wherein Ri is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.

65. The method any one of claims 60-64 wherein Ri is thiazolyl, isothiazolyl, or thiadiazolyl.

66. The method any one of claims 60-65, wherein Ri is thiazolyl.

67. The method any one of claims 60-65 wherein Ri is l,2,4-thiadiazol-5-yl.

68. The method any one of claims 60-67, wherein R₂ is independently at each occurrence -F or -Cl.

69. The method of any one of claims 60-68, wherein n is 1, 2, or 3.

70. The method of any one of claims 60-69, wherein n is 2.

71. The method of any one of claims 60-70, wherein Z is -0-.

72. The method of any one of claims 60-71 wherein R₃ is independently at each occurrence -H, -F, -

Cl, or -Br.

73. The method of any one of claims 60-72, wherein R₃ is -H or -Cl.

74. The method of any one of claims 60-73, wherein R₃ is -Cl.

75. The method of any one of claims 60-74, wherein m is 1, 2, or 3.

76. The method of any one of claims 60-75, wherein m is 1.

77. The method of claim 5, wherein the compound is 3-(4-(2-(4-(N-(l,2,4-thiadiazol-5-yl)sulfamoyl)- 2-chloro-5-fluorophenoxy)-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,

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,

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-carboxybc 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,

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,

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,

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

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

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

(thiazol-2-yl)benzenesulfonamide,

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-l-yl)amino)acetic acid,

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

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

1-yl)amino)acetic acid,

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

78. The method of claim 5, wherein the compound is

2-((3-(5-chloro-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-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop- 2-yn-l-yl)amino)acetic acid;

79. The method of of claim 5, wherein the compound is

1-yl)amino)acetic acid, or

80. The method of any of claims 5-79, wherein the method comprises preventing or treating at least one symptom induced by or associated with peripheral nerve damage.

81. The method of claim 80, wherein the at least one symptom induced by or associated with

peripheral nerve damage is one chosen from burning, tingling (“pins and needles” feeling), loss of

feeling (numbness or just less ability to sense pressure, touch, heat, or cold), trouble using fingers to pick up or jolt things, dropping things, balance problems, trouble with tripping or stumbling while walking, pressure or temperature hurt more than usual (mostly cold; this is called cold sensitivity), shrinking muscles, muscle weakness, trouble swallowing, constipation, trouble passing urine, blood pressure changes and altered nerve conduction velocity with decrease or no reflexes, headache, and general pain.

82. The method of claim 81, wherein said symptom is pain.

83. The method of any one of claims 1-82, wherein the method comprises preventing peripheral nerve damage in a subject in need of such treatment.

84. The method of any one of claims 1-82 wherein the method comprises treating peripheral nerve damage in a subject in need of such treatment.

85. The method of any one of claims 1-84, wherein the peripheral nerve damage is induced by, or associated with treatment of the subject with at least one chemotherapeutic agent.

86. The method of any one of claims 1-84, wherein the peripheral nerve damage is induced by, or associated with nerve injury, surgery, viral infection, bacterial infection, parasitic infection or neuron damaging disease.

87. The method of any one of claims 1-84, wherein the peripheral nerve damage is induced by, or associated with metabolic dysregulation.

88. The method of any one of claims 1-84, wherein the peripheral nerve damage is induced by, or associated with autoimmune disease.

89. The method any one of claims 1-88 wherein the compound is administered for the duration of administration of the nerve damage inducing agent or insult.

90. The method of any one of claims 1- 88 wherein the compound is administered prior to administration of the nerve damage inducing agent or insult.

91. The method of any one of claims 1-88 wherein the compound is administered simultaneously or in conjunction with the nerve damage inducing agent or insult.

92. The method of any one of claimsl-88 wherein the compound is administered following

administration of the nerve damage inducing agent or insult.

93. The method of claims 1-92, wherein the nerve damage is induced by at least one

chemotherapeutic agent.

94. The method of claim 93, wherein said at least one chemotherapeutic agent is selected from:

Amiodarone, Bortezobid, Carboplatin, Chloramphenicol, Chloroquine, Cisplatin, Colchicine, Cytarabine, Dapsone, Didanosine, Disulfiram, Docetaxel, Etanercept, Ethambutol,

Fluoroquinolones, Gold, Hydralazine, Hydeoxychloroquine, Infliximab, Isoniazid (antibiotic), Lefhmomide, Lenalidomide, Metronidazole, Misonidazole, Nitrofurantoin, Oxaliplatin, Paclitaxel, Phenytoin, Procainamide, Procarbazine, Pyridoxine (vitamin B6), Atorvastatin, Pitavastatin, Lovastatin, Simvastatin, Pravastatin, fluvastatin, rosuvastatin, Stavudine, Suramin, Thalidomide, Vinblastine, Vincristine, Zalcitabine, and Perhexiline or compounds with similar mechanism of action.

95. The method of claim 94, wherein the chemotherapeutic agent is oxiplatin or an analogue or derivative thereof.

96. The method of any one of claims 1-95, wherein the compound is administered orally,

intravenously, topically, transdermally, patch, buccal, intramuscular, interperitoneally, or subcutaneously.

97. The method of any one of claims 93-95, wherein the compound and the chemotherapeutic agent are administered via the same route.

98. The method of any one of claims 93-95, wherein the compound and the chemotherapeutic agent are administered via different routes.

99. The method of any one of claims 1-98, wherein the compound is administered to said subject in a pharmaceutically acceptable formulation.

100. The method of any one of claims 1-99, wherein the peripheral nerve damage is the result of damage selected from damage to the neuronal cell body, axonal transport system, the myelin sheet, glial support structures, or any combination of the foregoing.

101. The method of any one of claim 1-100, further comprising the step of selecting a subject in need of prevention or treatment of peripheral nerve damage.

102. The method of claim 101 wherein the subject is a mammal.

103. The method of claim 101 wherein the mammal is a human.

104. The method of any one of claim 1-95, wherein the therapeutically effective amount is effective to alleviate pain in a subject, wherein a compound according to any one of claims 1-95, or a pharmaceutically acceptable salt, or a tautomeric form thereof, shows a reduction in pain 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.

105. Use of a compound according to any one of claims 1-104 as a neuroprotective agent.

106. Use of a compound according to any one of claims 1-104 for the manufacture of a medicament for the prevention or treatment of peripheral nerve damage.

107. A composition comprising a compound according to any one of claims 1-104 when used for prevention or treatment of peripheral nerve damage.

108. The composition of claim 107, wherein said peripheral nerve damage is induced by, or associated with treatment by at least one chemotherapeutic agent.

109. 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 peripheral nerve damage together with a pharmaceutically acceptable carrier, wherein the pharmaceutical agent comprises a compound according to any of claims 1- 107, or a pharmaceutically acceptable salt, or a tautomeric form thereof.