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WO2025096773A1 - Inhibiteurs de fabp7 pour le traitement de tumeurs résistantes à l'immunothérapie - Google Patents

Inhibiteurs de fabp7 pour le traitement de tumeurs résistantes à l'immunothérapie Download PDF

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WO2025096773A1
WO2025096773A1 PCT/US2024/053882 US2024053882W WO2025096773A1 WO 2025096773 A1 WO2025096773 A1 WO 2025096773A1 US 2024053882 W US2024053882 W US 2024053882W WO 2025096773 A1 WO2025096773 A1 WO 2025096773A1
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mda1180
attorney docket
patent attorney
alkyl
tetrahydro
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Inventor
James Welsh
Maria Angelica CORTEZ
Athisayamani Jeyaraj DURAISWAMY
Mahanandeesha S. HALLUR
Srinivas Kolli
Remya RAMESH
Rajendra KRISTAM
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Jubilant Biosys Ltd
University of Texas System
University of Texas at Austin
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Jubilant Biosys Ltd
University of Texas System
University of Texas at Austin
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/82—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • 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.
  • 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.
  • Fatty acid binding protein 7 also known as brain lipid binding protein (BLBP) is expressed in various regions of the brain and has strong affinity for polyunsaturated fatty acids.
  • BLBP brain lipid binding protein
  • 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 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.
  • 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.
  • a method of treating an immunotherapy resistant tumor in a subject comprises administering to the subject a compound of embodiments herein.
  • 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.
  • FIG. 1 depicts compound 6’s (JBMD-000165 or 165) specificity using Surface Plasmon Resonance (SPR) based assay. 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO
  • FIG. 2 depicts compound 7’s (JBMD-000167 or 167) specificity using Surface Plasmon Resonance (SPR) based assay.
  • FIG. 3 depicts compound 8’s (JBMD-000169 or 169) specificity using Surface Plasmon Resonance (SPR) based assay.
  • FIG.4 depicts the IV, IP, and PO PK profile of compound 2 (JBMD-000087 or 87) in C57 BL/6 mice.
  • FIG.5 depicts the IV and PO PK profile of compound 65 (JBMD-000306 or 306) in C57 BL/6 mice.
  • FIG.6 depicts the IV and PO PK profile of compound 69 (JBMD-000319 or 319) in C57 BL/6 mice.
  • FIG.7 depicts the IV and PO PK profile of compound 116 (JBMD-000299 or 299) in C57 BL/6 mice.
  • FIG.8 depicts the IV and PO PK profile of compound 120 (JBMD-000311 or 311) in C57 BL/6 mice.
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • FIG.12 depicts the change in IFNG after 24 hours upon treatment with compounds 2 (JBMD-000087 or
  • 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.
  • 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).
  • 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.
  • FIG. 17 depicts mouse tissues upon treatment with vehicle (control), anti-PD1, and compound 2 (JBMD-000087 or 87).
  • FIG.18 depicts the results of compound 2 (JBMD-000087 or 87) using Migration assay in Glioblastoma cells (FABP7-U87MG cells).
  • FIG. 19 depicts the results of compound 7 (JBMD-000167 or 167) using Migration assay in Glioblastoma cells (FABP7-U87MG cells).
  • 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).
  • 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).
  • 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.
  • the only active ingredient(s) in the composition or method that treats the specified condition e.g., nutrient depletion
  • the specifically recited therapeutic(s) in the particular embodiment or claim is the specifically recited therapeutic(s) in the particular embodiment or claim.
  • 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.
  • an embodiment wherein one group is CH2 is mutually exclusive with an embodiment wherein the same group is NH.
  • 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.
  • 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.
  • 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 ⁇ M (micromolar),” which is intended to include 1 ⁇ M, 3 ⁇ M, and everything in between to any number of significant FIG.s (e.g., 1.255 ⁇ M, 2.1 ⁇ M, 2.9999 ⁇ M, etc.).
  • alkenyl refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms.
  • alkenyl will comprise from 2 to 6 carbon atoms.
  • suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like.
  • alkenyl may include “alkenylene” 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO.
  • alkoxy refers to an alkyl ether radical, wherein the term alkyl is as defined below.
  • suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
  • alkyl 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.
  • alkyl will comprise from 1 to 8 carbon atoms.
  • Alkyl groups may be optionally substituted as defined herein.
  • alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl and the like.
  • 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-).
  • alkyl may include “alkylene” groups.
  • alkynyl 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.
  • alkynylene 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.
  • alkynylene ).
  • 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.
  • alkynyl may include “alkynylene” groups.
  • 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.
  • aryl embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.
  • 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 439994.000043 PATENT ATTORNEY DOCKET NO.
  • 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.
  • said cycloalkyl will comprise from 5 to 7 carbon atoms.
  • cycloalkyl groups examples 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.
  • halo or halogen, as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl 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.
  • 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.
  • heteroaryl 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 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO from N, O, and S.
  • said heteroaryl will comprise from 1 to 4 heteroatoms as ring members.
  • said heteroaryl will comprise from 1 to 2 heteroatoms as ring members.
  • said heteroaryl will comprise from 5 to 7 atoms.
  • 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.
  • 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,
  • heterocyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.
  • 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.
  • heterocycle groups include aziridinyl, azetidinyl, 1,3- benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
  • the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
  • 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 hal
  • 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).
  • 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
  • E exo
  • Z isomers as well as the appropriate mixtures thereof.
  • compounds may exist as tautomers; all tautomeric isomers are provided by this invention.
  • 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.
  • 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.
  • the formulas are shown without a definitive stereochemistry at certain positions.
  • 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.
  • 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 439994.000043 PATENT 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.
  • racemic forms of the compounds as well as the individual enantiomers, diastereomers, stereoisomers and stereoisomer-enriched mixtures.
  • 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).
  • HPLC high pressure liquid chromatography
  • 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).
  • 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 439994.000043 PATENT ATTORNEY DOCKET NO.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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-naphthalenedisul
  • 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 439994.000043 PATENT 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.
  • 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.
  • mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate
  • 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.
  • 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.
  • hydrate is employed when said solvent is water.
  • 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.
  • 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.
  • isotopes suitable for inclusion in the compounds of embodiments herein include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 31 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • isotopically- labeled compounds of embodiments herein, for example, those incorporating a radioactive isotope are useful in drug and/or substrate tissue distribution studies.
  • radioactive isotopes tritium, 3 H, and carbon-14, 14 C 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, 2 H, 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 as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • 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.
  • Preferred isotopically-labeled compounds include deuterated derivatives of the compounds of embodiments herein.
  • deuterated derivative embraces compounds of embodiments herein where in a particular position at least one hydrogen atom is replaced by deuterium.
  • Deuterium (D or 2 H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
  • 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 439994.000043 PATENT 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 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.
  • 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).
  • 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'.
  • 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.
  • prodrugs can be slowly converted to a compound 16 1614154462.1 439994.000043 PATENT 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.
  • prodrug 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).
  • 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.”
  • carrier pharmaceutically acceptable carrier
  • diluent pharmaceutically acceptable diluent
  • 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.
  • 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 439994.000043 PATENT ATTORNEY DOCKET NO.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • an enzyme e.g., FABP7
  • Certain compounds disclosed herein have been 1614154462.1 439994.000043 PATENT 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.
  • 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.
  • 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.
  • embodiments of the present invention are directed to the treatment of a disease or disorder associated with sodium channel mediated activity.
  • 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.
  • 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.
  • 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 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • treat 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.
  • 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.
  • 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.
  • 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 439994.000043 PATENT ATTORNEY DOCKET NO.
  • R2 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
  • 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 439994.000043 PATENT ATTORNEY DOCKET NO.
  • the compound of Formula (I) may be selected from: 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 24 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 28 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO.
  • the compound of Formula (II) may be selected from: 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO or a derivative thereof.
  • the compound of Formula (II) may be selected from: 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO.
  • the compounds as disclosed herein, a derivative thereof, or a combination thereof further comprise a cell penetrating peptide (CPP).
  • CPP cell penetrating peptide
  • ADC antibody drug conjugate
  • a pharmaceutical composition comprising a compound as disclosed herein, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may comprise about 0.01% to about 50% of one or more compounds disclosed herein.
  • 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 0.5% to about 30%, about 0.5% to about 20%
  • 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.
  • the compounds as disclosed herein are in a therapeutically effective amount.
  • 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.
  • 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 439994.000043 PATENT 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.
  • 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
  • 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 439994.000043 PATENT 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.
  • 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.
  • 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.
  • the pharmaceutical compositions for use in accordance with embodiments herein can be formulated in conventional manner using one or more physiologically acceptable excipients.
  • the compounds When employed as pharmaceuticals, 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.
  • 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 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO pharmacologic references for guidance.
  • 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.
  • the compound is in a therapeutically effective amount.
  • the therapeutically effective amount is an amount disclosed herein.
  • 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).
  • 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.
  • a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • 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.
  • 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.
  • 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.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending 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 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO [0112]
  • the pharmaceutical compositions can be formulated in a unit dosage form.
  • 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.
  • 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.
  • 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.
  • 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 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO to provide slow or controlled release of the active ingredient therein.
  • 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.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Dragee cores are provided with suitable coatings.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 439994.000043 PATENT 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.
  • 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.
  • 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.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • the pharmaceutical compositions administered to a patient can be in the form of pharmaceutical compositions described above.
  • 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.
  • 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.
  • Preferred unit dosage pharmaceutical compositions are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
  • 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 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO [0122]
  • 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 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.
  • 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.
  • 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.
  • the pharmaceutical composition may include a pharmaceutically acceptable excipient, acceptable salt, solvate or prodrug thereof.
  • a compound as disclosed herein for use in the manufacture of a medicament for the treatment of an immunotherapy resistant tumor is also provided.
  • 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.
  • the immunotherapy resistant tumor is a solid tumor or a metastases from a tumor.
  • 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.
  • the primary brain tumor is a glioma or a glioblastoma.
  • the pharmaceutical composition is administered locally or systemically. 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO [0135]
  • 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.
  • 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.
  • 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.
  • the checkpoint inhibitor is an anti-PD-1 agent.
  • the anti-PD-1 agent is an antibody.
  • the antibody is selected from pembrolizumab, nivolumab, atezolizumab, avelumab, or durvalumab.
  • 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.
  • 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 439994.000043 PATENT 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.
  • 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.
  • 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, 4 th Ed., Wiley (2006). General methods of organic synthesis and functional group transformations are found in: Trost, B. M. et al., eds,.
  • Step 2 NaH(1.2eq), bromo ester(1.2eq), DMF, 0°C, 1 h.
  • Step 3 NaOH(3eq), MeOH, THF, H2O, RT to 60°C, 4 h.
  • 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.
  • Step 2 NaH(4 eq), bromo ester(1.2eq), THF, 0°C to RT, 16 h.
  • Step 3 NaOH(3eq), MeOH, THF, H2O, RT to 60°C, 4 h.
  • EXAMPLE 1 Synthesis of 2-((6-methoxy-1,2,3,4-tetrahydro-9H-carbazol-9-yl) methyl) benzoic acid (Compound 1) 65 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO.
  • Step 2 Synthesis of methyl 2-((6-methoxy-1,2,3,4-tetrahydro-9H-carbazol-9-yl) methyl) benzoate
  • 6-methoxy-2,3,4,9-tetrahydro-1H-carbazole 0.05 g, 248 ⁇ mol
  • sodium hydride 11.9 mg, 298 ⁇ mol
  • Step 3 Synthesis of 2-((6-methoxy-1,2,3,4-tetrahydro-9H-carbazol-9-yl) methyl) benzoic acid
  • Step 2 Synthesis of 2-[(2,3,4,9-tetrahydro-1H-carbazol-9-yl)methyl ] benzoic acid
  • methyl 2-[(2,3,4,9-tetrahydro-1H-carbazol-9-yl)methyl]benzoate 0.5 g, 1.57 mmol
  • THF(3mL) THF(3mL)
  • water(3mL) was added lithium(1+) hydrate hydroxide (0.65g, 15.7 mmol).
  • Table 1 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO
  • 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).
  • 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.
  • 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 439994.000043 PATENT ATTORNEY DOCKET NO.
  • Method C Analytical conditions: Column : CHIRALPAK® IC ( 100 mm X 4.6 mm X 3 ⁇ m) Mobile phase : n-Hexane:IPA with 0.1% DEA (70:30) Flow rate : 1.0 mL/min.
  • Method D Analytical conditions: Column: CHIRALPAK® IC (100 mm x 4.6 mm x3 ⁇ m) Mobile phase : n-Hexane:Ethanol with 0.1% TFA (70:30) Flow rate : 1.0 mL/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 ⁇ M) was used using the 100% sample loop volume setting at a flow rate of 40 ⁇ L/min.
  • FIG.s 1-3 show the results o theSPR based assay for compounds 6-8 respectively.
  • Table 3 94 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 95 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO 96 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO
  • EXAMPLE 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 4 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO
  • Table 5 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO [0177] Results are shown in Tables 6 and 7.
  • Table 6 AUC0-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; t 1/ 2: terminal half-life; T max : time to the maximum observed plasma concentration; C0 Plasma concentration at 0 min.
  • HLM Human liver microsomes
  • RLM Rat liver microsomes
  • MLM Mice liver microsomes
  • NI No inhibition
  • 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 8 100 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO. MDA1180-1WO Table 9 Table 10 Table 11 1614154462.1 439994.000043 PATENT ATTORNEY DOCKET NO.
  • 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- ⁇ m 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.
  • IACUC Institutional Animal Care and Use Committee
  • mice 129 Sv with 344SQR non-small cell lung cancer
  • 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.

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Abstract

La présente invention divulgue des composés de formule structurale I ainsi que ceux de formule structurale II. Ces composés sont des inhibiteurs de la protéine de liaison aux acides gras 7 (FABP7) et sont utiles dans le traitement de tumeurs solides systémiques, de tumeurs cérébrales primaires (par exemple, un glioblastome, GBM) et de métastases cérébrales à partir de tumeurs solides.
PCT/US2024/053882 2023-11-03 2024-10-31 Inhibiteurs de fabp7 pour le traitement de tumeurs résistantes à l'immunothérapie Pending WO2025096773A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6358992B1 (en) * 1998-11-25 2002-03-19 Cell Pathways, Inc. Method of inhibiting neoplastic cells with indole derivatives
US20120190696A1 (en) * 2009-10-08 2012-07-26 Schering Corporation Inhibitors of fatty acid binding protein (fabp)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6358992B1 (en) * 1998-11-25 2002-03-19 Cell Pathways, Inc. Method of inhibiting neoplastic cells with indole derivatives
US20120190696A1 (en) * 2009-10-08 2012-07-26 Schering Corporation Inhibitors of fatty acid binding protein (fabp)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM SUBSTANCE 1 December 2008 (2008-12-01), ANONYMOUS : "4a-benzyl-2,3,4,4a-tetrahydro-1Hcarbazole", XP093311996, retrieved from NCBI Database accession no. 17132793 *
DATABASE PUBCHEM SUBSTANCE 13 February 2015 (2015-02-13), ANONYMOUS : "SCHEMBL14894319", XP093312006, retrieved from NCBI Database accession no. 239861446 *

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