WO2025240752A1 - Mmp-13 antagonists - Google Patents

Mmp-13 antagonists

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Publication number
WO2025240752A1
WO2025240752A1 PCT/US2025/029576 US2025029576W WO2025240752A1 WO 2025240752 A1 WO2025240752 A1 WO 2025240752A1 US 2025029576 W US2025029576 W US 2025029576W WO 2025240752 A1 WO2025240752 A1 WO 2025240752A1
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alkyl
6alkyl
compound
ring
optionally substituted
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French (fr)
Inventor
Yangbo Feng
Sandra RIEGER
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University of Miami
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University of Miami
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • FIG.1 depicts a timeline of an experiment to assess chemotherapy-induced neuropathy.
  • FIG.2A depicts the results of a von Frey test for allodynia/hyperalgesia in mice treated with paclitaxel alone, paclitaxel with CL-82198, paclitaxel with AVX523, or paclitaxel with AVX536.
  • FIG.2B depicts the results of a cold sensitivity test in mice treated with paclitaxel alone, paclitaxel with CL-82198, paclitaxel with AVX523, or paclitaxel with AVX536.
  • FIG.2C depicts bodyweight measurement in mice treated with paclitaxel alone, paclitaxel with CL-82198, paclitaxel with AVX523, or paclitaxel with AVX536.
  • FIG.3A-3C depict PK data and MMP-13 inhibitory activity of AVX338 and AVX561.
  • FIG 4A-4B depict in vitro and in vivo pharmacokinetic data for AVX561.
  • FIG.5A depicts MMP-13 inhibitors do not affect a paclitaxel-dependent reduction in survival.
  • FIG.5B depicts paclitaxel treatment significantly reduces the heart rate compared with vehicle controls.
  • FIG.5C depicts mild distal fin necrosis with paclitaxel, which is rescued when AVX338/561 are co-administered.
  • FIG.5D depicts a touch response assay performed to elicit a response when the distal tail fin was stimulated with a microloader pipette tip. The number of stimuli that elicited an escape response were quantified.27% of the larvae did not respond to touch after 5 days of treatment with 0.0012mg/ml paclitaxel.
  • FIG.6A depicts a dosing schedule for a mouse experiment. Mice received 4 bi-daily intraperitoneal (i.p.) injections of 2mg/kg paclitaxel and daily i.p. injections of AVX338 and AVX561 for 9 days.
  • FIG.6B depicts significant differences in mouse weight among the different treatment groups
  • FIG.6C depicts that survival is not affected by any of the treatments.
  • FIG.6D depicts paclitaxel-injected mouse skin fixed and stained with hematoxylin/eosin (H&E) to visualize cells (blue) and collagen (magenta).
  • H&E hematoxylin/eosin
  • Left and right panels show different regions in same animal. Arrows point to regions that are disorganized in paclitaxel-treated animal when compared to similar region in the vehicle control. The dermis that is rich in collagen appears to tear in the presence of paclitaxel.
  • AVX338 and AVX561 co-administration with paclitaxel largely rescues the disorganization induced by paclitaxel alone.
  • salts are acid addition salts formed with inorganic acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids and the like; salts formed with organic acids such as acetic, oxalic, tartaric, succinic, maleic, fumaric, gluconic, citric, malic, methanesulfonic, p- toluenesulfonic, napthalenesulfonic, and polygalacturonic acids, and the like; salts formed from elemental anions such as chloride, bromide, and iodide; salts formed from metal hydroxides, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesium hydroxide; salts formed from metal carbonates, for example, sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate; salts formed from metal bicarbonates, for example, sodium bicarbonate and potassium bicarbonate; salts formed from metal sulfates,
  • alkyl refers to a radical of a straight-chain or branched hydrocarbon group having a specified range of carbon atoms (e.g., a "C1-16 alkyl” can have from 1 to 16 carbon atoms).
  • An alkyl group can be saturated or unsaturated, i.e., an alkenyl or alkynyl group. Unless specified to the contrary, an “alkyl” group includes both saturated alkyl groups and unsaturated alkyl groups.
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a C 1-6 heteroalkyl group includes, but is not limited to, the following structures: . [00 carbon atoms and can be fully saturated or partially unsaturated.
  • a cycloalkyl includes bi- and tricyclic ring systems that are not aromatic as a whole, but contain aromatic portions (e.g., fluorene, tetrahydronapthalene, dihydroindene, and the like).
  • the rings of multi-ring cycloalkyl groups can be either fused, bridged and/or joined through one or more spiro unions.
  • heterocyclyl refers to a non-aromatic ring system that includes at least one heteroatom in the cycle.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)).
  • a heterocyclyl group can be fully or partially saturated.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be substituted one or more time, wherein a hydrogen atom is replaced by a non-hydrogen atom or group.
  • a hydrogen atom is replaced by a non-hydrogen atom or group.
  • two hydrogen atoms are replaced.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the invention is not intended to be limited in any manner by the exemplary substituents described herein.
  • R a and R b in this context can be the same or different and independently hydrogen or alkyl, which may be substituted by halogen hydroxyl, amino, COOH, or cyano.
  • R a and R b in this context can be the same or different and independently hydrogen or alkyl, which may be substituted by halogen hydroxyl, amino, COOH, or cyano.
  • C1-6 alkyl is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1- 4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a "substituted aryl”) with one or more substituents. 5 Attorney Docket No.
  • alkyl is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl").
  • heteroaryl groups that contain one or more nitrogen atoms
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • the designation of a polyvalent moiety without specifying the specific order of attachment is intended to cover all possible arrangements.
  • a chemical bond depicted represents either a single, double, or triple bond, valency permitting. By way of example, .
  • Tautomers are interconvertible structural isomers that differ in the position of one or more protons or other labile atom. By way of example: 6 Attorney Docket No. 11348-056WO1 .
  • the point of attachment indicates that the y y possible atom.
  • the substituent may be present at any o sible carbon atoms.
  • the term “null,” w hen referring to a possible identity of a chemical moiety, indicates that the group is absent, and the two adjacent groups are directly bonded to one another.
  • the resulting compound has the formula CH 3 -CH 3 .
  • a group having the subscript ‘0’ is understood to define a null group as well.
  • the compound CH 3 -(X) z -CH 3 if X is CH 2 and z is 0, then the compound has the formula CH 3 -CH 3 .
  • variable groups may together form a ring (which may be designated a ring system). It is understood that any depicted atoms separated the identified groups will themselves form part of the ring: When the vari be a fused ring, and unless specified to the contrary may be either aromatic, cycloalkyl, heterocyclyl, or heteroaryl: g formed by the variable groups, which includes the atoms separating the variable groups: p 2 y , y together forming a six membered (or six atom) ring. [0043] Disclosed herein are compounds of Formula (1): 7 Attorney Docket No.
  • X 1 is N or CR x1 ;
  • X 2 is N or CR x2 ;
  • X 3 is N or CR x3 ;
  • Z 1 is N-(CR n1 )a, CR z1 , or C-*,
  • Z 2 is N-(CR n2 )a, CR z2 , or C-*,
  • Z 3 is N-(CR n3 )a, CR z3 , or C-*, wherein a is independently selected from 0 or 1 to provide a trivalent nitrogen atom;
  • R n1 is H, C 1-6 alkyl, C 3-6 cycloalkyl or -*;
  • R n2 is H, C 1-6 alkyl, C 3-6 cycloalkyl or -*;
  • R n3 is H, C 1-6 alkyl
  • the compound of Formula (1) is a compound having the formula: . [0046] In some implem mpound having the formula: . [0047] In some impleme mpound having the formula: . [0048] In some implem pound having the formula: , Attorney Docket No.11348-056WO1 [00 la: 10 Attorney Docket No. 11348-056WO1 , , , , [00 ula: , , Attorney Docket No.
  • X 1 , X 2 , and X 3 are each C-R x1/2/3 . In some implementations, X 1 , X 2 , and X 3 are C-H. In some implementations one of X 1 , X 2 , and X 3 is N and the other two are C-R x1/2/3 . In some implementations one of X 1 , X 2 , and X 3 is N and the other two are C-H. [0052] In some implementations, X 1 is N, X 2 is C-R x2 , and X 3 is C-R x3 .
  • X 2 and X 3 are each C-H.
  • X 3 is N and X 1 is C-R x1
  • X 2 is C-R x3 .
  • X 1 and X 3 are each C-H.
  • X 2 and X 3 are N and X 1 is C-R x1 .
  • one of R 1a , R 1b , R 1c , R 1d , and R 1e is F, Cl, Br, Q 1* C 1-6 alkyl, NHC 1-6 alkyl, N(C1-6alkyl)2, and COOH wherein said alkyl groups may be substituted one or more times by halo.
  • L 1 is CH2 or CH2CH2. 12 Attorney Docket No. 11348-056WO1
  • R N is H, CH 3 , cyclopropyl, or CH 2 cyclopropyl. In some implementations, R N is H or CH 3 .
  • R N and the A ring form a ring system.
  • the A ring is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted benzimidazolyl, or an optionally substituted benzofuranyl.
  • the A ring is an optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrimidinyl.
  • the A ring is an otherwise unsubstituted phenyl, pyridinyl, or pyrimidinyl ring.
  • R a1 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1- 6alkyl, or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl.
  • R a2 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1- 6alkyl, or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl.
  • R a3 is F, Cl, unsubstituted C 1-6 alkyl or OC 1-6 alkyl, or substituted C 1- 6 alkyl, or OC 1-6 alkyl, for example C 1-6 haloalkyl or OC 1-6 haloalkyl.
  • R a4 is F, Cl, unsubstituted C 1-6 alkyl or OC 1-6 alkyl, or substituted C 1- 6 alkyl, or OC 1-6 alkyl, for example C 1-6 haloalkyl or OC 1-6 haloalkyl.
  • R a5 is F, Cl, unsubstituted C 1-6 alkyl or OC 1-6 alkyl, or substituted C 1- 6 alkyl, or OC 1-6 alkyl, for example C 1-6 haloalkyl or OC 1-6 haloalkyl.
  • one of R a1 , R a2 , R a3 , R a4 , and R a5 is COOH, another is C3- 10heterocyclyl, and the remainder are H.
  • the C3-10heterocyclyl having the formula: , - y, p y .
  • R a1 and R a2 together form a five or six membered aromatic ring.
  • R a2 and R a3 together form a five or six membered aromatic ring.
  • R a3 and R a4 together form a five or six membered aromatic ring.
  • R a4 and R a5 together form a five or six membered aromatic ring.
  • one of R a1 or R a5 may form a ring with any of R n , R 1a , R 1b , R 1c , R 1d , and R 1e .
  • R a1 and R n together form a ring. In some implementations, R a5 and R n together form a ring. [0071]
  • the indicated portion of the compound of Formula (1): may have the for , , , whe ormula (1).
  • L 1 is C x alkylene and R n is C y alkylene, wherein x is 0-3 and y is 0-3, providing that x+y is at least 2. In some implementations, x+y is 2.
  • the A ring has the formula: COOH N , , , H , Attorney Docket No. 11348-056WO1 , [007 p , . p , L 1 and R n is CH 2 CH 2 the other is CH 2 .
  • the B ring is substituted one or two times by F, Cl, NH 2 , C 1-3 alkyl, OC 1-3 alkyl, C 3- 10 heterocyclyl, NHC 1-3 alkyl, or N(C 1-3 alkyl) 2 .
  • the B ring is substituted by a substituted C1-6alkyl or substituted OC1-6alkyl, for example the B ring is substituted by C1-6haloalkyl or OC1-6haloalkyl.
  • the B ring may include other substituents, for example F, Cl, unsubstituted C1-6alkyl, or unsubstituted OC1-6alkyl.
  • the B ring is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally 17 Attorney Docket No. 11348-056WO1 substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted benzimidazolyl, or an optionally substituted benzofuranyl.
  • the B ring is a partially saturated or fully saturated analog of such systems, e.g., cyclohexyl, piperidinyl, pyrrolidinyl, etc.
  • the B ring is an optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrimidinyl.
  • R b2 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl
  • R b1 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl.
  • R b2 is substituted C 1-6 alkyl or OC 1-6 alkyl, for example C 1-6 haloalkyl or OC 1-6 haloalkyl.
  • R b3 is substituted C 1-6 alkyl or OC 1-6 alkyl, for example C 1-6 haloalkyl or OC 1-6 haloalkyl.
  • R b4 is substituted C 1-6 alkyl or OC 1-6 alkyl, for example C 1-6 haloalkyl or OC 1-6 haloalkyl.
  • R b5 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl.
  • R b1 and R b2 together form a five or six membered aromatic ring.
  • R b2 and R b3 together form a five or six membered aromatic ring.
  • R b3 and R b4 together form a five or six membered aromatic ring.
  • R b4 and R b5 together form a five or six membered aromatic ring.
  • one of R b1 or R b5 may form a ring with any of R 2a , R 2b , R 2c , R 2d , and R 2e .
  • all of R b1 , R b2 , R b3 , R b4 , and R b5 are H.
  • R b1 , R b2 , R b3 , R b4 , and R b5 are F, Cl, Br, unsubstituted C1-4alkyl, unsubstituted OC1-4alkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, or C 3-10 heterocyclyl, wherein said C 3-10 heterocyclyl is optionally substituted one or more times by F, Cl, Br, C 1-4 alkyl, OC 1-4 alkyl.
  • the C 3-10 heterocyclyl can be substituted by a substituted C 1-4 alkyl or substituted OC1-4alkyl, for example C1-4haloalkyl or OC1-4haloalkyl.
  • R B is F, CF3, or OCF3.
  • R B is a C3-10heterocyclyl having the formula: , Attorney Docket No. 11348-056WO1 wherein R B1 is H or C 1-4 alkyl, and R B2 and R B3 are independently selected from H and F.
  • Also disclosed herein are methods of treating neuropathies using the compounds disclosed herein. In certain implementations, the compounds may be used to treat peripheral neuropathies.
  • the compounds may be used to treat neuropathies of arm and/or hand, neuropathies of the leg and/or foot, or combination of such neuropathies.
  • the compounds disclosed herein may be used to treat idiopathic neuropathies and neuropathies secondary to another conditions. In some implementations the compounds disclosed herein may be used to treat hereditary neuropathies. In certain implementations, the compounds disclosed herein may be used to treat diabetic neuropathies. In some implementations, the compounds disclosed herein may be used to treat chemotherapy induced neuropathies. [0095] In some implementations, the compounds disclosed herein may be used to treat neuropathy induced by chemotherapy, diabetes, alcohol consumption, autoimmune disorder, or systemic sclerosis.
  • the compounds disclosed herein can be used to treat and prevent neuropathies induced by administration of one or more cancer chemotherapeutics. In some implementations the compounds are used to treat and prevent neuropathies in a subject undergoing chemotherapy for cancer.
  • the subject is undergoing chemotherapy for breast cancer, lung cancer, uterine cancer, non-small cell lung cancer, Karposi sarcoma, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, head and neck cancer, penile cancer, small cell lung cancer, angiosarcoma, testicular germ cell cancer, thymoma, thymic carcinoma, adenocarcinoma, endometrial carcinoma, melanoma, thyroid cancer, and/or ovarian cancer.
  • the subject is undergoing chemotherapy for ovarian cancer, breast cancer, non-small cell lung cancer, or Karposi sarcoma.
  • the compounds disclosed herein may be used to treat and prevent neuropathies in a subject receiving paclitaxel.
  • the compounds disclosed herein may be administered in combination with one or more additional therapeutic agents, for example analgesics, antiepileptics (gabapentin, pregabalin), antidepressants (SSRI, SNRI, antipsychotics), and the like.
  • the compounds may be topically applied to the area of a subject’s skin in the region where the neuropathy is located.
  • the compounds disclosed herein may be formulated in pharmaceutical compositions for administration to a subject. Exemplary compositions will include at least one pharmaceutically acceptable excipient.
  • compositions include, but are not limited to, unit dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet 21 Attorney Docket No. 11348-056WO1 units, multiple unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), powders for reconstitution, transdermal patches and sprinkles, however, other dosage forms such as controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like.
  • Liquid or semisolid dosage form liquids, suspensions, solutions, dispersions, ointments, creams, emulsions, microemulsions, sprays, patches, spot-on
  • injection preparations parenteral, topical, inhalations, buccal, nasal etc. may also be envisaged.
  • Suitable excipients may be used for formulating the dosage forms according to the present invention such as, but not limited to, surface stabilizers or surfactants, viscosity modifying agents, polymers including extended release polymers, stabilizers, disintegrants or super disintegrants, diluents, plasticizers, binders, glidants, lubricants, sweeteners, flavoring agents, anti-caking agents, opacifiers, anti-microbial agents, antifoaming agents, emulsifiers, buffering agents, coloring agents, carriers, fillers, anti-adherents, solvents, taste-masking agents, preservatives, antioxidants, texture enhancers, channeling agents, coating agents or combinations thereof.
  • the compounds disclosed herein may be administered by a number of different routes.
  • the compounds may be administered orally, topically, transdermally, intravenously, subcutaneously, by inhalation, or by intracerebroventricular delivery.
  • the compounds may be administered to a patient systemically, e.g., by oral or intravenous administration, topically, i.e., by application of a cream, lotion or the like, or locally, e.g., by direct perfusion of a composition containing the compound to a target tissue.
  • EXAMPLES [0104] The following examples are for the purpose of illustration of the invention only and are not intended to limit the scope of the present invention in any manner whatsoever.
  • mice 30 male C57BL6/J (7 weeks old) mice were obtained from The Jackson Laboratory. Upon arrival mice were housed 2-3 cage and allowed to acclimate to the facility for 5 days. Animals were then habituated to testing chambers and baseline behavior measurements were obtained using von Frey (tactile) and dry ice testing chambers (thermal - cold). [0111] Mice were divided into six treatment groups and dosed according to the schedule depicted i n Figure 1: AVX or CL-82198: 1x Daily (day 0, 1, 2, 3, 4 and 5); Paclitaxel (PTX) - every other day (day 0, 2, 4 and 6). On days where both behavior and drug injections occur, all behavior was completed prior to injections.
  • AVX or CL-82198 1x Daily (day 0, 1, 2, 3, 4 and 5); Paclitaxel (PTX) - every other day (day 0, 2, 4 and 6).
  • mice were acclimated to the behavior room and testing chambers for 6 0 minutes.
  • von Frey filaments were used (filament size: 3.61, 4.08, 4.31 and 4.56).
  • the up-down method of testing was used on the left hind paw of each mouse.
  • von Frey filaments were pressed into the soft spot on the foot and pressed upward until the filament bent in half for a duration of 5 seconds. If the mouse expressed no response (licking or withdrawal of the paw) it was marked as an ‘o’ and the next highest filament was then tested. If a response occurred it was marked as an ‘x.’
  • Tactile thresholds (g) were calculated for the ‘xo’ pattern of each animal.
  • a compound of Formula (1) [Formula (1)], or a pharma 1 s N or CR x X i 1 ; X 2 is N or CR x2 ; X 3 is N or CR x3 ; Z 1 is N-(CR n1 )a, CR z1 , or C-*, Z 2 is N-(CR n2 )a, CR z2 , or C-*, Z 3 is N-(CR n3 )a, CR z3 , or C-*, wherein a is independently selected form 0 or 1 to provide a trivalent nitrogen atom; R n1 is H, C1-6alkyl, C3-6cycloalkyl or -*; R n2 is H, C1-6alkyl, C3-6cyclo
  • X 1 is C-R x1
  • X 2 is C-R x2
  • X 3 is C-R x3
  • X 1 is N
  • X 2 is C-R x2
  • X 3 is C-R x3
  • X 1 is C-R x1
  • X 2 is N
  • X 3 is C-R x3
  • X 1 is C-R x1
  • X 2 is N
  • X 3 is C-R x3
  • X 1 is C-R x1
  • X 2 is C-R x2
  • X 3 is N.
  • L 1 is CH2 or CH2CH2.
  • R n is H, CH3, cyclopropyl, or CH2cyclopropyl, or R n forms a ring system with A and/or L 1 .
  • a ring is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted benzimidazolyl, or an optionally substituted benzofuranyl.
  • 34 Attorney Docket No. 11348-056WO1
  • a ring is optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrimidinyl.
  • R a1 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl.
  • R a2 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl.
  • R a3 is substituted C 1-6 alkyl or OC 1-6 alkyl, for example C 1-6 haloalkyl or OC 1-6 haloalkyl.
  • R a4 is substituted C 1-6 alkyl or OC 1-6 alkyl, for example C 1-6 haloalkyl or OC 1-6 haloalkyl.
  • R a5 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl.
  • R a6 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl.
  • R a1 and R a2 together form a five or six membered aromatic ring
  • R a2 and R a3 together form a five or six membered aromatic ring
  • R a3 and R a4 together form a five or six membered aromatic ring
  • R a4 and R a5 together form a five or six membered aromatic ring.
  • R a1 or R a5 forms a ring with R n .
  • A-COOH is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted benzimidazolyl, optionally substituted benzofuranyl, [0143] The compound according to any preceding embodiment, wherein A-COOH has the formula: COOH , , Attorney Docket No.
  • B is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted benzimidazolyl, optionally substituted benzofuranyl.
  • a group independently selected from F, Cl, Br, OH, NH 2 , C 1-6 alkyl, OC 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 haloalkyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , CO
  • B is optionally substituted by one or more of F, Cl, Br, C1-4alkyl, C1-4alkoxyl, C1-4haloalkyl, C1-4haloalkoxy, C3-10heterocyclyl, wherein said C3-10heterocyclyl is optionally substituted one or more times by F, Cl, Br, C1-4alkyl, C1- 4alkoxyl, C1-4haloalkyl, C1-4haloalkoxy, [0151] The compound according to any preceding embodiment, wherein B is an optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrimidinyl.
  • R b1 is C3-10heterocyclyl.
  • R b2 is C3-10heterocyclyl.
  • R b3 is C3-10heterocyclyl.
  • R b4 is C3-10heterocyclyl.
  • R b5 is C3-10heterocyclyl.
  • R b1 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl.
  • R b2 is substituted C1-6alkyl or OC 1-6 alkyl, for example C 1-6 haloalkyl or OC 1-6 haloalkyl.
  • R b3 is substituted C 1-6 alkyl or OC 1-6 alkyl, for example C 1-6 haloalkyl or OC 1-6 haloalkyl.
  • R b4 is substituted C 1-6 alkyl or OC 1-6 alkyl, for example C 1-6 haloalkyl or OC 1-6 haloalkyl.
  • R b5 is substituted C 1-6 alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl.
  • R b1 and R b2 together form a five or six membered aromatic ring
  • R b2 and R b3 together form a five or six membered aromatic ring
  • R b3 and R b4 together form a five or six membered aromatic ring
  • R b4 and R b5 together form a five or six membered aromatic ring.
  • R b1 , R b2 , R b3 , R b4 , and R b5 are H; or one or two of R b1 , R b2 , R b3 , R b4 , and R b5 are F, Cl, Br, unsubstituted C1-4alkyl, unsubstituted OC1-4alkyl, C1-4haloalkyl, OC1-4haloalkyl, or C3-10heterocyclyl, wherein said C3-10heterocyclyl is optionally substituted one or more times by F, Cl, Br, C1-4alkyl, OC1-4alkyl, and the remainder are H.
  • R b1 , R b2 , R b3 , R b4 , and R b5 is F, Cl, Br, unsubstituted C 1-4 alkyl, unsubstituted OC 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, or C 3- 10 heterocyclyl, wherein said C 3-10 heterocyclyl is optionally substituted one or more times by F, Cl, Br, C 1-4 alkyl, or OC 1-4 alkyl.
  • R B is F, Cl, CF 3 , OCF 3 , or C 3- 10 heterocyclyl, wherein said C 3-10 heterocyclyl is optionally substituted one or more times by F, Cl, Br, C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, [0169]
  • R B has the formula: 42 Attorney Docket No. 11348-056WO1 , whe
  • the neuropathy comprises peripheral neuropathy.
  • the neuropathy comprises diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy.
  • the subject is undergoing chemotherapy for the treatment of cancer.
  • the subject is undergoing chemotherapy for the treatment of breast cancer, lung cancer, or ovarian cancer.
  • the neuropathy comprises peripheral neuropathy caused by chemotherapy, diabetes, alcohol consumption, autoimmune disorder, or systemic sclerosis.
  • the neuropathy comprise hereditary peripheral neuropathy or idiopathic peripheral neuropathy.
  • the neuropathy is secondary to administration of a chemotherapeutic agent.
  • the neuropathy is secondary to administration of paclitaxel.

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Abstract

Disclosed herein are compounds having MMP-13 inhibiting activity. The compounds may be used to treat neuropathies, including chemotherapy-induced peripheral neuropathy.

Description

Attorney Docket No. 11348-056WO1 MMP-13 ANTAGONISTS CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of U.S. Provisional Application 63/647,874 filed May 15, 2024, the contents of which are hereby incorporated in its entirety. STATEMENT OF GOVERNMENT SUPPORT [0002] This invention was made with government support under grant/contract number R41CA261451-A01 and 1R01CA215973-05 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE DISCLOSURE [0003] The disclosure relates to compounds having MMP-13 antagonistic behaviour. The disclosure relates to methods of treating neuropathies, including chemotherapeutic induced neuropathy. BACKGROUND [0004] There remains a need for improved systems and methods for treating neuropathy. There remains a need for improved systems and methods for treating peripheral neuropathy. There remains a need for improved systems and methods for treating neuropathy induced by administration of chemotherapeutic agents. There remains a need for improved systems and methods for treating peripheral neuropathy induced by administration of chemotherapeutic agents. BRIEF DESCRIPTION OF THE FIGURES [0005] FIG.1 depicts a timeline of an experiment to assess chemotherapy-induced neuropathy. [0006] FIG.2A depicts the results of a von Frey test for allodynia/hyperalgesia in mice treated with paclitaxel alone, paclitaxel with CL-82198, paclitaxel with AVX523, or paclitaxel with AVX536. [0007] FIG.2B depicts the results of a cold sensitivity test in mice treated with paclitaxel alone, paclitaxel with CL-82198, paclitaxel with AVX523, or paclitaxel with AVX536. [0008] FIG.2C depicts bodyweight measurement in mice treated with paclitaxel alone, paclitaxel with CL-82198, paclitaxel with AVX523, or paclitaxel with AVX536. [0009] FIG.3A-3C depict PK data and MMP-13 inhibitory activity of AVX338 and AVX561. [0010] FIG 4A-4B depict in vitro and in vivo pharmacokinetic data for AVX561. [0011] FIG.5A depicts MMP-13 inhibitors do not affect a paclitaxel-dependent reduction in survival. [0012] FIG.5B depicts paclitaxel treatment significantly reduces the heart rate compared with vehicle controls. AVX338 and AVX561 co-administration partially rescues the heart rate reduction induced by paclitaxel. 1 Attorney Docket No. 11348-056WO1 [0013] FIG.5C depicts mild distal fin necrosis with paclitaxel, which is rescued when AVX338/561 are co-administered. [0014] FIG.5D depicts a touch response assay performed to elicit a response when the distal tail fin was stimulated with a microloader pipette tip. The number of stimuli that elicited an escape response were quantified.27% of the larvae did not respond to touch after 5 days of treatment with 0.0012mg/ml paclitaxel. AVX338 and AVX561 co-administration significantly rescued the reduced response to touch induced by paclitaxel. [0015] FIG.6A depicts a dosing schedule for a mouse experiment. Mice received 4 bi-daily intraperitoneal (i.p.) injections of 2mg/kg paclitaxel and daily i.p. injections of AVX338 and AVX561 for 9 days. [0016] FIG.6B depicts significant differences in mouse weight among the different treatment groups [0017] FIG.6C depicts that survival is not affected by any of the treatments. [0018] FIG.6D depicts paclitaxel-injected mouse skin fixed and stained with hematoxylin/eosin (H&E) to visualize cells (blue) and collagen (magenta). Left and right panels show different regions in same animal. Arrows point to regions that are disorganized in paclitaxel-treated animal when compared to similar region in the vehicle control. The dermis that is rich in collagen appears to tear in the presence of paclitaxel. AVX338 and AVX561 co-administration with paclitaxel largely rescues the disorganization induced by paclitaxel alone. DETAILED DESCRIPTION [0019] Before the present methods and systems are disclosed and described, it is to be understood that the methods and systems are not limited to specific synthetic methods, specific components, or to particular compositions. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. [0020] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includesfrom the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. 2 Attorney Docket No. 11348-056WO1 [0021] “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. [0022] Throughout the description and claims of this specification, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. “Exemplary” means “an example of” and is not intended to convey an indication of a preferred or ideal embodiment. “Such as” is not used in a restrictive sense, but for explanatory purposes. [0023] Disclosed are components that can be used to perform the disclosed methods and systems. These and other components are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these components are disclosed that while specific reference of each various individual and collective combinations and permutation of these may not be explicitly disclosed, each is specifically contemplated and described herein, for all methods and systems. This applies to all aspects of this application including, but not limited to, steps in disclosed methods. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods. [0024] Compounds disclosed herein may be provided in the form of acceptable salts. Examples of such salts are acid addition salts formed with inorganic acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids and the like; salts formed with organic acids such as acetic, oxalic, tartaric, succinic, maleic, fumaric, gluconic, citric, malic, methanesulfonic, p- toluenesulfonic, napthalenesulfonic, and polygalacturonic acids, and the like; salts formed from elemental anions such as chloride, bromide, and iodide; salts formed from metal hydroxides, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesium hydroxide; salts formed from metal carbonates, for example, sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate; salts formed from metal bicarbonates, for example, sodium bicarbonate and potassium bicarbonate; salts formed from metal sulfates, for example, sodium sulfate and potassium sulfate; and salts formed from metal nitrates, for example, sodium nitrate and potassium nitrate. [0025] The term "alkyl" refers to a radical of a straight-chain or branched hydrocarbon group having a specified range of carbon atoms (e.g., a "C1-16 alkyl" can have from 1 to 16 carbon atoms). An alkyl group can be saturated or unsaturated, i.e., an alkenyl or alkynyl group. Unless specified to the contrary, an “alkyl” group includes both saturated alkyl groups and unsaturated alkyl groups. 3 Attorney Docket No. 11348-056WO1 [0026] The term "heteroalkyl" refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. By way of example, a C1-6heteroalkyl) group includes, but is not limited to, the following structures: . [00 carbon atoms and can be fully saturated or partially unsaturated. A cycloalkyl includes bi- and tricyclic ring systems that are not aromatic as a whole, but contain aromatic portions (e.g., fluorene, tetrahydronapthalene, dihydroindene, and the like). The rings of multi-ring cycloalkyl groups can be either fused, bridged and/or joined through one or more spiro unions. [0028] The term “heterocyclyl” refers to a non-aromatic ring system that includes at least one heteroatom in the cycle. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")). A heterocyclyl group can be fully or partially saturated. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. [0029] Affixing the suffix "-ene" to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl. The term “alkyl” is inclusive of alkylene when the context indicates the alkyl group is used in a divalent manner. 4 Attorney Docket No. 11348-056WO1 [0030] Affixing the prefix “halo” to a group indicates the group is substituted with one or more halogen atoms, which may be the same or different. The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I). [0031] Unless specifically indicated to the contrary, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be substituted one or more time, wherein a hydrogen atom is replaced by a non-hydrogen atom or group. In the case of an oxo substituent ("=O") and similar groups, two hydrogen atoms are replaced. The term "substituted" is contemplated to include substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the exemplary substituents described herein. Example substituents within this context can include halogen, nitro, cyano, oxo, COOH, hydroxy, alkyl, heteroalkyl, alkoxy, carbocyclyl, carbocycloalkyl, heterocyclyl, heteroaryl, aryl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, - NRaSO2Rb, -C(=O)Ra, - C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, - S(=O)2Ra, -OS(=O)2Ra and -S(=O)2ORa. Ra and Rb in this context can be the same or different and independently hydrogen or alkyl, which may be substituted by halogen hydroxyl, amino, COOH, or cyano. [0032] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, "C1-6 alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1- 4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. [0033] The term "alkoxy" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. [0034] The term "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14 aryl"). "Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. 5 Attorney Docket No. 11348-056WO1 [0035] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety. [0036] The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). [0037] As used herein, the designation of a polyvalent moiety without specifying the specific order of attachment is intended to cover all possible arrangements. By way of example, a compound represented by the formula: A-X-B, wherein X is NHC(=O) embraces both: and . [0038] As used herein, a chemical bond depicted: represents either a single, double, or triple bond, valency permitting. By way of example, . [0039] Some compound tomers. Tautomers are interconvertible structural isomers that differ in the position of one or more protons or other labile atom. By way of example: 6 Attorney Docket No. 11348-056WO1 . [0040] Unless stated to the c explicitly specifying the point of attachment indicates that the y y possible atom. For example, in a benzofuran depicted: , the substituent may be present at any o sible carbon atoms. [0041] As used herein, the term “null,” w hen referring to a possible identity of a chemical moiety, indicates that the group is absent, and the two adjacent groups are directly bonded to one another. By way of example, for a genus of compounds having the formula CH3-X-CH3, if X is null, then the resulting compound has the formula CH3-CH3. A group having the subscript ‘0’ is understood to define a null group as well. By way of example, in the compound CH3-(X)z-CH3, if X is CH2 and z is 0, then the compound has the formula CH3-CH3. [0042] In certain instances, two or more variable groups may together form a ring (which may be designated a ring system). It is understood that any depicted atoms separated the identified groups will themselves form part of the ring: When the vari be a fused ring, and unless specified to the contrary may be either aromatic, cycloalkyl, heterocyclyl, or heteroaryl: g formed by the variable groups, which includes the atoms separating the variable groups: p 2 y , y together forming a six membered (or six atom) ring. [0043] Disclosed herein are compounds of Formula (1): 7 Attorney Docket No. 11348-056WO1 [Formula (1)], or a pharmac eu ca y accep a e sa ereo , w eren X1 is N or CRx1; X2 is N or CRx2; X3 is N or CRx3; Z1 is N-(CRn1)a, CRz1, or C-*, Z2 is N-(CRn2)a, CRz2, or C-*, Z3 is N-(CRn3)a, CRz3, or C-*, wherein a is independently selected from 0 or 1 to provide a trivalent nitrogen atom; Rn1 is H, C1-6alkyl, C3-6cycloalkyl or -*; Rn2 is H, C1-6alkyl, C3-6cycloalkyl or -*; Rn3 is H, C1-6alkyl, C3-6cycloalkyl or -*; wherein -* represents the bond to L2 and a single -* is present; Y1 and Y2 are independently selected from C and N, provided that when both of Y1 and Y2 are N, then Z1 is N-(CRn1)a and/or Z3 is N-(CRn3)a; Rx1 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rx2 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rx3 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rz1 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rz2 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rz3 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; L1 is null, C1-4alkylene or C1-4heteroalkylene; A is an aryl or heteroaryl; Rn is H, C1-6alkyl, C3-6cycloalkyl, or together with one or both of Ring A and L1 forms a ring system; L2 is null, Q*C0-4alkylene, or Q*C0-4heteroalkylene, wherein Q* is null, C(=O), NHC(=O), OC(=O), NHC(=O)NH; and B is aryl, heteroaryl, C3-10cycloalkyl, or C3-10heterocyclyl. [0044] The skilled person understands that [4.3.0] aromatic structure depicted above will necessarily have at least one nitrogen atom in the ring to preserve aromaticity. 8 Attorney Docket No. 11348-056WO1 [0045] In some implementations, the compound of Formula (1) is a compound having the formula: . [0046] In some implem mpound having the formula: . [0047] In some impleme mpound having the formula: . [0048] In some implem pound having the formula: , Attorney Docket No.11348-056WO1 [00 la: 10 Attorney Docket No. 11348-056WO1 , , , , [00 ula: , , Attorney Docket No. 11348-056WO1 , , [0051] In some implementations, X1, X2, and X3 are each C-Rx1/2/3. In some implementations, X1, X2, and X3 are C-H. In some implementations one of X1, X2, and X3 is N and the other two are C-Rx1/2/3. In some implementations one of X1, X2, and X3 is N and the other two are C-H. [0052] In some implementations, X1 is N, X2 is C-Rx2, and X3 is C-Rx3. In some implementations, X2 and X3 are each C-H. [0053] In some implementations, X3 is N and X1 is C-Rx1, and X2 is C-Rx3. In some implementations, X1 and X3 are each C-H. [0054] In some implementations, X2 and X3 are N and X1 is C-Rx1. [0055] In some implementations, L1 is null or -CR1aR1b-Q1-, wherein Q1 is null, O, CR1cR1d, or NR1e; wherein R1a, R1b, R1c, and R1d are independently selected from H, F, Cl, Br, Q1*C1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, and COOH, wherein said alkyl groups may be substituted one or more times by halo; wherein Q1* is C(=O), C(=O)O, or C(=O)NR1e, and R1e is independently H or C1-6alkyl; wherein any of R1a, R1b, R1c, R1d, and R1e may form a ring with L1 or the A ring. [0056] In some implementations, one of R1a, R1b, R1c, R1d, and R1e is F, Cl, Br, Q1*C1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, and COOH wherein said alkyl groups may be substituted one or more times by halo. [0057] In some implementations, L1 is CH2 or CH2CH2. 12 Attorney Docket No. 11348-056WO1 [0058] In some implementations, RN is H, CH3, cyclopropyl, or CH2cyclopropyl. In some implementations, RN is H or CH3. In some implementations RN and the A ring form a ring system. [0059] The A ring in the compound of Formula 1 may be optionally substituted one or more times by F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, C1-6haloalkyl, OC1-6haloalkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl. When present these substituent groups are in addition to the depicted carboxylic acid moiety already defined by the compound of Formula (1). [0060] In certain implementations, the A ring is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted benzimidazolyl, or an optionally substituted benzofuranyl. [0061] In some implementations, the A ring is an optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrimidinyl. In some implementations, the A ring is an otherwise unsubstituted phenyl, pyridinyl, or pyrimidinyl ring. [0062] In some implementations, the A ring has the formula: Ra3 N Ra1 , , wherein: Ra1 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, or C3-10heterocyclyl, or C3- 8cycloalkyl; Ra2 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, or C3-10heterocyclyl, or C3- 8cycloalkyl; Ra3 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, or C3-10heterocyclyl, or C3- 8cycloalkyl; 13 Attorney Docket No. 11348-056WO1 Ra4 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, or C3-10heterocyclyl, or C3- 8cycloalkyl; Ra5 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, or C3-10heterocyclyl, or C3- 8cycloalkyl; providing that at least one of the Ra1, Ra2, Ra3, Ra4, and Ra5 groups present on the A ring is a COOH group, wherein any two of Ra1, Ra2, Ra3, Ra4, and Ra5 may together form a ring. [0063] In some implementations Ra1 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1- 6alkyl, or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0064] In some implementations Ra2 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1- 6alkyl, or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0065] In some implementations Ra3 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1- 6alkyl, or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0066] In some implementations Ra4 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1- 6alkyl, or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0067] In some implementations Ra5 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1- 6alkyl, or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0068] In some implementations one of Ra1, Ra2, Ra3, Ra4, and Ra5 is COOH, another is C3- 10heterocyclyl, and the remainder are H. In some implementations the C3-10heterocyclyl having the formula: , - y, p y . [0069] In some implementations, Ra1 and Ra2 together form a five or six membered aromatic ring. In some implementations, Ra2 and Ra3 together form a five or six membered aromatic ring. In some 14 Attorney Docket No. 11348-056WO1 implementations, Ra3 and Ra4 together form a five or six membered aromatic ring. In some implementations, Ra4 and Ra5 together form a five or six membered aromatic ring. [0070] In some implementations, one of Ra1 or Ra5 may form a ring with any of Rn, R1a, R1b, R1c, R1d, and R1e. In certain implementations, Ra1 and Rn together form a ring. In some implementations, Ra5 and Rn together form a ring. [0071] In some implementations, the indicated portion of the compound of Formula (1): , may have the for , , , whe ormula (1). In some implementations of the above polycyclic systems, one of L1 and Rn is CH=CH or CH=N, 15 Attorney Docket No. 11348-056WO1 and the other is null. In some implementations, L1 is Cxalkylene and Rn is Cyalkylene, wherein x is 0-3 and y is 0-3, providing that x+y is at least 2. In some implementations, x+y is 2. [0072] In certain implementations, the A ring has the formula: COOH N , , , H , Attorney Docket No. 11348-056WO1 , [007 p , . p , L1 and Rn is CH2CH2 the other is CH2. [0074] In some implementations, L2 is null, C(=O), or -CR2aR2b-Q2-; wherein Q2 is null, O, CR2cR2d, or NR2e; R2a, R2b, R2c, and R2d are independently selected from H, F, Cl, Br, C1-6alkyl, C1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1- 6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, wherein R2a and R2b may together form an oxo, and R2e is H or C1-6alkyl. [0075] In some implementations, L2 is C(=O), CH2, C(=O)CH2, CH2CH2, CH2O, or CH2CH2O. [0076] In some implementations, the B ring in the compound of Formula 1 is optionally substituted one or more times by F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, C1-6haloalkyl, OC1-6haloalkyl, NHC1- 6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3-8cycloalkyl. In certain implementations, the B ring includes one or two substituents independently selected from F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1- 6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3-8cycloalkyl. [0077] In some implementations, the B ring is substituted a single time by a group chosen from F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3-8cycloalkyl. In some implementations, the B ring is substituted one or two times by F, Cl, NH2, C1-3alkyl, OC1-3alkyl, C3- 10heterocyclyl, NHC1-3alkyl, or N(C1-3alkyl)2. [0078] In some implementations the B ring is substituted by a substituted C1-6alkyl or substituted OC1-6alkyl, for example the B ring is substituted by C1-6haloalkyl or OC1-6haloalkyl. The B ring may include other substituents, for example F, Cl, unsubstituted C1-6alkyl, or unsubstituted OC1-6alkyl. [0079] In certain implementations, the B ring is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally 17 Attorney Docket No. 11348-056WO1 substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted benzimidazolyl, or an optionally substituted benzofuranyl. In certain implementations, the B ring is a partially saturated or fully saturated analog of such systems, e.g., cyclohexyl, piperidinyl, pyrrolidinyl, etc. [0080] In some implementations, the B ring is an optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrimidinyl. [0081] In some implementations, the B ring has the formula: , , Rb1 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3- 8cycloalkyl.; Rb2 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3- 8cycloalkyl.; 18 Attorney Docket No. 11348-056WO1 Rb3 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3- 8cycloalkyl.; Rb4 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3- 8cycloalkyl.; Rb5 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3- 8cycloalkyl.; wherein any two of Rb1, Rb2, Rb3, Rb4, and Rb5 may together form a ring. [0082] In some implementations Rb1 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0083] In some implementations Rb2 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0084] In some implementations Rb3 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0085] In some implementations Rb4 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0086] In some implementations Rb5 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0087] In some implementations, Rb1 and Rb2 together form a five or six membered aromatic ring. In some implementations, Rb2 and Rb3 together form a five or six membered aromatic ring. In some implementations, Rb3 and Rb4 together form a five or six membered aromatic ring. In some implementations, Rb4 and Rb5 together form a five or six membered aromatic ring. [0088] In some implementations, one of Rb1 or Rb5 may form a ring with any of R2a, R2b, R2c, R2d, and R2e. [0089] In some implementations, all of Rb1, Rb2, Rb3, Rb4, and Rb5 are H. In some implementations, one or two of Rb1, Rb2, Rb3, Rb4, and Rb5 are F, Cl, Br, unsubstituted C1-4alkyl, unsubstituted OC1-4alkyl, C1-4haloalkyl, OC1-4haloalkyl, or C3-10heterocyclyl, wherein said C3-10heterocyclyl is optionally substituted one or more times by F, Cl, Br, C1-4alkyl, OC1-4alkyl. In some implementations the C3- 10heterocyclyl can be substituted by a substituted C1-4alkyl or substituted OC1-4alkyl, for example C1- 4haloalkyl or OC1-4haloalkyl. [0090] In some implementations, the B ring has the formula: 19 Attorney Docket No. 11348-056WO1 , , , herein said C3-10heterocyclyl is optionally substituted one or more times by F, Cl, Br, C1-4alkyl, or OC1-4alkyl. In some implementations the C3-10heterocyclyl can be substituted by a substituted C1-4alkyl or substituted OC1-4alkyl, for example C1-4haloalkyl or OC1-4haloalkyl. [0091] In some implementations, RB is F, CF3, or OCF3. [0092] In some implementations, RB is a C3-10heterocyclyl having the formula: , Attorney Docket No. 11348-056WO1 wherein RB1 is H or C1-4alkyl, and RB2 and RB3 are independently selected from H and F. [0093] Also disclosed herein are methods of treating neuropathies using the compounds disclosed herein. In certain implementations, the compounds may be used to treat peripheral neuropathies. In some implementations, the compounds may be used to treat neuropathies of arm and/or hand, neuropathies of the leg and/or foot, or combination of such neuropathies. [0094] The compounds disclosed herein may be used to treat idiopathic neuropathies and neuropathies secondary to another conditions. In some implementations the compounds disclosed herein may be used to treat hereditary neuropathies. In certain implementations, the compounds disclosed herein may be used to treat diabetic neuropathies. In some implementations, the compounds disclosed herein may be used to treat chemotherapy induced neuropathies. [0095] In some implementations, the compounds disclosed herein may be used to treat neuropathy induced by chemotherapy, diabetes, alcohol consumption, autoimmune disorder, or systemic sclerosis. [0096] In some implementations, the compounds disclosed herein can be used to treat and prevent neuropathies induced by administration of one or more cancer chemotherapeutics. In some implementations the compounds are used to treat and prevent neuropathies in a subject undergoing chemotherapy for cancer. In some implementations the subject is undergoing chemotherapy for breast cancer, lung cancer, uterine cancer, non-small cell lung cancer, Karposi sarcoma, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, head and neck cancer, penile cancer, small cell lung cancer, angiosarcoma, testicular germ cell cancer, thymoma, thymic carcinoma, adenocarcinoma, endometrial carcinoma, melanoma, thyroid cancer, and/or ovarian cancer. In certain implementations, the subject is undergoing chemotherapy for ovarian cancer, breast cancer, non-small cell lung cancer, or Karposi sarcoma. [0097] In some implementations, the compounds disclosed herein may be used to treat and prevent neuropathies in a subject receiving paclitaxel. [0098] In some implementations, the compounds disclosed herein may be administered in combination with one or more additional therapeutic agents, for example analgesics, antiepileptics (gabapentin, pregabalin), antidepressants (SSRI, SNRI, antipsychotics), and the like. [0099] In some implementations, the compounds may be topically applied to the area of a subject’s skin in the region where the neuropathy is located. [0100] The compounds disclosed herein may be formulated in pharmaceutical compositions for administration to a subject. Exemplary compositions will include at least one pharmaceutically acceptable excipient. Such compositions include, but are not limited to, unit dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet 21 Attorney Docket No. 11348-056WO1 units, multiple unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), powders for reconstitution, transdermal patches and sprinkles, however, other dosage forms such as controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like. Liquid or semisolid dosage form (liquids, suspensions, solutions, dispersions, ointments, creams, emulsions, microemulsions, sprays, patches, spot-on), injection preparations, parenteral, topical, inhalations, buccal, nasal etc. may also be envisaged. [0101] Suitable excipients may be used for formulating the dosage forms according to the present invention such as, but not limited to, surface stabilizers or surfactants, viscosity modifying agents, polymers including extended release polymers, stabilizers, disintegrants or super disintegrants, diluents, plasticizers, binders, glidants, lubricants, sweeteners, flavoring agents, anti-caking agents, opacifiers, anti-microbial agents, antifoaming agents, emulsifiers, buffering agents, coloring agents, carriers, fillers, anti-adherents, solvents, taste-masking agents, preservatives, antioxidants, texture enhancers, channeling agents, coating agents or combinations thereof. [0102] The compounds disclosed herein may be administered by a number of different routes. For instance, the compounds may be administered orally, topically, transdermally, intravenously, subcutaneously, by inhalation, or by intracerebroventricular delivery. [0103] The compounds may be administered to a patient systemically, e.g., by oral or intravenous administration, topically, i.e., by application of a cream, lotion or the like, or locally, e.g., by direct perfusion of a composition containing the compound to a target tissue. EXAMPLES [0104] The following examples are for the purpose of illustration of the invention only and are not intended to limit the scope of the present invention in any manner whatsoever. Preparative Example 1: 4-((2-benzylimidazo[1,2-a]pyridine-7-carboxamido)methyl)benzoic acid 22 Attorney Docket No. 11348-056WO1 [0105] CO3, 148.7 g (0.87 mol) of 1-chloro-3-phenylpropan-2-one and leave to stir at RT for 48 hours. The reaction mixture is poured into water, and the precipitate formed is filtered off, washed with water, and dried in a vacuum. Yield - 185.2 g (96.7 %). [0106] To a solution of 185.2 g (0.76 mol) (2) in 800 mL of DMSO, add 300 mL of 20 % aqueous KOH and leave to stir at 60°C overnight. The reaction mixture is cooled to RT, poured into 4 L of water, and acidified with 10 % HCl to pH=3. The formed precipitate was filtered off, washed with water, IPA, hexane, and dried in a vacuum. Yield - 155.6 g (89.2 %). [0107] To a solution of 20.2 g (88.5 mmol) of acid (3) in 400 mL of MeCN, add 17.8 g (216.9 mmol) of 1-methyl-1H-imidazole, cool to -10°C and add dropwise 10.6 g (92.8 mmol) MsCl. The reaction mixture is stirred at -10°C for 30 minutes, 20.8 g (86.8 mmol) methyl 4-(aminomethyl)benzoate is added and left to boil overnight. After completion of the reaction, the reaction mixture is cooled to RT, filled with water, and placed in an ultrasonic bath for 30-40 minutes. The formed precipitate was filtered off, washed with water, IPA, hexane, and dried in a vacuum. The product is recrystallized from MeCN. Yield - 21.3 g (54.6 %). [0108] To a solution of 21.3 g (87.4 mol) (4) in 800 mL of DMSO, add 300 mL of 20 % aqueous KOH and leave to stir at 60°C overnight. The reaction mixture is cooled to RT, poured into 4 L of water, and acidified with 10 % HCl to pH=3. The formed precipitate was filtered off, washed with water, IPA, hexane, and dried in a vacuum. Yield – 17.9 g (89.2 %). [0109] According to protocols analogous to Preparative Example 1, the following compounds were prepared: Preparative Example 2: 23 Attorney Docket No. 11348-056WO1 24 Attorney Docket No. 11348-056WO1 25 Attorney Docket No. 11348-056WO1 F O N N N H OH OH OH H H O Preparative Example 41: 4-((2-benzyl-1H-benzo[d]imidazole-5-carboxamido)methyl)benzoic acid 26 Attorney Docket No. 11348-056WO1 O O O O N O H2N O HN O N H H2N P P Attorney Docket No. 11348-056WO1 [0110] 30 male C57BL6/J (7 weeks old) mice were obtained from The Jackson Laboratory. Upon arrival mice were housed 2-3 cage and allowed to acclimate to the facility for 5 days. Animals were then habituated to testing chambers and baseline behavior measurements were obtained using von Frey (tactile) and dry ice testing chambers (thermal - cold). [0111] Mice were divided into six treatment groups and dosed according to the schedule depicted in Figure 1: AVX or CL-82198: 1x Daily (day 0, 1, 2, 3, 4 and 5); Paclitaxel (PTX) - every other day (day 0, 2, 4 and 6). On days where both behavior and drug injections occur, all behavior was completed prior to injections. PTX (paclitaxel) (4mg/kg, IP) + Vehicle (IP) PTX (4mg/kg, IP) + AVX532 (20mg/kg, IP) PTX (4mg/kg, IP) + AVX 536 (20mg/kg, IP) PTX (4mg/kg, IP) + AVX 545 (20mg/kg, IP) – did not show clear response) PTX (4mg/kg, IP) + AVX 586 (20mg/kg, IP) – did not show clear response) PTX (4 mg/kg, IP) + CL-82198 (known MMP-13 inhibitor) (10mg/kg, IP) Vehicle = 5%DMSO, 5% Tween 80, 90% Saline, PTX. Attorney Docket No. 11348-056WO1 [0112] For behavioral studies, mice were acclimated to the behavior room and testing chambers for 60 minutes. von Frey filaments were used (filament size: 3.61, 4.08, 4.31 and 4.56). The up-down method of testing was used on the left hind paw of each mouse. von Frey filaments were pressed into the soft spot on the foot and pressed upward until the filament bent in half for a duration of 5 seconds. If the mouse expressed no response (licking or withdrawal of the paw) it was marked as an ‘o’ and the next highest filament was then tested. If a response occurred it was marked as an ‘x.’ Tactile thresholds (g) were calculated for the ‘xo’ pattern of each animal. Group means and SEMs were calculated and graphed. Results are presented in Figure 2A. Dry Ice Test [0113] Mice were acclimated to the behavior room and testing chambers for 60 minutes. A piece of tempered glass was elevated, and chambers were placed on top to separate the mice. Dry ice was placed in a syringe and held up against the bottom of the glass underneath the hind paw. The time taken in seconds for each mouse to respond was recorded by a trained observer using a stopwatch. A response was recorded as removal of the paw from the cold source (lifting, shaking or licking). The test was stopped at 30sec if no response was observed. Group means and SEM’s were calculated and graphed. Results are presented in Figure 2B. [0114] The body weight of mice in each arm was recorded daily over the course of the experiment. Results are presented in Figure 2C. Additional Embodiments 29 Attorney Docket No. 11348-056WO1 [0115] A compound of Formula (1): [Formula (1)], or a pharma 1 s N or CRx X i 1; X2 is N or CRx2; X3 is N or CRx3; Z1 is N-(CRn1)a, CRz1, or C-*, Z2 is N-(CRn2)a, CRz2, or C-*, Z3 is N-(CRn3)a, CRz3, or C-*, wherein a is independently selected form 0 or 1 to provide a trivalent nitrogen atom; Rn1 is H, C1-6alkyl, C3-6cycloalkyl or -*; Rn2 is H, C1-6alkyl, C3-6cycloalkyl or -*; Rn3 is H, C1-6alkyl, C36cycloalkyl or -*; wherein -* represents the bond to L2 and a single -* is present; Y1 and Y2 are independently selected from C and N, provided that when one or both of Y1 and Y2 are N, then Z1 is N-(CRn1)a and/or Z3 is N-(CRn3)a; Rx1 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rx2 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rx3 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rz1 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rz2 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rz3 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; L1 is null, C1-4alkylene or C1-4heteroalkylene; A is an aryl or heteroaryl; Rn is H, C1-6alkyl, C3-6cycloalkyl, or together with one or both of Ring A and L1 forms a ring system; L2 is null, Q*C0-4alkylene, or Q*C0-4heteroalkylene, wherein Q* is null, C(=O), NHC(=O), OC(=O), NHC(=O)NH; and B is aryl, heteroaryl, C3-10cycloalkyl, or C3-10heterocyclyl. [0116] The compound according to any preceding embodiment, having the formula: 30 Attorney Docket No. 11348-056WO1 , [011 Attorney Docket No. 11348-056WO1 [01 , , , Attorney Docket No. 11348-056WO1 COOH L 2 X1 2 B Rn X , [01 , , , 33 Attorney Docket No. 11348-056WO1 , [01 X1 is C-Rx1, X2 is C-Rx2, and X3 is C-Rx3; X1 is N, X2 is C-Rx2, and X3 is C-Rx3; X1 is C-Rx1, X2 is N, and X3 is C-Rx3; or X1 is C-Rx1, X2 is C-Rx2, and X3 is N. [0121] The compound according to any preceding embodiment, wherein X1 is N and X2 and X3 are both CH. [0122] The compound according to any preceding embodiment, wherein X3 is N and X1 and X2 are both CH. [0123] The compound according to any preceding embodiment, wherein X2 and X3 are N and X1 is CH. [0124] The compound according to any preceding embodiment, wherein L1 is null or -CR1aR1b-Q1-; wherein Q1 is null, O, CR1cR1d, or NR1e; R1a, R1b, R1c, and R1d are independently selected from H, F, Cl, Br, Q1*C1-6alkyl, NHC1-6alkyl, N(C1- 6alkyl)2, and COOH, wherein said alkyl groups may be substituted one or more times by halo; and R1e is H or C1-6alkyl; wherein any of R1a, R1b, R1c, R1d, and R1e may form a ring with L1 or the A ring. [0125] The compound according to any preceding embodiment, wherein L1 is CH2 or CH2CH2. [0126] The compound according to any preceding embodiment, wherein Rn is H, CH3, cyclopropyl, or CH2cyclopropyl, or Rn forms a ring system with A and/or L1. [0127] The compound according to any preceding embodiment, wherein the A ring is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted benzimidazolyl, or an optionally substituted benzofuranyl. 34 Attorney Docket No. 11348-056WO1 [0128] The compound according to any preceding embodiment, wherein the A ring is optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrimidinyl. [0129] The compound according to any preceding embodiment, wherein the A ring is only substituted by the depicted COOH, or the A ring is substituted one or more times by F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, C1-6haloalkyl, OC1-6haloalkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1- 6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, or a combination thereof. [0130] The compound according to any preceding embodiment, wherein the A ring has the formula: Ra3 N Ra1 , , wherein: Ra1 is H, F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl; Ra2 is H, F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl; Ra3 is H, F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl; Ra4 is H, F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl; Ra5 is H, F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl; providing that at least one of the Ra1, Ra2, Ra3, Ra4, and Ra5 groups present is COOH, wherein any two of Ra1, Ra2, Ra3, Ra4, and Ra5 may together form a ring. [0131] The compound according to any preceding embodiment, wherein Ra1 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0132] The compound according to any preceding embodiment, wherein Ra2 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. 35 Attorney Docket No. 11348-056WO1 [0133] The compound according to any preceding embodiment, wherein Ra3 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0134] The compound according to any preceding embodiment, wherein Ra4 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0135] The compound according to any preceding embodiment, wherein Ra5 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0136] The compound according to any preceding embodiment, wherein Ra6 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0137] The compound according to any preceding embodiment, wherein: Ra1 and Ra2 together form a five or six membered aromatic ring; Ra2 and Ra3 together form a five or six membered aromatic ring; Ra3 and Ra4 together form a five or six membered aromatic ring; or Ra4 and Ra5 together form a five or six membered aromatic ring. [0138] The compound according to any preceding embodiment, wherein one of Ra1 or Ra5 forms a ring with Rn. [0139] The compound according to any preceding embodiment, having the formula: COOH Rn , Attorney Docket No. 11348-056WO1 , of Formula (1). [0140] The compound according to any preceding embodiment, wherein: one of L1 and Rn is CH=CH or CH=N, and the other is null; or L1 is Cxalkylene and Rn is Cyalkylene, wherein x is 0-3 and y is 0-3, providing that x+y is at least 2. [0141] The compound according to any preceding embodiment, wherein: L1 and Rn are each CH2; or one of L1 and Rn is CH2CH2 the other is CH2. [0142] The compound according to any preceding embodiment, wherein A-COOH is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted benzimidazolyl, optionally substituted benzofuranyl, [0143] The compound according to any preceding embodiment, wherein A-COOH has the formula: COOH , , Attorney Docket No. 11348-056WO1 , H , [01 CR2aR2b-Q2-; wherein Q2 is null, O, CR2cR2d, or NR2e; 38 Attorney Docket No. 11348-056WO1 wherein R2a, R2b, R2c, and R2d are independently selected from H, F, Cl, Br, C1-6alkyl, C1-6alkyl, NHC1- 6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, wherein R2a and R2b may together form an oxo and R2e is H or C1-6alkyl. [0145] The compound according to any preceding embodiment, wherein L2 is C(=O), CH2, CH2CH2, CH2O, or CH2CH2O. [0146] The compound according to any preceding embodiment, wherein B is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted benzimidazolyl, optionally substituted benzofuranyl. [0147] The compound according to any preceding embodiment, wherein B is optionally substituted one or more times by F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, C1-6haloalkyl, OC1-6haloalkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1- 6alkyl, C3-10heterocyclyl, or C3-8cycloalkyl. [0148] The compound according to any preceding embodiment, wherein B is substituted once or twice by a group independently selected from F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, C1-6haloalkyl, OC1-6haloalkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3-8cycloalkyl. [0149] The compound according to any preceding embodiment, wherein B is substituted a single time by F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, C1-6haloalkyl, OC1-6haloalkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3- 10heterocyclyl, or C3-8cycloalkyl. [0150] The compound according to any preceding embodiment, wherein B is optionally substituted by one or more of F, Cl, Br, C1-4alkyl, C1-4alkoxyl, C1-4haloalkyl, C1-4haloalkoxy, C3-10heterocyclyl, wherein said C3-10heterocyclyl is optionally substituted one or more times by F, Cl, Br, C1-4alkyl, C1- 4alkoxyl, C1-4haloalkyl, C1-4haloalkoxy, [0151] The compound according to any preceding embodiment, wherein B is an optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrimidinyl. [0152] The compound according to any preceding embodiment, wherein B has the formula: 39 Attorney Docket No. 11348-056WO1 , , Rb1 is H, F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3- 8cycloalkyl.; Rb2 is H, F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3- 8cycloalkyl.; Rb3 is H, F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3- 8cycloalkyl.; Rb4 is H, F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3- 8cycloalkyl.; 40 Attorney Docket No. 11348-056WO1 Rb5 is H, F, Cl, Br, OH, NH2, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3- 8cycloalkyl.; wherein any two of Rb1, Rb2, Rb3, Rb4, and Rb5 may together form a ring. [0153] The compound according to any preceding embodiment, wherein Rb1 is C3-10heterocyclyl. [0154] The compound according to any preceding embodiment, wherein Rb2 is C3-10heterocyclyl. [0155] The compound according to any preceding embodiment, wherein Rb3 is C3-10heterocyclyl. [0156] The compound according to any preceding embodiment, wherein Rb4 is C3-10heterocyclyl. [0157] The compound according to any preceding embodiment, wherein Rb5 is C3-10heterocyclyl. [0158] The compound according to any preceding embodiment, wherein Rb1 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0159] The compound according to any preceding embodiment, wherein Rb2 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0160] The compound according to any preceding embodiment, wherein Rb3 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0161] The compound according to any preceding embodiment, wherein Rb4 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0162] The compound according to any preceding embodiment, wherein Rb5 is substituted C1-6alkyl or OC1-6alkyl, for example C1-6haloalkyl or OC1-6haloalkyl. [0163] The compound according to any preceding embodiment, wherein: Rb1 and Rb2 together form a five or six membered aromatic ring; Rb2 and Rb3 together form a five or six membered aromatic ring; Rb3 and Rb4 together form a five or six membered aromatic ring; or Rb4 and Rb5 together form a five or six membered aromatic ring. [0164] The compound according to any preceding embodiment, wherein all of Rb1, Rb2, Rb3, Rb4, and Rb5 are H; or one or two of Rb1, Rb2, Rb3, Rb4, and Rb5 are F, Cl, Br, unsubstituted C1-4alkyl, unsubstituted OC1-4alkyl, C1-4haloalkyl, OC1-4haloalkyl, or C3-10heterocyclyl, wherein said C3-10heterocyclyl is optionally substituted one or more times by F, Cl, Br, C1-4alkyl, OC1-4alkyl, and the remainder are H. [0165] The compound according to any preceding embodiment, wherein one Rb1, Rb2, Rb3, Rb4, and Rb5 is F, Cl, Br, unsubstituted C1-4alkyl, unsubstituted OC1-4alkyl, C1-4haloalkyl, OC1-4haloalkyl, or C3- 10heterocyclyl, wherein said C3-10heterocyclyl is optionally substituted one or more times by F, Cl, Br, C1-4alkyl, or OC1-4alkyl. 41 Attorney Docket No. 11348-056WO1 [0166] The compound according to any preceding embodiment, wherein one Rb1, Rb2, Rb3, Rb4, and Rb5 is C3-10heterocyclyl, wherein said C3-10heterocyclyl is optionally substituted one or more times by F, Cl, Br, C1-4alkyl, or OC1-4alkyl. [0167] The compound according to any preceding embodiment, wherein B has the formula: , , , whe rein said C3-10heterocyclyl is optionally substituted one or more times by F, Cl, Br, C1-4alkyl, C1-4alkoxyl, C1- 4haloalkyl, or C1-4haloalkoxy. [0168] The compound according to any preceding embodiment, wherein RB is F, Cl, CF3, OCF3, or C3- 10heterocyclyl, wherein said C3-10heterocyclyl is optionally substituted one or more times by F, Cl, Br, C1-4alkyl, C1-4alkoxyl, C1-4haloalkyl, C1-4haloalkoxy, [0169] The compound according to any preceding embodiment, wherein RB has the formula: 42 Attorney Docket No. 11348-056WO1 , whe [0170] A method of treating neuropathy in a subject in need thereof, comprising administering to the subject a compound according to any preceding embodiment. [0171] The method according to any preceding embodiment, wherein the neuropathy comprises peripheral neuropathy. [0172] The method according to any preceding embodiment, wherein the neuropathy comprises diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy. [0173] The method according to any preceding embodiment, wherein the subject is undergoing chemotherapy for the treatment of cancer. [0174] The method according to any preceding embodiment, wherein the subject is undergoing chemotherapy for the treatment of breast cancer, lung cancer, or ovarian cancer. [0175] The method according to any preceding embodiment, wherein the neuropathy comprises peripheral neuropathy caused by chemotherapy, diabetes, alcohol consumption, autoimmune disorder, or systemic sclerosis. [0176] The method according to any preceding embodiment, wherein the neuropathy comprise hereditary peripheral neuropathy or idiopathic peripheral neuropathy. [0177] The method according to any preceding embodiment, wherein the neuropathy is secondary to administration of a chemotherapeutic agent. [0178] The method according to any preceding embodiment, wherein the neuropathy is secondary to administration of paclitaxel. [0179] The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and 43 Attorney Docket No. 11348-056WO1 methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein or less, however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated. The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific embodiments of the invention and are also disclosed. Other than in the examples, or where otherwise noted, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches 44

Claims

Attorney Docket No. 11348-056WO1 CLAIMS What is claimed is: 1. A compound of Formula (1): 1)], or a pharmaceut 1 X is N or CRx1; X2 is N or CRx2; X3 is N or CRx3; Z1 is N-(CRn1)a, CRz1, or C-*, Z2 is N-(CRn2)a, CRz2, or C-*, Z3 is N-(CRn3)a, CRz3, or C-*, wherein a is independently selected from 0 or 1 to provide a trivalent nitrogen atom; Rn1 is H, C1-6alkyl, C3-6cycloalkyl or -*; Rn2 is H, C1-6alkyl C c cloalk l or -*; Rn3 is H, C1-6alkyl, C3-6cycloalkyl or -*; wherein -* represents the bond to L2 and a single -* is present; Y1 and Y2 are independently selected from C and N, provided that when both of Y1 and Y2 are N, then Z1 is N-(CRn1)a and/or Z3 is N-(CRn3)a; Rx1 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rx2 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rx3 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rz1 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rz2 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; Rz3 is H, halo, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, C3-6cycloalkyl, or C2-7heterocyclyl; L1 is null, C1-4alkylene or C1-4heteroalkylene; A is an aryl or heteroaryl; Rn is H, C1-6alkyl, C3-6cycloalkyl, or together with one or both of Ring A and L1 forms a ring system; L2 is null, Q*C0-4alkylene, or Q*C0-4heteroalkylene, wherein Q* is null, C(=O), NHC(=O), OC(=O), NHC(=O)NH; and 45 Attorney Docket No. 11348-056WO1 B is aryl, heteroaryl, C3-10cycloalkyl, or C3-10heterocyclyl. 2. The compound of claim 1, having the formula: 3. The compound of clai . 4. The compound of cla . 5. The compound of cla , Attorney Docket No. 11348-056WO1 6. 47 Attorney Docket No. 11348-056WO1 , , , , 48 Attorney Docket No. 11348-056WO1 , , , , 9. The compound of any of claims 1-7, wherein X1 is C-H, X2 is C-H and X3 is C-H. 10. The compound of any of claims 1-7, wherein X1 is N, X2 is C-Rx2 and X3 is C-Rx3. 11. The compound of any of claims 1-7, wherein X1 is N, X2 is C-H and X3 is C-H. 12. The compound of any of claims 1-7, wherein X3 is N and X1 is C-Rx1, and X2 is C-Rx3. 13. The compound of any of claims 1-7, wherein X3 is N and X1 is C-H, and X2 is C-H. 14. The compound of any of claims 1-7, wherein X2 and X3 are N and X1 is C-Rx1. 15. The compound of any of claims 1-7, wherein X2 and X3 are N and X1 is C-H. 16. The compound of any of claims 1-15, wherein L1 is null or -CR1aR1b-Q1-, wherein Q1 is null, O, CR1cR1d, or NR1e; 49 Attorney Docket No. 11348-056WO1 wherein R1a, R1b, R1c, and R1d are independently selected from H, F, Cl, Br, Q1*C1-6alkyl, NHC1- 6alkyl, N(C1-6alkyl)2, and COOH, wherein said alkyl groups may be substituted one or more times by halo; wherein Q1* is C(=O), C(=O)O, or C(=O)NR1e, and R1e is independently H or C1-6alkyl; wherein any of R1a, R1b, R1c, R1d, and R1e may form a ring with L1 or the A ring. 17. The compound of claim 16, wherein one of R1a, R1b, R1c, R1d, and R1e is F, Cl, Br, Q1*C1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, and COOH wherein said alkyl groups may be substituted one or more times by halo. 18. The compound of any of claims 1-15, wherein L1 is CH2 or CH2CH2. 19. The compound of any of claims 1-18, wherein RN is H, CH3, cyclopropyl, or CH2cyclopropyl, preferably H or CH3. 20. The compound of any of claims 1-18, wherein RN and the A ring form a ring system. 21. The compound of any of claims 1-20, wherein the A ring is unsubstituted except for the depicted carboxylic acid, or the A ring is substituted one or more times by F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, C1-6haloalkyl, OC1-6haloalkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl in addition to the depicted carboxylic acid. 22. The compound of any of claims 1-21, wherein the A ring is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted benzimidazolyl, or an optionally substituted benzofuranyl, preferably optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrimidinyl. 23. The compound of any of claims 1-22, wherein the A ring is an unsubstituted phenyl, pyridinyl, or pyrimidinyl ring, excepting the depicted COOH substituent. 24. The compound of any of claims 1-23, wherein the A ring has the formula: a1 , Attorney Docket No. 11348-056WO1 , wherein: Ra1 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1- 6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, or C3- 10heterocyclyl, or C3-8cycloalkyl; Ra2 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1- 6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, or C3- 10heterocyclyl, or C3-8cycloalkyl; Ra3 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1- 6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, or C3- 10heterocyclyl, or C3-8cycloalkyl; Ra4 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1- 6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, or C3- 10heterocyclyl, or C3-8cycloalkyl; Ra5 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1- 6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, or C3- 10heterocyclyl, or C3-8cycloalkyl; providing that at least one of the Ra1, Ra2, Ra3, Ra4, and Ra5 groups present on the A ring is a COOH group, wherein any two of Ra1, Ra2, Ra3, Ra4, and Ra5 may together form a ring. 25. The compound of claim 24, wherein Ra1 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1-6alkyl or OC1-6alkyl, preferably C1-6haloalkyl or OC1-6haloalkyl. 26. The compound of claim 24, wherein Ra2 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1-6alkyl or OC1-6alkyl, preferably C1-6haloalkyl or OC1-6haloalkyl. 27. The compound of claim 24, wherein Ra3 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1-6alkyl or OC1-6alkyl, preferably C1-6haloalkyl or OC1-6haloalkyl. 28. The compound of claim 24, wherein Ra4 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1-6alkyl or OC1-6alkyl, preferably C1-6haloalkyl or OC1-6haloalkyl. 29. The compound of claim 24, wherein Ra5 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1-6alkyl or OC1-6alkyl, preferably C1-6haloalkyl or OC1-6haloalkyl. 51 Attorney Docket No. 11348-056WO1 30. The compound of claim 24 wherein one of Ra1, Ra2, Ra3, Ra4, and Ra5 is COOH, another is C3- 10heterocyclyl, and the remainder of Ra1, Ra2, Ra3, Ra4, and Ra5 are H. 31. The compound of claim 30, wherein the C3-10heterocyclyl has the formula: , 32. The compound of any of claims 24-31, wherein Ra1 and Ra2 together form a five or six membered aromatic ring. 33. The compound of any of claims 24-31, wherein Ra2 and Ra3 together form a five or six membered aromatic ring. 34. The compound of any of claims 24-31, wherein Ra3 and Ra4 together form a five or six membered aromatic ring. 35. The compound of any of claims 24-31, wherein Ra4 and Ra5 together form a five or six membered aromatic ring. 36. The compound of any of claims 1-20, having the formula: , wherein the bo p 52 Attorney Docket No. 11348-056WO1 , , , und of Formula (1). 37. The compound of claim 36, wherein one of L1 and Rn is CH=CH or CH=N, and the other is null. 38. The compound of claim 36, wherein L1 is Cxalkylene and Rn is Cyalkylene, wherein x is 0-3 and y is 0-3, providing that x+y is at least 2, preferably x+y is 2. 39. The compound of any of claims 1-19, wherein the A ring has the formula: 53 Attorney Docket No. 11348-056WO1 , , Attorney Docket No. 11348-056WO1 . , , 40. 2b-Q2-; wherein Q2 is null, O, CR2cR2d, or NR2e; wherein R2a, R2b, R2c, and R2d are independently selected from H, F, Cl, Br, C1-6alkyl, C1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, wherein R2a and R2b may together form an oxo, and R2e is H or C1-6alkyl. 41. The compound of claim 40, wherein L2 is C(=O), CH2, C(=O)CH2, CH2CH2, CH2O, or CH2CH2O. 42. The compound of claim 1, wherein the B ring is unsubstituted or substituted one or more times by F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, C1-6haloalkyl, OC1-6haloalkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3-8cycloalkyl. 43. The compound of any of claims 1-41, wherein the B ring has one or two substituents independently selected from F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1- 6alkyl)2, COOH, C(=O)OC1-6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3-10heterocyclyl, or C3-8cycloalkyl. 44. The compound of any of claims 1-41, wherein the B ring has a single substituent selected from F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1- 55 Attorney Docket No. 11348-056WO1 6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3- 10heterocyclyl, or C3-8cycloalkyl. 45. The compound of any of claims 1-44, wherein the B ring is substituted by a substituted C1- 6alkyl or substituted OC1-6alkyl. 46. The compound any of claim 1-44, wherein the B ring is substituted by an unsubstituted C1- 6alkyl or unsubstituted OC1-6alkyl. 47. The compound of any of claim 1-44, wherein the B ring is substituted by F or Cl. 48. The compound of any of claims 1-47, wherein the B ring is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted benzimidazolyl, or an optionally substituted benzofuranyl, or a completed saturated analog thereof. 49. The compound of any of claims 1-48, wherein the B ring is an optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrimidinyl. 50. The compound of any of claims 1-47, wherein the B ring has the formula: , Attorney Docket No. 11348-056WO1 wherein: Rb1 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1- 6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3- 10heterocyclyl, or C3-8cycloalkyl.; Rb2 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1- 6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3- 10heterocyclyl, or C3-8cycloalkyl; Rb3 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1- 6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3- 10heterocyclyl, or C3-8cycloalkyl.; Rb4 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1- 6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3- 10heterocyclyl, or C3-8cycloalkyl.; Rb5 is H, F, Cl, Br, OH, NH2, CN, C1-6alkyl, OC1-6alkyl, NHC1-6alkyl, N(C1-6alkyl)2, COOH, C(=O)OC1- 6alkyl, O(C=O)C1-6alkyl, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(C=O)C1-6alkyl, C3- 10heterocyclyl, or C3-8cycloalkyl.; wherein any two of Rb1, Rb2, Rb3, Rb4, and Rb5 may together form a ring. 51. The compound of claim 50, wherein Rb1 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1-6alkyl, or OC1-6alkyl, preferably C1-6haloalkyl or OC1-6haloalkyl. 52. The compound of claim 50, wherein Rb2 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1-6alkyl, or OC1-6alkyl, preferably C1-6haloalkyl or OC1-6haloalkyl. 53. The compound of claim 50, wherein Rb3 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1-6alkyl, or OC1-6alkyl, preferably C1-6haloalkyl or OC1-6haloalkyl. 54. The compound of claim 50, wherein Rb4 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1-6alkyl, or OC1-6alkyl, preferably C1-6haloalkyl or OC1-6haloalkyl. 55. The compound of claim 50, wherein Rb5 is F, Cl, unsubstituted C1-6alkyl or OC1-6alkyl, or substituted C1-6alkyl, or OC1-6alkyl, preferably C1-6haloalkyl or OC1-6haloalkyl. 56. The compound of any of claims 40-55, wherein one of Rb1 or Rb5 forms a ring with any of R2a, R2b, R2c, R2d, and R2e. 57. The compound of claim 40, wherein all of Rb1, Rb2, Rb3, Rb4, and Rb5 are H. 58. The compound of claim 40, wherein two of Rb1, Rb2, Rb3, Rb4, and Rb5 are F, Cl, Br, unsubstituted C1-4alkyl, unsubstituted OC1-4alkyl, C1-4haloalkyl, OC1-4haloalkyl, or C3- 57 Attorney Docket No. 11348-056WO1 10heterocyclyl, wherein said C3-10heterocyclyl is optionally substituted one or more times by F, Cl, Br, C1-4alkyl, OC1-4alkyl, and the rest of Rb1, Rb2, Rb3, Rb4, and Rb5 are H. 59. The compound of claim 40, wherein one of Rb1, Rb2, Rb3, Rb4, and Rb5 are F, Cl, Br, unsubstituted C1-4alkyl, unsubstituted OC1-4alkyl, C1-4haloalkyl, OC1-4haloalkyl, or C3- 10heterocyclyl, wherein said C3-10heterocyclyl is optionally substituted one or more times by F, Cl, Br, C1-4alkyl, OC1-4alkyl, and the rest of Rb1, Rb2, Rb3, Rb4, and Rb5 are H. 60. The compound of any of claims 1-41, wherein the B ring has the formula: , , wherein said C3-10heterocyclyl is optionally substituted one or more times by F, Cl, Br, C1- 4alkyl, or OC1-4alkyl. 61. The compound of claim 60, wherein RB is F, CF3, or OCF3. 62. The compound of claim 60, wherein RB is a C3-10heterocyclyl having the formula: 58 Attorney Docket No. 11348-056WO1 , 63. A method of treating neuropathy in a subject in need thereof, comprising administering to the subject a compound of any of claims 1-62. 64. The method according to claim 63, wherein the neuropathy comprises peripheral neuropathy. 65. The method according to claim 63, wherein the neuropathy comprises diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy. 66. The method according to any of claims 63-65, wherein the subject is undergoing chemotherapy for the treatment of cancer. 67. The method according to any of claims 63-65, wherein the subject is undergoing chemotherapy for the treatment of breast cancer, lung cancer, or ovarian cancer. 68. The method according to any of claims 63-67, wherein the neuropathy comprises peripheral neuropathy caused by chemotherapy, diabetes, alcohol consumption, autoimmune disorder, or systemic sclerosis. 69. The method according to any of claims 63-67, wherein the neuropathy comprise hereditary peripheral neuropathy or idiopathic peripheral neuropathy. 70. The method according to any of claims 63-67, wherein the neuropathy is secondary to administration of a chemotherapeutic agent. 71. The method according to any of claims 63-67, wherein the neuropathy is secondary to administration of paclitaxel. 72. A pharmaceutical composition, comprising the compound of any claims 1-62. 59
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