Fabp7 inhibitors for the treatment of immunotherapy resistant tumors

Abstract

The present invention discloses compounds of structural formula I as well as those of structural formula II. These compounds are inhibitors of the fatty acid binding protein 7 (FABP7) and are useful in the treatment of systemic solid tumors, primary brain tumors (for example, glioblastoma, GBM) and brain metastasis from solid tumors.

Description

PATENT ATTORNEY DOCKET NO. MDA1180-1WO FABP7 INHIBITORS FOR THE TREATMENT OF IMMUNOTHERAPY RESISTANT TUMORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 37 C.F.R. §119(e) to Indian Patent Application No. 202341075148, filed November 3, 2023 and U.S. Provisional Application No. 63 / 638,894, filed April 25, 2024. The content of the prior applications is considered part of and are hereby incorporated by reference herein in their entirety. FIELD OF THE INVENTION

[0002] The present disclosure relates generally to the identification of new compounds and more specifically to FABP7 inhibitors and methods of use thereof. BACKGROUND INFORMATION

[0003] Lipids are vital components of many biological processes and crucial in the pathogenesis of numerous common diseases, but the specific mechanisms coupling intracellular lipids to biological targets and signalling pathways are not well understood. This is particularly the case for cells burdened with high lipid storage, trafficking and signalling capacity such as adipocytes and macrophages.

[0004] Fatty acid binding proteins are transporters that serve as carriers of hydrophobic molecules, specifically long chain fatty acids and other hydrophobic ligands. FABPs are thought to play roles in fatty acid uptake, transport, and metabolism. Fatty acids function both as an energy source and as metabolic signalling molecules and affect many vital processes. This complexity combined with the chemical characteristics of lipids present many challenges in their trafficking, compartmentalization and specific target engagement properties within and between cells.

[0005] At least nine isoforms of FABPs have been identified to date, which exhibit unique patterns of tissue expression. The family contains liver (L-), intestinal (I-), heart (H-), adipocyte (A-), epidermal (E-), ileal (Il-), brain (B-), myelin (M-) and testis (T-) FABPs. 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0006] Fatty acid binding protein 7 (FABP7) also known as brain lipid binding protein (BLBP) is expressed in various regions of the brain and has strong affinity for polyunsaturated fatty acids. Hence, FABP7 could be a target for small molecules and it may also be used in combination with other therapeutics for anticancer treatment. SUMMARY OF THE INVENTION

[0007] Some embodiments disclosed herein are directed to a compound of Formulas (I) and (II):where the L, R, X, Y, and Z groups are defined as further described herein.

[0008] In some embodiments, the compounds disclosed herein may possess useful FABP7 inhibiting activity. Some embodiments herein are directed to treatment or prophylaxis of an immunotherapy resistant tumor plays an active role using the compounds disclosed herein. In some embodiments, a method of treating an immunotherapy resistant tumor in a subject comprises administering to the subject a compound of embodiments herein.

[0009] Some embodiments provide methods for treating an immunotherapy resistant tumor in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound or composition according to the present disclosure. Also provided is the use of compounds disclosed herein in the manufacture of a medicament for the treatment of an immunotherapy resistant tumor. BRIEF DESCRIPTION OF THE FIG.S

[0010] FIG. 1 depicts compound 6’s (JBMD-000165 or 165) specificity using Surface Plasmon Resonance (SPR) based assay. 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0011] FIG. 2 depicts compound 7’s (JBMD-000167 or 167) specificity using Surface Plasmon Resonance (SPR) based assay.

[0012] FIG. 3 depicts compound 8’s (JBMD-000169 or 169) specificity using Surface Plasmon Resonance (SPR) based assay.

[0013] FIG.4 depicts the IV, IP, and PO PK profile of compound 2 (JBMD-000087 or 87) in C57 BL / 6 mice.

[0014] FIG.5 depicts the IV and PO PK profile of compound 65 (JBMD-000306 or 306) in C57 BL / 6 mice.

[0015] FIG.6 depicts the IV and PO PK profile of compound 69 (JBMD-000319 or 319) in C57 BL / 6 mice.

[0016] FIG.7 depicts the IV and PO PK profile of compound 116 (JBMD-000299 or 299) in C57 BL / 6 mice.

[0017] FIG.8 depicts the IV and PO PK profile of compound 120 (JBMD-000311 or 311) in C57 BL / 6 mice.

[0018] FIG.9 depicts the depicts the plasma concentration vs time of compounds 2 (JBMD- 000087 or 87), 7 (JBMD-000167 or 167), and 57 (JBMD-000253 or 253).

[0019] FIG.10 depicts the depicts the plasma concentration vs time of compounds 18 (JBMD- 000190 or 190), 24 (JBMD-000199 or 199), and 47 (JBMD-000226 or 226).

[0020] FIG.11 depicts the depicts the plasma concentration vs time of compounds 2 (JBMD- 000087 or 87), 18 (JBMD-000190 or 190), 24 (JBMD-000199 or 199), and 57 (JBMD-000253 or 253).

[0021] FIG.12 depicts the change in IFNG after 24 hours upon treatment with compounds 2 (JBMD-000087 or 87), 64 (JBMD-000304 or 304), 116 (JBMD-000299 or 299), 118 (JBMD- 000300 or 300), and 119 (JBMD-000309 or 309).

[0022] FIG. 13 depicts the change in IL2 after 24 hours upon treatment with compounds 2 (JBMD-000087 or 87), 64 (JBMD-000304 or 304), 65 (JBMD-000306 or 306), 116 (JBMD- 000299 or 299), 118 (JBMD-000300 or 300), and 119 (JBMD-000309 or 309). 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0023] FIG.14 depicts the change in IFNG after 24 hours upon treatment with compounds 2 (JBMD-000087 or 87), 66 (JBMD-000310 or 310), 67 (JBMD-000312 or 312), 69 (JBMD-00319 or 319), 70 (JBMD-00320 or 320), 71 (JBMD-00321 or 321), 72 (JBMD-00322 or 322), and 120 (JBMD-000311 or 311).

[0024] FIG. 15 depicts the change in IL2 after 24 hours upon treatment with compounds 2 (JBMD-000087 or 87), 66 (JBMD-000310 or 310), 67 (JBMD-000312 or 312), 68 (JBMD-00318 or 318), 69 (JBMD-00319 or 319), 70 (JBMD-00320 or 320), 71 (JBMD-00321 or 321), 72 (JBMD-00322 or 322), and 120 (JBMD-000311 or 311).

[0025] FIG. 16 depicts tumor growth upon treatment of IgG antibodies (control), anti-PD1, compound 2 (JBMD-000087 or 87), and compound 2 (JBMD-000087 or 87) + anti-PD1.

[0026] FIG. 17 depicts mouse tissues upon treatment with vehicle (control), anti-PD1, and compound 2 (JBMD-000087 or 87).

[0027] FIG.18 depicts the results of compound 2 (JBMD-000087 or 87) using Migration assay in Glioblastoma cells (FABP7-U87MG cells).

[0028] FIG. 19 depicts the results of compound 7 (JBMD-000167 or 167) using Migration assay in Glioblastoma cells (FABP7-U87MG cells).

[0029] FIG.20 depicts the results of the evaluation of compounds 2 (JBMD-000087 or 87), 18 (JBMD-000190 or 190), 24 (JBMD-000199 or 199), and 57 (JBMD-000253 or 253).

[0030] FIG.21 depicts the results of the evaluation of compounds 2 (JBMD-000087 or 87), compound 7 (JBMD-000167 or 167), 24 (JBMD-000199 or 199), 47 (JBMD-000226 or 226), and 57 (JBMD-000253 or 253).

[0031] FIG.22 depicts the results of the evaluation of compounds 2 (JBMD-000087 or 87), 65 (JBMD-000306 or 306), 69 (JBMD-00319 or 319), 116 (JBMD-000299 or 299), and 120 (JBMD-000311 or 311). DETAILED DESCRIPTION OF THE INVENTION

[0032] Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, compositions, or methodologies described, 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of embodiments herein which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of embodiments herein, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein is to be construed as an admission that embodiments herein are not entitled to antedate such disclosure by virtue of prior invention.

[0033] It must also be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “a sodium channel inhibitor” is a reference to one or more sodium channel inhibitors / modulator and equivalents thereof known to those skilled in the art, and so forth.

[0034] The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50 mg means in the range of 45 mg to 55 mg.

[0035] In embodiments or claims where the term “comprising” is used as the transition phrase, such embodiments can also be envisioned with replacement of the term “comprising” with the terms “consisting of” or “consisting essentially of.”

[0036] As used herein, the term “consists of” or “consisting of” means that the pharmaceutical composition, composition or the method includes only the elements, steps, or ingredients specifically recited in the particular claimed embodiment or claim.

[0037] As used herein, the term “consisting essentially of” or “consists essentially of” means that the pharmaceutical composition, or the method includes only the elements, steps or ingredients 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO specifically recited in the particular claimed embodiment or claim and may optionally include additional elements, steps or ingredients that do not materially affect the basic and novel characteristics of the particular embodiment or claim. For example, the only active ingredient(s) in the composition or method that treats the specified condition (e.g., nutrient depletion) is the specifically recited therapeutic(s) in the particular embodiment or claim.

[0038] As used herein, two embodiments are “mutually exclusive” when one is defined to be something which is different from the other. For example, an embodiment wherein two groups combine to form a cycloalkyl is mutually exclusive with an embodiment in which one group is ethyl the other group is hydrogen. Similarly, an embodiment wherein one group is CH2 is mutually exclusive with an embodiment wherein the same group is NH.

[0039] The term “inhibit” means to limit, prevent or block the action or function of a target enzyme and / or, to prevent, alleviate or eliminate the onset of one or more symptoms associated with a disease, condition or disorder, or to prevent, alleviate or eliminate a disease, condition or disorder.

[0040] When ranges of values are disclosed, and the notation “from n1 … to n2” or “between n1 … and n2” is used, where n1 and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 µM (micromolar),” which is intended to include 1 µM, 3 µM, and everything in between to any number of significant FIG.s (e.g., 1.255 µM, 2.1 µM, 2.9999 µM, etc.).

[0041] The term “alkenyl,” as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms. The term “alkenylene” refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene [(-CH=CH-), (-C::C-)]. Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwise specified, the term “alkenyl” may include “alkenylene”1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0042] The term “alkoxy,” as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

[0043] The term “alkyl,” as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl will comprise from 1 to 8 carbon atoms. Alkyl groups may be optionally substituted as defined herein.

[0044] Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl and the like. The term “alkylene,” as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (- CH2-). Unless otherwise specified, the term “alkyl” may include “alkylene” groups.

[0045] The term “alkynyl,” as used herein, alone or in combination, refers to a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term “alkynylene” ).

[0046] Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term “alkynyl” may include “alkynylene” groups.

[0047] The term "aryl," as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together. The term "aryl" embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.

[0048] The term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes (e.g., tritium, deuterium) of the structures depicted. 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0049] The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. In certain embodiments, said cycloalkyl will comprise from 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like. “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

[0050] The term “halo,” or “halogen,” as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.

[0051] The term “haloalkoxy,” as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0052] The term “haloalkyl,” as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-) and the like.

[0053] The term "heteroaryl," as used herein, alone or in combination, refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom chosen 8 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO from N, O, and S. In certain embodiments, said heteroaryl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said heteroaryl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said heteroaryl will comprise from 5 to 7 atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.

[0054] The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated (but nonaromatic) monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently chosen from nitrogen, oxygen, and sulfur. In certain embodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said hetercycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said hetercycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, said hetercycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said hetercycloalkyl will comprise from 5 to 6 ring members in each ring. “Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycle groups include aziridinyl, azetidinyl, 1,3- benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3- dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, quinolinonyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited.

[0055] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

[0056] When a group is defined to be “null,” what is meant is that said group is absent.

[0057] The term “optionally substituted” means the anteceding group may be substituted or unsubstituted. When substituted, the substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Where structurally feasible, two substituents may be joined together to form a fused five-, six-, or seven- membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH2CF3). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as “substituted,” the substituted form is specifically intended. Additionally, different sets of optional substituents to a 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, “optionally substituted with.”

[0058] Stereogenic centers exist in the compounds disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic center. It should be understood that the invention encompasses all stereoisomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d- isomers and 1- isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain defined stereochemical configurations or by separation of mixtures of stereoisomeric products by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of stereoisomers by chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular configurations are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, endo, exo entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0059] Compounds described herein may contain one or more stereogenic centers and may thus exists as stereoisomers. Embodiments herein includes all such possible stereoisomers as substantially pure resolved stereoisomers, racemic mixtures thereof, as well as mixtures of diastereomers. In some embodiments, the formulas are shown without a definitive stereochemistry at certain positions. In other embodiments, the compounds are isolated as single stereoisomers, but the absolute configurations of the stereogenic centers are unknown or only the relative stereochemical configuration (i.e., cis or trans isomerism) is known. In such embodiments, the formulas are shown with provisionally assigned absolute assignments to denote that they are single stereoisomers and relative stereochemical configuration is likewise described. Embodiments herein include all stereoisomers of such formulas and pharmaceutically acceptable salts thereof. 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or on a chiral HPLC column. Further, any stereoisomer of a compound of the general formula may be obtained by stereospecific or stereoselective synthesis using optically pure or enantioenriched starting materials or reagents of known configuration. The scope of embodiments herein as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers, stereoisomers and stereoisomer-enriched mixtures.

[0060] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable enantioenriched or optically pure precursors or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of embodiments herein (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomer conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g., "Stereochemistry of Organic Compounds" by Ernest L. Eliel (Wiley, New York, 1994).

[0061] As used herein, the term “a derivative thereof” refers to a salt thereof, a pharmaceutically acceptable salt thereof, an ester thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a co-crystal thereof, a deuterated derivative thereof, a hydrate thereof, an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO thereof, a geometric isomer thereof, a tautomer thereof, a mixture of tautomers thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination thereof.

[0062] By "pharmaceutically acceptable", it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0063] As used herein, the term “pharmaceutically acceptable salt” refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. The term “pharmaceutically acceptable salts” embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Such salts can be derived from pharmaceutically- acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.

[0064] Suitable pharmaceutically acceptable acid addition salts of the compounds of embodiments herein may be prepared from an inorganic acid or an organic acid. All of these salts may be prepared by conventional means from the corresponding compound of embodiments herein by treating, for example, the compound with the appropriate acid or base.

[0065] Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, phosphoric and diphosphoric acid; and organic acids, for example formic, acetic, trifluoroacetic, propionic, succinic, glycolic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, xinafoic (1-hydroxy-2-naphthoic acid), napadisilic (1,5-naphthalenedisulfonic acid) and the like.

[0066] Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, arylalkyl 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, chloroprocaine, diethanolamine, N-methylglucamine, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0067] Other preferred salts according to embodiments herein are quaternary ammonium compounds wherein an equivalent of an anion (X-) is associated with the positive charge of the N atom. X- may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate. X- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X- is chloride, bromide, trifluoroacetate or methanesulphonate.

[0068] The compounds of embodiments herein may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of embodiments herein and an amount of one or more pharmaceutically acceptable solvent molecules. The term hydrate is employed when said solvent is water. Examples of solvate forms include, but are not limited to, compounds of embodiments herein in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in embodiments herein one solvent molecule can be associated with one molecule of the compounds of embodiments herein, such as a hydrate.

[0069] Furthermore, it is specifically contemplated that in embodiments herein, more than one solvent molecule may be associated with one molecule of the compounds of embodiments herein, such as a dihydrate. Additionally, it is specifically contemplated that in embodiments herein less than one solvent molecule may be associated with one molecule of the compounds of embodiments herein, such as a hemihydrate. Furthermore, solvates of embodiments herein are contemplated as 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO solvates of compounds of embodiments herein that retain the biological effectiveness of the non- solvate form of the compounds.

[0070] Embodiments herein also include isotopically-labeled compounds of embodiments herein, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of embodiments herein include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as31Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S. Certain isotopically- labeled compounds of embodiments herein, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium,3H, and carbon-14,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0071] Isotopically-labeled compounds of embodiments herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0072] Preferred isotopically-labeled compounds include deuterated derivatives of the compounds of embodiments herein. As used herein, the term deuterated derivative embraces compounds of embodiments herein where in a particular position at least one hydrogen atom is replaced by deuterium. Deuterium (D or2H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.

[0073] Hydrogen deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial. 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0074] Typically, a deuterated derivative of a compound of embodiments herein has an isotopic enrichment factor (ratio between the isotopic abundance and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen) for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation).

[0075] In some embodiments, the isotopic enrichment factor is at least 5000 (75% deuterium). In some embodiments, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent from the other deuteration sites.

[0076] The isotopic enrichment factor can be determined using conventional analytical methods known to one of ordinary skilled in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR).

[0077] The term "prodrug" refers to a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Prodrugs of the compounds described herein are also within the scope of embodiments herein. Thus, certain derivatives of the compounds of embodiments herein, which derivatives may have little or no pharmacological activity themselves, when administered into or onto the body may be converted into compounds of embodiments herein having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association) or Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley- VHCA, Zurich, Switzerland 2003).

[0078] Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound 16 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound. Prodrugs in accordance with embodiments herein can, for example, be produced by replacing appropriate functionalities present in the compounds of embodiments herein with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

[0079] The terms “excipient” and “pharmaceutically acceptable excipient” as used herein are intended to be generally synonymous, and is used interchangeably with, the terms “carrier,” “pharmaceutically acceptable carrier,” “diluent,” “pharmaceutically acceptable diluent.”

[0080] In the case of compounds of embodiments herein that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystalline or polymorphic forms, or in an amorphous form, all of which are intended to be within the scope of embodiments herein.

[0081] The compounds disclosed herein can exist as and therefore include all stereoisomers, conformational isomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.

[0082] The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life. 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0083] “Administering” when used in conjunction with a therapeutic means to administer a therapeutic directly into or onto a target tissue or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering”, when used in conjunction with a compound of embodiments herein, can include, but is not limited to, providing the compound into or onto the target tissue; providing the compound systemically to a patient by, e.g., intravenous injection whereby the therapeutic reaches the target tissue; providing the compound in the form of the encoding sequence thereof to the target tissue (e.g., by so-called gene-therapy techniques). “Administering” a composition may be accomplished by injection, topically, orally, or by any of these methods in combination with other known techniques.

[0084] The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0085] The terms “fatty acid binding protein 7 inhibitor” and, interchangeably, “FABP7 inhibitor,” as used herein, alone or in combination, each refer to a compound that binds to and / or inhibits the target with measurable affinity. In certain embodiments, a modulator has an IC50 and / or binding constant of about 50 M, about 45 M, about 40 M, about 35, about 34 M, about 33 M, about 32 M, about 31 M, about 30 M, about 29 M, about 28 M, about 27 M, about 26 M, about 25 M, about 24 M, about 23 M, about 22 M, about 21 M, about 20 M, about 19 M, about 18 M, about 17 M, about 16 M, about 15 M, about 14 M, about 13 M, about 12 M, about 11 M, about 10 M, no more than about 9 M, no more than about 8 M, no more than about 7 M, no more than about 6 M, no more than about 5 M, no more than about 4 M, no more than about 3 M, no more than about 2 M, no more than about 1 M, no more than about 0.5 M, about 0.1 M, about 0.05 M, or about 0.01 M. In certain embodiments, a modulator has an IC50 and / or binding constant of about 1 M to 50 M, between about 1 M and about 40 M, or about 1-25 M. IC50 is that concentration of inhibitor that reduces the activity of an enzyme (e.g., FABP7) to half-maximal level. Certain compounds disclosed herein have been 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO discovered to exhibit inhibition against FABP7. An example of an assay used to measure IC50 of the disclosed compounds is shown in Example XX.

[0086] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint.

[0087] As used herein, the term “therapeutic” or “therapeutic agent” or “pharmaceutically active agent” means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient. In part, embodiments of the present invention are directed to the treatment of a disease or disorder associated with sodium channel mediated activity.

[0088] A “therapeutically effective amount” or “effective amount” of a composition is a predetermined amount calculated to achieve the desired effect, e.g., to inhibit, block, or reverse the activation, migration, or proliferation of cells. The activity contemplated by the present methods includes both medical therapeutic and / or prophylactic treatment, as appropriate. The specific dose of a compound administered according to this invention to obtain therapeutic and / or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated. The compounds are effective over a wide dosage range and, for example, dosages per day will normally fall within the range of from 0.001 to 1000 mg / kg, more usually in the range of from 0.01 to 1000 mg / kg. However, it will be understood that the effective amount administered will be determined by the physician in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. A therapeutically effective amount of compound of this invention is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue.

[0089] The term “therapeutically acceptable” refers to those compounds, or a derivative thereof, which are suitable for use in contact with the tissues of patients without undue toxicity, 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO irritation, and allergic response, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0090] The terms "treat," "treated," "treating", or “treatment” as used herein refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total, whether induction of or maintenance of), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Treatment may also be preemptive in nature, i.e., it may include prevention of disease. Prevention of a disease may involve complete protection from disease, for example as in the case of prevention of infection with a pathogen, or may involve prevention of disease progression. For example, prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease to a clinically significant or detectable level. Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease and prolonging disease-free survival as compared to disease-free survival if not receiving treatment and prolonging disease-free survival as compared to disease-free survival if not receiving treatment.

[0091] Also provided is a compound chosen from the Examples disclosed herein. The compounds of embodiments herein may also refer to a salt thereof, an ester thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a co-crystal thereof, a deuterated derivative thereof, a hydrate thereof, an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a mixture of tautomers thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination of the foregoing of the compounds of embodiments herein.

[0092] The detailed description set-forth herein is provided to aid those skilled in the art in practicing the present disclosure. However, the disclosure described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed because these embodiments are intended as illustration of several aspects of the disclosure. Any equivalent embodiments are intended to be within the scope of this disclosure. Indeed, various modifications of the disclosure in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description, which do not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims.

[0093] All references cited in this specification are hereby incorporated by reference. The discussion of the references herein is intended merely to summarize the assertions made by their authors and no admission is made that any reference constitutes prior art relevant to patentability. Applicant reserves the right to challenge the accuracy and pertinency of the cited references. COMPOUNDS

[0094] Embodiments are directed to a compound of Formula (I):wherein: R1 is at each instance is independently C1-C6 alkyl, OC1-C6 alkyl, OC1-C6 haloalkyl, C6-C10 aryl, C3-C8 cycloalkyl, or C1-C6 aryl-C1-C6 alkyl; R2 is at each instance is independently halogen, C1-C6 alkyl, OC1-C6 alkyl, C1-C6 haloalkyl, OC1-C6 haloalkyl, C6-C10 aryl, 3-8 membered heteroaryl, C1-C6 aryl- C1-C6 alkyl, OH, =O, CN, COOH, C(O)NH2, NH2, or NHR3; 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO 2 or more R2’s may be optionally joined together to form a ring; R3 is at each instance is independently halogen, CN, OH, NH2, C1-C6 alkyl, OC1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl C6-C10 aryl, C(O)R4, OR4, or SO2R4; R4 is at each instance is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkyl-C3-C8 cycloalkyl, C1-C6 alkyl-O-C1-C6 alkyl, C6-C10 aryl, 3-8 membered heteroaryl, or 3-8 membered heteroaryl-COOH; 2 or more R3’s may be optionally joined together to form a ring; R5 is at each instance is independently hydrogen, C1-C6 alkyl or C6-C10 aryl; L is C(R5)2, CO, or SO2; x is is at each instance is independently CH, N, or is absent; y is is at each instance is independently CH2, NH, NR3, S, SO2, or O; z is is at each instance is independently CH, O, N, NH, S, or is absent; m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, or 2; q is 0, 1, or 2; and s is 0, 1, or 2; or a derivative thereof.

[0095] Some embodiments are directed towards a compound of Formula (II):wherein: R1 is at each instance is independently halogen, C1-C6 alkyl, OC1-C6 alkyl, C1-C6 haloalkyl, OC1-C6 haloalkyl, C6-C10 aryl, C3-C8 cycloalkyl, 3-8 membered heteroaryl, or C1-C6 aryl-C1-C6 alkyl; 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO R2 is at each instance is independently halogen, C1-C6 alkyl, OC1-C6 alkyl, C1-C6 haloalkyl, OC1-C6 haloalkyl, C6-C10 aryl, 3-8 membered heteroaryl, C1-C6 aryl- C1-C6 alkyl, OH, =O, CN, COOH, C(O)NH2, NH2, or NHR3; 2 or more R2’s may be optionally joined together to form a ring; R3 is at each instance is independently halogen, CN, OH, NH2, C1-C6 alkyl, OC1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl C6-C10 aryl, C(O)R4, OR4, or SO2R4; R4 is at each instance is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkyl-C3-C8 cycloalkyl, C1-C6 alkyl-O-C1-C6 alkyl, C6-C10 aryl, 3-8 membered heteroaryl, or 3-8 membered heteroaryl-COOH; 2 or more R3’s may be optionally joined together to form a ring; R5 is at each instance is independently hydrogen, C1-C6 alkyl or C6-C10 aryl; x is is at each instance is independently CH, N, or is absent; y is is at each instance is independently CH2, NH, NR3, S, SO2, or O; z is is at each instance is independently CH, O, N, NH, S, or is absent; m is 1, or 2; n is 0, 1, or 2; p is 0, 1, or 2; q is 0, 1, or 2; and s is 0, 1, or 2; or a derivative thereof.

[0096] In some embodiments, the compound of Formula (I), may be selected from:1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO24 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO28 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO30 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WOor a derivative thereof.

[0097] In some embodiments, the compound of Formula (II), may be selected from:1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0098] In some embodiments, the compounds as disclosed herein, a derivative thereof, or a combination thereof, further comprise a cell penetrating peptide (CPP).

[0099] Some embodiments are directed towards an antibody drug conjugate (ADC) comprising a compound as disclosed herein, a derivative thereof, or a combination thereof.

[0100] Also provided is a pharmaceutical composition comprising a compound as disclosed herein, and a pharmaceutically acceptable excipient.

[0101] In certain embodiments, the pharmaceutical composition may comprise about 0.01% to about 50% of one or more compounds disclosed herein. In some embodiments, the one or more compounds is in an amount of about 0.01% to about 50%, about 0.01% to about 45%, about 0.01% to about 40%, about 0.01% to about 30%, about 0.01% to about 20%, about 0.01% to about 10%, about 0.01% to about 5%, about 0.05% to about 50%, about 0.05% to about 45%, about 0.05% to about 40%, about 0.05% to about 30%, about 0.05% to about 20%, about 0.05% to about 10%, about 0.1% to about 50%, about 0.1% to about 45%, about 0.1% to about 40%, about 0.1% to about 30%, about 0.1% to about 20%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.5% to about 50%, about 0.5% to about 45%, about 0.5% to about 40%, about 0.5% to about 30%, about 0.5% to about 20%, about 0.5% to about 10%, about 0.5% to about 5%, about 1% to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to about 5%, about 5% to about 45%, about 5% to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 45%, about 10% to about 40%, about 10% to about 35%, about 10% to about 30%, about 10% to about 25%, about 10% to about 20%, 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO about 10% to about 15%, or a value within one of these ranges. Specific examples may include about 0.01%, about 0.05%, about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, or a range between any two of these values. The foregoing all representing weight percentages of the pharmaceutical composition.

[0102] In some embodiments, the compounds as disclosed herein are in a therapeutically effective amount. In some embodiments, the therapeutically effective amount may be about 0.01 mg to about 1000 mg, about 0.01 mg to about 900 mg, about 0.01 mg to about 800 mg, about 0.01 mg to about 700 mg, about 0.01 mg to about 600 mg, about 0.01 mg to about 500 mg, about 0.01 mg to about 400 mg, about 0.01 mg to about 300 mg, about 0.01 mg to about 200 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 50 mg, about 0.01 mg to about 25 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 5 mg, about 0.1 mg to about 1000 mg, about 0.1 mg to about 900 mg, about 0.1 mg to about 800 mg, about 0.1 mg to about 700 mg, about 0.1 mg to about 600 mg, about 0.1 mg to about 500 mg, about 0.1 mg to about 400 mg, about 0.1 mg to about 300 mg, about 0.1 mg to about 200 mg, about 0.1 mg to about 100 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 25 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5 mg, about 1 mg to about 1000 mg, about 1 mg to about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 100 mg to about 1000 mg, about 200 mg to about 1000 mg, about 300 mg to about 1000 mg, about 400 mg to about 1000 mg, about 500 mg to about 1000 mg, about 10 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 10 mg to about 300 mg, about 50 mg to about 300 mg, from about 100 mg to about 300 mg, about 10 mg to about 150 mg, about 50 mg to about 150 mg, about 60 mg to about 120 mg, about 50 mg to about 120 mg or a range between any two of these values. Specific examples include, for example, about 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 750 mg, about 600 mg, about 500 mg, about 400 mg, about 450 mg, about 300 mg, about 250 mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg, about 120 mg, about 54 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO 110 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 30 mg, about 20 mg, about 10 mg, about 5 mg, about 1 mg, about 0.1 mg, about 0.01 mg, or any value between the ranges disclosed above.

[0103] In some embodiments, the compounds as disclosed herein may be administered at a dose of about 0.01 mg / kg to about 1000 mg / kg, about 0.01 mg / kg to about 900 mg / kg, about 0.01 mg / kg to about 800 mg / kg, about 0.01 mg / kg to about 700 mg / kg, about 0.01 mg / kg to about 600 mg / kg, about 0.01 mg / kg to about 500 mg / kg, about 0.01 mg / kg to about 400 mg / kg, about 0.01 mg / kg to about 300 mg / kg, about 0.01 mg / kg to about 200 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.01 mg / kg to about 25 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1000 mg / kg, about 0.1 mg / kg to about 900 mg / kg, about 0.1 mg / kg to about 800 mg / kg, about 0.1 mg / kg to about 700 mg / kg, about 0.1 mg / kg to about 600 mg / kg, about 0.1 mg / kg to about 500 mg / kg, about 0.1 mg / kg to about 400 mg / kg, about 0.1 mg / kg to about 300 mg / kg, about 0.1 mg / kg to about 200 mg / kg, about 0.1 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 1 mg / kg to about 1000 mg / kg, about 1 mg / kg to about 900 mg / kg, about 1 mg / kg to about 800 mg / kg, about 1 mg / kg to about 700 mg / kg, about 1 mg / kg to about 600 mg / kg, about 1 mg / kg to about 500 mg / kg, about 1 mg / kg to about 400 mg / kg, about 1 mg / kg to about 300 mg / kg, about 1 mg / kg to about 200 mg / kg, about 1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 50 mg / kg, about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, about 10 mg / kg to about 1000 mg / kg, about 50 mg / kg to about 1000 mg / kg, about 100 mg / kg to about 1000 mg / kg, about 200 mg / kg to about 1000 mg / kg, about 300 mg / kg to about 1000 mg / kg, about 400 mg / kg to about 1000 mg / kg, about 500 mg / kg to about 1000 mg / kg, about 10 mg / kg to about 500 mg / kg, about 50 mg / kg to about 500 mg / kg, about 100 mg / kg to about 500 mg / kg, about 10 mg / kg to about 300 mg / kg, about 50 mg / kg to about 300 mg / kg, from about 100 mg / kg to about 300 mg / kg, about 10 mg / kg to about 150 mg / kg, about 50 mg / kg to about 150 mg / kg, about 60 mg / kg to about 120 mg / kg, about 50 mg / kg to about 120 mg / kg or a range between any two of these values. Specific examples include, for example, about 1000 mg / kg, about 900 mg / kg, about 800 mg / kg, about 700 mg / kg, about 750 mg / kg, about 600 mg / kg, about 500 mg / kg, about 400 mg / kg, about 450 mg / kg, about 300 mg / kg, about 250 mg / kg, about 200 mg / kg, about 55 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO 175 mg / kg, about 150 mg / kg, about 125 mg / kg, about 120 mg / kg, about 110 mg / kg, about 100 mg / kg, about 90 mg / kg, about 80 mg / kg, about 70 mg / kg, about 60 mg / kg, about 50 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 1 mg / kg, about 0.1 mg / kg, about 0.01 mg / kg, or any value between the ranges disclosed above.

[0104] While it may be possible for the compounds described herein to be administered as the raw chemical, it is also possible to present them as a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions which comprise one or more of certain compounds disclosed herein, or a derivative thereof, together with one or more pharmaceutically acceptable excipients thereof and optionally one or more other therapeutic ingredients. The excipient(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation of the pharmaceutical composition is dependent upon the route of administration chosen. Any of the well-known techniques and excipients may be used as suitable and as understood in the art. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0105] In some embodiments, the pharmaceutical compositions for use in accordance with embodiments herein can be formulated in conventional manner using one or more physiologically acceptable excipients.

[0106] When employed as pharmaceuticals, the compounds can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical arts, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.

[0107] Administration of the disclosed compounds or compositions may be oral administration. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. The compounds can be contained in such formulations pharmaceutical compositions with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like. The artisan can refer to various 56 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO pharmacologic references for guidance. For example, Modern Pharmaceutics, 5th Edition, Banker & Rhodes, CRC Press (2009); and Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, 13th Edition, McGraw Hill, New York (2018) can be consulted.

[0108] In some embodiments, a method of treating a disease or disorder associated with sodium channel mediated activity comprises administering a compound or a pharmaceutical composition of embodiments disclosed herein. In some embodiments, the compound is in a therapeutically effective amount. In some embodiments, the therapeutically effective amount is an amount disclosed herein.

[0109] Some embodiments disclosed herein also include pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds disclosed herein in combination with one or more pharmaceutically acceptable carriers (excipients).

[0110] In some embodiments, a method of making a pharmaceutical composition comprises mixing the active ingredient with an excipient, diluting the active ingredient using an excipient, or enclosing the active ingredient within a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the pharmaceutical compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, as well as soft and hard gelatin capsules.

[0111] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose, including eutectic solvents, eutectic-based ionic liquids, or ionic liquids. The pharmaceutical compositions can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The pharmaceutical compositions can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0112] The pharmaceutical compositions can be formulated in a unit dosage form. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, intrathecal, intradural, transmucosal, transdermal, rectal, intranasal, topical (including, for example, dermal, buccal, sublingual and intraocular), intravitreal, or intravaginal administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound disclosed herein or a derivative thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired composition.

[0113] Compositions of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[0114] Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO to provide slow or controlled release of the active ingredient therein. All compositions for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0115] For preparing solid compositions such as tablets, the principal active ingredient can be mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these pre- formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the pharmaceutical composition so that the pharmaceutical composition can be readily subdivided into equally therapeutically effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.01 to about 1000 mg of the active ingredient.

[0116] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0117] The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0118] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Compositions for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0119] In some embodiments, the pharmaceutical compositions administered to a patient can be in the form of pharmaceutical compositions described above. In some embodiments, these compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. In some embodiments, the pH of the compound preparations is about 3 to about 11, about 5 to about 9, about 5.5 to about 6.5, or about 5.5 to about 7.5. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0120] Preferred unit dosage pharmaceutical compositions are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.

[0121] It should be understood that in addition to the ingredients particularly mentioned above, the pharmaceutical compositions described above may include other agents conventional in the art having regard to the type of pharmaceutical composition in question, for example those suitable for oral administration may include flavoring agents. 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0122] In some embodiments, the therapeutically effective amount can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, composition of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0123] The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications.

[0124] The active compound can be effective over a wide dosage range and can be generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0125] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0126] The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition 61 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO being treated. In addition, the route of administration may vary depending on the condition and its severity.

[0127] Some embodiments herein are directed to a method of treating an immunotherapy resistant tumor comprising administering to a patient in need thereof a therapeutically effective amount of a compound as disclosed herein, a derivative thereof, or a combination thereof. In certain embodiments, the therapeutically effective amount of a compound as disclosed herein, a derivative thereof, or a combination thereof, may be in the form of a pharmaceutical composition. In embodiments, the pharmaceutical composition may include a pharmaceutically acceptable excipient, acceptable salt, solvate or prodrug thereof.

[0128] Also provided is a compound as disclosed herein for use in the manufacture of a medicament for the treatment of an immunotherapy resistant tumor.

[0129] Some embodiments are directed to a method of treating an immunotherapy resistant tumor comprising administering to a patient in need thereof a therapeutically effective amount of a compound as disclosed herein, a derivative thereof, or a combination thereof.

[0130] Some embodiments are directed to a method of treating an immunotherapy resistant tumor comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition as disclosed herein.

[0131] In some embodiments, the immunotherapy resistant tumor is a solid tumor or a metastases from a tumor.

[0132] In some embodiments, the tumor or metastases is a lung tumor, a colorectal tumor, melanoma, a urothreial tumor, non-small cell lung cancer, a kidney tumor, a prostate tumor, a breast cancer, adenocarcinoma, systemic solid tumor, a primary brain tumor, a brain metastasis from a solid tumor, metastatic melanoma or a combination thereof.

[0133] In some embodiments, the primary brain tumor is a glioma or a glioblastoma.

[0134] In some embodiments, the pharmaceutical composition is administered locally or systemically. 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0135] In some embodiments, the pharmaceutical composition is administered by injection or oral delivery. In some embodiments, the injection is intravenous, intraperitoneal, subcutaneous, intramuscular, by infusion, intratumorally, or peritumorally.

[0136] Some embodiments of the method of treating an immunotherapy resistant tumor further comprise the administration of a checkpoint inhibitor. Checkpoint inhibitors may be selected from inhibitors of CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, BTLA, B7H3, B7H4, TIM3, KIR, or A2aR for example. In one method, an FABP7 inhibitor compound of the invention is administered in combination with an immune checkpoint inhibitor such as an anti-PD-1 antibody to enhance innate anti-tumor immunity. It is well known that tumors evolve during their initiation and progression to evade destruction by the immune system. While the recent use of immune checkpoint inhibitors to reverse this resistance has demonstrated some success, the majority of patients do not respond these treatments. The present invention overcomes challenges associated with current technologies by providing methods and compounds to overcome resistance and to enhance anti-tumor immune responses. In some embodiments, the checkpoint inhibitor is an anti-PD-1 agent.

[0137] In some embodiments, the anti-PD-1 agent is an antibody.

[0138] In some embodiments, the antibody is selected from pembrolizumab, nivolumab, atezolizumab, avelumab, or durvalumab.

[0139] Some embodiments are directed towards a method for sensitizing a PD-1 resistant cancer cell to treatment comprising contacting the PD-1 resistant cell with a compound as disclosed herein, a derivative thereof, or a combination thereof, thereby sensitizing the cell to anti- PD1 treatment. GENERAL SYNTHETIC METHODS FOR PREPARING COMPOUNDS

[0140] The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being affected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformation proposed. This will sometimes require a judgement to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.

[0141] The novel compounds of this invention may be prepared using the reactions and techniques described in this section. Also, in the description for the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvents, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. Restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods then be use.

[0142] The compounds of the present invention may be prepared by the expemplary processes described in the following schemes and working examples, as well as relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures from the reactions appear hereinafter and in the working examples. Protection and de-protection of functional groups in the processes belowmay be carried out by procedures generally known in the art (see, for example, Green, T. W. et al., Green’s Protecting Groups in Organic Synthesis, 4thEd., Wiley (2006). General methods of organic synthesis and functional group transformations are found in: Trost, B. M. et al., eds,. Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, New York, N.Y. (1991); March, J., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4thEd., Wiley & Sons, New York, N.Y. (1992); Katrizky, A. R. et al., eds., Comprehensive Organic Functional Groups Transformation II, Elsevier Science Inc., Tarrytown, N.Y. (2005); Larock, R. C., Comprehensive Organic Transformations, Wiley Publishers, Inc., New York, N.Y. (2018); and reference therein. 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0143] Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of the ordinary skill in the art. Starting materials are commercially available or can be readily prepared by one of ordinary skill in the art using known methods.

[0144] General Synthesis Procedure 1

[0145] Hydrazine hydride (1) was reacted with cycloketone (2) in acetic acid to obtain cyclisation compound (3), bromo ester compound react with compound 3 to form compound 4 using sodium hydride, hydrolysis was done by using base to obtain final product as acid.

[0146] Conditions: Step 1: 2 (1.2eq), acetic acid, 100°C, 16 h.

[0147] Step 2: NaH(1.2eq), bromo ester(1.2eq), DMF, 0°C, 1 h.

[0148] Step 3: NaOH(3eq), MeOH, THF, H2O, RT to 60°C, 4 h.

[0149] General Synthesis Procedure 2

[0150] Hydrazine hydride (1) was reacted with cycloketone (2) in acetic acid to obtain cyclisation compound (3), bromo ester compound react with compound 3 to form compound 4 using sodium hydride, hydrolysis was done by using base to obtain final product as acid.

[0151] Conditions: Step 1: 2 (1.2eq), acetic acid, 100°C, 16 h.

[0152] Step 2: NaH(4 eq), bromo ester(1.2eq), THF, 0°C to RT, 16 h.

[0153] Step 3: NaOH(3eq), MeOH, THF, H2O, RT to 60°C, 4 h. EXAMPLES EXAMPLE 1 Synthesis of 2-((6-methoxy-1,2,3,4-tetrahydro-9H-carbazol-9-yl) methyl) benzoic acid (Compound 1) 65 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0155] To a stirred solution of (4-methoxyphenyl)hydrazine hydrochloride (0.3g, 1.72 mmol) in acetic acid (5 mL) was added cyclohexanone (213 µL, 2.06 mmol) portion wise at 0°C. The reaction mixture was stirred at 100°C for 16h. Progress of the reaction was monitored through TLC. Reaction mixture was distilled and quenched with saturated sodium bicarbonate solution (10 mL) extracted with ethyl acetate (2 x50 mL). Combined organic layer were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated through vacuum to get the crude product. The crude was purified by flash column chromatography using EA / hexane to get product as yellow solid (0.25 g, yield 74.3%). LC-MS calcd for C13H15NO, 201.1; m / z found, 202.1[M+H]+.

[0156] Step 2: Synthesis of methyl 2-((6-methoxy-1,2,3,4-tetrahydro-9H-carbazol-9-yl) methyl) benzoate

[0157] To a stirred solution of 6-methoxy-2,3,4,9-tetrahydro-1H-carbazole (0.05 g, 248 µmol) in DMF (5 mL) was added sodium hydride (11.9 mg, 298 µmol) portion wise at 0°C then continued at same temperature for 30 minutes, after 30 minutes added methyl 2-(bromomethyl)benzoate 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO (68.3 mg, 298 µmol) at 0°C. Stirred the reaction mixture for 1h at 0°C. Progress of the reaction was monitored through TLC. Reaction mixture was quenched with cold water (10 mL) and extracted with ethyl acetate (2x30 mL) Combined organic layer was washed with brine solution (5 mL), dried over sodium sulfate, filtered and evaporated through vacuum to get the crude (0.05g, crude) which was taken for next step without any further purification. LC-MS calcd for C22H23NO3, 349.4; m / z found, 350.2[M+H]+.

[0158] Step 3: Synthesis of 2-((6-methoxy-1,2,3,4-tetrahydro-9H-carbazol-9-yl) methyl) benzoic acid

[0159] To a stirred solution of methyl 2-[(6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-9- yl)methyl]benzoate (0.04 g, 258 µmol) in THF (5 mL), methanol (5 mL) & water (5 mL) was added sodium hydroxide (30.9 mg, 773 µmol) portion wise at 0°C. Stirred the reaction mixture for 2 h at RT. Still starting material was there so the reaction mixture was stirred at 60°C for 4 h. Progress of the reaction was monitored through TLC. Reaction mixture was distilled, neutralized(PH=7) with 1N HCl (4 mL), and extracted with DCM (2x30 mL). The Combined organic layer was washed with brine solution (10 mL), dried over sodium sulfate, filtered and evaporated through vacuum to get the crude. Crude was purified by Prep-HPLC to afford 2-((6- methoxy-1,2,3,4-tetrahydro-9H-carbazol-9-yl) methyl) benzoic acid as off white solid (0.007 g, 8% yiled). LC-MS calculated: C21H21NO3, 335.4; m / z found, 336.3 [M+H]+, HPLC purity 99.8%.1H NMR (400 MHz, DMSO-d6 J = 6.8 Hz, 1H), 7.3 (s, 2H), 7.06 (d, J = 8.7 Hz, 1H), 6.92 (s, 1H), 6.61 (d, J = 8.8 Hz, 1H), 6.08 (d, J = 6.8 Hz, 1H), 5.61 (s, 2H), 3.73 (s, 3H), 2.65-2.61 (m, 4H), 1.79 (brs, 4H). 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO EXAMPLE 2 Synthesis of 2-[(2,3,4,9-tetrahydro-1H-carbazol-9-yl) methyl] benzoic acid (Compound 2)

[0160] Step 1: Synthesis of methyl 2-[(2,3,4,9-tetrahydro-1H-carbazol-9-yl) methyl] benzoate

[0161] To a stirred solution of 2,3,4,9-tetrahydro-1H-carbazole (0.5 g, 1eq) in N,N- dimethylformamide (5mL) was added sodium hydride (0.23 g, 5.84 mmol) at 0°C. Stirred the reaction mixture 30 min at 0°C then added methyl 2-(bromomethyl)benzoate (0.66g, 2.92 mmol) at 0°C. Stirred the reaction mixture 1 h at 0°C. Progress of the reaction was monitored through TLC. Reaction mixture was quenched with ice cold water (10mL), extracted with ethyl acetate (2 x 30mL). Combined organic layers were washed with brine (10mL), dried over sodium sulfate, filtered and evaporated under vacuum to get the methyl 2-[(2,3,4,9-tetrahydro-1H-carbazol-9-yl) methyl] benzoate (05 g, crude). LC-MS: Mass calcd for C21H21NO2, 319.1; m / z found, 320.1 [M+H]+. 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0162] Step 2: Synthesis of 2-[(2,3,4,9-tetrahydro-1H-carbazol-9-yl)methyl ] benzoic acidTo a stirred solution of methyl 2-[(2,3,4,9-tetrahydro-1H-carbazol-9-yl)methyl]benzoate (0.5 g, 1.57 mmol) in methanol(3mL), THF(3mL), water(3mL) was added lithium(1+) hydrate hydroxide (0.65g, 15.7 mmol). Stirred the reaction mixture for 20h at RT. Progress of the reaction was monitored by TLC. Reaction mixture was distilled, dissolved with water (4mL) and neutralized (PH=7) by using dil HCl, extracted with DCM (2 x50mL), Combined organic layers were washed with brine (10mL), dried over sodium sulfate, filtered and evaporated to get the crude. Crude was purified by flash column chromatography using ethyl acetate / hexane to give 2-[(2,3,4,9- tetrahydro-1H-carbazol-9-yl )methyl]benzoic acid as off white solid (0.37 g,77.4% yield). LC-MS: Mass calcd for C20H19NO2, 305.1; m / z found, 306.2 [M+H]+. HPLC purity 99.7%.1H NMR (400 MHz, DMSO-d6 J = 6.8 Hz, 1H), 7.41 (t, J = 5.2 Hz, 1H), 7.32-7.3 (m, 2H), 7.17 (t, J = 3.9 Hz, 1H), 6.98 -6.96 (m, 2H), 6.08 (d, J = 6.4 Hz ,1H), 5.66 (s, 2H), 2.68 -2.65 (m, 2H), 2.52-2.48 (m, 2H), 1.79 (d, J = 4.4 Hz, 4H).

[0163] The examples found in Table 1 were synthesized using the above procedure as exemplified for Example 1 Table 11614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO85 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WOEXAMPLE 3 Synthesis of 3-chloro-2-((1,2,3,4-tetrahydro-4aH-carbazol-4a-yl) methyl) benzoic acid (Compound 127)

[0164] Step 1: Synthesis of methyl 3-chloro-2-((1,2,3,4-tetrahydro-4aH-carbazol-4a-yl) methyl) benzoate

[0165] To a stirred solution of 2,3,4,9-tetrahydro-1H-carbazole (1 g, 1eq) in THF (20mL) was added sodium hydride (0.56 g, 23.3 mmol) at 0°C. Stirred the reaction mixture 1 h at room temperature then added methyl 2-(bromomethyl)benzoate (1.54 g, 5.84 mmol) at 0°C. Stirred the reaction mixture 16 h at room temperature. Progress of the reaction was monitored through TLC. Reaction mixture was quenched with ice cold water (50mL), extracted with ethyl acetate (2 x 100mL). Combined organic layers were washed with brine (10mL), dried over sodium sulfate, filtered and evaporated under vacuum to get the methyl 3-chloro-2-((1,2,3,4-tetrahydro-4aH- 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO carbazol-4a-yl)methyl) benzoate. (1 g, crude). LC-MS: Mass calcd for C21H21NO2, 353.81; m / z found, 354.2 [M+H]+.

[0166] Step 2: Synthesis of 3-chloro-2-((1,2,3,4-tetrahydro-4aH-carbazol-4a-yl) methyl) benzoic acid:

[0167] To a stirred solution of methyl 3-chloro-2-((1,2,3,4-tetrahydro-4aH-carbazol-4a- yl)methyl) benzoate (1 g, 2.82 mmol) in methanol(10 mL), THF(10 mL), water(5mL) was added sodium hydroxide (0.566g, 14.16 mmol). Stirred the reaction mixture for 16h at RT. Progress of the reaction was monitored by TLC. Reaction mixture was distilled, dissolved with water (10mL) and neutralized (PH=7) by using dil HCl, extracted with DCM (2 x100mL), Combined organic layers were washed with brine (10mL), dried over sodium sulfate, filtered and evaporated to get the crude. Crude was purified by Prep HPLC to give 3-chloro-2-((1,2,3,4-tetrahydro-4aH- carbazol-4a-yl) methyl) benzoic acid as off white solid (0.37 g,77.4% yield). LC-MS: Mass calcd for C20H18ClNO2, 339.10; m / z found, 340.25 [M+H]+,1H NMR (400 MHz, DMSO-d6 s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 7.6 Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.15 - 7.11 (m, 1H), 6.79 (t, J = 7.2 Hz, 1H), 6.30 (d, J = 6.8 Hz, 1H), 4.05 (br s, 1H), 2.80 - 2.75 (m, 2H), 2.52 - 2.47 (m, 2H), 2.15 (d, J = 12.4 Hz, 1H), 2.0 -1.96 (m, 1H), 1.60 (d, J = 13.6 Hz, 1H), 1.29 - 1.26 (m, 1H), 0.83 – 0.80 (m, 1H).

[0168] The examples found in Table 2 were synthesized using the above procedure as exemplified for Example 3 Table 289 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WOEXAMPLE 4 Prep HPLC Method

[0169] Method A: Analytical conditions: Column: XSelect CSH C-18(250 mm X 4.6 mm X 5 mic) Mobile phase (A): 5mM Ammonium Acetate in water Mobile phase (B): Acetonitrile Flow rate: 1.0 ml / min % of B :0 / 2,18 / 98,25 / 98,27 / 2,30 / 2.

[0170] Method B: Analytical conditions: Column: XSelect CSH C-18(250 mm X 4.6 mm X 5 mic) Mobile phase (A):0.1% Formic acid in water Mobile phase (B): Acetonitrile Flow rate: 1.0 ml / min % of B :0 / 2,18 / 98,25 / 98,27 / 2,30 / 2. 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO EXAMPLE 5 Chiral HPLC Method

[0171] Method C: Analytical conditions: Column : CHIRALPAK® IC ( 100 mm X 4.6 mm X 3 µm) Mobile phase : n-Hexane:IPA with 0.1% DEA (70:30) Flow rate : 1.0 mL / min.

[0172] Method D: Analytical conditions: Column: CHIRALPAK® IC (100 mm x 4.6 mm x3 µm) Mobile phase : n-Hexane:Ethanol with 0.1% TFA (70:30) Flow rate : 1.0 mL / min.

[0173] Method E: CHIRALPAK® IG Mobile Phase :CO2:{0.1% TEA in MeOH:IPA (80:20)}_80:20 Flow Rate : 2.0 mL / min Column Temperature : 25°C. BIOLOGICAL ACTIVITY ASSAYS EXAMPLE 6 FABPs SPR binding assay

[0174] The Pioneer COOHV sensor (PS17AFB) was installed and primed (usually 4X) using the Sodium acetate pH 4.5 buffer followed by injection of the activation solution (0.2 M EDC + 0.05 M NHS) for 25 min at 10 µL / min in channel 1-2-3. After the activation, the target protein (FABP3 / 4 / 5 or 7) was injected at a conc. of 50-100µg / ml diluted in sodium acetate Buffer pH 4.5 for 30 min at 7 µL / min. The target protein was immobilized via amine coupling method to give surface densities of 6000-15000 RU and deactivated by injecting 1M Ethanolamine HCl pH 8.5 for 5 min. For best baseline stability, the capture injection was stopped before it reaches full saturation. The reversible analytes were injected using OneStep® Injection mode. For OneStep Injections, one sample concentration (50 µM) was used using the 100% sample loop volume setting at a flow rate of 40 µL / min. All interaction experiments were performed at 25 °C in 1X PBS, 2%DMSO,1 mM DTT and 0.005% Tween 20. The binding capacity of the two sensor surfaces (Ch1 & Ch3, Ch2 was used as reference) was assayed by injections of 50 µM of the two tool compounds. Sensorgrams or extracted report points from reference surfaces and blank injections were subtracted from the raw data prior to data analysis by the PioneerFE Qdat software. The data were fitted into a two state model and the kinetic parameters including Ka, Kd and KD were determined using the Qdat software. 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0175] The compounds of the disclosure were tested in SPR assay described above, the resulting data are shown below Table 3. FIG.s 1-3 show the results o theSPR based assay for compounds 6-8 respectively. Table 394 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO95 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO96 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WOEXAMPLE 7 PK Studies

[0176] A pharmacokinetic (PK) study of several compounds was conducted. Table 4 contains the PK study protocol for compound A and table 5 contains the PK study protocol for compound 3. Table 41614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WOTable 51614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO

[0177] Results are shown in Tables 6 and 7. Table 6AUC0-t: area under the plasma concentration-time curve from zero to last measurable time point; AUC : area under the plasma concentration-time curve from time zero to infinity; CL: clearance; Cmax: maximum observed plasma concentration; t1 / 2: terminal half-life; Tmax: time to the maximum observed plasma concentration; C0 Plasma concentration at 0 min. 99 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO Table 7HLM: Human liver microsomes, RLM: Rat liver microsomes, MLM: Mice liver microsomes, NI: No inhibition,

[0178] Similiar PK studies were conducted with compounds 2 (JBMD-000087 or 87), 7 (JBMD-000167 or 167), 18 (JBMD-000190 or 190), 24 (JBMD-000199 or 199), 47 (JBMD- 000226 or 226), 57 (JBMD-000253 or 253), 65 (JBMD-000306 or 306), 69 (JBMD-00319 or 319), 116 (JBMD-000299 or 299), and 120 (JBMD-000311 or 311). Results are shown in tables 8-14 shows the IV and PO PK profile of compounds 2, compound 116, and compound 120 as well as FIG. 4 (compound 2), FIG. 5 (compound 65), FIG. 6 (compound 69), FIG. 7 (compound 116), FIG.8 (compound 120), FIG. 9 (compounds 2, 7, and 57), FIG.10 (compounds 18, 24, and 47) and FIG.11 (compounds 2, 18, 24, and 57). Table 8100 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO Table 9Table 10Table 111614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO Table 12Table 13Table 14EXAMPLE 8

[0179] Co-culture of CD8 T cells with PD1-resistant cells 344SQR treated with compounds 2 (JBMD-000087 or 87), 64 (JBMD-000304 or 304), 65 (JBMD-000306 or 306), 66 (JBMD-000310 or 310), 67 (JBMD-000312 or 312), 68 (JBMD-00318 or 318), 69 (JBMD-00319 or 319), 70 (JBMD-00320 or 320), 71 (JBMD-00321 or 321), 72 (JBMD-00322 or 322), 116 (JBMD-000299 102 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO or 299), 118 (JBMD-000300 or 300), 119 (JBMD-000309 of 309), 120 (JBMD-000311 or 311) (each at 10 M). Viable cells were counted with a hemocytometer (0.4% Trypan blue solution) and diluted to 40,000 cells per well in 24-wells plates.344SQR cells were seeded at the top inserts (24- mm Transwell with 0.4-µm pore polycarbonate membrane insert, Sigma-Aldrich), and CD8+T cells were seeded at the bottom of the transwell system. CD8+T cells were isolated from splenocytes by using Dynabeads Untouched Mouse CD8 Cells Kit (Thermo Fisher Scientific–Life 2 for isolated from CD8+T cells and analyzed for IL2, and IFNG expression with quantitative PCR. Total RNA was isolated from cells and tumors with Triazol (Life Technologies) according to the manufacturer’s protocol. mRNA was retrotranscribed with the iScript gDNA Clear cDNA Synthesis Kit (BioRad) and analyzed by quantitative PCR using SYBR Green (Life Technologies) with specific primers according to the manufacturer’s protocol. The comparative Ct method was used to calculate the relative abundance of mRNAs compared with CD45 expression for immune cells.

[0180] Results are shown in FIG.s 12-15. EXAMPLE 9

[0181] In vivo study of compound 2 (JBMD-000087 or 87) in mice bearing 344QR tumors. All mouse studies were approved by the Institutional Animal Care and Use Committee (IACUC) of The University of Texas MD Anderson Cancer Center before their initiation; animal care was provided according to IACUC standards, and all mice had been bred and were maintained in our own specific pathogen-free mouse colony. Primary tumors were established by subcutaneous 6 mice (female, 12–16 weeks old), which were then given intraperitoneal injections of anti-PD1 mg / kg) (n=5) via oral gavage 5 days a week; starting on day 4 after tumor cell inoculation. Tumors 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO were measured with calipers three times per week and recorded as tumor volume (in mm3 2t tests.

[0182] Results are shown in FIG.16. EXAMPLE 10

[0183] IHC analysis in 344SQR tumors treated with anti-PD1 and compound 2 (JBMD- 000087 or 87). Tumor growth analysis of mice 129 Sv with 344SQR (non-small cell lung cancer) tumors treated with IgG ctrl (n=5) or anti-PD1 (10 mg / kg) (n=5) twice a week or FABP7 inhibitor compound 2 (10 mg / kg) (n=5) via oral gavage 5 days a week. Tissues were collected for IHC analysis for. Formalin-fixed patient samples and mouse tissues were processed in an automatic was done in an automated staining system (Leica Bond Max, Leica Microsystems, Vista, CA, USA). In brief, slides were deparaffinized and hydrated, and antigen was retrieved by incubating antibodies according to the manufacturer’s protocol. Slides were examined with a Leica DMI6000B microscope (Leica, Buffalo Grove, IL), and images were captured by a charge-coupled device camera and imported into the Advanced Spot Image analysis software package.

[0184] Results are shown in FIG.17.

[0185] Although the invention has been described with reference to the presently preferred embodiment, it should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims. 1614154462.1 439994.000043

Claims

PATENT ATTORNEY DOCKET NO. MDA1180-1WO What Is Claimed Is:

1. A compound of Formula (I):wherein: R1 is at each instance is independently C1-C6 alkyl, OC1-C6 alkyl, OC1-C6 haloalkyl, C6-C10 aryl, C3-C8 cycloalkyl, or C1-C6 aryl-C1-C6 alkyl; R2 is at each instance is independently halogen, C1-C6 alkyl, OC1-C6 alkyl, C1-C6 haloalkyl, OC1-C6 haloalkyl, C6-C10 aryl, 3-8 membered heteroaryl, C1-C6 aryl- C1-C6 alkyl, OH, =O, CN, COOH, C(O)NH2, NH2, or NHR3; 2 or more R2’s may be optionally joined together to form a ring; R3 is at each instance is independently halogen, CN, OH, NH2, C1-C6 alkyl, OC1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl C6-C10 aryl, C(O)R4, OR4, or SO2R4; R4 is at each instance is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkyl-C3-C8 cycloalkyl, C1-C6 alkyl-O-C1-C6 alkyl, C6-C10 aryl, 3-8 membered heteroaryl, or 3-8 membered heteroaryl-COOH; 2 or more R3’s may be optionally joined together to form a ring; R5 is at each instance is independently hydrogen, C1-C6 alkyl or C6-C10 aryl; L is C(R5)2, CO, or SO2; x is is at each instance is independently CH, N, or is absent; y is is at each instance is independently CH2, NH, NR3, S, SO2, or O; z is is at each instance is independently CH, O, N, NH, S, or is absent; m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, or 2; 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO q is 0, 1, or 2; and s is 0, 1, or 2; or a derivative thereof.

2. A compound of Formula (II):wherein: R1 is at each instance is independently halogen, C1-C6 alkyl, OC1-C6 alkyl, C1-C6 haloalkyl, OC1-C6 haloalkyl, C6-C10 aryl, C3-C8 cycloalkyl, 3-8 membered heteroaryl, or C1-C6 aryl-C1-C6 alkyl; R2 is at each instance is independently halogen, C1-C6 alkyl, OC1-C6 alkyl, C1-C6 haloalkyl, OC1-C6 haloalkyl, C6-C10 aryl, 3-8 membered heteroaryl, C1-C6 aryl- C1-C6 alkyl, OH, =O, CN, COOH, C(O)NH2, NH2, or NHR3; 2 or more R2’s may be optionally joined together to form a ring; R3 is at each instance is independently halogen, CN, OH, NH2, C1-C6 alkyl, OC1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl C6-C10 aryl, C(O)R4, OR4, or SO2R4; R4 is at each instance is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkyl-C3-C8 cycloalkyl, C1-C6 alkyl-O-C1-C6 alkyl, C6-C10 aryl, 3-8 membered heteroaryl, or 3-8 membered heteroaryl-COOH; 2 or more R3’s may be optionally joined together to form a ring; R5 is at each instance is independently hydrogen, C1-C6 alkyl or C6-C10 aryl; x is is at each instance is independently CH, N, or is absent; y is is at each instance is independently CH2, NH, NR3, S, SO2, or O; z is is at each instance is independently CH, O, N, NH, S, or is absent; m is 1, or 2; 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO n is 0, 1, or 2; p is 0, 1, or 2; q is 0, 1, or 2; and s is 0, 1, or 2;or a derivative thereof.

3. The compound of Claim 1, wherein the compound is:1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO 2-(2,3,4,9-tetrahydro-1H-carbazole-9-carbonyl)benzoic acid, 2-(1-(3-(trifluoromethyl)-1,2,3,4-tetrahydro-9H-carbazol-9- yl)ethyl)benzoic acid, 2-((2-(methylsulfonyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5- yl)methyl)benzoic acid, 9-(2-carboxybenzyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2- ium 2,2,2-trifluoroacetate, 2-((3-hydroxy-7-methoxy-1,2,3,4-tetrahydro-9H-carbazol-9- yl)methyl)benzoic acid,1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO 2-methoxy-6-((1,2,3,4-tetrahydro-9H-carbazol-9-yl)methyl)benzoic acid, 3-ethoxy-2-((1,2,3,4-tetrahydro-9H-carbazol-9-yl)methyl)benzoic acid, 2-((5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)methyl)benzoic acid, 9-(2-carboxybenzyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylic acid,1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO 2-((2-methyl-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5- yl)methyl)benzoic acid, 9-(2-carboxybenzyl)-2,3,4,9-tetrahydro-1H-carbazole-7-carboxylic acid, 4-((1,2,3,4-tetrahydro-9H-carbazol-9-yl)methyl)benzo[d][1,3]dioxole-5- carboxylic acid, 9-(2-carboxybenzyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid, 9-(2-carboxy-6-methoxybenzyl)-2,3,4,9-tetrahydro-1H-carbazole-7- carboxylic acid,1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO 2-((7-chloro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)methyl)benzoic acid, 9-(2-carboxybenzyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 3-cyclopropoxy-2-((1,2,3,4-tetrahydro-9H-carbazol-9-yl)methyl)benzoic acid, 2-((8-methoxy-2-methyl-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5- yl)methyl)benzoic acid, 2-((3,4-dihydrothiopyrano[4,3-b]indol-5(1H)-yl)methyl)-3- methoxybenzoic acid,1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO 2-((6-chloro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)methyl)benzoic acid, 2-((8-chloro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)methyl)benzoic acid, and 2-((8-chloro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)methyl)-3- methoxybenzoic acid,or a derivative thereof.

4. The compound of Claim 2, wherein the compound is:1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO 5-methoxy-2-((1,2,3,4-tetrahydro-4aH-carbazol-4a-yl)methyl)benzoic acid, 5-((1,2,3,4-tetrahydro-4aH-carbazol-4a-yl)methyl)thiophene-2-carboxylic acid, 2-((8-chloro-1,2,3,4-tetrahydro-4aH-carbazol-4a-yl)methyl)benzoic acid, 3-cyano-2-((1,2,3,4-tetrahydro-4aH-carbazol-4a-yl)methyl)benzoic acid, 2-((6-chloro-1,2,3,4-tetrahydro-4aH-carbazol-4a-yl)methyl)benzoic acid,1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO 3-chloro-2-((1,2,3,4-tetrahydro-4aH-carbazol-4a-yl)methyl)benzoic acid HCl, and 3-cyano-2-((1,2,3,4-tetrahydro-4aH-carbazol-4a-yl)methyl)benzoic acid,or a derivative thereof.

5. A pharmaceutical composition comprising a compound of any one of claims 1-4, or a derivatives thereof, and a pharmaceutically acceptable excipient.

6. A method of treating an immunotherapy resistant tumor comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 5.

7. The method of claim 6, wherein the immunotherapy resistant tumor is a solid tumor or a metastases from a tumor.

8. The method of claim 7, wherein the solid tumor is a lung tumor, a colorectal tumor, melanoma, a urothreial tumor, non-small cell lung cancer, adenocarcinoma, a kidney tumor, a prostate tumor, a breast cancer,, a primary brain tumor, abrain metastasis from a solid tumor, or a combination thereof.

9. The method of claim 8, wherein the primary brain tumor is a glioma or a glioblastoma.

10. The method of claim 6, wherein the pharmaceutical composition is administered locally or systemically.

11. The method of claim 10, wherein the pharmaceutical composition is administered by injection or oral delivery. 1614154462.1 439994.000043PATENT ATTORNEY DOCKET NO. MDA1180-1WO 12. The method of claim 11, wherein the injection is intravenous, intraperitoneal, subcutaneous, intramuscular, by infusion, intratumorally, or peritumorally.

13. The method of claim 6, further comprising administration of a checkpoint inhibitor.

14. The method of claim 13, wherein the checkpoint inhibitor is an anti-PD1 agent.

15. The method of claim 14, wherein the anti-PD1 agent is an antibody.

16. The method of claim 15, wherein the antibody is selected from pembrolizumab, nivolumab, atezolizumab, avelumab, or durvalumab.

17. A method for sensitizing a PD-1 resistant cancer cell to treatment comprising contacting the PD-1 resistant cell with a compound of claims 1-4, thereby sensitizing the cell to anti- PD1 treatment.

18. A compound of any of claims 1-4, further comprising a cell penetrating peptide (CPP).

19. An antibody drug conjugate (ADC) comprising a compound of any of claims 1-4. 1614154462.1 439994.000043

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